DRESS SYNDROME.pptx

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1. DRESS SYNDROME - DR. VISALI P (PG)

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 P olymorphism 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 P olymorphism 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 A mong these polymorphisms,  CYP2C9*3  showed the most significant association

8. 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. P resented 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. P ro-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. N umber 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.

10. Pathogenesis :

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. 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.

14. Systemic inflammation Lymphadenopathy – with enlargement of atleast 2 cm in diameter is considered to be clinically significant. E arly 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

15. 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. R atio 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) C holestatic type - R ratio less than 2 (MC) H epatocellular type - R ratio greater than 5 (2 nd mc) M ixed type - R ratio greater than 2 but less than 5

16. 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.

17. Pulmonary involvement I mpaired pulmonary function I nterstitial pneumonitis P leuritis A cute respiratory distress syndrome Seen with usage of Minocycline

18. Cvs Linked with Minocycline, Sulfonamides and Ampicillin. T wo 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.

19. 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

20. Common drugs causing dress syndrome Allopurinol Anti epileptics – Carbamazepine, Oxcarbamazepine, Phenytoin, Lamotrigene Antibiotics- Minocycline, Amoxycillin, Vancomycin Anti tuberculosis drugs Anti retroviral – Abacavir, Nevirapine Sulpha drugs – Dapsone, sulfasalazine, sulphadiazine Furosemide Omeprazole Ibuprofen, Acetominophen, Diclofenac

21. 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

22. 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. 

23. 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

24. Clinical course and prognosis D elayed 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

25. 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

26. 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

27. Management Identify and eliminate the culprit drug Supportive measures Thermoregulation Iv fluids O2 supplementation Maintaining fluid balance Organ specific management

28. 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

29. Third line : Cyclophosphamide Cyclosporine Mycophenolate mofetil Rituximab Valganciclovir – virus reactivation N acetyl cysteine for severe liver involvement ECMO – for cardiac insufficiency

30. References Rooks textbook of Dermatology 9 th 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.

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