Approach to a patient with Exanthem

Dr Sanjay Singh

Exanthem

Non scaly maculopapular rash which can encompass other abruptly appearing lesions

such as papules, pustules & vesicles & affecting several areas simultaneously

Greek origin “exanthema” which means “a breaking out”

Poorly defined in literature, few literature restrict exanthem as maculopapular rash

Enanthem (enanthema) :

An eruption upon a mucous membrane

• 6 Classic Exanthem

First disease : Measles (Rubeola)

Second disease : Scarlet fever

Third disease : German measles (Rubella)

Fourth disease : Duke’s Filatow disease (scarlet fever variant)

Fifth disease : Erythema infectiosum

Sixth disease : Roseola, Erythema subitum

All other exanthems are broadly described as atypical exanthems

The challenge of diagnosing atypical exanthems: a clinico-laboratory study.

Drago F, Paolino S, Rebora A et al. J Am Acad Dermatol. 2012 Dec;67(6):1282-8.

• Seven Morphological Pattern

Macular erythema

Papular erythema

Macular-papular erythema

Erythematovesicular

Macular-papular erythema with petechiae

Erythema with pustules

Urticarial

Assessment of Maculopapular Exanthem

• Skin eruption consisting of macules and papules which does not form scale

Classification of Maculopapular Exanthem

Drugs Infections Unknown? Infectious

Non – Infectious Inflammatory

Miscellaneous

Maculopapular Drug Rash

Viral Kawasaki ds Familial inflamm. syndromes

Acute GVHD

Dress Syndrome Bacterial Still’s ds AILD

SJS - TEN Rickettsial

Maculopapular Drug Exanthem

When clinical presentation is Maculopapular rash, the cause is drug induced in 50% to 70% of adults and 10% to 20% of children

Develop within days to weeks (usually within 4 to 12 days) after initiation of a novel drug and usually last up to 2 weeks after cessation of the culprit medication

Common drugs responsible are antibiotics such as penicillins, quinolones, and sulfonamides, anticonvulsants, allopurinol, and NSAIDs

Bolognia textbook of Dermatology

Clinical Findings

Dusky red macules predominate initially, then become confluent patches with papular areas within

Symmetric distribution of rash – usually starting from trunk extending towards extremities but face may be spared.

Moderate to Severe pruritus

Mucous membranes are typically spared

Eruption generally fades over 1 to 2 weeks after discontinuation of drug

Post-inflammatory desquamation is common

Drug eruption participants : 1317

Maculopapular exanthem : 1201 (91.11 %)

Most common implicated drugs Penicillin Sulfonamides

NSAIDS

Development of Rash : 1-12 days

Comprehensive hospital drug monitoring (CHDM): adverse skin reactions, a 20-year survey.

Hunziker T, Kunzi UP, Braunschweig S et al. Allergy 1997 Apr;52(4):388-93.

DRESS syndrome

Drug rash with eosinophilia and systemic symptoms

Hypersensitivity syndrome develops 2 to 6 weeks after drug initiation

Fever and cutaneous eruption are most common symptoms

Cutaneous involvement usually begins as morbilliform eruption, which later becomes edematous, often with follicular accentuation.

Edema of face is frequent finding and is hallmark of DRESS

MC (and usually most severe) site of visceral involvement is liver & is responsible for majority of deaths associated with this syndrome

Every organ system can be affected

Important implicated drugs :Aromatic anticonvulsants (phenobarbital, carbamazepine and phenytoin)LamotrigineSulfonamides MinocyclineAllopurinol

Diagnostic criteria for drug-induced hypersensitivity syndrome (DIHS) established by a Japanese consensus group

Maculopapular rash developing > 3 weeks after starting with suspected drug

Prolonged clinical symptoms 2 weeks after discontinuation of suspected drug

Fever (> 38˚C)

Liver abnormalities (alanine aminotransferase > 100 U⁄ L)*

Leucocyte abnormalities : Leucocytosis (> 11 × 109 ⁄ L)Eosinophilia (> 1.5 × 109 ⁄ L)Atypical lymphocytosis (> 5%)

Lymphadenopathy

Human herpesvirus 6 reactivation7 Criteria : Typical DRESS5 Criteria : Atypical DRESS

Viral Exanthem

Clinical features suggestive of viral exanthem

Fever with or without constitutional symptoms Patterned distribution

Asymptomatic to mild pruritus

Enanthem – in most cases associated with viral exanthem

Rash is self limiting – usually subsides spontaneously within 7 days

Usually affects children

Maculopapular rash with petechie - in most cases associated with viral exanthem

Seasonal clustering of cases

Season Characteristics of Rash Enanthem Characteristic Features

Measles Late winter/spring

Begin on forehead, hairline and behind the ears and then spread in a cephalocaudal direction. On the fifth day, the exanthem starts to fade in the same order as it appeared

Koplik’s spots

Rubella Late winter/spring

Rose-pink macules with cephalocaudal spread

Forschheimer’s spots

Lymphadenopathy (retroauricular and suboccipital). Arthritis and arthralgias (adult)

Erythema infectiosum

Winter / spring

Bright red macular erythema of cheeksLacy, reticulated erythematous macules and papules on the extremities and (to a lesser extent) the trunk

Erythema over cheeksMild ProdromeArthralgiaAplastic crisis

Exanthem subitum

No seasonal variation

Discrete non-confluent rash appears when fever disappearsOnset in thorax and trunk, progress to face and limbs.

Nagayama spotsUvular and palatoglossal junctional ulcer

Seizures occur during febrile period in up to 10% of patients

Koplik’s spot Forschheimer’s spots

Nagayama spots

MeaslesErythema

infectiosum

Measles Rubella Erythema infectiosum

Epstein Barr Virus

Human Herpes Virus 4

MC age group affected : 14 – 25Y

Incubation Period : 4 to 8 weeks

Preferentially affects oropharyngeal mucosa and is transmitted primarily through infected saliva.

Clinical Findings

Triad of fever, lymphadenopathy, and pharyngitis develops in 80% of cases

Rash begins on day 4 to 6 of illness, initially on the trunk and upper extremities

Forearms and face, with petechiae commonly present

Spectrum of Infectious Mononucleosis

EBV and ampicillin/amoxycillin

Complex Interaction between drug and virus

Generalised copper-coloured eruption in most patients

Occurs 1 week after taking the medicine and is related to EBV antibodies cross-reacting with the drug

10 % of children with Infectious mononucleosis develop an exanthem, administration of ampicillin or amoxicillin causes exanthem in 80-100 % cases

Exanthem is not reproducible after re-exposure to drug after subsidence of infectionViral exanthems in childhood. Part 3: Parainfectious exanthems

and those associated with virus-drug interactions.Fölster-Holst R, Kreth HW. Dtsch Dermatol Ges. 2009;7(6):506-10.

Copper-colored maculopapular rash on trunk and extremities after taking oral amoxicillin in a patient of infectious mononucleosis

Complications

• Dehydration (due to severe pharyngitis)

- Streptococcal pharyngitis: 25% G-A strep infection

- Splenic rupture hemorrhage shock death. Rupture occurs between 4th /21th day after onset of symptoms.

- Chronic fatigue syndrome

- Hepatitis frequently accompanies IM. High liver enzymes, hepatomegaly

Coxsackievirus, echovirus, and enterovirus

Most common cause of viral exanthem

Transmitted by the faecal-oral or respiratory routes

More common in summer

Incubation Period : 3 to 6 days

Rash is typically generalised and maculopapular, with petechiae, oral erosions, and conjunctival haemorrhage

Fever and pharyngitis are common

Hepatitis & HIV

During the viraemic phase of acute infection

Primary HIV infection : 10% to 12% will develop an acute syndrome 3 to 6 weeks after exposure.

Syndrome includes a morbilliform eruption, fatigue, malaise, headache, and myalgia.

MC arthropod-borne viral (arboviral) illness in humans

Transmitted by mosquitoes of the genus Aedes

Characteristic exanthem in 50-82% of patients with DF

After incubation period of 3–8 days, pt. develops nausea, vomiting, headaches, biphasic fever, severe myalgias, arthralgia and retro-orbital pain

Rash : Morbilliform or scarlatiniform, with some areas of sparing (“white islands in a sea of red”)

Minor hemorrhagic manifestations can occur, including petechiae, epistaxis and gingival bleeding; severe hemorrhage is rare

Dengue Fever

Dengue Rash

Kawasaki disease

Acute multi-system febrile disease

Peak incidence : children 2 years of age and younger, and 85% of patients are <5 years of age

More common in children of Asian descent

Rash is typically generalised and maculopapular, rarely EM - like, urticarial, scarlatiniform or pustular lesion can develop.

Vesiculobullous lesions, crusting and petechiae are all unusual in the exanthem of KD.

Ulceration at the site of BCG vaccination is one of specific feature

Perineal erythema is particularly pronounced which often desquamates within 48 hours

Edema and brawny induration of the hands and feet are common early in course of disease, with eventual desquamation that is prominent in the periungual regions

Eye Changes : Conjunctival injection, typically bulbar with sparing of the limbusKeratitis and photophobia are uncommon and should suggest an alternative diagnosis

Kawasaki disease

Perineal Erythema on 2nd day of fever Desquamation after 2 days

Edema of Hands Periungual Desquamation

Oropharyngeal Changes : Dry, fissured lips Strawberry tongue Diffuse hyperaemia of the oral mucous membrane

Cardiac Involvement : Coronary aneurysm (Most common cause of death) Myocarditis Congestive Heart failure

Multi-organ involvement is common and affects the CNS, eyes, kidney, and GI system

Vasculitis of small and medium-sized vessels contributes to the pathology

Cheilitis Strawberry Tongue

Fever for 5 days plus 4 of the following 5 :1) Bilateral non-purulent conjunctival injection

2) Cervical lymphadenopathy (usually unilateral)

3) Oropharyngeal changes (including hyperaemia, oral fissures, strawberry tongue)

4) Peripheral extremity changes (including desquamation of hands and feet, erythema, oedema)

5) Polymorphous rash

Diagnostic criteria

Bacterial Exanthems

Meningococcemia

Close living conditions such as college dormitories, prisons, military barracks

Poor Immune status ( Young children, Older people, splenectomy)

History of Travel

Clinical Findings

May start as transient, blanchable macular erythema on the extremities

1/3rd to 1/2 of patients present with a petechial eruption, typically in association with fever, chills, myalgias and headache

Retiform purpura and ischemic necrosis may follow

Purpuric Lesion

RICKETTSIAL INFECTIONS

Summer/autumn incidence corresponding with outdoor activities and with possible tick exposure

Antecedent tick bite or tick attachment is made in 45% to 60% of cases

Cutaneous Features

Eschar formationCentral area of dermal and epidermal necrosis (0.5–2 cm)

surrounded by a zone of erythema appears

Tick / Mite / Flea bite

4–10 days

3 to 6 days

Petechiae and Purpura in generalized distribution

Rash begins as erythematous macules around the wrists and ankles (spotted fevers) or axillae (typhus fevers)

Spreads on most of the body, often with relative sparing of the face

Eschar

Dusky red maculopapular rash over ankle Multiple purpuric lesions

Toxin Mediated Bacterial Infections

Toxin produced by group A beta-haemolytic Streptococcus, typically following pharyngitis or tonsillitis.

MC in young children (80% of children have antibodies by 10 years of age)

Autumn to spring season

Sudden onset of a sore throat, headache, malaise, chills, anorexia, nausea and high fevers

Patients, especially young children, may experience vomiting, abdominal pain and seizures

Scarlet Fever

Eruption begins 12–48 hours later as blanchable erythema on the neck, chest and axillae

Subsequent generalization and development of tiny superimposed papules with sandpaper-like texture

Pastia’s lines (linear petechial streaks) are seen in the axillary, antecubital and inguinal areas

Cheeks are flushed with circumoral pallor

Strawberry tongue : initially white with bright red papillae, later becomes beefy red

Throat is red and edematous, developing an exudate after 3–4 days; palatal petechiae and tender cervical adenopathy are often evident

Desquamation occurs after 7–10 days, most prominently on the hands and feet and can last for 2–6 weeks.

sandpaper-like texture Pastia’s lines

Staphylococcal Scalded Skin Syndrome

Caused by exfoliative toxins ET-A and ET-B

Toxins target granular layer of epidermis, causing loss of adhesion and blistering

Young children (age ≤6 years) are most commonly affected

Prodrome of fever, malaise, and severally tender skin precedes the rash

Erythema begins on the head and rapidly (hours) generalises

Skin becomes swollen, and fragile superficial vesicles and bullae form

Superficial desquamation/exfoliation occurs in 2 to 5 days, leaving denuded and crusted underlying skin

Toxic shock syndrome

Caused by Staphylococcus aureus exotoxin (TSS-toxin-1)

TSS is characterised by high fever (>39.6°C), hypotension (systolic BP <90 mmHg), pharyngitis, headache, GI symptoms, and a diffuse scarlatiniform rash

Rash starts on the trunk and spreads centripetally. Extremities become oedematous, and the oral mucosa and tongue become hyperaemic

Desquamation occurs 1 to 2 weeks after onset, starting on the palms and soles

• Clinical Criteria• An illness with the following clinical manifestations :

• Fever ≥ 102.0°F

• Rash: diffuse macular erythroderma

• Desquamation: 1-2 weeks after onset of rash

• Hypotension: SBP ≤ 90 mm Hg

• Multisystem involvement (three or more of the following organ systems):

(GI, Renal, Hepatic, Haematologic, CNS, Muscular & Mucous membrane)

• Laboratory Criteria • Negative results on the following tests, if obtained : Blood or cerebrospinal fluid cultures (blood

culture may be positive for Staphylococcus aureus)

• Negative serologies for Rocky Mountain spotted fever, leptospirosis, or measles

Macular Erythema Conjuctival suffusion

Desquamation Of Palms

Post Transplantation : Acute GVHD

Sudden onset of maculopapular exanthema occurs 1 to 3 weeks after transplant

Can appear after blood product transfusion or solid organ transplant

Occurs in 25% to 40% of HLA identical siblings and in 50% of non-HLA-identical transplants

Predilection for acral areas (e.g. dorsal hands and feet, palms, soles, forearms, ears, as well as the upper trunk).

Pruritus is variable and a follicular pattern may be observed

Severe cases : Diffuse erythroderma and desquamation, and mucous membranes (particularly conjunctiva) may be involved

GI tract and liver involvement occur several days after cutaneous findings appear.

CLINICAL STAGING OF ACUTE GRAFT-VERSUS-HOST DISEASEStage Skin

Maculopapular Exanthem

Liver

(Bilirubin)

Gut

Diarrhea

Grade Histologic Findings

1 <25% BSA 2 to <3 mg/dl 500–1000 ml/day, or persistent nausea

I Focal vacuolar change of basal keratinocytes

2 25–50% BSA 3–6 mg/dl 1000–1500 ml/day II Grade 1 plus necrotic keratinocytes in the epidermis and/or hair follicle and dermal lymphocytic infiltrate

3 >50% BSA to generalized erythroderma

6–15 mg/dl >1500 ml/day III Grade 2 plus fusion of basilar vacuoles to form clefts and microvesicles

4 Generalized erythroderma with bulla formation

>15 mg/d Severe abdominal pain with or without ileus

IV Grade 3 plus large areas of separation of epidermis from dermis

Investigations

Drug Exanthem

Maculopapular Drug Rash DRESS Syndrome

TLC, DLC & Peripheral Blood Smear

LFT/RFT

DRESS syndrome

Viral Exanthem

Haemogram with Peripheral Blood smear

Serology

• Viral Exanthem : IgM antibodies• Infectious Mononucleosis : Heterophile antibodies

PCR & Culture

Bacterial Exanthem

Platelet count

LFT/RFT Toxic shock syndrome

ASO titre : Scarlet Fever

PCR & Culture : Scarlet fever Meningococcaemia

Histopathology & Immunohistochemistry

Primary changes of maculopapular drug eruptions are -

Inter and intracellular edema as well as disruption of epidermal basal cells, showing pyknotic nuclei

Vacuolar alteration of basal keratinocytes with scattered individual dyskeratotic and necrotic keratinocytes

Pathogenesis of drug-induced exanthems.Pichler W, Yawalkar N, Schmid S et al. Allergy. 2002 Oct;57(10):884-93.

Interface dermatitis with superficial, mainly perivascular infiltrate of CD4 T-cells

CD4 and CD8 T-cells in equal number in DEJ zone and in epidermis

Some eosinophil is also found in dermis

Histologic features of most drug eruptions are not entirely specific

Superficial infiltrates composed variably of L, N and Eo with or without interface changes suggest possibility of maculopapular drug exanthem

Clinical correlation is very helpful to confirm diagnosis

Cutaneous drug eruptions: a 5-year experience.Gerson D, Sriganeshan V, Alexis JB. J Am Acad Dermatol. 2008 Dec;59(6):995-9.

Epidermis of drug exanthem patients showed infiltration of CD4>CD8 cells

Marked enhancement of perforin and granzyme B immunostaining

Infiltration of cytotoxic T cells in drug-induced cutaneous eruptions.

Yawalkar N, Egli F, Hari Y et al. Clin Exp Allergy. 2000 Jun;30(6):847-55.

Most common pattern of drug eruption is vacuolar interface dermatitis.

Sparse P/V & interstitial infiltrate of N, Eo with subtle vacuolar changes at DEJ junction : virtually diagnostic of a drug eruption

Viral exanthems can be associated with lymphocytic vasculitis – rare in drug eruption

Some viral exanthem can be recognized by distinctive changes- Ballooning and multinucleated keratinocytes in measles

Histopathology of drug eruptions - general criteria, common patterns, and differential diagnosis.

Weyers W, Metze D. Dermatol Pract Concept. 2011 Jan 31;1(1):33-47.

Role of Immunohistology

Soluble FAS ligand: a discriminating feature between drug-induced skin eruptions and viral exanthemas.

Stur K, Karlhofer FM, Stingl G. J Invest Dermatol. 2007 Apr;127(4):802-7

Levels of sFASL in diseases of comparison groups

Diseases Quantity sFASL (ng/ml) %

Chickenpox 11 Negative 0

Shingles 11 Negative 0

Rubella 1 Negative 0

Fifth disease 1 Negative 0

Infectious mononucleosis

2 Negative 0

Based on FAS-ligand staining on tissue specimen

Fas-ligand staining in non-drug- and drug-induced maculopapular rashes.

Wang EC, Lee JS, Tan AW et al. J Cutan Pathol. 2011;38(2):196-201.

DRUG Induced Maculopapular

exanthem (n=10)

Non DRUG induced Maculopapular

exanthem (n=10)p Value

FAS ligand staining

5 1 < 0.05

Tissue eosinophilia

6 (Moderate to dense)

2 (Moderate)

0.17

Maculopapular Drug Exanthem Maculopapular Viral Exanthem

Evidence for a role for IL-5 and eotaxin in activating and recruiting eosinophils in drug-induced cutaneous eruptions.

Yawalkar N, Shrikhande M, Hari Y et al. J Allergy Clin Immunol. 2000 ;106(6):1171-6.

Acute drug exanthem Normal subjects p Value

IL-5 N < 0.05

Eotaxin N < 0.05

Staphylococcal Scalded Skin Syndrome

Acute GVHD

Algorithm to a patient with Maculopapular Exanthem

Maculopapular Rash

Drugs

Tender Rash with

mucosal erosions

InfectiousMiscellaneous

Non Infectious Inflammatory

Cause

Characteristic History &

Clinical features With

associated Systemic

features & Eosinophilia

Maculopapular drug Rash

GVHD

Dress Synd.

Evolving into typical clinical manifestations

SJS/TEN

UnknownRickettsialViral Bacterial

Clinical Suspicion

Clinical Criteria

1. Familial Inf. syndromes2. Still’s ds

Kawasaki ds

Drug provocation

HPE & IHC

AEC

CBCPBSLFT/RFT

HPEHPE

SerologyHPE

Serology

Culture

ASLO

Serology

Antigen detection

Culture

Acute-phase reactants

CBC

ECHO, ECG, Cardiac enzymes

HPE

H/o TransplantD ˂ 100 days

Inv. Based on clinical suspicion of ds

Laboratory Findings