Clinics in Dermatology (2019) 37, 88–98

The rash that becomes an erythroderma

Arun C. Inamadar, MD, FRCP (Edin) a,⁎, Shivanna Ragunatha, MD b
a
Department of Dermatology, Venereology & Leprosy, Shri B.M.Patil Medical College, Hospital & Research Center, BLDE
Deemed University, Vijayapur, Karnataka, India
b
Department of Dermatology, Venereology & Leprosy, ESI Medical College & Hospital, Bengaluru, Karnataka, India

Abstract Erythroderma is a dermatologic emergency with potentially serious consequences. Several dis-
eases with different etiologies characteristically appear as erythroderma. Depending on the age groups, con-
genital ichthyosiform disorders, infections, preexisting dermatoses, drug eruptions, and internal
malignancies commonly present with, or progress to, erythroderma. The course, prognosis, and manage-
ment strategies also vary depending on the cause of erythroderma; hence, an accurate diagnosis is essential
in minimizing associated morbidity and mortality. The generalized erythema and scaling often obscure the
classic clinical features of the underlying skin diseases, posing a diagnostic challenge to dermatologists.
Awareness and elicitation of subtle signs and clinical manifestations are crucial. A step-wise approach en-
sures completeness of clinical evaluation and avoids missing any relevant clinical data. The initial clinical
presentation, cutaneous examination findings, and systemic clues reveal important information regarding
the diagnosis, course, and prognosis of erythroderma. The age at onset, symptomatology, duration of illness,
initial lesions, initial site of onset, clinical course, family history, types of scales, changes in cutaneous in-
teguments and systemic clues will assist in delineating the nature of underlying disease.
© 2018 Elsevier Inc. All rights reserved.

Introduction patients with dermatologic conditions in India, and 30-44

Erythroderma is an extreme state of anatomic and physio-
logic dysfunction of skin, characterized by extensive erythema
and scaling involving more than 90% of body surface area.
Neonatal and infantile erythroderma are very rare, and their
frequency is not known. An Indian study showed incidence
in 20 out of 19,000 pediatric patients (0.11%) attending a der-
matology unit.1 The annual incidence of erythroderma in
adults varies geographically, ranging from 0.9 cases per
100,000 persons in the Netherlands to 1-2 cases per 100,000
persons in Finland. The hospital incidence has been reported
as 4.9 cases per year in Thailand, to 35 cases per 100,000
⁎ Corresponding author.
E-mail address: aruninamadar@gmail.com (A.C. Inamadar).
cases per 100,000 patients with dermatologic conditions in
Tunisia.2
Overall, the patients presenting with erythroderma usually
are men; however, gender distribution in different etiologies
has been reported to be the same.3 Various diseases with dif-
ferent etiopathologic processes can present as or progress to
erythroderma (Table 1). It is associated with significant mor-
bidity and mortality in addition to the variable prognosis inher-
ent to the underlying etiology.
The precise diagnosis of erythroderma is essential for
proper management and better therapeutic outcome; hence, a
step-wise clinical approach is described to reveal the evolution
of a rash into erythroderma. The diseases presenting as, and
those with a tendency to develop erythroderma, are many.
The diseases presenting with predominantly vesiculobullous

https://doi.org/10.1016/j.clindermatol.2018.12.002
0738-081X/© 2018 Elsevier Inc. All rights reserved.
Rash progressing to erythroderma 89

Table 1 Etiopathogenesis list of diseases causing erythroderma Table 2 Age list of common diseases causing erythroderma
○ Inflammation ○ Neonates and Infants
▪ Psoriasis ▪ Congenital
▪ Pityriasis rubra pilaris ● Nonsyndromic congenital ichthyosis
▪ Lichen planus ● Syndromic congenital ichthyosis
▪ Eczemas ● Omenn syndrome and graft-versus-host disease
○ Infection and Infestation ● Congenital cutaneous candidosis
▪ Staphylococcal scalded skin syndrome ● Psoriasis
▪ Toxic shock syndrome ● Diffuse cutaneous mastocytosis
▪ Congenital cutaneous candidosis ● Staphylococcal scalded skin syndrome
▪ Dermatophytoses ▪ Noncongenital
▪ Crusted scabies ● Psoriasis
○ Infiltration ● Eczemas: Atopic dermatitis
▪ Sézary syndrome ● Seborrheic dermatitis
▪ Mycosis fungoides ● Staphylococcal scalded skin syndrome
▪ Diffuse cutaneous mastocytosis ● Drugs: Vancomycin and ceftriaxone
▪ Internal malignancy ● Metabolic disorders:
○ Ingestion ○ Holocarboxylases synthetase and biotinidase deficiency
▪ Drugs ○ Essential fatty acid deficiency
▪ Alternative medicines ○ Childhood (Preschool and School-Age)
▪ Systemic contact dermatitis ▪ Infections
○ Inherited ● Staphylococcal scalded skin syndrome
▪ Ichthyosiform disorders ● Crusted scabies
▪ Primary immunodeficiency disorders ▪ Drugs: Antiepileptics, amoxicillin, sulfonamides,
▪ Metabolic disorders antitubercular drugs
○ Immunologic ▪ Eczemas: Atopic dermatitis
▪ Graft-versus-host disease ▪ Psoriasis
▪ Dermatomyositis ○ Adults
▪ Subacute cutaneous lupus erythematosus ▪ Preexisting dermatoses: Psoriasis, contact dermatitis,
▪ Sarcoidosis airborne contact dermatitis, chronic actinic dermatitis atopic
○ Idiopathic dermatitis
▪ Drugs: Antiepileptics, antimicrobials, analgesics
▪ Cutaneous T cell lymphomas: Sézary syndrome, mycosis
fungoides
lesions, and those with a transient, self-limiting and benign ▪ Internal malignancies
course, such as transient neonatal skin diseases and viral ▪ Multisystem disorders: Dermatomyositis, subacute
exanthema, are excluded. cutaneous lupus erythematosus
▪ Idiopathic

Clinical approach
The clinical homogeneity of generalized erythema and
scaling often obscure classic clinical features of underlying
dermatoses posing a diagnostic challenge for dermatologists.
In neonates, identifying the underlying cause for erythroderma
is quite difficult due to overlapping clinical features and hesi-
tancy in subjecting newborns to an array of invasive investiga-
tions. It leads to delay in diagnosis by 3 to 11 months, and, in
10% of cases, the diagnosis remains unconfirmed even after
3 to 5 years.4 The main objective of effective and efficient
clinical approach to any disorder is chronologic elicitation of
signs and symptoms through history taking and clinical
examination. A step-wise approach ensures completeness
of clinical evaluation and avoids missing any relevant
clinical data. Detailed history usually reveals preexisting der-
matoses and predisposing factors that are responsible for
generalized spread, leading to erythroderma. Thorough clini-
cal examination, focusing on subtle clinical clues and tests
helps in the differential diagnosis. The erythroderma, irrespec-
tive of underlying causes, culminates in a state of acute skin
failure, characterized by loss of barrier and metabolic func-
tions; hence, the clinical inquiry should also extend to identify
the local or systemic complications of erythroderma. The inter-
pretation of documented clinical data provides important in-
formation on diagnosis, etiologic and predisposing factors,
systemic associations, complications, prognosis, management
strategy, and monitoring of course of the disease.
Clinical presentation
Patients with erythroderma present to dermatologists with
varied clinical presentations. They differ in age at onset, dura-
tion of illness, symptomatology, mode of onset, initial site of
involvement, initial lesion, clinical course of disease, predis-
posing factors, and family history. The detailed evaluation of
90
Table 3 Initial site of involvement in diseases progressing to erythroderma
Sl no Disease
1 Staphylococcus scalded skin syndrome
2 Pityriasis rubra pilaris
3 Airborne contact dermatitis
4 Holocarboxylase synthetase deficiency
5 Essential fatty acid deficiency
6 Psoriatic erythroderma in neonates and infants
7 Pemphigus foliaceous
clinical presentation helps in understanding the nature and se-
verity of underlying etiology.
Age at onset
Erythroderma can affect all age groups from neonates to the
elderly. The prevalence of underlying causes for erythroderma
varies across the spectrum of age (Table 2). Infants with
erythroderma usually present before the age of 4 months.
Erythroderma at birth, also known as congenital erythroderma,
is caused by congenital ichthyosiform erythroderma (CIE),
primary immunodeficiency, and Netherton syndrome.4 Holo-
carboxylase synthetase deficiency manifests clinically at birth
or neonatal period. Biotinidase deficiency presents in early
infancy at 3 months of age.5 Atopic dermatitis (AD) and
seborrheic dermatitis develop at 6 to 8 weeks of life. Psoriatic
erythroderma, though rare, may occur in early infancy. Congen-
ital cutaneous candidosis (CCC) may appear during the first
week of life.4 Drug-induced erythroderma is common in
children.2
In adults, preexisting dermatoses are the predominant cause
of erythroderma, with psoriasis being the most common
among them.6 Internal malignancies, which may present as ery-
throderma, are reticuloendothelial, solid organ, and blood vessel
malignancies. Multisystem disorders, including dermatomyositis,
Fig. 1 Diffuse erythema with pustules characteristic of pustular
psoriasis.
A.C. Inamadar, S. Ragunatha
Initial site of involvement
Face and flexural folds
Scalp and face
Eyelids, retroauricular area, and nasolabial folds
Periorificial areas
Intertriginous regions
Diaper area
Seborrheic area
systemic lupus erythematosus, and sarcoidosis, may rarely
present with erythroderma.7 Erythroderma of unknown
etiology is common in patients older than 60 years.3
Duration of illness
Duration of disease is shortest with a drug-induced etiology.
In the absence of preexisting dermatoses, a longer duration from
the onset of the disease has been reported with cutaneous T cell
lymphoma (CTCL) and internal malignancy.7
Symptoms
The associated symptoms may be variable as they depend
on the underlying cause. Generally, some grade of itching is
expected in erythroderma due to generalized dry scales and
tightness of skin. Irritant contact dermatitis is associated with
pain and a burning sensation. The patients with allergic contact
dermatitis, chronic actinic dermatitis, crusted scabies, lichen
planus, and Sézary syndrome often present with severe
itching.6 Severe pruritus is characteristically seen in Omenn
syndrome; however, the ability to scratch develops in infants
only after 3 months.5 Moderate to severe itching is present in
thymoma associated multiple organ disease.8 Patients with
Fig. 2 Erythematous follicular papules with tendency to coalesce
and islands of sparing in pityriasis rubra pilaris.
Rash progressing to erythroderma 91

Table 4 Morphologic list of diseases progressing to

erythroderma
● Erythema
○ Vancomycin-induced erythroderma
○ Staphylococcus scalded skin syndrome
○ Diffuse cutaneous mastocytosis
● Morbiliform
○ Graft-versus-host disease
○ Congenital cutaneous candidosis
○ Drug hypersensitivity syndrome
● Papules and plaques
○ Nonfollicular
▪ Psoriasis
▪ Lichen planus
▪ Subacute lupus erythematosus
▪ Dermatophytoses Fig. 3 Scale-crusts with a few erosion in pemphigus foliaceus.
▪ Crusted scabies Reproduced with permission from Dr. Sharad Mutalik, Pune, India.
▪ Mycosis fungoides
○ Follicular graft-versus-host disease (GVHD), SSSS, or complications,
▪ Pityriasis rubra pilaris such as secondary bacterial infection.6 Low-grade fever and
▪ Follicular psoriasis weight loss can be seen in TAMA.8 Fever associated with ap-
● Pustular pearance of new crops of pustules is characteristic of acute gen-
○ Pustular psoriasis eralized pustular psoriasis. The association of fever, fatigue,
○ Acute generalized exanthematous pustular eruption gastrointestinal symptoms, and myalgia indicates increased
○ Congenital cutaneous candidosis (scattered)
levels of cytokines. This paradoxical reaction resulting in exac-
○ Pemphigus foliaceous
erbation of underlying psoriasis has been reported in patients re-
○ Drug hypersensitivity syndrome
● Vesicular/erosive ceiving antitumor necrosis factor alpha drugs.9
○ Bullous congenital ichthyosiform erythroderma
○ Pemphigus foliaceous Mode of onset
○ Staphylococcal scalded skin syndrome
○ Diffuse cutaneous mastocytosis The initial clinical presentation can be varied, depending on
○ Congenital cutaneous candidosis (scattered) the underlying cause. Drug-induced erythroderma presents as a
○ Essential fatty acid deficiency (Intertriginous)
sudden onset of skin lesions. The acute exacerbation of primary
● Eczematous
cutaneous disorders can also present as sudden onset of skin
○ Atopic dermatitis
○ Seborrheic dermatitis lesions with the background of characteristic chronic skin le-
○ Sézary syndrome sions. Such a scenario warrants a look into possible predispos-
○ Contact dermatitis ing factors. The onset and progression of the lesions is gradual
○ Holocarboxylase and biotinidase deficiency in erythroderma secondary to primary cutaneous disorders.6
○ Essential fatty acid deficiency
● Collodion membrane
○ Harlequin ichthyosis
○ Nonbullous ichthyosiform erythroderma
○ Lamellar ichthyosis
○ Pleomorphic ichthyosis
○ Netherton syndrome
○ Sjögren-Larsson syndrome
○ Conradi-Hunerman-Happle syndrome
● Ichthyosiform
○ Diseases presenting with collodion membrane
○ Bullous congenital ichthyosiform erythroderma

vesiculobullous diseases, such as pemphigus foliaceous and

staphylococcal scalded skin syndrome (SSSS), may present
with pain. Skin tenderness is characteristically present in
SSSS, leading to a baby crying when held. Fever is associated Fig. 4 Branlike or small husklike scales with characteristic follicu-
with drug hypersensitivity syndrome (DHS), maternal-fetal lar papules in pityriasis rubra pilaris.
92 A.C. Inamadar, S. Ragunatha

Fig. 5 Erythema with white large scales in acute generalized pustu-

lar psoriasis.

Initial site of involvement

Certain diseases characteristically affect a particular site at

the onset of the illness (Table 3). It gives an important clue
in the differential diagnosis.

Fig. 7 Diffuse erythema and desquamation in staphylococcal

scalded skin syndrome. Erythema is not readily appreciated due to
the darker skin color.

Fig. 6 Large, brown, platelike scales with mild erythema and alo-
pecia in lamellar ichthyosis. Fig. 8 Cornflake skin in pemphigus foliaceous.
Rash progressing to erythroderma 93

Table 5 Type of scales in different diseases causing

erythroderma
Sl Type of scale Disease
no
1 Corn flakelike (Figure 8), Pemphigus foliaceous
scale-crusts
2 Branlike, yellow greasy scales Seborrheic dermatitis
3 Fine scales Atopic dermatitis,
dermatophytoses
4 Double-edged scales Netherton syndrome
(ichthyosis linearis
circumplexa)
5 Large, dark, platelike scales Lamellar ichthyosis
6 Fine, feathery scales Nonbullous congenital
ichthyosiform erythroderma
7 Perioral scale-crusts Staphylococcal scalded skin
syndrome Fig. 9 Palmoplantar keratoderma with keratodermic sandal in pity-
8 Hyperkeratotic crusts Crusted scabies riasis rubra pilaris.
9 Collaret scales Congenital cutaneous
candidosis
10 Branlike or small husklike Pityriasis rubra pilaris diagnosis of erythroderma. The progression of erythroderma
dry scales (furfuraceous) depends on underlying disease. Erythroderma due to DHS,
11 Desquamation Staphylococcal scalded skin contact allergy, CTCL, leukemia, and SSSS show faster
syndrome, Acute progression, whereas a slower progression is characteristic of
generalized exanthematous primary cutaneous disorders like psoriasis and AD.7 The
pustular eruption pattern of progression of disease is unique in pityriasis rubra
pilaris and CCC. The former show typical cephalocaudal pro-
gression and in the latter, the rash spreads from the truncal to
Initial lesions
acral areas, including the palms and soles.4 In erythroderma
due to infectious causes, generalized erythema and scaling
The clinical state of erythroderma usually evolves from the occurs during the subsiding phase of the disease.1
localized appearance of one or more primary lesions unique to Drug-induced erythrodermas usually do not relapse, unlike
underlying etiology (Figures 1 and 2; Table 4). Nonbullous those due to other causes. On the contrary, psoriatic erythro-
congenital ichthyosiform erythroderma (NBCIE) and lamellar derma is known for recurrences. Resolution of the disease is
ichthyosis may present as a collodion baby at birth. After the faster in drug-induced erythroderma. Idiopathic erythroderma
shedding of the collodion membrane at around 3 weeks of should be closely monitored, as some of these patients may
age, erythema and scaling that cover the entire body are re- evolve into CTCL. Others may be categorized into senile
vealed in NBCIE.10 DHS initially presents with morbiliform, AD and drug-induced erythroderma. In the latter, there is a
lichenoid, pustular, or urticarial lesions. Erythematous annular possibility that the patient has forgotten the drugs they took,
or polycyclic scaly plaques are typically seen in subacute cuta- or it may be neglected by the physician during the evaluation
neous lupus erythematosus.11 of erythroderma.2 In adults, progressive worsening and refrac-
toriness to treatment indicate the possibility of internal
Clinical course malignancy.7

The speed and pattern of how lesions spread, response to

treatment, and history of recurrence help in the differential Predisposing factors

Occupational, recreational, traditional, or therapeutic expo-

Table 6 Diseases causing erythroderma involving palms and
soles sure to irritants or contact allergens support the diagnosis of
erythroderma due to contact dermatitis. It is a common
● Congenital ichthyosiform erythroderma practice in India to apply a paste of Neem leaves or various
● Omenn syndrome other native medications for any exanthematous condition that
● Congenital cutaneous candidosis
predisposes to erythroderma. Seasonal exacerbation and ag-
● Psoriasis
● Pityriasis rubra pilaris
gravation of disease on sun exposure indicate airborne contact
● Sézary syndrome dermatitis and chronic actinic dermatitis, respectively. HIV
● Crusted scabies infection is known to increase the risk of drug-induced
erythroderma.
94 A.C. Inamadar, S. Ragunatha

Fig. 11 Black dots or follicular keratotic papules on the proximal

phalanx diagnostic of pityriasis rubra pilaris.

Antiepileptics and drugs used in upper respiratory tract infec-

tions are common culprits in drug-induced erythroderma in
children. A history of transplacental–maternal–fetal transfu-
sion in neonates indicates possibility of GVHD, especially in
the presence of T cell immunodeficiency. Premature infants
with CCC are at increased risk of invasive systemic infections
leading to respiratory distress.4 A history of parenteral nutri-
tion may lead to nutritional deficiencies like essential fatty acid
deficiency,1 whereas a history of intrauterine device implanta-
tion in the mother and white macules on the placenta and
umbilical cord may be present in a newborn with CCC.5 In
case of crusted scabies, an enquiry should be made regarding
immunosuppression either due to drugs or HIV and human
T-lymphotropic virus infection; severe systemic diseases like
leprosy, systemic lupus erythematosus, rheumatoid arthritis,
or leukemia; and conditions leading to the inability to scratch
like mental illness, paresis, sensory neuropathy, or senility.12

Family history

In neonates and infants with psoriatic erythroderma, the

family history is highly positive. A family history of atopy
helps in the diagnosis of AD. Family pedigree helps in inher-
ited disorders like CIE, primary immunodeficiency disorders,
and metabolic diseases.4 There may be the presence of an epi-
dermal nevus with epidermolytic hyperkeratosis in parents of
patients with NBCIE.13 Unexplained death of siblings indi-
cates primary immunodeficiencies like Omenn syndrome and
Netherton syndrome.14 Elicitation of a history of drug hyper-
sensitivity in the family not only assists in the diagnosis of
DHS but also is essential in choosing an appropriate drug in
the management of erythroderma.

Fig. 10 Nonbullous congenital ichthyosiform erythroderma and

scarring alopecia in nonbullous congenital ichthyosiform
erythroderma.
Rash progressing to erythroderma
Fig. 12 Perioral radiating scale-crusts diagnostic of staphylococcal
scalded skin syndrome.
Clinical examination
During the evolution of erythroderma from preexisting der-
matoses, the classic lesions of underlying dermatoses are evi-
dent in making the diagnosis quite obvious; however, a fully
developed erythroderma, irrespective of underlying cause, is
clinically characterized by generalized erythema and scaling.
In such a presentation, thorough examination of the skin and
its integument is crucial for recognizing subtle clinical features
that act as diagnostic clues.
Cutaneous examination
Erythema, scaling, and induration are the fundamental cuta-
neous examination findings in erythroderma. The description
of each aids in eliciting the underlying cause of erythroderma.
Erythema
The hue of erythema can be prominent in some dermatoses
causing erythroderma. These colors are described and appreci-
ated in the background of white colored skin; hence, due con-
sideration should be given to the color of the skin when
interpreting a hue of erythema. Salmon-colored or orange-
red erythema in pityriasis rubra pilaris, deep purple-red in
CTCL, melano-erythroderma in paraneoplastic erythroderma,
and red-brown papules in papulo-erythroderma of Ofuji have
been described in literature.15
95
Scaling
The nature of scaling indicates the stage of erythroderma. The
larger and crusted scales are seen in the acute phase, whereas in
the chronic phase smaller and dry scales are seen. The type of
scales sometimes indicates the underlying cause (Figures 3-8;
Table 5).
Induration
Erythroderma can be diffuse or localized to a particular area.
Erythroderma with induration of skin is characteristic of primary
immunodeficiency disorders like Omenn syndrome.14 Diffuse
infiltration of the skin is also seen in Sézary syndrome.15 In
pre-existing dermatoses, the thickening of classic sites of in-
volvement is evident. Flexural areas are lichenified in AD,
and extensor surface of extremities are thickened in psoriasis.
Palms and soles
The involvement of palms and soles is characteristically
present in several disorders causing erythroderma (Table 6).
Palmoplantar keratoderma is more prominent in NBCIE
among CIE disorders. Hyperkeratotic crusts on the palms
and soles indicate crusted scabies. Palmoplantar keratoderma
in pityriasis rubra pilaris has been described characteristically
as “keratodermic sandal” with yellow tinge (Figure 9). In
CCC, erythema typically involves palms and soles.15
Hair
Examination of scalp hair gives important clues to the diag-
nosis in neonatal and infantile erythroderma. Alopecia, a com-
mon feature of CIE, may be present in half of the infants with
AD. Sparse hair and bamboo hairs are characteristic of Netherton
syndrome. The latter may not be present until 10 months of age.4
Scarring alopecia is seen in NBCIE (Figure 10), patchy alope-
cia is seen in biotinidase deficiency,5 and severe alopecia is seen
in Omenn syndrome.14 Progressive alopecia is also seen in bi-
otin and essential fatty acid deficiency.1 Hypertrichosis affect-
ing dorsum of hands is characteristic of reticular ichthyosis.16
Nail
The nail changes of preexisting dermatoses are evident in
patients with erythroderma due to a slower growth rate of
nails.15 Onycholysis, with subsequent complete shedding of
the nail plate, indicates an acute erythrodermic process.17
The nail changes seen in patients with erythroderma include
discoloration, brittleness, dullness, subungual hyperkeratosis,
Beau lines, paronychia, and splinter hemorrhages.15
In neonates and infants, onychodystrophy is seen in NBCIE
96 A.C. Inamadar, S. Ragunatha

Table 7 Cutaneous examination clues for the diagnosis of diseases causing erythroderma15,18
Sl Cutaneous examination clues Disease
no
1 Preexisting plaques, involvement of periumbilical area (infants), typical nail Psoriasis
changes
2 Preexisting eczematous/lichenified flexural lesions, prurigo, sparing of diaper Atopic dermatitis
area (infants)
3 Black dots or follicular hyperkeratotic papules on proximal phalanx of fingers, Pityriasis rubra pilaris
islands of sparing of skin
Annular and polycyclic erythematous plaques Subacute cutaneous lupus erythematosus,
dermatophytosis
4 Facial edema, purpuric rash on dependent areas Drug reactions
5 Sparing of skin folds (deck-chair sign) in elderly men Papuloerythroderma of Ofuji
6 Macerated and malodorous intertriginous area, positive Nikolsky sign Pemphigus foliaceous
7 Tenderness of skin, perioral radiating scale-crusts, positive Nikolsky sign Staphylococcal scalded skin syndrome
8 Linear and swirled pattern of hyperkeratosis/hyperpigmentation Conradi-Hunerman-Happle syndrome
9 Scalp involvement with or without alopecia Omenn syndrome
10 Erythema without scaling, Darier sign, doughy skin, flushing Diffuse cutaneous mastocytosis
11 Marked periorificial eczematous lesions Holocarboxylase synthetase deficiency
12 Multiple confettilike normal skin Reticulate ichthyosiform erythroderma (ichthyosis
with confetti)16
13 Leonine facies Cutaneous T cell lymphoma, chronic actinic dermatitis
13 Heliotrope rash, Gottron papules/sign, poikiloderma Dermatomyositis

Table 8 General physical and systemic examination clues15,18

Sl Systemic examination clues Diseases and complications
no
1 Lethargy Holocarboxylase deficiency, severe dehydration
2 Irritability SSSS, dehydration
3 Failure to thrive Netherton syndrome, GVHD, Omenn syndrome, psoriasis in children
4 Loss of weight Malignancy, chronic erythroderma
5 Pallor (Anemia) GVHD, chronic erythroderma
6 Lymphadenopathy Omenn syndrome, dermopathic lymphadenopathy, Sézary syndrome
7 Icterus GVHD
8 Pedal edema DHS, hypoproteinemia
9 Cold and calmly extremities Hypovolemic or septic shock
10 Decreased sweating CIE (especially pleomorphic ichthyosis (PI))
11 Fever Drug hypersensitivity, SSSS, toxic shock syndrome, GVHD, acute generalized
pustular psoriasis, sepsis
12 Hypotension SSSS, toxic shock syndrome, vancomycin induced erythroderma, severe
dehydration, sepsis
13 Hepatosplenomegaly Omenn syndrome
14 Diarrhea Omenn syndrome, diffuse cutaneous mastocytosis, GVHD
15 Recurrent infections/pneumonia Netherton syndrome, Omenn syndrome, biotin deficiency, atopic dermatitis
16 Hypernatremic dehydration Netherton syndrome, Omenn syndrome, Increased TEWL in neonates and infants
17 Dehydration Holocarboxylase deficiency, increased TEWL
18 Cardiac failure Complication of erythroderma in elderly
19 Seizures Sjögren-Larsson syndrome, biotinidase deficiency, severe dehydration
20 Spastic diplegia/tetraplegia, psychomotor delay Sjögren-Larsson syndrome
21 Severe ketoacidosis, metabolic coma, Holocarboxylase synthetase deficiency
hyperammonemia, hypoglycemia
22 Ectropion, eclabium NBCIE, lamellar ichthyosis, PI, harlequin ichthyosis (HI)
23 Cataract Conradi-Hunerman-Happle syndrome
24 Glistening dots (crystalline deposits) on fundoscopy Sjögren-Larsson syndrome
CIE, congenital ichthyosiform erythroderma; DHS, drug hypersensitivity syndrome; GVHD, graft-versus-host disease; NBCIE, Nonbullous congenital
ichthyosiform erythroderma; SSSS, staphylococcal scalded skin syndrome; TEWL, transepidermal water loss.
Rash progressing to erythroderma 97

Erythroderma in neonates
Eczematous and/or peri -
orificial involvement
Onset at birth/ early neonatal period
Yes
No
Yes
Collodion membrane No
Holocarboxylase
synthetase deficiency
Scales Blisters
No
No Yes

Plate like Large thick scales Ichthyosis linearis Fine scales Indurated skin Skin tenderness
separated by fissures Circumplexa and/or desquamaon
Yes No
Yes
Lamellar Harlequin Netherton Systemic No
Hepatosplenomegaly
Ichthyosis Ichthyosis Syndrome involvement

No Yes Staphylococcus
Scaered Pustules
Scalded Skin
Syndrome
Hypernatremic Omenn Syndrome
Cataract and/or No systemic Psoriasis
dehydraon Neurological
Swirled paern involvement No
Yes

Sjogren-Larsson Conradi-Hunerman- Non-Bullous Congenital Congenital Cutaneous Bullous Congenital

syndrome Happle Syndrome Ichthyosiform Erythroderma Candidiasis Ichthyosiform Erythroderma

Fig 13 An algorithmic approach to differential diagnosis of erythroderma presenting at birth or in the early neonatal period.

and Omenn syndrome.18 Examination of nailbed capillaries SSSS, and it differentiates CCC from neonatal candidosis.
help in the diagnosis of dermatomyositis and lupus The presence of mucositis and cheilitis should suggest drug
erythematosus. hypersensitivity reactions or nutritional deficiencies.

Oral mucosa Cutaneous examination clues

The involvement of oral mucosa is absent in the majority of The recognition of diagnostic clinical clues is very crucial
diseases causing erythroderma. The oral mucosa is spared in in the diagnosis of causes of erythroderma (Figures 11

Onset of erythroderma in infancy

Follow algorithm 1
Yes Pre-exisng lesions No (Trichorrhexis invaginata on
microscopy is diagnosc of
Diaper area involved Netherton syndrome aer 10
No Blisters
Yes No
Only Erythema
Atopic Dermas Periumbilical area No
Skin tenderness and/or Indurated skin Scales
Yes desquamaon
No Doughy skin
Scales Psoriasis Yes Yes
No No Hepatosplenomegaly

Staphylococcus Yes
Yes Darier’s sign No
Bran-like White dry Red Man Syndrome Scalded Skin
greasy (Vancomycin) Syndrome
No Psoriasis Maternal-fetal
transfusion
Diffuse Cutaneous Bullous Congenital Yes
Seborrheic Dermas Mastocytosis Ichthyosiform No
Erythroderma
Maternal-fetal
Omenn Syndrome
Gra Versus Host Disease

Fig 14 An algorithmic approach to differential diagnosis of erythroderma presenting during infancy.

98
and 12). These include characteristic clinical features, clinical
signs, and clinical tests (Tables 3, 5-7).
Systemic examination
Detailed history and cutaneous examination findings help
in identifying underlying cause and severity of erythroderma.
The general physical and systemic examination gives addi-
tional diagnostic clues and prognostic clues (Table 8). The in-
volvement of other organ systems is common in syndromic
congenital ichthyosis, primary immunodeficiency, metabolic
disorders and malignancy. Erythroderma results in hemody-
namic changes and secondary bacterial infections, especially
in extremes of age groups.
Laboratory investigations
Simple and relevant laboratory investigations, like a potas-
sium hydroxide (KOH) preparation and staining, aid in con-
firming the clinical diagnosis. KOH preparation helps
demonstrate fungal elements in CCC and dermatophytoses,
and mites in crusted scabies. Gram staining of pustules con-
firms the diagnosis of candidosis or secondary bacterial infec-
tions. Pemphigus foliaceous can be diagnosed by the
demonstration of acantholytic cells on a Tzank smear. Charac-
teristic trichorrhexis invaginate, also known as “bamboo hair,”
can be seen upon microscopic examination of hairs in infants
with Netherton syndrome. Dermatoscopic examination, a non-
invasive method of visualizing subepidermal structures, sup-
ports the diagnosis of preexisting dermatoses. It is also very
useful in identifying hair and nail changes, including nailbed
capillary changes.
Conclusions
Erythroderma is a diagnostic and therapeutic challenge in
the majority of cases. It is a dermatologic emergency, necessi-
tating immediate therapeutic intervention. The diagnosis of the
underlying cause of erythroderma and early recognition of
consequences of erythroderma are crucial in reducing associ-
ated morbidity and mortality. The diagnostic and prognostic
clues can be revealed by a detailed history and thorough clin-
ical examination. Important features that are vital in the differ-
A.C. Inamadar, S. Ragunatha
ential diagnosis include age at onset, as well as the cutaneous
and systemic examination findings. An algorithmic approach
simplifies the clinical evaluation of erythroderma, especially
in neonates (Figure 13) and infants (Figure 14). Further evalu-
ation of the patient with basic or advanced laboratory investi-
gations is required to confirm the clinical diagnosis and to
monitor the progression and consequences of erythroderma.
References
1. Sarkar R, Garg V. Erythroderma in children. Indian J Dermatol Venereol
Leprol 2010;76:341-347.
2. Khaled A, Sellami A, Fazaa B, et al. Acquired erythroderma in adults: a
clinical and prognostic study. J Eur Acad Dermatol Venereol 2010;24:
781-788.
3. Zhang P, Chen HX, Xing JJ, et al. Clinical analysis of 84 cases of erythro-
dermic psoriasis and 121 cases of other types of erythroderma from
2010–2015. J Huazhong Univ Sci Technolog Med Sci 2017;37:563-567.
4. Boull Cl, Hook KP. Neonatal erythroderma-clinical perspective. Res Rep
Neonatol 2017;7:1-9.
5. Hoeger PH, Harper JI. Neonatal erythroderma: Differential diagnosis and
management of the “red baby”. Arch Dis Child 1998;79:186-191.
6. Sehgal VN, Srivastava G, Sardana K. Erythroderma/exfoliative dermati-
tis: A perspective. Int J Dermatol 2004;43:39-47.
7. Okuduwa C, Lambert WC, Shwartz RA, et al. Erythroderma: Review of a
potentially life threatening dermatosis. Indian J Dermatol 2009;54:1-6.
8. Fukushima A, Ichimura Y, Obata S, et al. Thymoma-associated multior-
gan autoimmunity: A case of graft-versus-host disease-like erythroderma
complicated by Good syndrome successfully treated by thymectomy. J
Dermatol 2017;44:830-835.
9. Benhadou F, Helgren G, Wilaert F, et al. Acute erythroderma in a patient
receiving TNF-alpha blocking therapy for hidradenitis suppurativa. Case
Rep Dermatol 2018;10:7-12.
10. Akiyama M, Sawamura D, Shimiju H. The clinical spectrum of nonbul-
lous congenital ichthyosiform erythroderma and lamellar ichthyosis.
Clin Exp Dermatol 2003;28:235-240.
11. Kalavala M, Shah V, Blackford S. Subacute cutaneous lupus erythemato-
sus presenting as erythroderma. Clin Exp Dermatol 2007;32:388-390.
12. Mehta V, Balachandran C, Monga P, et al. Norwegian scabies presenting
as erythroderma. Indian J Dermatol Venereol Leprol 2009;75:609-610.
13. Kotrulja L, Murat-Sušić S, Husar K. Differential diagnosis of neonatal and
infantile erythroderma. Acta Dermatovenerol Croat 2007;15:178-190.
14. Pruszkowski A, Bodemer C, Fraitag S, et al. Neonatal and infantile ery-
throdermas. Arch Dermatol 2000;136:875-880.
15. Sterry W, Steinoff M. Erythroderma. In: Bolognia JL, Jorizzo JL, Schaffer
JV, eds. Dermatology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012.
p. 171-182.
16. Dvorakova V, Watson RM, Terron-Kwiatkowski A, et al. Congenital re-
ticular ichthyosiform erythroderma. Clin Exp Dermatol 2016;41:576-577.
17. Mistry N, Gupta A, Alavi A, et al. A review of diagnosis and management
of erythroderma (Generalized Red Skin). Adv Skin Wound Care 2015;28:
228-236.
18. Ott H, Hütten M, Baron JM, et al. Neonatal and infantile erythrodermas. J
Dtsch Dermatol Ges 2008;6:1710-1786.
Clinics in Dermatology (2019) 37, 148–158

The rash that presents as target lesions

Ronni Wolf, MD a,b,⁎, Jennifer L. Parish, MD c,d , Lawrence Charles Parish, MD, MD (Hon) c
a
The School of Medicine, Hebrew University, Jerusalem, Israel
b
Hadassah Medical Center, Jerusalem, Israel
c
Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia,
Pennsylvania, USA
d
Tulane University School of Medicine, New Orleans, Louisiana, USA

Abstract We have explored the rash that appears as target lesions, with the central and dominant diseases
belonging to the Stevens-Johnson syndrome/toxic epidermal necrolysis group. After presenting the clinical
patterns of an individual target lesion and classifying them into different types of lesions, the contribution
has been organized with groups characterized by such specific findings according to the type of lesion: flat
or raised, typical or atypical, presence or absence of fever, presence or absence of mucosal ulcerations, pres-
ence or absence of arthralgias, and/or internal organ involvement. Other specific features, such as histologic
appearance, immunofluorescence findings, and laboratory changes, are considered. We provide clinicians
with an algorithmic, systematic, and logical approach to diagnose the condition of the patients who present
with targetoid lesions, and enable them to differentiate between those with serious systemic and life-
threatening diseases from others with ordinary skin ailments.
© 2018 Elsevier Inc. All rights reserved.

Introduction Historical background

Our approach is directed toward helping clinicians to arrive
at an initial diagnosis, identify critical situations, recognize red
flags that signal real emergencies, and differentiate ordinary
skin ailments from conditions that are genuinely serious to
the point of being life-threatening. The focus is on the mor-
phology of the eruptions, their reaction patterns, and the cuta-
neous manifestations of serious systemic diseases.
⁎ Corresponding author. Tel.: 000-000-000.
E-mail address: wolf_r@netvision.net.il (R. Wolf).
The prototypes of diseases with target lesions are erythema
multiforme (EM) and Stevens-Johnson syndrome (SJS). What
is probably the first description of a targetoid or iris lesions, as
they appear in EM, can be found in Thomas Bateman’s (1778-
1821) textbook Practical Synopsis of Cutaneous Diseases Ac-
cording to the Arrangement of Dr. Willan.1
In his classic 1866 treatise, “On Disease of the Skin,” Fer-
dinand von Hebra (1816-1880) precisely described EM as
erythema exudativum multiforme.2 In 1922, two American
physicians, Albert Stevens (1884-1934) and Frank Johnson
(1894-1934), described the cases of two boys, aged 7 and 8
years, who had “an extraordinary, generalized eruption with
continued fever, inflamed buccal mucosa, and severe purulent

https://doi.org/10.1016/j.clindermatol.2018.12.008
0738-081X/© 2018 Elsevier Inc. All rights reserved.
Rash that presents as target lesions
conjunctivitis,”3 which was later given the name “Stevens-
Johnson syndrome”. In 1950, Bernard Thomas divided EM
into 2 categories, EM minor (von Hebra) and EM major, also
known as SJS.4 In 1956, Alan Lyell (1917-2007) wrote the
most highly cited contribution ever to appear in the British
Journal of Dermatology, in which he described the cases of
four patients with a scalding disease, which was later given
the name “toxic epidermal necrolysis” (TEN), also known as
Lyell syndrome or Lyell’s disease.5,6 These severe, acute,
life-threatening adverse drug reactions were not classified
and defined according to their clinical appearance and linked
to their etiology and prognosis until around 1993.7
Definition and classification
EM was initially described as an acute self-limited skin dis-
ease, symmetrically distributed on the extremities with typical
concentric “target” lesions and often being recurrent.2 The ter-
minology “EM minor” was later proposed to separate the mild
cutaneous syndrome from the more severe forms that involved
mucous membranes, “EM major.” SJS had for years been con-
sidered an extreme variant of EM, and TEN as being a differ-
ent entity. In 1993,7 a group of contemporary experts proposed
a new classification in which they separated SJS from the EM
spectrum and added it to TEN, thereby creating a new spec-
trum of drug-related severe diseases (eg, SJS/TEN). Two dis-
ease spectra were created:
1. EM consisting of EM minor and EM major
2. SJS/TEN. (The former is often a recurrent, postinfectious
disorder [especially due to herpetic and mycoplasma infec-
tions] with low morbidity and almost no mortality. The lat-
ter is usually a severe drug-induced reaction with high
morbidity and poor prognosis.)
According to the new “consensus definition and classifica-
tion,”7 these diseases are categorized essentially by the per-
centage of skin detachment and by the characteristic
appearance of the typical individual “EM-like” or “target” le-
sions. Accordingly, the clinical pattern of an individual skin le-
sion was classified into four different types:
1. Typical targets—individual lesions less than 3 cm in diam-
eter with a regular round shape, well-defined border, and at
least three different zones (ie, two concentric rings around a
central disk). One ring consists of palpable edema, paler
than the center disk.
2. Raised atypical targets—round, edematous, palpable le-
sions, similar to EM but with only two zones and/or a
poorly defined border.
3. Flat atypical targets—round lesions characteristic of EM
but with only two zones and/or a poorly defined border
and nonpalpable with the exception of a potential central
blister.
149
4. Macules with or without blisters—nonpalpable, erythema-
tous or purpuric macules with an irregular shape and size
and often confluent. Blisters often occur on all or part of
the macule.
The involved body surface area (BSA) should measure the ex-
tent of detached and detachable epidermis (which is often much
less than the area of erythema) at the worst stage of the disease.
Accordingly, the following consensus classification was
created:
1. EM—detachment b10% of BSA, localized typical targets,
or raised atypical targets.
2. SJS—detachment b10% of BSA, widespread erythematous
or purpuric macules, or flat atypical targets.
3. Overlap SJS/TEN—detachment between 10% and 30% of
BSA, widespread purpuric macules, or flat atypical targets.
4. TEN with spots—detachment N30% of BSA, widespread
purpuric macules, or flat atypical targets.
5. TEN without spots—detachment N10% of BSA, large epi-
dermal sheets, and no purpuric macules.
The group suggested a practical algorithm, according to the
definition and categorization of these diseases based on their
classification.
1. The first question the clinician needs to ask is: “What is the
percent of detachment?”
2. The second question is: “What is the nature of the discrete
lesions?”
They also suggested that their purely descriptive clinical
classification might indicate a causative agent, namely, that
SJS, TEN, and overlap are drug induced, whereas the diseases
in the EM group are due to infectious agents.
Because the involved area of detachment is defined as such
at the worst stage of the disease, it cannot always be delineated,
when the clinician first sees the patient. Consequently, the most
—and often the only—reliable means of classifying the cases is
through observing the pattern of the individual lesions.
One of us8 proposed a small modification of the current
classification to enable the clinician to quickly and precisely
pinpoint the type of lesion to implement the appropriate treat-
ment without delay. We have observed that patients in the SJS/
TEN group occasionally also have typical targets that are flat
with a flat ring around the center instead of a palpable one.
We, therefore, suggested adding another type of lesion to the
Table 1 Original classification
EM SJS/overlap/TEN
Typical targets Flat atypical targets
Raised atypical targets Macules with/without blisters
EM, erythema multiforme; SJS, Stevens-Johnson syndrome; TEN, toxic
epidermal necrolysis.
150 R. Wolf et al.

Table 2 Proposed new classification How? Just by adding the words “raised” and “flat” to all the le-
EM SJS/overlap/TEN sions. If a patient is found to have raised lesions (raised typical
or raised atypical targets), the clinician is directed toward a di-
Raised typical targets Flat typical targets agnosis of postinfectious EM (Figure 1). Should the patient
Raised atypical targets Flat atypical targets
have flat lesions (flat typical targets, flat atypical targets, or
Macules with/without blisters
macules with or without blisters), the diagnosis of drug-
EM, erythema multiforme; SJS, Stevens-Johnson syndrome; TEN, toxic induced SJS/TEN (Figures 2 to 4) should be considered.
epidermal necrolysis.

nomenclature, namely, “flat typical target,” and to refer to the
original typical target as “raised typical target.” The new clas-
sification will thus contain five types of lesions instead of four
(see Tables 1 and 2). (See Tables 3 and 4.)
Our proposed modification gives the classification greater
leeway for incorporating all the variations characteristic of
these lesions. The new addition makes the classification easier
to understand and, not less importantly, easier to remember.
Other diseases with targetoid lesions
Diseases presenting with flat targetoid lesions
Paraneoplastic pemphigus
Paraneoplastic pemphigus (PNP) is a distinct autoimmune
blistering skin disease that, by definition, is always associated
with a neoplasm.

Table 3 Diseases presenting with flat targetoid lesions

Disease Target lesion Mucosa Detachment Fever Associated condition Immunologic
Paraneoplastic pemphigus Flat Yes, early severe Yes No Malignancy Yes, specific
Generalized bullous fixed drug eruption Flat 2 zones Occasionally Yes No Drug ingested hours before No
Linear IgA bullous dermatosis LABD Flat targetoid Rare Yes No Yes, specific
Drug-induced LABD Flat targetoid ~50% Yes No Vancomycin Yes, specific
LABD, linear immunoglobulin A bullous disease.

Table 4 Diseases presenting with raised targetoid lesions

Disease Target lesion Mucosa Detachment Fever Associated condition Immunologic
Mycoplasma-induced dermatitis Sparse raised Prominent, Vesiculobullous Yes Pneumonia No
& mucositis targets ≥2 sites
Acute hemorrhagic edema of Raised typical & Rare Never Yes, After viral infection No
infancy atypical prodromal
Bullous lupus erythematosus Raised urticarial Yes Bullae Occasional Systemic lupus Yes
erythematosus
Rowell’s syndrome Raised, 2 zones Occasional Vesicular No
borders
Polymorphic eruption of Raised Never Vesicles No Pregnancy No
pregnancy
Pemphigus gestationis Raised Never Vesicles No Pregnancy Yes
Bullous pemphigoid Raised Rare Bullae No Yes
Kawasaki syndrome Raised atypical & Yes No Always No
typical (nonerosive)
Toxic shock syndrome Raised & flat Yes Yes Always Sepsis No
atypical (nonerosive)
Serum sickness–like reaction Raised, urticarial Yes No Always Drugs No
(nonerosive)
Annular urticaria = Urticaria Raised, urticarial Yes No Never No
multiforme (nonerosive)
Sweet syndrome Raised Very rare No Almost Malignancy, drugs, No
pseudovesicles always IBD
Syphilis (congenital and secondary) Raised Yes Bulla Always No
Annular leukocytoclastic Raised purpuric No No Never Systemic diseases, No
vasculitis drugs
Rash that presents as target lesions
Fig. 1 Erythema multiforme major in a 6-month-old febrile child.
The most consistent and, in most of the cases, also the earliest
clinical feature of PNP is the development of a painful stomatitis
and severe painful oral erosions.9–12 The nasopharynx, ano-
genital region, and esophagus could also be affected by large
and painful mucosal lesions. Ocular involvement occurs in
70% of PNP cases, thus resembling SJS. The cutaneous lesions
of PNP are much more variable than those of SJS, however, and
different morphologies may also be observed in an individual
patient at various times. Confluent erosive lesions can develop
Fig. 2 Macules without blisters in a patient with toxic epidermal
necrolysis.
151
Fig. 3 Face of the patient.
on the upper areas of the chest and back, producing a picture re-
sembling TEN. The similarity of the mucocutaneous features to
SJS/TEN and the rapid onset of both conditions explain why
SJS/TEN is the most common differential diagnosis for PNP.10
An associated neoplasia, most frequently a hematologic
one (84%), might help in the diagnosis; however, PNP pre-
cedes the detection of the tumor in about 30% of the patients.11
Notably, TEN also occurs in patients with neoplasia who are
undergoing chemotherapy or other treatments.
The five criteria defined in 19909 are still valid today, but
with minor modifications, and help to differentiate PNP from
other blistering diseases.
1. Clinical features: Painful mucosal erosions with or without poly-
morphous skin eruption producing blisters and erosions and oc-
curring in association with an occult or discernible neoplasm.
2. Histopathology: Suprabasal intraepithelial acantholysis,
vacuolar interface changes, and necrosis of individual
keratinocytes.
Fig. 4 Same patient 1 week later. She had a detachment area of
nearly 90%.
152
3. Direct immunofluorescence: Deposition of IgG and com-
plement in the epidermal intercellular spaces, as well as
granular-linear complement deposition along the epidermal
basement membrane zone.
4. Indirect immunofluorescence: Serum autoantibodies that
bind to the cell surface of skin and mucosa in a pattern typ-
ical of pemphigus, but additionally bind to simple, colum-
nar, and transitional epithelia.
5. Immunoprecipitation: A complex of four proteins (250,
230, 210, and 190 kD) immunoprecipitated from keratino-
cytes by these autoantibodies. The 250-kD antigen appar-
ently comigrates with desmoplakin I, and the 230-kD
antigen comigrates with the 230-kD antigen of bullous
pemphigoid (BP). The 210-kD desmoplakin II and the
190-kD periplakin are the most consistently and heavily la-
beled proteins.
Generalized bullous fixed drug eruption
Fixed drug eruption is a distinct cutaneous drug eruption
characterized by well-demarcated dusky red or heavily pig-
mented patches involving the skin and mucosa. The lesions
tend to recur at the same sites after repeated exposure to the
same drug.
Generalized bullous fixed drug eruption (GBFDE) is a dis-
tinct subtype of fixed drug eruption characterized by wide-
spread blisters and erosions involving the skin of the whole
body, as well as oral and genital mucous membranes. The tar-
get lesions of GBFDE often have two zones, are flat, and usu-
ally have a darker, dusky hue in the center. GBFDE has many
features in common with SJS/TEN. Differentiating between
these two diseases can be difficult and even impossible, mak-
ing the cause a real challenge to the intensive care physician.
There are some differences that can help distinguish be-
tween these two diseases, and most of them are quantitative,
suggesting that they appear more often in one of these diseases
but can appear in both.
• GBFDE usually has a more abrupt onset than SJS/TEN,
with the full-blown disease appearing within hours of in-
gestion of the offending drug, as opposed to SJS/TEN,
which develops within several days.
• GBFDE does not have a prodromal phase, whereas SJS/
TEN usually has a “fluelike” prodromal phase of 1 to 3
days’ duration.
Constitutional clinical manifestations (fever, chills, or
malaise) are seen in more than 50% of patients with SJS/
TEN, whereas patients with GBFDE usually appear healthy
and very rarely have fever or other constitutional clinical
manifestations.
Painful inflammation and erosions of mucosal surfaces oc-
cur in 87% to 100% of cases of TEN, most of them with in-
volvement of at least two sites.13 GBFDE patients can
occasionally show mucosal membrane involvement, in 43%
of cases according to one study,14 and there are no conjuncti-
val lesions.
R. Wolf et al.
Some lesions characteristic of FDE can often be found
among other lesions of GBFDE.
A history of recurrent lesions at the same sites has been re-
ported by almost 70% of patients with GBFDE,15 providing a
definite clue to the diagnosis.
In a retrospective study14 that analyzed patients for 10
years, specific features of patients with GBFDE were com-
pared with patients with SJS/TEN. The GBFDE patients
showed more eosinophil infiltration and dermal macrophages
histologically. Lesional infiltrates in GBFDE had more dermal
CD4+ cells, including Foxp3+ regulatory cells, fewer intraepi-
dermal CD56+ cells, and fewer intraepidermal granulysin+
cells. The serum level of granulysin in GBFDE was also sig-
nificantly lower than that in SJS/TEN. The authors concluded
that “the expression of granulysin both in lesional skin and in
serum is the most important discriminator to differentiate
GBFDE from SJS/TEN.” We believe that clinical features
and history are more important.
As for the prognosis of these two diseases, there is a gener-
ally accepted concept that GBFDE has a better prognosis than
SJS/TEN. The prognosis of 58 patients with GBFDE, matched
by age and extent of skin detachment to 170 control patients
with a validated diagnosis of SJS or SJS/TEN overlap, was
compared in a study16 that used data extracted from the Euro-
SCAR (SCAR = severe cutaneous adverse drug reaction) and
RegiSCAR databases. The investigators concluded that
GBFDE did not show a better prognosis than SJS or SJS/
TEN of similar disease extent. Accordingly, severe cases of
GBFDE should be regarded with the same level of urgency,
seriousness, gravity, and attention as cases of SJS/TEN.
Linear immunoglobulin A (IgA) bullous disease
Linear immunoglobulin A (IgA) bullous disease (LABD)
encompasses a heterogenous group of subepidermal autoim-
mune blistering diseases, characterized by linear deposition
of IgA along the basement membrane zone on direct immuno-
fluorescence. LABD may be subclassified: as spontaneous or
as drug-induced LABD associated with various drugs, vanco-
mycin being the most common.
In children, annular or polycyclic plaques and papules with blis-
tering around the edges (string of pearls sign) is the classic presen-
tation of LABD. In adults, there is a variety of presentations,
mimicking many other bullous diseases (eg, dermatitis herpetifor-
mis, BP, cicatricial pemphigoid, pemphigus, and SJS/TEN; the lat-
ter is very rare, with 16 cases having been reported until 201317).
The individual lesion presents as a flat target lesion with a
tense bulla at the center. Lesions tend to coalesce. They appear
on the trunk and extremities, and many patients also show pal-
moplantar involvement. Nikolsky’s sign is positive. There is
no fever. Mucosal involvement is highly variable (~50% of re-
ported cases). The majority of cases are drug-induced, mostly
by vancomycin, followed by phenytoin.17 The clue to diagno-
sis is the histology of subepidermal blister and linear deposi-
tion of IgA along the basement membrane zone on direct
immunofluorescence.
Rash that presents as target lesions 153

Diseases presenting with raised targetoid lesions very low (3%), and the reported deaths occurred in the prean-
tibiotic 1940s.
Mycoplasma-induced dermatitis and mucositis
Mycoplasma-associated mucocutaneous disease has for de- Acute hemorrhagic edema of infancy
cades and until very recently been classified into the framework Acute hemorrhagic edema of infancy (AHEI) is an acute,
of EM-spectrum or SJS/TEN. In 2015,18 based on a systematic benign, self-limiting leukocytoclastic vasculitis affecting in-
literature review comprising 202 reported cases, it was sug- fants and young children.20,21
gested that the disease be designated as a distinct clinical en- In 1996, a group of Israeli dermatologists and pediatrician
tity, named “Mycoplasma-induced dermatitis and mucositis” defined AHEI as a separate entity and proposed the following
(MIRM). Five criteria were proposed for the diagnosis of the clinical criteria for its diagnosis21:
classic cases of MIRM:
1. Patients younger than 2 years
2. Purpuric or ecchymotic target–like skin lesions with edema
1. Detachment of b10% BSA
on the face, auricles, and extremities, with or without mu-
2. Involvement of ≥2 mucosal membranes
cosal involvement.
3. Few vesiculobullous lesions or scattered atypical targets
3. Absence of systemic disease or visceral involvement.
4. Targetoid lesions (not mandatory) 4. Spontaneous recovery within a few days or weeks
5. Clinical evidence of atypical pneumonia (fever, cough,
positive auscultatory findings) and laboratory findings (in-
AHEI has a sudden appearance and is characterized by the
crease in mycoplasma IgM antibodies, mycoplasma in oro-
triad of fever, purpuric eruption, and edema. The patient is
pharyngeal or bullae cultures or PCR and/or serial cold
usually not toxic and is in good general condition. The skin
agglutinins)
eruption generally starts with erythematous macules or urticar-
ial plaques that rapidly progress into annular, rounded, medal-
It was later suggested to add an age range as an additional
lionlike, or targetoid purpuric lesions. The targets are a mixture
criterion, for example, 5 to 15 years, because anyone younger of typical three-zone and raised atypical two-zone targets that
than 2 years of age or older than 20 years is less likely to have
are symmetric and occur on the face (mainly cheeks), auricles,
MIRM.19
and extremities. Other locations may be involved. Nonpitting
An excellent systematic review18 synthesized the following
edema of the face and extremities is common and is often
clinical presentations of the reported cases of MIRM.
the presenting sign. Mucous membranes are only rarely in-
volved.20,21 The histopathology of AHEI classically shows
• The patients were young, with a mean age of 11.9 ± 8.8 features of dermal leukocytoclastic vasculitis with or without
years. fibrinoid necrosis.
• Prodromal clinical manifestations were nearly universal AHEI looks more alarming than it really is, but it should be
and included cough, malaise, and fever that preceded the differentiated from SJS/TEN and other severe diseases, having
eruption by approximately 1 week. a similar appearance.
• The skin eruption was vesiculobullous in 77% of patients,
targetoid in 48%, papular in 14%, macular in 12%, and Rowell’s syndrome (Figure 5)
morbilliform in 9%. In 1963, Neville Rowell (1926- ) and his group22 reported a
• The extent of skin involvement was usually sparse and new syndrome, characterized by lupus erythematosus, EM-
characterized by single or few scattered lesions in 47% of
the patients, severe mucositis alone with no skin lesions
in 34%, and moderate cutaneous involvement in 19%, the
latter including 2 cases of TEN-like presentation.
• Predominant acral distribution was most common (46%),
followed by generalized (31%), and truncal (23%)
distribution.
• The hallmark of the disease is severe mucosal involvement,
with oral lesions in 94% of cases, ocular in 82%, and uro-
genital in 63%.

MIRM has a milder disease course than SJS/TEN, with the

exception of more frequent pulmonary disease, which proba-
bly stems from the M pneumoniae infection itself. Patients
with MIRM usually recover fully with infrequent recurrence Fig. 5 Histologically and immunologically proven Rowell’s syn-
(8%). The mortality of the reported cases in the review was drome in a 20-year-old woman of Arabic origin.
154
Fig. 6 Urticaria multiforme. Courtesy Prof. Alex Zvulunov.
like lesions, speckled pattern of antinuclear antibody, anti-La,
and positive rheumatoid factor. In 2000 major and minor cri-
teria for the diagnosis were proposed.23
• The major criteria:
1. Systemic LE, discoid LE, or subacute cutaneous LE
2. Erythema multiforme–like lesion (with or without in-
volvement of the mucous membranes)
3. Speckled pattern of antinuclear antibody
• The minor criteria:
1. Chilblains
2. Anti-Ro antibody or anti-La antibody
3. Positive rheumatoid factor
• All three major and at least one minor criteria are required
to establish the diagnosis.
The targetoid EM-like lesions are usually two zones
raised erythematous lesions with vesicular borders. (See
Figs. 6 and 7.)
In a review of 71 cases reported until 2012,24 an Italian
group of researchers raised doubts whether Rowell’s syn-
drome is indeed a distinct entity. According to them, and in
agreement with several other cited authors, LE with EM-like
dermatitis represents a subset of subacute cutaneous LE with
targetoid lesions. Although we are not convinced that the dra-
matic title of their paper “The last word on the so-called
‘Rowell’s syndrome’?” really reflects the last word, the present
Fig. 7 Urticaria multiforme. Courtesy Prof. Alex Zvulunov.
R. Wolf et al.
presentation is not an appropriate arena for conflict. The acute
appearance of targetoid lesions can occur in several forms of
LE and can easily be differentiated from EM by their charac-
teristic immunologic features.
Polymorphous eruption of pregnancy
Polymorphous eruption of pregnancy (PEP) is the most
common specific skin eruption in pregnancy, affecting 1 of
160 deliveries.25 The classic clinical presentation of PEP in-
cludes intensely pruritic urticarial papules and plaques (PUPP)
starting within and/or adjacent to striae and sparing the peri-
umbilical area. The lesions can later spread to nonabdominal
sites. Approximately one-half of the patients develop poly-
morphic skin lesions. According to a large case series,25
49% of the 181 reported patients with PUPP remained with
PUPP-like lesions. All the others (51%) developed additional
features, including eczematous lesions (22%), vesicles
(17%), nonurticarial, at times polycyclic erythema (6%), and/
or targetoid or EM-like lesions (6%). An earlier report on 57
patients showed similar results, with 5.3% of the patients pre-
senting targetoid lesions.26
PEP should be considered in the differential diagnosis of
EM in pregnant women presenting with PUP, even though
only ~6% of patients with PEP will have this type of lesion.
The target lesions are raised erythematous pruritic plaques
with a central dusky red area and vesicle. There will not be
any mucosal involvement, immunofluorescence studies are
generally negative, and the histologic examination can be ex-
pected to be nonspecific.
Bullous pemphigoid
BP is the most common chronic autoimmune bullous der-
matosis; nonetheless, erythema multiforme–like BP has rarely
been reported, with only 9 cases found in the literature.27 The
clinical findings include manifestations of EM and BP.27 The
lesions are mostly raised and edematous, with essentially no
mucosal involvement (one out of the nine patients had muco-
sal membrane involvement).
Kawasaki disease
Kawasaki disease (KD) is an acute, self-limited multisys-
tem medium-vessel vasculitis of unknown etiology. It predom-
inantly affects infants and young children with a predilection
for the involvement of coronary arteries. Because mucocuta-
neous signs make up four of the five clinical criteria for the di-
agnosis of KD, dermatologists have an important role in the
early diagnosis of this disease, which has potential morbidity
and mortality.
The diagnosis of KD is based on the presence of fever of
≥5 days as an obligatory criterion and the presence of at least
4 of the following 5 criteria:
1. Bilateral conjunctival injection without exudate
2. Changes in the lips and oral cavity (erythema, fissured lips,
strawberry tongue, injected pharynx)
3. Polymorphous exanthem
Rash that presents as target lesions
4. Changes in the extremities (acute: erythema or edema of
hands and feet; subacute: periungual desquamation of fin-
gers and toes from week 2)
5. Cervical lymphadenopathy
The clinical signs do not present simultaneously and the
typical acral desquamation is often a late sign.28 The skin erup-
tion is nonspecific and has been described as scarlatiniform,
morbilliform, maculopapular, or urticarial exanthema.
Annular EM-like lesions, as a manifestation of KD, are ex-
tremely rare, having been reported in fewer than 10 cases.29,30
The EM-like lesions are raised atypical or typical classic tar-
gets. The mucosal membrane involvement is not ulcerative;
however, the crusted lips together with conjunctivitis or con-
junctival injection in febrile children can easily lead to an erro-
neous diagnosis of SJS.
Toxic shock syndrome
Toxic shock syndrome is a condition caused by either local-
ized superficial (Staphylococcus aureus) or invasive (Strepto-
coccus pyogenes) bacterial superantigens. Staphylococcal
toxic shock syndrome is characterized by high fever, hypoten-
sion, dermatitis, skin desquamation (later), and multiorgan
dysfunction.31 Target lesions have been described in fewer
than five patients,32 and it is included here for the sake of
completeness.
Serum sickness–like syndrome
Serum sickness was first described in 1905 by Clemens von
Pirquet (1974-1929) and Bela Schick (1877-1967)33 after the
use of horse serum containing diphtheria antitoxin.
A serum sickness–like reaction (SSLR) is a nonprotein
drug reaction that demonstrates several of the clinical findings
of serum sickness disease but usually lacks the immune com-
plex formation characteristic of the latter. SSLR is caused by
various drugs, such as beta-lactam antibiotics, penicillins, sul-
fonamides (among the most frequent), minocycline, ciproflox-
acin, nonsteroidal anti-inflammatory drugs, anticonvulsants,
and antidepressants. More recently, immune modulators, com-
monly referred to as “biologicals,” have attracted some atten-
tion.34 The interval from the introduction of the medication
to the onset of SSLR is usually 8 to 14 days, but it can some-
times take up to 3 weeks.
An SSLR consists of a triad of dermatitis, fever, and arthral-
gia, without any evidence of cutaneous or systemic vasculitis.
Cutaneous eruptions can be seen in up to 95% of cases. The
most common skin findings include macular exanthem, urti-
carial dermatitis, morbilliform dermatitis, and an eruption
mimicking EM.35 Urticarial lesions that have a dusky-to-
purple center may well resemble the target lesions of EM.36
Unlike urticaria, SSLR lesions tend to persist for more than
24 to 36 hours, and are generally ecchymotic. Periocular
edema is common,35 and the hands and feet are often erythem-
atous and edematous. Another primary clinical feature is joint
involvement manifested by arthralgia and joint swelling.
155
Elbows, knees, and ankles are the most commonly affected
joints.35
Laboratory findings of SSLR include leukocytosis, a high
erythrocyte sedimentation rate, and mild proteinuria or hema-
turia.35 SSLR has a benign course and favorable prognosis.
Urticaria multiforme
In 2007, the term “urticaria multiforme” (UM) was intro-
duced to replace acute annular urticaria to highlight the distinct
clinical features of the disease.37
UM is a common and benign cutaneous hypersensitivity re-
action seen in children and characterized by typical annular,
arcuate, and polycyclic urticarial lesions in association with
acral edema. It is most commonly misdiagnosed as EM,
SSLR, or urticarial vasculitis.37
The individual lesion is a blanchable annular, arcuate, and
polycyclic erythematous wheal. The lesions may display either
central clearing or a dusky, ecchymotic center, which may be
mistaken as a target lesion of EM. The most important clinical
feature of a UM lesion is that the duration of an individual le-
sion is less than 24 hours. There is often an associated angio-
edema of the face, hands, and feet, and dermographism is
common.
UM is confirmed by applying the diagnostic criteria.37
1. Typical annular and polycyclic morphology and the config-
uration of urticarial lesions; absence of true target lesions
and/or skin necrosis or blistering; absence of mucous mem-
brane involvement with blisters or erosions
2. Duration of individual lesions b24 hours
3. Dermographism
4. Angioedema but not arthralgia or arthritis. Angioedema
typically involves the hands and/or feet but may also in-
volve the periocular or oral mucosa. Children with signifi-
cant edema of the feet may find walking difficult, which
should not be confused with arthritis or arthralgia.
5. Favorable response to antihistamines.
6. Modest but nonsignificant elevations in acute-phase reac-
tants, but not the elevations typically seen in patients with
rheumatologic disorders, serious systemic infections, or
KD.
UM mostly affects children between 4 months and 4 years
of age. Pruritus is an almost universal finding associated with
UM, and fever occurs in ~40% of the patients.37
In the 2007 report,37 the authors provided a table describing
distinguishing features of UM, EM, and SSLR, a table that has
been adapted by many forthcoming reports on this disease.
The main features include:
• The duration of the individual lesion in UM is b24 hours
and in UM and EM days to weeks.
• The total duration of the dermatitis in UM is 2 to 12 days,
compared with 2 to 3 weeks in EM and 1 to 6 weeks in
SSLR.
156
• Erosions are present in EM and absent in UM and SSLR,
the latter two featuring oral edema. Facial and acral edema
are present in UM and SSLR and absent in EM, and dermo-
graphism is seen only in UM.
The comparison of UM is to EM, not so much to SJS/TEN.
Sweet’s syndrome
Febrile neutrophilic dermatosis was first described by
Robert Sweet (1918-2001) in 1964 and hence called Sweet’s
syndrome. Although abrupt onset of painful erythematous pla-
ques or nodules is an obligatory major criterion of Sweet’s
syndrome (SS),38,39 coexisting atypical targetoid lesions have
also been reported.
A large retrospective study of 90 cases from a tertiary care
center in Tunisia40 reported atypical targetoid lesions in 11 out
of the 90 studied patients, and 9 of those 11 had the classic id-
iopathic form. In a Brazilian study of 73 SS cases,41 targetoid
lesions were found in 12 (18.5%) of the patients. Sixty-eight
percent of the patients had a second diagnosis of EM. Those
authors mentioned that 13 of 21 cases of SS (62%) had a sec-
ond diagnosis of EM in another study from the same hospital.
SS can easily be distinguished from EM, particularly in
view of the fact that the targetoid lesions— if there are any
—almost always appear along with classic lesions, which are
the major and obligatory criterion of SS.
Congenital and secondary syphilis
Syphilis was referred to “the great imitator” by Sir William
Osler (1849-1919) due to its manifold presentations, which
make the diagnosis in the emergency room difficult.
There are very few cases of syphilis presenting with targe-
toid lesions and mimicking EM. Six cases of EM-like second-
ary or congenital syphilis were described in a case series that
appeared in 2013,42 and two additional cases were reported
later on.43,44 It is not yet known whether the form of an EM-
like presentation of syphilis is a true EM triggered by some
type of immune response against T pallidum (T pallidum–
induced EM) or a presentation of the disease itself.
Annular leukocytoclastic vasculitis
Annular leukocytoclastic vasculitis (ALV) is a rarely re-
ported clinical variant of leukocytoclastic vasculitis. ALV
has been linked to various systemic diseases and drugs.
A 1996 report revealed that some patients with ALV consti-
tute a distinct subtype, which satisfies the following 6
criteria45:
1. Multiple attacks for years with a sudden onset and sponta-
neous regression after 7 to 10 days
2. Annular purpuric patches that show a centrifugal extension
3. Extension over the limbs and trunk creating polycyclic le-
sions that clear with mild hemosiderin deposition
4. No extracutaneous clinical manifestations and good general
health during the attacks
R. Wolf et al.
5. Histologic changes of leukocytoclastic vasculitis with mild
vascular changes and intense polymorphonuclear cell
infiltration
6. Complete clearance of all lesions with dapsone therapy
Many of the following cases showed only several of the 6
criteria.46 Also not all47 of the reported cases showed target-
like appearance and had a resemblance to EM, like the initial
cases.
TEN-like diseases without target lesions
In 2004, a group of dermatologists48 described a case of
TEN-like acute cutaneous lupus erythematosus and drew atten-
tion to the fact that TEN-like skin manifestations can occur in
LE and in some other diseases not associated with drug-
induced TEN. They proposed the term “acute syndrome of ap-
optotic pan-epidermolysis (ASAP)” for this syndrome, which is
characterized by acute and massive cleavage of the epidermis
resulting from hyperacute epidermal basal cell apoptotic injury.
The three diseases included in this syndrome were LE, acute
graft versus host disease (GVHD), and pseudoporphyria.
These authors also proposed an alternative definition of the
acronym ASAP, one that is often used (“as soon as possible”)
to reinforce the sense of urgency that is required in clinically
managing patients in this setting. The importance of this paper
is not so much the proposed name of the syndrome, although it
is appropriate, but in drawing attention to the idea that a differ-
ential diagnosis of other diseases should be considered in cases
of drug-induced TEN.
TEN-like systemic lupus erythematosus
The first report on the association of systemic lupus erythe-
matosus (SLE) and TEN appeared in Spanish in 1977,49 and
the first report in the English literature appeared in 1984.50
In the latter publication, LE was considered as a cofactor in
the causation of drug-induced TEN. Two out of 17 described
cases of drug-induced TEN also suffered from SLE, and the
causative drug was penicillamine in one patient and metroni-
dazole in the other. Very few cases have appeared in the sub-
sequent 20 years.51–55
In 2004,48 a new designation of ASAP was applied to cases
of TEN-like appearance. These authors proposed new classifi-
cation for vesiculobullous skin disorders that can be encoun-
tered in LE patients. Relevant for the current paper are the
findings that TEN-like lesions can appear in acute and sub-
acute cutaneous LE and in SLE with no LE-specific skin
lesions.
In 2013, a Turkish group reviewed all of the 21 published
cases of TEN-like SLE and an additional one of their own. 56
The patients had progressive epidermal necrosis and
sloughing. Mucosal involvement was seen in ~30% of
patients. All 22 patients had TEN-like histopathology. They
had various degrees of systemic involvement resulting from
SLE, such as hematological anomalies (36%) and lupus
nephritis (27%).
Rash that presents as target lesions
Few cases have been reported since then. TEN-like SLE
and drug-induced TEN share clinical and histopathologic sim-
ilarities. The main differences are as follows:
1. Presence of photodistribution
2. Discrete or absence of mucosal membrane involvement
3. Positive antinuclear antibody, and/or anti–double-stranded
DNA, and/or anti-Ro or anti-La antibodies
4. Positive lupus band test in direct immunofluorescence in
TEN-like SLE but not in drug-induced TEN
Acute graft-versus-host disease
Acute severe stage 4 GVHD can bear a striking clinical re-
semblance to TEN and is potentially indistinguishable from it.
Both diseases show extensive erythema with epidermal de-
tachment and skin sloughing of N10% BSA. Both diseases
are characterized by mucous membrane involvement, fever,
bone marrow depression, and internal organ involvement
(eg, gastrointestinal mucosa and abnormal liver function tests),
and both show a rapid progression to death.57–60
There is an overlap of histologic appearance as well. Both
diseases show keratinocyte apoptosis, subepidermal blister
formation, and satellite cell necrosis. There is almost no in-
flammatory lymphocytic infiltrate in the papillary and reticular
dermis in either of them. Unfortunately, there is currently no
reliable way to distinguish between TEN and severe acute
GVHD. At the same time, it is of paramount importance to
do so early in the disease course, because the therapy is differ-
ent for the two conditions. Whereas the mainstay therapy for
GVHD is immunosuppression, including corticosteroids, such
treatments—particularly if continued over time—might
worsen the prognosis of TEN.
Some methods have been proposed for differentiating these
two conditions:
• The demonstration of a chimerism (significant number of
donor lymphocytes) in circulating lymphocytes has been
suggested to favor GVHD over TEN.58,61
• A high dermal CD8+/CD4+ T-lymphocyte ratio (≥4) has
been proposed as a guide for the diagnosis of TEN over
GVHD.57
These and other findings can be suggestive at best but not
confirmatory of either one of the two diseases. As the authors
write, they are contributory if they appear “in the appropriate
clinical setting.”57 Several authors have also suggested that
TEN can be a manifestation of GVHD.60
Conclusions
Our purpose has been to assist clinicians to quickly and cor-
rectly identify critical situations, recognize life-threatening
conditions, and interpret red flags that signal real emergencies
so that they can differentiate them from dermatitis that do not
157
pose immediate danger. To best treat sick patients who present
with a dermatitis, it is appropriate to focus on the morphology
of the eruptions and their reaction pattern after having taken
the vital comprehensive history.
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Clinics in Dermatology (2019) 37, 129–135

The rash with painful and erythematous nodules

Arun C. Inamadar, MD, FRCP (Edin) ⁎, Keshavmurthy A. Adya, MD
Department of Dermatology, Venereology & Leprosy, Shri B. M. Patil Medical College, Hospital & Research Center, BLDE
Deemed University, Vijayapur, Karnataka, India

Abstract Erythematous painful cutaneous nodular lesions are associated with a host of disorders that may
erupt acutely as a generalized or localized dermatitis or be associated with chronic and/or recurrent illnesses.
This review discusses such disorders presenting with painful nodular lesions and attempts to provide a sys-
tematic approach to their clinical diagnosis.
© 2018 Elsevier Inc. All rights reserved.

Introduction and classification borderline lepromatous or lepromatous leprosy. As opposed

Many dermatoses present with painful and erythematous nod-
ular lesions, either localized or generalized. An appropriate clinical
diagnosis is essential for further appropriate workup to confirm the
diagnosis and for timely management. Disorders presenting with
painful inflamed erythematous nodules generally reflect a deep
dermal or subcutaneous pathology. Panniculitides, vasculitides,
and dermal infiltrative disorders commonly account for such clin-
ical presentation (Table 1). The clinical diagnostic approach can
be based on the mode of onset, distribution, and spread of the
lesions as depicted in Figures 1 to 5. Certain accompanying
clinical findings help to support the clinical diagnosis and to
carry out relevant laboratory tests (Table 2).
to erythema nodosum (see Erythema nodosum section), ENL
is generalized in distribution and characterized by evanescent,
erythematous, tender nodules occurring in crops (Figure 6).
They favor the extensors of the arm and medial aspect of
thigh and typically spare the preexisting leprosy lesions. It is
a multisystem disease and is accompanied by constitutional
clinical manifestations. Laboratory evaluation reveals
neutrophilic leukocytosis such elevated markers of
inflammation-as C-reactive protein, and erythrocyte sedimen-
tation rate. Histopathologically, ENL is characterized by septal
panniculitis.1 Some patients may also have a chronic recurrent
form of the disease.
Sweet’s syndrome

Sweet’s syndrome (acute febrile neutrophilic dermatosis) is

Acute onset generalized painful nodules
Erythema nodosum leprosum
Erythema nodosum leprosum (ENL) is a prominent
cutaneous manifestation of type 2 lepra reaction occurring in
⁎ Corresponding author. Tel.: +91 8352 262770 Extn 2020/2021.
E-mail address: aruninamadar@gmail.com (A.C. Inamadar).
an acute febrile neutrophilic dermatoses associated with
infection, drugs, malignancies, and autoimmune disorders.
Clinically, it is characterized by the acute onset of erythema-
tous tender plaques and nodules favoring the head and neck
region and proximal aspects of the extremities that may
extend beyond, involving the trunk and legs (Figure 7). A di-
agnostic pointer can be the characteristic “pseudovesicular”
appearance of the lesions due to marked dermal edema. Fever,

https://doi.org/10.1016/j.clindermatol.2018.12.006
0738-081X/© 2018 Elsevier Inc. All rights reserved.
130 A.C. Inamadar, K.A. Adya

Table 1 Disorders presenting with painful inflamed nodules Cytophagic histiocytic panniculitis
Disorder Conditions
Cytophagic histiocytic panniculitis is a rare multisystem dis-
Panniculitides Erythema nodosum order characterized by recurrent widespread acute onset of in-
Erythema nodosum leprosum
flammatory subcutaneous nodules occurring in recurrent
Sclerosing panniculitis
crops associated with fever, arthritis, hepatosplenomegaly, ane-
Pancreatic panniculitis
Cytophagic histiocytic panniculitis mia, and pancytopenia. The nodular lesions later break down to
Alfa1-antitrypsin deficiency form ulcers, discharging oily material. The disease is consid-
Vasculitides Nodular vasculitis ered a specific cutaneous manifestation of the hemophagocytic
Cutaneous polyarteritis nodosa syndrome, wherein there is a widespread phagocytically active
Neutrophilic dermatoses Behçet's disease histiocytic proliferation throughout the reticuloendothelial
Sweet’s syndrome system. The histiocytic proliferation may also be secondary
Neoplastic Cutaneous metastases to various infections, malignancies, or autoimmune disorders.
Vasculopathic Superficial thrombophlebitis Many of the cases represent subcutaneous panniculitis-like T-
Calciphylaxis cell lymphoma. The specific histologic feature is the prolifera-
Infective Chronic meningococcemia
tion of histocytes in the subcutis that are phagocytically active
Pseudomonas hot foot syndrome
and are seen to have engulfed blood cells and nuclear frag-
Others Idiopathic palmoplantar hidradenitis
Accelerated rheumatoid nodulosis ments (bean bag histiocytes).3

Alfa1-antitrypsin deficiency panniculitis

marked neutrophilic leukocytosis, arthralgia, conjunctivitis,
episcleritis, and systemic features of neutrophilic alveolitis;
multifocal sterile osteomyelitis; and acute renal failure may de-
velop. The histology is characterized by marked dermal edema
and diffuse nodular and perivascular neutrophilic infiltrate in
the dermis.2
Alfa1-antitrypsin is a serine protease inhibitor involved in
the regulation of various proteases involved in tissue destruc-
tion. It is also known to be involved in regulating various proin-
flammatory cellular and immunological phenomena. Patients
with severe deficiency of the enzyme are prone for ulcerating

Fig. 1 Painful erythematous nodules.

Fig. 2 Generalized painful nodules.

Painful and erythematous nodules 131

Fig. 3 Generalized erythematous painful nodules.

Fig. 4 Acute localized erythematous painful nodules.

Fig. 5 Chronic and recurrent localized erythematous painful nodules.

132 A.C. Inamadar, K.A. Adya

Table 2 Clinical pointers to the diagnosis of dermatitis presenting as painful inflamed nodules
Disorder Conditions
Panniculitides Erythema nodosum
Erythema nodosum leprosum
Sclerosing panniculitis
Pancreatic panniculitis
Cytophagic histiocytic panniculitis
Alfa1-antitrypsin deficiency panniculitis
Vasculitides Cutaneous polyarteritis nodosa
Neutrophilic Behçet's disease
dermatoses
Sweet’s syndrome
Vasculopathic Superficial thrombophlebitis
Calciphylaxis
Infective Chronic meningococcemia
Pseudomonas hot foot syndrome
Neoplastic Cutaneous metastases
Others Idiopathic palmoplantar hidradenitis
Accelerated rheumatoid nodulosis
Clinical diagnostic pointers
Limited to lower extremities commonly or may be generalized with constitutional
clinical manifestations
Generalized evanescent lesions occurring in crops with constitutional clinical
manifestations. Evidence of leprosy in the background
Painful nodules with a background of clinical changes due to chronic venous
insufficiency
Crops of painful erythematous nodules with constitutional clinical manifestations
that rupture to discharge cheesy or oily material
Other clinical evidence of vasculitis-like palpable purpura, livedo reticularis, and
punched-out ulcers
Characteristic oral and genital aphthae and other cutaneous lesions of Behçet’s
disease with arthralgia/arthritis
Constitutional clinical manifestations, typical “pseudovesicle” appearance of the
lesions
Inflammatory edema of the leg, tenderness, and prominent cordlike thickening of
superficial veins accompanying the nodules
Frequent in the setting or chronic renal failure on dialysis. Nodules progressing to
form characteristic stellate ulcers with surrounding noninflammatory retiform purpura
Remitting and relapsing episodes of fever with arthritis, splenomegaly, and
polymorphic skin lesions
Common in children typically with a history of swimming in pools. Associated with
mild constitutional clinical manifestations
Sudden or gradual onset of lesions in the setting of an underlying internal
malignancy. Cutaneous metastases are generally asymptomatic, but on occasions
they may be painful and tender. Some of the malignancies metastatize to specific
cutaneous sites
Common in children, acute-onset lesions, self-limiting lesions predominantly on the
soles
Typical in the setting of treatment with methotrexate. As opposed to the painless
subcutaneous nodules of the disease, these are painful

neutrophilic panniculitis in addition to disorders of liver, lung,
and kidney. Lesions appear as tender erythematous nodules that
eventually break open to form indolent ulcers discharging oily
or cheesy material that heal with scarring. Involvement of the
trunk (Figure 8) and proximal extremities is a clue, and the le-
sions may later extend beyond. Fever, pleural effusion, and
pulmonary embolization may be accompanied in severe cases.
The histology is characterized by acute neutrophilic lobular
panniculitis with destruction of fat lobules.3
Acute-onset localized painful nodules
Erythema nodosum
Erythema nodosum is an acute inflammatory nodular erup-
tion occurring as a reactive phenomenon in association with
various infections (eg, tuberculosis), autoimmune diseases
(eg, inflammatory bowel disease), and drugs (eg, sulfon-
amides). It is characterized by acute bilaterally symmetrical
erythematous and painful nodules typically involving the pre-
tibial areas of the leg (Figure 9). They are associated with
constitutional clinical manifestations such as fever,
malaise, headache, and gastrointestinal complaints. Erythema
nodosum is histologically characterized by as septal
panniculitis. A chronic form of the disease is also described
but is quite rare.4
Pancreatic panniculitis
Pancreatic or enzymatic panniculitis is a form of subcutane-
ous fat necrosis associated with a variety of pancreatic disor-
ders mediated by pancreatic lipase, amylase, and tryptase.
Multiple tender erythematous subcutaneous nodules develop
predominantly on the legs, which may uncommonly spread
centripetally to involve the proximal areas of the thighs, arms,
chest, and abdomen. Similar to other panniculitides, the nod-
ules rupture to form ulcers discharging oily material. Pancre-
atic panniculitis precedes the systemic clinical manifestations
of pancreatic disease by 1 to 7 months, and when associated
with pancreatic carcinoma, it usually indicates an advanced
metastatic stage. Systemic features may include fever, polyar-
thritis, and pleural effusion. Subcutaneous nodules associated
with polyarthritis and eosinophilia (Schmid’s triad) are indica-
tive of a poor prognosis.5,6
Painful and erythematous nodules 133

Fig. 8 Resolving erythematous nodules on the back of a woman with

alfa1-antitrypsin deficiency panniculitis. (Image courtesy: Sharad
Mutalik, MD, Pune, India.)

erythema nodosum. In addition, typical erythema nodosum

may also be associated with Behçet’s disease.7

Superficial thrombophlebitis

Superficial thrombophlebitis is clinically characterized by

acutely inflamed and swollen extremity, associated with mul-
tiple tender nodules in a linear configuration (along the course
Fig. 6 Erythematous tender nodules on the trunk in a patient with
lepromatous leprosy.

Behçet’s disease

Erythema nodosum–like lesions presenting as acute painful

erythematous nodules on the legs can occur in Behçet’s
disease, especially in women. They may also involve the but-
tocks and are difficult to distinguish histologically from typical

Fig. 7 Erythematous nodule with scaling on the dorsum of the Fig. 9 Typical erythematous tender nodules of erythema nodosum in-
hand in a woman with Sweet’s syndrome. volving the pretibial area.
134
of the vein). Dilated collaterals and diffuse erythema around
the nodules are also present. Frequently, the great saphenous
vein is involved. Superficial thrombophlebitis is an underre-
ported condition, and the risk factors are similar to those with
deep venous thrombosis (most commonly immobilization,
obesity, pregnancy, trauma, underlying malignancy, or hyper-
coagulable states, and a history of superficial or deep venous
thrombosis). It is prudent to look for accompanying deep vein
thrombosis, as superficial thrombophlebitis may coexist with
deep vein thrombosis and may also represent a risk factor.8
Calciphylaxis
Calciphylaxis (calcific uremic arteriolopathy) is an uncom-
mon disorder with high mortality, seen most often in the set-
ting of end-stage renal disease associated with secondary
hyperparathyroidism. It often affects middle-aged women,
with a greater frequency in the presence of comorbidities such
as diabetes, hypothyroidism, obesity, liver disorders, and ma-
lignancies. Patients without renal failure and with normal
calcium-phosphate product have also been described. The
lower portions of the legs are commonly involved (distal
form). Involvement of areas with high subcutaneous fat, such
as proximal areas of the thighs, buttocks, and abdomen, appear
to carry a worse prognosis. Initial lesions appear as fixed
livedo (racemose type) overlying indurated plaques or nodules
that eventually transform into stellate purpuric lesions that
breakdown to form deep ulcers with violaceous margins and
a black eschar. Exquisite pain and tenderness disproportionate
to the clinical manifestations are the hallmark features.9,10
Pseudomonas hot foot syndrome
Pseudomonas hot foot syndrome is primarily a disease of
childhood that is characterized by sudden development of very
painful and tender papules and nodules with edema over the
plantar surface of the feet. Exposure to swimming pool water
contaminated with Pseudomonas aeruginosa is frequently im-
plicated. Mild systemic clinical manifestations may accom-
pany the rash and resolve spontaneously within a week or
two with only symptomatic management. Perivascular and
perieccrine neutrophilic infiltrate and occasional dermal
microabscesses are typical histologic features.11
Idiopathic palmoplantar hidradenitis
Idiopathic palmoplantar hidradenitis is another benign self-
limiting disease seen in children, characterized by the sudden
onset of painful erythematous nodules on the soles and less
commonly on the palms. Trauma or vigorous physical activity
is implicated in the pathogenesis, and the disease is histologi-
cally characterized by a neutrophilic infiltrate involving the
ductal and secretory components of the eccrine glands and for-
mation of microabscesses. This disorder, in contrast to neutro-
philic eccrine hidradenitis, is seen in healthy children.
A.C. Inamadar, K.A. Adya
Neutrophilic eccrine hidradenitis is a disease of adults,
typically in the setting of chemotherapy and often occurring
on the abdomen, ears, and face.12
Accelerated rheumatoid nodules
Painless subcutaneous nodules are characteristic extraarticu-
lar manifestations of rheumatoid arthritis usually associated
with elevated titers of rheumatoid factor and presence of other
autoantibodies, and generally reflect a greater inflammatory
process. Sudden onset or worsening of nodules in rheumatoid
arthritis is commonly associated with methotrexate therapy. It
is also described with other drugs, such as azathioprine, lefluno-
mide, and immunobiologics, including tocilizumab and antitu-
mor necrosis factor agents. These lesions typically suddenly
develop and are often painful and typically favor the hands, feet,
and ears. Lesions generally regress with discontinuation of
methotrexate and may recur with reinitiation.13,14
Chronic/recurrent localized painful nodules
Nodular vasculitis
Nodular vasculitis or erythema induratum is a disorder
characterized by an indolent eruption of painful erythematous
nodules involving the calves, which may rupture and ulcerate
to heal with atrophic scars. Women are more commonly af-
fected. It was initially described in association with tuberculo-
sis, but not always; hence, nodular vasculitis has been
classified into two predominant types—erythema induratum
of Bazin, which is associated with tuberculosis, and the Whit-
field type, which is not associated with tuberculosis and may
be seen with a host of autoimmune, infectious, and neoplastic
disorders. Histologically, nodular vasculitis is characterized by
a lobular panniculitis with vasculitis.13
Sclerosing panniculitis
Sclerosing panniculitis (lipomembranous panniculitis) is a
common form of chronic panniculitis frequently in the setting
of long-standing chronic venous hypertension on the legs of
middle-aged, frequently obese, women. Initial manifestations
of sclerosing panniculitis are characterized by multiple painful,
indurated erythematous nodules, resembling erythema nodo-
sum, either unilaterally or bilaterally. Features of long-
standing venous hypertension, such as varicosities, venous ul-
cers, and stasis dermatitis, may be seen on the affected leg. The
lesions evolve into diffuse sclerotic thickening of the entire leg
with hyperpigmentation (lipodermatosclerosis), giving an
“inverted champagne bottle” appearance. The histotopathology
in early stages is characterized by ischemic necrosis of fat
lobules with septal lymphocytic infiltrate. As the lesion
advances, there is progressive sclerosis of the interlobular septae
and lipomembranous changes characterized by thickened,
Painful and erythematous nodules
undulating membranes, derived from degenerated lipocyte
membranes and forming cystic and papillary configurations.6
Cutaneous polyarteritis nodosa
Cutaneous polyarteritis nodosa is a form of polyarteritis
nodosa that is common in children and associated frequently
with streptococcal infections, being limited to the skin with min-
imal and mild constitutional clinical manifestations. Clinically,
it is characterized by painful subcutaneous nodules involving
the legs that are associated with other features of vasculitis such
as livedo reticularis and punched-out ulcers. The disease is be-
nign but runs a chronic and relapsing course. About half
of the patients with systemic polyarteritis nodosa exhibit cutane-
ous manifestations described above, but the painful nodules
are more frequently seen with the cutaneous form of the
disease.15,16
Chronic meningococcemia
Chronic meningococcemia is a rare disorder, characterized
by recurrent fever, without meningitis, lasting for 2 to 7 days,
and associated with arthralgia and arthritis, splenomegaly, and
a polymorphous eruption, characterized by petechiae, purpura,
and painful subcutaneous nodules, frequently involving the
legs and less frequently the arms and trunk. With treatment,
the disease remits with clearance of the bacteremia only to re-
cur in 1 to 4 days.17,18
Cutaneous metastases
Cutaneous metastases from systemic malignancies generally
indicate an advanced stage and poor prognosis. Classically, these
lesions are known for being asymptomatic and painless, with
some of the malignancies showing preference for specific cuta-
neous sites. In certain instances, however, the lesions resemble
inflammatory cutaneous lesions characterized by chronic, pain-
ful erythematous nodules. Adenocarcinoma of the esophagus
and colon, renal transitional cell carcinoma, and chondrosarcoma
have been reported to produce painful cutaneous metastases
commonly involving the extremities and scalp.19
Conclusions
An in-depth clinical knowledge of such conditions, pre-
senting as painful erythematous cutaneous nodules, is essential
not only for their clinical diagnosis but also for differentiation
from other disorders with similar presentation. A systematic
algorithmic approach to such presentations, together with
awareness of the symptomatology, etiopathology, and associ-
135
ations, will assist in making a more precise diagnosis and pro-
viding appropriate management.
References
1. Kawahita IP, Walker SL, Lockwood DNJ. Leprosy type 1 reactions and
erythema nodosum leprosum. An Bras Dermatol 2008;83:75-82.
2. Moschella SL, Davis MDP. Neutrophilic dermatoses. In: Bolognia JL,
Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. London: Elsevier;
2012. p. 423-438.
3. McGibbon DH. Subcutaneous fat. In: Burns T, Breathnach S, Cox N,
Griffiths C, eds. Rook’s Textbook of Dermatology. 8th ed. Oxford:
Wiley-Blackwell; 2010. p. 46.1-46.49.
4. James WD, Berger TG, Elston DM, et al. Diseases of subcutaneous fat. In:
James WD, Berger TG, Elston DM, Neuhaus IM, eds. Andrews’ Diseases
of the Skin Clinical Dermatology. 12th ed. Philadelphia: Elsevier
Saunders; 2016. p. 480-490.
5. Rongioletti F, Caputo V. Pancreatic panniculitis. G Ital Dermatol Venereol
2013;148:419-425.
6. Patterson JW. Panniculitis. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds.
Dermatology. 3rd ed. London: Elsevier; 2012. p. 1641-1662.
7. Misago N, Tada Y, Koarada S, et al. Erythema nodosum-like lesions in
Behçet’s disease: a clinicopathological study of 26 cases. Acta Derm
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8. Cho KH. Inflammatory nodules of the leg. Ann Dermatol 2012;24:383-
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9. James WD, Berger TG, Elston DM, et al. Cutaneous vascular diseases. In:
James WD, Berger TG, Elston DM, Neuhaus IM, eds. Andrews’ Diseases
of the Skin Clinical Dermatology. 12th ed. Philadelphia: Elsevier
Saunders; 2016. p. 807-855.
10. Lester J, Robinson-Bostom L. Pruritus and other dermatological problems
in chronic kidney disease. In: Arici A, ed. Management of Chronic Kidney
Disease. 1st ed. Berlin: Springer-Verlag; 2014. p. 287-296.
11. Adya KA, Inamadar AC. Gram negative bacterial infections. In: Singal A,
Grover C, eds. Comprehensive Approach to Infections in Dermatology.
1st ed. New Delhi: Jaypee Brothers Medical Publishers; 2015. p. 52-82.
12. Simon Jr M, Cremer H, von den Driesch P. Idiopathic recurrent palmo-
plantar hidradenitis in children: report of 22 cases. Arch Dermatol
1998;134:76-79.
13. Requena L. Panniculitis. In: Griffiths CEM, Barker J, Bleiker T, Chalmers
R, Creamer D, eds. Rook’s Textbook of Dermatology. 9th ed. Oxford:
Wiley-Blackwell; 2016. p. 99.1-99.62.
14. Talotta R, Atzeni F, Batticciotto A, et al. Accelerated subcutaneous nodu-
losis in patients with rheumatoid arthritis treated with tocilizumab: a case
series. J Med Case Rep 2018;12:154.
15. Subbanna PK, Singh NV, Swaminathan RP. Cutaneous polyarteritis
nodosa: a rare isolated cutaneous vasculitis. Indian Dermatol Online J
2012;3:21-24.
16. Chung L, Kea B, Fiorentino DF. Cutaneous vasculitis. In: Bolognia JL,
Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. London: Elsevier;
2008. p. 347-367.
17. Pollard AJ. Meningococcal infections. In: Longo DL, Fauci AS, Kasper
DL, et al, eds. Harrison’s Principles of Internal Medicine. 18th ed. New
York: McGraw-Hill; 2012. p. 1211-1219.
18. Bonville CA, Suryadevara M, Ajagbe O, et al. Chronic meningococcemia
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Clinics in Dermatology (2019) 37, 136–147

The life-threatening rash of poisoning

Michael Joseph Lavery, MB, BCh, BAO, MRCP (UK) a,b,⁎, Ronni Wolf, MD c
a
Department of Dermatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
b
Department of Dermatology, Royal Liverpool & Broadgreen University Hospitals NHS Trust, Liverpool, UK
c
Dermatology Unit, Kaplan Medical Center, Rehovot, Israel, and affiliated with the School of Medicine, Hebrew University and
Hadassah Medical Center, Jerusalem, Israel

Abstract Dermatology is frequently viewed by physician and surgical colleagues as a specialty with few
emergencies. Although the majority of dermatology practice is in the office setting, cutaneous emergencies
do occur through referrals from primary care and as ward consults. Even though cutaneous signs of poison-
ing would be an uncommon emergency consultation, it is important for dermatologists to be aware of the
clinical presentations so as to be able instigate appropriate time critical treatments.
© 2018 Elsevier Inc. All rights reserved.

Introduction compound that inhibits acetylcholinesterase with subsequent

Although thorough history taking is of the utmost impor-
tance, examination findings often yield important differential
diagnoses, and this is even more relevant with a focused skin
examination. Frequently, a detailed skin examination yields
diagnostic clues and confirms the diagnosis in patients with a
constellation of varying clinical features. In patients with sys-
temic poisoning, there can be such an array of different clinical
manifestations and systemic signs that amalgamating all of
these into one unifying diagnosis is often challenging, yet
life-saving.
Over recent years poisoning has become the focus of much
media attention, with the death of Alexander Litvinenko from
polonium-210-induced acute radiation syndrome1,2; the mor-
bidity inflicted upon Charlie Rowley, Sergei, and Yulia Skri-
pal; and the subsequent death of Dawn Sturgess from the
nerve agent Novichok.3–5 Novichok is an organophosphate
⁎ Corresponding author. Tel.: +44 1517062000.
E-mail address: michael.lavery@rlbuht.nhs.uk (M.J. Lavery).
contraction and paralysis of muscles—notably respiratory
and cardiac muscle—and eventually death.3,6
The media coverage of these events, along with the increas-
ing internet and social media use,7 will inevitably lead to fur-
ther patient inquiries as well as expectations of “spot
diagnoses.”
This article focuses on three major areas of cutaneous poi-
soning: metallic poisoning (mercury, arsenic), carbon monox-
ide (CO) poisoning, and dioxin (chloracne) poisoning. In
addition, Agent Orange (herbicide) and its cutaneous effects
are also discussed.
Mercury poisoning
Mercury has been around for thousands of years. Archeol-
ogists in Turkey identified that cinnabar (mercury sulfide),
mercury’s common red ore, and mercury were mined and pro-
duced more than 8000 years ago.8 Mercury was also discov-
ered in an Egyptian tomb at Kurna in 1500 BCE.9 Over the

https://doi.org/10.1016/j.clindermatol.2018.12.007
0738-081X/© 2018 Elsevier Inc. All rights reserved.
The chemical process of obtaining mercury from its common ore
Table 1 Mercury and its compounds
Mercury compound Chemical symbol
Mercuric sulfide HgS
Mercuric chloride HgCl2
Mercurous/mercury chloride Hg2Cl2
Mercury nitrate Hg(NO3)2
Mercuric oxide HgO
ensuing years, mercury and its compounds have been used in
many fields, including science and construction (Table 1).10
Mercury can still be purchased in its powdered form for use
in artwork.8,11 Due to mercury’s shiny appearance and resem-
blance to silver, Aristotle coined the phrase “quick silver,” and
Pliny, in 77 CE, labeled its chemical symbol “hydrargyrum”
(Hg), Greek for water silver.12 Mercury was also used for
extracting metals, including vermeil (gold-plated silver), and
some of the tableware made through this process is evident to-
day in the Vermeil Room in the White House.8,13 The term
“mad as a hatter” and “Danbury shakes” have their origin from
the exposure of workers in the felt hat industry to mercury ni-
trate and other mercuric compounds. Subsequently, the
workers developed neurologic impairment, including tremors,
slurred speech, abnormal gait, and hallucinations.14
Mercury’s use in medicine spans thousands of years and
was the first reported treatment for syphilis as documented
by the Persian physician Ibn Sina (Avicenna) (980-1037
AD) in the Canon of Medicine 1025 CE. Mercury had many
other medicinal uses, including as an antihelminthic, antipara-
sitic, antiseptic, and for treating leprosy and typhus.12,14 In
dermatology, mercury was used for treating pruritus and was
also commonplace in beauty soaps and skin-lightening
creams, due to its melanotoxin properties. A study in the late
1990s performed in Saudi Arabia showed 45% of 38 different
skin-lightening creams had mercury levels greater than the
Food and Drug Administration’s (FDA) acceptable amount
of 1 part per million (ppm).15 A more recent study testing
549 skin-lightening products available in different countries
showed that 6% had mercury levels of greater than 1000
ppm, and those products bought in the United States revealed
that 3.3% of creams had mercury levels greater than 1000
ppm.16 This has led to further safety alert warnings issued by
the American Academy of Dermatology, the World Health Or-
ganization, and the FDA.17–19
Fig. 1 A, Cinnabar is ground up and heated to 1076°F with the presence of oxygen. Cinnabar contains around 0.011% to 2.98% of divalent
mercury. Mercury is released as a gas/vapor along with sulfur dioxide, which is subsequently removed. B, The mercury vapor is cooled, and it
becomes liquid mercury. C, Liquid mercury is washed with nitric oxide for purification and then it is distilled.
137
Examples of use
Mercury common ore (cinnabar)
Red paint pigment (vermilion)
Wound disinfectant
Antiseptic
Skin lightening (calomel)
Industry—felt hats, cleaning animal pelts
Batteries
To this day, mercury still remains a water contaminant,
through the improper disposal of paints, lights, and batteries
and from the burning of coal from power plants.20 Once mer-
cury enters the water, there is a continual cycle with sea-life
contamination, subsequent mercury accumulation in humans
through seafood consumption, and secretion of mercury,
which may re-enter the sea or river. Figure 1 highlights the
chemical process of obtaining mercury from its common ore
cinnabar.21
Clinical features
Mercury has three distinct forms—elemental, organic, and
inorganic—and the clinical findings will vary depending on
the type of mercury exposure.22 Other pertinent factors deter-
mining clinical signs include the source of exposure, exposure
duration, medical comorbidities, age of the patient, and differ-
ing sensitivity to mercury. Table 2 summarizes the different
mercury forms and their clinical effects.23 Exposure to mer-
cury may also manifest with other cutaneous conditions, in-
cluding acrodynia, baboon syndrome, cutaneous granuloma,
contact dermatitis, or as a mercury exanthem. Table 3 summa-
rizes these clinical features.23
When determining which investigative modality to employ,
it is important to decipher to which form of mercury the patient
was exposed. Although this can be challenging, it will be of
clinical relevance when interpreting the results. For example,
measurement of urine mercury levels in organic mercury poi-
soning will be of limited use, as organic mercury is predomi-
nately excreted in feces. Urine levels of elemental mercury
may display a falsely low or negative result due to poor gastro-
intestinal absorption. Table 4 summarizes the main investiga-
tive methods employed—serum, hair, and urine analysis.24,25
138 M.J. Lavery, R. Wolf

Table 2 An overview of the different mercury forms

Different forms Elemental (metallic) Organic Inorganic
of mercury
Type Mercury vapor Methylmercury—converted to elementalMercury vapor—commonest source
Earth’s crust mercury in the brain Divalent mercury salt—
Atmospheric Ethylmercury most toxic source
Thimerosal (49.6% ethylmercury) Converted to elemental
Alkyl mercury mercury in water
Source Dental amalgams Seafood (alkyl mercury) Skin-whitening products;
Seafood Multidose vials influenza antiseptic facial creams;
Thermometers vaccines (thimerosal) bleaching creams
Lamps Plastics, paper Lamps
Mercury-laden latex paint Processed wood Wood preservatives
Cutaneous Insecticides Pesticides, germicides
Half-life 60 days 45-70 days 42 days
Absorption Respiratory tract (oxidized to GI tract (≥95%) Respiratory tract
inorganic mercury at alveoli) Respiratory tract (80%) GI tract (2%-10%)
Limited GI absorption Skin (3%-4%)
Pharmacokinetic 99% circulates in: 99% circulates in: 99% circulates in:
distribution • Blood (plasma protein, • Blood (plasma protein, glutathione, • Blood (plasma protein, glutathione,
glutathione, metallothionein bound) metallothionein bound) metallothionein bound)
• RBC (Hb bound) • RBC (Hb bound) • RBC (Hb bound)
Excretion Predominantly urine Predominantly feces (90%) Urine and feces
Feces Urine (b10%) Also sweat, breast milk, saliva, tears
Clinical features Acute Neurological (cross BBB as lipid soluble) Gastrointestinal (mercuric salts)
• Flu-like prodrome • Ataxia • Esophageal erosions
• Pulmonary, GI, Renal, CNS, • Demyelination • Gingivitis
and GU involvement • Autonomic dysfunction • Burning tongue
Chronic • Mental retardation Renal failure (mercuric salts)
• Neuropsychiatric clinical • Cerebral palsy Neurological (mercury vapor)
manifestations. Triad: Renal, liver involvement • Tremor
intention tremor, gingivitis, erethism Birth defects • Dementia
Cutaneous Blue line across gingiva Rare or nonexistent Acrodynia
features Lichenoid reaction Blue line across gingiva and tongue
Erythematous papular eruption (marker of systemic poisoning);
stomatitis
Slate-gray pigmentation
(exogenous ochronosis)
Principal organs Kidney Brain GI tract
affected Brain Kidney Kidney
Placenta Placenta Liver—periportal area
Treatment Chelation Chelation Chelation
• DMSA (PO) • DMPS (IV/PO) • DMPS (IV/PO)
• D-penicillamine (PO) • DMSA (PO) • DMSA (PO)
• Note: no FDA approval to • D-penicillamine (PO)
treat methylmercury or
ethylmercury poisoning
with chelation therapy
BBB, blood-brain barrier; CNS, central nervous system; DMPS, 2,3-dimercaptopropane sulfonate; DMSA, 2,3-dimercaptosuccinic acid; FDA, Food and Drug
Administration; GI, gastrointestinal; GU, genito-urinary; Hb, hemoglobin; IV, intravenous; PO, per os (oral); RBC, red blood cell; μg/l, microgram per liter.
From Lavery et al.23 Reproduced with permission from CRC Press.

Treatment
Treatment initiation is often delayed due to delay in diag-
nosis. The initial step is to remove the patient from the mer-
cury source—moving the patient to a different environment,
removing the patients clothing, fomite decontamination,
thorough skin cleansing with soap and water, and eye irriga-
tion. Treatment is often reserved for symptomatic patients
and those with toxic serum and urine levels. 2,3-Dimercap-
tosuccinic acid (DMSA) and dimercaptopropane sulfonate
(DMPS) are the two main chelation medicines used; how-
ever, the latter does not have FDA approval.26 Both of these
The chemical process of obtaining mercury from its common ore 139

agents are analogs of dimercaprol, but dimercaprol is rarely
used now, due to its adverse neurological profile. Despite
DMPS having greater oral bioavailability, DMSA has been
shown, in animal studies, to be more effective at chelating
methylmercury in the brain.24 Although there is no set treat-
ment regime, DMPS is generally started at a dose of 5 mg/kg
orally, 6 to 8 hourly. DMSA may be administered orally or
intravenously at a dose of 10 mg/kg, initially 8 hourly. Alter-
native chelation therapies include D-penicillamine and chela-
tion combination therapies. It is important to note that there
is no FDA approval for any chelation therapy modality for
ethylmercury or methylmercury poisoning.24 Plasma ex-
change, hemodialysis, and peritoneal dialysis may also be
employed.

Table 3 Distinct cutaneous syndromes associated with mercury poisoning

Cutaneous diseases Features
Acrodynia (pink disease) dermatologic
• Pink, puffy, painful, (pruritic) paresthetic, perspiring, peeling hands
• Involvement of the feet, tip of the nose, and cheeks
• “Salaam position” (sit with head between the legs while rubbing both hands)
• Cold and moist skin
• Excoriations, lichenification
• Trichotillomania causing alopecia
• Erythematous and swollen gingivae from excessive salivation
• Oral mucosal ulceration; tooth loss
• Nail loss
Other
• Hypertension, tachycardia
• Photophobia
• Pelvic girdle and pectoral muscle hypotonia
Acute generalized exanthematous pustulosis dermatologic
(AGEP) • Widespread nonfollicular pustules with underlying edematous erythema
Other
• Pyrexia
• Leucocytosis
Baboon syndrome/SDRIFE (symmetrical dermatologic
drug-related intertriginous and flexural exanthema) • Diffuse, well-demarcated, symmetrical, erythematous maculopapular
eruption of the gluteal/perianal area, intertriginous/flexural folds
• V-shaped pattern of the inguinal/perigenital area
Mercury exanthema dermatologic
• Diffuse, symmetrical erythema affecting the flexural and proximal extremities.
Associated pruritus and burning
• Non follicular sterile pustules
• Purpura
• Desquamation during resolution at around 2 weeks after exposure
Other
• Fever, malaise
• Polydipsia
Contact dermatitis Acute contact dermatitis
• Swelling, vesicles, scaling, irritation
Tattoo reaction (red pigment from mercuric sulfide)
• Localized swelling and scaling at site of tattoo
• Psoriasiform verrucous reaction
Dental amalgam reaction
• Brown to violaceous papules and plaques; usually adjacent to the dental amalgam
Hyperpigmentation dermatologic
• Slate-gray pigmentation of the treated skin
• Mercurialitis—discoloration of the lens from prolonged peri-ocular cream application
Cutaneous granuloma dermatologic
• Flesh-colored to erythematous granulomatous lesion at site of exposure
Other
• Visceral organ involvement: lungs, kidneys, liver, spleen
From Lavery et al.23 Reproduced with permission from CRC Press.
140 M.J. Lavery, R. Wolf

Table 4 Investigation modalities for mercury exposure

Investigation Clinical indication Result
Blood Useful for acute exposure Organic mercury—high blood:plasma ratio up to 20:1
Inorganic mercury: 1:1 to 2:1 ratio
Hair Useful for chronic exposure especially Positive if N1 mg/kg
methylmercury (organic mercury)
Urine Useful for exposure to inorganic mercury Raised VMA and HVA levels
HVA, homovanillic acid; VMA, vanillylmandelic acid.

Arsenic poisoning
Arsenic, from the Greek arsenikon meaning potent, is an
odorless, tasteless metal that has had a wide array of uses over
the years. It had many uses in traditional Chinese medicine,
even to this day,21 and, along with mercury, was used to treat
syphilis. It also had cosmetic uses, with the topical application
of arsenic, chalk, and vinegar being applied for skin-lightening
purposes.25
Newspapers in the United States even advertised
“arsenic complexion wafers” to remove facial blem-
ishes such as moles and pimples (Figure 2).27,28 Table
5 highlights common sources for arsenic (and mercury)
exposure.

Fig. 2 A, Advertisement for Dr. Campbell’s Arsenic Complexion Wafers. Smithsonian. National Museum of American History. B, Advertise-
ment for Dr. Simms’ Arsenic Complexion Wafers. The Salt Lake Tribune, March 26, 1893: p. 10.

Table 5 Common arsenic and mercury sources of exposure

Arsenic Mercury
Occupational Occupational
• Smelting industry • Mining industry
• Mining industry • Chemical/electrical engineering
• Semiconductors • Incineration processes
• Chemical plant • Agriculture
• Glass manufacturing Nonoccupational
• Agriculture/factory worker (animal feed, pesticides, fertilizers) • Seafood—contaminated fish/shellfish
• Painter • Medicinal (dental amalgams, dermatologic creams/cosmetics)
• Wine maker • Medical devices—thermometer, sphygmomanometer
Nonoccupational • Household devices—light bulbs, batteries
• Drinking water (deep water well) • Horticulture—fungicides, bactericides
• Food • Electronic devices
• Chinese/Indian/Korean traditional medicine
From Lavery et al.23 Reproduced with permission from CRC Press.
The chemical process of obtaining mercury from its common ore
Fig. 3 Acute and chronic cutaneous findings of arsenic poisoning. Adapted and revised from Lavery et al.23 Reproduced with permission from
CRC Press.
Clinical features
The cutaneous features of arsenic poisoning can be divided
into acute and chronic, as highlighted in Figure 3. Acute poi-
soning signs can be subtle and nonspecific and may include
periorbital edema, a maculopapular intertriginous eruption,
and palmoplantar hyperkeratosis. Nails are often a relevant
source of clinical information and this holds true when
Fig. 4 Mees lines on the fingernails. Courtesy of Louise Barnes,
MB, FRCPI; Dublin, Ireland. From Fig. 33.1 of Lavery et al.23 Repro-
duced with permission from CRC Press.
141
assessing a patient with arsenic poisoning. Mees lines
(Figure 4) depict arsenic deposition at the nail bed29 and are
evident after 2 months of exposure.30 These transverse bands
are 1 to 2 mm wide but are broader in the pediatric population.
Patient may also exhibit brittle nails. Although these nail signs
are not pathognomonic, it is the constellation of these findings,
the presence of other cutaneous signs and clinical features, and
the evidence of arsenic exposure through detailed history tak-
ing that can be suggestive of arsenic toxicity.
Chronic arsenic poisoning has two main features:
• Hyperpigmentation may present as widespread dark brown
papules and plaques, raindrop-shaped depigmented mac-
ules (also described as raindrops on a dusty road)31 and
papules, or diffuse hyperpigmentation on the upper and
lower limbs and trunk (Figure 5). Leukomelanoderma
may also be evident.32
• The second cutaneous feature in chronic arsenicism is ar-
senical keratosis (Figure 6), with two variants, simple and
nodular. In simple keratosis there is bilateral thickening of
acral skin; in nodular keratosis there are nodules on acral
sites and/or the feet.30 There is an increased lifetime risk
of malignancies, notably lung and bladder cancer,33 as well
as cutaneous malignancy, both in situ and invasive carci-
noma. The invasive cutaneous carcinomas include nonme-
lanoma skin cancers, as well as Merkel cell carcinoma.34
Systemic organ dysfunction can also occur, involving the
142 M.J. Lavery, R. Wolf

Fig. 5 A, and B, Leucomelanoderma in a woman and a boy exposed to arsenic. C, Leucomelanoderma with raindrop-shaped depigmentation on
the left breast. Photographs courtesy of Sue Evans, MD, Liverpool, UK.
The chemical process of obtaining mercury from its common ore 143

gastrointestinal tract, central and peripheral nervous sys-
tem, and cardiopulmonary, hepatic, and bone marrow in-
volvement. These features are summarized in Table 6.
Management
Once arsenic toxicity is suspected, a serum and urine sam-
ple should be sent for immediate analysis. Hair and nail sam-
ples are useful in chronic exposure, with pubic hair being
preferable and more specific due to less potential
contamination, compared with scalp hair.23 Chelation therapy
with DMSA is the mainstay of treatment. Twenty-four-hour
urine measurements are subsequently collected for monitoring
treatment response. Of note, if signs of carcinogenesis are
present, then urine and serum arsenic levels may be too low
to measure, and as such chelation treatment may be ineffec-
tive.35 Oral retinoids are often employed as prophylaxis in pa-
tients who developed multiple squamous cell carcinomas,
especially in the immunosuppressed cohort, and there are re-
ports that oral retinoids may also be of benefit for chemopro-
phylaxis in patients with arsenic toxicity.33

Fig. 6 A, Arsenical keratosis and palmar pitting on the palm of the left hand. This patient had received arsenic in her teenage years for colitis. B,
Closer inspection of arsenical keratosis and punctate palmar pitting. C, Gross arsenical palmoplantar keratosis. D, Arsenical keratosis and hyper-
pigmentation on the palms of both hands. Figure 6A: courtesy of Andrea Franks, FRCP, Chester, UK. Figures 6B-D: courtesy of Sue Evans, MD,
Liverpool, UK.
144 M.J. Lavery, R. Wolf

Table 6 Other features of arsenic poisoning

System Manifestation
Neurological Symmetrical sensory (axonal, large fiber; glove & stocking distribution) and motor (small muscles hand/feet) neuropathy
Weakness, headache
Encephalopathy
Negative affect on intellectual function
Cognitive impairment
Gastrointestinal Colicky abdominal pain
Nausea and vomiting
Profuse watery diarrhea (“bloody rice water”)
Excessive salivation
Liver Hepatomegaly; portal hypertension
Lung Interstitial pulmonary fibrosis
Pulmonary edema
Cardiac Arrhythmias, cardiomyopathy, peripheral vascular disease
Hematological Bone marrow suppression
Hemolytic anemia
Malignancy Skin—in situ carcinoma (AK, Bowens disease); invasive carcinoma (BCC, SCC, Merkel cell)
Lung
Genitourinary: renal, bladder
Gastrointestinal
Hepatic
Other Conjunctival congestion; edema of limbs
AK, actinic keratosis; BCC, basal cell carcinoma; SCC, squamous cell carcinoma.
From Lavery et al.23 Reproduced with permission from CRC Press.

Carbon monoxide poisoning
CO is a colorless, odorless gas, making it so deadly. Once
inhaled, it is converted to carboxyhemoglobin. This renders
the hemoglobin molecule to retain oxygen, leading to tissue
hypoxia and cell death. Patients may be exposed to CO
through active and passive cigarette smoke, charcoal grills,
fireplaces, and fuel-burning devices. In a number of states it
is a regulatory requirement to have CO alarms fitted in homes
and workplaces, with Minnesota making CO alarms a require-
ment in motorboats.36
Clinical features can be vague and nonspecific, but become
more severe with increasing carboxyhemoglobin levels. Table
7 summarizes these clinical features. Pulse oximetry is not a
useful observational modality in patients with CO toxicity as
the machine cannot distinguish between carboxyhemoglobin
and oxyhemoglobin molecules. An uncoagulated venous sam-
ple or an arterial blood sample may be collected for analysis of

Table 7 Clinical features of carbon monoxide poisoning

Clinical manifestations Signs
Mild (carboxyhemoglobin level b30%) Cutaneous
• Headache, dizziness, drowsiness, confusion, fatigue, fasciculations • Cherry red discoloration of skin, mucous membranes
• Palpitations • Nail: pink discoloration becoming dark blue-red postmortem;
• Nausea and vomiting Mees lines; erosion and loss of curvilinearity at nailbed border
• Generalized erythema, vesicles, bullae
• Scalp edema, erythema, alopecia
Moderate (carboxyhemoglobin level 30%-40%) Systemic
• Shortness of breath • Tachycardia
• Chest pain • Tachypnea
• Hypotension
• Cardiac arrhythmias
• Seizures, coma
Severe (carboxyhemoglobin level N40%)
• Palpitations
• Confusion
• Paralysis
The chemical process of obtaining mercury from its common ore
the CO level. Treatment involves either high flow oxygen for
up to 6 hours, with carboxyhemoglobin levels decreasing in 80
minutes37; or hyperbaric oxygen with carboxyhemoglobin
levels decreasing in 22 minutes.38
Dioxin poisoning
Dioxins are a group of lipophilic polyhalogenated, poly-
chlorinated aromatic hydrocarbons,39 with 2,3,7,8-tetrachloro-
dibenzoparadioxin (TCDD) being the most toxic chemical in
this family.23 Dioxins are generated as byproducts in chemical
reactions, which use chlorine. Herbicides are produced
through chemical reactions,40 and as TCDD may also be
formed as a byproduct, dioxins can be found in soil and water
and may be inadvertently consumed, either directly or through
consumption of meat and fish. Dioxins may also be used as a
poison, with Viktor Yushchenko, poisoned in 2004 at a dinner
party in London, being the most infamous case (Figure 7).40
Dioxin was also inadvertently released from the ICMESA
chemical plant in Meda, Italy, in 1976, leading to a large-scale
industrial exposure, and subsequent development of both cuta-
neous and internal signs of dioxin toxicity.41,42
During the Vietnam War, Agent Orange was commonly
employed to destroy enemy crops. Agent Orange is a concoc-
tion of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-tri-
chlorophenpxyacetic acid (2,4,5-T). 2,4,5-T is produced
through a chemical process, with TCDD produced as a bypro-
duct; Agent Orange, therefore, unwittingly became contami-
nated with dioxin and led to mass exposure among American
veterans.
Exposure was mainly through handling of Agent Orange,
rather than through incidental exposure to ground troops. This
was due to the rapid photochemical degradation and limited
bioavailability of TCDD, as well as accurate delivery of
TCDD to the crop fields by the airplanes.43
Fig. 7 Photographs of Victor Yushchenko before poisoning A, and 3 months B, and 3.5 years C, after poisoning with 2,3,7,8-tetrachlorodi-
benzo-p-dioxin. Image from Sorg et al.48 Reproduced with permission from Elsevier.
145
Chloracne is pathognomonic for dioxin exposure, and there
is a strong association between plasma levels of TCDD and
chloracne.44 Dioxin is excreted from sebaceous glands, and
therefore chloracne is predominantly characterized by come-
donal lesions, mainly closed comedomes, although inflamma-
tory lesions such as nodules and cysts may also occur. The
face is the most common site afflicted; however, chloracne
may also be seen at postauricular, axillary, and inguinal sites,
with the trunk and genitalia rarely being involved.23 Chloracne
may be difficult to distinguish from other variants of acne, but
the predominance of comedonal lesions and the involvement
of virtually every vellus hair follicle histologically can aid in
differentiation. Histopathology may also reveal multiple infun-
dibular cysts with central collections of eosinophilic granular
or laminated sebum.45 These histopathology findings are wit-
nessed in small numbers of patients who had biopsies. Other
cutaneous manifestations include porphyria cutanea tarda, dif-
fuse hyperpigmentation, soft-tissue sarcomas (eg, leiomyosar-
coma and dermatofibrosarcoma protuberans), and cutaneous
lymphoma.39 The U.S. Department of Veterans Affairs has
recognized chloracne and porphyria cutanea tarda as condi-
tions with presumptive connections to exposure to Agent
Orange.46
The liver is the most common internal organ involved, with
other clinical features such as diarrhea, polyneuropathy, head-
ache, conjunctivitis, thrombocytopenia, and hypertriglyc-
eridemia.47 Clinical manifestations may occur many months
to years after the original exposure, and may be due to the long
half-life of dioxin (5-10 years with TCDD)48 as well as the
storage of dioxin in fatty tissue with subsequent slow elimina-
tion. Persistently high levels of plasma TCDD in patients ex-
posed to dioxin after the Seveso disaster, 20 years prior,
highlight this.44
Treatment can be challenging. Due to the predominance of
comedonal lesions, both topical and oral retinoids have been
employed with some improvement. Medication to hasten the
elimination and excretion of TCDD has been trialed, with
146
Olestra, a lipophilic dietary fat substitute, showing a reduction
in dioxin half-life from 7 years to 1 to 2 years.49
Conclusions
Cutaneous signs of poisoning are not regularly encountered
by dermatologists in the office, but recent media coverage
highlighting exposure to different toxins has brought this topic
to the fore. It is imperative to take a detailed history from the pa-
tient, close relative, or friend; perform a thorough detailed phys-
ical examination; remove any source of contamination; perform
relevant investigations; and instigate appropriate treatment, both
to the patient and to those exposed, to improve patient outcome.
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Clinics in Dermatology (2019) 37, 99-108

The rash that leads to eschar formation

Carly Dunn, BA, Ted Rosen, MD ⁎
Department of Dermatology, Baylor College of Medicine, Houston, Texas, USA

Abstract When confronted with an existent or evolving eschar, the history is often the most important factor
used to put the lesion into proper context. Determining whether the patient has a past medical history of sig-
nificance, such as renal failure or diabetes mellitus, exposure to dead or live wildlife, or underwent a recent
surgical procedure, can help differentiate between many etiologies of eschars. Similarly, the patient’s overall
clinical condition and the presence or absence of fever can allow infectious processes to be differentiated
from other causes. This contribution is intended to help dermatologists identify and manage these various
dermatologic conditions, as well as provide an algorithm that can be utilized when approaching a patient pre-
senting with an eschar.
© 2018 Elsevier Inc. All rights reserved.

Introduction recognize key sign and symptom patterns which signify an

To constitute an emergency, a condition should be acute at
onset, associated with clinical manifestations, have risk of
morbidity or mortality, and require a timely diagnosis to avoid
these consequences. One such dermatologic emergency is the
eschar. The eschar is cutaneous necrosis, which is character-
ized by the formation of a thick, black, adherent crust.
Although an eschar may be localized at the time of presenta-
tion, this cutaneous manifestation often represents a systemic
disorder or the potential for developing a systemic disorder.
Often an eschar is infectious in etiology; however, it may be
toxic, embolic, or vasculitic in nature. The clinical context is
key when assessing a patient for proper management and ther-
apeutic decision making.
This contribution is intended to help dermatologists and
other providers identify and describe dermatologic conditions
that progress to an eschar so that clinicians are better able to
⁎ Corresponding author. Tel.:+1 713 794 7129.
E-mail addresses: vampireted@aol.com, rosen@bcm.edu (T. Rosen).
emergency (Table 1). A basic diagnostic algorithm is shown
in Figure 1 for the workup of a patient presenting with
an eschar.
Flap necrosis
Obtaining an ideal outcome for skin reconstruction has
long been a challenge for dermatologists, as well as for plastic
and other surgeons. One complication of skin grafts and flaps
is flap necrosis. Patients present with a focal area of necrosis in
the region of their flap or graft during the postoperative pe-
riod.1 One study of reverse sural artery flaps found that partial
flap necrosis occurred in 11.2% of the 179 flaps,2 and a pro-
spective study of flap necrosis after 606 mastectomies with im-
mediate reconstruction found a rate of flap necrosis of 14%.3
In regard to predisposing risk factors, these studies reported
conflicting conclusions as to whether body mass index, diabe-
tes, surgical technique, and flap variables contributed to the
risk of developing flap necrosis.2,3 In dermatologic surgery,

https://doi.org/10.1016/j.clindermatol.2018.12.003
0738-081X/© 2018 Elsevier Inc. All rights reserved.
100
Table 1 Major causes of eschar
Disease/Etiology Age Number of lesions
Flap necrosis Adults One area
Embolic Adults Few
Mucormycosis Adults One area
Fungal sepsis Any Few
Bacterial sepsis (EG) Any Few
Miscellaneous infections: anthrax, Any One to many
tularemia scrub typhus, plague
Anticoagulant Adults One
Calciphylaxis Adults One to few
Necrotizing fasciitis or Fournier gangrene Older adults Large area
Snake or spider bite Any One
EG, ecthyma gangrenosum; GI, gastrointestinal; GU, genitourinary.
reported rates of flap necrosis are lower. A recent retrospective
evaluation of the safety of large skin flaps or grafts and inter-
polation flap surgery reported postoperative necrosis rates of
3% out of 331 reconstruction procedures.4 This is similar to
previous reports, which ranged from 1.4% to 4.8%.5–8
One clear risk factor for development of tissue necrosis af-
ter a tissue flap or graft is use of tobacco products. Heavy
smokers, those consuming one or more packs per day, develop
flap or graft necrosis three times more often compared with
nonsmokers, light smokers, and former smokers.7 For patients
with risk factors for flap necrosis, such as heavy smokers or
patients with vascular compromise, limiting tissue dissection
and undermining or using a delay phenomenon can improve
flap viability.9–11 Use of phosphodiesterase type 5 inhibitors,
such as tadalafil or sildenafil, have been shown in animal
models to decrease the rate of flap necrosis. 12,13 In the case
of flap necrosis, management should include local wound
care. Maintaining a moist environment and using an antimi-
crobial ointment that penetrates the eschar can prevent infec-
tion and promote separation, facilitating reepithelialization
and healing.14 In a letter to the editor, five patients with flap
necrosis were described, each of whom had received conserva-
tive treatment while being followed 6 weeks postoperatively
by in-office debridement to remove the superficial necrosis.15
Embolic
Cholesterol emboli are the result of shearing forces causing
atherosclerotic plaque rupture. These emboli can be either iat-
rogenic or spontaneous. For this reason, there is often a history
of cardiovascular disease in patients who experience this phe-
nomenon. Presentation can include a variety of findings such
as livedo reticularis, purpura, cyanosis, blue toes, digital gan-
grene (eschar formation), painful subcutaneous nodules, and
renal failure. A skin biopsy of the lesion will characteristically
show biconvex needle-like clefts in vessels in approximately
92% of patients; therefore, this finding is considered a specific
sign for cholesterol emboli. Treatment involves withdrawal of
C. Dunn, T. Rosen
Presence of fever Additional notes
No Postoperative
No Cardiovascular history
Yes Diabetes mellitus
Yes History
Yes History
Usually Travel history
No History
No Renal disease
Yes Recent trauma or GI/GU procedure
Maybe History
anticoagulants if possible, optimization of nutritional status,
initiation of a statin to stabilize plaques, and systemic cortico-
steroids if there is evidence of recurrent cholesterol emboli or
inflammation.16
Arterial emboli are commonly seen in patients who have
had surgery and patients in intensive care, with additional risk
factors of advanced age, hypercoagulability, cardiac abnor-
malities, and atherosclerotic disease. Common manifestations
include stroke and lower limb ischemia. Management of arte-
rial emboli involves immediately restoring blood flow, initiat-
ing anticoagulation if the source is cardiac, and optimizing
therapy of any comorbid conditions.17
Septic emboli can present similarly to cholesterol emboli as ei-
ther palpable purpura, petechiae, hemorrhagic plaques, pustules,
nodules, cyanosis, or livedo reticularis. The most common causes
of septic emboli are bacterial endocarditis, infected endovascular
devices, and infected pseudoaneurysms after endovascular proce-
dures. Skin biopsy of these lesions will show thrombi of neutro-
phils in the dermal blood vessels. Once a diagnosis of septic
emboli is made, treatment includes empiric antimicrobial therapy
and imaging to localize the primary focus of infection.18
Mucormycosis
Mucormycosis is a life-threatening fungal infection that is
most commonly seen in diabetic or immunocompromised pa-
tients. It often begins with acute onset of pain and swelling on
or near the eye or nose that later develops ischemia, followed
by a well-defined eschar. Mucormycosis is due to one
of several nonseptate fungi, notably Mucor, Rhizopus, or
Absidia.19,20 (Note the genus Absidia is also known as
Lichtheimia.) Diagnosis is based on history, as well as direct
microscopy of a wound exudate, histologic evaluation of a bi-
opsy specimen, and the result of a fungal culture. Another aid
in diagnosing mucormycosis is the use of molecular assays,
such as polymerase chain reaction, to identify the responsible
organisms.21 Depending on the site of infection, treatment
consists of vigorous surgical debridement in conjunction with
Rash eschar formation 101

Fig. 1 Diagnostic algorithm for an eschar.

the administration of an antifungal agent, such as lipid-based is posttraumatic mucormycosis. This differs from other forms
amphotericin B (first line), posaconazole, or isavucona- by increased frequency of cutaneous localization, rarity of an
zole.19,20 Even with adequate treatment, mortality is approxi- underlying condition such as diabetes mellitus, and involve-
mately 40%.19 One uncommon variant of this fungal illness ment of different species (Apophysomyces elegans complex
102
and Saksenaea vasiformis). These patients will have a history
of trauma, often from traffic accidents (37%), domestic vio-
lence (15.1%), or natural disasters (13.4%). Posttraumatic
mucormycosis also commonly requires surgical intervention
(extensive debridement) but is associated with a better survival
than other forms of cutaneous mucormycosis.22
Fungal sepsis
Invasive fungal diseases are difficult infectious disorders to
recognize clinically, particularly among patients in intensive
care units.23 In recent years, the incidence of invasive fungal
diseases has increased. These infections are associated with a
high mortality rate, even with the development of multiple
new antifungal drugs. Invasive aspergillosis and invasive can-
didosis represent the majority of invasive fungal infections,
and the mortality rate for these mycoses is as high as 30% to
40% (Figure 2).24 Conditions that can indicate an invasive fun-
gal disease include clinical manifestations consistent with
pneumonia, sino-nasal disease that can present with an ulcer
followed by an eschar, and disease of the central nervous sys-
tem. Comorbid patient factors include neutropenia, chronic
obstructive pulmonary disease, hepatic cirrhosis, HIV infec-
tion, nonlymphoma cancer, steroid use, solid organ transplan-
tation, and a prolonged stay in an intensive care unit.23
Diagnosis of invasive fungal diseases can be made by various
methods, the full extent of which are beyond the scope of this
review; however, one such method is the serum 1,3-beta-D-
Fig. 2 Tender eschar as a sign of candidemia in a febrile patient.
C. Dunn, T. Rosen
glucan assay which detects a polysaccharide of the fungal cell
wall that is released into the bloodstream. A recent meta-
analysis assessed the diagnostic accuracy of 1,3-beta-D-glucan
assay for diagnosis of invasive fungal infections.24 The results
of this study found that N80 pg/mL of 1,3-beta-D-glucan can
be used to distinguish patients with invasive fungal infections
from those without, with an indeterminate level between 60 to
80 pg/mL. This highly sensitive (98% to 100%) and specific
(97% to 98%) assay detects Candida species, Acremonium,
Aspergillus, Fusarium, Histoplasmosis, Coccidioidomycosis,
and Sporothrix schenckii, but does not detect Cryptococcus,
Blastomyces dermatitidis, or Zygomycetes.24 Management
should include removal of central venous catheters or im-
planted devices, performing a fundoscopic examination to rule
out endocular infection, and antifungal therapy.25 Broad spec-
trum antifungals are initially used and can be narrowed once
the precise fungal species is identified. Documented candido-
sis should be treated with an echinocandin, per the Infectious
Diseases Society of America’s 2016 update; fluconazole and
amphotericin B, or its lipid formulation, are alternative thera-
pies.26 For Aspergillus, voriconazole is first line, with ampho-
tericin B, azoles, and echinocandins as alternatives.
Amphotericin B is first line for mucormycosis. Duration of
treatment ultimately depends on the extent of disease, clinical
response, status of the patient’s immune system, and precise
fungal species.25
Bacterial sepsis
One classic manifestation of bacterial sepsis is ecthyma
gangrenosum. This condition is most often caused by Pseu-
domonas aeruginosa but may also be seen in conjunction with
septicemia due to Klebsiella spp, Escherichia coli, Serratia,
and rarely Staphylococcus aureus. Ecthyma gangrenosum
starts as a solitary, painless, red swelling, possibly develops
a fragile bulla, and then progresses rapidly to a painless
eschar-covered ulcer (Figure 3). This whole progression of
the lesions typically occurs within 12 to 24 hours. Patients will
be toxic-appearing and febrile, and they often are immuno-
Fig. 3 Painless, solitary ecthyma gangrenosum in a neutropenic
patient.
Rash eschar formation
compromised or neutropenic.27,28 A meta-analysis of 167
cases in the literature from 1975 to 2014 showed the responsi-
ble organism was most commonly P. aeruginosa (73.65%),
followed by other bacteria in 17.35%, and fungi in 9% of pa-
tients. This review also revealed that up to 33% of patients
were sick but not immunocompromised, and up to 4.2% were
previously healthy.29 At least one case report has documented
an instance where ecthyma gangrenosum occurred in a previ-
ously healthy 3-month-old infant.30 Management should include
blood and skin cultures, survey for the focus of infection, and ini-
tial treatment with appropriate intravenous antimicrobials for pre-
sumed P. aeruginosa.28 After confirmation of the diagnosis of
ecthyma gangrenosum, aggressive antimicrobial or antifungal
therapy should be started, based on culture and sensitivity re-
sults. An additional component of treatment often includes sur-
gical debridement or even excision for management of the
necrotic skin lesions.30
Vibrio vulnificus
Vibrio vulnificus can be a deadly pathogen. Ingestion of
raw or undercooked seafood can lead to septicemia; whereas,
the skin infection caused by Vibrio vulnificus is from exposure
to contaminated water or related to an injury by contaminated
marine life, such as shrimp or fish.31 Clinically, wound-related
infections present with hemorrhagic bullae, fever, and a his-
tory of wound exposure to contaminated water. The infection
can progress rapidly to necrotizing fasciitis with the risk of
limb loss. The most common time of the year for this infection
is during the summer months.32 One risk factor for this condi-
tion is liver insufficiency, which is thought to be related to the el-
evated serum ferritin, percentage of transferrin iron saturation,
and disrupted iron physiology leading to enhanced bacterial
growth and decreased phagocytosis.31 After diagnosis, treat-
ment involves antimicrobials and debridement of necrotic tis-
sue.32 Antimicrobial resistance has become more prevalent,
leading to alteration in the current recommended treatment regi-
men to include ceftriaxone and concomitant doxycycline or min-
ocycline.32,33 Even with antimicrobial therapy, fatality rates
are approximately 20% for wound-related Vibrio vulnificus
infections.32
Anthrax
Anthrax is a zoonotic infection caused by the gram-positive
rod Bacillus anthracis. Transmission of cutaneous anthrax
(which accounts for approximately 95% of cases), is via the in-
troduction of spores through breaks in exposed skin.34,35 Al-
though anthrax infections are rare in developed countries, the
2001 bioterrorism attack in the United States and the anthrax
outbreak among intravenous drug abusers in Europe in 2009
and 2010 have demonstrated the importance of being aware
of and being able to recognize this infection.35 Clinically, an-
thrax presents as a pruritic painless papule, similar to a bug
103
bite, that progresses to an ulcerated lesion with a central es-
char.34 Fever and regional lymphadenopathy may also be pres-
ent. Shock is rare in cutaneous anthrax, being more commonly
associated with inhalational disease. When anthrax is suspected,
diagnosis can be made with Gram stain and culture, polymerase
chain reaction, or immunohistochemistry. Treatment involves an-
timicrobial administration, pending confirmatory tests.35 An-
thrax is susceptible to multiple antimicrobials, including
intravenous penicillin G, chloramphenicol, tetracycline, eryth-
romycin, streptomycin, fluoroquinolones, and cefazolin.34,35
Based on case reports, glucocorticoids may be entertained as
an adjunctive therapy in cutaneous anthrax.36 Estimated mor-
tality for cutaneous anthrax infection is less than 1%.35
Tularemia
Tularemia is an often serious, rare disease caused by a
gram-negative coccobacillus, Francisella tularensis, which is
found in the northern hemisphere.37 Approximately 125 to
200 cases are reported annually in the United States, mostly
in the south central region, the Pacific Northwest, and parts
of Massachusetts.38 Patients range in age, and the most com-
mon clinical presentations are respiratory disease, ulcero-
glandular or glandular lesions with lymphadenopathy, and a
febrile illness without localizing signs. The cutaneous form
of tularemia is caused by direct contact with infected animals,
such as rabbits, cats, and coyotes, or arthropod bites (eg, ticks
or deerflies).39 Case mortality ranges from 2% to 24%. Diag-
nosis can be made with culture or by polymerase chain reac-
tion from skin lesions, lymph nodes, or a blood sample.
Serologic studies would show a four-fold increase in immuno-
globulin G titers from patients in the acute and convalescent
stages of infection. First-line treatment is with streptomycin;
gentamicin, doxycycline, and ciprofloxacin are second-line
therapies. In Western states, where tularemia is more common,
a higher suspicion for this rare infection is required in patients
with compatible signs and symptoms.37
Scrub typhus
This rickettsial infection, transmitted by the bite of the
trombiculid mite (chigger), is caused by Orientia tsutsuga-
mushi. Clinically, patients present with a high fever, head-
aches, myalgias, and occasionally a maculopapular rash;
however, the pathognomonic rash is an eschar which occurs
at the site of the insect bite.40 This infection should be included
in the differential diagnosis in any sick traveler from an endemic
area (which extends from Japan and Russia, to Australia, to
Pakistan, and is prevalent in India) presenting with these fea-
tures, meningoencephalitis, or hepatorenal failure.40,41 In the
case of suspected scrub typhus, the patient should be started
on empiric doxycycline while awaiting confirmatory tests.40
104 C. Dunn, T. Rosen

Plague Heparin-induced thrombocytopenic necrosis is an uncom-

mon immune-related phenomenon in which antibodies bind to
The plague is a rare, highly contagious, life-threatening, flea- a heparin-containing antigen complex causing thrombosis. Risk
borne zoonosis caused by Yersinia pestis. From 2001 to 2017, factors are the same as in warfarin-induced skin necrosis, and
the annual number of reported cases ranged from 1 to 17 with a rare cases of heparin-induced skin necrosis have been described
median of three cases. Transmission to humans occurs through in patients who are pregnant.48 Typically, this condition pre-
the bite of infected fleas, direct contact with infected tissues or sents around 5 to 7 days after initiating heparin. Lesions may be-
body fluids, or inhalation of respiratory droplets from ill con- gin as bruises that progresses to necrosis and cyanosis.45
tacts or animals. Nonspecific clinical manifestations of the pla- Because clinically this is similar to skin necrosis related to other
gue include fever, malaise, abdominal pain, nausea, and causes, a detailed medical history is necessary, when heparin-
vomiting. Bubonic plague, which accounts for 80% to 85% induced skin necrosis is suspected.49 The presence of antibodies
of cases, presents with a painful swelling of one or more lymph and a platelet count drop by 50% can confirm the diagnosis of
nodes. In addition, the skin may turn black and form an eschar, heparin-induced skin necrosis. Treatment involves immediate
especially on the fingers, toes, or nose, resulting in this disease cessation of heparin and initiation of a different anticoagulant.
being associated with the term “The Black Death.” Streptomy- In certain cases, thrombolytic therapy and thrombectomy are
cin or gentamicin are first-line therapies, which can be performed to allow for reperfusion of the affected area. Wound
switched to tetracycline or doxycycline, once the patient be- care is similar to that for warfarin-induced skin necrosis; how-
comes afebrile.42 An alternative antimicrobial class that can be ever, unlike in warfarin-induced skin necrosis, heparin should
used is the fluoroquinolone group. Anttimicrobial prophylaxis not be restarted as this condition is immune-related and will re-
after contact with rodents in an endemic area is accomplished cur. Even with treatment, mortality rates are as high as 25%.45
with either levofloxacin or doxycycline. Although there is no li-
censed vaccine currently available in the United States, a subunit
vaccine is in development.43 With the advent of antimicrobials, Calciphylaxis
mortality has been reduced to approximately 16%.44
Calciphylaxis is the sudden development of tender, viola-
ceous, and reticulate lesions that progress to necrotic, excep-
Anticoagulant skin necrosis tionally painful eschar-covered ulcers (Figure 4). This
condition is due to occlusion of microvessels by calcification
Warfarin-induced skin necrosis is an unusual complication in areas with thick adipose tissue. Patients affected classically
of use of this anticoagulant, occurring in approximately 1 out
of every 10,000 patients who receive the drug. Lesions com-
monly occur within 10 days of warfarin initiation and are
found on the buttock, breast, abdomen, or thigh because of
the reduced blood supply to adipose tissue.45,46 Clinically, it
appears as painful petechiae which develop into hemorrhagic
bullae before progressing to an eschar. Typical patients in-
clude middle-aged women (with a women-to-men ratio of
9:1.3), persons who are obese, and those who are hospitalized
for an acute illness that requires initiation of an anticoagu-
lant.45 Underlying risk factors also include deficiency of pro-
tein C, protein S or factor V Leiden, hyperhomocysteinemia,
antithrombin III, and antiphospholipid antibodies.46 A pa-
tient’s complaint of pain or discomfort in susceptible areas of
the body should arouse suspicion, and diagnosis is clinical,
as neither protein C nor S levels are sensitive nor specific.45,46
Therapy of warfarin-induced skin necrosis is to reverse the ef-
fect of warfarin. This is done by discontinuing the drug and
initiating heparin for anticoagulation,45 as well as administer-
ing 10 mg intravenous vitamin K, 10 mL/kg fresh frozen plasma
(1 unit of fresh frozen plasma is approximately 200 mL), or pro-
thrombin complex concentrate.47 Wound treatment includes
debridement and topical therapy with either local antimicro-
bials or special dressings.45 Warfarin can later be reintroduced
with continuation of heparin until the international normalized
ratio is within the normal range.46 Fig. 4 Calciphylaxis, with both penile and scrotal eschars.
Rash eschar formation
have renal failure and are on chronic hemodialysis, with an an-
nual incidence in the United States of approximately 35 cases
per 10,000 patients.50 Other risk factors include obesity, diabe-
tes mellitus, liver disease, systemic corticosteroid use, female
sex, and an elevated calcium phosphorus product.16,50 There
is one case report of calciphylaxis due to recurrent pancreatitis,
with no underlying renal failure; however, this is exceedingly
rare.51 Diagnosis is clinical, and the medical provider must
have a high index of suspicion for this condition.51 Skin bi-
opsy is not required, as the findings can be difficult to identify;
however, in patients without end-stage renal disease or in cases
of early or atypical lesions, a biopsy should be strongly consid-
ered. Biopsies are contraindicated for acral, penile, or infected
calciphylaxis lesions.50 Histologically, calcification of the me-
dia and intima of vessel walls is seen, and this calcification
leads to thrombosis and infarction of the skin. Additionally,
the findings of superficial vascular calcifications on radio-
graphic imaging can be sensitive for the diagnosis of calciphy-
laxis. Arteriolar calcification is described as having a
“railroad,” “tram track,” or “pipestem” pattern.52 One study
found that out of 10 patients with biopsy-confirmed calciphy-
laxis, nine had radiographic imaging demonstrating moderate-
to-severe vascular calcification in the area of the biopsy.53
Treatment is mainly supportive, with analgesics, local wound
care, and normalization of any calcium homeostasis imbalances.
Additional therapy with bisphosphonates, cinacalcet, and so-
dium thiosulfate have been utilized to help improve pain and
wound healing.16 Sodium thiosulfate is beneficial, as it increases
the solubility of calcium deposits, and it can be used in both ure-
mic and nonuremic calciphylaxis. To help prevent episodes in
the future, supplemental calcium, vitamin D, and other medica-
tions that may trigger calciphylaxis should be avoided.51 Prog-
nosis is generally poor, with a 1-year mortality rate of 45%
to 80% in patients who have end-stage renal disease.50
Necrotizing fasciitis
Necrotizing fasciitis is a life-threatening deep soft tissue in-
fection, including the fascia. Differentiating necrotizing fasci-
itis from other soft tissue infections is critical, as necrotizing
fasciitis is a surgical emergency that requires timely diagnosis
followed by aggressive surgical debridement.54 Predisposing
factors include diabetes mellitus, alcoholism, immunosuppres-
sion, smoking, and sedentary lifestyle.55 Classically, this in-
fection is caused by group A Streptococcus and may develop
into shock and multiple organ failure, known as streptococcal
toxic shock syndrome. In the early stages, necrotizing fasciitis
resembles cellulitis and erysipelas, with nonspecific signs such
as swelling, tenderness or pain, and erythema at the site. This
then can rapidly progress over 24 to 72 hours to dusky, bullous
lesions.56 The cardinal sign is crescendo or abrupt pain that is
out of proportion to examination findings; however, pain may
be absent or attenuated in patients who have received analge-
sics, including nonsteroidal antiinflammatory drugs. Patients
105
are usually tachycardic (59%), and other signs may also be
present such as fever (44%), tachypnea (26%), and hypoten-
sion (21%).54,55 Streptococcus pyogenes can gain entry into
the skin through breaches due to insect bites, penetrating
trauma, drug injections, chicken pox, surgical incisions, or
childbirth; however, as many as 50% of cases start in the deep
tissues, such as after a muscle strain or bruise.56
When necrotizing fasciitis is suspected, broad spectrum an-
tibiotics should be started to cover the commonly suspected or-
ganisms and can later be narrowed based on culture results.
The mainstay of treatment is prompt, wide and deep surgical
debridement. Studies have shown that debridement of tissue
improves mortality compared with cases where surgery is de-
layed for even a few hours.54 One adjunctive therapy is hyper-
baric oxygen, which might reduce morbidity and mortality by
inhibiting bacterial growth; however, the effectiveness of hy-
perbaric oxygen remains controversial, as studies have con-
flicting outcomes.55,56 The mortality for necrotizing fasciitis
ranges from 30% to 80%,56 with better outcomes in patients
who are diagnosed early and receive prompt surgical interven-
tion and appropriate antimicrobial coverage.
Fournier gangrene
This is a polymicrobial necrotizing fasciitis of the genital or
perineal skin and soft tissues due to an infection after trauma or
instrumentation. The basic pathophysiology involves vascular
thrombosis and tissue necrosis. Clinically, this condition pre-
sents initially as swelling, with progression to purulence, then
ischemia, then eschar formation, then tissue sloughing. The
source of the infection is most commonly from the lower gas-
trointestinal tract, followed by the skin, then the urogenital
tract.57,58 Different case studies from Greece and from Brazil
found that the most common organisms associated with Four-
nier gangrene are Escherichia coli, Staphylococcus aureus,
Streptococcal species, and Pseudomonas aeruginosa.59,60
Fournier gangrene is seen most commonly in diabetic patients
aged 50 to 60 years old, with a man to woman ratio of 10-25:1.
Other risk factors include alcoholism, cancer, and HIV-
positivity. In men, the most common sites in descending order
are the scrotum, penile shaft or perineum, and abdomen. In
women, the vulva is more common than the perineum. Treat-
ment involves aggressive debridement of necrotic tissue and
antimicrobial administration based on culture results, with de-
layed surgical repair as needed. Case reports have found ben-
efit with adjunctive wound care measures, such as hyperbaric
oxygen and negative pressure wound therapy.61,62
Snake bite
Snake bites can cause local tissue damage, resulting in pain,
edema, necrosis, and coagulopathy. In North America, coral
106
snakes and pit vipers, which include rattlesnakes, cottonmouth
snakes (also called water moccasins), and copperheads, are the
most common groups of venomous snakes.63 Many vipers, pit
vipers, and cobras are known to cause tissue necrosis, slough-
ing, and eschars.64 For diagnosis, a history of a snake bite is
key. Initially, tight jewelry or clothing that might be constric-
tive should be removed, and the use of tourniquets, wraps, in-
cision, suction, cooling, electric shocks, and the like should be
avoided.63,65 During transportation to the hospital, the extrem-
ity should be elevated and immobilized for comfort. Identifica-
tion of the species of snake is important so that the appropriate
antivenom can be given; however, capture or killing of the
snake is not necessarily advised. Pain control should be accom-
plished with acetaminophen or opioids instead of nonsteroidal
antiinflammatory drugs due to their antiplatelet effects.63 A
more detailed description of snake bites and their management
is beyond the scope of this contribution; however, more infor-
mation regarding snake bites, their clinical manifestations, and
treatments can be found in the chapter entitled, “Overview of
Venomous Snakes of the World,” in Medical Toxicology,64
this review66 on North American snake envenomation, the
World Health Organization’s database on snakes and anti-
venom, or the database created by the University of Adelaide,
Australia, which is available at http://www.toxinology.com.
Spider bite: Brown recluse
Loxoceles reclusa, known as the brown recluse spider, and
related species are found in the Midwestern and Southern
United States but not on the East Coast, and have a painless
bite that can result in dermonecrosis and, less commonly, a
systemic illness that can be deadly.67–69 Within 8 hours, pain,
erythema, and swelling develop which progresses first to is-
chemia and then to overt eschar formation (Figure 5). The lat-
ter usually sloughs off to form a deep ulcer. The majority of
cases (67% to 90%) remain a localized phenomenon; however,
Fig. 5 Typical eschar from verified brown recluse spider bite.
C. Dunn, T. Rosen
10% to 30% of cases develop into a viscerocutaneous form. In
this form, sequential signs and symptoms begin 2 to 4 days after
the bite. First, a morbilliform rash, fever, nausea, and vomiting
appear, followed by hemolysis, thrombocytopenia, and hematu-
ria. Lastly, the patient can develop shock, disseminated intravas-
cular coagulation, acute renal failure, and ultimately death.70
History of a spider or bug bite is important in the diagnosis of this
condition; and the standard of diagnosis includes collecting and
properly identifying the spider responsible. There is no proven
effective treatment for Loxosceles bites, and proper treatment
remains controversial. Therapeutic intervention typically in-
cludes rest, elevation of the affected area, and ice application;
nonsteroidal antiinflammatory drugs can be utilized to relieve
pain and swelling. Additional therapies may include a nitro-
glycerin patch, systemic steroids in severe cases, dapsone (this
may prolong healing time and worsen scar formation), and an-
tivenom. All have been used with variable results.70
Context
When confronted with an existent or evolving eschar, it is
important to put the lesion into proper context:
• History is often important, including enumeration of recent
travels and exposure to living or dead wildlife.
• Past medical history may be critical, including the presence of di-
abetes, kidney disease, neutropenia, cancer, and atherosclerosis.
• Recent medical interventions, such as cystoscopy and vas-
cular cannulation, must be noted.
• Is the patient febrile? The latter suggests an infectious etiol-
ogy, although an afebrile patient may have an eschar due to
calciphylaxis or cholesterol emboli.
• Is the eschar painful? Lesions due to calciphylaxis are usually
associated with exquisite pain, early mucormycosis is tender,
and ecthyma gangrenosum characteristically painless.
The algorithm in Figure 1 helps organize contextual diag-
nostic clues.
Conclusions
Although there are many potential causes of an eschar, it is
important to differentiate between them, as many etiologies
can be life-threatening. This review is intended to provide clini-
cians with an algorithm in working up a patient with an eschar
to ensure that patients receive prompt management and therapy.
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Clinics in Dermatology (2019) 37, 109–118

The rash with maculopapules and fever in adults

Sonal Muzumdar, MD, Marti Jill Rothe, MD, Jane M. Grant-Kels, MD ⁎
Dermatology Department, University of CT Health Center, Farmington, Connecticut, USA

Abstract There is a broad differential diagnosis for the presentation of fever and maculopapular rash in an
adult. Although some causative conditions are benign, others are medical emergencies that require prompt
diagnosis. We describe various conditions that result in a fever and maculopapular rash in adults. These in-
clude infectious processes (meningococcemia, infectious mononucleosis, West Nile virus, zika virus, ru-
bella, primary human immunodeficiency virus, parvovirus B19, ebolavirus), tick-borne illnesses (Rocky
Mountain spotted fever, ehrlichiosis), and hypersensitivity reactions (exanthematous drug reactions). We
also provide an algorithm to aid in the diagnosis of the patient with fever and maculopapular rash. Such con-
ditions that can occur in adults but are seen predominantly in children are discussed in the article “Rash with
maculopapules and fever in children” of this issue.
© 2018 Elsevier Inc. All rights reserved.

Introduction 1. Did you notice any clinical manifestations before the

The differential diagnosis for adults presenting with fever
and maculopapular rash is broad. It includes bacterial and viral
infections as well as such hypersensitivity reactions as those
due to drugs (Table 1). Although some of these eruptions are
benign, others are medical emergencies. Prompt diagnosis is,
therefore, crucial. We describe some of the more common
causes of maculopapular rashes and fever in adults and how
to identify and treat them.
Diagnostic algorithm
rash started?
2. Are there any clinical manifestations associated with the
rash?
3. Have you started any new medications recently?
4. Is anyone around you sick with similar clinical manifestations?
5. Have you traveled anywhere recently?
6. Describe the distribution of the rash. Where did the rash
start? Has it changed over time?
A diagnostic algorithm for evaluating patients with fever and
maculopapular rash is provided in Figure 1.

Because a number of conditions can cause fever and macu-

lopapular rash in adults, eliciting a thorough history is crucial Drug reactions
for diagnosis. Questions that should be asked of all patients in-
clude the following1: Etiology

⁎ Corresponding author. Tel.: 860-519-7008. Exanthematous (maculopapular) drug eruptions are de-
E-mail address: grant@uchc.edu (J.M. Grant-Kels). layed (type IV) hypersensitivity reactions, which are mediated

https://doi.org/10.1016/j.clindermatol.2018.12.004
0738-081X/© 2018 Elsevier Inc. All rights reserved.
110 S. Muzumdar et al.

by T cells. Classically, drugs bind proteins or peptides within
the body to form haptens. These haptens are presented to
T cells by antigen-presenting cells, eliciting a hypersensitivity
reaction.2
Epidemiology
More than 4 billion medications are prescribed annually
in the United States. 3 Cutaneous reactions are one of the
most common adverse events secondary to medications,
with an average incidence of 10 cases for every 1000 new
medication users. 2 Exanthematous drug eruptions are the
most common type of cutaneous drug reaction.4 Drugs that
are commonly implicated in cutaneous drug reactions include
antiepileptics, such as carbamazepine, phenytoin, and lamotri-
gine (100 cases/1000 new users), and antibiotics, such as
penicillins, cephalosporins, and sulfonamides (50 cases/1000
new users).2 In addition, most patients with infectious

Table 1 Selected causes of fever and maculopapular rash in adults

Disease Epidemiology in adults Characteristic clinical presentation
Rubeola (measles) Unvaccinated populations Cough, coryza, and conjunctivitis. Punctate white or
gray lesions on erythematous base on buccal mucosa
(Koplik spots). High fever and a blanching
maculopapular rash originates on forehead and
upper neck; descends to the trunk and lower extremities.
Rubella (German measles) Unvaccinated populations Tender adenopathy in the posterior auricular,
posterior cervical, and suboccipital lymph nodes.
Pink maculopapular rash that starts on the face
and spreads to the trunk and extremities. May be
associated with petechiae on the soft palate
(Forchheimer’s sign).
Zika virus Travelers from endemic regions Maculopapular rash that starts on trunk and
(Africa, Southeast Asia, South and descends to lower extremities. Associated with
Central America, Pacific Islands and Caribbean) numerous birth defects in fetuses of infected
pregnant women, including microcephaly.
Parvovirus B19 Adults who work with children High fever followed by rash that originates
(teachers, daycare workers, etc.) on trunk and spreads to extremities. Rash
starts as discrete pale, pink macules and may
become confluent. Arthralgias and arthritis common
in adults and may be the only sign of infection.
Rocky Mountain Throughout United States; especially Fever, nausea, abdominal pain, and headache.
spotted fever North Carolina, Oklahoma, Arkansas, Pink macular rash that starts on the ankles
Tennessee, and Missouri and wrists and spreads to the trunk.
Meningococcemia Young adults aged 16-23 Fever, nuchal rigidity, photophobia, and altered
mental status. Rash is found on the trunk
and extremities and may be maculopapular,
petechial, or purpuric.
Hand foot mouth disease Less common in adults; highest incidence Maculopapular or vesicular rash on the
(Coxsackie virus) in infants and children aged b5 y hands, feet, buttocks, legs, and arms.
Ehrlichiosis Increased incidence in the Southeast and Widespread, erythematous maculopapular
South Central United States. Males and rash with fever, headache, and malaise.
people aged N50 y were most frequently infected.
Exanthematous Typically 4-21 days after initiation of a new drug. Rapidly evolving, symmetric, diffuse erythematous
drug eruption Increased risk with antiepileptics (carbamazepine, maculopapular rash with a low-grade fever.
lamotrigine, and phenytoin) and antibiotics
(penicillins, cephalosporins, and sulfonamides)
Infectious mononucleosis Adolescents and young adults Fever, cervical lymphadenopathy, and pharyngeal
inflammation. Maculopapular rash on
trunk and arms.
West Nile virus Africa, Europe, Middle East, North America, Fever, headache, myalgias, and a maculopapular
and West Asia. Increased frequency in elderly. rash on the trunk. Complications include
severe central nervous system disease and death.
Primary HIV infection Prominent in the United States, with increased Maculopapular rash on the face, upper
incidence in gay men and heterosexual extremities, and trunk associated with fever and
African American women. myalgias. Clinical manifestations typically
manifest 2-6 weeks after exposure and last for 1 week.
Maculopapules and fever in adults
Maculopapular rash with fever
Recent Sick Contact?
Yes
Centrally Peripherally
distributed rash distributed rash
Rubeola Hand-foot-mouth
Rubella disease*
Parvovirus B19 Meningococcemia
Fig. 1 Diagnostic algorithm for fever and maculopapular rash in adults. *Hand foot mouth disease is much more common in children under the
age of 5 years, but can rarely occur in adults.
mononucleosis, who are treated with aminopenicillins, de-
velop a maculopapular eruption.2
Clinical manifestations
Exanthematous drug eruptions typically present 4 to 21
days after the initiation of a new medication and evolve rap-
idly.2 They consist of symmetric erythematous macules and
papules (Figures 2A and B) that start on the trunk and intertri-
ginous areas.5 The lesions may be pruritic and are commonly
associated with a low-grade fever (b38.5°C). Mucous mem-
branes are not characteristically involved. Most drug eruptions
fade within a week of discontinuation of the offending drug.2
A high-grade fever (N38.5°C), mucous membrane involve-
ment, or lymphadenopathy may be indicative of a more seri-
ous evolving reaction, including Stevens-Johnson syndrome,
toxic epidermal necrolysis,2 or drug reaction with eosinophilia
and systemic clinical manifestations, which is often associated
with inflammation of various internal organs (such as the liver
and less commonly the kidney, lung, and heart, and rarely pan-
creas) and a 10% incidence of mortality.
Diagnosis and treatment
An exanthematous drug reaction should be considered in any
patient presenting with a symmetric, widespread maculopapular
rash and low-grade fever. Maculopapular drug reactions can
mimic viral exanthems, such as measles, rubella, erythrovirus
111
No
Travel to
endemic area?
Yes No
Exposure to
Rocky new drug?
Mountain
spotted fever
Ehrichiosis Yes
Zika virus
West Nile virus
Exanthematous
Drug reaction
(parvovirus B19), chikungunya (alphavirus), zika, and even var-
icella (when vaccinated persons exhibit clinical manifestations),
and so it is critical for clinicians to take a thorough history and
identify any new drugs that the patient may be taking. Cutaneous
reactions typically appear 4 to 21 days after the initiation of a
new drug.2 Resolution of the rash after cessation of the sus-
pected drug may also help identify the causative medication.2
The reaction will typically resolve within 2 weeks of with-
drawal of the causative drug but has been reported to resolve
slower over the course of many weeks.4
Treatment of exanthematous drug eruptions primarily in-
volves discontinuing the causative drug and managing the pa-
tient’s clinical manifestations. Pruritus may be controlled with
topical or oral antihistamines. Glucocorticoids (topically or
systemically) may also be used to control clinical manifesta-
tions. If it appears that a serious drug reaction is evolving (ie,
Stevens-Johnson syndrome or toxic epidermal necrolysis),
the patient may need to be hospitalized for monitoring and
supportive therapy.2
Meningococcemia
Microbiology
Neisseria meningitidis, an encapsulated, gram-negative
diplococcus, causes meningococcemia.6 Disease is most com-
monly caused by serogroups B, C, and Y.7
112
Fig. 2 A, Papular drug eruption (courtesy Justin Finch, MD, and
the UCONN Department of Dermatology). B, Close-up of lesions
of a papular drug eruption (courtesy Justin Finch, MD, and the
UCONN Department of Dermatology).
Epidemiology and incidence
The incidence of meningococcemia has been declining in
the United States, with only 370 cases reported in 2016.7
Meningococcemia occurs in all age groups, but infection is
most common in infants and young adults aged 16 to 23.7 Risk
of infection is also increased in patients with human immuno-
deficiency virus (HIV), complement deficiencies, and func-
tional or anatomic asplenia.7 Patients taking eculizumab
(Soliris), a monoclonal antibody that is a terminal complement
inhibitor used to treat paroxysmal nocturnal hemoglobinuria
and atypical hemolytic uremic syndrome, are also at increased
risk for meningococcemia.7
Clinical findings
Meningococcemia presents with fever, nuchal rigidity,
photophobia, and altered mental status. On clinical examina-
tion, Kernig and Brudzinski signs may be positive. Patients
have a diffuse, erythematous maculopapular rash that evolves
S. Muzumdar et al.
into petechiae and purpura that are most commonly found on
the trunk and extremities.8 Large, hemorrhagic lesions may
be found in some patients and are associated with a poor
prognosis.6
There are a number of complications, which may result
from meningococcal infection. Acutely, vasodilation and cap-
illary leak may result in decreased intravascular volume with
subsequent cardiovascular collapse. Patients may also experi-
ence pulmonary edema, acute respiratory distress syndrome,
disseminated intravascular coagulation, or bilateral hemor-
rhage into the adrenal glands (Waterhouse-Friderichson syn-
drome). Of the patients, 10% to 15% will die of
meningococcemia,9 and 10% to 20% of survivors will suffer
from long-term neurologic complications, including deafness,
mental retardation, and seizures.9
Diagnosis and treatment
Meningococcal disease can be diagnosed in a variety of
ways, including culture, gram stain, bacterial polymerase
chain reaction (PCR), and antigen detection using latex agglu-
tination.9 Meningococcemia should be considered in all pa-
tients presenting with fever, headache, nausea, vomiting, and
a maculopapular or petechial rash. Because of the high compli-
cation rate secondary to this infection, all patients with sus-
pected disease should be treated promptly.
Ceftriaxone is the first-line antibiotic for treating meningo-
coccemia due to its effective penetrance into the cerebrospinal
fluid.9 If possible, blood cultures should be drawn before anti-
biotic administration to confirm the diagnosis; however, anti-
microbial therapy should not be delayed if a culture report is
not readily available. Close contacts of the patient (defined
as individuals with N8 hours of contact in proximity b3 feet
to the patient or those with direct contact with oral secretions
from 1 week before the onset of clinical manifestations to 24
hours after patient antibiotic initiation) should be given antibi-
otic prophylaxis.9 Rifampin is the first-line prophylactic agent
for meningococcal meningitis.9
Infectious mononucleosis
Virology
Infectious mononucleosis is caused by the Epstein-Barr vi-
rus (EBV), also known as human herpes virus-4, an enveloped
DNA virus, which is part of the herpes virus family.10
Epidemiology and incidence
Infection with EBV is prominent globally, with 90% to
95% of adults testing seropositive.11 When EBV is acquired
in childhood, it is typically mild or asymptomatic. In contrast,
approximately 75% of adolescents who are infected present
Maculopapules and fever in adults
with symptomatic infectious mononucleosis. In developing
countries, infection with EBV occurs earlier in childhood
and clinical infectious mononucleosis is rare. The disease
is more common in developed countries, where infection
tends to occur later in adolescence or early adulthood. 12
The peak incidence of infectious mononucleosis occurs be-
tween 15 and 24 years of age.11 The disease is most commonly
spread by saliva but can also be transmitted via semen and
blood.
Clinical findings
Clinical manifestations of infectious mononucleosis typi-
cally present 4 to 6 weeks after infection with EBV.13 The pro-
drome consists of usually severe persistent fatigue and
myalgias and typically lasts 1 to 2 weeks.12 After the pro-
drome, patients present with cervical lymphadenopathy, fever,
severe sore throat due to pharyngeal inflammation, hepato-
megaly, and spenomegaly.14 A generalized maculopapular,
urticarial, or petechial rash may also be seen in some
patients.11 The characteristic exanthem is a maculopapular rash
that involves the trunk and arms. It appears shortly after the on-
set of clinical manifestations, lasts for 1 to 6 days, and is identi-
fied in 3% to 15% of patients.14 Complications from infectious
mononucleosis are rare but may include splenic rupture, hepa-
titis, myocarditis, and central nervous system dysfunction sec-
ondary to meningitis or encephalitis.15 Ten percent of patients
will develop persistent fatigue that lasts for more than 6
months.12
Diagnosis and treatment
Infectious mononucleosis is typically diagnosed clinically.
Serology may be used to confirm infection with EBV.10 In
cases with inconclusive serologic results, real-time PCR and
measurement of EBV viral load may be used. Patients typically
have lymphocytosis with greater than 10% atypical
lymphocytes.12
Treatment for infectious mononucleosis is symptomatic. Pa-
tients should receive adequate rest. Nonsteroidal anti-
inflammatory drugs (NSAIDs) may be used to manage pain. Pa-
tients should be instructed to avoid vigorous physical activity in
the first month, as this may increase the risk for splenic rup-
ture.12 Most patients with infectious mononucleosis, who are
treated with amoxicillin or ampicillin, will develop a maculo-
papular rash.2
West Nile virus
Virology
West Nile virus (WNV) is a positive-sense RNA virus,
which is part of the Flavivirus genus. WNV is primarily trans-
mitted by the Culex mosquito.16
113
Epidemiology and incidence
WNV is most frequently found in North America, Africa,
Europe, the Middle East, and West Asia.17 WNV is the lead-
ing cause of arboviral encephalitis in the United States.18 In
2016, there were 2149 reported cases of WNV in the United
States with 106 deaths. Incidence of infection is highest in
older adults. Infections peak between August and October.19
Clinical findings
Eighty percent of patients who are infected with WNV are
asymptomatic.19 Those who are symptomatic typically present
3 to 14 days after infection with fever, headache, myalgias, di-
arrhea, nausea, and vomiting.18 Patients may also develop a
maculopapular rash, which is concentrated on the trunk.18
Complications from WNV may include encephalitis, central
nervous system damage, and death.18 These occur more fre-
quently in the elderly and in patients with hypertension or di-
abetes. One in 150 patients will develop severe central
nervous system infection, and out of those, 1 in 10 will die.19
For those patients who are pregnant, it is possible for the virus
to cross the placenta and infect the fetus19; however, transpla-
cental infection appears to be rare.20
Diagnosis and treatment
WNV infection may be diagnosed using serology. Anti-
WNV IgM may be detected 3 to 8 days after infection. PCR
or viral culture may also be used for diagnosis.19 Treatment
for WNV is primarily supportive. Patients should receive ade-
quate hydration. NSAIDs may be used to control pain and fe-
ver. Patients with severe disease may need to be hospitalized
for supportive care.19
Rocky Mountain Spotted Fever
Virology
Rocky Mountain spotted fever (RMSF) is caused by Rickett-
sia rickettsii, an obligatory intracellular gram-negative bacillus
that is part of the Rickettsiacae family. It is transmitted through
tick bites, with Dermacentor variabilis (American dog tick) be-
ing the most common source of RMSF infection in the United
States.6 Other ticks in the United States that can transmit the
RMSF bacteria include the Rocky Mountain wood tick (Der-
macentor andersoni), the lone star tick (Amblyomma ameri-
canum), and the brown dog tick (Rhipicephalus sanguineus).6
Epidemiology and incidence
RMSF occurs in all age groups, with the highest incidence
of infection in people aged above 40 years. Men are more
114
commonly infected than women.21 Native Americans often
have higher rates of RMSF than other ethnic groups.21
RMSF occurs throughout the year, with the highest incidence
during the summer months.21 Although RMSF infections have
been reported throughout the contiguous United States, more
than 60% of cases have been reported in 5 states (North Caro-
lina, Oklahoma, Arkansas, Tennessee, and Missouri).21 In
2012, in total 4470 cases of RMSF were reported to the Cen-
ters for Disease Control and Prevention (CDC).21
Clinical findings
RMSF has an incubation period of 3 to 12 days.21 Patients
may present with a fever, headache, nausea, vomiting, and ab-
dominal pain. Two to 4 days after the onset of fever, patients
usually develop rash. The rash is highly variable but classically
presents with small, pink macules (Figure 3) that originate on
the wrists and ankles and spread to the trunk. The palms and
soles may be involved. Petechiae might develop 5 to 6 days af-
ter the onset of illness and are indicative of progression to se-
vere disease.21 Additional clinical manifestations, which can
present in children, are altered mental status and edema around
the eyes and/or on the dorsum of the hands. Untreated RMSF
may result in severe complications, including encephalitis,
shock, seizures, acute respiratory failure, and renal failure.
The majority of deaths from RMSF occur within the first 8
days.21
Diagnosis and treatment
RMSF is primarily diagnosed clinically. Sera may appear
negative for the first 7 to 10 days after infection and cannot
be relied upon for diagnosis. Doxycycline is the first-line treat-
ment for all patients with suspected RMSF, including children
(adults: 100 mg every 12 hours; children under 45 kg: 2.2 mg/kg
body weight every 12 hours). Despite the fact that doxycycline,
being a tetracycline, is usually not given to children under age 8
years due to the risk of permanent teeth staining, treating RMSF
adequately outweighs this risk. Pregnant women should be
counseled on the risks and benefits of treatment. Treatment
Fig. 3 Spotted eruption of Rocky Mountain spotted fever on the
wrist and hand of a child. (Image courtesy of the Centers for Disease
Control and Prevention).
S. Muzumdar et al.
should continue until 3 days after fever subsides and clinical im-
provement. A child, who has had RMSF, cannot be re-infected.
Protective clothing and insect repellants are recommended in
high-risk areas.21
Ehrlichiosis
Virology
In the United States, ehrlichiosis is caused by Ehrlichia
chaffeensis, Ehrlichia ewingii, and Ehrlichia muris–like.22
Ehrlichia are obligate intracellular, gram-negative bacteria that
are part of the Anaplasmataceae family. Ehrlichiosis is trans-
mitted by the lone-star tick, A americanum, found in wooded
areas.23 It generally requires a tick carrying the bacterium that
causes ehrlichiosis to feed for at least 24 hours to transmit the
bacterium. The lone-star tick can also transmit Lyme disease,
anaplasmosis, and babesiosis; RMSF coinfections have been
reported.22
Epidemiology and incidence
Ehrlichiosis occurs most frequently in the Southeast and
South Central United States. Disease is primarily reported
during the summer months, with peak incidence in June
and July. In 2016, in total 1377 cases of ehrlichiosis caused
by E chaffeensis were reported in the United States, with the
highest frequency of cases in males and people aged above
50 years. Severe infection may be more common in immuno-
compromised patients.22
Clinical findings
The incubation period for ehrlichiosis is typically 7 to 14
days. Most patients will present with fever, headache, myalgias,
and malaise. Less common clinical manifestations include
gastrointestinal upset and respiratory clinical manifestations, in-
cluding cough and dyspnea. The rash is identified in approxi-
mately 30% of patients, with a higher frequency in children.
The eruption associated with ehrlichiosis typically presents
5 days after the onset of clinical manifestations. It may be macu-
lopapular, petechial, or even widespread erythema. The rash is
typically diffuse and may involve the face, trunk, extremities,
palms, and soles.23
Diagnosis and treatment
Ehrlichiosis should be considered in patients presenting
with fever, headache, and rash in an endemic region. Serology
can be used to make a diagnosis. Antibody levels typically rise
after clinical manifestations present and therefore may not be
elevated within the first few days after infection. Additionally,
during this time, a Wright- or Giemsa-stained peripheral blood
Maculopapules and fever in adults 115

smear can be used to visualize morulae within monocytes Rubella (German Measles)
(E chaffeensis) or granulocytes (E ewingii).23
Doxycycline is the antibiotic of choice for treatment Virology
of ehrlichiosis in adults and children of all ages (100 mg
twice a day for adults; 2.2 mg/kg twice a day for children
Rubella virus is an enveloped, single-stranded RNA virus
under age of 8 years). In pregnant patients or those with
in the togavirus family.29
a life-threatening tetracycline allergy, rifampin may be
used.22
Epidemiology and incidence

Zika virus With increased vaccination efforts, the incidence of rubella

has fallen significantly. Between 2005 and 2011, a median of
11 cases of rubella were reported annually in the United
Virology
States.30 Although rubella is no longer endemic in the United
States, approximately 10% of U.S.-born persons remain sus-
Zika virus is a single-stranded RNA virus, a member of the
ceptible to infection. Risk of infection is highest in those
Flaviviridae family. It is an arbovirus, which is primarily
who are less likely to be vaccinated, such as people born out-
transmitted by mosquitoes of the Culicudae family and the
side of the United States and social groups who reject vaccina-
Aedes genus.24
tion.29 Since 2004, 60% of rubella infections have occurred in
patients aged 20 to 49 years. The median age of infection is 32
Epidemiology and incidence years.30 Rubella’s peak incidence is during the late winter and
early spring.29
Before 2007, zika infections were rare and occurred
mainly in Asia and Africa. Since 2007, multiple zika Clinical findings
outbreaks have been reported in Southeast Asia and the
Western Pacific. In 2015, zika was first documented in the The prodrome for rubella presents with malaise and adeno-
Western Hemisphere, with multiple large outbreaks re- pathy in the posterior auricular, posterior cervical, and suboc-
ported in Brazil. Subsequent to 2015, zika has spread cipital lymph nodes. The exanthem for rubella consists of pink
throughout most of the Americas. 25 In 2016, the incidence macules and papules 1 to 4 mm in diameter (Figure 4) and
of zika reached an all-time high in the United States with
5168 symptomatic cases reported of which 4897 occurred in
travelers from endemic areas and 224 resulting from presumed
mosquito-borne transmission in Florida and Texas. In 2017
the incidence of symptomatic zika in the United States fell to
433 cases. Travelers to zika-affected regions are most at risk
of contracting the infection. High-risk zika regions include
Africa, Southeast Asia, the Caribbean, the Pacific islands,
and South and Central America.25

Clinical findings

The majority of zika infections are asymptomatic. Those

that are symptomatic are typically mild.25 Common clinical
manifestations include fever, arthralgias, headache, and a
maculopapular rash that typically originates on the trunk and
then progresses to involve the lower extremities.26,27 The most
serious consequence of zika infection is the increased inci-
dence of birth defects in infants born to zika-infected pregnant
women. These include central nervous system defects such as
microcephaly, brain abnormalities, eye abnormalities, and
neural tube defects. The incidence of birth defects in fetuses
of women with laboratory evidence of zika infection reported
to the CDC’s US Zika Pregnancy Registry was 5% between
January 15 to December 26, 2016. For women with confirmed
zika infection in their first trimester of pregnancy, this number Fig. 4 Exanthem of rubella. (Image courtesy of the Centers for Dis-
rose to 15%.28 ease Control and Prevention.)
116
originates on the face, neck, and scalp with subsequent exten-
sion to the trunk and extremities. It may occur with fever, my-
algias, and arthralgias. Forchheimer’s sign, the enanthem for
rubella, occurs in 20% of patients and consists of petechiae
on the soft palate. It may occur during the prodrome or with
the onset of the rash.29
Complications of rubella are not common. They include
arthritis, which occurs primarily in women and increases
in incidence with age, and rarely thrombocytopenia and
encephalitis. An infected pregnant woman may infect
the fetus who can develop congenital rubella syndrome.
Although congenital rubella syndrome is classically charac-
terized by a fetal triad of congenital cataracts, deafness,
and patent ductus arteriosus, multiple fetal organs may be
involved. The incidence of congenital rubella syndrome
depends on the time when the mother contracts rubella.
Congenital rubella syndrome affects 50% of women in-
fected in the first 12 weeks of pregnancy. This falls to
25% for women infected between weeks 13 and 24 of preg-
nancy. Infection after 24 weeks of pregnancy rarely causes
congenital rubella syndrome.29
Diagnosis and treatment
Rubella is typically mild and treatment is primarily support-
ive in nature. NSAIDs may be used to treat severe arthralgias.
Pregnant women who are infected with rubella in early
pregnancy should consider treatment with intramuscular
immunoglobulin.29
HIV: primary infection
Virology
HIV is a member of the Retroviridae family. Its genome is
made up of two pieces of single-stranded RNA. There are two
types of HIV that can cause infection, HIV-1 and HIV-2. HIV-
1 is found globally and is the subtype that is responsible for most
HIV infections in the United States. HIV-2 is primarily found in
Western Africa and has a lower infectivity than HIV-1.31
Epidemiology and incidence
Since the height of the HIV epidemic in the 1980s, the inci-
dence of HIV in the United States has decreased, with 37,600
new infections reported in 2014 compared with 130,000 in
1985.32 Advances in HIV therapy have led to increased sur-
vival with a resultant increase in the prevalence of HIV. In
2015 the CDC estimated that 1.1 million people were living
with HIV in the United States. All populations may be affected
by HIV. Incidence is highest in men who have sex with men,
followed by heterosexual African American women.32 HIV is
transmitted through contact with infected bodily fluids, includ-
ing semen, preseminal fluids, blood, rectal fluids, vaginal
S. Muzumdar et al.
fluids, and breast milk. In the United States, HIV is primarily
transmitted through sexual intercourse and sharing of infected
needles.33
Clinical findings
Primary HIV infection typically presents with fever, mal-
aise, myalgias, and lymphadenopathy 2 to 6 weeks after expo-
sure,34 and 30% to 50% of patients will develop a rash. The
exanthem for primary HIV is maculopapular and occurs on
the face, upper extremities, and trunk. The rash may also in-
clude the palms and soles. Patients may have oral lesions with
resultant dysphagia. Clinical manifestations of primary HIV
typically resolve within 1 to 3 weeks.35
Diagnosis and treatment
Initial diagnosis of primary HIV may be made by
nucleic acid testing or testing for p24 antigen or HIV viral
load. 36 Most patients will test positive 7 to 28 days after
infection. Antibody testing for HIV will not be positive until
3 to 12 weeks after initial infection.32 Antiretroviral therapy
should be started in all patients who test positive for HIV as
soon as possible.36
Parvovirus B19
Parvovirus B19 is described in “The Rash with Fevers and
Maculopapules in Children.” Although parvovirus B19 is pre-
dominantly an infection of childhood, adults who work closely
with children, such as daycare workers and teachers, are also at
risk for infection. In adults, parvovirus B19 is more likely to
cause arthralgias than it is in children, with up to 60% of adults
who are affected developing arthralgias. The arthropathy is
characteristically symmetrical and involves multiple joints.
The metacarpophalangeal and proximal interphalangeal joints
are typically affected. Arthralgias typically resolve within a
few weeks; however, in women, they can last for months to
years.37 In adults, infection with parvovirus B19 may rarely
manifest as papular-purpuric gloves and socks syndrome.
This syndrome typically presents with erythema, pruritus, and
symmetrical edema of the hands and feet. It is generally self-
limiting, with spontaneous resolution typically occurring 7 to
14 days after onset.38
Ebolavirus
Virology
Ebolavirus is an enveloped, single-stranded RNA virus,
which is part of the Filoviridae family. 39 Three species
of ebolavirus have been responsible for the majority of
recent outbreaks in Africa: Zaire, Bundibugyo, and Sudan
ebolavirus.40
Maculopapules and fever in adults
Epidemiology and incidence
Ebolavirus is found primarily in Western Africa. It was first
discovered in 1976. Since then, it has periodically caused out-
breaks. The largest outbreak to date occurred from 2014 to
2016 and was centered in Guinea, Sierra Leone, and Liberia.
It spread to several other countries, including Italy, Spain,
the United Kingdom, and the United States. In total, 28,616
suspected infections occurred, with 11,310 deaths.40 There
were 4 cases of ebola in the United States during the outbreak.
People affected were travelers to West Africa and health care
workers who cared for patients with ebola. Since the 2014 to
2016 outbreak, the incidence for ebola has dropped substan-
tially. In 2017 there were only 8 known cases of ebolavirus,
found in the Democratic Republic of Congo.40 In 2018, there
has been one outbreak of ebola in the Democratic Republic of
Congo, resulting in 59 cases and 27 deaths as of June 7,
2018.41 People at risk for ebolavirus include travelers to en-
demic regions in West Africa and health care workers who
may be exposed to ebolavirus.
Clinical findings
The incubation period for ebolavirus is 8 to 12 days. Pa-
tients present with an abrupt onset of fever, chills, and malaise.
After 5 days, patients develop gastrointestinal clinical manifes-
tations. They may also have chest pain, shortness of breath,
headache, and possibly conjunctival injection. Bleeding may
occur, with patients developing petechiae, ecchymosis, or ooz-
ing from venipuncture sites. Between days 5 and 7, patients
may develop a diffuse maculopapular rash on their neck,
trunk, and arms, with subsequent desquamation.40
There may be multiorgan failure and septic shock, leading to
death. There is a high case fatality rate for ebolavirus, ranging from
18.5% in the United States and Europe to 74% in parts of Western
Africa. In nonfatal cases of ebola, patients usually start to improve
on day 6. They typically have a long recovery period.40
Diagnosis and treatment
Treatment of ebolavirus infection is primarily supportive.
Volume should be maintained, along with blood pressure
using vasopressors if needed and oxygenation. Pain control
and nutritional support are usually required. The use of
broad-spectrum antimicrobials, especially in the setting of sep-
tic shock, may be required.40
Conclusions
There is a broad differential diagnosis for maculopapular
rash with fever in adult patients. Because some conditions
are medical emergencies and highly contagious, prompt iden-
tification is critical. A thorough history can help to differenti-
ate a benign condition from the more severe. Important
117
factors to consider are the distribution of the rash, presence
of sick contacts, travel to possible endemic areas, and the ini-
tiation of new medications.
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Clinics in Dermatology (2019) 37, 119–128

The rash with maculopapules and fever in children

Sonal Muzumdar, MD, Marti Jill Rothe, MD, Jane M. Grant-Kels, MD ⁎
Dermatology Department, University of CT Health Center, Farmington, Connecticut, USA

Abstract Several medical conditions can cause children to present with fever and a maculopapular rash Al-
though some presentations are benign, others may be medical emergencies, which warrant a prompt diagno-
sis. We review some of the more common causes of fever and maculopapular dermatitirs, rash including
infectious processes (roseola; rubeola; rubella; parvovirus B19; hand, foot, and mouth disease; scarlet fever;
meningococcemia; Epstein-Barr virus infection), hypersensitivity reactions (exanthematous drug reactions),
and vasculitis syndromes (Kawasaki disease). We have included a diagnostic algorithm to facilitate rapid
identification of the etiology of the rash and fever. Those conditions that can occur in children but are seen
predominantly in adults are discussed in the contribution “Rash with maculopapules and fever in adults” in
this issue.
© 2018 Published by Elsevier Inc.

Introduction eruption in “Rash with maculopapules and fever in adults”.

A number of conditions may cause children to present with
fever and a maculopapular eruption. These include viral and
bacterial illnesses, vasculitis syndromes, and drug reactions
(Table 1). Many causative conditions are medical emergen-
cies. Prompt recognition and treatment are crucial. The differ-
ential diagnosis for maculopapular dermatitis with fever is
broad. Eliciting a thorough history and physical examination
is important for diagnosis. Factors to consider in any patient
presenting with maculopapular dermatitis and fever include
the distribution of the patient’s dermatitis (central versus pe-
ripheral), exposure to sick contacts, new medications, and re-
cent travel. We describe many of the common causes of
maculopapular eruptions with fever in children and ways to
identify and treat them. In this issue, we also describe those
conditions that affect adults with fever and a maculopapular
⁎ Corresponding author. Tel.: 860-519-7008.
E-mail address: grant@uchc.edu (J.M. Grant-Kels).
For many of the diseases discussed, the conditions can present
in children as well as in adults.
Diagnostic algorithm
Because the differential diagnosis for a child presenting
with a maculopapular dermatitis and fever is broad, eliciting
a thorough history is critical for making a prompt diagnosis.
The following questions should be asked of all patients pre-
senting with fever and dermatitis as well as their
caregivers1:
1. Did you have any clinical manifestations before you no-
ticed the dermatitis?
2. Have you noticed any associated clinical manifestations
with the dermatitis?
3. Does anyone else around you have the same clinical
manifestations?
4. On which part of the body did the dermatitis present? Has it
changed over time?

https://doi.org/10.1016/j.clindermatol.2018.12.005
0738-081X/© 2018 Published by Elsevier Inc.
120 S. Muzumdar et al.

Table 1 Common selected causes of fever and maculopapular dermatitis in children

Disease Epidemiology in children Characteristic clinical presentation in children
Rubeola (measles) Infants and unvaccinated children Cough, coryza, and conjunctivitis. Punctate white or
gray lesions on erythematous base on buccal mucosa
(Koplik spots). High fever and blanching
maculopapular dermatitis that originates on the
forehead and upper neck and descends to cover the
trunk and lower extremities.
Rubella (German Unvaccinated populations, including immigrants Tender adenopathy in the posterior auricular,
measles) posterior cervical and suboccipital lymph nodes.
Pink maculopapular dermatitis that starts on the face
and spreads to the trunk and extremities. May be
associated with petechiae on the soft palate
(Forchheimer’s sign).
Roseola (exanthem Infants and young children High fever followed by dermatitis that originates on
subitum) trunk and spreads to extremities. Dermatitis starts as
discrete pale, pink macules and may become
confluent. Spares face.
Zika virus Travelers from endemic regions (Africa, Southeast Asia, South Maculopapular dermatitis that starts on trunk and
and Central America, Pacific Islands, and Caribbean) descends to lower extremities.
Kawasaki disease Infants and children, with a higher incidence in Japanese Diffuse maculopapular dermatitis that spares face;
populations bilateral conjunctival infection; cervical adenopathy;
erythema of palms and soles; oral findings include
“strawberry tongue.” May precipitate coronary
artery aneurysms in children.
Parvovirus B19 School-aged children High fever followed by a dermatitis that originates
on trunk and spreads to extremities. Dermatitis starts
as discrete pale, pink macules and may become
confluent.
Rocky Mountain Throughout US; especially North Carolina, Oklahoma, Fever, nausea, abdominal pain, and headache. Pink
spotted fever Arkansas, Tennessee, and Missouri macular dermatitis starts on the ankles and wrists
and spreads to the trunk. Children may present with
altered mental status.
Meningococcemia Increased incidence in infants and young adults aged 16-23 y Fever, nuchal rigidity, photophobia, and altered
mental status. Dermatitis on the trunk and
extremities and may be maculopapular, petechial, or
purpural.
Hand, foot, and Infants and children younger than age 5 y Maculopapular or vesicular dermatitis on the hands,
mouth disease (cox- feet, buttocks, legs, and arms.
sackie virus)
Ehrlichiosis Increased incidence in Southeast and South Central US Widespread, erythematous maculopapular
dermatitis with fever, headache, and malaise.
Exanthematous drug Typically 4-21 days after initiation of a new drug. Increased risk Rapidly evolving, symmetric, diffuse erythematous
eruption with antiepileptics (carbamazepine, lamotrigine, and phenytoin) maculopapular dermatitis with a low-grade fever.
and antibiotics (penicillins, cephalosporins, and sulfonamides)
Infectious Adolescents and young adults Fever, cervical lymphadenopathy, and pharyngeal
mononucleosis inflammation. Maculopapular dermatitis on trunk
and arms.
West Nile virus Africa, Europe, Middle East, North America, and West Asia Fever, headache, myalgias, and maculopapular
dermatitis on trunk. Complications include severe
central nervous system disease and death.
Scarlet fever Most common in children aged 5-15 y. Sudden-onset fever, malaise, pharyngitis, or
tonsillitis. Strawberry tongue with enlarged papillae.
Blanching erythematous dermatitis that starts on the
trunk and spreads outward, typically sparing the
face, palms, and soles.
Pediatric maculopapular rash with fever 121

5. Have you traveled anywhere recently? Clinical findings

6. Have you started any new medications recently?
The answers to these questions can help health care pro-
viders differentiate between infectious and noninfectious
causes of maculopapular dermatitis. They may also help dif-
ferentiate benign conditions from emergent ones. Figure 1 pro-
vides a diagnostic algorithm for evaluating fever and
maculopapular dermatitis in a child.
Selected conditions
Roseola (exanthem subitum)
Virology
Roseola is caused by human herpes virus 6 (HHV-6), a
double-stranded DNA virus. There are two major groups of
HHV-6 (variants A and B),2 and 97% to 100% of primary in-
fections with HHV-6 are caused by variant B.3 Primary infec-
tion with HHV-7 may also present as typical roseola.4
The majority of primary infections with HHV-6 are asymp-
tomatic or subclinical, presenting with a nonspecific low-grade
fever. The classic presentation of roseola infantum occurs in
20% of children infected with HHV-6.5 Roseola has an incu-
bation period of 9 to 10 days. The disease first presents with
a high fever (102°F to 105°F) that lasts for 3 days. Roseola-in-
duced febrile seizures are common in patients and are reported
to be the etiology of 33% of febrile seizures and recurrent fe-
brile seizures seen in emergency rooms. The exanthem of rose-
ola may occur concurrently with the fever or after the fever
subsides. The dermatitis consists of discrete pale, pink macules
1 to 5 mm in diameter, which commonly originate on the
trunk, neck, and behind the ears and spread to the proximal ex-
tremities (Figure 2). It commonly spares the face and distal ex-
tremities. The dermatitis lasts for 2 to 48 hours, may become
confluent, and may be preceded by an enanthem of erythema-
tous macules on the soft palate.2
In immunocompromised patients, HHV-6 may reactivate,
causing a number of manifestations, including dermatitis, hep-
atitis, pneumonia, and encephalitis.2

Epidemiology and incidence Diagnosis and treatment

Roseola is a common childhood disease that is not seasonal
and occurs throughout the year. From birth to the age of 6
months, the disease is rare as newborns are protected by mater-
nal antibodies against HHV-6. After the age of 6 months, in-
fection with HHV-6 is common, with 80% of infants
becoming infected by the age of 2 years.2
Sera for HHV-6 may be used to diagnose roseola. Anti-
HHV-6 IgM is detectable 7 to 14 days after onset of illness
and may become undetectable after only a few weeks. Anti-
HHV-6 IgG develops 2 to 4 weeks after onset of the clinical
illness and can be detected indefinitely. HHV-6 may also be
cultured from saliva. Polymerase chain reaction (PCR) can

Maculopapular rash with fever

Recent Sick Contact?

Yes No

Travel to
endemic area?
Yes No

Exposure to
Rocky new drug?
Mountain Yes No
spotted fever
Ehrlichiosis
Zika
West Nile virus
Centrally Peripherally
distributed rash distributed rash

Exanthematous Kawasaki
drug eruption disease

Rubeola Hand-foot-mouth
Rubella disease
Roseola Meningococcemia
Parvovirus B19
Infectious
mononucleosis

Fig. 1 Diagnostic approach for adults with fever and maculopapular dermatitis.
122
Fig. 2 Erythematous maculopapular dermatitis of roseola on the trunk of a child. (Image from Wikimedia commons; courtesy:
Emiliano Burzagli.)
be used to detect viral DNA in the blood and cerebrospinal
fluid.2
In immunocompetent patients, roseola is self-limiting, and
no treatment is usually required; however, in immunosup-
pressed patients, ganciclovir, foscarnet, or cidofovir may be
used for treatment.2
Rubeola (measles)
Virology
Rubeola is caused by an RNA virus in the Morbillivirus ge-
nus in the Paramyxoviridae family.2
Epidemiology and incidence
The incidence of rubeola, or measles, has declined substan-
tially in the past few decades due to increased vaccination ef-
forts globally; however, it remains an important public health
issue, with 254,928 reported cases of measles in 2015 world-
wide.6 Historically, measles has primarily been a disease of
young children. Although the incidence of measles has de-
creased across all age groups with increased vaccination ef-
forts, the relative incidence of measles has increased in
groups that may be less likely to be vaccinated, including older
adults, children under the age of 1 year, and social groups that
eschew vaccinations.7
Clinical findings
Measles presents in a relatively characteristic fashion in im-
munocompetent patients. The incubation period for measles
ranges from 10 to 12 days and is followed by a prodrome of
malaise, headache, and low-grade fever. This may precede or
occur concurrently with cough, coryza, and conjunctivitis. Dur-
ing the prodrome, patients may develop Koplik spots, the
S. Muzumdar et al.
typical enanthem of measles, which appear as punctate white
or gray lesions on an erythematous base (Figure 3A). Koplik
spots originate on the buccal mucosa and may spread to the
hard or soft palate. After approximately 4 days, patients will
develop a high fever and an erythematous, blanching maculo-
papular dermatitis (Figure 3B). The typical dermatitis origi-
nates on the patient’s hairline, forehead, and upper neck and
spreads to the trunk and extremities over the next 3 days.
The dermatitis persists for 2 to 4 days. Coryza and conjuncti-
vitis typically clear with the dermatitis, while cough may per-
sist for another 5 days.2 Immunosuppressed patients may have
an atypical presentation, may not develop the characteristic
dermatitis of measles, and therefore may be challenging to
recognize.2,8
Respiratory and central nervous system complications may
occur as a result of measles infection; 0.1% of children de-
velop acute encephalitis, which commonly causes permanent
brain damage; 0.1% to 0.2% of children expire from neuro-
logic or respiratory complications. Seven to 10 years after pri-
mary measles infection, children may develop subacute
sclerosing panencephalitis, a rare degenerative disease of the
central nervous system, which is commonly fatal. This may
present with seizures and behavioral changes in a child who
was previously infected with measles.8
Diagnosis and treatment
Although viral cultures can confirm the diagnosis of mea-
sles, they may be technically challenging to obtain. Clinically,
measles infection may be confirmed through sera for measles
antibody. A significant rise in measles IgG is diagnostic. Mea-
sles IgM may also be detected 3 to 30 days after dermatitis on-
set. PCR of viral RNA is also diagnostic but may not be readily
available.2
Pediatric maculopapular rash with fever
Treatment for measles is primarily symptomatic. Nonste-
roidal anti-inflammatory drugs or acetaminophen may be used
to manage pain and fever. Oral vitamin A has been shown to
decrease morbidity in patients who are malnourished. The
World Health Organization recommends daily supplementa-
tion with vitamin A for 2 days for all children with acute mea-
sles; however, specific doses of vitamin A vary with age2;
excess vitamin A supplementation in pregnant women can
cause severe fetal malformations.9
Rubella (German measles)
Rubella can cause fever with maculopapular dermatitis in
both adults and children. A description of rubella infection
can be found in the article “Dermatitis with maculopapules
and fever in adults” in this issue. Rubella infection is typically
mild in infants and children. Up to 50% of infections in this
age group may be asymptomatic.2
Parvovirus B19
Virology
Parvovirus B19 is a single-stranded, nonenveloped DNA
virus, which is part of the Parvoviridae family in the
Erythrovirus genus.10
Epidemiology and incidence
Parvovirus B19 is a common global infection with sero-
prevalence increasing with age: 15% of preschool-aged
children, 50% of young adults, and 85% of older adults
demonstrate sera indicating past infection. B19 infection is
most common during the winter and early spring.
Epidemics typically strike every 3 to 4 years, with most
occurring in children. Adults who work closely with chil-
dren, such as teachers and daycare workers, are also at risk
of infection.10
Clinical findings
Infection with parvovirus B19 in immunocompetent
children is typically mild. Patients may develop a low-grade
fever. One to 4 days after the onset of fever, the characteris-
tic exanthem induced by B19 may appear. At this time, chil-
dren are typically afebrile. The exanthem starts as an
erythematous facial dermatitis (Figure 4A), also known as a
“slapped cheek” dermatitis. After 1 to 4 days, the dermatitis
becomes maculopapular and spreads to the trunk and extrem-
ities (Figure 3B). Central clearing of the dermatitis may give it
a reticular, lacelike appearance. The dermatitis on the trunk
and extremities persists for 1 to 6 weeks. During this time,
the intensity of the dermatitis may vary with exposure to sun-
light or heat.10,11
Arthralgias after infection with B19 occur in 8% of chil-
dren but are more common in adolescents and adults. In
children, arthralgias characteristically involve the knees
and ankles. 11 B19 can precipitate aplastic crises in patients
with chronic hemolytic anemias, such as those due to sickle
123
cell disease or hereditary spherocytosis. These patients less
commonly develop a dermatitis but may present with such
clinical findings as anemia, pallor, or malaise, after a mild fe-
brile illness.12
The most severe complication of B19 infection is fetal loss
that can occur in 5% to 10% of infected pregnant women. Fe-
tuses may develop hydrops fetalis as a result of maternal
infection.10
Diagnosis and treatment
Diagnosis of parvovirus B19 can be made through serology
or PCR. Detection of viral RNA or DNA through PCR is in-
dicative of acute or persistent infection. B19 IgM may be de-
tected 10 days after infection and can persist for up to 4
months. B19 IgG is present shortly after IgM and persists
indefinitely.10
B19 infection in immunocompetent patients is typically
self-limited. In patients with aplastic crises from B19, hos-
pitalization and transfusion may be required. The fetuses
of women with B19 infection should be monitored weekly
with ultrasonography for the development of hydrops feta-
lis. In fetuses with hydrops fetalis due to B19, the adminis-
tration of intrauterine erythrocyte transfusions can reduce
fetal mortality.10
Hand, foot, and mouth disease
Virology
Hand, foot, and mouth disease (HFMD) is caused by sero-
types of enterovirus, a single-stranded RNA virus. Coxsackie-
virus A16 and enterovirus A71 cause the majority of cases of
HFMD.13
Epidemiology and incidence
Although HFMD can occur in patients of all ages, it typi-
cally affects infants and children under the age of 5 years.14
Cases of HFMD occur worldwide, with an increased incidence
in the summer and early fall.13
Clinical findings
HFMD characteristically presents with mouth or throat pain.
In young, nonverbal children, this may manifest as refusal to
eat. The enanthem of HFMD typically occurs on the tongue
and buccal mucosa (Figure 5A). The enanthem starts as ery-
thematous macules and progresses to vesicles and then to su-
perficial ulcers. The exanthem of HFMD usually presents on
the hands, feet, buttocks, legs, and arms and may be maculo-
papular and/or vesicular (Figure 5B). It lasts for 3 to 4 days
and is not classically pruritic or painful.13 Prognosis is gener-
ally good. Rarely, patients may develop meningitis or enceph-
alitis.14 In 2012, the CDC reported a number of atypical
HFMD infections, many of which were caused by coxsackie-
virus A6. Fever and dermatitis associated with atypical HFMD
is more severe than that associated with typical HFMD, and
hospitalization is more likely.15 The exanthem of atypical
HFMD includes diffuse vesicles, bullae, and erosions. In
124 S. Muzumdar et al.

Fig. 3 A, Koplik spots on the buccal mucosa of a patient with rubeola. (Image courtesy: the Public Health Image Library from the CDC.) B,
Widespread, erythematous maculopapular exanthem of rubeola. (Image courtesy: the Public Health Image Library from the CDC.)

addition to the classic locations of HFMD (hands, feet, but-
tocks, oral mucosa), atypical HFMD also occurs on the torso
and perioral area.16
Kawasaki disease
Etiology
Kawasaki disease is an acute vasculitis syndrome. Etiology
is unknown; however, it is hypothesized that it is caused by an
immunologic response to an unknown trigger in a genetically
susceptible person.17
Epidemiology and incidence
Kawasaki disease primarily affects infants and children,
with 80% of cases occurring in children under the age of 5
years. Older children and adolescents may also be affected.
The highest incidence of Kawasaki disease is found in
Japan, with 265 cases per 100,000 children under the age
Pediatric maculopapular rash with fever
Fig. 4 A, Slapped face exanthema secondary to parvovirus. (Image courtesy: Dr. Justin Finch and the UConn Department of Dermatology.) B,
Maculopapular eruption on trunk due to parvovirus. (Image courtesy: Dr. Justin Finch and the UConn Department of Dermatology.)
of 5 years. In the United States, the incidence of Kawasaki
disease is 19 cases per 100,000 children under the age of 5
years.17
Clinical findings
Early detection of Kawasaki disease is crucial to prevent
complications in otherwise healthy children. The diagnostic
criteria include a fever for at least 5 days and at least four of
the following criteria in the absence of another illness to ac-
count for the clinical manifestations:
1. Bilateral conjunctival injection: typically occurs shortly af-
ter fever onset and is usually painless and without an
exudate.18
2. Distinct oral findings: red, cracked lips; an erythematous,
“strawberry” tongue with prominent fungiform papillae;
and erythema of the mucosa of the oropharynx (Figure
6A).18
3. Cervical lymphadenopathy: typically unilateral and located
in the anterior cervical triangle.18
4. Dermatitis: erythematous dermatitis that appears within 5
days of the onset of fever and has multiple appearances,
125
with the most common being a diffuse, maculopapular der-
matitis that spares the face (Figure 6B).18
5. Distinct findings of the extremities: in the acute phase, pa-
tients may present with erythema and/or induration of the
palms and soles; 2 to 3 weeks after the onset of fever, des-
quamation of the fingers and toes may occur.18
In children aged less than 6 months or greater than 5 years,
Kawasaki disease may present atypically with a high fever and
at least two of the criteria enumerated above.19 All clinical
manifestations of Kawasaki disease may not present simulta-
neously, and children may present with only a few of the clin-
ical manifestations listed above at a given time.18
The most severe complication from Kawasaki disease is
coronary artery aneurysm. It is estimated that 20% of children
who are not treated with intravenous immunoglobulin in the
acute phase of Kawasaki disease may develop coronary artery
aneurysms.17
Diagnosis and treatment
Kawasaki disease is diagnosed clinically. Intravenous im-
munoglobulin (IVIG) may be used to treat acute Kawasaki
126
Fig. 5 A, Enanthem of hand, foot, and mouth disease. (Image courtesy: Dr. Justin Finch and the UConn Department of Dermatology.) B, Ex-
anthem of hand, foot, and mouth disease. (Image courtesy: Dr. Justin Finch and the UConn Department of Dermatology.)
disease. Standard therapy in the United States is 2 g/kg
IVIG infused over a period of 10 to 12 hours.19 High-dose
aspirin is given while children are febrile; once fever resolves,
patients are switched to low-dose aspirin. Systemic corticoste-
roids can be used in cases of Kawasaki disease, which are
refractory to IVIG. After the resolution of clinical manifesta-
tions, children should be monitored at regular intervals with
echocardiograms to screen for the development of coronary
artery aneurysms.20
Scarlet fever
Microbiology
Pyrogenic exotoxin-producing Streptococcus pyogenes
(Lancefield group A streptococci) causes scarlet fever. S pyo-
genes is a gram-positive, beta-hemolytic cocci.21
Epidemiology and incidence
Although scarlet fever affects all age groups, it most com-
monly occurs in children aged 5 to 15 years. Children in close
S. Muzumdar et al.
contact with infected persons (as those at school or daycare)
are at risk of infection.21
Clinical findings
Scarlet fever presents with sudden onset of fever and mal-
aise 2 to 3 days after infection. Patients may have pharyngitis
or tonsillitis. The tongue develops enlarged papillae, which
initially appear furry and then become erythematous, resulting
in a strawberry tongue appearance. The characteristic dermati-
tis of scarlet fever is typically seen 2 days after the onset of in-
fection.22 It is a blanching, erythematous dermatitis, which
starts on the trunk and spreads outward (Figure 7). The derma-
titis typically spares the face, palms, and soles. It can last
for up to a week and result in desquamation. Other cutane-
ous findings include Pastia’s lines, linear accentuations of
the dermatitis in flexor creases. Complications from scarlet
fever include acute rheumatic fever and poststreptococcal
glomerulonephritis. 21 Prompt antibiotic treatment may de-
crease the risk of developing rheumatic fever as well as peri-
tonsillar and retropharyngeal abscesses. Antibiotics also
Pediatric maculopapular rash with fever 127

Fig. 6 A, Erythematous, “strawberry” tongue of Kawasaki disease. (Image courtesy: the Kawasaki Disease Foundation.) B, Erythematous,
maculopapular exanthem of Kawasaki disease on the back of a child. (Image courtesy: the Kawasaki Disease Foundation.)

shorten the duration of clinical manifestations by approxi-
mately 16 hours.23.
Diagnosis and treatment
The gold-standard for diagnosis of scarlet fever is a throat
culture. Rapid antigen detection test may also be used. Scarlet
fever should be treated with antibiotics. Penicillin and
amoxicillin are the first-line antibiotics for treatment. In patients
with penicillin allergy, narrow-spectrum cephalosporins, azi-
thromycin, clarithromycin, or clindamycin are recommended.21
Meningococcemia
Meningococcemia commonly causes fever and maculopapu-
lar dermatitis in infants and young adults. The characteristic

Fig. 7 Blanching, erythematous dermatitis of scarlet fever. (Used with permission of Mayo Foundation for Medical Education and Research. All
rights reserved.)
128
clinical presentation of meningococcal infection is described in
the article “Dermatitis with maculopapules and fever in adults”
in this issue. Infants with meningococcal infection may present
differently from adults. Infants typically have nonspecific clini-
cal manifestations early in disease, including fever, irritability,
nausea, vomiting, and poor feeding. Focal seizures have also
been reported. Septic shock is more common in children than
in adults and is characterized by cold extremities, leg pain,
and abnormal skin color. A rapidly progressive hemorrhagic
dermatitis, which begins on the lower extremities in children,
is usually indicative of sepsis.24
Diagnosis and treatment
Early diagnosis and treatment of meningococcal infection
is crucial. Lumbar puncture should be performed in patients
with suspected infection. Contraindications to lumbar punc-
ture include prolonged seizures, space-occupying lesions,
and severe shock. Gram stain and PCR of cerebrospinal fluid
are accomplished to confirm meningococcal infection. Ceftri-
axone (100 mg/kg/day) or cefotaxime (100 mg/kg/day divided
into 3 doses) are the first-line antibiotics for treatment. Intrave-
nous penicillin is the second-choice treatment. Treatment is
recommended for 7 to 10 days. Rifampicin or ciprofloxacin
may be used for prophylaxis of close contacts.24
Infectious mononucleosis
Infectious mononucleosis can cause fever and a maculopap-
ular dermatitis. Although it is more common in adolescents and
young adults, Epstein-Barr virus infection may also occur in
children. The characteristics of infectious mononucleosis are de-
scribed in the article “Dermatitis with maculopapules and fever
in adults” in this issue. In children, Epstein-Barr virus infection
may present differently compared with that in young adults. It is
typically mild or asymptomatic and may present with mild phar-
yngitis or tonsillitis.25
Exanthematous drug reactions
Exanthematous drug reactions are common in both adults
and children. Please refer to the article “Dermatitis with maculo-
papules and fever in adults” in this issue for a detailed
description.
Conclusions
A number of conditions can cause fever and maculopapular
dermatitis in children. Because some conditions are medical
emergencies and highly contagious, prompt diagnosis is cru-
cial. Causative factors to consider in all patients include recent
sick contacts, travel to endemic regions, drugs that may re-
cently have been started, and the distribution of the dermatitis.
We have presented some of the more common causes of child-
hood fever and maculopapular dermatitis and ways to identify
and treat them.
S. Muzumdar et al.
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