rash, exanthem, approach to exanthem, maculopapular exanthem, Exanthem seminar, Fever and Rash, Approach to patient with maculopapular exanthem

1. Approach to a patient with Exanthem
Dr Sanjay Singh

2. 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

3. • 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

4. 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

5. 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

6. 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

7. 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

8.  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.

9. 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

10. 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)
Lamotrigine
Sulfonamides
Minocycline
Allopurinol

11. 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 reactivation 7 Criteria : Typical DRESS
5 Criteria : Atypical DRESS

12. Viral Exanthem
Clinical features suggestive of viral exanthem
 Fever with or without constitutional symptoms
 Patterned distribution
 Asymptomatic to mild pruritus

13.  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

14. 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 cheeks
Lacy, reticulated erythematous macules and
papules on the extremities and
(to a lesser extent) the trunk
Erythema over cheeks
Mild Prodrome
Arthralgia
Aplastic crisis
Exanthem
subitum
No
seasonal
variation
Discrete non-confluent rash appears when
fever disappears
Onset in thorax and trunk, progress to face
and limbs.
Nagayama spots
Uvular and
palatoglossal
junctional ulcer
Seizures occur during
febrile period in up to
10% of patients

15. Koplik’s spot Forschheimer’s spots
Nagayama spots

16. Measles
Erythema
infectiosum

17. Measles Rubella Erythema infectiosum

18. 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.

19. 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

20. Spectrum of Infectious Mononucleosis

21. 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 infection
Viral 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.

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

23. 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

24. 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

25. 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.

26. 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

27. Dengue Rash

28. 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.

29. 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 limbus
Keratitis and photophobia are uncommon and should suggest an alternative diagnosis

30. Kawasaki disease
Perineal Erythema on 2nd day of fever Desquamation after 2 days

31. Edema of Hands Periungual Desquamation

32. 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

33. Cheilitis Strawberry Tongue

34. 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

35. Bacterial Exanthems

36. Meningococcemia
Close living conditions such as college dormitories, prisons, military barracks
Poor Immune status ( Young children, Older people, splenectomy)
History of Travel

37. 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

38. Purpuric Lesion

39. 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

40. Cutaneous Features
Eschar formation
Central area of dermal and epidermal necrosis (0.5–2 cm)
surrounded by a zone of erythema appears
Tick / Mite / Flea bite
4–10 days

41. 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

42. Eschar

43. Dusky red maculopapular rash over ankle Multiple purpuric lesions

44. 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

45.  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

46. 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.

47. sandpaper-like texture Pastia’s lines

48. 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

49.  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

50. 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

51. • 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

52. Macular Erythema Conjuctival suffusion

53. Desquamation Of Palms

54. 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).

55. 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.

56. CLINICAL STAGING OF ACUTE GRAFT-VERSUS-HOST DISEASE
Stage 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

57. Investigations

58. Drug Exanthem
 Maculopapular Drug Rash
 DRESS Syndrome
TLC, DLC & Peripheral Blood Smear
LFT/RFT
 DRESS syndrome

59. Viral Exanthem
 Haemogram with Peripheral Blood smear
Serology
• Viral Exanthem : IgM antibodies
• Infectious Mononucleosis : Heterophile antibodies
PCR & Culture

60. Bacterial Exanthem
Platelet count
LFT/RFT
 Toxic shock syndrome
ASO titre : Scarlet Fever
PCR & Culture : Scarlet fever
Meningococcaemia

61. Histopathology & Immunohistochemistry

62. 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.

63.  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

64. 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.

65. 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.

67. 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.

68. 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

69. 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

70. 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

71. Maculopapular Drug Exanthem Maculopapular Viral Exanthem

72. 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

73. Staphylococcal Scalded Skin Syndrome

74. Acute GVHD

75. Algorithm to a patient with
Maculopapular Exanthem

76. Maculopapular Rash
Drugs
Tender Rash
with
mucosal
erosions
Infectious
Miscellaneous
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.
syndromes
2. Still’s dsKawasaki
ds
Drug
provocation
HPE & IHC
AEC
CBC
PBS
LFT/RFT
HPE
HPE
Serology
HPE
Serology
Culture
ASLO
Serology
Antigen
detection
Culture
Acute-phase
reactants
CBC
ECHO, ECG,
Cardiac enzymes
HPE
H/o Transplant
D ˂ 100 days
Inv. Based
on clinical
suspicion
of ds
Laboratory Findings