2. • Also known as
• Drug induced hypersensitivity syndrome (DiHS)
• Hypersensitivity syndrome (HSS)
• Drug – induced delayed multiorgan hypersensitivity syndrome (DIDMOHS)
3. • Drug hypersensitivity reactions (DHR) are classified as immediate and non-
immediate.
• Immediate DHRs include urticaria, angioedema and anaphylaxis and occur
immediately or within the first 6 h after administration of the drug.
• Non-immediate DHRs tend to appear after many days of treatment, with a
delayed T-cell-dependent type of allergic mechanism and DRESS syndrome is
considered as one of them
4. History
• Presentation of Dress was initially noted with patients taking, phenytoin and termed
as Dilantin hypersensitivity.
• Patients presented with cutaneous adverse reaction, fever, lymphadenopathy and
systemic symptoms like hepatitis.
• Later was noticed with newer anticonvulsant like carbamazipine, and led to the term
‘Anticonvulsant hypersensitivity syndrome’
• Further severe adverse effects were noticed with Allopurinol and sulfones.
• Broadly termed as – DRESS by Bocquet et al.
5. Introduction
• Drug reaction with eosinophilia and systemic symptoms syndrome, one of the drug
induced Severe Cutaneous Adverse Reactions (SCARs)
• It is a life-threatening hypersensitivity disorder characterised by cutaneous lesions,
haematogical abnormalities and internal organ dysfunction.
• Mortality rate is about 10%
6. • Incidence : Varies between 1 in 1000 to 1 in 10,000
• Age group : Mean age of onset being 48 years
• Sex : Slight female preponderance
GENETIC FACTORS
Polymorphism in genes encoding HLA molecules
• Allopurinol - B*58:01
• Carbamazepine - A*31:01
• Phenytoin - B*13:01 and B*51:01
• Dapsone - B*13:01
7. Pathogenesis
1. Polymorphism in genes encoding the enzymes required for drug
metabolism, such as cytochrome P (CYP) 450 enzyme and N-
acetyltransferase.
- Decreased activity of metabolizing enzymes accumulation of drugs or their
active metabolite rendered antigenic when bound with a protein drug
specific immune response in patients with genetic background.
- This is known as Haptenization theory
- Among these polymorphisms, CYP2C9*3 showed the most significant
association
8. 2. p-i concept – pharmacological interaction of drugs with immune receptor
• Drug molecule will bind to the MHC via a protein bind to MHC or directly
through MHC groove.
• Presented by antigen-presentation cells, and are recognized as foreign antigens
• Eliciting a cascade of T cell response
9. • Viral reactivation
- Occurs in sequential fashion with HHV 6 and EBV, detected earlier in the course of the disease
followed by HHV 7 and CMV.
- Either due to direct effect of drugs or metabolites on viral reactivation.
- Or due Drug induced immunosuppressed state characterized by hypogammaglolubulinaemia
causing initial reactivation of latent herpesvirus.
- Cytokine storm due to anti drug immune response.
- Pro-inflammatory cytokines and chemokines, such as TNF-α, IFN-γ, IL-1, IL-2, IL-6, are seen in
lower levels in the early stage of the disease in patients with HHV-6 reactivation than in those
without HHV-6 reactivation.
- Number of plasmacytoid dendritic cells (pDCs), decreased in the blood and increased in the skin
around the time of viral reactivation related to the reactivation of viruses.
11. Clinical features
• Cardinal features include widespread skin lesion and systemic inflammation – fever, internal
organ involvement, lymphadenopathy and haemotological abnormalities.
• Long latent period of about 2 – 6 weeks between ingestion of drug and onset of symptoms.
• Prodromal phase of high grade fever 38 to 40 C, asthenia, malaise, fatigue, accompanied by
pharyngitis and cervical lymphadenopathy
12. Cutaneous manifestations :
• Presentations include
- Purpuric infiltrative urticarial papules and plaques (most common variant)
- Erythroderma
- Morbilliform eruption resembling measles
- Erythema multiforme like dusky or purpuric atypical target lesions
- Others - Polymorphic presentations like maculopapular, urticarial, exfoliative, lichenoid, pustular,
bullous, target-like, or eczema-like lesions
13.
14.
15. • Rash accompanied by facial edema is usually the first clinical feature to appear.
• Facial edema is the hallmark of the disease and might be due to vascular endothelial
growth factor pathway.
• Most noticeable at ears
• Mucosal lesions are frequently associated, with mouth and lips being the most commonly
involved
• Desquamation seen at the stage of resolution.
16.
17. Systemic inflammation
• Lymphadenopathy – with enlargement of atleast 2 cm in diameter is considered to be
clinically significant.
• Early phase of DRESS syndrome may show decreased numbers of B lymphocytes with
hypoglobulinemia.
• Haematological abnormalities :
- Eosinophilia is most commonly seen in blood and tissue
- Atypical lymphocytosis
- Leucopenia
- Lymphopenia
- Thrombocytopenia
18. Hepatic manifestations
• Liver is the first most common organ to be affected and the damage can occur even before onset of
cutaneous lesions.
• Injury is more severe and is the primary cause of mortality in DRESS
• Liver injury is divided into 3 types based on ALT and ALP.
• Ratio of serum ALT results to ALP results with respect to their upper limits of normal range
(ULNs)
R = (serum ALT/ULNs of ALT)/(serum ALP/ULNs of ALP)
• Cholestatic type - R ratio less than 2 (MC)
• Hepatocellular type - R ratio greater than 5 (2nd mc)
• Mixed type - R ratio greater than 2 but less than 5
19. Renal manifestations :
• Risk factor for kidney injury – old age, underlying renal dysfunction and
cardiovascular disorders.
• Higher risk of kidney injury is with Allopurinol induced Dress.
• Proteinuria, haematuria, urinary eosinophils.
• Usually mild and will be recovered from in time without obvious sequelae. Rarely can
cause severe interstitial nephritis, acute tubular necrosis, or vasculitis, leading to
renal failure.
• Treatment includes hemodialysis in severe cases.
20. Pulmonary involvement
• Impaired pulmonary function
• Interstitial pneumonitis
• Pleuritis
• Acute respiratory distress syndrome
• Seen with usage of Minocycline
21. Cvs
• Linked with Minocycline, Sulfonamides and Ampicillin.
• Two forms : hypersensitivity myocarditis and acute necrotizing eosinophilic
myocarditis.
• Hypersensitivity myocarditis - mild and self-limiting.
• Acute necrotizing eosinophilic myocarditis is a more severe form of
hypersensitivity and with a high mortality rate of more than 50%
• Symptoms : Chest pain, dyspnoea
• On Examination : Tachycardia, Hypotension
• Echocardiogram, Ecg- T wave inversion, Elevated cardiac enzymes.
22. Nervous system
• Meningitis
• Encephalitis
Endocrine :
• Seen in later phase than the acute phase
• Thyroid gland, most frequently involved
• Both hypo and hyperthyroidism are seen
• Also can be associated with Alopecia areata
24. RegiSCAR DRESS scoring system
Clinical features Score
Rash >50% Body surface area 1 point
Rash suggestive of DRESS 1 point
Systemic involvement Maximum 6 points
lymphadenopathy, eosinophilia
atypical lymphocytosis,
organ involvement
Relevant negative serological tests 1 point
< 2 points – no case
2-3 point – possible case
4-5 point – probable case
> 5 point – definite case
25. Histology
• Spongiosis with focal subcorneal pustules
• Erythema multiforme-like interface dermatitis: basal vacuolar change and multiple
scattered apoptotic keratinocytes in the epidermis
• Lichenoid dermatitis: prominent infiltrations of cells in the upper dermis
• perivascular infiltration with prominent endothelial cells, red blood cell
extravasation, and some extent of vessel wall damage, resembling a feature of
lymphocytic vasculitis
• Leukocytoclastic vasculitis: fibrinoid necrosis, leukocytoclasia, and red blood cell
extravasation
• Superficial perivascular dermatitis.
26.
27. Differential diagnosis
• Septicemia and viral infection
• Acute generalised exanthematous pustulosis – pustules are mainly flexural,
whereas in DRESS unlikely to be localised. Latency period of <5 days
• Erythema multiforme
• SJS/ TEN – Latency period of 7-10 days
• Acute severe eczema
• Psoriasis
• Cutaneous lymphoma
• Systemic vasculitis
28. Clinical course and prognosis
• Delayed onset and a prolonged and protracted evolution of the disease
• The duration of illness of DRESS syndrome is usually more than 15 days, with a
waxing-and-waning course with several flare-ups after recovery from initial
presentation.
• Risk factors for a prolonged evolution of the clinical course in DRESS syndrome –
increased baseline lymphocytosis, a higher value of liver enzyme levels, ethnicity,
and culprit drugs
29. Complications:
- Severe and life threatening : Fulminant hepatic failure, requiring transplant
- Mortality rate of 5-10%
• Delayed onset interstitial nephritis
• Interstitial pneumonitis
• Myocarditis
• Infections are the major complications due to treatment for DRESS syndrome,
including herpes labialis, herpes zoster, pneumonia, and soft tissue abscess - can
lead to septic shock and death
• Autoimmune disease may arise after DRESS- lupus erythematosus and
autoimmune thyroid disease
30. Investigations
• CBC
• LFT, Lactate dehydrogenase, Ferritin, Hepatitis B and C
• ECG, Echo, cardiac enzymes
• RFT, urine analysis, ultrasound
• CSF for culture and sensitivity, microscopy, CT/MRI head
• Chest Xray, PFT
• TFT
• Blood culture
• Amylase, Lipase, Triglycerides
31. Management
• Identify and eliminate the culprit drug
• Supportive measures
- Thermoregulation
- Iv fluids
- O2 supplementation
- Maintaining fluid balance
- Organ specific management
32. First line of management
• Oral corticosteroid - Prednisolone 0.5–1.0 mg/kg/day with a gradual tapering over
2–3 month.
• Failure to respond to oral prednisolone, iv is required- Methylprednisolone is
indicated.
• Methyl Prednisolone 1g/day for 3 days
Second line
- Intravenous immunoglobulin (IVIG) – can also cause severe adverse effects if used
as monotherapy
33. Third line :
- Cyclophosphamide
- Cyclosporine
- Mycophenolate mofetil
- Rituximab
- Valganciclovir – virus reactivation
- N acetyl cysteine for severe liver involvement
- ECMO – for cardiac insufficiency
34. References
• Rooks textbook of Dermatology 9th edition
• Iadvl
• Fitzpatrick’ dermatology 9th edition
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): An Interplay among
Drugs, Viruses, and Immune System - PMC [Internet]. [cited 2022 Oct 20]. Available
from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486066/
• Castellazzi ML, Esposito S, Claut LE, Daccò V, Colombo C. Drug reaction with eosinophilia
and systemic symptoms (DRESS) syndrome in two young children: the importance of an
early diagnosis. Italian Journal of Pediatrics. 2018 Aug 15;44(1):93.
