CPM7th TB in Infancy and Childhood
CPM7th TB in Infancy and Childhood
CPM7th TB in Infancy and Childhood
Board of Trustees
President
Vice-President
Secretary
Assistant Secretary
Treasurer
Assitant Treasurer
Immediate Past President
Honorary President
Members
Mindanao
Visayas
Luzon
Estrella Paje-Villar, MD
Jocelyn J. Yambao-Franco, MD
Victor S. Doctor, MD
Aurora F. Bauzon, MD
Genesis C. Rivera, MD
Margaret L. Fong, MD
Joel S. Elises, MD
Fe Del Mundo, MD
Melinda M. Atienza, MD
Milagros S. Bautista, MD
Salvacion R. Gatchalian, MD
Alexander O. Tuazon, MD
Gregorio G. Cardona, Jr., MD
Suzette R. Elegado, MD
Roberto A. Espos, Jr., MD
Chair
Co-chair
Members
Contributors
Council Advisers
Handbook Advisers
1
TB
Exposure
Class I
3
Repeat
Mantoux Test
after 3 months
N
(+) result ?
Radiologic
findings &/or
signs/symptoms
suggestive of TB ?
N
9
Discontinue INH
If no BCG scan,
give BCG
TB infection
(Class II)
11
Continue > 6
months INH
Figure 1
infection
TB
(Class III)
10
Multiple drug
therapy
Pathogenesis
I. Portal of Entry
Entry into the body occurs largely by inhalation of
aerosolized particles containing 1-3 tubercle bacilli that
are deposited in the alveoli. Ghon and Kuedlich showed
in 1930 that the primary focus in 2,114 autopsies in
children was in the lung in 95.93 percent of case.1
III. Immunopathogenesis
There are four stages of the pulmonary pathology as
described by Dannenberg.2 In the first stage scavenging
nonactivated alveolar macrophages ingest the tubercle
bacilli which gets destroyed or inhibited depending on
the virulence of the organism and the innate microbicidal
ability of the macrophages.
The second stage is the stage of symbiosis. If the original macrophage fails to destroy the bacilli, the bacilli
undergo unrestrained replication, eventually destroying the macrophage. Other alveolar macrophages and
blood-borne monocytes are then attracted by chemotaxis
to wherever the bacilli are released. With time, more
and more macrophages and more and more bacilli accumulate in the developing lesion called tubercle or
granuloma2,4.
In the third stage, the logarithmic increase in the
number of bacilli is inhibited by the development
of cell-mediated immunity (CMI) and delayed-type
hypersensitivity (DTH). Although the macrophages
that first ingest M. tuberculosis may not kill these
organisms, they initiate both DTH and CMI, which
eventually contain the infection. Infected macrophages
present tuberculous antigens to T lymphocytes. T
lymphocytes get sensitized, to produce a progeny
of similarly reactive cells and secrete lymphokines
(IFN gamma and TNF) that activate macrophages.
Activated macrophages secrete lytic enzymes and
reactive metabolites that greatly enhance killing of
bacilli; but if released into surrounding tissue may
also cause tissue necrosis. This enhanced microbicidal
IV. Pathology
The lung lesion of primary tuberculosis is known as
the Ghon focus. It is usually located in the subpleural
area of the upper segment of the lower lobe or in the
lower segment of the upper lobes. It starts as a small,
ill-defined area of inflammatory consolidation. Concurrent with the onset of primary infection, the tubercle
bacilli, either free or within macrophage are carried via
lymphatics to regional (most often hilar and mediastinal)
lymph nodes. The primary pulmonary focus, infected
lymph nodes and associated lymphangitis form the
3,6
timing of the initial infection and its common complications. Figure 1 provides the clinician with a "realistic
prognosis, an understanding of what complication to
look for and when, and a more productive approach to
finding the infectious contact"1.
V. Timetable of Tuberculosis
Walgren's timetable described the usual early course and
Clinical Manifestations
I. Classification
II. Clinical Forms
A. Pulmonary/Endothoracic TB
1. Asymptomatic or Latent TB Infection (LTBI)
2. Primary/Childhood TB
3. Pleurisy with Effusion
4. Progressive Primary TB
5. Endobronchial TB
6. Miliary TB
7. Chronic Pulmonary TB
8. Tuberculoma
9. Pericardial TB
B. Extrapulmonary TB
1. TB of the Cervical Lymph Nodes (Scrofula)
2. TB of the Central Nervous System
TB meningitis
Tuberculoma/TB Abscess
3. Skeletal TB
TB of bone and joints: TB of the spine
(Pott's disease)
TB arthritis
4. Gastrointestinal TB
TB enteritis (tabes mesenterica)
TB peritonitis
Hepatobiliary TB
TB of the pancreas
5. Cutaneous TB (scrofuloderma)
6. Ocular TB (phlyctenular kerato conjunctivi-
tis)
7. Genitourinary TB
Renal TB
Genital TB
8. TB of the Middle Ear
III. Children with Tuberculosis in Special Situations
Congenital TB: Newborns of Tuberculous Mothers
Others
I. Classification
Overview
The onset of pleurisy is usually abrupt resembling bacterial pneumonia, with fever, chest pain, shortness of
breath and on physical examination, dullness to flatness
and diminished breath sounds. Fever may be high and in
untreated cases, last for several weeks. Lateral roentgenographic views are helpful in confirming the presence
of pleural fluid. Obliteration of the costophrenic sinus
may be the earliest radiologic sign of minimal fluid accumulation. Moderate effusion causes layering of fluid
density along the lateral chest wall. Massive effusion
may occupy one hemithorax, which demonstrates a
uniform density and dis-placement of the mediastinum
towards the contralateral side.
4. Progressive Primary Tuberculosis
Latent primary infection and childhood TB with chronicity becomes progressive, resulting in an area of advancing pneumonia, or it may result in acute dissemination
with meningeal or other localizing manifestations.
This is a serious complication in which the primary
pulmonary focus, instead of resolving or calcifying,
enlarges steadily and develops a large caseous center.
More severe fever, cough, malaise and weight loss as
well as classical signs of cavitation often accompany
a progressive primary lesion. Lung findings consist
of crepitant rales and/or diminution of breath sounds
over the area. Lymph node enlargement or lympha
denopathy often accompany the previously mentioned
manifestations.
5. Endobronchial Tuberculosis
Bronchial obstruction can be due to enlargement of
peribronchial lymph nodes. As the nodes enlarge,
they frequently impinge upon the neighboring regional bronchus, thus compressing it and causing
diffuse tuberculous inflammation of its wall even to
the point of obstructing the lumen. Three possible
immediate results of the bronchial obstruction are
the following:
Sudden death by asphyxia
Obstructive hyperaeration of a lobar segment,
a lobe or even an entire lung (emphysema)
Segmental lesions representing mainly atelectasis
and almost always involving the very segment
occupied by the pulmonary focus in endo-bronchial tuberculosis. Infected nodes adhere to an
adjacent bronchus and with extension of the
disease through the airway wall of the mucosa,
obstruction of the lumen results in atelectasis.
This is more likely to be present in the right lung,
particularly in the right middle lobe and to a lesser
extent, the right upper lobe. The right middle lobe
is most vulnerable when there is enlargement of
the hilar lymph nodes.
8.Tuberculoma
Asymptomatic rounded lesions may develop as a residual of parenchymal disease in the initial infection
or as caseation. Tuberculomas can form with small
caseous or granulomatous tissue surrounded by concentric fibrous tissue sometimes with calcification, often
confused with cancer.
This is an uncommon condition, complicating only
0.4% of untreated tuberculous infections in children.
It is due to direct invasion or lymphatic drainage from
caseous subcarinal nodes, serofibrinous or hemorrhagic
fluid accumulating between the visceral and parietal
surfaces of the pericardium. Sometimes extensive
fibrosis leads to obliteration of the pericardial sac,
with development of constrictive pericarditis some
years later.
The presenting symptoms are usually nonspecific and
include low-grade fever, anorexia, poor weight gain,
but rarely chest pain. On examination, a pericardial
friction rub may be appreciated. When pericardial
effusion is already present, distant heart sounds,
tachycardia, and narrow pulse pressure are noted14,15.
The diagnosis is established by examination of the
pericardial fluid, which is usually sanguineous, with
a predominantly lymphocytic cellular reaction. When
Ziehl-Neelsen stains of pericardial fluid are negative,
pericardial biopsy has been suggested as having
higher yield.
9.Pericardial Tuberculosis
Other endothoracic forms include: myocardial and
pericardial tuberculosis secondary to direct spread from
mediastinal glands by direct invasion or by lymphatic
spread. Pericardial tuberculosis is an uncommon condition complicating only 0.4% of untreated tuberculous
infections in children. It is due to direct invasion or
lymphatic drainage from caseous subcarinal nodes, serofibrinous or hemorrhagic fluid accumulating between
the visceral and parietal surfaces of the pericardium.
Sometimes extensive fibrosis leads to obliteration of
the pericardial sac, with development of constrictive
pericarditis some years later.
The presenting symptoms are usually nonspecific and
include low-grade fever, anorexia, poor weight gain, but
rarely chest pain. On examination, a pericardial friction
rub may be appreciated. When pericardial effusion is
already present, distant heart sounds, tachycardia, and
narrow pulse pressure are noted24,25. The chest roentgenogram often reveal "cardiomegaly". ECG changes
include diminution in the amplitude of the QRS complex
and abnormalities of the S-T segment and T waves.
The diagnosis is established by examination of the
pericardial fluid, which is usually sanguineous, with
a predominantly lymphocytic cel-lular reaction. Peri-
(Pott's abscess), retropharyngeal abscess, psoas abscess, and neurologic lesions are seen in 10-30% of
the TB of the spine. Neurologic involvement such
as paraplegia or even paresis range from 25-39% in
foreign literature and 17-44% in the Philippines. These
result from inflammation of the spinal cord secondary
to an adjacent cold abscess, granuloma in the extradural
space, or by spinal vessel thrombosis.
Signs and symptoms include "night cries" and restless
sleep, daily low-grade fever and peculiar position (such
as torticollis with cervical lesions) or gait. Physical
examination findings include marked "guarding" because of dorsal muscle spasm, gibbus, or reflex changes
including clonus. Occasionally, the presence of referred
chest pain leads to the discovery of paravertebral abscess on the chest roentgenogram.
Next to the spine, the hip, knee and ankle, being
weight-bearing joints, appear to be susceptible to the
implantation and proliferation of the tubercle bacilli.
Since joints are directly affected by motion, pain is a
prominent symptom and usually localized rather than
referred, except in TB of the hip where the pain may be
referred to the knee, due to intra-articular tension and to
destructive processes. Hence, stiffness, and limitation
of motion, as evidenced by a limp on walking or refusal
to walk, are early manifestations.
Tuberculous arthritis is rare in children8. Joints of
the upper extremities are the only ones affected with
monoarticular involvement.
4.Gastrointestinal Tuberculosis
Tuberculous enteritis may occur after ingestion of
tubercle bacilli or as part of generalized lympho-hematogenous spread. Primary TB of the intestinal tract
is uncommon in the Philippines because Filipinos are
not fresh milk drinkers and because of widespread milk
pasteurization. Occasionally, tuberculous enteritis,
although rare, accompanies extensive pulmonary cavitation. Involvement of the intestinal tract commonly
the ileocecal area19 with extension to the mesenteric
lymph nodes and peritoneum results from ingestion of
bronchial secretions containing tubercle bacilli from
a caseous pulmonary focus. The bacilli are taken up
by the lymphoid tissues, giving rise to local ulcers
followed by mesenteric lymphadenitis and sometimes
peritonitis.
Symptoms and signs include vague abdominal pain,
intussusception, blood in the stool and sinus formation after an uncomplicated appendectomy. Enlarged
caseous and calcified mesenteric lymph glands (tabes
mesenterica) are often accidentally discovered on
roentgenogram of the abdomen as "shadows of increased density." Inciting local inflammatory reaction,
they become matted and result in adhesions interfering
with intestinal motility producing intestinal obstruc-
5.Cutaneous Tuberculosis
45-70.
3. Anane T and Grangaud J. Diagnosis of TB in Children.
In Chaulet P, ed. Children in the Tropics. Childhood
Tuberculosis Still With Us. Paris 1992 pp. 21-29.
4. McSherry G and Connor E. Current Epidemiology of
Tuberculosis in Children, Sem Ped Inf Dis. Oct 1993;
22(10): 600-604.
5. Jereb J, et al. The Epidemiology of Tuberculosis in
Children. Sem Ped Inf Dis. Oct 1993; 4(4): 220-231.
6. Waagner DC. Clinical Presentation of Tuberculous
Disease in Children. Ped Annals Oct 1993; 22(10): 622628.
7. National Consensus on Childhood Tuberculosis. 1997.
8. Feigin, Ralph and James Cherry eds. Textbook of
Pediatric Infectious Diseases. W.B. Saunders Company.
1998.
9. Tuberculosis in Infancy & Childhood Task Force on
Tuberculosis. Philippine Pediatric Society. 1993.
10. Jawahar MS. Scrofula revisited: an update on the
diagnosis and management of tuberculosis of superficial
lymph nodes. Indian J Pediatr 2000 Feb; 67 (2 Suppl):
S28-33.
11. Starke JR. The tuberculin skin test. Ped Annal. Oct, 1993.
62(10): 612-620.
12. J h a BC , D a s s A , e t a l. C e r v ic a l t u b e r c u lou s
lymphadenopathy: changing clinical pattern and concepts
in management. Postgrad Med J 2001 Mar, 77(405): 185187.
13. Seth V, Kabra SK, et al. Tubercular lymphadenitis: clinical
manifestations. Indian J Pediatr 1995 Sept-Oct; 62(5): 565570.
14. Farinha NJ, Razali KA, et al. Tuberculosis of the central
nervous system in children: a 20-year survey. J Infect 2000
Jul; 4(1): 61-68.
15. Lee LV. Neurotuberculosis among Filipino children: an
11 years experience at the Philippine Children's Medical
Center. Brain Dev 2000 Dec; 22(8) 469-474.
16. Bagga A, Kaira V and Ghai OP. Intracranial tuberculoma
evaluation and treatment. Clin. Pediatr. 27; 487-490,
1988.
17. Gomez V, Espina RJ. Pott's disease with neurologic
involvement in children: results of treatment after
conservative management or surgery. Phil J Ortho Vol
13(1). Dec, 1994, 42-44.
18. Catbagan A. Non-operative treatment of Pott's disease
with neurologic involvement. Phil J Ortho 1986, 1822.
19. Marshall JB. Tuberculosis of the gastrointestinal tract
and peritoneum. Am J Gastroenterol 1993 Jul; 88(7):
989-999.
20. Bhargava DK, Shriniwas, et al. Peritoneal tuberculosis:
laparoscopic patterns and its diagnostic accuracy. Amer J
of Gastroent. 1992 87(1): 109-112.
21. Gurkan F, Ozates M, et al. Tuberculous peritonitis in 11
children: clinical features and diagnostic approach. Pediatr
Int 1999 Oct; 41(5): 510-513.
22. Rom, William and Stuart Garay. Tuberculosis. Little, Brown
and Co. 1996.
23. Alvarez SZ & Carpio R. Digestive Disease Science March
1983 28(3) 193-200.
24. Hugo-Hamman CT, Scher H, et al. Tuberculous pericarditis
in children: a review of 44 cases. Pediatr Infect Dis J 1994
Jan; 13(1) 13-18.
25. Weber S. Tuberculosis and pericarditis in children. Trop
Doct 1999 Jul; 29(3): 135-138.
26. Ramesh V, Misra RS, et al. A study of cutaneous
tuberculosis in children. Pediatr Dermatol 1999 Jul-Aug
16(4): 264-269.
27. Bodaghi B, LeHoang P. Ocular tuberculosis. Curr Opin
Extrapulmonary Tuberculosis
1. Musculoskeletal Tuberculosis
2. Central Nervous System
3. Abdominal Tuberculosis
4. Renal Tuberculosis
Overview
Chest radiography still has its value in the diagnosis
of TB. It is helpful in localizing the site of TB lesions.
Although not specific for the diagnosis of pulmonary
TB, it becomes important in the diagnosis of pulmonary
TB in places where prevalence of TB is high and where
facilities for bacteriologic examination are not easily
available1.
Radiographic evidences seen in x-ray studies parallel the pathologic changes of tuberculous infection.
These are divided into 1) initial exposure or primary
tuberculosis and 2) postprimary or primary progressive tuberculosis. Reactivation of previous infection
or progression of an initial infection exemplifies the
latter. In radiologic studies, lateral projections are
important for complete and accurate identification
and interpretation of the primary complex. Partially
calcified mediastinal nodes may be visible only in
lateral projections.
The most common cause of calcification in children
is tuberculosis. However, other diseases such as histoplasmosis, coccidioidomycosis and aspergillosis may
also produce intrathoracic calcifications that cannot
be differentiated by radiograph from those due to tuberculosis. Calcifications can also be demonstrated in
the nodes regional to inoculations with BCG vaccine.
These, however, tend to disappear more quickly than
those associated with natural infections.
There are no pathognomonic radiographic findings.
Perhaps the only finding that may be highly suggestive of tuberculosis in infants and children is the
uniform stippling of both lungs found in miliary
tuberculosis.
Special imaging techniques such as computed tomography and magnetic resonance imaging may be of
particular value in defining nodules, cavities cysts,
calcifications, contours of large bronchi and vascular
details in lung parenchyma 3. Bronchography may
be useful in the definition of bronchial stenosis or
bronchiectasis.
"A clear chest x-ray does not rule out the existence of
a small focus of progressive tuberculosis; nor are there
pathognomonic roentgen features in a fresh primary
tuberculous complex. Moreover, not all shadows are
tuberculous infiltrates."M Pardo de Tavera (1975)
I. Primary Tuberculosis
In the same way that clinical manifestations of the
initial tuberculous infection are meager or absent,
there are usually no abnormal radiologic signs in the
thorax and the sole evidence of infection is a positive
tuberculin test. The initial radiographic picture, whether
in a child or adult, is usually parenchymal infiltration
accom-panied by ipsilateral lymph node enlargement.
Lymph node changes tend to persist longer than the
paren-chymal shadows.3
In primary tuberculous infection, the radiologic patterns
reflect the development of the pathologic complex seen
with initial exposure to the tubercle bacilli. The infection, being primarily spread by inhaled droplet, is seen
mostly in the lung. In its complete form, the primary
complex is composed of the following; however not all
features are necessary to make the diagnosis.2
size and shape in the radiolucent lung,
enlarged regional nodes,
lymphangitis that produces linear shadows of
increased density connecting the pulmonary focus
and the regional nodes, and
a localized pleural effusion that appears as a
shadow of increased density in the pleural space
contiguous to the primary focus
As a rule, pleural exudates and the lymphangitis are not
clearly seen. Common radiologic findings are enlarged
retrocardiac lymphadenopathy in 70% of cases, hilar
adenopathy with pulmonary infiltrates in 20% and
pleural effusion4. Chest radiographs may be normal
in up to 10% of patients who have proven primary
tuberculosis5.
Hilar adenopathy has a specifity of 36%. Because of
its low specificity, this radiologic finding should not
C. Airway Involvement
5. Miliary Tuberculosis
8. Tuberculoma
Parenchymal disease can occur with or without meningitis and usually manifests as tuberculomas. These
may be solitary but are more commonly multiple. The
frontal and parietal lobes are the most commonly affected regions. At CT, tuberculomas appear as rounded
or lobulated masses with low or high attenuation. They
demonstrate homogenous or ring enhancement and have
irregular walls of varying thickness 8.
3. Abdominal Tuberculosis
Ileocecal involvement is seen in 80-90% of patients
with abdominal TB 12. Thickening of the valve lips or
wide gaping of the valve with narrowing of the terminal ileum (the Fleischner sign) has been described as
a characteristic of tuberculosis. At CT scan, one half
of patients with gastrointestinal TB show circumferential thickening of the cecum and terminal ileum,
enlargement of the ileocecal valve and mesenteric
lymph-ade-nopathy4.
Hepatosplenic TB generally manifests in a micronodular (miliary) or macronodular (tuberculoma) form.
On CT scans, numerable tiny, low attenuation foci may
be seen. The macronodular form is rare. The spleen
probably always is seeded during the initial lymphohematogenous spread. Only rarely are the tubercles
numerous enough and large enough to undergo caseation and calcify6.
4. Renal Tuberculosis
The earliest urographic abnormality is a "motheaten" calix due to erosion. This finding is followed
by papillary necrosis. Poor renal function, dilatation
of the pelvocalyceal system due to a stricture of the
ureteopelvic junction, or destructive dilatation or
localized hydrocalycosis related to an infundibular
stricture may be seen. Cavitation with the renal
parenchyma may be detected as irregular pools of
contrast material8
Reference:
1. Kendig EL. Pulmonary and Pleural TB. Seminars in
Pediatric Infectious Disease. 1993; 4: 214-249.
2. Singson-Perlas P. Phil. Surgical Journal July-December
1995; 28: 47-52.
3. Bass JB, Fares LS, Hopewell PC, Jacobs RF, Snider JR DE.
Diagnostic Standards and Classification of Tuberculosis.
I. Diagnostic Mycobacteriology
A. Staining and Microscopy
B. Mycobacterial Culture
C. Collection and Transport of Specimens
1. Sputum
2. Gastric aspirate
3. Bronchial Washings
4. Urine
5. Other Body Fluids and Tissue
B. Mycobacterial Culture
A positive culture for M. tuberculosis from body fluids and tissues confirms the diagnosis of tuberculosis.
Culture examinations should be done on all specimens,
regardless of AFB smear results. A positive AFB smear
may represent either M. tuberculosis or some non-tuberculous mycobacterium. Therefore, an AFB-positive smear is not sufficient evidence for bacteriologic
diagnosis of tuberculosis and offers only presumptive
diagnosis of tuberculosis.5
I. Diagnostic Mycobacteriology
A. Staining and Microscopic Examination
Detection of acid fast bacilli (AFB) in stained smears
examined microscopically is the first bacteriologic
evidence of the presence of mycobacteria in clinical
specimens. It is the easiest, least expensive and most
rapid procedure for obtaining preliminary information
and provides the physician with a presumptive diagnosis
of active tuberculosis. It also gives a quantitative estimation of the number of bacilli on the smear and implies
infectiousness of the patient. Studies in adults have
demonstrated the high specificity of sputum microscopy
ranging from 97.5-99.8%1. The major disadvantage of
the test is its low sensitivity (51.8-53.1%). It is estimated
that the lowest concentration of organisms that can be
detected by miscrocopic examination is 104 bacilli per
mL of sputum.
Therefore, culture examination should be done on all
specimens regardless of AFB smear results. In a local
study by Mendoza and Narciso, sputum AFB smear
was compared with mycobacterial culture as the gold
standard. The sensitivity was 51.8%, specificity 97.5%
computed positive predicted value (PPV) 76.3%, and
negative predictive value (NPV) 93.0%.2 Acid fast
smear gave a likelihood ratio of 21.58. In children,
AFB smears have lower sensitivity. In a study of 156
children with culture-proven tuberculosis, only 53
(34%) of clinical specimens were positive for acid
fast bacilli.3 Although the sensitivity is low, a positive
smear allows a significantly earlier identification of
patients with mycobacterial infections when compared
to culture.4
When non-invasive techniques have not provided a diagnosis, tissue or other body fluids should be obtained
for histologic evaluation and culture. Tissue specimens
for culture of M. tuberculosis should be placed in saline solution (not in formalin) and should be delivered
to the laboratory promptly. Alternatively, lymph node
aspirates and bits of biopsy tissue can also be inoculated
directly into a fluid medium such as Middlebrook 7H9.
In-patients with hematogenous of disseminated disease,
bone marrow biopsy, lung biopsy and liver biopsy for
histologic examination must be considered.8
Immunoassays may involve either detection of antibodies against the TB bacilli or detection of the tuberculous antigen. A variety of mycobacterial antigens such
as complex antigens from Bacillus Calmette-Guerin
(BCG) and tubercle bacilli or purified glycolipids and
proteins from M. tuberculosis have been evaluated
by means of the enzyme-linked immunosorbent assay (ELISA) method for their diagnostic potential in
tuberculosis.
1. Antibody Detection
Several studies have used the enzyme-linked immunosorbent assay (ELISA) to detect antibodies to
various purified or complex antigens of M. tuberculosis. Sensitivity of these tests would depend on the
prevalence of tuberculosis in the area, the sensitivity
being higher in highly prevalent areas. Specificity
on the other hand will depend on the antigen used.
Mycobacterial sonicates and autoclaved suspensions
of M. tuberculosis were examples of crude bacillary
antigens used. In adults, the sensitivity of these tests
were shown to range from 49-92% and specificity between 84-98%.15 Utilizing an adsorbed mycobacterial
sonicate in an enzyme-linked immunosorbent assay
on samples from 21 children with clinical tuberculosis,
Rosen found the TB ELISA to have sensitivity of 25.8%
and a specificity of 39.5%. 16
2. Antigen Detection
Other investigations have attempted to detect structural
components of mycobacteria directly, such as tuberculostearic acid in sputum, serum, and CSF. These tests
yielded high sensitivity and specificity in various clinical specimens from adults with tuberculosis.22,23,24,25,26
However, these have not been evaluated in a systematic
fashion in children. Measurement of tuberculostearic
acid, a mycobacterial mycolic acid has been used to
detect M. tuberculosis in clinical specimens. Sada and
colleagues established ELISA for detection of mycobacterial antigen in CSF. Among patients diagnosed
to have TB meningitis, the test was shown to have a
sensitivity of 81% and a specificity of 100%.27 Brooks
demonstrated a sensitivity of 95% and specificity of
91% when a chromatographic profile of carboxylic acids
and detection of tuberculostearic were combined and
compared with culture results in adults with pulmonary
tuberculosis.28
Wadee and coworkers utilized double-antibody sandwich ELISA to detect M. tuberculosis antigens in CSF,
pleural and ascitic fluids of diagnosed tuberculous
patients.25 In this report, ELISA demonstrated specificities of 96% for CSF, 96.7% for pleural fluid and
97.1% for ascitic fluids. Sensitivity was 100% for all
three body fluids. In a later report, Chanteau utilized a
45/47 kilodalton antigen immunocapture ELISA test
on sputum specimens and demonstrated that although
the specificity of the test was 95.6%, the sensitivity
was less than 40%.29 Due to variable sensitivity and
specificity results, these tests cannot be recommended
for the routine diagnosis of tuberculosis. In addition,
these techniques require use of complex techniques
such as gas chromatography, mass spectrometry with
ion monitoring and expertise which are not commonly
available. Moreover, their sensitivity and specificity in
children are completely unknown.
Overall, no available serodiagnostic tests for TB has
adequate sensitivity, specificity or reproducibility under
various clinical conditions to be useful for diagnosis of
TB in children. The search for new diagnostic techniques
Delacourt, et al studied 199 specimens from 68 children with suspected tuberculosis. An IS6110-based
PCR identified M. tuberculosis in clinical samples
from 83% of children with disease compared to the
low yield from positive AFB smears (21%) and positive cultures (42%).35 PCR identified 70% of children
with clinical pulmonary TB but no other microbio
logic proof of the infection. Sensitivity of the PCR
was increased by testing multiple samples from the
same child although the ideal number of samples to
be collected from each child could not be determined.
False positive PCR results were seen in 39% of children
with infection but no radiographic or clinical disease.
These results again demonstrate the arbitrariness of
the distinction between TB infection and disease in
children.
Nested amplification is a method devised to increase
both sensitivity and specificity and has been used
under actual clinical conditions in several laboratories. 36,37 In a local study, Montoya and co-workers
evaluated PCR with nested application utilizing 18
and 20 oligonucleotide primers encoding a gene of
protein antigen B on cerebrospinal fluid from patients
with smear negative but bacteriologically-confirmed
tuberculous meningitis.38 Seven out of 8 samples were
positive by PCR implying the usefulness of PCR as a
rapid diagnostic test for tuberculosis. Further evaluation on more samples and other clinical samples are
recom-mended.
It appears that PCR may have a useful but limited place
in evaluating children for TB. A negative PCR result
never eliminated TB as a diagnostic possibility, and a
positive result does not confirm it. Performing PCR on
gastric aspirates will not distinguish between TB in
fection and disease and should not be used for children
with normal chest radiographs.39 The high cost of the
test, its labor intensity and problems in specificity preclude its use as part of the routine initial evaluation of
patients suspected to have tuberculosis. Until advances
in PCR technique improve sensitivity and specificity,
PCR alone is insufficient as a single diagnostic test
for tuberculosis in children. The major use of PCR in
children is when the diagnosis of active tuberculosis
is difficult and need to be confirmed rapidly to exclude
other diagnosis especially in cases of negative AFB
smears and TB cultures. PCR may be particularly
helpful in evaluating immunocompromised children
with pulmonary disease, although published reports
of PCR performance in such children are lacking.
Reference:
1. Klein NC, Duncanson FB, Lenox TH, et al. Use of
mycobacterial smears in the diagnosis of pulmonary
tuberculosis in AIDS/ARC patients. Chest 1989; 95: 11901192.
2. Mendoza MT, Narciso CP. The reliability of sputum AFB
microscopy. Phil J Microbiol Infect Dis 1987; 16: 30-35.
3. Burroughs M, Beitel A, Kawamura A, et al. Clinical
presentation of tuberculosis in culture-positive children.
Ped Inf Dis J 1999; 18 (%): 440-446.
4. Berean K, Roberts FS. The reliability of acid fast smears of
gastric aspirate specimens. Tubercle 1988; 69: 205-208.
5. Heifets LB, Good RC. "Current laboratory methods for
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pp 85-110.
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36.
37.
38.
39.
I. Overview
2. PPD-S
Table 1 Factors that may cause false negative reactions to the Mantoux test
1. Factors related to the person being tested
a. Infections: viral - measles, mumps, chicken
pox bacterial - typhoid fever, brucellosis,
typhus, leprosy, pertussis tuberculous,
pleurisy; fungal - South American blastomycosis
b. live attenuated virus vaccinations against
measles, mumps, polio, chicken pox
c. metabolic derangements - e.g. chronic renal
failure
d. nutritional factors - e.g. severe protein
depletion
e. diseases affecting lymphoid organs such
as Hodgkin's disease, lymphoma, chronic
lymphocytic leukemia and sarcoidosis
f. corticosteroids and other immunosuppressive agents
g. age: newborns and elderly patients with
"waned" sensitivity
h. incubating or recent, far advanced or over
whelming infection with M. tuberculosis
i. stresses such as surgery, burns, mental illness, and graft versus host reactions
Table 2. The sensitivity and specificity of the 5-TU PPD-S among Filipino children12,22,23
Authors
No. of
Age
Subjects (Range in Years)
Sensitivity
Specificity
Year
166
0 to 5 yrs
64.7%
74.5%
1999
218
7 to 14 yrs
84.7%
54%
1997
Chan, et. al
270
3 mos to 10 yrs
59.3%
97.7%
1994
I. Principles of Therapy
The successful management of tuberculosis depends
upon an understanding of the pathophysiology of the
disease. The need for multiple drugs and prolonged
duration of therapy is explained by the following characteristics of the causative organism 1:
(1) Naturally occurring drug resistant mutants are
present within large bacterial populations even
before chemotherapy is started.
(2) Mycobacteria replicate slowly, can remain
dormant for prolonged periods, and can be
eradicated only during replication.
(3) Bacilli live in several sites within the host, and
each site contains organisms with a different
population size, metabolic activity and rep-lication rate.
Table 4 shows the initial empiric therapy of TB in infants, children and adolescents 9.
II. Chemotherapy
Treatment can only be successful within the framework of overall clinical and social management of
patients and their contacts; the ultimate elimination of
tuberculosis requires an organized and smoothly functioning network of primary and referral services based
on cooperation between the private and public sectors
of medical care. 8
Anti-tuberculosis drugs have traditionally been classified as first-line drugs, with superior efficacy and
acceptable toxicity or second-line drugs, having either
less efficacy, greater toxicity or both. Isoniazid (INH),
rifampicin, pyrazinamide (PZA), streptomycin, and
ethambutol are all classified as first-line drugs: except
for ethambutol, these are all bactericidal agents. A
special concern for the pediatric age group is the bioavailability of suspensions used for therapy, which can
have a significant impact on patient response.
Table 5 lists the essential antituberculosis drugs including details on the mechanisms of action, dosing, and
adverse effects associated with these agents.
Ethionamide, prothionamide, cycloserine, kanamycin,
capreomycin, thiacetazone and para-aminosalicylic
acid (PAS) are classified as second-line agents, and are
used as alternatives when there is either resistance or
hypersensitivity to first-line drugs. Unfortunately, none
of these drugs are locally available.
Quinolones are also classified as second-line agents and
have been demonstrated to be bactericidal against TB
bacilli. Ciprofloxacin, ofloxacin and sparfloxacin are
among the most studied of the quinolones, which are
presumed to act by inhibition of DNA gyrase. Because
Class II TB infection
PPD conversion within past 1-2
years, (-) CXR
PPD (+) not due to BCG, (-) CXR,
(-) previous treatment
PPD (+) with stable / healed lesion,
(-) previous treatment
PPD (+) with stable / healed lesion,
(+) previous treatment, at risk of
reactivation due to:
(a) Measles, pertussis, etc
(b) Conditions / drugs inducing
immunosuppression (IDDM,
leukemia, chronic dialysis)
HIV infection / persons at risk for
infection but HIV status unknown
Class III TB Disease
Pulmonary
(a) Fully susceptible: based on
culture results of index case,
(-) previous treatment, <10%
local prevalence of primary INH
resistance
(b) Susceptibility unknown or
initial drug resistance suspected
because of big bacillary population, previous treatment ( 3
1 month), close contact with
resistant source case, residence
in area with 10% primary INH
resistance
Extrapulmonary
(a) Severe, life-threatening disease:
disseminated/miliary, meningitis, bone/ joint disease
(b) Other pulmonary sites
3 months INH
9 months INH
9 months INH
9 months INH
1-2 months
For the duration of im-munosuppression
12 months INH
INH
Rifampicin
Mechanism
of Action
Bactericidal agent
Acts on extra- and
intra-cellular bacil
lary
populations
Presumed to inhibit
biosynthesis of mycolic acid (cell wall
component) and affects glycolysis, nucleic acid syn-thesis
Dose (mg/kg)
2-3x/week
(DOT)
Daily
5-10
max
300
mg
max
300
mg
10-15
Bactericidal agent
Acts on extra- and
intra-cellular bacil max
600
lary populations
Inhibits nucleic acid mg
synthesis
Bactericidal
Other Comments
Gastrointestinal intolerance:
may be severe
If intermittent administration:
rash, fever, thrombocytopenia,
flu-like symptoms
Increased risk of hepatotoxicity
if used with INH: recommend
INH at 5-10 mg/kg/day and
rifampicin 10-15 mg/kg/day
when given together
10
max
600
mg
Streptomycin
Adverse Reactions
20-40
15
max max
900 900
mg mg
10-20
10
max max
600 600
mg mg
50-70
max
4g
Hypersensitivity reactions:
rare
Moderate rises in transaminase
levels common in early phase
of treatment; may normalize
even if drug is continued
Hyperuricemia; occasional
reports of gout
Arthralgia, particularly of
shoulders
Sterile abscess
Diffuses well into extracellular
Vestibular, auditory function
compartment of most body tisimpairment
sues, tuberculous cavities; little
Hemolytic anemia, lupoid
enters CSF
reactions: rare
Do not give together with other
nephrotoxic, ototoxic drugs
Monitor renal function and reduce dose by 50%, if dec-reased
urine output, (+) casts/albumin in
urine
Retrobulbar neuritis (reduced Oral dose: 80% absorbed
visual acuity, contraction of Dose reduction recommended if
visual fields, green-red color
with renal disease
blindness): not usually seen at Should not be given to children
recommended doses
6 years because cannot reliably
monitor visual acuity
20-30
15
25-30
max
1g
max
1g
If 2x/wk:
max 1.5 g
If 3x/wk:
max 1 g
Appendix 1.
Table 7. World Health Organization. Treatment of Tuberculosis. Guidelines for national programmes2
TB Treament Category
Initial Phase
Continuation
Phase
2 HRZE
4 HR
II
2 HRES/1 HRZE
5 HRE
III
2 HRZ
4 HR
IV
Chronic cases
Refer to specialized
Appendix 2
This index lists drugs/drug classifications mentioned in the treatment guideline. Prescribing information of these
drugs can be found in PPD reference systems.
Antituberculosis
Ethambutol
Am-Europharma
Ethambutol HCl
Biogenerics
Ethambutol
Odetol
Pharex Ethambutol
Ethambutol/Isoniazid/
Vit B6
Alveodril/
Alveodril Forte
Ebutol
EMB Forte
Etham 500
Ethambin-INH
Ethamizid
Ethi 400
Fevram
Forbutol
Norvit Plus
Pacibutol
Ethambutol/Isoniazid/
Rifampicin
Myrin
Ethambutol/Rifampicin/
Isoniazid/Pyrazinamide
4D
Econokit
Econokit-MDR
Myrin-P Forte
Quadtab
Rimstar 4
Ethambutol/Rifampicin/
Pyrazinamide/Vitamins
Continukit Plus
Ethambutol/Rifampicin/
Pyrazinamide/Isoniazid/
Vitamins
SCC Kit
Viper
Isobutol
Bisobutol
Isobutol/Rifampicin/
Pyrazinamide
Molecure 1 & 2
Isoniazid
Am-Europharma
Isoniazid
Bacciter
Biogenerics Isoniazid
Curazid Forte
Norvit
Pharex Isoniazid
UL Isoniazid 400
Isoniazid/Rifampicin
Continupack
Isoniazid/Vit B6
Comprilex Pediatric Syrup
Isoxin
Koccid
Nicetal
Norvit Plus
Odinah
Therabacule
Trisofort
Trisovit
UL Isoniazid 400
Isoniazid/Vitamins
Trisofort
Trisovit
Pyrazinamide
Am-Europharma
Pyrazinamide
Biogenerics Pyrazinamide
Drugmaker's Biotech
Pyrazinamide
Mycobak
Pharex Pyrazinamide
Pyramin
Pyrasol
PZA-Ciba
RiteMED Pyrazinamide
Zapedia
Zcure
Zinaplex
Rifampicin
Am-Europharma
Rifampicin
Biogenerics Rifampicin
Carfamin
Crisarfarm
Dipicin
Drugmaker's Biotech
Rifampicin
Fampisec
Fevram
Koccifam
Lypro-cap
Medifam
Natricin Forte
Odifam
Pharex Rifampicin
PMI Rifampicin
Ramicin
Refam
Rexilan
Ricyn
Rifadin
Rifamax
Rimactane
Rimaped
RiteMED
Rifampicin
Tubercox
Rifampicin/Isoniazid
Bifix
Continupack
Kidz Kit 2
Rifinah
Rifzin
Rimactazid 225/
Rimactazid 300/
Rimactazid 450/
Rimactazid 600
Rifampicin/Isoniazid/
Ethambutol
Combikids
Combi Pack
Continukit
TRES
Tri-Pack
Tritab
Rifampicin/Isoniazid/
Pyrazinamide
Bio Combi Pack 1/
Bio Combi Pack 2
Econopack
Econopack-TDR
Kidz Kit 3
M-O-P/M-O Compliance Pack
Rifater
Streptomycin
YSS Streptomycin Sulfate
Corticosteroids
Prednisone
Drazone
Drugmaker's Biotech Prednisone
GXI Prednisone
Orasone 5/Orasone 20
Organon Prednisone
Pred 5/10/50
Roidrenal