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