Similaire à rash, exanthem, approach to exanthem, maculopapular exanthem, Exanthem seminar, Fever and Rash, Approach to patient with maculopapular exanthem
Similaire à rash, exanthem, approach to exanthem, maculopapular exanthem, Exanthem seminar, Fever and Rash, Approach to patient with maculopapular exanthem (20)
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
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
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.
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
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
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
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
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
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
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.
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
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
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.
66.
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
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
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
Notes de l'éditeur
Rarely, neoplasms like angioimmunoblastic lymphadenopathy with dysproteinemia and Familial syndromes like TNF associated periodic syndrome, familial Mediterranean fever, hyperimmunoglobulinemia D syndrome are causes of maculopapular exanthem.
Additional manifestations include vesicles, tense bullae induced by dermal edema, follicular as well as non-follicular pustules, erythroderma and purpuric lesions
Erythema infectiosum : Bright red macular erythema of cheeks, with sparing of the nasal bridge and circumoral regions
A common phenomenon is the repeated fading and recurrence of the exanthem, triggered by local irritation, high temperatures (e.g., hot baths, sunlight), and emotional stress
Nagayama spots : An enanthem of red papules on the soft palate and uvula can develop, and uvular and palatoglossal junctional ulcers represent a characteristic finding
3-5 days of high temperature are followed by 3-5 days of low temperature
Vaccination is recommended for persons traveling to the meningitis belt in sub-Saharan Africa during the dry season (December through June)
When endothelial cell destruction leads to more severe vascular injury, petechiae appear within the lesions, which can coalesce and become purpuric
Macules and papules develop on the palms and soles (often relatively late in the disease course) in approximately half of the patients with spotted fevers
Cutaneous necrosis, including gangrene of the digits, extremities, ears or prepuce in acral sites with a cooler temperature that is more favorable for rickettsial growth
Subsequent generalization (usually within 12 hours) and development of tiny superimposed papules with a sandpaper-like texture (“sunburn with goose pimples”).
Gastrointestinal: vomiting or diarrhea at onset of illness
Muscular: severe myalgia or creatine phosphokinase level at least twice the upper limit of normal
Mucous membrane: vaginal, oropharyngeal, or conjunctival hyperemia
Renal: blood urea nitrogen or creatinine at least twice the upper limit of normal for laboratory or urinary sediment with pyuria in the absence of urinary tract infection
Hepatic: total bilirubin, alanine aminotransferase enzyme, or asparate aminotransferase enzyme levels at least twice the upper limit of normal for laboratory
Hematologic: platelets less than 100,000/mm3
Central nervous system: disorientation or alterations in consciousness without focal neurologic signs when fever and hypotension are absent
Probable case: a case which meets the laboratory criteria and in which 4 or 5 of the clinical findings are present.
Confirmed case: a case which meets the laboratory criteria and in which all 5 of the clinical findings are present (including desquamation, unless the patient dies before desquamation).
Heterophile means it reacts with proteins across species lines. Heterophile also can mean that it is an antibody that reacts with antigens other than the antigen that stimulated it (an antibody that crossreacts)
Patients were identified based on a final diagnosis of ‘drug rash’ or ‘adverse drug eruption’ and ‘viral exanthem’ for non-drug-induced cases