Huuerolocrc DTsoRDERS / 391

Survival in these patients is inversely proportional to Acute LymphogenoLts Leukemia

age. Long-term survival in those over 60 years old is less
than 20o/o despite intensive chemotherapy. Remission ALL is the proliferation of immature lymphoid cells in
induction therapy along with symptomatic treatment is the bone marrow. The incidence of this disease is
the primary goal in AML. Remission is often achieved bimodal, peaking in the teenage years and again rising in
after treatment with a combination of medications such individuals over the age of 45 years old. ALL has an
as cytarabine and an anthracycline such as daunorubicin. interesting association with Down syndrome, occurring
Many treatment protocols add 6-thioguanine to this com- 20 times more commonly in these patients. Strong clini-
bination. Once remission has been achieved, cytarabine is cal suspicion and detailed history and physical examina-
usually continued at a lower dosage for maintenance ther- tion are required to make the early diagnosis of ALL
apy. BMT has been most successful in patients younger because patient presentations are often vague or nonspe-
than 40 to 45 years during their first remission. cific. Typical symptoms and signs of illness are manifes-
Symptomatic treatment often includes platelet transfu- tations of anemia, thrombocytopenia, and neutropenia.
sions for bleeding secondary to thrombocytopenia. Fil- Fatigue, pallor, weakness, tachycardia, and chest pain
tered platelets to reduce the number of white blood cells may result from anemia. Patients may have an underlying
transferred to these patients are preferred. Fever is of neutropenia with fever and chills secondary to infection.
major concern in these patients especially when the Ecchymosis, petechia, and mucosal bleeding are charac-
absolute neutrophil count is less than 500/mm3. It is rec- teristic manifestations of thrombocytopenia. CNS
ommended that treatment with broad-spectrum antibi- involvement, often without clinically apparent neurologic
otics be maintained until bone marrow function returns, changes, may occur in2o/o to l0% of patients. As in other
even ifthe fever resolves and cultures are negative. Elec- forms of leukemia, lymphadenopathy and hepatospleno-
trolyte abnormalities are also common. Hypokalemia can megaly are common findings on physical examination. T
be present secondary to renal tubular damage. Tirmor cell variants of this disease may present as an incidental
lysis syndrome can produce hypocalcemia, hyperphos- mediastinal mass on chest film.
phatemia, hyperkalemia, and hyperuricemia. The latter
can lead to nephropathy and often requires treatment with
hydration, allopurinol to block conversion ofxanthine to Chronic Lymphogenous Leukemia
uric acid, and urine alkalinization to maintain the more
soluble urate form. This is the most common form of adult leukemia in
Several special considerations arise in AML during western countries. CLL is more prevalent in males than
advanced disease including leukostasis and females and has no known risk factors. It should be sus-
extramedullary leukemia. When the myeloblast count pected when a sustained increase in small mature-
increases to levels over 100,000/mm3, the patient is appearing lymphocytes is encountered on a peripheral
placed at increased risk for microinfarction and hemor- smear. Criteria for diagnosing CLL requires that >30oh
rhage in small blood vessels as a result of sludging and of the bone marrow be infiltrated with lymphocytes.
thrombus formation. The pulmonary vasculature is fre- Although many lymphocytes may appear morphologi-
quently affected, resulting in radiologic infiltrates and cally mature, extensive immune dysfunction is associ-
hypoxemia. Involvement of the CNS vasculature leads ated with CLL. The B cells produce decreased amounts
changes in mental status, cerebral infarction, and death. of immunoglobulin in response to antigenic presenta-
Treatment is aimed at vigorous hydration and reducing tion. The number and function of T cells and natural
the WBC count with hydroxyurea. Leukapheresis and killer cells are also decreased. However, T cell CLL is
whole-brain irradiation may be essential in more extreme considered to be a distinct and separate classification of
cases. It is interesting that these symptoms do not appear leukemia.
to occur in ALL. Staging of CLL involves the degree of lymphocytosis
As the number of myeloblasts increases, deposition of and the presence or absence ofvarious physical findings
cells into extramedullary tissue occurs. Common sites of and symptoms. Secondary malignancy, particularly lung
involvement are the skin, lungs, CNS, gingiva, and buc- cancer and melanoma, occurs with increased frequency
cal mucosa. Dentists often diagnose this disease when the patients with CLL. A small proportion of CLL patients
findings of painful gums with gingival hyperplasia are can progress to a more aggressive disease. Richter syn-
discovered. Chest films may prove useful to demonstrate drome is the most common form of advanced and aggres-
pleural effirsion or infection in these situations. sive CLL, characterizedby worsening adenopathy, fevers,
Chemotherapeutic agents achieve poor levels in the CNS abdominal pain, and anemia. There is a rapid rise in
and therefore the addition of intrathecal methotrexate is peripheral lymphocyte count and a decreased response to
often necessary to treat extramedullary leukemia involv- treatment. Median survival once CLL has progressed to
ing the CNS. Headache, nausea, and cranial nerve palsies this stage is 4 to 5 months. Several other transformations
are the most common presentations of CNS involvement. are possible from the chronic course of CLL, including
392 / EunncrNcv MrorcrNr: THn Conn CunnrculuM

the development of ALL, multiple myeloma (MM), and TABLE 7-5. Causes of leukemoid reaction
even Hodgkin's lymphoma. lnfections
Treatment is noncurative and is associated with signif- Presenting as myelocytic reaction
icant toxicity, including a predisposition to secondary Pneumonia (5. Aureus)
tumors. It is usually initiated only after disease-related Meningitis (H. influenzae, N. meningitidis)
Tuberculosis
symptoms have become well established. Alkylating
Bubonic plague
agents such as chlorambucil and nucleoside analogues Presenting as a lymphocytic reaction
such as fludarabine are among the most common agents Chicken pox
chosen to treat this disease. Very few complete remis- Whooping cough
sions defined by the absence of clinical symptoms are lnfectious mononucleosis
Tuberculosis
achieved. Several multidrug therapies have been studied
lntoxications
and show no advantage over single-drug therapy. BMT Eclampsia
and radiotherapy are not recommended in the treatment Burns
of CLL. An increased frequency of opportunistic infec- Mercury poisoning
tions is seen during advanced stages of disease due to Malignancies
Multiple myeloma
diminished opsonization and the adverse effects of Hodgkin's disease
chemotherapy. Myelofibrosis
Gastric/breast CA
Other
Leukemoid Reaction (7.6.2) Hemorrhage/hemolysis
Rheumatoid arthritis
A leukemoid reaction is typically defined as a persis-
tent neutrophiliaof 30,000 to 50,000/mm3 or greater.
However, a leukemoid reaction can be a difficult entity to
A logical approach to the patient with suspected infec-
diagnose in patients with a hematologic picture of
tion and an otherwise unknown source of leukocytosis is
leukemia who do not have a clinical course consistent
to obtain cultures and treat with broad-spectrum antibi-
with leukemia. Anemia, young WBC forms, thrombocy-
otics. Antileukemic therapy should only be instituted
topenia, splenomegaly, and fever can be present in both
once it is clear that the patient is presenting with a true
leukemia and leukemoid reaction, making the clinical pre-
leukemia and not simply a leukemoid reaction.
sentations nearly indistinguishable. Even at the time of
autopsy, some cases have remained indeterminate. There
are many causes of a leukemoid reaction, including infec- Leukopenia (7.6.3)
tion, intoxication, and rnalignancy. Adding to the com-
plexity of this entity is the fact that there are numerous The term leukopenia describes a decreased number of
grades of leukemoid reaction ranging from simple leuko- white blood cells of any type. Neutropenia is a specific
cytosis without immature forms to a complex picture form of leukopenia in which there is a decreased number
indistinguishable from AML. Table 7-5 demonstrates a of neutrophils. The normal neutrophil count ranges from
portion of the known causes of leukemoid reaction. 1500 to 8000 cells/mm3 in peripheral blood samples. When
the neutrophil count falls below 1000 cells/mm3, there is a
definite increase in the risk of infection. Individuals with
Dffirentiation from Leukemia
<500 neutrophils/mm3 are considered to be at high risk for
bacterial and fungal infections alike. The inflammatory
Leukemoid reactions can occur as a result of multiple
response sharply disappears at neutrophil counts below
causative factors and can mimic any class of leukemia.
200 cells/mm3. The most common cause of neutropenia is
The differentiation between leukemia and a leukemoid
iatrogenic, resulting from immunosuppressive therapy.
reaction may require thorough testing of the bone marrow
and/or lymph node biopsy, including cultures and spe-
cialized stains. Reactions that mimic myeloid leukemias C o nditio ns As s o ciated lltith N eatropen ia
can be the result of various infections, malignancies, and
intoxications. A CML-type picture can result from pneu- Clinical Signs and Symptoms
monia, meningitis, chicken pox, infectious mononucleo-
sis, tuberculosis, eclampsia, burns, and various malig- The most worrisome presentation of neutropenia is
nancies. In difficult cases, presence of the Philadelphia when it is associated with a fever (generally accepted as a
chromosome, and elevations of the leukocyte alkaline temperature -100.5"F), as this combination represents a
phosphatase and serum vitamin Brz levels can be very true medical emergency. Neutropenia often masks what
useful in distinguishing true leukemia from a leukemoid would otherwise be an obvious infection (Table 7-6). The
reaction. lack of neutrophils results in a diminished or absent
 Hnrraerorocrc DTsoRDERS / 393
TABLE 7-6. Conditions associated with neutropenia Indwelling catheters warrant special consideration.
lnfection Patients often require them for essential vascular access
Human immunodeficiency virus and hemodynamic monitoring. Although catheters may
Epstein-Barr virus often be retained when an exit-site infection or uncompli-
Measles/ch ickenpox/ru bel la cated bacteremia is present, catheter removal is indicated
Tuberculosis
Colorado tick fever/yellow fever
in the presence of tunnel infections, endocarditis, systemic
Drugs fungal infections, infections that fail antibiotic treatment,
lmmunosuppressive agents or bacteremia with diphtheroids.
Antithyroid medications
Antibiotics (chloramphenicol, AZT, bactrim)
Anticonvulsants Multiple Myeloma (7,6,4)
Phenothiazines
lbuprofen Multiple myeloma (MM) is a disorder in which there is
Antihistamines
a malignant proliferation of plasma cells stemming from
Other
Malnourishment and debilitated states (alcoholism) a single clone. InMM the maturation of B lymphocytes
Splenomegaly into antibody-secreting plasma cells is no longer con-
Anaphylaxis trolled. The normal situation in which conversion into
Congenital causes mature plasma cells requires exposure to a particular
Modified from Lee GR, BithellTC, Foerster J, et al. antigen is lost in these cells.
Wintrobe's clinical hematology, 9th ed. Philadelphia: About 95o/o of patients with MM possess an increased
Lea & Febiger, 1993;1590.
concentration of hypersecreted immunoglobulin referred
to as the monoclonal or "M-component." The most com-
mon immunoglobulin found in these patients is IgG;
inflammatory response, thereby damplning the usual signs however, IgA is observed in up to 25oh of patients. The
and symptoms associated with infection. The production of finding of an M-component is useful as a tumor marker
purulent material is minimal, as are redness and swelling at but serves as a poor screening test due to its low speci-
the site of infection. Fever, however, is usually preserved in ficity. M-component can also be found in patients with
the neutropenic patient as a result ofendogenous pyrogens CLL, lymphomas, breast cancer, cirrhosis, and several
released from fixed macrophages in the liver, spleen, and other conditions.
lungs, and should be taken seriously when present. Immunoglobulins are constructed of both heavy and
light chains. Approximately 20%o of patients have only
the light chain detectable. When observed this light chain
Management
is referred to as the Bence Jones protein.

It is extremely important to search carefully for infec-

tions in neutropenic patients with fever. These infections Incidence and Epidemiologt
can lead to life-threatening or fatal sepsis in hours. There-
fore, it is vital that empiric antibiotic treatment be initi- MM accounts for 10% to l5o/o of hematologic neo-
ated rapidly. The majority of infections are caused by plasms in Caucasians and up to one-third of hematologic
endogenous flora particularly from the skin and gastroin- neoplasms in African-Americans. The incidence is
testinal tract. Bacteria from the surrounding environment approximately 4 cases per 100,000lyear and is currently
are also common sources of infection. Gram-negative rising. The median age at onset is 68 years with >90% of
bacteria have previously accounted for up to 50% of patients being over the age of50. This disease is very rare
infections. However, there has been a recent rise in gram- in individuals younger than 40. Males have a slight pre-
positive bacteia due to the increasing use of indwelling ponderance.
catheters and invasive critical care.
Meticulous physical examination with particular atten-
tion to the skin and mucosal surfaces often demonstrates Diagnosis snd Clinical Manifestations
the source of fever. Cultures of blood and other potential
sites are indicated when the source of fever is less obvious. Bone marrow plasmacytosis, lytic bone lesions, and
Cultures should be obtained rapidly and antibiotics admin- the finding of an M-component make up the classic triad
istered promptly. Standard antibiotic regimens include of MM. This triad should be sought if the diagnosis of
broad coverage of synergistic and bactericidal combina- MM is being considered. The most common presentation
tions such as an aminoglycoside and extended-spectrum of MM is that of bone pain affecting nearly 70oh of
penicillin or third-generation cephalosporin. Vancomycin patients. Commonly this manifests as unexplained back
is the agent of choice when an infection with methicillin- pain. The bone pain of MM is worsened by movement.
resistant S. aureus is suspected. This is in contrast to the bone pain of metastatic cancer,
 394 / Err,rtncnNcy MnucrNn: Tun Conr CunnrcutuM

which is often worse at night and while resting. Lytic activity. Urine dipstick an.:lysis does not reveal Bence
bone lesions can lead to pathologic fractures. Spinal cord Jones proteins. X-ray investigation of the skull, pelvis,
compression syndromes may occur. A high index of sus- lumbar, and any tender areas is often useful in locating
picion should be utilized when encountering prolonged or lytic lesions. Bone scan is typically nondiagnostic due to
unexplained back pain in the older individual. the lack ofosteoblastic activity.
The finding of a normochromic, normocytic anemia in
an older individual is another common presentation of
Treatment an d D isp o s itio n
MM. This is caused by bone marrow myelophthisis,
resulting in decreased erythropoiesis in addition to Symptomatic treatment is usually the first priority in
increased destruction of red blood cells. Platelet dysfunc-
MM and should be directed by the individual presenta-
tion as a result of the M-component predisposes to bleed-
tion. Treatment of pain, dehydration, and hypercalcemia
ing, which contributes to the anemic state. Anemia com-
should be handled initially. Severe bone pain requiring
plicates up to 80% of myeloma patients.
adequate opiate analgesia can be experienced by these
Approximately 25% of patients present with recurrent
patients. Vigorous hydration is important and some-
bacterial infection. Pneumonia and pyelonephritis are
times the critical component of therapy to reverse dehy-
common, and frequent pathogens include Staphylococ-
dration that can compound hypercalcemia, which is
cus, Streptococcus, and gram-negative organisms. These
often concurrently present. Dehydration can also
infections are due to hypogammaglobinemia and dimin-
worsen renal failure and intensify symptoms due to
ished neutrophil migration. Hypogammaglobinemia hyperviscosity. Severe hypercalcemia may require high-
results from increased destruction of both monoclonal
dose steroid treatment or dialysis when hydration and
and normal antibodies. Regulatory mechanisms lead to
diuresis are not sufficient.
decreased production of normal antibodies due to the
Chemotherapeutic treatment of MM provides only
high concentration of total immunoglobulin.
modest prolongation of survival. Due to the toxic nafure
Several other abnormalities are often encountered in
of treatment it is generally delayed until the patient is suf-
MM. Renal failure eventually complicates approximately
ficiently symptomatic to warrant such medications.
one-fourth of myeloma patients and results from Bence
Occasionally treatment is initiated to control severe
Jones proteinuria and hypercalcemia. Neurologic symp-
hypercalcemia. The most common medications are alky-
toms occur in the setting of hyperviscosity and hypercal-
lating agents such as Melpalan combined with oral
cemia. Hypercalcemia results from the osteoclastic acti-
steroids. Treatment leads to a mild neutropenia and a
vating factors released by the increased number of plasma
gradual decline in the concentration of M-component.
cells. Symptoms of hypercalcemia include weakness,
Complete remission is only achieved in approximately
anorexia, abdominal cramping, constipation, and mental
l}oh to 15% of patients as defined by disappearance of
status changes. Hyperviscosity commonly leads to blurred
the M-component. Approximately 50o/o of myeloma
vision, headache, fatigue, and mental status changes.
patients achieve control of their disease once treatment is
Laboratory investigation is useful in the definitive initiated. The asymptomatic patient should be followed
diagnosis of MM. Bone marrow aspirate and biopsy help
continuously with laboratory testing every 3 to 6 months
to measure the degree of marrow plasmacytosis. By def-
and periodic x-ray evaluation. Median survival is around
inition this is greater than l5o/o in patients with myeloma.
3 years from the time of presentation.
Serum and urine electrophoresis assist in determining the
levels of M-component and Bence Jones proteins, if pre-
sent. CBC can demonstrate the anemia commonly asso- SELECTED READING
ciated with myeloma. Rouleaux formation is another use-
AbeloffMD, Armitage JO, LichterAS, Niederhuber JE. Clinical oncologt.
ful finding on CBC that is seen as the M-component New York: Churchill Livingstone, I 995.
concentration increases. The anion gap can be calculated Dameshek W. Wlliam Dameshek and Frederick Gunz s Leukemia, 5th ed
in these patients and is characteristically decreased due to Philadelphia: Saunders, 1 990.
Henderson ES, ListerTA. Leukemia Philadelphia: Saunders, 1990.
the high concentration of cationic M-component that Isbister JP, Pittiglio DH. Clinical hematology: a problem-oriented
leads to chloride retention. Pseudohyponatremia may be approach. Baltimore: Williams & Wilkins, 1988.
observed also, due to the high concentration of M-com- Lee GR, Bithell TC, Foerster J, et Wintrobeh clinical hematology, gth ed.
^1.
Philadelphia: Lea & Febiger, i993.
ponent. Alkaline phosphatase is usually normal despite
Nealon TF. Management of the patient with cancer, 3rd ed. Philadelphia:
bone involvement because of the lack of osteoblastic Saunders, 1986.
CFIAPTER B

Immune System Disorders

Michael S. Beeson
Immune System Disorders (8.0); Humoral Immunity (8.1); Cellular Immunity (8.2);
Chemical Mediators (8.3); Complement (8.4)
Paul T. Preisz
Autoimmune Diseases (8.5)
DietrichV. K. Jehle
Immune Deficiency Syndromes (8.6)
Susan P. Graham
Transplant-Related Problems (8. 7)

Richard S. Krause
Hypersensitivity (8.8)

TMMUNE SYSTEM DTSORDERS (8.0) different antibody molecules with differing antigen speci-
ficities. The immunoglobulins are secreted into the
The science of immunology has progressed dramati- plasma where they may form specific antigen-antibody
cally over the last 20 years. Today, it is recognized that the complexes. Additionally, some immunoglobulins are
immune system is composed of complex interactions membrane bound on antigen-specific memory B lym-
between humoral and cellular immunity components. phocytes, allowing for a secondary humoral response.
These complex interactions result in an interdependent Before B lymphocytes can become antigen specific,
response to antigenic challenge. The result is a coordi- they must first be activated. This activation occurs with
nated and efficient response to antigens introduced into the assistance of helper T lymphocytes. There are numer-
the human body. However, in its quest for efficiency, the ous chemical mediators secreted by the T helper cells as
immune system may develop hypersensitivity responses well as the B lymphocytes that facilitate B lymphocyte
to antigenic challenge. These hypersensitivity reactions activation. Once activate4 the B lymphocytes differenti-
are not purely humoral or cellular in terms of immune ate into plasma cells that produce large amounts of solu-
response. Rather, they are complex interactions involving ble plasma-bound immunoglobulin, and memory B cells
both humoral immunity (marrow-derived B lymphocytes) that have membrane-bound immunoglobulin present.
and thymus-derived T lymphocytes. Memory B lymphocytes have pivotal roles in the sec-
ondary immune response, e.g., when an immunized indi-
vidual is challenged again with the same or nearly identi-
HUMORAL TMMUNTTY (8.1) cal antigen.
There are three recognized types of hypersensitivity.
The humoral immune response begins with B lympho- Type I hypersensitivity reactions result in anaphylaxis.
cytes that produce immunoglobulins. This immunity is These reactions involve the combining of a specific anti-
antigenically quite specific. There are literally millions of gen to mast cell membrane-bound immunoglobulin E

395
396 / EvrncrNcy MnorcrNn: Tur, Coru CunnrculuM

(IgE) and to basophils. Membrane-bound IgG can also (APC). Macrophages are the prototypical antigen pro-
cause the same reaction, although IgE antibody is much cessing cells. The macrophage ingests the antigen, and
more predominant. The antigen-antibody complex that processes it in such a way that it can be presented on its
forms on the membranes of the mast cells and basophils cell membrane to a T lymphocyte helper cell. The helper
causes the release of chemical mediators. These media- T lymphocyte cells become activated, and cause the
tors are very potent vasoactive and inflammatory media- secretion of chemical mediators that in turn activate cyto-
tors including histamine, heparin, serotonin, eosinophil toxic T lymphocytes and antibody-secreting plasma cells.
chemotactic factor (ECF-A), neutrophil chemotactic fac- Activation of the cytotoxic T lymphocytes causes the
tor (NCF-A), a variety of proteases, and other mediators secretion of additional chemical mediators that lead to the
that are synthesized at the time of mast cell or basophil death ofthe infected target cell.
stimulation. These additional mediators include platelet The prototypic hypersensitivity reaction involving cel-
activating factor (PAF), slow reaction substance of ana- lular immunity is type IV This hypersensitivity reaction
phylaxis (SRS-A), and several prostaglandins and throm- involves T lymphocytes, and does not rely on antibodies
boxanes. These mediators may cause the classic signs and or complement. This reaction is a delayed hypersensitiv-
symptoms of anaphylaxis including smooth muscle con- ity reaction. This reaction is delayed because ofthe need
traction, increased capillary permeability, chemotaxis of for T cell lymphocytes to become sensitized after contact
eosinophils and neutrophils, platelet aggregation, and with the specific antigen. This in turn causes chemical
bronchoconstriction. The overall physiologic effects of mediators to be expressed that altract more T cell lym-
these mediators are bronchospasm and profound vasodi- phocyes to migrate to the area of antigen challenge.
latation, resulting in severe hypotension. Examples of type IV hypersensitivity reactions include
I
The prototypical type hypersensitivity reaction is skin testing for tuberculosis, contact dermatitis, hyper-
termed atopy. Atopy refers to the production of increased sensitivity pneumonitis, allograft rejection, and hypersen-
amounts of IgE to common substances that are inhaled or sitivity reactions to drugs. Manifestations of delayed
ingested. These common allergies include ragweed, hypersensitivity to drugs usually occur 24 to 48 hours
pollen, and others that cause allergic rhinitis. Type II after exposure. However, exposure may not occur until
hypersensitivity reactions occur when circulating anti- the patient has nearly finished a course of treatment with
body combines with cellular antigenic components. This the offending drug. Clinical manifestations include
reaction usually results in complement activation and in urticaria, fever, eosinophilic pulmonary infiltrates, and,
phagocytosis or cytolysis of the cell with the antigenic rurely, vasculitides. Treatment includes removing the
component. Examples of type II hypersensitivity reaction offending agent, symptomatic relief of urticaria, and, in
include hemolytic anemias resulting in incompatible patients demonstrating multisystem involvement, the
transfusions, pemphigus, and Goodpasture's syndrome. administration of corticosteroids.
Type III hypersensitivity reactions occur when antigen-
antibody complexes (i.e., immune complexes) are formed
and deposited in blood vessels or tissues. Components of
CHEMTCAL MEDTATORS (8.3)
this reaction include the activation of complement. Cer-
tain components of complement are formed increasing Central to the functioning of both the cellular and
humoral immune systems is the communication between
vascular endothelial permeability as well as causing neu-
trophilic chemotaxis. Clinical features of type III hyper- cells. This communication is in the form of chemical
sensitivity reactions include the Arthus reaction. This mediators (Table 8-1) that are secreted by cells in
type of reaction is typified with the localized angry cel-
responseto antigen exposure or exposure to activated
immune cells. These chemical mediators serve multiple
lulitis reaction to repeated antigenic challenge by immu-
nization. Other clinical entities associated with type III
functions including stimulation of the immune and
hypersensitivity reactions include serum sickness, post-
inflammatory responses. These chemical mediators are
streptococcal glomerulonephritis, autoimmune disease,
important in that they cause the further production of
other mediators that further stimulate B and T cell prolif-
and hypersensitivity pneumonitis.
eration, immunoglobulin production, and effects on other
inflammatory cells such as macrophages. Collectively,
CELLULAR TMMUNTTY (8.2) the soluble chemical mediators are called cytokines. They
are produced primarily by lymphocytes and
As noted previously, it is difficult to separate immunity macrophages. Their effects are primarily local. There are
on the basis of function. Cellular immunity refers to the only a few cy4okines that are detectable in quantities suf-
immune response by T lymphocytes. It is now recognized ficient to produce a generalized effect. Cytokines are
however that cellular immunity function is integral to secreted in response to specific stimuli and produce
humoral immunity as well. When an antigen is initially effects locally on target cells. These effects are an
encountered, it is processed by an antigen-processing cell absolute requirement in the overall functioning of the
 Irr,rvruNr, Svsrnu DIsorutns / 397

TABLE 8-1. Chemical mediators of inflammation way. There is an alternative pathway to complement acti-
Histamine vation that bypasses the need for antigen-antibody com-
Platelet-activating factor (PAF) plexes. However, both pathways converge early in the
Prostaglandins cascade sequence, ultimately resulting in a membrane
Leukotrienes (includes SRS-A, or slow-reacting substance attack complex that ultimately results in the lysis of the
of inflammation)
Cytokines [interleukins = 1, 2, 3,4, 5, 6, 7, 8, 9,and 10; offending cell.
tumor necrosis factor (TNF); eosinophil chemotactic One of the by-products of complement activation is a
factor (ECF-A); neutrophil chemotactic factor (NCF-A)l protein fragment termed C3b. This protein coats either
Complement components bacteria or antigen-antibody complexes. Numerous cell
Heparin types have surface receptors for C3b, including neu-
Serotonin
lnterferons
trophiles, eosinophiles, macrophages, B cells, and
basophiles. When attached to bacteria or antigen-anti-
body complexes, cells with C3b receptors ultimately
ingest the particles. Genetic lack of the C3 protein frag-
immune system as they perform a required function of ment results in an inability to opsonize with the subse-
co-stimulation of T and B lymphocytes. Cytokines are quent recurrent pyogenic infections.
either peptides or glycoproteins in nature and number in Finally, activation of the complement pathway results
the hundreds that have been identified thus far. These in numerous small protein fragments, each of which has
include the interleukins, tumor necrosis factor (TNF), the important biological functions such as immunoregulatory
interferons, and colony-stimulating factors. effects, opsonization, release of histamine and other
Chemical mediators as a whole are secreted in chemical mediators, and the release of polymorphonucle-
response to contact with specific antigens, contact with ocytes sites from bone marrow.
specific activated T:cell helper lymphocytes and by stim-
ulation by other cytokines. The effect of the chemical
mediators is to co-stimulate the various responses within SELECTED READING
the immune system.
Frank MM. Complement and kinin. In: Stites DP, Terr AI, Parslow TG, eds.
Basic and clinical immunology,8th ed Norwalk, CT: Appleton & Lange,
1994:124-136.
COMPLEMENT (8.4) Goodman JW. The immune response. In: Stites DP, Terr AI, Parslow TG,
eds. Basic and clinical inmunology, 8th ed. Norwalk, CT: Appleton &
Lange, 1994;4049.
Complement is a term that refers to over 25 proteins
Haynes BF, Fauci AS. Cellular and molecular basis of immunity. In: Issel-
present in the plasma and cell membranes of immuno- bacher KJ, Braunwald E, Wilson JD, et al., eds. Harrison s principles of
logic cells. These proteins cascade in a sequence of inlernal medicine, l3th ed. NewYork: McGraw-Hill, 1994;1543-1559.
Nossal GJV Current concepts: immunology: the basic components of the
events, activating each subsequent component of the
immune system. N Engl J Med 1987;316:1320.
complement pathway. The ultimate function of comple-
ment is to lyse infected cells, bacteria, and viruses. Com-
plement also serves in the process called opsonization in AUTOTMMUNE DISEASES (8.s)
which complement protein fragments coat bacteria,
viruses, or other infected cells, allowing them to be rec- Immunology and Autoimmune Diseases
ognized by macrophage cells. Complement plays an inex-
act role in the regulation of immune and inflammatory Immune responses are characterized by specificity,
responses. including the ability to differentiate between what is nor-
There are two pathways to complement activation mal self and what is not, and by memory, the ability to
(Table 8-2). The first pathway is initiated by the interac- recognize a previously encountered foreign antigen and
tion of antigen-antibody complexes. This is followed by a to mount a rapid and intense response upon reexposure.
cascade of complement protein components that enzy- The mechanisms by which immune tolerance to self
matically catalyze the sequential activation of the path- develops are incompletely understood but are thought to

TABLE 8-2. Complement activation

Classic pathway (Ag/Ab complex) Alternative pathway Common components of both pathways

Cl + Ag/Ab forms activated C1 C3 + factor B + properdin forms C5 + C3B forms C5b

activated
Activated C1 + C4 forms activated C14 Activated C3BP + C3 forms C3b CSb + C6 + C7 forms C567
Activated C14 + C2 forms activated C142 C5667 + C8 + C9 forms C56789
Activated C142 + C3 forms C3b (the MHC)
398 / ErraencnNcy MntlcrNr: THn Conr CunrucuLUM

involve such processes as central deletion (e.g., deletion which interact with B cells by releasing cytokines during
of self-recognizing T cells during development in the thy- antibody-mediated immune responses. These cytokines
mus), sequestration of some antigens so they are not are small polypeptides that bind specific receptors on tar-
exposed to the immune system (e.g., in the cornea), get cells to exert their effects. Important examples of
anergy, peripheral deletion, and suppression. Memory is cytokines include the interleukins, tumor necrosis factor,
achieved by the formation, during an initial immune and interferon.
response, of specific long-lived memory cells capable of T cells recognize foreign antigens that have been frag-
recognizing a particular antigen. mented and transported to the surface of cells where they
Immune responses occur constantly in normal individ- are bound to class I or class II major histocompatibility
uals and are a part of normal homeostasis. They involve complex (MHC) antigens. These MHC antigens are
multiple interactions eventually resulting in a response encoded by genes on chromosome 6, with MHC class I
characterized by a particular type ofcellular activity and proteins encoded at HLA-A, HLA-B, and HLA-C loci,
requiring assistance from other cells and systems for the and MHC class II proteins encoded at the HLA-DB
response to be effective. This is particularly true of the HLA-DQ, and HLA-DR loci.
interactions between B and T lymphocytes. It is not known why a number of diseases are associ-
Lymphocytes arise from progenitor cells that have ated with particular HLA epitypes (e.g., HLA-827 and
migrated to the primary lymphoid organs and have under- ankylosing spondylitis, HLA-DR3 and Graves' disease).
gone a process of development and maturation. In the Cytotoxic T cells carry the CD8 surface glycoprotein.
thymus these progenitor cells develop into T lympho- They recognize antigens displayed on the surface ofcells
cytes, and in the fetal liver and in bone marrow they associated with class I HLA and attack these cells by
develop into B lymphocytes. After release lymphocytes releasing protein molecules to disrupt the cell membrane
aggregale in secondary lymphoid organs such as the and by releasing cytokines. Natural killer cells are large
spleen and lymph nodes from which they may circulate granular lymphocytes that are not categorized as T or B
throughout the body. B lymphocytes produce antibodies in type. They play an important role as antiviral and anti-
that recognize free antigens made of protein, polysaccha- tumor agents as well as being involved in graft rejection.
ride, or nucleic acid. With help from activated T helper Many other cells, including mast cells, dendritic cells,
cells the B lymphocytes will proliferate and secrete anti- and macrophages, play vital roles in normal immune
body that can specifically recognize and bind to the anti- homeostasis.
gen that initiated the process. Inappropriate reactivity of components of the immune
Antibody binding to antigen can lead to opsonization, system with aberrant responses to self antigens are fea-
netfiralization of free antigen, and further stimulation of tures of those diseases that are described as autoimmune.
immunocytes, platelets, and other cells (such as mast The mechanisms by which these processes occur are
cells), in addition to stimulation of vascular smooth mus- incompletely understood but include cross-reactivity of
cle and increased vascular permeability. In a number of epitopes (e.g., hepatitis B and polyarteritis nodosa), loss
settings these effects are mediated through plasma of active suppression, release of hidden antigens (e.g.,
enzymes known collectively as the complement system. Dressler's syndrome), generation of modified self anti-
When complement is activated by interaction with anti- gens, T cell bypass, and superantigen stimulation ofT cell
gen-antibody complexes, this is known as activation by populations (e.9., by streptococcal antigens in rheumatic
the classical pathway. Complement can also be activated fever).
via an alternative pathway by interaction with some
microorganism polysaccharides and endotoxins. Acute Rheumatic Fever (8.5.1)
Immunoglobulin antibodies consist of a number of basic
units. Each antibody unit has two light and two heavy Rheumatic fever is most often a disease of children
chains. These are arranged such that the molecule has two between the ages of 5 and 15 years. The disease has a
variable F(Ab) binding sites for antigen and two fixed or degree of familial predominance, and affected individu-
constant F(c) binding sites for binding to immunocytes als are prone to recurrent attacks.
and to complement. While the exact pathophysiologic mechanisms remain
Great variability exists in the F(Ab) binding sites so unproven, rheumatic fever is thought to be due to an
that a large number of foreign antigens can be recognized uncommon dysfunctional immune response following
by different antibody molecules. The five classes of pharyngeal infection with some strains of group A p-
immunoglobulin have different structure and functions hemolytic streptococcus resulting in inflammatory
and are referred to as IgG, IgA, IgM, IgD, and IgE. changes in the heart, skin, joints, and other tissues. While
T cells carry glycoprotein antigens on their surface. the history of antecedent pharyngitis is often lacking,
Some of these antigens such as CD3 occur on all T cells, patients with acute rheumatic fever usually have
others occur on T cells, B cells, macrophages, and other increased titers of antibodies to streptococcal antigens,
cells. The CD4 glycoprotein is found on T helper cells, indicating infection within the preceding month.
 InruuNe Svsrnu DrsoRltRs / 399

Focal inflammation around small blood vessels with recurrence must be determined on an individual basis.
fibrinoid degeneration of the surrounding collagen is Patients with subsequent rheumatic heart disease require
usually seen. In the myocardium small granulomas prophylaxis to prevent bacterial endocarditis.
(Aschoff bodies) are classically described. In joints an Salicylates are usually adequate to relieve the syrnp-
exudative arthritis that resolves without sequelae is typi- toms of arthritis. Corticosteroids are prescribed for sev-
cal. The subcutaneous nodules are fibrinoid granulomas. eral weeks in patients with carditis who have not
No typical neurologic lesion has been identified and the responded to salicylate therapy. Sedatives, tranquilizers,
cerebrospinal fluid is often normal. reassurance, and appropriate nursing care are indicated in
The clinical presentation is most commonly as an acute the management of chorea. Rheumatic fever typically is
febrile illness with fever greater than 38'C and migratory self-limiting and can be expected to last for several
polyarthritis of the larger limb joints. Cardiac symptoms months. The ESR and CRP are useful laboratory markers
and signs are less common, although the murmurs of ofdisease activity.
mitral, or less often aortic, incompetence usually appear Prevention ofrecurrent attacks and subsequent cumu-
ifcarditis is present. lative cardiac damage is important. In some patients
Marked tachycardia, pericarditis, and in severe cases, emergency management of significant cardiac failure,
cardiac enlargement and failure may occur. First- or sec- arrhythmias, or other complications may be urgently
ond-degree heart block may also be seen. required.
Sydenham's chorea, when present, occurs late in the
illness and may develop insidiously. It is characteizedby
Collagen Vascular Diseases (8.5.2)
sudden erratic jerking movements that are most marked
on effort, anxiety, or excitement, and that are not present
Collagen vascular diseases are a group of disorders
during sleep. Muscle weakness may be quite severe and
characterized by abnormalities of the immune system,
emotional lability may also be present.
vasculitis, and varying multisystem involvement. They
Erythema marginatum is an evanescent, macular, pink
may be difficult to diagnose and may themselves mimic
rash that is nonpruritic and has irregular borders with
infections, malignancies, thromboses, or a number of
central clearing. It occurs most often on the trunk and
other diseases. Some connective tissue disorders such as
proximal limbs. Subcutaneous nodules tend to be pea-
thyroiditis are relatively organ specific, others such as
sized, painless, and positioned over prominences of bone.
systemic lupus erythematosis are less so. The types and
Rheumatic fever is a clinical diagnosis using the
sites ofvessels involved also vary and this largely deter-
revised Jones criteria. The major criteria are carditis, pol-
mines the clinical manifestations. As the clinical presen-
yarthritis, chorea, erythema marginatum, and subcuta-
tations of this group of disorders are legion, they must be
neous nodules. The minor criteria are fever, arthralgia (in
considered as a part of the differential diagnosis in a wide
the absence of arthritis), previous rheumatic fever or
variety of clinical settings.
rheumatic heart disease, acute phase reaction such as
Despite a number of attempts to standardize classifica-
leukocytosis, elevated erythrocyte sedimentation rate
tion, the incomplete understanding of the underlying
(ESR) or abnormal C-reactive protein (CRP), and ECG
processes has meant that all systems have their limita-
changes such as prolonged PR interval. Evidence of
tions and that many patients will not fit easily into one
recent streptococcal throat infection (e.g., positive throat
category. Such patients may display features of several
swab culture or raised antistreptolysin antibodies) and
diseases and may continue to evolve for quite some time
either two major or one majcr and two minor criteria are
before conforming to a recognizable pattern.
required to make the diagnosis. Other symptoms that may
occur include fatigue, weight loss, and abdominal pain.
History physical examination, ECG, and chest x-ray D ermatomyositis (8. 5. 2. 1) and Po lymyositis (8. 5. 2. 2)
are all of importance in establishing the diagnosis. Labo-
ratory tests may determine the presence of recent group Polymyositis is an uncommon inflammatory disease of
A streptococcal pharyngeal infection by throat swab cul- muscle characterized by lymphocytic infiltration without
ture or by serologic testing and may demonstrate nonspe- suppuration; when it is associated with skin involvement,
cific markers of inflammation such as raised ESR, CRP, it is called dermatomyositis. A significant proportion of
leukocytosis, and anemia. Further investigations such as patients also have connective tissue disease such as
echocardiography should be undertaken in conjunction rheumatoid arthritis or systemic lupus erythematosus,
with specialist consultation. and up to l0o/o are ultimately found to have an underlying
Having established the diagnosis, bed rest and support- malignancy, most commonly in patients over 60 years of
ive therapy are instituted as clinically indicated. Par- age. There is some familial predominance, and the dis-
enteral penicillin or an acceptable alternative antibiotic ease is more common in patients with some particular
should be administered. The nature and duration of long- HLA epitypes. The role of viral infection in pathogenesis
term antibiotic prophylaxis to prevent rheumatic fever is as yet unclear. Polymyositis can occur in patients with
400 / Evr,RcrNcy MnorcrNr: Tun Conn Cunruculuru

AIDS and less commonly as a side effect of zidovudine low back are common sites, although upper limb joints
therapy. including fingers (dactylitis) may also be involved. Fasci-
The clinical symptoms usually appear gradually. Prox- itis and tendonitis are also common. Mild conjunctivitis
imal muscle weakness sometimes with pain and tender- and less frequently uveitis is seen. Superficial, relatively
ness may precede or be preceded by a rash. The rash may painless oral and penile ulcers may be present. Typical
appear lilac colored (heliotrope) and present in a butter- skin lesions (keratoderma blenorrhagica) consist of vesi-
fly facial distribution, or it may present in a variefy of cles on the palms, soles, and elsewhere, which later
ways including erythema or even as an itchy dermatitis. become hyperkeratotic and encrusted.
Rarely the onset may be as dramatic weakness, some- Initial laboratory investigations demonstrate nonspe-
times with rhabdomyolysis. cific markers of acute inflammation. Rheumatoid factor
Reflexes may be normal or brisk. Involvement of stri- and antinuclear antibody (ANA) are usually negative and
ated esophageal muscle leads to dysphagia, and cardiac most patients are HLA-B27 positive. At the time of first
involvement may manifest as arrhythmias or as heart fail- presentation x-rays may be normal, and, while joint fluid
ure. Typically ESR and creatine kinase (CK) elevation is often nondiagnostic, it may still be required to exclude
can be expected. septic arthritis or gout. In some cases it is possible to cul-
The electromyogram often demonstrates muscle irri- ture chlamydia from the urogenital tract.
tability as well as changes typical of myopathy. Muscle Treatment with tetracyclines should be initiated when
biopsy provides confirmation; however, it should be chlamydial infection is present. Nonsteroidal antiinfl am-
borne in mind that muscle involvement is patchy, and matory drugs (NSAIDs) are effective in treating arthritis.
obtaining a representative sample may be difficult. Evi- In some situations local steroid injection may be helpful.
dence of associated connective tissue disorder should be If uveitis is present, topical and oral glucocorticoids
sought as well as a search for malignancy in older should be given. Rarely, aggressive or refractory disease
patients. may require treatment with cytotoxics. Some patients suf-
Treatment with glucocorticoids should be instituted fer recurrent illness and a small number have permanent
once the diagnosis has been established. Prednisone 1 to residual disability.
2 mglkg is usually adequate. The dose may be reduced as
clinical improvement occurs, although the duration of ini-
tial therapy is often several weeks and alternate day dos-
Rh eumatoid Art hriti s (8, 5. 2. 4)
ing should be considered. Monitoring is by clinical
Rheumatoid arthritis is a relatively common disease
assessment, as serial CK measurements are initially unre-
that can be seen in all age groups but is most common in
liable.
women between the ages of 35 and 50 years. Its patho-
Severe, refractory, or relapsing disease may require
genesis is incompletely understood but it is highly likely
treatment with cytotoxic drugs such as azathioprine or
that an element of genetic predisposition is present; in
cyclophosphamide, either alone or in combination with
particular there seems to be a high incidence in patients
lower dose steroid therapy.
with specific types of a beta chain found on HLA-DR4 in
Older patients, those with severe, chronic, widespread or
a number of population groups and HLA-DRI in others.
resistant disease, and those with associated malignancy or
The role of infectious agents and other environmental
connective tissue disease have a worse prognosis.
factors remains unclear.
The predominant pathologic changes initially seen in
Reiter's Syndrome (8. 5. 2.3) joints consist of synovial hyperplasia, T cell infiltration,
and microvascular injury, resulting in damage to cartilage
Reiter's syndrome is a relatively coflrmon form of reac- and bone. There is an increase in the secretion ofsynovial
tive athritis triggered by urogenital chlamydial infection. fluid with evidence of active inflammation, including a
It is most common inHLA-827-positive young men and predominance of polymorphs in the fluid. Rheumatoid
is part of the spectrum of reactive arthritis that also nodules are thought to be a result of vasculitis in periar-
includes arthritis following gastrointestinal infection with ticular structures, and consist of an area of central necro-
salmonella, shigella, or other enterobes. sis surrounded by macrophages and an outer zone of
Reiter's syndrome is characterized by arthritis, urethri- granulation tissue. Vasculitis may also involve skin,
tis, conjunctivitis, and mucocutaneous lesions. The initial nerves, or other organs, although renal disease is rare.
symptoms are typically of intermittent, sometimes pain- Low-grade fever and constitutional symptoms such as
less, urethral discharge, followed by constitutional symp- fatigue and lethargy are in part due to cytokine release.
toms such as fever, fatigue, and malaise. Prostatitis may Joint disease often begins as the slow onset of a symmet-
also be present. The arthritis is acute, painful, and asym- rical, peripheral polyarthritis, with morning stiffness. The
metrical, involving few joints at first, with others being wrists, metacarpophalangeal and proximal interpha-
affected over days to weeks. The lower limbs, feet, and langeal joints, elbows, knees, and feet are commonly
 IuuuNn Svsrsu DtsoRlsns / 401

involved. Spinal disease usually involves the upper cervi- tibodies (ANCA) should be performed. Imaging of
cal region. The hallmarks of inflammation are usually involved organs should be done, particularly if ischemia
present, although atypical presentations do occur. Long- is suspected.
standing disease leads to deformities, especially in the Treatment depends on identifying the clinical syn-
wrists, fingers, and feet. Synovial inflammation spread- drome and any associated diseases or precipitants and
ing beyond the knee into the popliteal space is a cause of then instituting appropriate therapy. In general, therapy
Baker's cyst. can be subdivided into management of organ failure, sup-
Extraarticular manifestations are relatively common and portive therapy, treatment for allergy or infection, treat-
tend to occur mostly when titers to rheumatoid factor are ment of associated diseases, and the use of immunosup-
high. Rheumatoid nodules occur around joints and occa- pression. It is often necessary to follow patients over a
sionally on serous membranes such as pleura. Pulmonary considerable period as evolution into a more serious syn-
nodules may cause respiratory impairment and may some- drome may occur later.
times cavitate. Vasculitis may present as necrotic areas of
skin, digital ischemia, or following infarction of gut or IMMUNE DEFICIENCY SYNDROMES (8.6)
other organs. Neurologic manifestations may be related to
compression entrapment or vasculitis. Dry eyes (Sjogren's Immunodeficiency syndromes are charactetized by a
syndrome) are relatively common; however, other oph- remarkable susceptibility to infections, autoimmune dis-
thalmic complications such as scleritis are much rarer' A ease, and lymphoreticular malignancies. The unusual
number of syndromes such as Caplan's syndrome (pul- types of infections often provide the initial clue to the
monary rheumatoid nodules in patients with pneumoco- presence of the immune defect. These disorders may be
niosis and pulmonary fibrosis) and Felty's syndrome spontaneously acquired, congenital, or iatrogenic. The
(rheumatoid arthritis, splenomegaly, neutropenia, and most common of the acquired disorders is the acquired
thrombocy'topenia) have been described. immunodeficiency syndrome (AIDS), which occurs as a
result of infection with the human immunodeficiency
Vasculitis (8.5.5) virus (HIV). Other causes of spontaneously acquired
immunodeficiency include malnutrition, protein-losing
The term vasculitis is used to describe pathologic enteropathy, and catabolic states such as myotonic dys-
inflammation of blood vessels of varying sizes and at trophy and lymphoreticular malignancy. Congenital
varying sites. Vessel lumen occlusion leads to ischemia of immunodeficiencies are categorized according to pattern
affected organs and increased vascular permeability, of inheritance and involvement of T lymphocytes, B lym-
which may lead to edema. Vasculitis may be localized or phocytes, or both. The iatrogenic immune disorders occur
widespread destructive or benign, and may be precipi- secondary to treatment with cytotoxic drugs, antilympho-
tated by infection, hypersensitivity, connective tissue dis- cyte serum, or radiation.
orders, malignancy, or unknown causes.
The manifestations of vasculitis vary widely. For many
patients the diagnosis requires the assessment of clinical HIV Disease/AIDS (8.6.1)
symptoms and signs, laboratory investigations including
serology, and imaging with biopsy of an involved organ. AIDS was initially recognized in the summer of 1981
Having made a diagnosis of vasculitis the following when five cases of Pnettmocystis carinii pneumonia and
steps should be underlaken to provide confirmation. The 26 cases of Kaposi's sarcoma were reported in otherwise
markers of active inflammation should be sought. Ele- healthy homosexual men. HIV was isolated and demon-
vated ESR, leukocytosis, the presence of C-reactive pro- strated as the etiologic agent of AIDS in 1984 and sero-
tein, and other acute-phase reactants as well as anemia logic testing for the virus soon followed. The earliest ret-
may be present. Assessment of liver and renal function as rospective diagnosis of AIDS has been made reviewing
well as tests specific to other organ systems potentially records from the late 1950s. The numbers of cases of
involved should be done. It should be noted that the find- AIDS has grown in epidemic proportions over the last
ing of vasculitis at one site does not always mean that one and one-half decades. Among adults ages 25 to 44,
other areas are involved" and other potential causes of AIDS disease is the number one cause of death for men
organ dysfunction should be sought and excluded. and the number four cause of death for women.
A search for precipitants and associated conditions HIV disease is fundamentally an infection of the
should be made, including screening for infection (e.g., immune system that results in progressive premature
syphilis, gonorrhea, hepatitis B), malignancy, allergy, and destruction of the Thelper (CD4) lymphocytes. There is a
connective tissue diseases. Specific testing of serum broad spectrum of HIV disease starting with a brief
immunoglobulins, ANA, rheumatoid factor, and comple- symptomatic or asymptomatic primary infection fol-
ment levels as well as antineutrophil cytoplasmic autoan- lowed by a relatively long asymptomatic phase. The
 402 / EnrncrNcy MrorcrNr: Tun Conn CunnrculuM

symptomatic phase that follows (AIDS) is characterized for the year 2000 are for this number to grow to 30 to 40
by an increased frequency of infections that are normally million HIV infections. The largest number of infections
kept in check by an ordinary immune system. In addition, (highest prevalence) are in sub-Saharan Africa; however,
involvement of the nervous system or hemopoietic tissues Asia is expected to surpass Africa as the region with the
may be seen during this progressive late stage. largest number of new cases (highest incidence) by the
year 2000. In the United States it is estimated that
Definition 750,000 to 1.4 million individuals are infected with the
HIV virus. There have been at least 501,000 AIDS cases
The current definition of AIDS includes all patients diagnosed in the United States from l98l through Octo-
with HIV infection and a CD4 count less than 200luI, ber 1995; of these, 620/ohave died. Roughly 40,000 new
CD4/CD8 ratio <0.14, and/or an AlDS-indicator (oppor- cases are diagnosed each year in the United States and an
tunistic) condition such as unusual secondary infections, equivalent number of patients die annually of this dis-
specific neoplasms, or neurologic disease (Table 8-3). ease.
The initial epidemiologic data from AIDS patients in
Etiologlt the United States found that among men with the disease,
670/o were homosexual, lJoh were IV drug users, 80%
There are two types of HIV viruses that have been were both homosexual and IV drug users, 3% received
identified as causingAIDS in humans: HIV-1 and HIV-2. blood products prior to 1985, 2%had heterosexual con-
The most common cause ofAIDS is the HIV-l virus. The tact with an HIV infected female, and 3Yo were without
HIV-2 has been most frequently identified in West Africa identified risk factors. Women with AIDS had the fol-
and parts of Asia; however, this virus is extremely rare in lowing risk factors: 53oh were IV drug users, 30%o had a
the United States, accounting for only 0.01% of HIV heterosexual contact with an HlV-infected male, l0o/o
infections (almost all traceable to Western Africa). The received blood products prior to 1985, and, joh had no
HIV-2 virus may be less virulent than HIV-I and resem- identified risk factors. In 1988, when HIV screening of
bles some members of the group of simian immunodefi- Job Corps applicants in the United States was initiated,
ciency viruses. The transmission and clinical features of men were found to be twice as likely as women to have
the HIV-l and HIV-2 viruses are similar. Routine screen- HIV infection. However, more recent seroprevalence
ing of blood donors in the United States for HIV-2 using studies of Job Corps applicants have now demonstrated a
a combined enzyme immunoassay for both HIV-1 and -2 higher rate of HIV infection among women than men,
was initiated in 1992. similar to the ratios seen in Africa and Asia for some
time. Behaviors or events that are associated with greater
Epidemiology risk of acquiring HIV infection include male homosexu-
ality, IV drug abuse, prostitution, tattooing, acupuncture,
Incidence and Prevalence heterosexual exposure to a partner at risk, having a large
number of sexual partners, receiving blood products prior
It is estimated that there are more than 19 million peo- to 1985, and being born to a HlV-infected mother.
ple worldwide infected with the HIV virus. Projections The prevalence of HIV infection varies greatly in dif-
ferent popul ations-7 5o/o in factor Vlll-deficient hemo-
philiacs to 0.02%o in voluntary blood donors (Table 8-4).
TABLE 8-3. Al DS-defining disorders There is also significant geographic variability in
Laboratory evidence of HIV with any of the following: seropositivity in emergency department (ED) popula-
Candidiasis, pulmonary or esophageal
tions; 4.2Yo to ll.3%o in large urban inner cities versus
Cervical cancer <l%o in suburban settings. A large percentage of these
Coccidioidomycosis patients are unaware of their HIV infection. Nonwhite
Cryptococcosis, extrapulmonary populations and victims of penetrating trauma are at sig-
Cryptosporidiosis
Cytomegalovirus, chronic (more than 1 month) or esophageal
nificantly higher risk of being seropositive when
Histoplasmosis screened in the ED.
Kaposi's sarcoma
Lymphoma
Mycobacterium avium
Transmission
Mycobacteri u m kansasii
Myco b acte ri u m tu be rc u I osi s HIV infection is most frequently transmitted via sexual
Pneumocystis intercourse, parenteral route, perinatal maternal-fetal
Pneumonia, recurrent inoculation, or breast milk. The HIV virus is concentrated
Progressive multifocal leukoencephalopathy
Salmonellosis
in cells; therefore, cellular fluids are significantly more
infectious than acellular secretions. Blood and its compo-
 IvnruNn Sysrnlr DrsononRs / 403
TABLE 8-4. Prevalence of HIV infection in selected infected and has not y"t developed detectable antibodies.
populations in the United States Transfer of the virus by HlV-contaminated needle-stick
Est. HIV to a health care worker carries a risk of 0.3% to 0.4Yo per
Population seroprevalence (%) exposure. The risk of transfer of HIV from a physician to
Homosexual men 30-50 a patient is extremely small.
lnjection drug users 2-60 Maternal-fetal transmission occurs in l3o/o to 39o/o of
Prostitutes 0-57 infants born to HlV-infected mothers. Breast-feeding
Hemophiliacs, factor Vll I 75 should be convincingly discouraged among HlV-infected
Hemophiliacs, factor lX 35
Blood donors 0.o2
mothers as there is additional risk of HIV transmission
Patients with tuberculosis 2-29 from infected milk.
Patients with sexually transmitted disease 1-5
Pregnant women 0.01-5
Hospitalized adults without hx of AIDS o.2-14 ksting
College students 0.2
Military applicants 0.13 The interval between HIV infection and antibody
Urban ED patients 4-9 response is fromI to 3 months. Antibodies to HIV usu-
Suburban ED patients <1.0
Urban penetrating trauma patients in ED 5-1 5
ally appear within 2 weeks of onset of the acute retroviral
syndrome (when present) and are almost always present
within 8 weeks. Enzyme-linked immunosorbent assay
(ELISA) for HIV antibody is the best of the currently
nents are probably the most infectious. Other documented available screening tests with sensitivities and specifici-
sources of HIV transmission include semen, cervical and ties of over 99 .5% and 99oh, respectively. In low-risk pop-
vaginal secretions, breast milk, cerebrospinal flui4 and ulations (e.g., blood donors), a majority of positive tests
pleural and peritoneal fluids. Infectivity correlates with represent false positives. The Western blot assay is uti-
degree of viremia; thus. the risk of HIV transmission is lized most frequently as a confirmatory test for positive
greatest during initial seroconversion and with advanced ELISA tests results. This test has sensitivities and speci-
disease when viremia is at its highest levels. There is no ficities that approach 100%;however, it is labor intensive
evidence to date that HIV infection can be spread by rou- and costly. Indeterminate test results should be repeated
tine casual contact. inlto3months.
Sexual transmission of HIV has been reported with The p24 antigen assay is an ELISA test that has a sen-
unprotected vaginal intercourse, oral intercourse with ejac- sitivity of approxim ately 30o/o in detecting HIV infection.
ulation, and anal intercourse. Sexual behaviors that are This sensitivity can be increased to 50oh using acid dis-
associated with the highest rates of transmission are anal sociation of immune complexes. This test is helpful in
intercourse and sex during menses. Worldwide, heterosex- diagnosing acute retroviral infection prior to the develop-
ual transmission is the most common mode of transmis- ment of HIV antibodies. The polymerase chain reaction
sion, although this is responsible for a minority of all HIV test (quantitative viral load assay) is extremely sensitive
cases in the United States. However, the number of cases and is now available outside of the university/research
that were transmitted heterosexually in the United States setting. Direct culture of HIV from blood has excellent
has increased from 3% between l98l and 1987 to l0% sensitivity and specificity; however, limited availability
from 1993 to 1995. The percent of cases among women in and time to grow (it requires at least 28 days) restricts its
the United States also rose from 8o/o to lSoh during this usefulness in the clinical arena.
time period. The risk of sexual transmission correlates with Measurement of the T-helper lymphocyte (CD4) level
the absence of mucosal integrity. The greater prevalence of and viral load are currently the most accurate ways to
untreated chancroid, syphilis, and genital herpes simplex assess the degree of immune suppression. Abrupt shifts in
(open ulcerated genital lesions) in Western Africa and parts CD4 counts should be cautiously evaluated as there may be
ofAsia may partially explain the higher rate of heterosex- diurnal variation of 50 to 150/pl in normal patients. How-
ual transmission in these populations. eveq the daily variation in counts is significantly less in
Parenteral transmission of HIV occurs most frequently patients with low CD4 counts. Certain opporlunistic infec-
secondary to sharing of needles and syringes among IV tions in AIDS patients are only seen with CD4 counts
drug users. In addition, donation of blood products by below specific levels. In general, patients with CD4 counts
HlV-infected individuals results in HIV infection in above 500/pl have a basically normal immune response,
approximately 90% of recipients. Testing blood donors while those below 200/pl are aI risk for AlDS-related sec-
for antibodies to HIV (initiated in 1985) significantly ondary infections (Table 8-5). There is a rare syndrome,
reduces the risk of transmission via transfusions; how- idiopathic CD4 T lymphocy'topenia (ICL), which is char-
ever, there is still a I in 40,000 to 250,000 risk of acquir- acteized by low CD4 counts without evidence of HIV
ing infection from a donor that has just recently been infection or explained under$ing defect in cellular immu-
404 / Enr,ncrNcy MrorcrNr: Tnr Conr Cunnrculuu

TABLE 8-5. Relationship between CD4 cell counts and infections

CD4 count Organism Presentation
<500 S. pneumoniae Pneumonia
H. influenzae Pneumonia
M. tuberculosis Pulmonary TB
Candida Oropharyngeal and vaginal candidiasis
Herpes simplex Orogenital herpes
Herpes zoster Shingles
Epstein-Barr virus Oral leukoplakia
<200 P carinii Pneumonia
Cryptosporidium Chronic diarrhea
<1 00 Toxoplasma gondii Encephalitis
Microsporida Diarrhea
Candida Esophagitis
Cryptococcus neoformans Meningitis
M. tuberculosis Extrapulmonary TB
Herpes simplex Disseminated herpes
Herpes zoster Disseminated zoster
Epstein-Barr virus CNS lymphoma
<50 MAC Disseminated MAC
Cytomegalovirus Retinitis, Gl disease, encephalitis
CNS, central nervous system; Gl, gastrointestinal; MAC, Mycobacterium avium complex; TB, tuberculosis.
Adapted from Gallant JE. lnfectious complications of HIV disease. Emerg Med Clin North Am 1995;13(1):73-104.

nity; it was first noted in l992.There is no evidence of sex- patients may have lymphadenopathy, but usually have no
ual transmission and the clinical course is more benign. other symptoms secondary to the HIV infection. In the
Opportunistic infections do occur in association with this intermediate disease group, patients may have candidia-
disorder and should be treated appropriately. sis, oral hairy leukoplakia, herpes simplex virus (HSV)
disease, herpes zoster, seborrheic dermatitis, TB, HIV-
related malignancies, or bacterial infections. Constitu-
Natural History
tional symptoms such as headache, fever, night sweats,
weight loss, diarrhea, and fatigue are common. Unusual
Acute Retroviral Infection
opportunistic infections are relatively infrequent in the
intermediate stage. The late symptomatic disease stage
The primary infection is estimated to be symptomatic
that follows is characterized by opportunistic infections
(acute retroviral syndrome) in 30Yo to 70oh of cases and
this generally follows 3 to 6 weeks after the primary
and generalized disease progression. Patients with
advanced disease have a high probability of developing
exposure to HIV The acute retroviral syndrome usually
multiple opportunistic infections. Disseminated, Myco-
presents as a mononucleosis-type illness with fever,
bacterium avium infections and cytomegalovirus infec-
pharyngitis, lymphadenopathy, headache, nausea, myal-
tions are characteristically seen only in this stage.
gias, arthralgias, and malaise. An erythematous macu-
lopapular rash, hepatosplenomegaly, meningismus, and
an encephalitic picture have been described. Symptoms
are generally self-limiting and usually resolve in 7 to 10
Clinical Manifestations and Management of
Associated Disease
days. The severity of the acute retroviral syndrome is usu-
ally relatively mild; however, 30o/o of patients seek med-
The symptomatic phase of HIV infection is character-
ical care for these complaints.
izedby a wide variety of infections secondary to bacteria,
viruses, parasites, and fungi. Some of these infections
Clinical Staging occur with only mild immune suppression, while others
develop only in the presence ofadvanced disease. Treat-
There is a long asymptomatic period (median: 9 to 10 ment and prophylaxis of some of the common HIV-
years for homosexual men, shorter forIV drug users) fol- related opportunistic infections are summarized in Table
lowing the primary infection. Staging of HIV disease 8-6. In addition, there are alarge group of noninfectious
subsequent to the primary infection is currently based on complications of HIV disease that involve almost every
CD4 counts: early disease >500/pl, intermediate disease organ system. With the exception of the HlV-related neo-
200 to 500/pl, late symptDmatic disease 50 to 200/pl, and plasms, these will be approached from atarget organ per-
advanced disease <50/pl. During the early disease phase, spective.
 ftutruNr Sysrrnr Drsononns / 405
HIV- Related Malignancies tic regimens have been rejected due to poor response rates
and complicating opportunistic infections.
Patients with HIV disease are at greater risk of devel- The patients with HlV-related primary CNS lymphoma
oping malignancies, as is the case with other immune can present with focal neurologic findings, headache,
deficiencies. The cancers that are identified with HIV changes in mental status, or seizures. On computed
disease include Kaposi's sarcoma, non-Hodgkin's lym- tomography (CT) scanning (with contrast), lymphoma
phoma, and anogenital malignancies. All of these tumors may be confused with CNS toxoplasmosis, since both dis-
have distinctive epidemiologic profiles among patients eases may demonstrate ring-enhancing lesions. Usually
with HIV disease. There are additional malignancies that patients with lymphoma have single lesions measuring
occur with equivalent frequencies in the HIV and greater than 3 cm at presentation, while CNS toxoplasmo-
non-HlV-infected patient; however, it is not unusual to sis has multiple smaller lesions. Magnetic resonance
see a more fulminant course in those with AIDS. imaging (MRI) and nuclear medicine studies have been
Kaposi's sarcoma (KS) is the most cornmon cancer utilized to assist in differentiating these diseases. In addi-
associated with HIV disease; however, most of the tion, a tridl ofantibiotic therapy directed against toxoplas-
reported cases (96%) have occurred in homosexual or mosis is frequently utilized to help make a tentative diag-
bisexual men. This has raised the possibility that the pres- nosis. Only patients who fail this regimen should undergo
ence of Kaposi's sarcoma may be related to a distinct brain biopsy. Treatment of primary CNS lymphoma is
infectious agent or cofactor (possibly a herpes type almost always futile; however, radiation therapy and
virus). Kaposi's sarcoma may present at any stage of HIV steroids have been palliative in some patients.
infection. The lesions may involve skin, mucous mem- Anogenital malignancies (cervical and anal squamous
branes, lymph nodes, gastrointestinal tract, or lungs. Typ- cell carcinomas) are seen slightly more often in the
ically, these sarcomas appear as raised, reddish to purple patient with HIV disease as a result of coincidental infec-
macules (may be papules or nodules) measuring from a tion with the human papilloma virus (HPV). Periodic rec-
few millimeters to several centimeters. KS can involve tal and pelvic examinations with Papanicolaou smears
any cutaneous location but is most commonly found on supplemented by colposcopy should be performed in the
the face, genitalia, and feet. The diagnosis of KS is estab- HlV-infected patient to identify early stages of disease
lished by the pathologic appearance oftissue on biopsy. (dysplasia or intraepithelial neoplasia).
The natural history ofthis disease varies from an indo-
lent to an aggressive course. However, in light of the fact
that less thanl}Yo ofAIDS patients with KS die directly of Pulmonary Involvement
this sarcoma, most authors support a cautious treatment
regimen that avoids fuither immune suppression. Treat- Respiratory tract infections are seen in practically all
ment with interferon-o, decreases tumor bulk and improves patients with AIDS. In the patient with early or interme-
survival in patients with greater than 200l1tl CD4 cells. diate disease there is an increased incidence ofbacterial
Combination chemotherapy with low-dose doxorubicin, pneumonia and tuberculosis. As the HIV disease pro-
bleomycin, and vinblastine plus radiation therapy is indi- gresses to the late stages (CD4 count < 200), a variety of
cated for patients with lifethreatening disease. opportunistic pulmonary infections are encountered. The
Non-Hodgkin's lymphoma (NHL) is generally a late most common of these, and one of the AlDs-defining
manifestation (CD4 <200/pl) of AIDS. Approximately infections, is Pneumocystis carinii pneumonia. Treatment
3o/o of all AIDS patients develop a lymphoma as a com- and prophylaxis for common HlV-related opportunistic
plication of their disease, with the highest prevalence in respiratory infections is outlined in Table 8-6.
hemophiliacs and lowest in African groups with hetero- Bacterial pneumonia and sinusitis are found in all
sexual transmission. The great majority of the HIV- stages of HIV infection. There may be a slightly
related lymphomas are high grade B-cell tumors. The increased incidence of disease with encapsulated bacteria
most common types include immunoblastic lymphoma, in AIDS, and infections with Streptococcus pneumoniae,
Burkitt's lymphoma, and primary CNS lymphoma. Occa- Haemophilus influenzae, and other classical encapsulated
sionally, Epstein-Barr virus (EBV) appears to play an eti- bacterial pathogens predominate. Bacterial pneumonia
ologic role, and EBV genetic material is found in half of usually presents with a relatively sudden onset of symp-
all HlV-related lymphomas. toms of fever, sputum production, and pleuritic chest pain
The clinical progression of systemic NHL in the AIDS over a period of 3 to 5 days. Radiographically, bacterial
patient is much more aggressive than that seen in the nor- pneumonia tends to display focal consolidation or cavi-
mal host. Characteristically, patients note a rapidly grow- tary disease; however, diffirse bilateral infiltrates are
ing mass or nonspecific symptoms (fever, night sweats, or occasionally reported. When the suspected respiratory
weight loss). Extranodal disease is found on presentation pathogens include both common bacteria and pneumo-
in98o/" ofAIDS patients, while this is only seen in 40% of cystis, treatment with high-dose trimethoprim-sul-
HlV-negative patients. Standard intensive chemotherapeu- famethoxazole (TMP/SMX) should be contemplated as
 IuuuNn Sysrtrrl Drsonnpns / 409
this gives adequate coverage for both groups. Sinusitis characteristically presents with fever and pneumonia in
generally involves the maxillary sinuses, but may involve the AIDS patient. Adenopathy, bone marrow involve-
the other sinuses as well. Treatment of sinusitis should ment, and mucocutaneous disease may occur. The dis-
include broad-spectrum antibiotics and decongestants. ease is diagnosed by culture or histopathologic appear-
Pneumocystis carinii pneumonia (PCP) was seen in ance of the organism from blood, bone marrow, or
80% ofAIDS patients during the mid-I980s. This dropped infected tissue.
to 40o/o in the early 1990s, as a result of the successful The incidence of tuberculosis (TB) has increased sig-
aggressive use of prophylaxis against PCP in patients with nificantly as a result of the spread of HIV disease. The
CD4 counts less than 200l1tl or patients with higher CD4 risk of reactivation and primary infection with Mycobac-
counts with prominent constitutional symptoms. P carinii terium tuberculosis is striking higher in the patient with
was originally classified as a protozoa; however, there is HIV disease. M. tuberculosls is one of the most virulent
some evidence to suggest that it actually represents a fun- opportunistic infections seen in HIV disease. As a result,
gus. Patients with PCP often describe prodromal symp- reactivation tuberculosis frequently occurs with only mild
toms of fever, fatigue, and weight loss for several weeks to moderate decreases in the CD4 counts. The radiologic
prior to onset of pulmonary manifestations of dyspnea and appearance of pulmonary tuberculosis in these patient is
nonproductive cough. The chest radiograph most often fairly typical with apical and cavitary infiltrates. When
demonstrates bilateral interstitial or alveolar infiltrates, yet tuberculosis occurs in patients with advanced HIV dis-
focal infiltrates, cavitary lesions, pleural effirsions, nodular ease (CD4 < 50/pl), the x-ray finding may be more atyp-
densities, and pneumothorax have been encountered. ical (lower lobe or miliary patterns also seen).
Upper lobe disease cavitary disease may be seen in patients A positive purified protein derivative (PPD) may sup-
receiving aerosolized pentamidine prophylaxis. When the port the diagnosis of TB; however, a negative test is less
diagnosis is unclear, sputum should be induced with nebu- useful since anergy is common in patients with HIV dis-
lized saline. Fluorescein staining has improved the sensi- ease. The diagnosis of TB is made by examination of the
tivity of sputum examination for P. carinii in comparison to sputum for acid-fast bacilli (AFB) with confirmatory cul-
the traditional silver stain technique. If this is unsuccessful, ture. Standard treatment of active TB in the HlV-seropos-
bronchoscopy with bronchoalveolar lavage/biopsy itive and HlV-seronegative patient is equally efficacious.
increases the sensitiviry to the 100% range. The arleial Because of the high risk of development of TB in early
blood gas generally demonstrates hlpoxemia or at least HIV disease, any HlV-positive patient with a PPD >5 mm
desaturation with exercise. Several trials have demon- induration, a history of a positive PPD, or a significant
strated that corticosteroids (prednisone 40 mg BID x 5 exposure should receive 12 months of isoniazid.
days, 40 mg QD x 5 days followed by 20 mg QD for 10 Multiple drug resistant TB (MDR-TB) has emerged as
days) prevent the alveolar inflammation and hypoxia asso- a problem particularly among HlV-infected patients in
ciated with the antibiotic treatment of pneumocystis. This institutional settings. Unfortunately, there is only margin-
reduces the risk ofintubation and death from respiratory ally effective treatment for MDR-TB in the HlV-infected
failure by approximately 50oh. Adjuvant steroids demon- patient. Most authorities recommend the standard four-
strate their benefit primarily in patients with a PaOz <70 drug regimen for TB plus two additional drugs based on
mm Hg or alveolar-arterial gradient >35 mm Hg on room local MDR-TB strain susceptibility. Nonimmunocompro-
air. mised patients with MDR-TB have only a 50% probabil-
Fungal disease of the lung in the AIDS patient may also ity of sterilizing their sputum cultures and the outcome is
be secondary to Cryptococcus, Coccidiomycosis, Histo- significantly worse in those with HIV disease.
plasmosis, or Aspergillus. Cryptococcus neoformans is the Mycobacterium kansasii produces a disease that is
second (to PCP) most common cause of fungal pneumonia clinically analogous to tuberculosis in patients with
in HIV disease and is discussed further in conjunction with advanced HIV disease. The organism is usually found in
cryptococcal meningitis. Although Aspergillus is an pulmonary secretions. It is relatively easy to treat,
important cause of pneumonia in immunocompromised responding well to 12 to 18 months of isoniazid, rifam-
hosts, it is an infrequent pathogen in the AIDS patient. pin, and ethambutol.
Coccidioides immitis is found primarily in the deserts
of the Southwest. Pneumonitis in the AIDS patient is usu-
ally the result of reactivation of the fungus. Patients pre- Neuro logic Manifes tations
sent with slowly progressive constitutional and respira-
tory symptoms. Radiographic findings are more Central nervous system disorders associated with HIV
extensive in HIV disease and diffirse nodular or intersti- disease include primary and secondary CNS infections,
tial infiltrates are frequently detected. peripheral neuropathies, myopathies, vascular complica-
Histoplasma capsulatum is endemic to parts of the tions, and neoplasms. Neurologic involvement occurs in
Mississippi and Ohio River valleys and exists in soil 75oh to 90o/o of patients with AIDS and is the first mani-
contaminated by bird or bat excrement. Histoplasmosis festation of AIDS in l0% to 20o/o of patients.
410 / ErrrnRcnNcv MnorcrNn: Tur Conn Cunnrculurvr

Tbxoplasma gondii, the etiologic agent of toxoplasmo- usually occurs late in the course of HIV disease. Deficits
sis, is a protozoa that typically infects humans through in attention, forgetfulness, and decreased cognitive func,
the ingestion of substances contaminated by cat feces or tion are initial symptoms. Apathy, withdrawal, ataxia, and
the consumption of undercooked meat. The primary deterioration of fine motor skills follow as the disease
infection is relatively asymptomatic, often occurring advances. In rare cases, an agitated or manic state may
early in life. Toxoplasmosis in patients withAIDS usually develop. During the later stages of this disorder, patients
occurs as the result ofreactivation of Z gondii cysts and may develop severe motor dysfunction and with inconti-
generally presents as an encephalitis; however, it may nence of bowel and bladder. Neuroimaging (CT/MRI)
present as transverse myelitis, retinochoroiditis, pul- typically shows cerebral atrophy, ventricular enlarge-
monary disease, peritonitis, or orchitis. It is the most fre- ment, subcortical gray matter lesion, and parenchymal
quently encountered secondary CNS infection in HIV changes in the white matter. The CSF may demonstrate
disease and the leading cause of intracranial mass lesions mild pleocytosis (25%) and elevation of the protein level
in patients with AIDS. Toxoplasmic encephalitis is usu- (65%). There is no clearly effective treatment of AIDS
ally seen in patients with CD4 counts less than 100/pl. dementia complex; however, there are anecdotal reports
Patients with CNS toxoplasmosis typically present with of improvement with antiretroviral therapy.
altered mental status, focal neurologic deficits, or seizures. Peripheral neuropathies are common manifestations of
Fever and headache are commonly present. Individuals HIV disease. An inflammatory demyelinating neuropathy
with lgGtoxoplasma seropositivity are at higher risk for similar to Guillain-Barr6 has been described in patients
CNS toxoplasmosis, yet this test is not particularly helpful with early HIV disease. In advanced disease, painful sen-
in making or ruling out this diagnosis. Lumbar puncture sory neuropathies are frequently noted. However, pain-
may show a mild pleocytosis and an elevated protein level, less sensory, pure motor, mixed" and autonomic neu-
however, this is contraindicated in patients with significant ropathies are also described. In addition, several of the
mass lesions. CT scanning with contrast or MRI scanning reverse transcriptase inhibitors (ddl, ddc, and d4T) can
(more sensitive) are the preferred techniques to confirm cause peripheral neuropathies.
the presence of toxoplasmosis. Thallium scanning may The myopathy associated with HIV disease is charac-
also help distinguish CNS toxoplasmosis from CNS lym- teized by slowly progressive proximal muscle weakness,
phoma (positive with malignancy, negative with toxoplas- wasting of upper and lower extremities, elevated creati-
mosis). The definitive diagnosis of CNS toxoplasmosis can nine phosphokinase, and a myopathic picture on elec-
only be made with a brain biopsy; however, in light of the tromyography. Prolonged treatment with azidothymidine
morbidity associated with this invasive procedure, this is (AZT) may also result in a myopathy that presents with
usually reserved for patients who clinically appear to have proximal muscle weakness, wasting of the buttocks and
toxoplasmosis yet do not respond to2to 4 weeks of appro- lower extremities, and elevated creatinine phosphokinase.
priate therapy. Chemoprophylaxis to prevent toxoplasmo- This diagnosis can be confirmed on muscle biopsy. The
sis reactivation is indicated in toxo-seropositive patients AZT should be discontinued and a short course ofpred-
with CD4 counts less than 20011t1. nisone may accelerate recovery of motor function.
Cryptococcus neoformans is the most common cause of The Jakob-Creutzfeldt (JC) virus is the etiologic agent
meningitis in individuals with HIV disease occurring in of progressive multifocal leukoencephalopathy (PML).
60/o to l2%o of all AIDS patients. This ubiquitous encapsu- This demyelinating disorder involves the cerebral hemi-
lated yeast is of low virulence, causing disease only in spheres, cerebellum, and brain stem, and is generally only
AIDS patients with CD4 counts less than 100/pl. The clin- seen in advanced AIDS. Patients may develop multiple
ical presentation of cryptococcal meningitis may be subtle focal neurologic deficits or have an encephalitic presen-
and subacute. Headache (76%), fever (65%), meningismus tation. The diagnosis is typically made with MRI scan-
(22%), and photophobia (18%) are the most commonly ning, which demonstrates multiple white matter lesions.
reported symptoms. Pulmonary disease is present in 40o/o There is no known effective treatment, and patients gen-
of patients with cryptococcal infections, 900% of whom erally die 3 to 9 months after onset of symptoms.
also have CNS involvement. Cerebrospinal fluid (CSF)
may demonstrate leukocyte counts between 0 and 700/pl
(most 0 to 20l1tl), protein elevation (55%), and a low glu- GI Complications
cose (24oh). The India ink stains (75%) and CSF crypto-
coccal antigen (95o/o) are more helpful than other CSF The most common gastrointestinal disturbance in
studies; however, neither test is as sensitive as the serum AIDS is diarrheal disease. HIV enteropathy, Kaposi's sar-
cryptococcal antigen (98%). The definitive diagnosis is coma, Cryptosporidium, Mycobacterium avium complex
based on culturing C. neoformans from the CSF. (MAC), and Microsporidia can all result in chronic diar-
AIDS dementia complex (also called HIV encephalo- rhea that is difficult to treat. In addition, patients with
pathy and HIV dementia) is characterized by impair- HIV disease are at risk for treatable causes of diarrhea
ments in cognitive, motor, and behavioral function. This that include Isospora, Giardiq, Entamoeba histolytica,
 InrrrluNn Srsrnrr,r Drsonnrns / 4Ll
Campylobacte4 Salmonella, and, Shi gella. Crypto sp orid- caused by Candida lvusei, Torulopsis glabrata, or resis-
ium parvum is the most frequent cause of diarrheal illness tant strains of C. albicans. These resistant infections may
in AIDS. It is characteized by copious watery diarrhea respond to higher dose "azoles" or may require treatment
and crampy abdominal pain. Examination of the stool with amphotericin B.
reveals no red or white blood cells. In addition, Cryp- Oral hairy leukoplakia is an Epstein-Barr virus associ-
tosporidium may involve the biliary tract, resulting in ated condition that presents with painless thick white
cholestatic jaundice and acalculous cholecystitis; lesions on the lateral surface of the tongue (buccal mucosa
cytomegalovirus (CMV) may also involve the biliary may also be involved). In contrast to typical thrush, these
tract. The diagnosis is made by acid-fast staining of lesions cannot be removed when scraped. Oral hairy
oocysts in stool or biopsy specimens. Therapy is sympto- leukoplakia is typically an early manifestation of HIV dis-
matic with antimotility agents and nutritional supple- ease, predating other opportunistic infections. No specific
ments. Strict enteric precautions are indicated since this treatment is generally required; however, the lesions may
parasite can be transmitted to otherwise healthy hosts, respond to oral acyclovir, AZT, and topical tretinoin.
resulting in an acute selfJimiting diarrheal illness. Rochalimaea henselae, the etiologic agent of bacillary
Esophagitis occurs in 40Yo to 50o/o of AIDS cases. angiomatosis, is a rickettsial organism that causes a pro-
Candida is the most common pathogen (50yo to 70o/o), liferative vascular disorder seen most commonly in
with Herpes simplex and CMV implicated for most of the patients with HIV disease. Patients present with
remaining cases. Most patients with esophageal candidi- angiomatous papules, skin nodules, or cellulitic plaques.
asis present with dysphagia, oral thrush, and a CD4 count Patients may have constitutional symptoms (fever, weight
less than 100/pl. Treatment of presumed esophageal can- loss, and malaise) and visceral involvement of the liver,
didiasis without fuither diagnostic testing in the setting of spleen, lymph nodes, bone marrow, CNS, and lungs. The
oral thrush is appropriate since it is easily treatable with diagnosis is confirmed by the histologic appearance of
14 to 2l days of fluconazole or ketoconazole. Patients the biopsy and the identification ofthe organism on the
who present with odynophagia or dysphagia of question- Warthin-Starry silver stain. Patients have been success-
able etiology or those patients that do not respond after fully treated with 4 weeks of either erythromycin or
several days of therapy for candida esophagitis should doxycycline.
undergo barium swallow or endoscopy (endoscopy is Recurrent herpes simplex virus (HSV) infections are
more sensitive and specific). frequently seen in HIV disease. In early HIV disease, the
course of HSV infection is similar to that in a nonim-
munocompromised host. With HIV disease progression
Cutaneous Manifes tations (CD4 counts <20011t1), HSV disease presents in a more
aggressive manner. The diagnosis of HSV infection is
Dermatologic conditions are described in over 90o/o of usually made clinically, yet patients with extensive dis-
AIDS patients. The cutaneous manifestations of HIV dis- ease or atypical presentations should have the diagnosis
ease may be secondary to the acute retroviral syndrome, confirmed with viral cultures. Acyclovir is the treatment
infections, malignancies, drug therapies, nutritional dis- of choice for these patients, although patients who have
orders, or autoimmune phenomenon. In addition, there a received prolonged treatment with acyclovir may develop
variety of common dermatologic conditions (e.g., sebor- resistant strains (may also occur with herpes zoster) that
rhea and psoriasis) that have an exaggerated presentation are responsive to foscarnet.
in the AIDS patient. Many of these are discussed in other Herpes zoster, representing reactivation of latent vari-
sections of this chapter; this section focuses predomi- cella-zoster virus (VZV), develops more commonly in
nantly on the infectious dermatosis seen in the patient the HlV-infected patient. Young, otherwise healthy
with HIV disease. patients who present with VZV infection should be tested
Oral and vaginal candidiasis is common in all stages of for HIV disease, as this may be the initial clinical mani-
HIV disease. Oropharyngeal candidiasis most often pre- festation of worsening immune suppression. As the
sents as "pseudomembranous" candidiasis that is charac- degree of immune suppression progresses, individuals
teized. by an easily removable white plaque. An erythe- are more likely to develop disseminated disease. Der-
matous form, with red patches on the mucous membranes matomal YZY can be treated with oral agents, while dis-
and angular cheilitis, is also frequently reported. Less seminated, ophthalmic, or visceral disease should be
commonly, patients present with candidal leukoplakia, treated with intravenous antivirals.
with white patches that cannot be removed. Treatment Treponema pallidum, the etiologic agent of syphilis, is
with topical or oral antifungal agents is usually effective a spirochete that enters the body through mucous mem-
for both oral and vaginal candidiasis. Candida albicans is branes or broken skin. The course of primary and sec-
the etiologic agent in most cases; however, the prolonged ondary syphilis in the patient with HIV disease is basi-
use of systemic antifungal agents has now led to the cally unaltered; however, treatment failure after standard
development of an occasional resistant yeast infections penicillin therapy may occur more frequently in AIDS,
472 / EunncrNcy MnorcrNn: Tsn Conr CunrucuLUM

and some authorities routinely recommend three weekly bone marrow involvement. MAC is simple to diagnose,
doses (rather than one dose) of penicillin in this setting. with sensitivities of two blood cultures approaching
There are several unusual manifestations of late syphilis 100%. MAC is often isolated from sputum in patients
that develop in the AIDS patient, including lues maligna with and without disseminated infection, yet it infre-
(necrotizing vasculitis) and atypical early neurosyphilis quently causes pulmonary disease. MAC infection cannot
(presenting with meningitis, stroke, blindness, or deaf- be completely eradicated; however, antibiotic therapy
ness). The diagnosis of neurosyphilis may be more diffi- reduces bacteremia and alleviates clinical symptoms.
cult to confirm in the AIDS patient, because of the coex- Chemoprophylaxis to prevent disseminated MAC is rec-
istent CSF abnormalities and the insensitivity of the CSF ommended for patients with CD4 counts less than 50 to
VDRL. 100/pl.

Op ht h alm o I o gi c M anife s t ati on s Treatment

CMV retinitis is the leading ocular complication of There is currently no treatment that cures AIDS. How-
HIV disease. This generally occurs as a manifestation of ever, there are several antiretroviral drugs that delay the
advanced HIV disease (CD4 <50/pl). There is a strong progression of HIV disease and may improve survival.
predilection of CMV to the retina. Approximately 90o/o of Most of the available drugs that have some efficacy in
patients with invasive disease develop eye involvement. HIV disease are nucleoside analogues that act as reverse
Patients generally describe floaters, decreased visual acu- transcriptase inhibitors or protease inhibitors. Of these
ity, or field deficits. The diagnosis is based on retinal agents, the greatest amount of experience has been with
findings (hemorrhage, exudates, dense opaque lesions, zidorudine (AZT or more recently ZDY), a nucleoside
and vasculitis) on indirect ophthalmoscopy. Serologic analogue reverse transcriptase inhibitor. Nonnucleoside
testing is nonspecific and does not help confirm the diag- reverse transcriptase inhibitors may have some utility in
nosis. If untreated, CMV retinitis is rapidly destructive, treating HIV disease and should be available in the near
leading to blindness. With appropriate antiviral therapy, future. Bone marrow transplantation, lymphocyte trans-
the progression of the disease is slowed significantly. fusions, interleukin-2, and interferon have been utilized
CMV infection may also involve the esophagus, stomach, with limited success.
colon liver, adrenals, and CNS. The role of oral ganci- Most patients with HIV produce a strong humoral and
clovir for CMV prophylaxis of patients with CD4 counts cellular response to the virus. Despite this vigorous
less than 50/pl appears promising and is undergoing fur- response, the immune system is ultimately incapable of
ther evaluation. Other less frequent causes of retinitis in blocking the progression ofthe disease. Unfortunately, no
the AIDS patient include herpes zoster, Pneumocystis effective vaccine against the HIV virus has been pro-
carinii, Tbxoplasma gondii, and ischemic retinitis. duced to date. The extremely high mutation rate of the
HIV virus has mediated against the success of several
attempted HIV vaccines. There has been some interest in
Renal Manifestations
developing a live attenuated HIV vaccine; however, there
are concerns that a HIV clone could change back to a vir-
HIV nephropathy is characteized by striking protein-
ulent form over time.
uria, hypoalbuminemia, anasarca, and rapidly progressive
azotemia. This condition occurs more frequently in
young black males (male/female ratio l0:l). The course Zidovudine (AZT/ZDV)
of HIV nephropathy is rapidly progressive with the devel-
opment of end-stage renal disease within 4 months. The Zidovudine therapy (500 to 600 mg/day in divided
kidneys are frequently enlarged and the diagnosis can be doses) is recommended for patients with CD4 counts less
confirmed with renal biopsy. Unfortunately, there is no than 500/pl. Some authors recommend delaying onset of
effective therapy for HIV nephropathy. therapy in asymptomatic patients with counts between
200 and 500/pl. Treatment of patients with CD4 counts
greater than 500/pl is not recommended. Headache, nau-
Systemic Disease sea, vomiting, myalgias, malaise, dyspepsia, and insom-
nia have been described after initiation of therapy. The
Mycobacterium avium complex causes disseminated most significant toxicities associated with AZT therapy
infections in patients with advanced HIV disease. Infec- are anemia leukopenia and neutropenia. These resolve
tion occurs as a result of ingesting contaminated soil or promptly after withdrawal of AZT.If the neutropenia or
water. These patients typically present with fever, sweats, anemia reoccurs with reinitiation of therapy, AZT should
abdominal pain, and diarrhea. Anemia and elevated alka- be switched to a different antiretroviral. Prolonged
line phosphatase levels are frequently reported, reflecting administration of AZT in patients with late disease is
 Ilrrr,ruNn Sysrnu DsoruBns / 4I3
associated with the development of drug resistance and Prevention
diminished effectiveness (assessed by viral load testing).
Prevention of sexual transmission of HIV includes
avoidance ofbehaviors associated with an increased like-
Other Reverse Transcriptase Inhibitors
lihood of transmission (e.g., anal intercourse and sex dur-
ing menses) and most importantly limiting the number of
Didanosine (ddl) in doses of 200 to 440 mglday
sexual partners coupled with the use of latex condoms.
increases CD4 counts and decreases p24 antigenemia in
Awareness of HIV seropositivity of potential partners can
the short term. Didanosine is effective in patients who
certainly decrease the risk of becoming HIV infected.
have become resistant to AZT therapy. Peripheral neu-
ropathy, pancreatitis, hyperamylasemia, hyperuricemia,
dry mouth, nausea, vomiting, diarrhea, liver toxicity, High-Risk Groups
electrolyte disturbances, and cardiac arrhythmias have
been reported with ddl. Patients with HIV infection need to understand how to
Zalcitabine (ddC) therapy in divided doses totaling prevent further transmission of the virus. These patients
1.125 to 2.25 mg day improves survival in patients intol- should be persuaded to abstain from sexual relationships
erant to AZT and has been advocated together with AZT if their partner is not infected. Although condoms are
as combination therapy in patients with late disease who very effective barriers to viral passage in the lab, they are
have yet to receive antiretroviral treatment. Side effects of not effective clinically unless used compulsively. Individ-
ddC include fevers, cutaneous eruptions, mucosal ulcers, uals with an intravenous drug habit should enter a sub-
and painful peripheral neuropathy. stance abuse program at time of diagnosis.
Stavudine (d4T) in doses 30 to 80 mg/day increases Antiretroviral therapy significantly reduces the inci-
CD4 counts and decreases p24 antigenemia. Stavudine dence of maternal-fetal HIV transmission (decreased by
has been shown to be more effective than continued AZT approximately twothirds). The HlV-positive mother
in patients who had been previously treated with AZT. should receive AZT during the second and third trimester
Headache, nausea, vomiting, confusion, elevations of of pregnancy followed by a 6-week course of treatment
hepatocellular enzymes, pancreatitis, and painful periph- for the newborn. Prenatal testing of fetal blood is not
eral neuropathy have been described with stavudine. indicated, as this is thought to increase the risk of HIV
Lamirudine (3TC) in doses of 150 mg BID when used infection in the baby.
withAZT results in synergistic inhibition of HIV disease.
When used alone, resistance to the drug develops rapidly.
Health Care Workers
Concurrent use of 3TC raises the serum levels of AZT.
Adverse effects of lamivudine include gastrointestinal
Precautions in handling potentially infectious fluids
distress, pancreatitis, and neutropenia.
are paramount in preventing occupational transmission.
Compliance with universal precautions is the most effec-
Protease Inhibitors tive preventive measure for health care workers. AZT has
been frequently used prophylactically for health care
Protease inhibitors are a new class of antiretroviral workers who have been exposed to HIV contaminated
drugs that prevent cleavage ofprotein precursors essen- material. There is limited data (one retrospective case-
tial for HIV infection. Recommended dosages of three control study) supporting the use of AZT in this setting,
protease inhibitors currently available are Saquinavir and it has significant side effects. There have been at least
600 mg TID, Ritonavir 600 mg BID, and Indinavir 800 14 clearly documented cases of HIV infection despite
mg TID. Saquinavir appears to be the least effective and early administration of AZT. In light of the limited
Ritonavir the poorest tolerated, and they are all rela- options, many authorities currently recommend triple
tively expensive in comparison to the reverse transcrip- drug therapy for significant exposures.
tase inhibitors. These drugs have generally been used in
combination therapy with the reverse transcriptase
SELECTED READING
inhibitors. Saquinavir and Ritonavir have gastrointesti-
nal side effects and interfere with the cytochrome P-450 Bartlett JG, ed. The Johns Hopkins Hospital guide to medical care of
enzyme system. Indinavir may cause mild elevations of patients with HIV infection, 4th ed. Baltimore: Williams & Wilkins,
indirect bilirubin and urolithiasis, but is usually well tol- 1994;52-61.
Beral ! Peterman TA, Berkelman RI, et al. Kaposi's sarcoma among per-
erated. These drugs have shown some efficacy in sons with AIDS: a sexually transmitted infection? Lancet 1990;335:
patients with advanced disease (for at least 6 months); 123-t28.
however, how long these effects persist and whether CDC. First 500,000 AIDS cases-United States, 1995. MMII/R 1995;44:
849-8s3.
these drugs are effective in early disease remain to be CDC. Case-control sfudy of HIV seroconversion in health-care workers
determined. after percutaneous exposue to HlV-infected blood-France, United
414 t EvmncnNcv Mrucnw: Tut Conn Cunnrculuu
Kingdom, and United States, January 1988-August 1994. MMWR 1995; tion, almost never occurs due to preoperative donor-
44:929-933.
Clark SJ, Saag MS, Decker WD, et al. High titers of cytopathic virus in recipient matching. Acute rejection is most common in
plasma of patients with symptomatic primary HIV-I infection. N Engl J the first weeks and months after transplantation, although
Med 1991;324:954-960. it can occur any time if the immunosuppressive medica-
Clifford DB, Campbell JW. Management of neurologic opportunities disor-
ders in human immunodeficiency virus infection. ,Semin Nettrol 1992;12:
tions are reduced or stopped. Chronic rejection is a more
28-33. insidious process leading to destruction of the organ
Fahey JL, Taylor JM, Detels R, et al. The prognostic value of cellular and months to years following transplantation.
serologic markers in infection with human immunodeficiency virus type
l. N Engl J Med 1990;322:166-172. The designations "acute" and "chronic" rejection have
Fischl MA, Daikos GL, Uttamchandani RB, et al. Clinical presentation and been supplemented by specific terms describing the
outcome of patients with HIV infection and tuberculosis caused by mul- pathologic processes as observed in a diagnostic biopsy
tiple-drug-resistant bacilli. Ann Intern Med 19921.117 :184-190.
Galetto G, Morrow CT Noninfectious manifestations of human immunod-
(Table 8-7). Acute rejection is characterizedby an active
eficiency virus infection. Emerg Med Clin North Am 1995;13(l): lymphocytic infiltrate and cellular necrosis. Chronic
105-132. rejection may occur early or late after transplantation but
Gallant JE. Infectious complications of HIV disease. Emerg Med Clin
North Am I 995; 1 3(l):73-104.
produces a different type ofdamage: progressive destruc-
Hardy WD, Feinberg J, Finklestein DM, et al. A controlled trial of trimetho- tion and fibrosis of the organ and its supporting elements.
prim-sulfamethoxazole or aerosolized pentamidine for secondary pro- Ductopenic rejection (liver), obliterative bronchiolitis
phylaxis ofPneumocystis carinii pneumonia in patients with the acquired
immunodeficiency sl.ndrome. AIDS Clinical Trials Group Protocol 021.
(lung), and cardiac allograph vasculopathy (heart)
N Engl J Med 1992;327:1842-1848. describe the irreversible process, which ultimately culmi-
Ho DD, Moudgil I Alam M. Quantitation of human immunodeficiency nates in organ (graft) failure. In the long run, the major-
virus type I in the blood of infected persons. N Engl J Med 1989;321:
t62t-r62s. ity of patients who survive the first 6 months of trans-
Janssen RS, St Louis ME, Satten GA, et al. HIV infection among patients plantation die of chronic rejection, infection, or
in U.S. acute care hospitals. Strategies for the counseling and the testing concurrent medical problems.
ofhospital patients. The hospital HIV Surveillance Group. N Engl J Med
1992;327:445452.
The reason why some individuals are more susceptible
National Institutes of Health-University of California Expert Panel for Cor- to rejection than others is not clearly understood.
ticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia. Con- Research has identified HLA antigens, gender, and
sensus statement on the use of corticosteroids as adjunctive therapy for
pneumocystis pneumonia in the acquired immunodeficiency syndrome.
genetic background as being important factors in organ
N Engl J Med 1990;321(21):1500-1504. survival, but the process is multifactorial and no simple
Phair J, Munoz A, Detels R, et al. The risk of Pneumocystis carinii pneu- answer can explain the patient-to-patient variability. By
monia among men infected with human immunodeficiency virus type l.
Multicenter AIDS Cohort Study Group. N Engl J Med 1990;322:
the end of the first year following transplantation, some
161-l 65. patients have experienced no episodes of acute rejection
Porter SB, Sande MA. Toxoplasmosis of the central newous system in the but most have had at least one to three episodes.
acquired immunodeficiency syndrome. N Engl J Med 1992;327:
r643-1648.
Powderly WG, Saag MS, Cloud GA, et al. A controlled trial of fluconazole
or amphotericin B to prevent relapse of cryptococcal meningitis in
patients with acquired immunodeficiency syndrome. The Mycoses Study TABLE 8-7. Terms used for rejection
Group. NEngl "/ Med 1992;326:793-798. Heart
Robertson KR, Hall CD. Human immunodeficiency virus-related cognitive
Acute
impairment and the acquired immunodeficiency syndrome dementia
complex. Semin Neurol 1992;12:18-27.
Cellular
Saag MS, Powderly WG, Cloud GA, et al. Comparison of amphotericin B Humoral
with fluconazole in the treatment of acute AlDS-associated cryptococcal Vascular
meningitis. The NIAID Mycoses Study Group. N Engl J Med Chronic
1992;326:83-89. Cardiac allograph vasculopathy
Sloand EM, Pitt E, Chiarello RL HIV testing. State of the art. JAMA Transplant coronary disease
l99l;266:2861-2866. Lungs
Smith PD Quinn TC, Strober W et al. NIH Conference. Gastrointestinal Acute
infections in AIDS. lnz Intern Med 1992;116:63-77.
Chronic
Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic
human immunodeficiency virus infection. A controlled trial in persons
Broncholitis obliterans
with fewer than 500 CD4-positive cells pre cubic millimeter. The AIDS Obliterative broncholitis
Clinical Trials Group ofthe National Institute ofAllergy and Infectious Chronic vascular rejection
Diseases. N Engl J Med 1990;322:941-949. Kidney
Acute
Cellular
TRANSPLANT:RELATED PROBLEMS (8.7) Humoral
Chronic
Tiansplant Rejection (8.7.1) Liver
Acute
Rejection of a transplanted organ is a consequence of Chronic
acute or chronic immunologic attack on the foreign tis- Ductopenic
Portal/periportal hepatitis, cholangitis, and/o( endothelitis
sue. Hyperacute rejection, immediately after implanta-
 IvrrvluNn Sysrrlr DrsonorRs / 415
Acute rejection is diagnosed by routine surveillance
TABLE 8-8. Common laboratory changes due to
biopsy or by tests confirming organ dysfunction. The ressive medicati on s
i m m u nos u pp
signs and symptoms of chronic rejection are usually sub-
WBC
tle. Patients usually present with nonspecific complaints
Reduction
of malaise, saying, "Something isn't right." It should be Azathioprine
assumed that patients with a transplanted organ who pre- Ganciclovir
sent to the ED have a serious illness and should be fully Acyclovir
evaluated even if they do not look particularly ill at the Tri methop ri m/s u lfamethoxazo le
OKT3
time.
ALG
Coming to a correct diagnosis in a transplant patient is Elevation
a major challenge. Immunosuppressive drugs alter the Prednisone
usual clues for diagnosis. Rejection, infection, and drug Creatinine
toxicity are the three principal diagnoses until proven oth- Elevation
Cyclosporine
erwise. Infections may be viral, fungal ,protozoal, or bac-
Tacrolimus
terial, with the signs and symptoms of infection modified Ganciclovir
by concurrent medications. Acyclovir
The most important sources of information are the Amylase
patient and a member of the transplant team. The patients Elevation
Pancreatitis f rom azathioprine,
may know more about themselves, their medical and sur-
tri methoprim/sulfamethoxazole
gical history, recent laboratory values, medications, and ECG
side effects than do nontransplant physicians. Prompt Heart transplants usually have right bundle branch block
communication with the transplant center is of key Liver function tests
importance to help interpret the data and arrive at an azathioprine, ganciclovir, acyclovir, cyclosporine
Glucose elevation
acceptable treatment plan.
Prednisone
Megaloblastic RBC indices (t MCV)
Kidney Azathioprine, thimethoprim/sulfamethoxazole

Rejection of a transplanted kidney may cause decreased

urine output. However, the patient may present with sys-
Viral infections, especially with CMV are common,
temic complaints of malaise, low-grade fever, abdominal
and the patient may present with nonspecific malaise or a
pain, nausea, myalgias, artbralgias, and other nonlocaliz-
severe systemic illness including pneumonitis encephali-
ing symptoms. Since the advent of cyclosporine, the trans-
tis. Milder symptoms are more common and the diagno-
planted kidney, which may be palpable in the abdomen,
sis of CMV may be difficult due to overlap with symp-
does not become swollen or edematous as it did in the pre-
cyclosporine era. Since patients are often discharged early
toms of rejection and of high serum levels of
cyclosporine or tacrolimus.
after renal transplantation, a postoperative surgical prob-
lem as well as rejection or infection, should be considered
in the differential diagnosis. Kidney-Pancreas
A serum creatinine and cyclosporine levels and an
abdominal ultrasound are the most valuable diagnostic Kidney-pancreas transplantation is becoming more
tests to evaluate for kidney rejection. The patient may frequent as a definitive treatment for diabetic nephropa-
know their baseline serum creatinine level. The immuno- thy. Other than the serum glucose level, there is no easy
suppressive drugs, cyclosporine and tacrolimus, raise the diagnostic test to measure pancreas function. Immuno-
creatinine level (Table 8-8). Thus, a single creatinine suppressive levels are kept high and the function of the
level is not sufficient information to lead to a diagnosis of kidney is followed for signs of rejection. High doses of
rejection. Proteinuria is not helpful since it is a nonspe- steroids used as immunosuppressive agents may increase
cific finding and may reflect spillage from the native kid- serum glucose levels (Table 8-8). Loss of pancreas func-
ney. An abdominal ultrasound identifies fluid around the tion with preservation of kidney function may occur,
kidney (lympocele) and flow in the renal artery and vein, although kidney failure with retention of pancreas func-
and visualizes any other abnormalities in the abdominal tion is rare.
cavity. An abdominal ultrasound is the best diagnostic test to
Chronic rejection is seen as worsening renal insuffi- search for an abscess in the pancreas bed or abdomen.
ciency over time, with the signs and symptoms of renal The presence ofa fluid collection should raise the possi-
failure predominating. The late occurrence of renal artery bility of a serious problem that may need prompt atten-
stenosis with renovascular hypertension may also occur. tion.
416 / EupncrNcy MBucrNr: Tun ConB CunnrculuM

Lung regrowth may occur with restoration of neural pathways

and the potential for angina.
The diagnosis of lung transplant rejection should be
highly suspected but may be difficult to prove without
Heart-Lang
invasive testing by bronchoalveolar lavage (BAL). The
patient may complain of malaise, low-grade fever,
increasing dyspnea, or cough. These symptoms may
In patients with heart and lung transplantation, the
management and diagnosis of rejection are usually based
occur with rejection or infection, and both possibilities
on findings in the lung since cardiac rejection is rare
should be entertained.
without simultaneous lung rejection.
A good-quality chest x-ray compared with previous
studies and spirometry are the two most useful noninva-
sive tests in the diagnosis of lung rejection. Some patients Liver
follow their own spirometry values and a drop of 10 to
l5% would support the diagnosis ofrejection. Interpreta- Patients undergoing liver transplantation usually
tion of the chest x-ray, the physical examination, and the remain in the hospital long enough to deal with the imme-
arterial blood gas may be confusing, depending on diate postoperative surgical complications. Liver rejec-
whether the patient has undergone a single- or double- tion may present subtly with symptoms of malaise. Lab-
lung transplantation. An infiltrate on chest x-ray may be oratory testing may or may not be useful in the acute
from rejection or infection. The sputum Gram stain is phase of rejection. Drug interactions and sepsis can affect
helpful to look for acute bacterial pathogens, but viral liver function tests and should be high on the list of diag-
infections and rejection cannot be diagnosed by this tech- nostic possibilities (Table 8-8).
nique. Additionally, contamination from the native lung, In severe rejection, there are abnormalities of the liver
in a single-lung transplant patient, may negate the useful- function tests. In ductopenic rejection, a more chronic
ness of a sputum sample. process affecting the biliary tree, elevation of the serum
bilirubin and alkaline phosphatase are useful parameters
to measure.
Heart
Diagnostic Testing
The diagnosis of acute cardiac rejection is made by
endomyocardial biopsy. However, a patient presenting
Measurement of serum chemistries, a complete blood
with increasing dyspnea, enlarging cardiac silhouette, or
count, and cyclosporine level (ifavailable) should be per-
evidence of cardiac failure would be assumed to have
formed on all patients, realizing that the immunosuppres-
rejection until proven otherwise. Arrhyhmias (both atrial
sive medications influence laboratory values (Table 8-8).
and ventricular) may be a harbinger of rejection. Brady-
For patients on azathioprine, a normal white blood count
cardia may be a sign of impending death or asystole.
(WBC) may be 3000 to 4000; a WBC of 7000 may reflect
Patients with heart rates below 70 bpm should be evalu-
an infectious process. With renal and pancreas trans-
ated promptly until further information is obtained. Iso-
plants, an abdominal ultrasound is useful. In lung and
proterenol may be necessary to treat a patient with brady-
heart patients, a good-quality chest x-ray (PA and lateral),
cardia and hypotension. The vast majority of cardiac
should be obtained and an electrocardiogram is important
transplant patients have a right bundle branch block pat-
in heart and heart/lung transplant recipients.
tern on their electrocardiograms (ECG) from the time of
After thorough evaluation, including a history physical
transplantation (Table 8-8). The denervated heart often
examination, and review of laboratory and diagnostic
has a resting sinus tachycardia that clouds the interpreta-
studies, it is essential to discuss the patient's case with the
tion of heart rate as a sign of rejection, heart failure, or
transplant center. Signs and symptoms of rejection and
infection. Sinus tachycardia is a physiologic rhythm and
infection as well as other illnesses are easily misinter-
should never be directly treated since it maintains cardiac
preted. Patients tend to look healthier than they are and
output and is a response to concomitant illness.
their appearance may hide a serious impending illness. In
Dyspnea may be the only symptom of rejection, infec-
tion, or myocardial ischemia since patients usually do not
all immunosuppressed patients, infections can progress
with alarming rapidity.
experience chest pain. Patients with a transplanted heart
can have an acute myocardial infarction, but the destruc-
tive process of cardiac vasculopathy primarily targets the Transfer and Tlansport of Rejection Cases
small perforating arterioles of the heart. Thus, significant
myocardial ischemia may occur without the classic find- Communication with the transplant center can deter-
ings of infarction. In a minority of patients, nerve mine the necessity of transfer of patients with an acute
 IN.trrtuNs Svsrrn Dlsonnnns / 417

problem. Stabilization in the ED and initiation of treat- mediated phenomenon. A nearly identical clinical syn-
ment may be required. For acutely ill patients, the current drome known as an anaphylactoid reaction does not
or recent use of prednisone should be ascertained to require previous exposure. It immediately follows an
decide if stress doses of steroids are required. The treat- exposure to an inciting substance. Anaphylactoid reac-
ment of acute rejection is augmentation of immunosup- tions involve the same mediators implicated in anaphy-
pressive agents, either as an inpatient or as an outpatient, laxis but is not IgE mediated. In the clinical setting, the
depending on patient stabiliry history, and organ func- term anaphylqxis is often used to describe both types of
tlon. phenomenon. In this chapter anaphylaxis will be used to
represent both conditions unless otherwise specified.
A variety of substances including foreign proteins and
Special Precautions drugs can elicit anaphylaxis. In the classic mechanism
exposure to a foreign substance, either in isolation or
Patients with transplanted organs may present with bound as a hapten to a carrier protein, elicits the genera-
local or systemic infections. Due to the possibility of tion of an IgE antibody. The antibody binds to receptors
cytomegalovirus, pregnant workers should not be on mast cells and basophils. The receptors are activated
exposed to patients if this infection is suspected. Health on reexposure and mediators are released causing the
care workers with upper respiratory infections should not of anaphylaxis. Certain other
clinical manifestations
be given direct patient responsibility due to the patients agents, such as radiocontrast, can directly trigger media-
vulnerability to viral infections. Hand washing before tor release. A third mechanism that may produce anaphy-
and after examining the patient is essential. laxis involves complement activation after exposure, with
Institutional water may be contaminated with
subsequent generation of mediators known as anaphyla-
Legionella, so transplant recipients should be given ster- toxins. For some substances, exposure leads to anaphy-
ile water to drink. It is important to maintain the patient's laxis with no clearly identified mechanism (NSAIDs are
schedule of immunosuppressive drugs and administer one example). In addition, in the entity known as idio-
medicines on time, even while they await the completion pathic anaphylaxis, no inciting agent can be identified.
of their evaluation in the ED. Appropriate cultures for The most commonly implicated medical agents that
bacterial, viral, protozoal, and fungal pathogens should cause anaphylaxis are antibiotics. Penicillins and
be obtained before instituting therapy. cephalosporins are the most often cited. Reactions are
much more common after parenteral administration and
SELECTED READING are more severe than those that follow oral exposures.
Approximately I in 5000 exposures leads to anaphylaxis.
Paul LC. Chronic rejection of organ allograft: magnitude of the problem. More than 100 deaths per year are reported. Approxi-
Tran s P ro c 1993 :25 :2022-2023.
Trulock EP. Management of lung transplant rejection. Chest
mately l0% of patients sensitive to penicillin may have
1993;103:1 566-1 576. cross-sensitivity to cephalosporins, even with no history
Wiesne RH. Advances in diagnosis, prevention, and management of hepatic of previous cephalosporin exposure. Aspirin and NSAIDs
allograft rejections. CIin Chem 19941'401 1 1(9):217 4-2185.
are common causes of medication-induced anaphylaxis.
Radiocontrast media administered intravenously may
HYPERSENSTTIVITY (8.8) cause an anaphylactoid reaction that is clinically very
similar to true anaphylaxis, although it is not IgE medi-
Anaphylactic/Anaphylactoid Reactions (8.8.1) ated and does not require previous exposure. One to two
percent ofpatients experience reactions, but fatalities are
The term anaphylaxis was first used 1902 to in rare. The use of low molecular weight contrast media or
describe a paradoxical reaction to an immunization pro- pretreatment with antihistamines and steroids leads to
tocol in which dogs repeatedly injected with an allergen lower rates of anaphylaxis. Gastrointestinal administra-
developed increased sensitivity rather than immunity. tion ofcontrast is an unlikely cause ofanaphylaxis.
Later, it became clear that the phenomenon required an Hymenoptera stings are the most common environ-
initial exposure to an allergen followed by a delay of days mental cause of anaphylaxis. The rate of reactions is not
to weeks before the reaction could be elicited by reexpo- well established. The fatality rate is low, with less than
sure. Subsequently it has been demonstrated that the clin- 100 deaths occurring per year in spite of the large num-
ical features of anaphylaxis are mediated by activation of bers of exposures. Less serious allergic reactions (e.g.,
antigen-specific IgE attached to mast cells and basophils' urticaria, local reactions) are also very common with
When reexposed to the allergen, IgE causes the release of stings. Foods are another common cause of anaphylaxis.
mediators from mast cells and basophils. These mediators Most cases are mild, but fatal anaphylaxis due to foods
are responsible for the observed clinical manifestations. has been reported. Nuts and seeds, legumes, shellfish,
The classic anaphylactic reaction is thus an immune- and chocolate are common offending agents.
418 / ErvrencnNcy MrolcrNr: Tnr Coru CunxrculuM

The major physiologic events in anaphylaxis include The diagnosis of anaphylaxis is clinical and based on
increased mucous secretion, bronchospasm, decreased the observation of the typical features. When these are
vascular smooth muscle tone, and increased capillary associated with a history of exposure to a foreign sub-
permeability. Mucous secretion and bronchospasm are stance, the diagnosis is virtually certain. Cutaneous reac-
responsible for the signs and symptoms of shortness of tions, airway obstruction, bronchospasm, cardiovascular
breath, chest tightness, tachypnea, wheezing, and effects, or GI symptoms may occur singly or in any com-
hypoxia. Airway mucosal edema also contributes to res- bination. Diagnostic confusion may occur when cuta-
piratory difficulty. Decreased vascular smooth muscle neous manifestations are lacking. Anaphylaxis should be
tone and increased capillary permeability can cause car- considered when a patient presents in shock or syncope
diovascular collapse. Many of the clinical and physio- without an obvious cause.
logic manifestations of anaphylaxis can be explained by The differential diagnosis of acute airway obstruction
the actions of histamine released from mast cells. Ele- includes infections of the upper airway and foreign body
vated plasma histamine has been measured in patients aspiration. The history and physical examination usually
experiencing anaphylaxis. Additional mediators have also allow these to be differentiated. Angiotensin-converting
been implicated and include leukotriene Cq, enzpe (ACE) inhibitors nray cause angioedema of the
prostaglandin D2, and tryptase. upper airway, and this diagnosis should be considered in
The degree of sensitivity and the dose, route, and rate patients taking these medications who develop facial or
of administration of the offending agent determine the airway swelling. Treatment for this condition is similar to
timing of onset of an anaphylactic reaction. Large, intra- that for anaphylaxis. Status asthmaticus may mimic the
venous doses are most likely to produce immediate, lower airway manifestations of anaphylaxis, but a history
severe reactions. Most reactions occur within minutes to of asthma is almost always present and a history of expo-
hours, but symptoms may be delayed up to 3 days after an sure less likely. Myocardial infarction can cause hypoten-
oral exposure. It is a generally accepted clinical maxim sion, pulmonary congestion, and changes in mental sta-
that the more rapidly the symptoms develop, the more tuS, but is usually accompanied by typical chest
severe the reaction is likely to be. A biphasic reaction in discomfort and ECG changes. Pulmonary embolism can
which recurrent symptoms develop hours after initial cause respiratory distress and shock, but symptoms are
improvement has been described. The incidence is not usually limited to the respiratory system and the lungs are
precisely known, but has been reported in up to 20o/o of usually clear. Chest pain is often present and there are
cases of severe anaphylaxis. Biphasic reactions are asso- often risk factors for deep venous thrombosis. Hereditary
ciated with a delayed onset of symptoms after initial angioedema is due to a deficiency of the enzyme C1
exposure. esterase inhibitor. It can cause airway obstruction,
Airway obstruction from upper airway edema is the angioedema, and GI symptoms. The GI symptoms are
most cornmon cause of death in anaphylaxis. Bron- often prominent and there may be a family history.
chospasm with wheezing, shortness of breath, and chest Urticaria does not occur and cardiovascular effects are
tightness are lower airway manifestations of anaphylaxis. not noted.
Respiratory failure can occur. Cardiovascular abnormali- The symptoms of scombroid fish poisoning are very
ties are responsible for the remaining major clinical man- similar to those of anaphylaxis. They occur when spoiled
ifestations of anaphylaxis. Hypotension is common and fish with a high histadine content are ingested. The histi-
thought to result from increased vascular permeability dine is broken down to histamine and this is responsible
with intravascular volume depletion and vasodilation. for the symptoms. Exposure to monosodium glutamate
Frank cardiovascular collapse may occur with profound (MSG) can cause flushing, chest discomfort, and nausea
hypotension leading to confusion, syncope, or seizures. in individuals susceptible to the "Chinese restaurant"
While ECG changes of ischemia may be seen, there is no syndrome. Headache is common and urticaria does not
evidence that mediators have direct cardiotoxicity. The occur. Patients may present with respiratory distress, stri-
cardiac effects are probably secondary to ischemia, dor, and inability to swallow due to globus hystericus. In
resulting from volume depletion, loss of vascular tone, this condition there is no identified pathology on indirect
hypotension, and decreased oxygen delivery. or fiber optic laryngoscopy. Globus hystericus is a diag-
The clinical picture of anaphylaxis almost always nosis of exclusion and may be a form of Munchausen's
involves the skin. One or more manifestations of pruritis, syndrome.
erythema, urticaria, or angioedema are noted in more Prehospital assessment and stabilization of patients
than 900/o of patients. Mucosal edema and erythema of with signs and symptoms of anaphylaxis begin with stan-
the nose, eyes, or mouth may also be seen with resultant dard interventions provided to all patients with poten-
tearing, itching, nasal congestion, and sneezing. The GI tially serious conditions. After airway patency is assured,
tract is also effected. Symptoms of abdominal pain, nau- high-flow oxygen and cardiac monitoring should be
sea, vomiting, and diarrhea are often observed. Visceral applied. Intubation, if needed, may be difficult due to air-
congestion is a common finding at autopsy. way edema. Bag/mask ventilation may be effective as a
 IulruNr Sysrrru Drsonnr,ns / 419

temporizing measure while drugs are administered. Sur- are predominantly cardiovascular. Hypertension and dys-
gical airway intervention may be needed in rare cases. A rhythmias occur, predominantly when the intravenous
large bore intravenous line with isotonic crystalloid solu- route is used in patients with preexisting cardiac disease
tion is advisable, even for a normotensive patient. or hypertension. Malignant dysrhythmias, myocardial
Hypotensive patients should receive vigorous fluid infarction, and death have been reported, especially after
resuscitation. An initial bolus of I L for adults or 20 intravenous use in patients older than 50 years. Dosages
mg/kg for children is often appropriate. In patients with for epinephrine and other drugs are noted in Table 8-9.
known or suspected cardiac or renal disease, fluid resus- Patients taking p-receptor blocking agents may be resis-
citation should be cautious. A systolic blood pressure of tant to the pressor effects of epinephrine. Glucagon may
80 to 100 mm Hg is acceptable in adults. The mainstay be effective as a treatment of refractory hypotension in
of management is pharmacologic. Epinephrine is the pri- these patients, due to positive inotropic and chronotropic
mary agent and should be available on all advanced life effects that are not mediated by p- receptors. Inhaled p-
support ambulances. Many patients with a history of agonists are useful as secondary therapy for bron-
Hymenoptera sting or food-induced anaphylaxis have an chospasm. Upper airway edema may respond to nebu-
epinephrine autoinjector. If epinephrine is not available lized racemic epinephrine. Antihistamines and
on the ambulance, the patient's autoinjector should be corticosteroids are not primary agents in serious anaphy-
sought and used. lactic or anaphylactoid reactions. While some authors
Epinephrine increases intracellular production of have theorized that corticosteroids decrease the incidence
adenosine 3',5'-cyclic monophosphate (cAMP) in mast or severity ofbiphasic or protracted reactions, this has not
cells and basophils with resultant inhibition of mediator been verified. Antihistamines seem to affect predomi-
release. In addition, epinephrine is a physiologic antago- nantly the cutaneous manifestations of anaphylaxis,
nist to the vasodilatory, bronchoconstricting, and cuta- although in theory histamine-induced vasodilatation
neous effects of histamine and other mediators. It there- should also respond. While both the Hr and H2 effects of
fore counteracts bronchospasm, hypotension, urticaria, histamine may play a role in anaphylaxis, H1 blocking
and angioedema. Subcutaneous administration is recom- agents have a more logical role and should be used first.
mended except for patients in profound shock, in which Some authors have suggested a role for Hz blockers in
case epinephrine may be given intravenously. Sublingual prevention of biphasic or protracted reactions, but this
injection is an alternative for patients in severe distress has not been verified. Corticosteroids are useful in treat-
who lack IV access. The adverse effects of epinephrine ment of bronchospasm and urticaria. The slow onset of

TABLE 8"+9. Pharmacologic treatment of anaphylaxis

Drug Dosage lndications Side effects
p-Agonists
Epinephrine Adults: 0.3m1 1:1000 dilution SQ q 15 min Shock, angioedema, airway Tachycardia,
or 1.0 ml 1:10,000 dilution slow lV obstruction, bronchospasm, hypertension,
Children: 0.01 ml/kg 1:1000 dilution urticaria tremor
SQ q 15 min or 0.01 ml/kg 1:10,000
dilution slow lV
Albuterol Adults:0.5 ml of 0.5% soln in 2.5 ml NS Bronchospasm Tachycardia,
nebulized q 15 min tremor,
Children:0.03 ml/kg of 0.5% disrythmias
soln via nebulizer q 15 min
Antihistamines
Hr-blocker Adults: diphenhydramine, 25-50 mg lV Hypotension, urticaria Sedation,
lM, or po q6-8h dry mouth,
Children: diphenhydramine, 2 mg/kg lV, urinary
lM, or po q6-8h retention
Hz-blocker Adults:cimetidine, 300 mg lV or po q6h
Children: cimetidine, 5-10 mg/kg lV or
po q6h
Corticosteroids
Hydrocortisone Adults:250-500 mg lV q6h Bronchospasm, urticaria, possible Edema,
Children:5 mg/kg lV q6h modification biphasic reactions hyperglycemia
Methylprednisolone Adults: 40-125 mg lV q6h
Children: 1-2 mg/kg lV q6h
Other agents
Glucagon Adults: 1-2 mg slow lV or lM Shock, for patients with beta-blockade Nausea
Children: dosage not established,
adult dose is equivalent to 150 mcg/kg
 420 / EurRcrNcy MrorcrNr: Tsr Conr Cunnrculul,r

action of corticosteroids and their lack of effect on the testinal tract. Causes of angioedema include those listed
cardiovascular manifestations of anaphylaxis make them for urticaria. In addition, there is an inherited form of
second-line agents. angioedema known as hereditary angioneurotic edema
Pretreatment with antihistamines and corticosteroids (HAE). HAE is inherited as an autosomal dominant but
prevents or ameliorates reactions to intravenous contrast may also occur sporadically. It is caused by a deficiency
agents. Prior to administration of contrast to patients at of the enzyme Cl esterase inhibitor. This deficiency
high risk of an anaphylactoid reaction, pharmacologic results in an inappropriate activation of the complement
prophylaxis should be administered with antihistamines pathway with the resultant clinical manifestations of
and corticosteroids. There are also short-term desensiti- angioedema.
zation regimens effective in preventing reactions to peni- Urticarial lesions are also known as hives. The lesions
cillin antibiotics. These should be considered when a are red and raised and vary in size from very small (papu-
patient with a history of a serious anaphylactic reaction lar urticaria) up to many centimeters (giant urticaria).
requires penicillin as a first-line agent for a life-threaten- There may be only a few, small lesions or they may be
ing infection. numerous and become large and confluent. Urticarial
Most patients treated in the ED for anaphylaxis lesions are pruritic. The individual lesions are evanescent
respond rapidly to treatment, but patients with persistent and tend to first enlarge and then resolve over several
manifestations involving the cardiovascular or respiratory hours with new lesions occurring at other locations.
systems require admission for further treatment and When lesions are fixed in one location and persist for
observation. Published materials regarding the majority more than 24 hours, the diagnosis of vasculitis should be
of patients who respond to treatment also recommend a considered. Urticarial lesions may occur on any part of
period of observation up to 24 hours. These recommen- the body. The deeper lesions of angioedema are nonpit-
dations are based on the occurrence ofa second phase of ting and are often nonpruritic. Angioedema may involve
the anaphylactic response occurring 4 to 8 hours after the the face, oral cavity, palms, soles, and genitalia. Airway
initial stimulus. Anaphylaxis with a delayed second phase compromise can result from edema of the tongue or phar-
is known as biphasic anaphylaxis and is reported in up to ynx. In HAE, symptoms of abdominal pain, nausea, and
20%o of cases. Prevention of biphasic anaphylaxis with vomiting are common and result from localized edema of
corticosteroids is theoretically attractive, but the true the gastrointestinal mucosa. The diagnosis of urticaria is
incidence ofbiphasic anaphylaxis and the efficacy ofcor- based on the history and observation ofthe characteristic
ticosteroids is not well established. Given the lack of skin lesions. Angioedema is diagnosed by observing the
definitive data, hospital admission for patients with air- typical pattern of asymmetric, nonpitting edema. Patients
way compromise or hypotension represents the most con- with HAE and abdominal pain usually carry the previous
servative approach and is therefore advised. Other diagnosis of HAE. Other causes of abdominal pain must
patients may be considered for discharge after a period of be ruled out.
observation. Most cases of urticaria are idiopathic. Specific causes
include many drugs and foods. Commonly implicated
drugs include the penicillins and sulfonamide antibiotics,
Angioedema and Urticaria (8.8.2) salicylates, other NSAIDs, insulin, codeine, and other
narcotics. Food substances associated with urticaria
Urticaria is a common cutaneous condition also known include shellfish, chocolate, aged cheeses, peanuts, and
as hives. Three major mechanisms of pathogenesis have many others. Viral infections including hepatitis, vari-
been described. Most commonly, urticaria is a manifesta- cella, and infectious mononucleosis are frequently asso-
tion of acute IgE-mediated hypersensitivity. As with the ciated with urticaria. Occult infections such as sinusitis
classic anaphylaxis, IgE-mediated urticaria occurs when and prostatitis may also precipitate urticaria. Physical
a sensitized host is reexposed to an antigen. Preformed urticaria may also occur due to a variety of physical stim-
mediators are then released from mast cells and uli including cold, heat, pressure, or sun exposure.
basophils. Histamine is the primary mediator. As with Urticaria may occur as a local allergic phenomenon at the
anaphylaxis, urticaria also may be caused by comple- site of exposure to an allergen. Acquired (e.g., nonhered-
ment-mediated reactions or specific drug reactions, or itary) angioedema is most often idiopathic. The ACE
may be idiopathic. Physical agents such as cold, sun inhibitors used for treatment of hypertension and conges-
exposure, and pressure also cause urticaria. Urticaria is tive heart failure may cause angioedema by an unknown
characteized by superficial dermal edema and vascular mechanism.
dilation with capillary leakage of plasma. Angioedema After the diagnosis is established, the ED evaluation of
can be regarded as a more severe form of urticaria. It is urticaria or angioedema is aimed at differentiating among
characterized by vasodilation and exudation of plasma common possible causes by the history and physical
into the deeper layers of the dermis and may also occur examination. Laboratory testing is not usually part of this
on the mucosal surfaces of the respiratory or gastroin- evaluation unless the history or physical points to an
 Ivttr,tuNn Svsrnrr,t DlsonnpRs / 421

underlying systemic illness. Important historical factors tion, drainage, and sneezing. Conjunctivitis is a com-
include exposure to commonly implicated agents and monly associated symptom. The pathophysiology
other inciting factors. Patients should be questioned involves sensitization and reexposure of mucosal mast
about the signs and symptoms of either systemic or local cells to an environmental allergen. Allergic rhinitis may
infections. The past history should include questions occur in a seasonal or perennial pattern. In the seasonal
about previous episodes and any previous evaluation. A form pollen is the inciting allergen and the condition
family history of similar episodes suggests HAE. The tends to reoccur at the same time each year. In perennial
physical should seek signs suggesting that the urticaria is allergic rhinitis, dust, dander, or chemical exposure may
a manifestation of a more severe episode of systemic ana- elicit symptoms at any time.
phylaxis. Airway patency should be assured and hlpoten- The diagnosis of allergic rhinitis is based on the history
sion or tachycardia regarded as possible indications of and the presence of characteristic symptoms. Typical
anaphylaxis. The symptoms of faintness, dizziness, or findings on physical examination include swollen, pale,
syncope are also indications of a possible anaphylactic boggy nasal mucosa. There may be associated conjunc-
reactlon. tivitis, but systemic signs and symptoms are lacking. The
The treatment of urticaria and angioedema is empiric main differential diagnosis is upper respiratory tract
and symptomatic. If potential inciting agents are identi- infection, which is not seasonal and is unrelated to envi-
fie4 further exposure should be avoided. Mild cases of ronmental factors. Upper respiratory infections are usu-
urticaria or angioedema may be treated with an oral anti- ally associated with systemic symptoms of fever, malaise,
histamine alone. Parenteral routes may be utilized for a and myalgias.
more rapid effect. Typical regimens are either diphenhy- Symptomatic treatment of allergic rhinitis consists
dramine (Benadryl), 25 to 50 mg, or hydroxyzine (Vis- mainly of antihistamines. The newer nonsedating agents
taril, Atarax) 25 mgevery 6 hours until the symptoms are are effective, but are more expensive than older Hr block-
resolved. Severe cases of urticaria with generalized hives ers. Nasal corticosteroids are also expensive but are
and severe itching or angioedema involving the upper air- effective and have few adverse effects. Topical nasal
way should be treated with both subcutaneous epineph- decongestants are effective, but tachyphylaxis and
rine and a parenteral antihistamine. Epinephrine often rebound nasal congestion limit their utility. Perennial
produces dramatic relief. Doses are outlined in Table 8-9. rhinitis also responds to antihistamines but is best treated
Corticosteroids are often used in the treatment of acute by avoiding inciting agents. If allergens cannot be
urticaria and angioedema but should be considered sec- avoide4 immunotherapy may be effective.
ond-line agents. Hz blockers have also been used but
their efficacy is unproven. Insect stings may cause reac-
tions that are purely local (swelling and itching adjacent Drug and Food Allergies (8.8.4)
to the sting) or progress to generalized urticaria or ana-
phylaxis. Urticaria and anaphylaxis are treated in the Allergic reactions to foods and food additives are com-
usual manner. Local reactions may be treated with ice and mon. Nuts, eggs, legumes, chocolate, peanuts, and dairy
antihistamines. products are often implicated. Most reactions are medi-
Most patients with urticaria or angioedema may be dis- ated by IgE-coated mast cells, which line the mucosa of
charged for outpatient follow-up. Patients with airway the GI tract. After prior sensitization, ingestion of the
involvement or possible anaphylaxis should be consid- allergen causes release of histamine and other mediators.
ered for observation. When a patient experiences gener- Non-IgE-mediated reactions may also occur.
alized urticaria or anaphylaxis as a result of an enveno- The diagnosis offood allergies depends on the history'
mation, they are at risk of anaphylaxis on subsequent Prior reactions are usual. Many patients give a history of
exposure. They should be instructed to avoid situations multiple allergic symptoms. The most common symp-
likely to lead to an exposure, and consideration should be toms of food allergy are limited to the GI tract. Crampy
given to prescribing an epinephrine autoinjector. When abdominal pain, nausea with or without vomiting, and
angioedema is associated with ACE inhibitor use, the local swelling of the lips, tongue, and pharynx are
drug should be discontinued and an agent from another observed. Occasionally, generalized urticaria or anaphy-
class of antihypertensives selected. laxis are seen. Treatment is symptomatic, with antihista-
mines used for mild symptoms and epinephrine for
severe urticaria or anaphylaxis. Ifthe offending agent can
Allergic Rhinitis (8.8.3) be identified" avoidance should be advised as a preventa-
tive measure.
Allergic rhinitis is an antibody-mediated reaction Drugs are commonly implicated in allergic reactions.
localized to the nasal mucous membranes. It is very com- Most drugs are not true allergens but function as haptens.
mon in adolescents with a reported prevalence of up to When the drug molecules are bound to plasma proteins,
25%. The clinical manifestations include nasal conges- they may become immunogenic. Many adverse allergic
 422 / Etrnncrucy MeuclNn: Tnn Conr CunnrculuM '

effects are not immunologically mediated but mimic true tions of serum sickness typically begin I to 3 weeks after
allergic reactions. ACE inhibitor associated angioedema the initial exposure to an agent and may occur much
and reactions to IV contrast are prominent examples. sooner (12 to 36 hours) ifthere has been prior sensitiza-
Penicillin is the most commonly implicated drug in tion. Typical signs and symptoms include fever, malaise,
severe allergic reactions, but allergy to almost any drug arthralgias, and cutaneous rashes. Gastrointestinal symp-
can occur. The clinical manifestations and treatment of toms, lymphadenopathy, and proteinuria also occur but
acute drug allergy does not differ from other acute aller- are less common. The skin eruption may be morbiliform
gic reactions. Topical reactions may be treated by avoid- or urticarial and is often confined to the trunk, though it
ance and topical corticosteroids or oral antihistamines. may be generalized. Less often, frank arthritis or vasculi-
Generalized urticaria or angioedema is treated using anti- tis may occur. Vasculitis may affect the kidney, central
histamines with epinephrine added in more severe cases. nervous system, and the coronary arteries.
When an allergic reaction occurs in the setting of expo- The diagnosis ofdrug-induced serum sickness is based
sure to a likely offending agent, patients should be coun- on the clinical presentation and a history ofexposure to a
seled regarding avoidance. likely offending agent. Laboratory tests to detect circulat-
ing immune complexes are available but are not helpful
Serum Sickness (8.8.5) during the initial patient encounter in the ED. Drug-
induced serum sickness typically resolves within days of
Serum sickness provides the classic model of an withdrawal of the offending drug, so no specific treat-
immune-complex disease and is most often caused by ment is usually needed. Antihistamines may provide
drug hypersensitivity. When an allergen is introduced relief from the cutaneous manifestations. Corticosteroids
into a sensitized individual, it binds to specific antibody are recommended for severe cutaneous manifestations or
and immune complexes are formed. Usually, these
if there is significant vasculitis. Acetaminophen may be
immune complexes are cleared by the reticuloendothelial used for arthralgias and fever.
system without complications. When the immune com-
plexes exceed a certain size and are present in large SELECTED READING
amounts they may be deposited in tissues with resultant
inflammation and tissue damage. The kidney, joints, Atkinson TP, Kaliner MA Anaphylaxis. Med Clin North Am 1992;76(4):
841.
skin, and blood vessels walls are the tissues usually Austen KL Diseases of immediate type hypersensitiviry In: Wilson JD, et
affected. al. Harrisonb principles of internal medicine, 12th ed. New york:
In drug-induced serum sickness, drug molecules act as McGraw-Hill, 1991.
B Med 1991;324(25):1755.
s. N Engt J
haptens with resulting sensitization and formation of spe- C Immune complex disease in experimental animals
cific antibody. On reexposure, immune complexes form / 1963;16:185.
Greenberger PA. Contrast media reactions. J Allergy CIin Immunol 19g4;
and serum sickness may result. Implicated agents include
74:600.
sulfonamides, penicillins, diphenylhydantoin, and thi- Lawley TJ, Frank MM. Immune-complex diseases. In: Wilson JD, et al.
azides. Blood products may also cause serum sickness. Harrison's principles of internal medicine, l2th ed. Newyork: McGraw-
Serum sickness and late-onset anaphylaxis has also been Hill, 1991.
Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J Altergy Ctin
reported to occur after insect stings. Clinical manifesta- Immtmol 1986;78:76.
CFIAPTER 9

Systemic Infectious Disorders

Gregory A. Volturo
Systemic Infectious Disorders (9.0); Meningococcemia (9.1.5); Plague (9.1.6); Spirochetes
(9.1.9); Rocky Mountain Spotted Fever (9.4.1); Ehrlichiosis (9.4.2)
Thomas Germano
Botulism (9.1.1); Gonococcal Disease (9.1.2); Sepsis (9.1.3); Mycobacterial Diseases (9.1.a);
Spirochetes (9.1.9) ; Slphilis (9.1.9.2)
Valerie Schevon Nicoletti
Chlamydia (9.1.10);Human ImmunodeficiencyVirus (9.5.1);Herpes SimplexVirus (9.5.10)
AjeetJ. Singh
Tetanus (9.1.7);Toxic Shock Syndrome (9.1.8); Infectious Mononucleosis (9.5.2);Influenza
(9.5.3); Mumps (9.5.4); Poliomyelitis (9.5.5); Rabies (9.5.6)
Laura Peterson
Malaria (9.3.1);Toxoplasmosis (9.3.2);American Trypanosomiasis (Chagas' Disease);African
Trypanosomiasis; Rubella (9.5.7); Roseola (9.5.8);Varicella-Zoster (9.5.9)

SYSTEMIC TNFECTTOUS DTSORDERS (9.0) whether to admit a patient to the hospital or arrange outpa-
tient therapy are often made in the ED. Culture and sensi-
While not as dramatic as trauma or cardiac care, the tivity results are usually not available, and as a result diag-
management of infectious diseases is vitally important to noses are presumptively based on clinical presentation.
the practice of emergency medicine. Illness resulting Treatment with antibiotics frequently is empiric. Many ED
from infection precipitates a large number of emergency patients do not have continuing care physicians, and they
department (ED) visits. Community acquired infections tend to be noncompliant with treatment and fail to return
in both pediatric and adult patients are primarily evalu- for follow-up, thereby affecting decisions about antibiotic
ated in the ED. Illness may range from benign self-limit- selection, dosage, and route of delivery.
ing conditions to more severe life-threatening infections. Emergency care providers have a relatively high expo-
Some infections may be routine and common, while oth- sure to communicable disease and must have a solid
ers are rare, elusive, or completely foreign to a specific knowledge regarding both treatment and prevention of
geographic area. Knowledge about all these diseases, disease. Human immunodeficiency virus (HlV)-related
however, is required by all emergency care providers. infections and the increasing incidence of tuberculosis
Infectious disease management issues facing emergency have further burdened the ED, requiring emergency
physicians are often different from those issues confronted physicians to have much more knowledge regarding
by physicians in other practice settings. The ability to dif- infectious diseases.
ferentiate between serious and minor illness based on data Lastly, with continued growth of managed care and
immediately available determines initial management as emphasis on cost reduction in medical care, the ED will
well as subsequent patient outcome. Decisions such as be key in developing and implementing new strategies to

423
 424 / EntncrNcy Mnorcrus: TFrn Conn CunnrculuM

manage more severe infections as an outpatient. While ciations are possible but have yet to be confirmed.
many infectious diseases are discussed throughout the Another possible risk factor is living in a rural or farm
text, this chapter discusses systemic infectious diseases community.
not covered elsewhere. Food-borne botulism has been associated with several
sources. As opposed to the infantile form, most cases of
BACTERTAL (9.1) the food-borne variety occur as a result of preformed
toxin. There is a well-known association of botulism and
inadequately processed canned foods. This has primarily
Botulism (9.1.1)
involved home-canned foods but several outbreaks ofthe
disease involving commercially canned foods are known
Botulism is a disease mediated through a protein exo-
to have occurred. While commercially and restaurant pre-
toxin that is produced by the bacteria Clostridium botu-
pared foods have been responsible for only a small per-
linum. Humans who contract the disease do so as a result
centage of outbreaks, they may represent a disproportion-
of the oral ingestion of preformed toxin or by the colo-
ate percentage of cases, since there is potential for any
nization of the gut or wounds by the causative organism.
one episode to involve multiple patients. Baked potatoes
The result is a syndrome characterized by autonomic dys-
that have been wrapped in foil have also been associated
function and muscular weakness, which may progress to
ventilatory failure and death. The disease is rare, the ini- with the disease as this may potentially create an anaero-
tial manifestations of the disease may be nonspecific, and bic environment suitable for the growth of the causative
symptoms may present with varying severity and rapidity,
organism. More unusual sources of botulism have
so proper diagnosis is frequently delayed resulting in included saut6ed onions, frozenpot pies, stew, and turkey
increased patient morbidity and mortality. In hopes of
loaf. The risk of botulism is increased in foods that are
not heated immediately prior to eating, as the toxin is heat
avoiding such delays, the emergency physician should be
labile.
knowledgeable about the pathophysrology of botulism
Wound botulism has been typically associated with
and the clinical situations where the disease should be
large, open contaminated wounds, especially if associ-
considered.
ated with devitalized tissue or compound fracture. There
is also an association recognized with IV drug use. Addi-
Etiology and Epidemiology tionally, it is an extremely rare complication of surgery.
This has been the rarest form of the disease with only
Clostridium botulinum is a gram-positive rod that is about 40 cases being reported in the English-language
obligately anaerobic and spore forming. The organism is literature prior to 1994. Colonization of the wound is
ubiquitous in soil and has worldwide distribution. The believed to occur with the subsequent production of exo-
spores are resistant to heat, desiccation, and radiation. toxin.
Sources of the bacteria and spores that have been impli- In a subset of patients no source of the toxin can be
cated in human disease have included contamination of identified. It is thought that an underlying gastrointestinal
open wounds by soil or other organic material, and abnormality predisposed some patients to GI coloniza-
ingestion of fruits, vegetables, fish, meats, and honey. tion by the organism similar to that in the infantile form
The disease has several forms including infantile botu- of the disease. It is believed that the normal intestinal
lism (the most common form), food-borne botulism, flora of the adult gut is protective and thus the infantile
and wound botulism. All human disease is mediated form of the disease generally does not occur in adults.
through an exotoxin produced by the bacteria, which Alteration in the normal flora may predispose the patients
acts to prevent the release of the neurotransmitter to colonization by clostridia with subsequent production
acetylcholine. of toxin.
Infantile botulism has been recognized since 1976. It
may affect children from several days to over a year of
age. While the disease has proven elusive for many years, Pathop hy sio logy and D iag no s is
several things have been made clear. The disease is more
common in breast-fed infants but for unknown reasons it Regardless of how the toxin is produced, the mecha-
seems to have a somewhat attenuated course when it nism for its action is the same. The exotoxin is a protein
occurs in bottle-fed infants. This may have to do with the that irreversibly binds the presynaptic membrane at the
varying Gl chemistry and bacteriology found in bottle- cholinergic neural junction. This has effects at the neuro-
fed versus breast-fed infants. In one study, while the muscular junction as well as at the ganglionic level of the
ingestion of honey was statistically significantly associ- sympathetic nervous system and at the pre- and postgan-
ated with the development of botulism, only 16% of glionic level of the parasympathetic nervous system.
infants with botulism had ingested honey. IJp to 25%o of Thus the typical symptoms of the disease ensue: motor
honey has been shown to contain spores. Other food asso- weakness and autonomic dysfunction. In the case of
 Svsrnrr,uc INrncrrous DnonorRs / 425

food-borne botulism the toxin is usually ingested, TABLE 9-1. Differential diagnosis
of botulism
whereas in wound and infantile botulism the toxin is
formed within the body of the host as a result of colo- Acute alcohol intoxication
nization with the causative organism. Hypermagnesemia
Hypocalcemia
In cases of food-borne botulism the onset of clinical Carbon monoxide poisoning
illness is usually within hours to a couple of days of Basilar artery thrombosis
ingestion of the toxin. An antecedent prodrome of nausea Sepsis
and vomiting may occur. This is followed by bulbar Meningitis/encephalitis
symptoms of blurred vision, diploplia, ptosis, dysarthria, Guillain-Barr6 syndrome
Eaton-Lambert syndrome
and dysphagia. These symptoms are followed by a Tick paralysis
descending paralysis that first involves the upper extrem- Myasthenia gravis
ities then the lower extremities. This descending type of Muscular dystrophy
paralysis occurs in all forms of the disease and helps to Poliomyelitis
distinguish botulism from other forms of weakness. Congenital myopathies
Heavy metal poisoning
Autonomic symptoms include dryness of the mouth, Organophosphate poisoning
pupillary abnormalities, urinary retention, and constipa- Saxitoxi n/tetrodotoxi n
tion. Milder forms of the disease may occur with only Hypothyroidism
bulbar symptoms noted. In addition to the findings
above, the physician may find diminished deep tendon
reflexes. Situations where multiple patients are affected;
action potential during repetitive stimulation and a
especially if they are known to have eaten together,
diminished response to a single stimulus. The edropho-
should cause the physician to consider the diagnosis more
nium challenge test may cause partial improvement in
seriously. A history of having eaten home-canned goods
the patient with botulism and is therefore not helpful in
is particularly suggestive.
distinguishing botulism from myasthenia gravis.
In wound botulism the onset of the symptoms may be
Hyponatremia may occur as a result of the associated
delayed up to 3 weeks, although the average length of
syndrome of inappropriate secretion of antidiuretic hor-
incubation is about I week. The onset of symptoms may
mone (SIADH).
be as soon as several days. Diplopia is a frequent first
symptom. A history of an antecedent wound, especially if
associated with a compound fracture or devitalized tis- Treatment, Disposition, and Prevention
sue, should be sought. In this form of the disease the
organism may be cultured from the wound. The most formidable risk to the patient with botulism
The diagnosis of infantile botulism is particularly chal- is that of airway or ventilatory compromise. Thus
lenging. The early manifestations of this form of the dis- patients with suspected botulism should be admitted to
ease are frequently nonspecific and include constipation, an ICU setting to be closely monitored. Early intubation
poor tone, and poor suck. Constipation is present in the with active ventilation prevents unnecessary morbidity
majority of cases and may precede the other manifesta- and mortality. While the causative agent is known to be
tions of the disease by weeks. It is likely that the toxin sensitive to penicillin, antibiotic therapy has not been
itself slows GI motility. While sepsis is frequently con- shown to alter the course of the disease. It should be
sidered in the differential diagnosis, the infants are usu- remembered that in cases of food-borne botulism the
ally afebrile. The disease may be the cause of death in toxin is ingested and not formed in vivo. Thus in this
some cases of sudden infant death syndrome (SIDS). form ofbotulism there is not even a hypothetical argu-
Eventually in the course of the illness there appears the ment for the administration of antibiotics. The use of
typical descending paralysis with potential respiratory antitoxin, which is available from the Centers for Dis-
compromise. A history of honey ingestion should be ease Control (CDC), is controversial. It does appear that
sought. there is some benefit from its use in wound botulism.
The differential diagnosis of botulism is complex and Since the antitoxin only binds free toxin and has no
is summarized in Table 9-1. Laboratory testing may effect on already bound toxin, it can only slow the pro-
assist in the confirmation of suspected cases of the dis- gression of the disease.
ease; however, this frequently will not occur soon Recovery is the general rule for the patient with botu-
enough to be helpful for patient management. The toxin lism assuming the patient experiences no formidable
may be detected in blood or stool, the latter being help- complications during the illness. Clinical improvement
ful in cases of infantile botulism. Electromyogram occurs as a result of the synthesis of new receptors that
(EMG) may also suggest the diagnosis, but a normal are free of toxin. Prevention of this disease may be
EMG does not rule it out. Findings on EMG that ate enhanced by adequate food preparation, especially
consistent with the diagnosis include potentiation of the among home canners, and proper wound care. In addi-
 426 / ErrarncrNcy MrucrNr: THn Conn Cunnrculuu
tion,it has been recommended that infants under 12 sexes the disease may well remain asymptomatic. The
months of age not be given honey. disease appears to be more easily transmitted from male
to female during vaginal intercourse rather than vice
versa.
SELECTED READING

Burningham M, Walter F, Mecham C, et al. Wound botulism. Ann Emerg

Med 1994;24:1184-1 1 87. Pathophysiologt
Cherington M. Botulism. Semin Neurol 1990;10:(1);27-31.
Ferrari N, Weisse M. Botulism. Adv Pediatr Infect Dis 1995;10:81-91.
Jagoda A, Renner G. Infant botulism: case report and clinical update. Am J Neisseria gonoruhoeae are gram-negative cocci that
Emerg Med 1990;8:318-320. are round or oval in shape, characteristically growing in
MacDonald K, Cohen M, Blake P The changing epidemiology of adult bor pairs but sometimes singly. They are fastidiously aerobic,
ulism in the United States. Am J Epidemiol 1986;124:794-799.
Schmidt R, Schmidt T. Infant botulism: a case series and review of the lit- with optimal growth occurring in an environment of 2o/o
eralxe. J Emerg Med 1992;10:713-718. to 5oh COz. The organism is frequently covered by fim-
Schreiner M, Field E, Ruddy R. Infant botulism: a review of 12 yeart expe-
brae, which assist the organism in adhering to mucosal
rience at the Childrent Hospital of philadelphia. pediahics l99l;g7:
1 59-l 65. epithelial cells of the host. Several protein mediators of
Spika J, Shaffer N, Hargrett-Bean N, et al. Risk factors for infant botulism host inflammation are present in the bacterial cell wall.
in the United States. AJDC 1989:143:828-832.
These proteins vary and play a pivotal role in the avoid-
ance of the Neisseria to host immune defenses. An immu-
noglobulin A (IgA) protease secreted by the organism
Gonococcal Disease (9.1.2) appears to be important in overcoming secreted human
immunoglobulin. There are a number of clinical syn-
Gonococcal infections occur as a result of mucosal dromes that are caused by the organism that will be con-
colonization by sexually transmitted Neisseria gonor- sidered here.
rhoeqe. Nearly a million gonococcal infections occur in In the heterosexual male the usual manifestation of
the United States each year. While many of these are the disease is acute urethritis. The typical period of
localized to the site of entry, both locally invasive and incubation is 2 to 5 days. Complications of this initial
widespread disease may occur, leading to disastrous com- urethral infection include epididymitis, orchitis, and
plications. The clinical presentation of these patients in prostatitis. The degree of symptomatology that an indi-
the ED may range from classic urethritis in a sexually vidual experiences in likely related to the particular
active male to frank sepsis of uncertain etiology. The dis- gonococcal auxotype causing the infection as well as
ease may also be asymptomatic in some patients and host factors.
therefore only be discovered as a result ofscreening stud- In women the clinical manifestations of gonococcal
ies done on an at-risk individual. While the treatment of illness usually occur as a result of an initial infection of
gonococcal disease was once straightforward, in recent the cervix. It is estimated that about l5%o of patients with
years pJactamase-producing strains resulting in drug mucopurulent cervicitis will develop ascending genital
resistance have caused an increased number of treatment tract disease involving the uterus, fallopian tubes, ovaries,
failures. Since ED physicians are likely to encounter gon- or peritoneum. The clinical syndrome that encompasses
orrhea with a continued high frequency, a strong database these infections is termed pelvic inflammatory disease
with regard to the clinical presentation, diagnosis, and (PID). Infection that involves the fallopian tubes, in addi-
treatment is crucial. tion to placing the patient at risk for peritoneal infection,
also is responsible for the serious sequelae of PID, specif-
ically pelvic adhesions and chronic pain, infertiliry and
Epidemiology ectopic pregnancy. The risk of sterility has been estimated
to be as high as 25Yo for each episode ofgonococcal salp-
While gonorrheal disease may affect individuals of any ingitis with a concomitant sixfold increase in the risk for
age, it is most prevalent in young, sexually active indi- ectopic pregnancy. It should be remembered that pID
viduals, having a peak incidence in males at ages 20 to may be caused by organisms other than the Neisseriq
24; the peak incidence in females occurs one to several species, such as Chlamydia, and as such a diagnosis of
years earlier. Risk factors for the disease include being PID does not immediately implicate the gonococcus as
single, living in an urban area, being a homosexual male, the etiologic agent.
indigence, and prostitution. Sexual intercourse without Other acute complications of PID include Fitz-Hugh-
barrier contraception is also a risk factor for acquiring Curtis syndrome (perihepatitis) and the formation of
gonorrhea. Transmission of the disease between individ- tubo-ovarian abscess. In addition to the ascending genital
uals may occur without the knowledge of either party infection, localized infection may occur in the female
since the male or female with gonorrhea may transmit the urethra, Skene's glands, or Bartholin's glands manifesting
disease prior to the onset of symptoms and since in both as dysuria, labial edema, or abscess. Obstetrical compli-
 SysrsN4rc INrncuous Drsonorns / 427
cations of gonorrhea include septic abortion, premature history, and thus even without a suggestive history the
rupture of the membranes, preterm delivery, and possibility should not be ruled out. While most emer-
intrauterine growth retardation. gency physicians will consider the possibility in the
In either males or females other sites of mucosal infec- patient with genital tract complaints, the diagnosis of
tion may occur as a result of oral or anal sex. Rectal infec- gonococcal illness might not be appropriately consid-
tion with resultant proctitis is frequently associated with ered in the more atypical presentation such as rash or
a purulent discharge. Pharyngitis is frequently asympto- arthralgia.
matic but appears to be associated with a higher risk of The symptoms of the male with urethritis include
dissemination. The natural history in most patients with dysuria and urethral discharge. The discharge is usually
pharyngeal infection involves spontaneous resolution by purulent but may also be described as white, mucoid, or
3 months. Neisseria gonorrhoeae, which may be blind- cloudy. While the disease may cause intense dysuria, and
ing, is an infrequent but important cause of conjunctivitis discharge, perhaps 50o/o or more of males with culture
in both adults and neonates. When responsible for con- proven infection are asymptomatic or have minimal
junctivitis in the neonatal perio( the illness is usually symptoms for which they don't seek medical attention.
acquired at birth from the mother's genital tract and pre- The female patient with genital tract disease may have
sents within a week following birth. It usually presents as several complaints including vaginal discharge or bleed-
a bilateral conjunctivitis with edema of the cornea and an ing, pelvic or abdominal pain, dyspareunia, labial pain, or
exudate. dysuria depending on the site of infection. Physical
Disseminated gonococcal disease occurs as a result of examination may reveal cervical injection and friability, a
the hematogenous spread of the organism from its orig- mucopurulent cervical or vaginal discharge, labial
inal site of mucosal infection, resulting in distant infec- swelling or mass, or findings suggestive of PID. Low
tion. While this may theoretically involve any site, it abdominal tenderness, cervical motion tenderness, and
most typically presents as a migratory polyarthritis, adnexal tenderness are required for the diagnosis ofPID.
tenosynovitis, or a rash. Patients may present with all or Additional findings include fever >38"C, an elevated
only one of these entities. Rare but devastating sites of WBC count or sedimentation rate, a purulent cervical
dissemination include the heart, with resultant endo- discharge, a positive Gram stain for gram-negative intra-
carditis, and the meninges. Perihepatitis may occur cellular diplococci, and the presence of an inflammatory
unassociated with clinical PID as a result of dissemina- mass on examination or ultrasound.
tion. Pelvic inflammatory disease may present with a wide
The typical pattern of joint involvement is that of an range of clinical acuities from the patient who appears well
oligo- or polyarthralgia that is migratory or less com- to the toxic-appearing patient with severe abdominal pain
monly additive and may be associated with constitu- and fever. The differential diagnosis of the female in the
tional symptoms such as fever and chills. While any joint reproductive years with abdominal pain is complex. Other
is a potential site of involvement, the knees, elbows, acute abdominal conditions, particularly appendicitis, may
wrists, hands, and ankle are the more frequently affected be frequently difficult to distinguish from PID. Other
sites. Of these, the knee is the most common. Less than gynecologic emergencies such as ruptured ovarian cyst and
half of the patients with arthralgia have a proven septic ectopic pregnancy may also be mistaken for PID. While
arthritis. Only approximately one-third develop a syn- PID can and does occur in the pregnant patient, a new diag-
ovial effrrsion. Permanent joint destruction may occur. nosis of PID should be made with caution, especially in the
An associated tenosynovitis frequently occurs and usu- gravid patient of greater than about 12 weeks' gestation.
ally involves the dorsum of the hands and wrists, fingers, By this time in the pregnancy, the attachment of the
ankles, or toes. chorion to the uterine decidua has obliterated the endome-
Skin lesions usually are relatively few in number (less trial cavity, making ascending genital tract disease less
than 20) and generally occur on the extremities. These likely. If previous documentation that the pregnancy is
lesions are usually pustules on an erythematous base that intrauterine has not been established, a confirmatory ultra-
frequently become hemorrhagic, necrotic, or ulcerative. sound would seem prudent prior to a diagnosis of PID.
In general the rash is painful and may infrequently be While PID enters into the differential diagnosis of all
macular or petechial. the aforementioned circumstances, a careful history and
meticulous physical examination should lead the physi-
cian to the correct diagnosis in most cases. Ancillary
Diagnosis studies including qualitative and quantitative human
chorionic gonadotropin (hCG), CBC, sedimentation rate,
When gonococcal disease is considered in the differ- liver profile, urinalysis, and plain abdominal x-rays
ential diagnosis, the patient should be queried regardi4g should be considered where appropriate. In addition,
sexual practices. However, the physician should bear in abdominal and vaginal probe ultrasound can be valuable
mind that patients frequently are evasive regarding this in the detection ofsalpingitis, tubo-ovarian abscess, ovar-
 428 / El,rnncrNcy Mnorcnn: Ttrr Cons Cunr,rculurr.l
ian cystic disease, or appendicitis and to confirm the sitivity of close to l00o/o in some reports. The sensitivity
presence or absence ofan intrauterine pregnancy. Rarely for a cervical Gram stain is considerably less, possibly in
the true nature of a patient's problem will be diagnosed the 600/o range. The sensitivity is also poor for men with
only at laparoscopy or surgical exploration. asymptomatic urethral infection as well as those with rec-
The diagnosis of disseminated gonococcal illness is tal disease. The specificity of a Gram stain that shows
particularly challenging. The differential diagnosis is gram-negative intracellular diplococci is about 95% if
complex and includes Reiter's syndrome, septic arthritis, taken from the urethra, cervix, rectum, or joint fluid but
gout and pseudogout, rheumatic fever, secondary is less reliable from the mouth due to native flora. Non-
syphilis, hepatitis, Lyme disease, meningococcemia, and culture methods for the detection of Neisseria gonor-
bacterial endocarditis. Since at the time of dissemination rhoeae include DNA probe and enzyme-linked immuno-
the initial mucosal infection may be asymptomatic, the sorbent assay (ELISA) technologies. These have the
diagnosis may easily be missed. Women have higher benefit of rapid turnaround time but have the disadvan-
incidences of asymptomatic infection and thus are at tages ofhigher costs.
higher risk for dissemination than their male counter- If the possibility of gonorrhea is considered in a child
parts. Dissemination is more likely to occur during the there must be a prompt evaluation for the possibility of
beginning of the menstrual cycle. While a toxic appear- sexual abuse. The recovery of Neisseria gonorrhoeae
ance, elevated WBC count, and fever may be present, from any pediatric patient beyond the neonatal period is
these findings may be notoriously absent in the patient highly predictive of a sexual contact. The most frequent
with disseminated disease. It is estimated that the preva- clinical manifestation of gonorrhea in girls is vulvo-
lence of dissemination is 0.5% to 3.\oh of all cases of vaginitis with clinical PID being uncommon. For the pur-
gonococcal infection. poses of medicolegal considerations the presence of the
The diagnosis of disseminated disease is confirmed by organism must be documented by culture.
the isolation ofthe diplococci from the blood or synovial
fluid or from its recovery from a mucosal surface such as
the urethra, cervix, rectum, or oropharynx. It must be Treatment and Disposition
remembered, however, that the sensitivity of cultures is
limited and the initial site of infection may be asympto- There are currently multiple regimens available for the
matic. Blood cultures in the patient with disseminated treatment of uncomplicated gonococcal disease. The four
disease are positive in less than 30Yo of cases. They are
regimens currently recommended by the CDC are listed
in Table 9-2. While some controversy exists regarding the
more likely to be positive in patients with the syndromes
oftenosynovitis and rash, as these patients are frequently treatment of gonococcal illness some principles are gen-
bacteremic. erally agreed upon:
When joint effirsion is present, arthrocentesis should l. Since infection with Chlamydia trachomatrs is so
be performed and the fluid analyzed for white blood cell prevalent in patients with gonorrhea and since the
count, glucose, crystal analysis, and Gram stain. WBC sequelae of this infection are similar to those of
count will usually be greater than 50,000 with a predom- infection with the gonococcus it should be assumed
inance of polymorphonuclear cells. A low glucose will to be present and treated as such, especially in the ED
also be frequently observed. Gram stain has a sensitivity population in whom follow-up cannot be guaranteed.
of about 30o/o and, culture of the fluid may confirm the 2. For reasons yet to be explained, pharyngeal infection
diagnosis in approximately one-half of cases. In one responds less well to treatment and carries a higher
study the sensitivity of culture was only 17%. risk of dissemination.
Probably the best methods to confirm the diagnosis of 3. Patients with disseminated disease and females with
gonorrhea is either by Gram stain or culture of the initial a toxic appearance, peritoneal signs, or possible
site of infection. Cultures of the mucosal site of involve- tubo-ovarian abscess cannot be treated with a one-
ment may have a sensitivity of 60ohto 80oh, with cultures time dose regimen.
of the cervix and urethra having the highest yields. To 4. Since it is unknown what the true prevalence of incu-
improve the sensitivity of culture the following points bating syphilis is in these patients nor what impact
should be kept in mind. First, in the female the culture treatment has on this disease where there is the pos-
must be taken from the endocervix as the cocci are found sibilify of concomitant syphilis, surveillance studies
there with greater concentration. When culturing sites should be arranged for or initiated in the ED and fol-
with other expected flora, a selective test such as Thayer- low-up arranged.
Martin media should be used. The cultures should be 5. Quinolone antibiotics, while being highly effective,
plated as soon as possible in an environment containing are contraindicated in pregnancy, lactating females,
3o/o to 5oh COz. and children under 12 due to associated arthropathy.
A Gram stain should not be overlooked, especially in a Quinolones and spectinomycin are believed to have
male with a symptomatic urethral discharge, as it has sen- minimal if any effect on incubating syphilis.
 Svsrnlrrc INrnctlous DlsononRs / 429

TABLE 9-2. Treatment of gonococcal infections

Uncomplicated infections
Male urogenital tract
Female urogenital tract-outpatient treatmenta
Pharyngeal infectionb
Rectal infection
Medication
1 . Ceftriaxone 125 mg lM or 250 mg lM: The lower dose has been shown to have nearly the same

efficacy for gonorrhea as the higher dose and at reduced costs. lt was previously recommended to
use the 250-mg dose based in part on the consideration that this dose could eradicate incubating
syphilis. Currently, it is not understood whether the possibility of incubating syphilis is a significant
or theoretical concern in most patients. Where it is deemed that the risk of incubating syphilis is
high the higher dose would seem prudent.
2. Ciprofloxacin 500 mg po
3. Ofloxacin 400 mg po
4. Cefixime 400 mg po
5. Alternative-spectinomycin 2 g lM may be useful for those who are not candidates for either
cephalosporin or quinolone therapy.
ln addition, a regimen to treat coexistent chlamydial disease such as doxycycline 100 mg bid x 7 days.
Complicated infections
Disseminated gonococcal disease
Medication
1. Ceftriaxone 1 g lV q8h
2. Cefotaxime 1 g lV q8h
3. Alternative-spectinomycin 2 g lM q12h
lV antibiotics should be continued for 48 hours after improvement is first noted. Treatment should
be continued with celixime 400 mg po bid or ciprofloxacin 500 mg po bid for least a full week of
treatment.
ln addition, a regimen to treat coexistent chlamydial disease such as doxycycline 100 mg lV q12h.
Female u rogenital tract-inpatient treatmenta
Medication
1. Cefoxitin 2 g lV q6h
2. Cefotetan 2 g lV q12h
3. Clindamycin 900 mg lV q8h + gentamicin (2 mg/kg load then 1.5 mg/kg q8h)
ln addition, a regimen to treat coexistent chlamydial disease such as doxycycline 100 mg lV q12h.
Gonococcal meningitis or endocarditis
Medication
Ceftriaxone 1-2 g lV q12h. For meningitis treatment should be continued for 10-14 days; for
endocarditis treatment should be continued for 4 weeks.
ln addition, a regimen to treat coexistent chlamydial disease such as doxycycline 100 mg lV q12h.
Ophthalmic disease
Ophthalmia neonatorum
Medication
Ceftriaxone 25-50 mg/kg (not to exceed 125 mg) lV or lM single dose
Adult gonococcal conjunctivitis
Medication
Ceftriaxone 1 g lM single dose; lavage eye with saline
usee Table 9-3 for guidelines for the treatment of PID inpatient vs. outpatient.
DOnly regimens of ceftriaxone and ciprofloxacin should be used to treat pharyngeal infection.
Adapted from Centers for Disease Control and Prevention. 1993 sexually transmitted disease treatment
guidelines. MMWR 1992;42(RR-14):1-1O2; and Moran J, Levine W. Drugs of choice for the treatment of
uncomplicated gonococcal infections. Clin lnfect Dis 1995;2O(suppl 1):s47-s65.

6. The sex partnersofindividuals treated for these and ual partners as well as barrier contraception is an effective
other sexually transmitted diseases should be means of controlling the transmission of the disease and
referred for evaluation and empiric treatment. should be reinforced by physicians whenever possible.
Patients with disseminated disease, locally invasive dis-
Since females are frequently asymptomatic, the screen- ease such as complicated PID, and those unable to comply
ing of high-risk female patients is important to containing with outpatient treatment or follow-up should be hospital-
the spread of the disease. Limitation of the number of sex- ized in most circumstances (Table 9-3).
 430 / Eur,ncrNcy MtorcNn: THr Conn Cunnrculurvr

TABLE 9-3. Pelvic inflammatory disease_

admission criteria
Diagnosis uncertain-possible acute abdominal or
. gynecologic/obstetric emergency
Not ruled out
Possible abscess Sup-
Pregnancy d the
Adolescent age-due to high probability of noncompliance
lmmunocompromised host
y the
Clinical toxicity
Significant nausea and vomiting making oral therapy
difficult Epidemiologt
Social circumstances-unable to comply with treatment or
follow-up within 72 hours
Failure to improve on adequate outpatient treatment due to sepsis and
Adapted from Moran J, Levine W. Drugs of choice for the leading cause of
treatment of uncomplicated gonococcal infections. Ctin lnfect an I year and the
Dis 1 995;2O(suppt 1 ):s47-s65. to 4. There is no
service within the hospital that can be considered

SELECTED READING

C seControl 993 sexually transmitted dis_

guidelines (RR-14):l_102.
H K. Gono Ann Intern Med l9g5;102:

C lin North Am 1990;7 4(6):1353_1366.

T. Disseminated gonococcal infection. Am Fam
9_214. the septic process has advanced to shock the associated
McNaby WK, WG Barnes. Urethral and endocervical culturing: gonorrhea
and chlamydia. Ann Emerg Med 1986;15:333_336. mortality may be 50o/o or more. In one study predictors of
McNeely G. Gonococcal infections in women. Obstet Gynecol CIin North an increased likelihood of death included J chest x-ray
Am 1989;16(3):467477. with bilateral interstitial infiltrates, an elevated serum
r the treatment of uncomplicated
1995;20(suppl 1):s47-s65. gulation profile. In addition,
inflammatory disease. Med CIin not febrile appeared to have
Scopelitis E, Martinez-Osuna p. Gonococcal arthritis. Rheum Dis Clin
well.
North Am 19(2):363177 .
Suleiman A, Grimes E, Jonas H. Disseminated gonococcal infections.
Obstet Gynecol 1983;61 :48-51. Pathophysiologt

The initial event in the downhill spiral from health to

Sepsis (9.1.3) death in the patient with sepsis is an initial infectious
focus. Common initial sources include the urinary tract,
Sepsis is a clinical syndrome manifested by systemic the lung, and the skin. Additionally, intraabdominai infec_
inflammation in the setting of infection. While sepsis is tion and sinusitis are examples of more occult sources of
associated with infection it is probably just one ficet of
the systemic inflammatory response syrdrome (SIRS).
This syndrome may be precipitated by trauma, pancreati_
tis, or other noninfectious etiologies but the end result is
the same-a systemic inflammatory response that is
manifested by multiple organ dysfunction and eventual
vascular collapse. A patient may experience minimal or some aspects of the inflammatory response have been
well elucidated, it is safe to conclude that much more
remains elusive.
One well-recognized trigger of the septic process is
exposure of the immune system to certain chemical moi-
c shock-is the global hypoperfu_ eties produced by various strains of bacteria or other
ollapse) of the body as a result of microbes. Bacterial exotoxins are inflammatory media-
onse to infection. tors that are secreted by viable organisms. Such sub-
The patient with manifestations of sepsis represents a stances may be liberated by either gram-positive or gram-
special challenge to emergency physicians from both a negative organisms. Examples of exotoxins are the
 SysrBurc INrncuous DrsorunRs / 437
proteins secreted by certain strains of Staphylococcus and further contribute to myocardial dysfunction. Pancreatitis
Streptococcu.s responsible for toxic shock syndromes or gastrointestinal bleeding may complicate the course of
observed in patients with these infections. These exotox- the patient with sepsis. Diminished urine output and ele-
ins are potent mediators of both the humeral and cellular vation of BUN and serum creatinine may occur as a result
components of the inflammatory response. of acute renal failure. Adrenal failure (Waterhouse-Frid-
Similar to the response characteized by exotoxins is erichsen syndrome) may result from septic shock.
that which is caused by bacterial endotoxin. Endotoxin is Patients with underlying vascular disease may experience
different from exotoxin in that it is not secreted but rather complications of hypoperfusion including limb ischemia,
is intrinsic to the bacterial cell wall. It has been identified mesenteric insufficiency, cerebral vascular accident, or
as the lipopolysaccharide (LPS) found in gram-negative myocardial infarction.
cell walls. Numerous humeral mediators of the inflam-
matory response have been described and it is likely that
many more have yet to be recognized. Of these mediators Diagnosis
several have been well characterized. Tumor necrosis fac-
tor (TNF) is a protein produced by macrophages, mono- Sepsis in any given patient may be clinically obvious
cytes, and other cells in response to exposure to endo- or notoriously occult. Emergency physicians must iden-
toxin. TNF is currently recognized as one of the earliest tiff at-risk individuals and institute appropriate therapy
and most potent mediators of the inflammatory cascade. early on since once the process becomes advanced the
TNF is believed to cause an amplified response of the likelihood of a "good" outcome is considerably reduced.
inflammatory cascade with subsequent increased produc- Historical clues to a probable difficult course in the set-
tion of various mediators of inflammation such as inter- ting of an infectious disease include patients at the
leukins, platelet activators, prostaglandins, and leukotri- extremes of age, patients with comorbid conditions such
enes. Subsequent activation of the complement cascade as heart disease or diabetes, those who are immunocom-
as well as degranulation of macrophages results in vascu- promised such as asplenic patients, HlV-infected individ-
lar endothelial damage allowing fluid leakage from cap- uals, patients undergoing chemotherapy for malignancy,
illary beds. This, along with an increased level of circu- and patients maintained on steroid therapy for a variety of
lating vasodilatory substances such as serotonin, maladies. As noted above, patients with indwelling
bradykinin, and histamine, results in systemic vasodila- catheters, whether urinary or intravenous, have additional
tion, causing relative hypovolemia. This peripheral risks from these sources. Where valvular heart disease or
vasodilation combined with a decreased responsiveness intravenous drug use is suspected, endocarditis is a con-
of arteriolar smooth muscle to catecholamines and the cern. Finally, physicians should approach patients who
third spacing described above results in a decrease in sys- have failed appropriate antibiotic therapy with some trep-
temic vascular resistance and a decrease in venous return idation as these patients also tend to have increased mor-
to the heart, with subsequent loss of cardiac output and bidity and mortality. Additionally, in this latter group the
blood pressure. This is poorly tolerated by the septic possibility of abscess, drug resistance, incorrect diagno-
patient, especially iffebrile, since these patients appear to sis, infectious complication, or foreign body should be
have an increased overall cellular oxygen demand. The considered. Failure to respond to treatment should never
situation is made worse by myocardial suppression, be immediately dismissed as patient noncompliance.
which results directly from TNF and other inflammatory Finally, although infrequent, persons with no previous
substances. Shock resistant to IV fluids and pharmaco- underlying medical history may develop sepsis and suc-
logic therapy may ensue as a preterminal event. cumb to an infectious illness despite adequate care.
The net results of the aforementioned circulatory dys- Again, the physician should be reluctant to discharge
function are widespread and can be severe. Third spacing patients who still appear ill even if there is a lack of risk
of fluid in the lung may lead to the adult respiratory dis- factors for a poor outcome.
tress syndrome (ARDS) with resultant hypoxemia and The presentation of the potentially septic patient varies
ventilatory failure. Activation of the coagulation cascade widely from the straightforward (flank pain, dysuria,
by endotoxin, TNR or other mediators of inflammation fever, and tachycardia in a young, previously healthy
may result in disseminated intravascular coagulation female) to the nonspecific (subtle alteration in mental
(DIC) with its own concomitant complications. Cerebral status in an elderly patient with underlying dementia). In
involvement may result in encephalopathic symptoms addition, the presentations of individuals who are either
that range from mild alteration of mental status to frank very young or old as well as those who are immunosup-
coma. Hepatic dysfunction may result in elevation of pressed are frequently nonspecific or bizarre. Examples
liver transaminases. Elsewhere in the GI tract loss of include the patient maintained on steroids with appen-
mucosal integrity may occur with resultant leakage of dicitis who displays minimal symptoms, or poor feeding
intestinal bacteria as well as other toxic substances into and irritability in a newborn. At times, particularly in
systemic circulation. Some of these toxins are thought to elderly patients, the chief complaint may not even seem
 432 / ErunRcrNcv MnnrcrNn: THB Conr Cunruculurr,r

to be related at all to infection. In one study of elderly a significant source of infection have an elevated WBC
patients with bacteremia, it was noted that about half pre- count. In adults and in pediatric patients there may be a
sented with alteration of mental status and one-third had crude association between the magnitude of the white
experienced falls, including several who were found on count and the seriousness of its underlying cause.
the floor at home. Historical data are of critical impor- Patients with WBC counts lower than normal should be
tance and should never be slighted as they will assist in approached with extra caution. In the absence of DIC,
the choice of ancillary studies, consultations, choice of use anemia or thrombocytopenia.
antibiotics, and disposition of these patients. for DIC exists, laboratory confir-
A fundamental rule of emergency practice is to ..know ried out. Chemistry values of spe-
the vital signs." With respect to the evaluation and diag- lude BUN and creatinine, which
nosis of the potentially septic patient this is of critical may suggest renal failure, serum glucose to rule out
importance. A rectal temperature is still the most impor- either hypo- or hyperglycemia, which may suggest dia-
tant modality to find a fever. Most patients who are sep- betic ketoacidosis (DKA) or hyperosmolar coma, as
tic or bacteremic are febrile, but normothermia and well as serum sodium and chloride, which when taken
hypothermia may occur, particularly in neonates, the together with the renal functions may reveal dehydra-
immunosuppressed, and the elderly. Physicians should be tion. Additionally, serum bicarbonate may become
wary of normothermic patients given antipyretics prior to depressed in the septic patient, which may be the result
ED presentation as well as infants whose parents report of systemic hypoperfusion, ischemia to an extremity or
either documented or subjective fever. Tachypnea may the bowel, or other metabolic derangements. Abnormal-
result from acidosis, agitation, or pulmonary pathology ities may occur in the liver functions with elevation of
such as pneumonia or ARDS. Tachycardia may result transaminases. Abnormal coagulation parameters
from fever alone, dehydration, or third space losses as a should be considered DIC until proven otherwise. Ele-
result of sepsis. Hypotension in the setting of an acute vations of pancreatic amylase and lipase may also occur.
infectious process is a late and ominous sign and should Arterial blood gases may reveal hyperventilation as the
be aggressively treated. Patients with septic shock are fre- result of agitation or sepsis or a high alveolar-arterial
quently warm and dry in the initial phases of their illness, oxygen gradient in the setting of pneumonia or ARDS.
unlike patients with hypovolemic or cardiogenic shock Hypoxemia unresponsive to supplemental oxygen may
who are vasoconstricted. result from ARDS. ECG and cardiac enzymes may iden-
Alterations of mental status may be subtle and difficult tify patients with underlying heart disease or concomi-
to recognize especially in patients with a history of tant myocardial ischemia.
dementia. Often, information regarding the patient,s pre- Blood cultures should be obtained from at least two
vious level of functioning is obtained by speaking with peripheral sites. In the immunocompromised, viral and
family members, nursing home staff, home health aides, fungal cultures should be obtained. Direct antigen detec-
or others who have frequent contact with the patient. A tion modalities may also prove to be valuable and may be
thorough neurologic examination helps to distinguish done on blood or urine. Gram stain and culture done on
sepsis from intracranial pathology. Patients should be potential sources of infection such as sputum may also be
completely undressed unless the source of their problem of value. Urinalysis and culture should be performed on
is obvious. Skin findings of importance include areas of any patient where the urinary tract may be the source of
cellulitis, petechiae, pu{pura, or rash. Inspecting the feet infection. A chest x-ray is warranted unless the patient
is important especially in diabetic patients and in those has a known source and is free of any pulmonary symp-
with vascular disease or at risk for neuropathy, such as the toms. Other radiologic studies such as abdominal plain
alcoholic. The back should be examined for perirectal or films or computed tomography (CT), ultrasound, or head
pilonidal abscess as well as decubitis ulcer. Costoverte- CT should be employed under the correct clinical para-
bral angle percussion tenderness should be sought; when digms. A CT is not a prerequisite for lumbar puncture in
present, it suggests pyelonephritis. Since pneumonia and the patient with a nonfocal neurologic examination and
intraabdominal sources of sepsis are common, careful without signs of increased intracranial pressure but
examination of the chest and abdomen is mandatory. should be performed in cases where the patient has a risk
Nuchal rigidity mandates lumbar puncture, although for an intracranial mass, such as those with a history of
nuchal rigidity may be absent in the elderly or those malignancy or immunosuppression.
under 24 months of age, even with meningitis. More
occult sources of infection would include the sinuses or
orthopedic foci in noncommunicative patients. Treatment and Disposition
Ancillary studies in the infected patient may provide
clues to the source and severity of the initial focus of As with all ED patients, securing the fundamental
infection. A complete blood count should be obtained ABCs is the physician's first priority. In the patient with
with an understanding that most but not all patients with an advanced septic process this may be a labor-intensive
 Sysrrrr,lc INnecrrous DrsoRotRs / 433

process requiring airway intervention, volume expansion, administration of antibiotics should not be significantly
and vasopressor therapy. In addition, the resuscitation of delayed to await ancillary tests or consultations from
any potentially septic patient should not be considered other services. A particular antibiotic choice may
complete until parenteral antibiotics have been given. As always be modified later. One such situation is that of
in the majority of emergency practice the choice of suspected nosocomial pneumonia where double pseudo-
antibiotics in the septic patient is empiric (not based on monal coverage is necessary. Another situation is that of
culture) most of the time. the febrile patient who is immunocompromised, such as
Patients who have minimal pulmonary reserve due to the febrile neutropenic cancer patient. In addition to the
underlying lung disease, congestive heart failure, or double drug regimen, some authors include vancomy-
pneumonia may require intubation and mechanical venti- cin, particularly in the presence of an indwelling IV
lation. Patients who have significant degrees ofhypoper- line.
fusion should also be considered for active airway man- Since the cascade ofevents that lead from infection to
agement since maximizing oxygen delivery in these shock and death are mediated by the host's immune sys-
patients is of critical importance. Similarly, those with tem, it seems reasonable that attempts to mitigate the
obtundation require airway protection to minimize the inflammatory response may be clinically useful. Such
risk of aspiration. Intravenous fluids may be all that is attempts have been made with steroid therapy as well as
required to restore normal perfusion in these patients. with the use of several mediators of the inflammatory
Since few EDs have the resources for invasive monitor- cascade. With respect to the use of steroids, some early
ing, clinical parameters of perfusion such as normaliza- work in animals suggested improvement in outcome
tion of blood pressure and capillary refill, resolution of when steroids were administered prior to the onset of sep-
tachycardia, and improvement in mental status should be sis; however, clinical work has not thus far demonstrated
followed. A urinary catheter also helps guide resuscita- any benefit. At this time the administration of steroids
tion, and a reasonable goal is a minimum hourly urine cannot be recommended. The administration of antiendo-
output of 0.5 to 1.0 cclkg. toxin monoclonal antibodies has also been evaluated in
There has been controversy in the past with respect to an effort to moderate the host immune response and thus
the choice of IV fluids to use in the resuscitation of the improve outcome in septic patients. While clinical trials
patient with sepsis or septic shock. Choices have using monoclonal antibodies HA-1A and E5 have been
included saline or Ringer's solutions or colloids such as promising, neither agent is currently considered more
dextran, hetastarch, albumin, or blood. Proponents of than experimental at this time.
colloids cite the fact that colloids remain in the intravas- Patients who are believed to have any significant
cular space longer and thus less volume is required to degree of sepsis should be hospitalized for intravenous
attain hemodynamic stability. Balanced crystalloids antibiotics. Concerns of patient noncompliance or a
tend to leak into the intravascular space rapidly and thus poor social situation may also warrant admission.
a greater total volume is required. They are cheaper to Patients who have persistently abnormal physiologic
use and in general more rapidly infused. The additional parameters should be strongly considered for admission
third spacing ofcrystalloids appears to have no clinical to an intensive care unit. Infrequently the etiology of
significance. If crystalloids are used then an isotonic shock may remain elusive in the ED and in these cases
solution should be used. Significantly anemic patients Swan-Ganz catheterization may provide valuable infor-
should receive bloo4 since the primary goal in the mation. Apart from basic resuscitation, the most signif-
treatment of the septic patient is to optimize tissue oxy- icant impact the emergency physician makes is the early
gen delivery. For frankly toxic-appearing patients or administration of appropriate empiric antimicrobial
those with hypotension, volume resuscitation should therapy.
proceed rapidly with close monitoring of the patient's
respiratory status. For pediatric patients an initial bolus
SELECTED READING
of 20 cclkg is indicated and may be repeated. Patients
who fail to respond to volume expansion or do so only Aube H, Milan C, Bleftery B. Risk factors for septic shock in the manage-
transiently require pressor agent support. The first-line ment of bacteremia. Am J Med 1992;93:283-288.
Bone R. Sepsis syndrome. New insights into its pathogenesis and treatment.
agents employed are usually dopamine and norepineph-
Infect Dis Clin NorthAm 1991;5(4):793-805.
rine. In one study norepinephrine was found to be the Cunha BA. The antibiotic treatment of sepsis. Med Clin North Am 1995;
more efficacious agent. 79(3):55 1-558.
For the emergency physician the early administration Esposito A, Gleckman R, Cramm S, et al. Community acquired bacteremia
in the elderly: analysis of one hundred consecutive episodes. J Am Geri-
of antibiotics is of critical importance. In patients who atr Soc 1980;28(7):315 319.
are possibly septic, only intravenous therapy will suf- Giamarellou H. Empiric therapy for the infections in the neutropenic com-
fice. Empiric monodrug therapy is usually adequate, but promisedhost. Med Clin NorthAm 1995;3:559 581.
Giroir B. Mediators of septic shock: new approaches for interrupting the
in several circumstances additional coverage is war- endogenous inflammatory cascade. Crit Care Med 1993;21:780-789.
ranted. Regardless of the specific regimen chosen, the Glauser MP, Heumann D, Baumgartner JD, Cohen J. Pathogenesis and
 434 / EtmncrNcy MrolcrNn: Tsn Conr CunrucuLUM

potential strategies for the prevention and treatment of septic shock: an

Etiology and Epidemiology
update. C/in Infect Dis 1994;18(suppl 2):s205-s216.
Haglund U. Systemic mediators released from the gut in critical illness. Crjr
Cate Med 1993;2 1 (suppl 2):s1 5-sl 8. Leprosy occurs in much of the world including sub-
Harris R, Musher D, Bloom K, et al. Manifestations of sepsis. Arch Intern
Saharan Africa, India, South America, Southeast Asia,
Med 1987 ;147 :1895-1 906.
Jafari H, McCracken G. Sepsis and septic shock: a review for clinicians. China, the Caribbean, southern Europe, and parts of the
Ped iatr Infect Dis 1992;l l(9):7 39-7 48. Pacific. In the United States the disease is usually
Lefering R, Neugebauer E. Steroid controversy in sepsis and septic shock:
encountered in foreign-born individuals who have immi-
a meta-analysis. Crit Car.e Med 1995;23:1294-1303.
Martin M. Epidemiology and clinical impact of gram negative sepsis. Infect grated to this country. It is indigenous to parts of the
Dis Clin North Am 1991;5(4):739-752. southeastern United States, California, Hawaii, and
Martin C, Papazian L, Perrin G, et al. Norepinephrine or dopamine for the
Puerto Rico. U.S. cities with large numbers of immi-
treatment of hyperdynamic septic shock. Chest 1993;103:1 826-1 83 l.
Parrillo J. Pathogenetic mechanisms of septic shock. N Engl J Med 1993; grants tend to have a higher prevalence of leprosy. The
328(20):147 1-1477 . disease usually is first diagnosed in adolescents and
Rangel-Frausto M, Pittet D, Costigan M, et al, The natural history of the young adults, although it may present atany age. Because
systemic inflammatory response (SIRS). A prospective sfidy. JAMA
1995;273:117-123. ofthe prolonged incubation period ofthe disease and the
Richardson J. Bacteremia in the elderly. J Gen Intern Med 1993;8:89-92. fact that documenting the exact time of exposure to the
Sheagran J. Corticosteroids for the treatment of septic shock. Infect Dis
etiologic organism is nearly impossible, much informa-
Clin North Am I 99 I ;5(4):875-882.
Shires Gl Barber A, Illner H. Current status of resuscitation: solutions tion regarding the epidemiology of Hansen's disease has
including hypertonic saline. Adv Surg 1995;28:133-163. remained elusive.
Talan D. Recent developments in our understanding of sepsis: evaluation of
Hansen's disease is caused by Mycobacterium leprae, a
anti-endotoxin antibodies and biological response modifierc. Ann Emerg
Med 1993 :22:187 l- I 890. slow-growing, acid fast bacillus. It is believed that once a
Thijs LG, de Boer JP, de Groot MCM, Hack CE. Coagulation disorders in person is exposed, the average length of incubation is
septic shock. Intensive Care Med 1993;19:s8-s15.
from 2 to 5 years, although in some individuals clinical
Vicent JL. Cardiovascular management of septic shock. Infect Dis Clin
North Am I 993;5(4):807-8 I 6. disease may not manifest for decades. Why some indi-
viduals infected with the bacilli develop disease and oth-
ers do not is poorly understood, but probably has to do
Mycobacterial Diseases (9.1.4) with genetic and environmental factors. In addition, there
are several forms of the disease that occur and these may
Mycobacterium is a genus that consists ofthree classes correlate with a patient's relative immunity to the bacilli
of organisms that are known to cause clinical disease in or lack thereof. Unlike the tubercle bacilli, the patho-
humans. These are the tubercle bacillus, which is respon- genicity of the organism is low and it is believed that
sible for tuberculosis in humans, the human leprosy most patients with Hansen's disease acquired the disease
bacillus, which is the causative agent of leprosy as a result of substantial exposure to the bacilli. It is
(Hansen's disease), and a group of organisms known as believed that the disease is transmitted by airborne
the afypical mycobacteria, which are responsible for dis- droplets. Skin to skin contact, transmission from the bites
ease affecting primarily immunocompromised hosts. of insects, breast milk, and vertical transmission are less
While Hansen's disease is relatively infrequent in the common routes of infection. Humans are the only impor-
United States, the recent epidemic caused by the human tant reservoir for the infection.
immunodeficiency virus (HIV) has resulted in increased
numbers of patients afflicted with tuberculosis and dis-
ease caused by the opportunistic atypical mycobacteria Pathophys iology and Diagnosis
presenting to emergency rooms. The former especially
has recently become a formidable public health concern Following infection the thermolabile bacilli dissemi-
again. Thus emergency physicians must have a good nate, preferentially to the cooler peripheral areas of the
understanding ofthese entities from both a clinical and an body. Leprosy is predominantly a disease of skin and
epidemiologic perspective. peripheral nerves, although involvement of the eyes and
upper respiratory tract also occurs. The disease is charac-
terized in two broad categories-tuberculoid and lepro-
Hsnsen's Disease (Leprosy) matous. It is unclear why certain patients exhibit one or
the other form, although cellular immunity probably
Although there are over seven million known world- plays an important role.
wide cases of Hansen's disease, the disease is rare in the Lepromatous leprosy occurs in patients who are aner-
United States. Thus many physicians, including emer- gic, and thus the lesions that occur in these patients har-
-,Jilc), piiysicians, fail tc, cver consider the diagnosis even bor large numbers of bacilli and few granulomas. Patients
in the applopriate setting. Delay in diagnosis contributes with this form of leprosy may carry huge numbers of
to an increased morbidity experienced by these patients, organisms. Numerous symmetric, ill-defined skin lesions
which potentially includes loss of limb. are the rule. These lesions may be maculopapular or
 Svsrnurc INrocuous Drsorunns / 435

nodular and may ulcerate. A symmetric peripheral neu- lesion is found to be hypoesthetic when tested by
ropathy occurs, resulting in sensory loss, which may dis- light touch;
play a "stocking and glove" distribution. The sensory 2. The presence of palpable thickening of a peripheral
neuropathy leads to abnormal pressure points and nerve;
repeated trauma. The result is ulceration and secondary 3. Sensory loss;
infection. Autonomic nerve dysfunction results in anhy- 4. A risk factor for the disease such as intimate contact
drosis, which leads to dry skin creating a portal for sec- with an untreated individual or being an immigrant
ondary infection. Neuronal dysfunction may occur as from a part of the world where the disease is preva-
well as direct infection of muscles by the bacilli, causing lent.
weakness and paralysis. The end result is limbs that are
Hansen's disease should be considered in the differen-
deformed as a result of pathologic fracture, trauma, and
tial diagnosis of any complaint of a chronic nature that
infections such as osteomyelitis. The disease preferen-
involves the skin, peripheral nerves, or other cooler areas
tially affects the cooler tissues of the body, including the
of the body. When suspected, appropriate consultation
anterior chamber of the eye, the upper airway, or the
should be arranged. The disease may be confirmed by
testes in men. The skin involvement may be so extensive
skin biopsy.
as to involve nearly the entire surface of the body.
Involvement of the head leads to loss of the eyebrows,
earlobe hypertrophy, and waxy nodular facial deposits, Treatment and Disposition
resulting in the characteristic leonine facies. The nose
may be affected with resultant septal collapse. Oral Individuals treated for leprosy become noninfectious
involvement may lead to loss of dentition. Involvement of in a matter of weeks. Treatment is generally with a mul-
the eyes may be the result of direct involvement, corneal tidrug regimen that usually includes dapsone, rifampin,
drying, trauma, and infection as a result of inadequate lid and clofazimine. Steroids have been used to control acute
closure stemming from facial nerve involvement. lepra reactions. Given the limited experience that most
Tuberculoid leprosy occurs in patients who have rela- ED physicians have with this entity, consultation is urged.
tively intact cell-mediated immunity. Thus lesions in this Assistance with diagnosis and referral to a practitioner
form of the disease exhibit well-formed granulomas and experienced in the long-term care of these patients may
a much less intense tissue burden of mycobacterium. be obtained from the National Hansen's Disease Center at
Tirberculoid leprosy more often presents as a solitary or Carville, Louisiana, telephone 504-642-'7771, ext. 406.
small number of skin lesions. The center of the lesion
may be hypoesthetic. Central healing may occur. A char-
Tuberculosis (9. 1.4. 1)
acteristic finding in this form of leprosy is the involve-
ment of only a few peripheral nerves. The affected nerve
Tuberculosis (TB) is a disease that is associated with
may be enlarged and palpable near the skin surface. This
chronic cell-mediated inflammation most often affecting
important diagnostic finding should be sought in relation
the lungs, although multiple extrapulmonary sites may be
to the nerves of the face as well as the ulnar, peroneal,
involved. In the United States during much of the 20th
and posterior tibial nerves. Nerve involvement with
century the incidence of TB has declined. However, since
enlargement may lead to a permanent neuropathy.
the mid-1980s there has been a resurgence of the disease
Many patients with leprosy have a form of the disease
owing to several factors including the HIV epidemic, the
that falls between the so-called borderline or dimorphous
rise in the number of individuals living in public shelters
forms of leprosy. The course of Hansen's disease may be
or other institutionalized settings, as well as the laxity of
punctuated by two types of "Lepra" reactions. These
public health efforts to control the disease after decades
occur as a response to the development of hypersensitiv-
of success. In addition, in recent years, the prevalence of
ity to certain leprosy antigens. They occur generally in
TB infection stemming from strains of the causative
patients who are being treated. The reactions may be
agent Mycobacterium tuberculosis, which have been
manifested by fever and general malaise as well as by an
resistant to standard antituberculous agents, has risen at
apparent acceleration in the dermatologic and neurologic
an alarming rate. Since the transmission of TB has been
involvement of the disease as a result of acute inflamma-
established to occur within municipal buildings, espe-
tion or immune complex deposition.
cially hospitals, the emergency physician has a unique
The diagnosis ofleprosy should be suspected ifany of
responsibility as "gatekeeper" to the hospital to identify
the following are discovered during the course of a
potentially infectious individuals and institute appropri-
patient assessment:
ate isolation procedures. This may prove difficult in many
1. Skin lesion or lesions that may be maculopapular and instances as TB may present with a myriad of symptoms
vary with respect to pigmentation; the possibility of and findings especially in the immunosuppressed. As TB
Hansen's disease is increased if the center of the can infect healthy, nonimmunocompromised individuals
 436 / ENrnncsNcy Mnorclun: Ttrr Conn CuRruculul,r
via airborne transmission with extremely high virulence, aerosolized by an individual with active pulmonary TB,
the risks to other patients and staff are formidable. With the length of exposure of a previously uninfected individ-
the public presenting to the ED now more than ever for ual, proximity to the source, and internal air sanitation
both emergent as well as nonemergent health care needs, measures within buildings.
the ED assumes a significant role in the control of TB in
this modern epidemic.
Pathophysiology

Epidemiology Tuberculosis is a disease of cell-mediated hypersensi-

tivity and granuloma formation within host tissues. The
Worldwide it is estimated that there are eight to ten causative agent Mycobacterium tuberculosis is a curved
million new cases and three million deaths annually as a aerophilic bacillus whose cell membrane contains alarge
result of TB. In the United States during the latter part of amount of surface lipids, rendering them difficult to
the 20th century reports of TB declined annually by decolorize with alcohol or to dilute with mineral acid ren-
approximately 6% resulting from improved standards of dering them "acid-fast." They are usually stained with
living and the development of the antituberculous drugs. carbolfuchsin stain. They are nonmotile, obligatory aero-
Since 1985, however, there has been an increase in the bic organisms whose cell walls contain lipid and nonlipid
number of new TB cases. The current HIV epidemic moieties, which render them highly immunoreactive. The
appears to be the single most important contributor to disease is spread by true airborne transmission. Minute
this resurgence of TB. Other factors have included non- droplet nuclei, which may contain one or several organ-
compliance with drug therapy, the increasing prevalence isms and measure less than l0 pm, account for the major-
of infection with multiple-drug-resistant strains of ity of TB transmission. Large droplet transmission is not
Mycobacterium tubercttlosis, and an increase in the an important mode of the spread of the disease. Once
number of homeless living in municipal facilities. It is aerosolized, these particles may remain suspended for
estimated that active TB is between 150 and 300 times hours to days in calm room air. They are resistant to dry-
more prevalent in the homeless. Urban areas have ing and remain infectious for days even if floating as dry
reported a disproportionately high incidence of TB, par- dust in the air. The organisms are highly virulent, with a
alleling their increased incidence of HIV disease. The single inhaled bacillus capable of producing clinical dis-
incidence of active TB is perhaps elevated 500-fold in ease regardless of an individual's immune status. Rare
patients with acquired immune deficiency syndrome cases of transmission via the alimentary or genitourinary
(AIDS). Black and Hispanic individuals have repre- route have occurred. In years past, infection from Myco-
sented a disproportionate increase in TB when compared bacterium bovis occttrred as a result ofthe use ofunsan-
to other segments of the population. In addition, there itized contaminated milk.
has been a recent increase in immigration to the United Bacilli contained in larger droplets usually impact the
States from nations where the prevalence of TB is high mucosa of the upper airways and are generally eliminated
such as Vietnam, the Philippines, and Mexico. For by the mucociliary system. It is the small droplet nuclei
decades TB was considered mainly a disease of the and free-floating bacilli that are responsible for the vast
elderly, and active pulmonary disease was thought to majority of transmission, as these particles settle in the
result from reactivation of dormant TB; however, in this alveoli. With primary infection, the lower lung segments
era of TB resurgence, primary infection is taking on a are most often involved, owing to gravity and the
more significant role than ever before. With alarming increased ventilation of these areas. Within the alveolus
frequency, primary TB infection is the active cause, the bacilli are ingested by macrophages. The bacilli are
affecting pediatric and middle-aged patients. Children resistant to killing by these macrophages. Organisms at
and the immunosuppressed are at increased danger of this primary site of infection multiply both intra- and
active pulmonary and disseminated TB. extracellularly and may be transported to mediastinal
Tuberculosis is spread from individuals by the airborne lymph nodes. Additionally, the organisms may dissemi-
route by droplet nuclei, which may remain suspended in nate elsewhere in the body via the lymphatics or blood-
room air for hours. Since the bacilli are highly sensitive stream. While the bacilli are not killed by the initial cel-
to the UV light found in sunlight, transmission occurs lular immune response in the majority of patients, the
almost exclusively indoors. Crowding in municipal build- spread of the infection is usually contained by the forma-
ings, including hospitals, is therefore known to contribute tion of tubercles for which the disease is named. Tuber-
greatly to the spread of TB. The organism may be spread cles represent foci of chronic granulomatous inflamma-
within buildings via ventilation and air conditioning tion mediated by macrophages and T lymphocytes, which
ducts. In addition, several cases ofTB acquired during air surround and contain organisms in the lung or elsewhere.
travel have also been reported. Transmission is dependent These tubercles may follow one of several courses includ-
on several factors including the number of bacilli ing caseation and central necrosis, coalescence with other
 Sysrrnrrc.INFECTrousDrsorunns / 437
granulomas, or calcification. Viable bacilli may remain failure may result if the process is bilateral. Likewise, the
within the tubercles for decades. It is reactivation of pre- adrenal glands may be affected with resultant addisonian
viously dormant TB, rather than new primary infection, crisis. In men, TB may cause mass lesions of the testes,
that accounts for the majority of active TB today, epididymis, or prostate, and be easily confused with
although the latter is recently taking on a more significant malignancy. In women, TB may cause pelvic masses,
role. Primary infection does not imply active disease infertility, or tuberculous salpingitis, with resultant tuber-
since at this stage most patients are asymptomatic. Indi- culous peritonitis developing in some patients. The ali-
viduals with primary infection may be identified only on mentary canal may become involved, causing a clinical
the basis of development of delayed type hypersensitivity presentation consistent with inflammatory bowel disease
to purified protein derivative (PPD) manifested by con- or malignancy. When TB involves the serosal surfaces of
version to a positive skin test. In about 90o/o of healthy the abdomen mass, adhesions or ascities may result. Mus-
individuals the disease never becomes symptomatic and culoskeletal TB frequently involves the axial skeleton.
remains dormant for the duration of the individual's life. Vertebral body involvement, known as Pott's disease, may
In addition to the initial site of infection, granulomas result in neurologic compromise. Tuberculous lym-
may form in the corresponding mediastinal lymph nodes phadenitis most frequently involves the mediastinum,
as a result of lymphatic spread of the organism. The find- although any lymphoid tissue may be involved. Involve-
ing of a calcified pulmonary granuloma and a calcified ment of the central nervous system is frequently rapidly
mediastinal lymph node on chest x-ray is known as the progressive. Tuberculous meningitis may result in com-
Ghon complex and is highly suggestive of TB exposure. pression ofneural structures, infarction, or obstruction of
With active pulmonary disease, tubercles continue to cerebrospinal fluid (CSF) flow with hydocephalus. Less
grow and may coalesce with adjoining granulomas to commonly, TB may present as an intracranial mass or
form large masses distorting normal pulmonary anatomy. with spinal cord involvement.
Caseation may occur with efflux of highly infectious liq- Tuberculosis may undergo widespread dissemination
uefied material leaving behind the empty tubercle caviry with a high degree of bacillemia and involvement of mul-
hence the typical appearance of cavitary TB on chest x- tiple pulmonary and extrapulmonary sites simultaneously
ray. Bacilli may be spread throughout the airways, result- known as miliary TB named for its millet-seed appear-
ing in pneumonitis, endobronchial disease, or tubercu- ance on chest x-ray. The progressive form of TB with a
lous laryngitis. Patients with the latter two forms of TB prominence of constitutional symptoms is fatal without
are highly contagious. The pleura and pericardium may treatment. It occurs more frequently in pediatric patients,
also become involved as a result of direct extension of the the anergic, and those with comorbidity, especially HIV
disease or as a result of hematogenous spread. The dis- infection.
ease may lead to constrictive pericarditis. Mediastinal In the patient with HIV the likelihood of the occur-
disease may also involve the great vessels, which carries rence of progressive forms of TB is inversely related to
a particularly poor prognosis. The inflammatory process the CD4* count. The finding of extrapulmonary TB in an
may also cause erosion into lymphatics or blood vessels, individual with HIV is considered an AIDS defining con-
with the latter resulting in hemoptysis and hematogenous dition. The immunosuppressed patient is at higher risk for
spread. the development of progressive pulmonary TB, dissemi-
Tuberculosis, even with the primary infection, may be nated or extrapulmonary TB, as well as reactivation of
progressive if the bacilli fail to become contained. Pro- dormant disease. Because of the high virulence of TB, it
gressive disease may appear clinically as atypical pneu- is more likely to cause active disease during the earlier
monia, pleuritis with effirsion, upper lobe involvement, or stages of HIV and may be the first manifestation of
as progression to extrapulmonary TB. Occasionally, the rmmunosuppresslon.
course of pulmonary disease may be fulminant. Progres-
sive disease occurs in approximately 5oh of individuals
and is more common in the immunosuppressed as well as Diagnosis
in the pediatric patient. Active disease often develops
within a year of exposure in these patients. Extrapul- Signs and Symptoms. The majority of patients remain
monary dissemination may occur concomitant with pro- asymptomatic during the initial stages of the disease.
gressive pulmonary disease. Most patients with extrapul- Others may develop only nonspecific symptoms, includ-
monary TB have clinically silent lung disease, and in ing fever, malaise, or erythema nodosum. Initial intratho-
about l5o/o of cases the initial presentation of TB is extra- racic disease may present with symptoms referable to
pulmonary. One-half of patients presenting with extra- marked hilar adenopathy, including bronchial compres-
pulmonary disease have a normal chest x-ray. sion or obstruction, hoarseness due to recurrent laryngeal
Patients with extrapulmonary disease may manifest nerve compression, odynophagia, and emesis as a result
disease in nearly any organ system. The kidneys are the of esophageal compression or symptoms referable to the
most commonly involved extrathoracic organs. Renal obstruction of blood or lymphatic flow to the upper
438 / EtrloncnNcv MnotctNr: THe Conn CunrucuLUM
immunosuppressed patients and those with chronic dis-
eases are attitgi.. Anergy may be checked for
by placing
a positive conirol on the patient at the tim-e of the TB test'
Because the Mantoux test using PPD allows for better
antigen use4 it is superior to the
control of the amount of
multiple puncture tests and is replacing those in most
clinical ,.tting.. PPD is injected intradermally and th9
patient evaluai'ed at 48 to 72 hours' The CDC has applied
test
variable criteria to the interpretation of the Mantoux
of induration in individuals at
*ith..gurd to the diameter
Jiff..itti risks for infection with TB (Table 9-4)' While
pr""i*i immunization with BCG may produce a positive
'N4antoux
test, a large percentage of individuals either fail
to convert to positive FPD ttutot after such immunization
or revert back to negative PPD status' Thus a history
of
BCG be disregarded
frerriorrs immunizat6n with
should
when interpreting the TB skin test, and a positive
test
should stilf imply infection with the bacilli' Immuniza-
tion with BCGIs never a contraindication to skin testing'
In individuals previously sensitized to tuberculin either
from BCG vaccination or from continued exposure to
the

Lacillus, repeat skin testing may result in an enlarging

zone of induration known is the "booster phenomenon'"
ili" at,i"g by itself does not cause the development be of
delayed-tfe irypersensitivity. The PhYsician should
awaie tnaf the positive predictive value of the Mantoux
test is questiottibl" in low-risk individuals' A chest
x-ray
newly reactive skin test
is warranted in any patient with a
of pulmonary disease in
as well as to follow the course
selzure.
puti"*. with clinical disease and to gauge the effect of
antituberculous therapy' Those with symptoms consistent
Physical Examination with infection or abnormal chest x-rays should be
referred for sputum examrnation and culture in an effort
to obtain microbiologic confirmation and sensitivity
analysis of the bacilli involved'
Wttit" the findings of TB on chest x-ray may be
entirely nonspecific (especially in the immunocompro-
level
misedj, certain patterns should raise the physician's
of susplcion tor fg. These include patchy or nodular
or
infiltrates in the superior segments of the lower lobes
in the apical or posterior subapical areas of the upper
lobes. Additionally, cavitation, especially if associated
with air fluid levels, is highly suggestive of the diagnosis'

TABLE 9-4. Criteria for positive skin test

ilestposn'te-inowation equal to or greater than 5 mm
HIV positive
Susoicious chest x-raY
AncillarY Studies Close contacts of infected individuals
f"ri poiitiue-induration equal to or greater than 10 mm
Children under 4 Years
Oir,"i nigh risk foi TB individuals including health care
workers
Low-risk individual younger than 35 years
f"ripotitiu"-induration e(ual to or greater than 15 mm
Low-risk individual 35 years of age or older
 Sysrsnnc INrr,crrous Drsorunns / 439
Apical lordotic views are helpful in evaluating the upper TABLE 9-6. lnitial treatment of active TB
lung segments. Any pneumonic process, if associated Option I

with hilar adenopathy, should suggest the possibility of INH + RIF + PYR daily for 8 weeks followed by
TB. Primary infection with containment may manifest as INH + RIF 2-3 times/week for 16 weeks (DOT)
a calcified granuloma possibly associated with a calcified lf local resistance to INH is possible, ETH or STP should
be added initially until bacteriologic confirmation of INH
enlarged hilar lymph node (Ghon complex).
sensitivity has been documented
Laboratory findings are nonspecific and include a mild Option 2
leukocytosis, which may exhibit a predominant monocy- INH + RIF + PYR + STP or ETH daily for 2 weeks
tosis, and anemia of chronic disease. Elevation of the ery- followed by same drugs 2 times/week for two weeks
throcyte sedimentation rate (ESR) may occur. Hypona- (DOT)followed by INH + RIF 2 times/week (DOT)for
1 6 weeks
tremia may occur with SIADH or tuberculous disease of
Option 3
the adrenal glands. Mild hypercalcemia has also been INH + RIF + PYR + ETH or STP 3 times/week (DOT) for
described. An increase in liver transaminases may be seen 6 months
with hepatic involvement. Pyuria or hematuria may result Note: ln all the scenarios above, patients should sympto-
from urinary system involvement. With tuberculosis matically improve and sputum cultures revert to negative
meningitis CSF findings include hypoglycemia, elevated within 3 months. Treatment of extrapulmonary disease is the
protein levels, and a moderate pleocytosis (100-1000 same as for confined pulmonary disease.
DOT, direct observation of therapy (see text).
cells/mm3) with a usual predominance of lymphocytes.
lNH, isoniazid 300 mg/d adult, 10-15 mg/kg/d pediatric
(maximum 300 mg/d), major side effects-hepatitis, periph-
Treatment eral neuropathy.
RlF, rifampin 600 mg/d adult, 10-20 mg/kg/d pediatric
(maximum 600 mg/d), side effects-Gl upset, rash, throm-
Classically five drugs-isoniazid, rifampin, ethambu- bocytopenia, jaundice, orange color to urine, tears.
tol, streptomycin, and pyrizinamide-have been used to ETH, ethambutol 25 mg/kg initial dose then 15 mg/kg
treat TB. The treatment of TB in the recent epidemic has (maximum 2.5 g), major side effect-ototoxicity, nephrotoxic-
ity; decrease dose or avoid in elderly patients. Major side
become more complicated owing to an increase in the
effect-retrobulbar neuritis. Not recommended for children.
occurrence of multiply resistant strains of TB. Multiple- STP, streptomycin 15 mg/kg lM (maximum 1 g), 20-30
drug-resistant TB (MDR-TB) has been defined by most mg/kg lM q12hr pediatric.
authors as drug resistance to at least isoniazid and
rifampin, the two most effective drugs used to treat TB.
Drug resistance may be acquired in patients with a his- States. The treatment of TB varies depending on the age
tory of previous treatment with clinical failure, or be the and immune status of the patient. Additionally, asympto-
result of primary infection with a multiply resistant matic patients who develop delayed-type hypersensitivity
strain. Patients are at high risk for being infected with a as manifested by a reactive Mantoux or Tine skin test
multiply resistant organism if they have a previous his- should be strongly considered for prophylaxis, even ifthe
tory ofinadequately treated TB for any reason or they are chest roentgenogram is negative, as about 5% of these
from an endemic area for MDR-TB. With increasing fre- patients develop active disease within I year of exposure
quency these areas include urban areas of the United (Table 9-5).
Current guidelines for the treatment of TB appear in
Table 9-6. As TB frequently affects populations of
TABLE 9-5. Guidelines for the prophylaxis of tuberculosis patients at high risk for noncompliance with therapy, and
For patients with new positive TB skin test, for high risk for since noncompliance has been implicated as a cause for
TB individuals with demonstrated anergy, and for the surge in the number of cases of MDR-TB, many
childhood close contacts of infectious individuals (even if
skin test negativea):
authors have advocated direct observation of therapy
INH (isoniazid) 300 mg/d adults (DOT) as the only modality used to treat patients with
10-15 mg/kg/d not >300 mg children TB. In some reports noncompliance has been estimated at
Duration-6 mo-normal host 50%.
Duration-9 mo-pediatric patients Emergency physicians can play a pivotal role in the
Duration-12 mo-immunocompetent patients
referral of patients with TB to treatment centers as well as
Note: Prophylaxis is indicated for patients, regardless of identifying patients who are noncompliant.
age, who are known to be HIV positive, at risk for HIV with
unknown serologic status, immunosuppressed, intravenous
drug users, have comorbid conditions, or are malnourished. Prevention, Control, and Disposition
Patients at higher risk for TB other than those above
should be given prophylaxis if they are younger than 35
years of age. This category includes health care workers. As mentioned above, the emergency physician's great-
aTreatment may be discontinued if repeat skin testing at 12 est potential impact on the control ofTB is to suspect the
weeks after the last contact is negative. diagnosis and to institute proper isolation procedures of
440 / EnnncrNcv MpuctNn: THn Coru CunrucuLUM

potentially infectious individuals. Especially in patients ease in immunocompetent hosts. As such they are less a
whose presenting complaint is pulmonary in nature, the public health concern than the tubercle bacilli.
physician should maintain a high index of suspicion for
TB and query the patient regarding risk factors for the
disease. It is again stressed that TB may mimic pneumo- Epidemiology
nia both symptomatically and radiographically, espe-
cially in the immunosuppressed. When in doubt and It is estimated that perhaps one-half of AIDS patients
where follow-up is believed to be possible, as well as for will acquire disease with MAC at some point in their dis-
admitted patients, the Mantoux skin test with anergy ease course. The nontuberculous mycobacteria are found
panel should be considered. If time or resources do not widely throughout nature and have been isolated from
permit this in the ED, provisions should be made for it water, soil, and certain foods. In humans the portals of
soon after patient disposition. Admitted patients at high entry and the sites of initial colonization are the respira-
risk for TB, especially if experiencing significant respi- tory and gastrointestinal tracts. In normal hosts this is
ratory symptoms, should be placed in isolation. It is generally of no consequence; however, in the immuno-
important that this be started in the ED since once a suppressed patient these sites serve as foci of blood-
patient is "labeled" with another diagnosis TB may go borne dissemination. Previous opportunistic infection
unsuspected or be discovered only by sputum examina- should alert the physician to advanced HIV and the pos-
tion or culture, which may take days, and all the while sibility of disseminated MAC. With the use of antiretro-
the patient aerosolizes bacilli within the hospital. In hos- viral drugs as well as improved care for the complications
pitals so equipped, adequate isolation may be accom- of HIY these patients are now living longer, and thus
plished by placing the patient in negative pressure isola- physicians can expect to encounter greater numbers of
tion rooms that vent air to the outside. Additionally, UV AIDS patients with disseminated MAC.
lighting within hospitals has recently been instituted to
cut the rate of nosocomially acquired disease. While it is
Pathophysiology
believed that UV lights kill airborne mycobacteria, no
clinical trials have proven their efficacy in preventing
Following colonization, blood-borne dissemination
nosocomial disease.
may occur with widespread distribution of MAC organ-
Where possible, TB should be treated in the outpatient
isms to virtually any site in the body. It is possible that
setting to lessen the possibility of nosocomial transmis-
colonization may not produce clinical disease particu-
sion. Individuals with comorbidity or extenuating social
larly in healthy individuals. The original site of colo-
circumstances, or who are likely to require more rigorous
nization may be transient and further dissemination may
diagnostic or therapeutic intervention, may require hospi-
occur as a result of new sites of infection with ongoing
talization.
bacterial replication. Regardless of mechanism, wide-
spread dissemination with high tissue burdens of MAC
Atypical My co b acteria (9. 1. 4. 2) organisms is the rule in the immunosuppressed. Unlike
disease caused by the tubercle bacillus, granuloma for-
The atypical or environmental mycobacteria are a mation is not a prominent feature of infection with
group of nontuberculous mycobacteria that are ubiqui- MAC. Contained localized disease is much less common
tous in nature that in general have low virulence in but may occur and be the cause of any number of clini-
healthy individuals. In recent years, however, physicians cal syndromes. These include pulmonary disease with
have cared for growing numbers of immunocompromised nodules, pneumonic infiltrates, and even cavitary dis-
patients with clinical disease stemming from these organ- ease, endobronchial disease, pericardial disease, muscu-
isms. While there are several species of these organisms, loskeletal disease, skin lesions, lymphadenitis, GI tract
the groups that accounts for the greatest percentage ofill- lesions with resultant malabsorption and chronic diar-
ness are Mycobacterium avium and Mycobacterium rhea, intraabdominal MAC including abscess formation,
intracellulsre, collectively known as the Mycobacterium as well as CNS disease. Any of these may be associated
avium-intracellulare complex (MAC). Infection with with dissemination. When MAC affects the lung, its
MAC is the most widely encountered bacterial oppor- clinical presentation may be identical to lhat of M.
tunistic infection in patients with AIDS. Other species tuberculosis.
that have been reported to cause clinical disease include It has been difficult to elucidate exactly the impact
M. kansasiL M. fortuitum, M. xenopi, M. simiae, M. MAC has by itself on morbidity and mortality in AIDS
haemophilum, and others. For the emergency physician, patients since it is so frequently associated with
these may all be considered in a similar way-each her- advanced HIV and the concomitant existence of other
alds a high degree of immunosuppression. Unlike M. opportunistic infections such as toxoplasmosis, cyto-
tuberculosis, these organisms do not cause clinical dis- megalovirus (CMV), and Pneumocystis carinii. By itself
 Svsrnurc INrecrous Drsonorns / 441

MAC is believed to have low pathogenicity, although in Treatment and Disposition

some individuals it has produced significant disease.
Exactly which patients develop clinically significant Rifabutin is an oral medication similar to rifampin that
infection with MAC and why they develop it has not has been approved for the prophylaxis of disseminated
been well understood. It is generally believed that dis- MAC in the AIDS patient. It is indicated in HlV-positive
ease caused by MAC does accelerate the downward spi- patients with CD4* counts less than 100/mm3. Prior to the
ral of the AIDS patient to death as co-infection with administration of this agent, at least one blood culture for
MAC has been observed to significantly shorten life MAC should be obtained since a positive culture would
expectancy. mandate more aggressive therapy. The proper adult dose
is 450 to 600 mg per day. Side effects include neutrope-
nia, thrombocytopenia, elevated liver function, as well as
Diagnosis
GI symptomatology.
Patients with proven disseminated MAC (positive
The manifestations of infection with MAC are protean.
blood culture) should be started on at least a two-drug
Furthermore, co-infection with other pathogens is the
regimen. One of these drugs should be either clar-
rule in patients who have disseminated MAC. Thus,
ithromycin or azithromycin. Ethambutol is frequently
attributing specific signs and symptoms to MAC infec-
used as the second drug. Third- and fourthline agents
tion has proven difficult. Constitutional symptoms such
include clofazimine, rifabutin, rifampin, ciprofloxacin,
as fever, night sweats, anorexia, generalized malaise, and
and amikacin. Once institute4 prophylaxis andJor treat-
weight loss are frequent. Diarrhea, abdominal pain, nau-
ment should continue for the duration of the patient's life.
sea, and vomiting have also been associated with dissem-
Clinical improvement from the constitutional symptoms
inated MAC. Pulmonary disease may present syndromes
of disseminated MAC with prolongation of life are the
consistent with bronchitis, pneumonia, or mass with goals of therapy. The emergency physician must realize
obstruction. While MAC does not involve the CNS with
that all patients with known disseminated MAC or at risk
high frequency, CNS involvement may present as
for it are severely immunocompromised and therefore
headache, alteration in mental status, or seizure. Histori-
careful evaluation for the other complications of immu-
cal factors that are valuable in the medical history include
nosuppression is warranted. Admission to the hospital is
risk factors for HI! the recent use of immunosuppressive
clearly mandated for some patients due to the presence of
drugs, or other comorbid conditions such as malignancy.
more significant opportunistic infections, poor social cir-
In patients with HIV infection, asking the patient or local
cumstance, or clinical deterioration.
doctor, or reviewing the medical record for the date and
level of the last CD4* count will prove helpful. Any pre-
vious opportunistic infection such as with Pneumocystis
carinii should be considered a definite risk for the pres- SELECTED READING
ence of disseminated MAC illness.
Physical examination may reveal a multitude of pul- Hansen's Disease
monary findings consistent with the above-named syn-
Pust R, Campos-Outcalt D. Leprosy in the United States. Risks, recogni-
dromes, abdominal tenderness or mass, hepatospleno- tion, regimens, resources. Postgrad Med 1 985 ;77(5): I 5 1-l 59.
megaly, or lymphadenopathy. CNS findings consistent Style A. Early diagnosis and treatment of leprosy in the United St^tes. Am
Fam Physician 1995;52(l):17 2-17 8.
with the diagnosis include nuchal rigidity and abnormal-
Simon H. Infections due to mycobacteitm. Sci Am Med 1995;18(9):1-26.
ities in mental status. Unfortunately, none of these exam- Trautman J. Epidemiological aspects of Hansen's disease. Buil NY Acad
ination findings is specific, and each may have several Me d 1 984 ;60(7 ):7 22-7 3 l.
etiologies in the patient with immunosuppressive disease.
The use of radiologic and laboratory data helps in the
Tuberculosis
diagnosis of infection with MAC as well as in evaluating
the possibility of other more serious opportunistic infec- Barclay D, Richardson J, Fredman L. Tuberculosis in the homeless. lrcft
tions in a given patient. There is no chest x-ray finding Fam Med 1995;4:541-546.
Barnes P, Le Hanh Quoc, Davidson P. Tuberculosis in patients with HIV
that is specific for the diagnosis of MAC infection nor
infection. Med CIin North Am 1993;6:1369-1390.
distinguishing disease caused by MAC from tuberculous Brausch L, Bass I The treatment of tuberculosis. Med Clin North Am 1993;
infection. Laboratory findings supporting the diagnosis 77 (6):1277 -1288.
Centers for Disease Control. Treatment of tuberculosis and tuberculosis
of MAC include a profound anemia as well as an ele- infection in adults and children. Am J Respir Crit Care Med 19941,149:
vated alkaline phosphatase. Lumbar puncture in cases of 13s9-t374.
CNS disease reveals a CSF leukocytosis. Smears taken Centers for Disease Control. Exposure of passengers and flight crew to
mycobacterium tuberculosis on commercial aircraft, 1992-1995.
from affected tissues display acid-fast bacilli. Blood cul-
MMWR 199 5 ;44(8): 1 37-1 40.
ture confirms the presence of disseminated MAC in Ciesielski S. BCG vaccination and the PPD: what the clinician needs to
many instances. know. J Fam Pract 1995;40:.76-80.
442 / ElrpncrNcy MnllcrNr: Tun Conr CunnrculuM

Huebner R, Castro K. The changing face oftuberculosis. Annu Rev Med meningococci. Early recognition of meningococcal dis-
1995;46:47-55.
Kent J. The epidemiology ofmultidrug-resistant tuberculosis in the United
ease is essential for successful treatment. The illness is
States. Med Clin North Am 1993;77(6):1391-1407. characterized by fever, systemic toxicify with or without
McSherry G, Connor E. Current epidemiology oftuberculosis. Pediatr Ann hypotension, petechial or purpuric rash, and high mor-
1993;22:600404.
Nardell E. Environmental control of tuberculosis. Med Clin North Am bidity and mortality. The mortality of meningococcemia,
1993;77 (6)13ts-t334. ranging from 10% to 30Yo, is higher than that of
Pozsik C. Compliance with tuberculous therapy. Med Clin North Anr meningococcal meningitis alone.
1991 ;7 7 (6) : 1289-130 l.
Simon H. Infections due to mycobacteilm. Sci Am Med 1995;18(9):1-26.
Meningococcemia has its highest incidence in children
Starke J. The tuberculin skin test. Pediatr Ann 1993;22(10):612-620. aged 6 months to 1 year and has its lowest incidence in
Telzak E, Sepkowitz K, Alpert P, et al. Multi-drug resistant tuberculosis in persons over 20 years of age. Transmission from person
patients without HIV infection. N Engl J Med 1995;333:907-911.
Waagler D. The clinical presentation of tuberculosis disease in children.
to person is principally through inhalation ofdroplets of
Pe di atr A n n 1993 ;22(1 0) :622-628. infected nasopharyngeal secretions, and close person-to-
Yamaguchi E, Reichman L. Pulmonary tuberculosis in the HIV positive person contact. The disease has occurred worldwide, as
patients. Infect Dis CIin NorthAm 199l;5(3):623-633.
the asymptomatic carrier state (the most common form),
sporadic cases, limited outbreaks, and widespread epi-
Atypical Mycobacterium demics. The peak incidence of occurrence is during mid-
winter and early spring. Patients with complement defi-
Beck K. Mycobacterial disease associated with HIV infection. J Gen Intern ciency, either congenital or due to underlying disease,
M e d 199 1 ;6(stppl) : s I 9-s23. seem to be at increased risk for invasive infection as do
Beson C. Disease due to the Mycobacterium avium complex in patients
with AIDS epidemiology and clinical syndrome. Clin Infect Dis 1994; asplenic patients and alcoholics. This may be an impor-
I 8(suppl):s2 I 8-s222. tant risk factor in the development of the first episodes of
Jacobson MP, Hopewell D, Yajko WK, et al. Natural history of disseminated nonepidemic meningococcal disease. The incubation
Mycobacterium avium complex infection in AIDS. J htfect Dis 1991;
164:994-998.
period from the initiation of nasopharyngeal infection to
Gyure K, Prayson R, Estes M, Hall G. Symptomatic Ml,cobacteriunt aviunt systemic bacteremia appears to be less than l0 days.
complex infection of the central nervous system. A case report and Once the organism has entered the bloodstream, over
review ofthe literature. Arch Pathol Lab Med 1995;119:836-839.
Masur H, and the Public Health Service Task Force on Prophylaxis and 90Yo of the patients present with either meningitis or
Therapy for Mycobacterium avium Complex. Recommendations on pro- meningococcemia.
phylaxis and therapy for disseminated Mycobacterium avium complex
disease in patients infected with the human immunodeficiency virus N
Engl J Med 1993;329(12):898-903.
Rigsby M, Curtis A. Pulmonary disease from nontuberculous mycobacteria Clinical Presentation
in patients with human immunodeficiency virus. Chest 19941'106:
913-919.
Meningococcemia usually follows an upper respiratory
infection. Initially, patients may be minimally sympto-
Meningococcemia (9.1.5) matic with flu-like symptoms of headache, cough, sore
throat, myalgias, nausea, and vomiting. More severe ill-
Meningococcemia is meningococcal bacteremia, ness develops with spiking fevers, chills, and arthralgias
which usually results from seeding from the nasophar- when nasopharyngeal infection has progressed to bac-
ynx. Neisseria meningitidis, a gram-negative coccus, col- teremia. Some 75% of the patients develop a petechial
onizes the nasal mucosa of 5% to 15% of humans in the rash that is characteristic. Lesions are usually sparse and
general population; however, it must invade the mucosa involve the axillae, flanks, wrists, and ankles. In severe
to cause disease. Most cases occur in children and ado- cases purpuric spots or ecchymosis develops. Absence of
lescents, with the highest incidence in the first year of a rash does not necessarily indicate a more mild illness.
life, although any age group may be affected. Military The disease can range from an indolent, slowly progress-
recruits are also particularly susceptible to meningococ- ing infection to sudden onset of fulminant disease that
cal disease, although outbreaks among this population may progress to death in a day or less. Meningococcemia
have decreased over the past 10 years with the routine use may manifest primarily as bacteremia, or as a localized
of vaccine. The disease may present as acute meningo- infection. Acute meningococcemia and acute meningitis
coccal septicemia, which may be fulminant (Waterhouse- are the most common forms of meningococcal disease.
Friderichsen syndrome), meningococcal meningitis, or Mild acute meningococcemia, the most common form
chronic meningococcemia. From 30% to 50%o of the of meningococcemia, is characterized by the rapid devel-
patients with meningococcal disease have meningococ- opment of malaise, chills, fever, arthralgias, and myalgias
cemia without meningitis. Meningococcemia may be an following an upper respiratory infection. Occasionally,
acute process, presenting either as a mild systemic infec- diarrhea has been reported as a symptom that has been
tion or one that is rapidly lethal, or may be a chronic associated with early meningococcemia. In its mildest
relapsing illness that may last for several months. From form, symptoms may spontaneously resolve within a few
2o/o to 15% of the patients may be chronic carriers of days, and diagnosis is only made in retrospect by blood
 Sysrnrurc INrncrlous DrsonorRs / 443
cultures growing N. meningitidis. In other cases, the ini- ranted. Occasionally during convalescence a nonseptic
tial symptoms are followedin24 to 48 hours by the recur- arthritis-pericarditis syndrome may develop; otherwise
rence of chills and the development of classic erythema- the features and complications of meningococcal menin-
tous skin lesions that may be petechial, macular, or gitis are similar to other meningitides.
maculopapular with pale gray vesicular centers. The rash Meningococcal pneumonia is more commonly of pri-
is most evident on the extremities. mary origin rather than a result of hematogenous spread.
Fulminant meningococcemia occurs in approximately The clinical presentation is similar to that of community-
IDoh to 200/o of the patients with meningococcemia. Ful- acquired pneumonia. The lower lobes are usually
minant meningococcemia characteristically has a very involved. Bacteremia occurs in about l5%" of the cases.
abrupt onset and is rapidly progressive. The illness pre- Meningococcal pneumonia occasionally develops during
sents with rigor, high fever, dizziness, headache, and pro- the course of meningococcemia or meningococcal
found malaise. All symptoms tend to develop over a few meningitis. The clinical picture, however, is dominated by
hours. Petechiae, purpura, and hypotension develop the extrapulmonary symptoms.
rapidly along with peripheral vasoconstriction and shock. Arthritis complicates from 2%o to 16Yo of the cases of
Extensive purpura, circumoral cyanosis, hemorrhagic acute meningococcal disease. The arthritis may present in
bullae, and peripheral gangrene are key features of ful- several forms: monoarticular acute suppurative meningo-
minant meningococcemia. Disseminated intravascular coccal arthritis (rare), polyarthritis (early onset), and
coagulation is frequently present with enlarging hemor- mono- or oligoarthritis (late onset). With acute suppura-
rhagic and necrotic areas on the skin. Mucosal, respira- tive arthritis the joint aspirate has the appearance of a
tory tract, and gastrointestinal bleeding may occasionally septic arthritis. Early-onset arthritis usually occurs during
develop. As the illness progresses, patients may become the first 1 to 3 days of meningococcal disease. This is the
hypothermic. Patients who recover may have extensive most common form of meningococcal-associated arthri-
sloughing of skin lesions due to gangrene, which may tis. It is polyarticular, and joints are acutely inflamed
require extensive skin grafting. without eftrsion or a very minimal effirsion.
Chronic meningococcemia, a rare form of meningo- Pericarditis also may complicate meningococcal dis-
coccal infection, is characterizedby periodic fevers last- ease in 2c/o to 20% of the patients. Like arthritib, it may
ing I to 6 days, presenting with chills, headache, myal- present early, in the course of the illness, or late, during
gias, and migratory arthralgias. Each episode of fever is recovery. Early pericarditis is usually purulent and due to
associated with the development of an erythematous the invasion of the pericardium by N. meningitidis. Late
macular and papular rash with rare petechiae and pur- pericarditis is usually sterile. Isolated purulent pericardi-
pura. The total number of lesions is small. Up to 20Vo of tis due to N. meningitidis withott signs of meningococcal
the patients may have splenomegaly. Up to two-thirds of disease is very rare. Ocular and genitourinary involve-
the patients may present with joint involvement. Patients ment complicate less thanl%o of the cases.
are only minimally toxic in appearance, fever is intermit-
tent, and infection may last for weeks or months. Diag-
nosis is made by blood culture drawn during the febrile Diagnosis
period. Failure to treat chronic meningococcemia may
result in the development of meningitis in 20o/o of the The diagnosis of meningococcemia should be enter-
patients. Endocarditis and epididymitis are rarer compli- tained in anyone who presents with fever, malaise, and a
catrons. petechial or maculopapular rash, with or without signs
Meningitis is a common form of meningococcal dis- and symptoms suggestive of meningeal infection. Aside
ease. Most cases of meningococcal meningitis occur in from bacteriologic data, other laboratory studies are of
children and adolescents. Commonly patients present little value in establishing a diagnosis of meningococcal
with symptoms of both meningitis and meningococ- disease. The diagnosis is confirmed by finding organisms
cemia. From 20%o to 40o/o of patients may have meningi- on stained smears from infected areas when appropriate,
tis without evidence of meningococcemia. The onset of by isolation of N. meningitidis from blood or infected
symptoms (fever, chills, stiff neck, headache, vomiting, body fluids, and by detection of N. meningitidis polysac-
malaise, confusion, or lethargy) may be very rapid, pro- charide antigen in blood or cerebrospinal fluid (CSF) by
gressing in less than 24 hours. It may be preceded by a latex agglutination or counterimmunoelectrophoresis.
mild upper respiratory infection. Unlike other pathogens Blood cultures are positive for N. meningitidis in 50% to
causing meningitis, meningococcal meningitis is not 75oh of the patients with meningococcemia, and in
associated with predisposing otitis media or pneumonia. approximately one-third of the patients with meningitis.
In patients presenting with delirium, N. meningitidis is In patients with meningitis, polysaccharide antigen in
more commonly the etiologic agent. When meningitis demonstrated in CSF approximately 70% of the time.
occurs in association with a petechial or purpuric rash, a The differential diagnosis should include other bac-
presumptive diagnosis of meningococcal disease is war- teremias. Occasionally meningitis caused by Haemophi-
444 t EnrRceNcy MnorcrNE: THo Conn Cunnrculuv

lus influenzae and Streptococcus pneumoniae may pre- Current vaccine, however is not effective in preventing
sent with a petechial skin rash. Acute bacterial endo- disease from all groups of meningococci, nor is it effec-
carditis caused by Staphylococcus aureus may also pre- tive in younger children who are at most risk for infec-
sent with petechial lesions, presenting a clinical picture tion.
that is almost indistinguishable from meningococcemia.
In addition, gonococcemia, vasculitis, viral exanthems,
SELECTED READING
and Rocky Mountain spotted fever should also be con-
sidered. Achtman M. Epidemic spread and antigenic variability of Neisseria menin-
gitidis Trends Microbiol 1995;3(5): 1 86-1 92.
Figueroa J, Andreoni J, Densen P. Complement deficiency states and
Treatment meningococcal disease. Immuno I Re s 1993 ;1 2:29 5-3 | l.
Hart CA, Rodgers TRF. Meningococcal disease. J Med Microbiol
1993;39:3-25.
Because of the rapidity with which this disease pro- Herrera R, Hobar PC, Ginsburg CM. Surgical intervention for the compli-
gresses, as soon as the diagnosis of meningococcemia or cations ofmeningococcal induced purpura fulminans. Pediatr Infect Dis
meningococcal meningitis is suspected, antibiotic therapy J 1994;13(8):734-737.
Jarvis GA. Recognition and control ofneisserial infection by antibody and
should be instituted. Patients should by placed in respira- complement. Trend s Mic robiol 1 995 ;3(5): 1 98-20 1.
tory isolation to minimize spread of infection. Antibiotics Klein NJ, Heyderman RS, Levin M. Management of meningococcal infec-
that have been shown to be effective include penicillin G tions. Br J Hosp Med 1993;50(l):4249.
Marhoum el Filali K. Noun M, Chakib A, et al. Ceftriaxone versus peni-
(2 million units every 2 hours), ampicillin (2 g every 6 cillin G in the short term treatment of meningococcal meningitis in
hours), chloramphenicol (4 glday), and ceftriaxone (up to adrits. Eur J Clin Mioobiol Infect Dis 1993;12(10):766-768.
4 glday; 100 mg/kg in children). Treatment should be Paulson E, ed. Guidelines for control of meningococcal disease. Canada
Communicable Disease Report 1994'20:17 17.
continued for a minimum of 7 days or for at least 4 to 5 Riedo FX, Plikaytis BD, Broome CV Epidemiology and prevention of
days after the patient becomes afebrile. Treatment of meningococcal disease. Pediatr lttfect Dis J 1995;14(8):643457.
severe meningococcemia requires aggressive supportive
care to manage shock, DIC, and other complications.
Plague (9.1.6)
This may include monitoring in an intensive care setting,
supplemental oxygen to maintain oxygenation, volume
Plague is a bacterial infection of humans and animals,
expansion and the utilization of vasoactive agents to
caused by the aerobic, gram-negative, nonmotile, coc-
maintain blood pressure, and the administration of bicar-
cobacillus Yersinia pestis. The disease may vary from a
bonate to correct acidosis. Most deaths occur within 24 to
local reaction at the regional lymph nodes proximal to the
48 hours of admission to the hospital.
site of inoculation-acute regional lymphadenitis called
bubonic plague, to a fulminant disseminated infection
Prevention without adenopathy-septicemic plague. Pneumonic
plague, the most serious epidemic form of plague, may be
Chemoprophylaxis should be administered to all close transmitted from person to person via aerosols. Menin-
contacts of patient with meningococcal disease. This geal plague is less common. Plague may be rapidly fatal
should include all same-household members, day-care if left untreated. Plague is usually transmitted to humans
center members, and medical personnel who have had by the bites of fleas that parasitize wild rodents. Plague
intimate contact with the patient, such as administering borne by rat fleas devastated Europe during the Middle
mouth-to-mouth resuscitation. Since secondary cases Ages, and has been recognized in North America since
usually occur within the first week after initial contact, the early part of this century. Since 1925 all known cases
prophylaxis should begin as soon as the initial case is of plague reported in the United States have been associ-
identified. Rifampin is the drug of choice for chemopro- ated with exposures to wild rodents and their fleas in the
phylaxis, and is 80% to 90% effective in eliminating western half of the country. Significant foci of plague
meningococci from the nasopharynx of asymptomatic also exist in Africa and Asia.
carriers. Rifampin is administered for 2 days at the fol- Plague in the United States appears to be geographi-
lowing dosages: adults (600 mg twice a day), children cally restricted to the western part of the country, and it is
younger than I month of age (5 mg/kg administered most common in New Mexico, Aizona, California, and
twice a day), children older than 1 month but younger Colorado. American Indians are disproportionately repre-
than 12 years (10 mglkg administered twice a day with a sented among plague cases in the United States, possibly
maximum dose of 1200 mg per day). Commercially because many reside in rural areas in the western part of
available meningococcal vaccine is not recommended for the country. Plague in the United States is most fre-
routine vaccination due to the low incidence of the dis- quently transmitted to humans from flea bites from
ease in the absence of outbreaks. Vaccination should be infested rock squirrels, California ground squirrels,
considered for individuals who are traveling to countries prairie dogs, chipmunks, and woodrats. Occasional cases
in which there is an epidemic of meningococcal disease. of human plague have been reported in hunters exposed
 Sysrnlrc INrncrrous DrsoRonRs / 445

to the incidentally infected carcasses of deer, antelope, days of the onset of symptoms. Nearly all fatal cases of
gray fox, badger, bobcat, and coyote. These animals plague in the United States are a result of delays in seek-
rarely develop overt illness and are not thought to be part ing treatment or in making the diagnosis.
of the usual endemic transmission cycle. Only rarely, dur- In patients with septicemic plague, hematogenous
ing epidemics of human pneumonic plague, is the infec- spread of bacteria from the bubo to the lung may result in
tion passed directly from person to person. pneumonia. Plague pneumonia is characterized by fever,
The occurrence of human plague is always linked to lymphadenopathy with cough productive of purulent spu-
the transmission of plague among the natural animal tum, chest pain, and often hemoptysis. Chest radiography
reservoirs, and the incidence of human plague is a func- may reveal a patchy bronchopneumonia or consolidation.
tion ofboth the frequency ofinfection in the local rodent When septicemic plague results in pneumonia, it is classi-
population and the rate of exposure to the infected fied as secondary plague pneumonia. Primary pneumonic
rodents and their fleas. Typically plague occurs in very plague is caused by the inhalation ofan infectious respira-
focal areas, involving one town or a city street, with adja- tory droplet, which may have originated from another
cent areas being plague free. This has been attributed to human pneumonic plague case. While this distinction is of
the parochial behavior ofrats, which tend to stay near one little therapeutic importance, the public health implications
food supply for extended periods of time. Rapid subur- are significant. Plague pneumonia is highly contagious by
banization of endemic states has increased the number of airborne transmission, it has a short incubation period, and
persons living in or near active plague foci. Plague pre- it can spread rapidly in close person-to-person contact.
dominantly occurs in warm tropical climates, and out- While primary pneumonic plague is now rare, it is a poten-
breaks tend to occur during humid warm seasons. In the tial threat to any person who is exposed to a patient with
United States, the majority of cases tend to occur during plague who has a cough. It may be so rapidly fatal that
the months of May through September, with the peak individuals have been reported to have been exposed,
incidence during the month of July. Due to the mild win- become ill, and died in the same day. Pneumonic plague is
ter months in some of the southwestern states, however, invariably fatal if antibiotic therapy is delayed more than
cases can occur during any month ofthe year. 20 hours after the onset of symptoms. Gram-negative sep-
The most common clinical form of human plague is ticemia and endotoxic shock account for many of the early
bubonic plague. Bubonic plague usually presents as a deaths from pneumonic plague.
febrile illness begindng 2 to 7 days following a bite from Primary pneumonic plague has also been reported to
an infected flea. During the incubation period, bacteria have been transmitted to humans by animals-most often
proliferate in the regional lymph nodes. Patients typically domestic cats, in whom plague produces a severe, often
present with the sudden onset of fever, chills, weakness, fatal infection. These animals probably develop sec-
and headache, followed by painful lymphadenopathy ondary pneumonic plague after ingesting infected wild
(buboes) proximal to the infected bite, usually at the same rodents, and may transmit the infection via infectious
time or within 12 to 24 hours. Pain and tenderness often aerosols from the animal's cough to their owners or vet-
precede palpable and visible adenitis. The most common erinary professionals caring for them.
sites are the groin and the axillae, resulting from the inoc- Plague meningitis, a rare complication of bubonic
ulation of the extremities by flea bites. Pain may be so plague, occurs usually as a result of inadequately treated
intense so as to restrict any movement of the affected areas. plague. It is characterizedby fever, headache, meningis-
Buboes are oval swellings that may vary from I to 10 cm mus, and CSF pleocytosis. As in secondary pneumonic
in length. The overlying skin may be elevated, or appear plague, it is a result of hematogenous spread of bacteria
sfretched or erythematous. The buboe may appear smooth from a bubo. When compared to uncomplicated bubonic
and egg shaped or may feel like an irregular cluster, with plague, the mortality rate is very high. There may be an
surrounding edema, which may be pitting or gelatinous in association between buboes located in the axilla and the
nature. Palpation typically elicits tenderness and warmth. development of meningitis. Occasionally, plague menin-
In uncomplicated bubonic plague, patients are usually gitis may appear as a primary infection, without any
prostrate and lethargic. They often exhibit restlessness antecedent lymphadenitis.
and agitation; seizures are common in children. The tem- Plague pharyngitis, a rare clinical form of plague, is
perature is usually in the 38.5 to 40.0'C range. Pulse is thought to result from the inhalation or ingestion of the
elevated and the blood pressure is usually in the range of plague bacilli. It may resemble acute tonsillitis with
100/60 mm Hg due to vasodilatation. The liver and spleen inflamed anterior cervical lymph nodes. Y. pestis may be
may be palpable and tender. There is no characteristic recovered by throat culture.
skin rash; however, pustules may develop at the sites of
flea bites. With fulminant systemic disease, patients may Diagnosis
develop purpura that may become necrotic resulting in
gangrene-the probable basis for the term black death. A The diagnosis of plague should be suspected in febrile
fulminant clinical course can produce death within 2 to 4 patients who have been exposed to rodents or other mam-
 446 / ElrencnNcy MnorclNr: Tnr Conn CunnrculuM

mals in known endemic areas of the world. Eliciting a Tetracycline is contraindicated in children and in preg-
history of recent travel in plague endemic areas of the nant women to avoid staining developing teeth. It is also
United States, South America, Africa, or Southeast Asia contraindicated in patients with renal failure.
is of obvious value. Because of the similarities between Intravenous chloramphenicol is the drug of choice for
plague and the recently discovered Hantavirus pulmonary patients who may have profound hypotension resulting in
syndrome, the diagnosis of plague may be further com- poor absorption of an intramuscular injection, and in
plicated. A bacteriologic diagnosis may be made in many patients who have meningitis and require a drug with
patients by smear and culture of bubo aspirate. This may good cerebrospinal fluid penetration. Chloramphenicol
be obtained by inserting a 2}-gauge needle on a 10-cc should be administered intravenously with a loading dose
syringe containing I ml of sterile saline solution into a of 25 mg per kilogram of body weight followed by 60 mg
bubo. The solution is then injected and aspirated several per kilogram per day in four divided doses. After clinical
times until it is blood tinged. Drops of the aspirate should improvement, oral chloramphenicol should be continued
then be placed onto slides and air dried for both Gram to complete a total course of l0 days. The dosage may be
and Wayson's or Giemsa stain. These will readily demon- reduced to 30 mg per kilogram per day to reduce the mag-
strate the bipolar ("saftey-pin") morphology that is char- nitude of bone marrow suppression.
acteristic, but not diagnostic, of Y pestis. Pus from a fluc- Other antibiotics that have been used for the treatment
tuant bubo or sputum also may be smeared and treated in of plague include ampicillin, sulfonamides, and trimetho-
the same fashion. Rapid presumptive identification of the prim-sulfamethoxazole. These have not been shown to be
organism can also be made using a fluorescent antibody as effective as streptomycin. Fluoroquinolones and p-lac-
test. Aspirate as well as blood should be sent for culture, tam antibiotics also appear to be effective in vitro against
which will confirm the diagnosis. Y pestis; however, further investigation is still needed.
Antibiotic resistance has not been seen with plague;
therefore, there is no indication for the use of multiple
Treatment antibiotics in the treatment of plague. Buboes usually
resolve spontaneously. Occasionally they may become
Untreated plague may evolve into a fulminant illness fluctuant and require incision and drainage. Despite the
complicated by septic shock, with an estimated mortality development of disseminated intravascular coagulation
of greater than 50oh. Hospitalization, fluid hydration, and and purpura in severely ill patients, neither heparin nor
early treatment with effective antibiotics can be lifesav- steroids have had any proven benefit in the treatment of
ing. Streptomycin is the drug of choice for the treatment plague. Many patients who present with plague are dehy-
ofplague. It can reduce the case fatality rate to less than drated due to fever, nausea, and vomiting, or they may be
5%. No other drug has been demonstrated to be more effi- hypotensive. In either case they may require vigorous
cacious or less toxic. Streptomycin should be adminis- fluid resuscitation with a balanced saline solution.
tered intramuscularly, in two divided doses daily, totaling
30 mg per kilogram of body weight per day for l0 days.
Most patients improve rapidly, and they defervesce in Prevention
approximately 3 days. A 10-day course of therapy is rec-
ommended because viable bacteria have been isolated As soon as a diagnosis of plague is suspected public
from buboes of patients with plague during convales- health officials should be notified. Patients with uncom-
cence. During a 1O-day course of streptomycin, the risk of plicated infections who are promptly treated are not a
vestibular damage and hearing loss is minimal. The health hazard to other persons. If pulmonary symptoms
antibiotic, however, should be used cautiously during were prominent from the beginning of the illness, a
pregnancy, in the elderly, and in patients with previously human or animal source and other contacts of that source
impaired hearing. In such patients, the course of therapy must be rapidly identified. Those patients with cough or
may be shortened to 3 days after the patient becomes other signs of pneumonic plague must be placed in respi-
afebrile. Renal failure with this regimen is rare; however, ratory isolation for at least a period of48 hours after the
the serum creatinine should be monitored, and the dose of start of antibiotic therapy, or until sputum cultures are
streptomycin reduced if the creatinine concentration rises negative. The close (within 2 m) contacts of an index case
significantly. In patients who present with renal impair- of plague must be identified and evaluated for prophy-
ment, the dosage of streptomycin should be adjusted laxis. Reliable contacts can be instructed to take their
accordingly. Other aminoglycosides known to be effective temperatures and to seek medical attention immediately
for treatment of plague are gentamicin and kanamycin. should they develop a fever or any respiratory symptoms,
Tetracycline is an alternative therapy for pfague in including a sore throat. Antibiotic prophylaxis may be
patients who are allergic to streptomycin or who prefer given to heavy contacts. Tetracycline is an excellent drug
oral treatment. Tetracycline is administered orally in a for the prophylaxis of plague in patients for whom it is
dose of2 to 4 g per day in four divided doses for 10 days. not contraindicated.
 Sysrervnc INpncrrous Drsorurns / 447

An inactivated plague vaccine is available for travelers in the 1950s, with the development of handheld manual
to endemic areas and for individuals who must live or ventilators for polio, did this mode of therapy become
work in close contact with wild rodents. It is recom- available.
mended for laboratory workers performing research with There are fewer than 100 cases of tetanus yearly in the
Y pestis or with frequent exposures to clinical or field- United States, the majority in the elderly. Worldwide,
collected materials possibly infected with plague. Persons over a million cases per year are recorded; 50% of these
in wilderness locations with limited access to medical occur in neonates, a reflection of inadequate maternal
care, such as park and forest rangers, and fish and immunization and unsterile obstetrical practices, with an
wildlife workers, may be candidates for vaccine. Simi- estimated mortality rate of 90%o.
larly, Peace Corps volunteers, journalists, photographers, When introduced into a wound under appropriate
disaster workers, and others who may have long-term anaerobic conditions, Clostridium tetani, a ubiquitous,
potential exposures in endemic areas with limited access gram-positive, anaerobic bacillus, forms a highly stable
to health care should be considered candidates for plague spore. The spores germinate and elaborate two toxins: (l)
vaccine. The vaccine is initially administered as a pri- tetanolysin, of unclear significance; and (2) Tetanospas-
mary series of two doses with a recommended 1- to 2- min, the prime etiologic agent of tetanus.
month interval between doses. Booster injections are Tetanospasmin is a 151-kd polypeptide that requires
given every 6 months as long as the exposure continues. cleavage for activation. The heavy chain facilitates
The control of plague by local health departments attachment and neurocellular internalization, whereas the
requires the knowledge of the epidemiology of the light chain inhibits neurotransmitter release. Initially,
infected animals, the vectors of transmission, and the alpha motor neurons are involved. The toxin is then trans-
potential sources of human contact. Control measures ferred to the neurons and the extracellular space of the
usually involve the use of insecticides to control fleas, central nervous system via retrograde transport and diffir-
trapping of animals, and the education of people to avoid sion. Once in the CNS, the toxin affects presynaptic T-
contact with certain animals. Persons living in endemic aminobutyric acid (GABA)ergic and postsynaptic glycin-
areas should provide themselves with personal protection ergic neurons, preventing the release of their inhibitory
such as living in rat-proof houses, wearing shoes and gar- neurotransmitters. The resulting disinhibition permits
ments that cover the legs, and applying insecticides. Sick uncontrolled agonist and antagonist muscular contraction
animals, especially cats, should not be handled. Dead ani- and spasm characteristic of generalized tetanus. In addi-
mals should not be skinned by hunters with ungloved tion to its local neuromuscular actions and CNS distur-
hands. bance, tetanospasmin also involves the autonomic
nervous system, clinically manifested as a labile, sympa-
thetic overflow, not unlike a pheochromocytoma. An
SELECTED READING important consideration during management is that once
internalized in a neuron, the toxin is no longer accessible
Bonacorsi SP, Scavizzi MR, Guiyoule A, et al. Assessment of a fluoro-
quinolone, three beta lactams, two aminoglycosides and a cycline in the to antitoxin, resulting in prolonged recovery until new
treatment of murine Yersinia pestis infection. Antimicrob Agents presynaptic receptors are formed.
C hemother 1 994;38(3):48 l-486. The diagnosis of tetanus is clinical; cultures are of
Butler T. Yersinia irfections: centennial of the discovery of the plague
bacillus. CIin Infect Dis 1994'19:655-663. minimal value. Up to 2lo/o of patients have no obvious
Craven RB, Barnes AM. Plague and tularemia. Infect Dis CIin North Am demonstrable wound. There are essentially four variants
I 99 I ;5( I ): I 65-l 75.
oftetanus, a reflection ofthe groups ofneurons involved:
Craven RB, Maupin GO, Beard ML, et al. Reported cases of human plague
in the United States, 1970-199 l. J Med E ntomol 1993;30(4):7 58-7 61. (1) generalize4 (2) cephalic, (3) neonatal, and (4) local
Doll J, Fink TM, et al. Plague. MMII/R 1992;41,(42):787-790. tetanus. The shorter the incubation period and period of
Morris JT, McAllister CK. Bubonic plaglue. South Med J 1992;85(3): onset, the worse the prognosis. The portal of entry is also
326-327.
Opulski A, MacNeil E, et al. Pneumonic plague-Arizona, 1992. MMWR an important prognostic indicator; burns, umbilical
1992;41(40):731-739. stumps, surgical procedures, open fractures, IM injec-
Weinberg AN. Respiratory infections transmitted by animals. Infect Dis tions, and septic abortions all potentiate the likelihood of
Clin North Am I 99 1 ;5(3):65 1-661.
Werner SB, Murry R, et al. Human plaglue. MMIIR 1994;43(13):242-246. severe disease.
Trismus, "lock jaw," is the most common presenting
symptom of generalized tetanus. Also common is risus
Tetanus (9.1.7) sardonicus, or "sneering grin." The most dramatic pre-
sentation, however, is generalized muscular contractions
Tetanus is a toxin-mediated disease first described by with opisthotonos and maintenance of consciousness.
the ancient Egyptians with subsequent graphic illustra- The diffirse spasms result in severe pain. Diaphragmatic
tions over the following centuries. In the early l9th cen- and vocal cord involvement may result in respiratory
tury, the use of curare, coupled with artificial ventilation, compromise. Progression of the disease for up to 2 weeks
was postulated as a treatment for tetanus. However, only followed by a prolonged recovery period may occur.
448 / ElarRcnNcv MnucrNs: Tsn Conn CuRrlculurr,r

Cephalic tetanus usually involves the lower cranial Individuals with complete immunization history
nerves.A Bell's palsy is often the first presenting com- should be reimmunized if the wound is tetanus prone
plaint. Cephalic tetanus has been linked to otitis (penetration wounds, those with dirt or saliva, burns,
media/externa and has occurred in fully immunized indi- frostbite injuries, wounds with devitalized tissue) and the
viduals. last booster was greater than 5 years.
Neonatal tetanus generally results from an infected Individuals with a history of incomplete immunization
umbilical stump. Nonimmunized mothers cannot confer or those with no recall should receive a Td and HTIG
passive immunity to their neonates. Newborns present I (250u IM) for a tetanus-prone wound followed by com-
to 2 weeks after birth with a weak sucking reflex rapidly plete immunization. For a clean wound, passive immu-
progressing to generalized spasms. A high mortality is nization is not required.
associated with severe autonomic dysfunction. In general, reactions to tetanus immunization are mild
Localized tetanus is characterized by rigidity within and include localized swelling, erythema, and pain.
the vicinity of the initial wound. Additionally, there is Rarely, a hypersensitivity reaction may occur.
muscular weakness and often enhanced deep tendon Along with appropriate immunization, proper wound
reflexes (DTRs). Symptoms usually resolve with appro- management is necessary to reduce the risk of tetanus
priate treatment, but progression to generalized tetanus and includes thorough wound irrigation and the debride-
may occur. ment of devitalized tissue.
Strychnine poisoning involves postsynaptic glyciner-
gic neurons and is the only close mimicker of generalized
SELECTED READING
tetanus. Dystonic reactions, meningitis, peritonsillar and
retropharyngeal abscesses, seizures, hypocalcemia and Bleck TP Tetanus: pathophysiology, management, and prophylaxis. Du
"stiff-man syndrome," a consequence of antibodies Mon 199 1 ;37 (9) :5 47 403.
toward GABAergic neurons, should be considered in the Giangrasso I Smith RK. Misuse of tetanus immunoprophylaxis in wound
carc. Ann Emerg Med 1985;14(6):573-579.
differential diagnosis. Kefer MP. Tetanus. Am J Emerg Med 1992;10(5):445448.
Therapy begins with early and appropriate airway La Force M, et al. Tetanus in the United States: epidemiologic and clinical
maintenance. Patients may require orotracheal intubation features NEngl J Med 1969;280(11):569-574
Peebles TC, Levine L, Eldred MC, Edsall G. Tetanus-toxoid emergency
or tracheostomy in the event of vocal cord and/or boosters. N Engl J Med 1969;280(11):575-581.
diaphragmatic spasms. Unregulated muscular contrac- Sutton DN, Tremlett MR, Woodcock TE, Nielsen MS. Management of
tions should be controlled with benzodiazepines as well autonomic dysfunction in severe tetanus: the use ofmagnesium sulphate
and clonodine. Intensive Care Med 1990;16(2):75-80.
as paralytics, if needed. The liberal administration of pain
medication is warranted. Human tetanus immunoglobulin
(HTIG) (500 U IM) and either tetanus-diphtheria toxoid Toxic Shock Syndrome (9.1.8)
(Td), diphtheria-pertussis-tetanus (DPT), or tetanus tox-
oid (TT) at a separate site (deltoid muscle), should be In the late 1970s Todd et al. first described toxic shock
given. The use of antibiotics iscontroversial but may syndrome (TSS) as a distinct clinical entity characteized
serve to reduce the overall toxic burden by eradicating by profound hypotension, fever, multiorgan involvement,
Clostridium tetqni. Control of autonomic dysfunction is and a diffuse erythroderma that subsequently desqua-
essential; the use of labetolol, clonidine, morphine, mates. TSS gained public notoriety in the early 1980s due
MgSOa, or epidural blockade has been suggested. to an unsettling number of cases noted in menstruating
Complications associated with tetanus include hypoxic women, epidemiologically related to the use of highly
organ injury, pneumonias, autonomic lability, rhabdomy- absorbent tampons. With the withdrawal from the market
olysis, spine and long bone fractures, gastrointestinal of these tampons and heightened awareness of the occur-
stress ulcerations, deep venous thrombosis (DVT) and rence of TSS, and most likely other concomitant factors,
pulmonary emboli, and decubitus ulcers. the number of catamenial-related cases of TSS has been
There is no natural immunity to tetanus and infection greatly reduced, with non-menses-related cases now con-
does not confer immunity. stituting the greater fraction.
Adsorbed toxoid should be given during infancy; three The development of TSS requires colonization or
initial doses of DPT I to 2 months apart followed by a infection by a toxigenic strain of Staphylococcus aureus
booster at age I and just prior to entering grammar (approximately 20%) elaborating the exotoxin toxic
school. Children younger than 7 receive DPT unless shock syndrome toxin-l (TSST-l), a22-to 24-kd protein.
allergic to the pertussis component. Greater than 90%o of the aureus isolates from patients
^S.
Following initial immunization, Td should be adminis- with menstrual related TSS produce TSSTI, whereas
tered every 10 years. The elderly with unclear immuniza- approximately 60% of isolates from non-menstrual-
tion history should receive a Td and two subsequent derived cases elaborateTSSTl. The effects ofTSSTl are
boosters, the first I to 2 months and the second 6 to 12 protean and it is likely that the manifestation of TSS is
months following the primary Td. related both to the direct activity of the toxin as well as
 Svsrnrulc INrncuous Drcorunns / 449

induction of other mediators such as interleukin-l and object. The vaginal walls are usually erythematous and a
tumor necrosis factor. In addition, host susceptibility is "strawberry cervix" may be appreciated. Menstrual
related to a deficiency in protective antibodies directed blood and a malodorous discharge may be present, with
toward TSST-1. An anaerobic, neutral pH, magnesium- Gram stain of the discharge revealing gram positive
deficient microenvironment is the ideal condition for the cocci in clusters.
elaboration of TSST1 by toxigenic S. qureus. The differential diagnosis of TSS includes staphylo-
Toxic shock syndrome is characterized by hyper- coccal-scalded skin syndrome, Kawasaki disease, scarlet
pyrexia, a fine, diffuse, erythroderma that spreads cen- fever, Rocky Mountain spotted fever, leptospirosis, ery-
trifugally and desquamates in I to 2 weeks (especially thema multiforme major, typhus, Lyme disease, menigo-
palms and soles), nausea, vomiting, diarrhea, cephalgia, coccemia, staphylococcal food poisoning, gram-negative
pharyngitis, painful myalgias. and profound hypotension. urosepsis, and toxic streptococcal syndrome. Toxic strep-
It is a specific clinical diagnosis that must meet the tococcal syndrome warrants special mention as it is a
CDC's strict case definition criteria (Table 9-7). Renal toxin-related condition that closely mimics staphylococ-
involvement is common and may be secondary to prere- cal TSS. Streptococcal pyrogenic exotoxin A, synthesized
nal failure, acute tubular necrosis, or rhabdomyolysis, by Streptococcus pyogenes, a group A streptococcus, is
resulting in elevated BUN, creatinine, metabolic acidosis, thought to be the etiologic agent responsible for the
and diminished urine output. Diarrhea, preceded by vom- hypotension, multisystem failure, hypocalcemia, and
iting, is often seen as is elevation in hepatic transami- thrombocytopenia observed in toxic streptococcal syn-
nases, most often the y-glutamyl transpeptidase (GGTP). drome, similar to staphylococcal TSS. Skin and soft tis-
Adult respiratory distress syndrome (ARDS) may occur, sue portals of entry as well as respiratory and genitouri-
and pleural effirsions are commonly present in severe nary sources have been identified as potential sites of
cases. Muscle breakdown may result in gross elevation of infection by toxigenic strains of S. pyogenes.
creatine kinase with resultant myoglobinuria. Therapy begins with aggressive management of the
Central nervous system encephalopathy may range shock state with the infusion of intravenous crystalloid
from a mild headache to severe disorientation and solution (normal saline or lactated Ringer's). In the pres-
seizures. Dermatologically, the classical rash associated ence of refractory hypotension, peripheral pressors are
with TSS is a scarlatiniform exanthem that is nonpru- employed. A concerted effort to identifl, and remove the
ritic, blanching, and generally begins on the lower torso, source of the infection (e.g., tampon, surgical wound
eventually spreading and involving the extremities. Con- infection, soft tissue abscess) is essential. The use ofanti-
junctival and tympanic membrane hyperemia is often staphylococcal antibiotics is controversial since this is
noted along with erythematous mucous membranes and primarily a toxin-mediated condition.
a "strawberry tongue." Mild anemia may be present However, antimicrobial agents may serve to eradicate
along with other hematologic abnormalities including toxin-producing staphylococci, thereby lowering the
microangiopathic hemolysis, leukocytosis, eosinophilia, overall toxic burden. The use of corticosteroids is also
thrombocytopenia, and disseminated intravascular coag- controversial and not well established. Estrogens may
ulation. A pelvic examination is essential in any woman improve catamenial-related TSS by the cessation of
with TSS for the removal of a tampon or other foreign menses. Patients with TSS have a low anti-TSSTI anti-

TABLE 9-7. Centers for Disease Control case definition of toxic shock syndrome
Fever: temperature >38.9oC (1 02"F)
Rash: diffuse macular erythroderma
Desquamation: 1-2 wk after onset of illness, particularly of palms and soles
Hypotension: systolic blood pressure <90 mm Hg, orthostatic drop in diastolic >15 mm Hg; orthostatic
syncope or dizziness
lnvolvement of three or more of the following organ systems
Gastrointestinal: vomiting or diarrhea at onset of illness
Muscular: severe myalgia or twice-normal creatine phosphokinase
Mucous membranes: vaginal, oropharyngeal, or conjunctival hyperemia
Renal: twice-normal BUN or creatinine or pyuria (>5 WBC/hpf)
Hepatic: twice-normal bilirubin or transaminases
Hematologic: platelets <1 00,000imm3
Central nerv-ous system: disorientation or alterations in consciousness without focal neurologic signs
when fever and hypotension are absent
Negative results on following tests, if obtained:
B-lood, throat, or cerebrospinal fluid cultures (blood culture may be positive for S. aureus)
Serologic tests for Rocky Mountain spotted fever, leptospirosis, or measles
BUN, serum urea nitrogen; WBC, white blood cells; hpf, high-power field.
450 / ElrpncrNcy MrorcrNn: Tnn Conn CunrucuLUM

body titer and therefore may benefit from the passive Lyme disease is endemic. Typically, Lyme disease occurs
immunization rendered by the administration of immuno- in areas where deer populations are increasing. This usu-
globulins. ally parallels suburban expansion into areas that were
previously farmland.
SELECTED READING

Brady WJ, DeBehnke D, Crosby DL. Dermatological emergencies. Am J Clinical Findings

E merg Me d 1 99 4;1 2(2) :2 17
-237 .
Freedman JD, Beer DJ. Expanding perspectives on the toxic shock syn-
Lyme disease can be divided into three groups: (l)
drome. Adv Intern Med 1991;36:363-397.
Reingold AL. Toxic shock syndrome: an update. Am J Obstet Gynecol early localized infection, (2) early disseminated infection,
199 I ;r 65 (4): 123 6-1239. and (3) late Lyme disease. Early disease may begin within
Resnick SD. Staphylococcal toxic-mediated syndromes in children. Senin
Dermatol 1992;1 1(1): I 1-18.
several hours of infection, or up to several weeks or
Strausbaugh LJ. Toxic shock syndrome: Are you recognizing its changing months later. Early localized infection is characterized by
presentations? Postgrad M ed I 993 ;94(6): 1 07-1 I 8. erythema chronicum migrans (ECM) without any other
manifestations. Erythema chronicum migrans occurs in
about half of the cases of Lyme disease. It is an expand-
Spirochetes (9.1.9)
ing erythematous rash usually with a well-demarcated
border. The primary lesion occurs at the site of the tick
Lyme Disease (9.1.9.1)
bite, with erythema expanding outward. ECM is often
raised, is usually not painful, and may become indurated,
Lyme disease was first observed in 1975 (as Lyme
warm, and itchy. It is usually larger than 5 cm in size, and
arthritis) due to an unusual epidemic of arthritis occur-
ring in a group of children in the town of Lyme, Con- may expand within hours. ECM may develop within
hours or up to 30 days after a tick bite, but rarely beyond
necticut. The arthritis was often preceded by a distinctive
this time. ECM may appear only occasionally during the
skin rash, erythema chronicum migrans (ECM). The cor-
day, most frequently in the morning. As ECM only causes
relation between the bite of a tick and ECM was already
moderate discomfort, it may go unnoticed by the patient.
known in Europe. The multisystem nature of the illness
was soon assesse4 and it was more correctly renamed
If left untreated the rash resolves, without scarring, sev-
eral days to several weeks after onset.
Lyme disease. Lyme disease, the entity as we know it
Early disseminated disease is characterized by ECM-
today, is a complex immune-mediated multisystem disor-
associated general systemic manifestations similar to
der that may affect patients of any age or sex. The disease
other infective diseases. Some patients may have minor
is caused by a spirochelte Borrelia burgdorferi, which is
constitutional symptoms such as headache, low-grade
transmitted to humans via a tick bite most commonly
fever, and myalgias in addition to ECM. Other patients
from the species lxodes (the deer tick). Lyme disease is
generally a benign disorder that is frequently overdiag-
may appear quite toxic with high fever, chills, severe
headache, stiff neck, malaise, arthralgias, and nonproduc-
nosed and overtreated. The disease has attracted great
tive cough. Patients may also present with hematuria and
media attention, and although it may be serious, inappro-
edema of the testes. Secondary skin lesions may cover the
priate public anxiety has developed.
entire body. Signs of hepatitis may be seen in 15% of the
patients with early disseminated disease. Mild to moder-
Epidemiology ate elevation of the transaminases resolves over several
weeks.
Lyme disease is particularly prevalent in North Amer- Lyme carditis occurs in l0o/o to l5Yo of patients with
ica and Europe, and has also been reported in South early disseminated Lyme disease in the United States. In
America, Asia, and Africa. In the United States, B. Europe, the prevalence of Lyme carditis is much lower.
burgdorferi infection has been reported in 46 states, and Similarly, while chronic cardiomyopathy secondary to
now ranks first among the arthropod-transmitted Lyme carditis has been reported in Europe, there have
zoonoses. Lyme borreliosis is secondary to infection with been no such cases reported in the United States. The dif-
a gram-negative microaerophilic bacterium belonging to ferent clinical manifestations in Europe and the United
the order Spirochetales. Ixodidae ticks may infest domes- States are thought to be due to strain heterogenicity of .8.
tic mammals,large, medium-sized, and small wild mam- burgdorferi. Lyme carditis is characterized by a mild
mals, reptiles, and birds. They are smaller than common myocarditis usually associated with variable degrees of
dog and wood ticks. The peak incidence of Lyme disease atrioventricular node conduction abnormalities. Approxi-
appears to be at the end of spring and early summer; how- mately 50o/o of the affected patients develop complete
eveq late manifestations may occur throughout the year. heart block, which is always reversible. Lyme carditis has
This coincides with the peak activity of ticks. Humans not been shown to affect heart valves or cause distal con-
may be exposed when frequenting woodlands where duction system disease.
 Svsrnrr,uc INrncrous Drsononns / 451

Neurologic manifestations can occur during any phase the eye early and remains dormant, accounting for both
of Lyme disease and frequently present the most signifi- early and late findings. Approximately l0% of the
cant diagnostic problem. In early disseminated Lyme dis- patients with early Lyme disease develop conjunctivitis.
ease, patients can develop disease of the peripheral ner- Several months later this may be followed by a keratitis,
vous system, meningitis, or encephalitis. Symptoms are iridocyclitis vasculitis ofthe retina, choroiditis, and optic
usually of acute onset. Cranial neuropathies are common. neurosis. Long-term inflammation can lead to loss of
Most common are Bell's palsies and ophthalmoplegia eyesight. Management includes the use of intravenous
with diplopia. The symptoms may be bilateral or unilat- antibiotics.
eral, may wax and wane, and present alone or associated
with other manifestations of Lyme disease. Headache,
fever, and stiffneck are common complaints in early dis- Diagnosis
seminated Lyme disease. A significant percentage of
these patients are found to have Lyme meningitis. Some The diagnosis of Lyme disease relies on clinical and
patients may present with signs and symptoms more sug- epidemiologic criteria, with the support of serologic and
gestive of a meningoencephalitis, with acute cognitive histologic investigations. There is no single highly sensi-
difficulties and emotional lability. If not treated, the neu- tive and highly specific marker for Lyme disease, but
rologic manifestations of Lyme disease may last for under the appropriate clinical conditions, standard
months, but they usually will resolve even without antibi- immunologic assays are very reliable. Anti-B. burgdor-
otic therapy. feri antibodies of the immunoglobulin M (igM) class are
Lyme arthritis is usually a late manifestation of Lyme detectable as early as 2 weeks after the onset of ECM, but
disease, but many patients develop arthralgias early in the may take as long as up to 2 months. They peak at 4 to 6
illness. Some patients may develop frank arthritis within weeks and are usually no longer detectable after 8 weeks.
days of the onset of the illness. Lyme arthritis may also Both immunofluorescent assays (IFA) and enzyme-linked
present as migratory musculoskeletal pain similar to that immunosorbent assays (ELISA) are available. ELISA
in patients with fibromyalgia. Articular manifestations tests are more sensitive and specific, with a sensitivity in
are more common in the United States, where 60% of the early Lyme disease of 40% to 60oh that increases to 95%o
cases develop arthritis. Lyme arthritis is an asymmetric, in late Lyme disease.
oligoarticular arthritis, fypically involving large joints. While serologic testing is extremely useful in diagnos-
Involved joints are painful, warm, erythematous, edema- ing Lyme disease, it is subject to inherent limitations.
tous, and are functionally impaired. The arthritis tends to Testing should not be used as a screening tool, and should
occur in intermittent attacks that may last from several only be performed when there is significant likelihood
days to several weeks. Approximately l0% of the cases that the disease is present. Both false-negative and more
develop a chronic arthritis that may last 2 to 3 years after commonly false-positive results occur. Therefore, labora-
a period of intermittence. The knees are the most com- tory testing must be interpreted within context of the
mon affected site for chronic arthritis. Large joint effrr- patient's clinical picture. In early Lyme disease serodiag-
sions are common in the knees. The arthritis is usually nosis may have low sensitivity, and clinical diagnosis
less painful than that of rheumatoid arthritis, and typi- based on symptoms, history of exposure, and associated
cally morning rigidity is absent. Lyme arthritis frequently ECM or rising convalescent titers 4 to 6 weeks later is
resolves without treatment and with little or no joint dys- more helpful. The assay may be reactive to antibodies of
function. A small group of patients may develop chronic other spirochetes, resulting in a false-positive Lyme
unremitting erosive arthritis that often fails to respond to assay. In addition, there may be a background seroposi-
antibiotic therapy. Although antibiotic therapy clearly tivity rate, ranging from5%oto25o/o, in populations resid-
affects the natural history of Lyme arthritis, not all ing in Lyme endemic areas due to subclinical exposure to
patients immediately respond and it may take several B. burgdorferi. In late Lyme disease it is important to
months for the symptoms to resolve even after successful determine whether signs and symptoms fit the clinical
antibiotic treatment. syndrome. In such individuals, serologic testing can be
Late Lyme disease can occasionally affect the central used to establish or exclude the diagnosis. Serologic test-
nervous system. Patients may have symptoms of low- ing is much more reliable in late Lyme disease than in the
grade encephalopathy such as forgetfulness, irritability, early stages of disease.
change in personality, drowsiness, fatigue syndromes, In patients with Lyme meningitis, the CSF is almost
and in some cases upper motor neuron disease. These universally abnormal. CSF abnormalities usually appear
patients almost always have earlier manifestations of the 3 to 4 weeks after inoculation and may persist for months.
disease such as ECM, cranial nerve palsies, or The CSF pleocytosis seen in Lyme meningitis is domi-
oligoarthritis. nated by lymphocytes and monocytes. Because of this,
Eye involvement in Lyme disease is rare, but can Lyme meningitis is often confused with viral meningitis.
occur at any stage ofthe illness. The spirochete invades An elevated CSF protein is common in patients with
452 / EruencrNcy MEucrNr: THr Conr CunnrcuI-uM

Lyme meningitis. Antibodies to B. burgdorferi can be with late disease should be treated with intravenous
found in the CSF of infected individuals. antibiotics. Tetracycline products should be avoided in
pregnancy.
Treatment Antibiotic prophylaxis following asymptomatic tick
bites in endemic areas is generally not recommended.
Therapy of Lyme disease is tailored to the individual Individuals with asymptomatic deer-tick bites are at low
patient (Table 9-8). In general, most patients with early risk for developing infection. In pregnancy, however, pro-
Lyrne disease are treated with oral antibiotics. Patients phylactic treatment with a l0- to 14-day course of oral
with carditis, meningitis, and necrologic manifestations are antibiotics is probably warranted based on the potential
adverse effects on the fetus.
usually treated with intravenous antibiotics. Lyme arthritis
and late or chronic Lyme disease can be treated either In most instances Lyme disease can easily be managed
orally or with intravenous antibiotics; however, oral ther- in the outpatient setting. Coordination with primary care
providers and home nursing providers can even allow for
apy may not be sufficient to sterilize a possible occult cen-
tral nervous system focus. Patients who fail oral therapy the administration of intravenous antibiotics without
admission to the hospital. Patients with Lyme carditis and
should be offered a course of parenteral antibiotics, but
meningitis should be admitted to the hospital and moni-
only after a period of observation of 2 to 4 months, as
tored.
Lyme arthritis may resolve gradually. The severity of Lyme
disease at its outset to some extent predicts the likelihood
of the development of late manifestations. Treatment rec- Prevention
ommendations offer arange of therapy duration, anticipat
ing that the initially sicker individuals will require longer Avoidance of the tick habitat would be the best pre-
periods of treatment. There are no studies that validate giv- vention of Lyme disease. With the continued expansion
ing several months of therapy in Lyme disease. of suburbs into rural woodlands, however, the likelihood
The treatment of Lyme disease in pregnancy is an area of exposure to a deer tick is increased. Pets such as dog
of special concern. Transplacental transmission of B. and cats can bring the tick into the home. Wooded patches
burgdorferi has been reported in the first trimester. There of landscape that can support deer increase the risk, and
have been several documented cases ofneonatal death as increased use of woodlands for recreation increase the
a result of untreated or inadequately treated Lyme disease exposure.
during pregnancy. Pregnant women with early Lyme dis- In high-risk areas for Lyme disease, individuals should
ease should be treated with oral antibiotics, and those take measures to protect themselves from tick bites.

TABLE 9-8. Therapy of Lyme disease

Drug Dose Duration
Oral therapy
Adults
Doxycycline 100 mg two times per day 14-28 days
Amoxicillin 500 mg three times per day 14-28 days
Tetracycline 500 mg four times per day 14-28 days
Cefuroxime 500 mg two times per day 14-28 days
Azithromycin 500 mg day 1;250 days 2 to 5
Children
Amoxicillin 40 mg/kg/day, divided dose 14-28 days
Erythromycina 30 mg/kg/day, divided dose 14-28 days
Penicillin G 25 to 50 mg/kg/day, divided dose 14-28 days
lntravenous therapy
Adults
Ceftriaxone 2 g per day or 19 two times per day 14-28 days
Cefotaxime 3 g three times per day 14-28 days
Penicillin G 20 million units/day, in six divided doses 14-28 days
Chloramphenicol 50 mg/kg/day in four divided doses 14-28 days
Children
Ceftriaxone 75-100 mg/kg/day per day 14-28 days
Cefotaxime 90-180 mg/kg/day, in two to three divided doses 14-28 days
Penicillin G 300,000 units/kg/day, in six divided doses 14-28 days
aErythromycin is less effective than the other drugs listed,
and should be reserved for chil-
dren under 9 years of age with documented penicillin allergy.
 Svsmwc INrncrous DrsononRs / 453

These measures include wearing light-colored clothing to house workers and fresh water fishing workers, and
make crawling ticks visible, tucking pant cuffs into socks recently nonvocational cases have been reported in those
to prevent ticks from gaining access to exposed skin, and engaged in recreational activities involving contact with
using repellents. Permethrin repellents can be applied to inland natural waterways. This is probably due to farm-
the clothes, which will enhance their protection, and lands draining into these bodies of water.
repellents containing DEET (1{N-diethyl-m-tolumide) In the United States leptospirosis is uncommon, with
can be applied to exposed skin areas. Daily inspections approximately 1 50 cases reported annually. Leptospirosis
for attached ticks should be routine in endemic areas. is more common in tropical and subtropical climates. The
Attached ticks should be removed immediately with a peak number of cases occurs in the summer months,
fine forceps. The transmission ofB. burgdorferi increases especially during periods of high rainfall. Leptospires are
with time. The maximum efficiency of transmission by extremely infectious. The mechanism by which lep-
the infected tick does not occur until after being attached tospirosis causes illness in unclear. It may be a combina-
for 48 hours. tion ofboth toxic factor produced by the organism as well
as damage secondary to an immunologic mechanism.
Many animals who carry the illness may exhibit pro-
SELECTED READING
longed urinary shedding of the organism without any
Couch P, Johnson CE. Prevention of Lyme disease. Am J Hosp Pharm clinical illness.
1992;49:1164-1173.
Fish D. Environmental risk and prevention of Lyme disease. Am J Med
1 995;98(suppl 4.A):s2-s9. Clinical Findings
Ilowite NT. Muscle, reticuloendothelial, and late skin manifestations of
Lyme disease. Am J Med 1995;98(suppl 4A):s63-s69. The diagnosis of leptospirosis should be suspected in
Jantausch BA. Lyme disease, Rocky Mountain spotted fever, ehrlichiosis:
emerging and established challenges for the clinician. Ann Allerg' 1994'.
patients who presents with fever, headache, severe myal-
73:4-11 gias, nausea, vomiting, and conjunctival suffirsion. Very
Lastavica CC, Wilson ML, Bernardi VP, et al. Rapid emergence of a focal commonly patients with leptospirosis are misdiagnosed
epidemic of Lyme disease in coastal Massachusetts. NErgl../ Med 1989;
320(3):133-137. with aseptic meningitis, which may occur in up to l8% of
Lesser RL. Ocular manifestations of Lyme disease. Am J Med 1995; the patients with leptospirosis. After exposure, the incu-
98(suppl 4,A'):s60-s62. bation period ranges from 2 to 20 days, with most infec-
Meyers SA, Sexton DJ. Dermatologic manifestations of artkopod-borne
diseases. Infect Dis Clin NorthAm 1994;8(3):689-712. tions occurring in the 7 - to 14-day range. One-half of the
Olsen LJ, Emmanuel OC, Clements IP. Cardiac involvement in Lyme dis- patients present with abrupt onset of symptoms over a 1-
ease: manifestations and management. Mayo Clin Proc 1986:61: to 2-hour perio4 which persist for 4 to 9 days. Some 60%
745-749.
PachnerAR. Early disseminated Lyme disease: Lyme meningitis . Am J Med of the patients have accompanying nausea and vomiting.
1 995;98(suppl 4,A.):s30-s42. Fever is usually greater than 102oF. Headache is usually
Scarpa C, Trevisan G, Stinco G. Lyme borreliosis. Dermatol CIin 1994; severe and retrobulbar or occipital in nature. Patients may
12(4):669-68s.
Schoen RT. Identification of Lyme disease. Rheum Dis Clin North Am also may complain of sore throat, lymphadenopathy, and
1994;20(2):361-369. rash,leading to the misdiagnosis of a viral illness. Rarely
Sigal LH. Lyme disease: testing and treatment. Rheum Dis Clin North Am patients may present with jaundice and gastrointestinal
1993;19(1):79-93.
Sigal LH. Management of Lyme disease refractory to antibiotic therapy. hemorrhage. On physical examination, up to 25o/o of the
Rheum Dis Clin North Am 1995;21 (l):217-230. patients have hepatomegaly. Splenomegaly is a less com-
Sigal LH. Current recommendations for the treatment of Lyme disease. mon finding. Muscle pain and tenderness are classic fea-
Drugs 1992;43(5):683-699.
Spach DH, Liles WC, et al. Tick borne diseases in the United States. NEngl tures of leptospirosis. The illness may mimic pancreatitis
J M e d 1 993 ;329 (1 3):93 6-9 47 . and cholecystitis as acute dilatation of the gallbladder
Zemel LS. L),rne disease-a pediatric perspective. J Rheumatol 1992; may occur with leptospirosis. Pulmonary involvement in
19(suppl 34):sl-s13.
leptospiral infection is common and usually mild, pre-
senting with cough. Rarely, however, it may be a pre-
Leptospirosis dominant symptom and the etiology for respiratory fail-
ure. Occasionally, patients may present with a change in
Leptospirosis is a disease caused by a tightly coiled mental status, encephalitis, and cranial nerve palsies. Pre-
spirochette Leptospira interrogans, with reservoirs of senting symptoms may range from a mild flu-like illness
infection in rodents, skunks, foxes, domestic livestock, to Weil's syndrome, characterized by profound jaundice,
and dogs. It is transmitted to humans when they come in mental status changes, hemorrhage, purpura or petechiae,
contact with infected tissues, fluids such as urine, or con- renal failure, and cardiovascular collapse. The first sign
taminated waters. Transmission may occur through cuts, of Weil's syndrome is usually jaundice, occurring
mucous membranes, and abraded skin. Leptospirosis is between the fifth and the ninth day. Often renal insuffi-
an occupationalhazzard of sanitation workers and farm- ciency accompanies the jaundice. Petechiae and purpura
ers. Leptospirosis has also been reported in slaughter- initially appear on mucosal surfaces. Most individuals
 454 / EvancrNcy MsucrNn: Tut Conr CunnrcuI-uM

rapidly recover; howeveq there is a l5o/o mortality with in the first 2 to 4 days of the illness. If given later, their
severe leptospirosis. effectiveness is unknown. The effect of antibiotic treat-
Leptospirosis usually lasts from 4 to 9 days, and ifleft ment on mortality is also unknown. Doxycycline prevents
untreated, most cases are nonfatal and self-limited. In the urinary shedding of bacteria. The mainstay of treat-
about 15% of the patients, the disease persists and may ment, however, is the close management of the renal,
last up to 7 weeks. Overall mortality from leptospirosis hepatic, hematologic, pulmonary, and central nervous
varies from 5o/o to l0%; however, it is age dependent, system complications of leptospirosis.
with30Yo mortality over age 60. Jaundiced patients have Young, otherwise healthy, non-toxic-appearing
a l5Yo mortality. patients can be managed with outpatient therapy. Elderly
patients or patients with other underlying illness need
Diagnosis close observation because of the sharp increase in mor-
tality in these groups.
The key to making a diagnosis of leptospirosis is to
have a high index of suspicion in patients who present
with symptoms of fever, headache, and myalgias, and Prevention
who have a history of potential exposure to animals,
sewage, or natural bodies of fresh water. An early symp- While effective vaccines for leptospirosis exist for ani-
tom in 80% of leptospirosis patients is an abnormal uri- mals, there is no such vaccine for humans. In high-risk
nalysis. Most commonly, microscopic hematuri a, piyuria, groups, doxycycline, 100 mg once a week, prevents lep-
and proteinuria are also found. Leukocyte counts are gen- tospirosis for periods up to 3 weeks. The efficacy for
erally less than 15,000 per cubic millimeter, but have longer periods is unknown.
been reported as high as 50,000 per cubic millimeter,
with a neutrophilic predominance. Anemia is uncommon. SELECTED READING
Thrombocytopenia and elevated prothrombin time have
been seen in some cases of leptospirosis, but this is not Alani FS, Mahoney LP, Ormerod Lp, et al. Leptospirosis presenting as atyp_
responsible for the hemorrhagic diathesis seen in patients ical pneumonia, respiratory failure and pyogenic mentngitis. J Infect
1993:27:281-283
with Weil's syndrome. da_Silva MD, Dias Carmargo E,yaz AJ, Batista L. Immunodiagnosis of
Liver function tests are frequently abnormal, with ele- human leptospirosis using salla. Trans R Soc Trop Ued nyg IISSZ;AA:
vations of up to 20 times normal being reported in some 560-56 I .
Farr RW. Leptospirosis. Clin Infect Dis 1995;21(1):l-6.
patients. The direct bilirubin may rise in severe lep-
Friedland JS, Warrell DA. The Jarisch-Herxheimer reaction in leptospiro_
tospirosis; however, it is usually below 20 mg per sis: possible pathogenesis and review. Rev ldect O* rcet;ti1Z|:
deciliter. Up to 25Yo of the patients may experience a rise 207-210.
Ue9!! Se, Johnson R. Leptospirosis. J Am Vet Med Assoc 1994;205(11):
in blood urea nitrogen. The creatinine kinase is frequently l5 l8-1523.
elevated in leptospirosis. O'Neit KM, Rickman LS, Lazarus AA. pulmonary manifestations of lep_
Cerebrospinal fluid examination may be abnormal in up tospirosis. Rev Infect Dis 1991;13:705-709.
Overstreet DS, Bowen MG, Hawkins SC, Roy TM. The respiratory compli_
to 90o/o ofthe patients. The total cell count is usually below
cations of leptospirosis. Kentuclq MedAssoc J 1991;99:270_213.
500 per cubic millimeter with a neutrophilic predomi- Shaked ! Shpilberg O, Samra D, Samra y Leptospirosis in pregnancy and
nance. The glucose concentration is usually normal and its effect on the fetus: case report and review. Clin Infeci nis 1-9ti3;fi:
protein usually ranges between 50 and 110 mg per 241143.
Teglia OF, Battagliotti C, Villavicencio RL, Cunha BA. Leptospiral pneu_
deciliter. The chest x-ray may appear abnormal in up to monia. Chest I 995; 108(3):874-875.
25o/o of the patients, with the most common abnormality Torre D, Giola M, Martegani R, et al Aseptic meningitis causedby Lep_
tospiru australis. Eur J Clin Microbiol Infect Dis 1994;13(6):496497
being a patchy bronchopneumonia, predominantly in the
lower lobes. ECG may reveal low voltage and bradycardia
or nonspecific ST changes in up to 40Yo ofthe patients. Syphilis (9.1.9.2)
The diagnosis can be confirmed by blood culture dur-
ing the first week of the illness, and by urine culture Syphilis, a disease caused by the organism Treponema
thereafter. Leprospires may be excreted in the urine for a pallidum, is characterized,by episodes of active and clin-
prolonged time even after clinical illness has resolved. An ically latent disease. The disease is almost always con-
ELISA is available to detect IgM antibodies to lep- tracted sexually; however, it can also be contracted con-
tospirosis in human serum and saliva, which is more genitally by transplacental inoculation. There have been
rapid than culture. occasional reports of unsuspecting health care workers
contracting the illness after examining a lesion. Congen-
Treatment ital syphilis is the oldest recognized congenital infection.
Syphilis may have alarge variety of presentations and at
The administration of tetracycline or doxycycline is one time was termed the "great imitator." If untreated" it
effective in shortening the course of leptospirosis if given may progress through primary, secondary, and tertiary
 Svsrnir,nc INrncrrous DrsonorRs / 455

stages. These episodes may overlap and exhibit a variable chancre by about 7 days. In women, the chancre may
course. Initial lesions may spontaneously heal, and the occur on the cervix and may be overlooked by the patient.
disease may remain clinically latent for a long period of While traditionally 90% of the chancres have occurred
time. In approximately 30% of the untreated patients, dis- in the genital region, extragenital chancres are occurring
ease ofthe heart, central nervous system, or other organs in higher proportion, especially in homosexual males, in
eventually develops. While syphilis is less cofirmon now whom rectal, perirectal, and oral chancres are commonly
than it had been in the prepenicillin era, over the past 10 seen. Rectal chancres may have an atypical appearance
years the disease has been on the rise. and mimic rectal fissures. Chancres may also appear on
the lips, fingers, nipples, and other body areas.
In general, the suspicion of syphilis should be raised
Ep i d e mi o I o gy / Path op hy s i o I o gy
with any ulcer occurring in the genital and rectal areas.
Several other conditions should also be included in the
Both the natural history and pathogenesis of syphilis
differential diagnosis. While herpes simplex or chancroid
are complicated and incompletely understood. T. pal- (Haemophilus ducreyi) may appear as a chancre, they are
lidum, a thin helical spirochete, was first discovered to be
typically painful. Chancroid usually presents with multi-
the causative agent in syphilis in 1905. The organism is ple ulcers that are exudative and nonindurated. Lym-
too thin to be visualizedby Gram stain, but can be visu- phogranuloma venereum may present as a small papule
alizedby dark-field microscopy, silver stains, or fluores-
with regional lymphadenopathy. Other conditions that
cent antibody methods. It has not been possible to culture
also must be considered include granuloma inguinale,
T pallidum in vitro.
drug eruptions, trauma, carcinoma, fungal infections, and
Syphilis is most prevalent in larger cities, and in lichen planus.
young, sexually active individuals. The peak incidence
Secondary syphilis usually develops 4 to 6 weeks after
for both men and women occurs between the ages of 20 the chancre has healed, although it may occur when the
and 24. There is an increased incidence with increased primary infection is still healing. This stage is character-
numbers of different sexual partners. By the mid 1950s,
izedby low-grade fever, headache, malaise, sore throat,
the efficacy of penicillin in treating syphilis had been and other systemic symptoms in 70Yo of the patients.
establishe4 and the incidence ofthe disease fell to a his- Most patients have generalized lymphadenopathy includ-
torical low in the early 1980s. Over the past 10 years, ing epitochlear nodes, which is believed to be unique to
however, the incidence of syphilis has been on the rise.
syphilis. Approximately 90% of the patients have a muco-
This presumably has been due to changes in sexual cutaneous rash that classically is characterizedby macu-
behavior.
lar and papular lesions on the palms and soles. The rash
T. pallidum may enter the body through minor abra-
usually begins on the trunk and spreads to the extremities,
sions in the epithelial surface or it may penetrate directly
eventually involving the entire body. The face, however,
through normal mucosa. The first lesions appear at the
is usually spared except around the mouth. The rash is
site of inoculation, presumably due to the high numbers
usually minimally symptomatic, nonpruritic, and varied
of treponemes at this site. Syphilis, however, is a systemic
in its appearance. The rash may be maculopapular, follic-
illness from its onset.
ular, or pustular in appearance, and is almost never vesic-
ular. The rash is usually widespread and symmetrical in
Clinical Findings distribution. Lesions ate typically polymorphic,
indurated (except in the earliest stages), and rounded,
The typical lesion of primary syphilis is the chancre, with a superficial scale. They range from pink and dusky
which usually presents as a papule at the site of T. pal- red to a coppery color. Upon healing, lesions may leave
lidum inoculation. The papule then ulcerates and its bor- areas of pigmentation or depigmentation. Ulceration of
ders become indurated" firm, and raised. Typically the the lesions may occur.
chancre is a painless, clean-based ulcer; however, on Lesions that occur around the hair follicles may result
occasion secondary infection may change the appearance in a patchy alopecia. In warm moist intertiginous areas,
of the ulcer and it may become painful. The inoculation large, flat-topped papular lesions may coalesce to form
period from the time of initial exposure to the develop- gray-white to erythematous plaques known as condylo-
ment of a primary lesion ranges from l0 to 90 days but is mara lata, which are highly infectious. Lesion of the
generally 14 to 2l days. Most chancres are solitary, rang- mucous membranes are very common. Superficial ero-
ing in size from several millimeters to 2 cm in diameter, sions called mucous patches may appear on the lips, oral
but multiple lesions are not uncommon. Most chancres mucosa, tongue, and genitalia. Mucous patches occur in
are found on the genitals and heal spontaneously in 4 to 6 approximately 35% of the patients, and are also very
weeks, often leaving a thin atrophic scar. They are usually infectious.
associated with painless regional lymphadenopathy, either Secondary syphilis is associated with ongoing spiro-
unilateral or bilateral, which follow the appearance of the chetemia, which accounts for the potential for multiple