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Drug Eruptions and Erythroderma

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DOI: 10.1007/978-1-4471-6729-7_23

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 Drug Eruptions and Erythroderma
23
Yuri T. Jadotte, Robert A. Schwartz,
Chante Karimkhani, Lindsay N. Boyers,
and Shivani S. Patel

Abstract
Erythroderma, also known as generalized exfoliative dermatitis, manifests
as widespread scaling and erythema of most of the body’s cutaneous sur-
face. Other than an apparent predilection for males, the disease occurs no
more or less commonly in any other specific subsets of the population. Its
etiology is highly variable, although the most common cause is a drug erup-
tion, flare of a pre-existing dermatologic condition or lymphoma or other
cancer. It may occur secondary to systemic use or topical application of the
medication. Other causes may include infections, particularly in immuno-
compromised patients, excessive exposure to solar radiation while taking
photosensitive drugs, and malignancy. Erythroderma is potentially life
threatening, due to the severe associated hemodynamic and metabolic com-
plications. The diagnosis of this disease is made clinically. Histological
findings tend to be non-specific. Treatment of hemodynamic instability
should be given precedence to reduce mortality, followed by rapid identifi-
cation of the underlying cause of disease, as this relates directly to the prog-
nosis of the condition as well as the likelihood of resolution from cessation
of the offending agent or treatment of the underlying disease.

Y.T. Jadotte, MD (*)

Division of Nursing Science and Department of
Quantitative Methods, Epidemiology and
C. Karimkhani, BA
Biostatistics, Rutgers University School of Nursing
Columbia University College of Physicians
and Rutgers University School of Public Health, 180
and Surgeons, New York, NY, USA
University Avenue, Ackerson Hall Room 364,
e-mail: [email protected]
Newark, NJ 07102, USA
e-mail: [email protected] L.N. Boyers, BA
Georgetown University School of Medicine,
R.A. Schwartz, MD, MPH, DSc (Hon)
Washington, DC, USA
Dermatology, Pediatrics, Medicine, and Preventive
e-mail: [email protected]
Medicine and Community Health, Rutgers University
New Jersey Medical School and Rutgers University S.S. Patel, BA BS
School of Public Affairs and Administration, Newark, Medical University of South Carolina,
NJ, USA Charleston, SC, USA
e-mail: [email protected] e-mail: [email protected]

© Springer-Verlag London 2015 251

J.C. Hall, B.J. Hall (eds.), Cutaneous Drug Eruptions: Diagnosis, Histopathology and Therapy,
DOI 10.1007/978-1-4471-6729-7_23
252 Y.T. Jadotte et al.

Keywords
Erythroderma • Exfoliative dermatitis • Generalized erythroderma • Drug
eruptions • Erythema • Drug reaction with eosinophilia and systemic
symptoms (DRESS) syndrome

Introduction Epidemiology

Erythroderma comes from the Greek words The epidemiology of erythroderma has been exam-
“erythro” and “derma,” meaning “redness” and ined, but the true incidence and prevalence of the
“skin,” respectively. It is a condition that is also disease remains unknown, as the epidemiological
known as generalized exfoliative dermatitis, evidence is not robust, and no systematic reviews
generalized erythroderma, or erythrodermatitis. have been conducted on this evidence. Studies
This disease manifests as widespread scaling suggest that the incidence of the disease may be as
and erythema of 90 % or more of the body’s low as 0.9 per 100,000 persons to as high as 35 per
cutaneous surface, involving substantially abnor- 100,000 persons, but there are no particular geo-
mal skin metabolism that may have major impli- graphic patterns of distribution of the incidence of
cations for morbidity and mortality. It is due to this disease. Also, there is little to no epidemiolog-
massive dilation of cutaneous capillaries ical evidence on the prevalence of erythroderma
throughout the body, followed by diffuse exfoli- in the published literature. However, the disease
ation or peeling of the epidermis. The challenge is thought to occur more often in men, with male
with erythroderma is twofold: first, it is a non- to female ratios as low as 2:1 and as high as 4:1.
specific cutaneous manifestation that is not due It also appears to be more common in adults than
to any single disease, but instead may be associ- in children, with the typical age ranging from
ated with a wide variety of underlying condi- 40–60 years or older. The reason for the greater
tions. It is usually due to a flare of a preexistent association of erythroderma with male gender or
skin disorder, a drug eruption, a lymphoma or middle-to-older age is unclear. The epidemiologi-
other cancer, or is classified as idiopathic. This cal evidence on the geographical prevalence of
includes cutaneous conditions and systemic dis- erythroderma is unclear; however, multiple case
eases, as well as causes which originate from studies and case series have documented occur-
within the body and those that are external to it. rence in diverse populations spanning all con-
Therefore, the presence of erythroderma requires tinents. Also, the global burden and impact of
the initiation of a systematic search for, and the this disease on the quality of life and survival of
prompt identification of, a specific causative fac- patients worldwide has not yet been studied.
tor. Second, treatment of hemodynamic instabil-
ity resulting from erythroderma, as well as any
potentially life-threatening infections, must Etiology
occur simultaneously as, or even prior to, a thor-
ough search for the identification of the underly- Erythroderma is a constellation of signs and symp-
ing causative agent, in order to reduce the risk of toms that are highly non-specific and indicative of
mortality. In essence, this condition is a derma- a number of underlying diseases, although the pat-
tologic emergency, and both diagnosis and man- terns of signs and symptoms can facilitate the iden-
agement must occur simultaneously. In addition, tification of an etiologic agent. The most common
erythroderma is commonly precipitated by a drugs that can precipitate erythroderma are listed
reaction to drugs taken either systemically or below. Table 23.1 presents some of the underlying
used topically, which is the focus of this conditions that may be associated with the disease.
chapter. They range from dermatologic conditions limited
23 Drug Eruptions and Erythroderma 253

Table 23.1 Potential underlying diseases associated Drugs Commonly Associated

with erythroderma
with Erythroderma
Diseases commonly associated with or preceding
erythrodermaa • Antihypertensive medications: beta-blockers
Dermatologic diseases
• Antibiotics: bactrim (trimethoprim-
Psoriasis
sulfamethoxazole), tobramycin, vancomycin,
Atopic dermatitis
penicillin, gentamycin, cefoxitin
Pityriasis rubra pilaris
• Antifungals: ketoconazole, griseofulvin
Contact and other types of dermatitis
• Calcium channel blockers: nifedipine
Dermatophytosis
• Proton pump inhibitors: omeprazole
Ichthyosis
• H2 blockers: cimetidine, ranitidine
Pemphigus foliaceus
• ACE inhibitors: captopril
Systemic diseases
• Anti-tuberculosis medications
Lymphoma: CTCL, Large cell, Hodgkin’s
Leukemia
• Carbamazepine
Carcinoma (of blood vessels, thyroid, lung, esophagus,
• Phenobarbital
colon, liver or prostate) • Paracetamol
Dermatomyositis • Lithium
Hepatitis • Plaquenil
Renal insufficiency • Antimalarials
Immunodeficiency (acquired or congenital)
Histoplasmosis Given this broad-based etiology, evaluation of
Toxoplasmosis a patient presenting with the signs and symptoms
Lupus erythematosus of erythroderma must include a systematic search
Thyrotoxicosis for potential etiologic agents, which most often
Sarcoidosis are drugs or pre-existing dermatoses. Other com-
Graft-versus-host disease mon categories of diseases that may manifest as
Hyper-eosinophilic syndrome erythroderma are cutaneous and internal malig-
a
Conditions that are more commonly associated with nancies, such as mycosis fungoides and cancers
erythroderma are in bold lettering of the GI tract, respectively. Patients with pre-
existing psoriasis can develop erythroderma sec-
to the epidermis, to those involving the dermis and ondary to the withdrawal of topical or systematic
subcutaneous tissues, as well as systemic diseases steroid treatments. Thus, it is important to not
for which erythroderma can be a cutaneous mani- only identify whether the patient began a new
festation. Psoriasis and atopic dermatitis are often drug regimen recently, but also to assess whether
associated with erythroderma. However, it is a drug has been ceased recently.
unclear whether this association is truly reflective Drug reactions may initially consist of morbil-
of an inherent pathophysiologic link between these liform, urticarial, or lichenoid rashes that eventu-
two diseases and erythroderma, or whether it is due ally coalesce to present as generalized
to the greater prevalence of these diseases in gen- erythroderma. This pattern may be a tell-tale sign
eral. For example, eczema is well known to be the that a drug is the etiologic agent in those cases.
most common dermatologic disease in the world Other patterns in the development of erythroder-
and has been rated as having the highest impact on mic symptoms and signs may be telling as well.
patients’ quality of life. In some cases of erythro- For example, patients with erythroderma due to
derma, an underlying condition is not found and underlying malignancy will likely present with a
the disease remains idiopathic. In children without history of gradual onset of skin manifestations,
pre-existing dermatoses (such as atopic eczema), combined with recalcitrance from standard thera-
drugs are the most commonly responsible etiologic peutic approaches and progressive decompensa-
agents. tion (as opposed to the rapid decompensation
254 Y.T. Jadotte et al.

Table 23.2 Molecular mechanisms implicated in the pathogenesis of erythroderma

Associated clinical and prognostic
Marker Mechanism of action findings
VCAM-1, ICAM-1, E- and Cellular adhesion Increased expression, leading to
P-selectins increased dermal and epidermal
inflammation
Th1 (Helper T-Cells) Type 4 hypersensitivity reaction Increased dermal inflammation
Interleukin 1, 2, 8 Inflammatory cytokines Increased epidermal mitosis and
turnover

which is more typical of drug-induced erythro- patients appears shiny, which is indicative of exten-
derma). Moreover, mucosal involvement sug- sive dermal edema, and is typically bright red,
gests the presence of toxic epidermal necrolysis suggesting widespread dilatation of dermal capil-
(TEN), which is life-threatening and must be laries. The patient may complain of dryness and
identified and treated immediately. It is usually the feeling of having tight skin. The patient may
due to a hypersensitivity-induced reaction to an also experience severe pruritus. Further physical
offending drug. TEN often has cardiac, pulmo- examination typically reveals that the skin is warm
nary, renal, and ocular complications, which can to touch, with diffuse scaling throughout the body.
also help identify the etiology of the disease. Scaly patches may be present on the face, scalp,
Lastly, some herbal preparations or non-tradi- trunk, arms and legs, as well as the palms and soles.
tional medical treatments may cause this disease; In some cases, the “nose sign” may be present,
however, the body of evidence to support this which occurs when the nasal and paranasal regions
claim is unclear at this time. are not affected. However, this is not a diagnostic
sign. Patients with drug eruption-related erythro-
derma may demonstrate evidence of leukonychia.
Pathogenesis Prolonged erythroderma may result in permanent
hair loss throughout the body (alopecia) severe nail
The molecular pathogenesis of erythroderma dystrophic changes, and coarse induration of the
remains elusive. However, a number of key changes skin. Dark-skinned individuals may also exhibit
have been noted. Table 23.2 lists some of the bio- widespread hypopigmentation.
chemical changes that have been documented in Since the disease is commonly associated
histologic samples from patients with erythro- with, or precipitated by, an underlying cutaneous
derma. Note that all of these histologic changes are disorder, the above signs and symptoms may
relatively non-specific and are unlikely, at this time, occur in confluence with evidence of the other
to be useful for making a diagnosis of erythro- disease. For example, patients with erythroderma
derma. However, they may be useful in diagnosing associated with pre-existing psoriasis will experi-
an underlying dermatosis if one is present. Given ence the above, as well as psoriatic plaques
the lack of evidence on their effectiveness as diag- (Fig. 23.1). Gotron’s papules, muscular weak-
nostic or prognostic markers at this time, use of ness, and the classic heliotropic rash may be seen
these biochemical changes in the management of in patients with underlying dermatomyositis.
erythroderma is not recommended. Some patients may experience erythroderma in
the context of the drug rash with eosinophilia
and systemic symptoms (DRESS) syndrome
Clinical and Histologic Manifestations (Fig. 23.2). The “red man syndrome” can present
as a result of rapid intravenous infusion of antibi-
Erythroderma begins as erythematous and pruritic otics, particularly vancomycin, and consists of
patches distributed throughout the body, which the acute appearance of an intensely erythema-
progressively or rapidly coalesce to involve 90 % tous rash that presents as erythroderma
or more of the cutaneous surface. The skin of these (Fig. 23.3). The erythema in red man syndrome
23 Drug Eruptions and Erythroderma 255

Diagnosis and Prognosis

The diagnosis of erythroderma is clinical. Patients

who present with the aforementioned clinical
signs and symptoms have this disease; the appro-
priate management steps should be taken.
However, a concerted effort must also be made to
identify the underlying causative agent, which can
be a drug, a pre-existing dermatosis, or both. The
previous list and Table 23.1 present the most com-
mon drugs and dermatoses associated with eryth-
roderma. The prognosis of this disease is directly
correlated with the underlying etiology. Patients
who develop drug-induced erythroderma experi-
ence a rapid onset of the disease, followed by
prompt resolution if the offending agent is
stopped. The disease may also progress fairly rap-
idly in patients with contact allergies or with toxic
shock or scalded skin syndrome. Patients with
chronic dermatoses, such as psoriasis and atopic
dermatitis, may experience a slower progression,
as well as greater recalcitrance.
The most common causes of death in patients
Fig. 23.1 Generalized erythema prior to exfoliation. with erythroderma relate to the metabolic and
(Hulmani M, NandaKishore B, Bhat MR, Sukumar D,
Martis J, Kamath G, et al. Clinico-etiological study of 30
hemodynamic imbalances that result from capil-
erythroderma cases from tertiary center in South India. lary dilation, which include protein, electrolyte,
Indian Dermatol Online J. 2014; 5(1):25–9. Figure 1, and fluid loss. Increased and widespread vasodi-
Psoriatic erythroderma, p 26. Used with permission: lation can also lead to hypothermia, which may
open-access article distributed under the terms of the
Creative Commons Attribution-Noncommercial-Share
precipitate the emergence of a compensatory
Alike 3.0 Unported) hypermetabolic state in which the body increases
production of energy while depleting cellular
energy reserves. All of these, in turn, increase the
tends to be continuous from the point of infusion, risk of heart failure as well as septicemia, both of
which is different than the appearance of the dis- which are more likely to occur in elderly patients.
ease in other conditions, although this is certainly Some patients may die of pneumonia. However,
not a specific sign. erythroderma may be linked with serious, possi-
Histological findings are usually non-specific bly fatal visceral involvement in the DRESS syn-
and can include hyperkeratosis (manifesting drome. For example, a patient with erythroderma
clinically as extensive scaling), parakeratosis and with fulminant hepatitis would be classified as
acanthosis (with lead to peeling of the epidermis), DRESS syndrome.
as well as a perivascular lymphocytic infiltrate.
Eosinophilia can be present within the context of
leukocytosis. The presence of this finding with Management
other systemic symptoms (especially hepatic dis-
ease) is characteristic of the Drug Reaction with The therapeutic approach for erythroderma is
Eosinophilia and Systemic Symptoms (DRESS) twofold. First, the management of erythroderma
syndrome. syndrome. Serum albumin may also be depends on identification of the etiologic agent.
low, which may contribute to the hemodynamic However, there are some basic steps that must be
instability of the patient. initiated regardless of the suspected etiologic agent.
256 Y.T. Jadotte et al.

Fig. 23.2 Erythematous macules and plaques over the symptoms syndrome due to anti-TB medication. J Family
lower extremities in top two photos. There is more conflu- Med Prim Care. 2013;2(1):83–5. Figure 1, Rash, p 84.
ence of the patches and plaques on the side of the neck in Used with permission: open-access article distributed
the lower left image, and on the lower right the redness under the terms of the Creative Commons Attribution-
and desquamation are becoming more generalized. Noncommercial-Share Alike 3.0 Unported)
(Kaswala DH. Drug rash with eosinophilia and systemic

X-rays. These baseline tools are used to moni-

tor the patient’s current status and provide an ini-
tial assessment of the most immediate therapeutic
approaches to take. For example, a chest X-ray sug-
gestive of pneumonia or other pulmonary or cardiac
abnormalities should also be explored, particularly
if potentially life-threatening (i.e., evidence of car-
diomegaly which could be indicative of heart fail-
ure). Other diagnostic tools may be used selectively
depending on clinical suspicion. For example, a his-
tory of gradual onset erythroderma should prompt
Fig. 23.3 Blanching erythema seen most often related to a work-up for possible malignancy, including stool
vancomycin infusion for occult blood, rectal exam, and computed tomog-
raphy scan. Skin cultures or KOH prep of skin
These include: close monitoring of vital signs scrapings should be performed if bacterial infection
and the patient’s weight and fluid intake, hepatic or scabies are suspected, respectively. HIV testing
and renal function tests, serum electrolytes and is appropriate if the patient presents with low white
complete blood count with lymphocytic differ- blood cell count and possible evidence of opportu-
entiation, as well as electrocardiograms and chest nistic infections.
23 Drug Eruptions and Erythroderma 257

Once a diagnosis is made, treatment should Suggested Reading

be geared toward the associated disease, with the
expectation that erythroderma will resolve com- Akhyani M, Ghodsi ZS, Toosi S, Dabbaghian
H. Erythroderma: a clinical study of 97 cases. BMC
plementarily. Given that erythroderma can be Dermatol. 2005;5(1):5.
associated with dozens of underlying dermatoses Botella-Estrada R, Sanmartin O, Oliver V, Febrer I, Aliaga
and systematic diseases, all of which require a A. Erythroderma: a clinicopathological study of 56
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