Difficult to diagnose and manage: The diagnosis and management process of drug hypersensitivity syndrome can be mastered in one article!

Drug hypersensitivity syndrome (DiHS), also known as drug reaction with eosinophilia and systemic symptoms (DRESS), is a serious adverse skin reaction characterized by rash, fever, hematologic abnormalities, and organ damage. Differential diagnoses include other cutaneous adverse effects, infections, inflammatory and autoimmune diseases, and neoplastic diseases. The key to treatment is immediate discontinuation of the suspected causative drug, with systemic corticosteroids being the first-line treatment, but the use of steroid-sparing agents is expanding.

It is difficult to diagnose and distinguish this disease in clinical practice, and there are three sets of diagnostic criteria, but there is still a lack of unified consensus. Therefore, based on the literature and clinical experience, Wei et al. proposed a diagnostic and management process for DiHS/DRESS.

PART ONE

There are three diagnostic criteria for DiHS/DRESS

There are three diagnostic criteria for DiHS/DRESS: Bocquet criteria, J-SCAR criteria, and RegiSCAR criteria (Table 1).

Table 1 Diagnostic criteria for DiHS/DRESS

Best	J-SCAR	RegiSCAR
hospitalization Suspected drug-related reactions
Drug-induced dermatitis	The time to appearance of macules after the use of the suspected causative drug > 3 weeks Clinical symptoms were prolonged > 2 weeks after discontinuation of the drug	Acute rash
Eosinophils ≥ 1.5×109/L or atypical lymphocytes are present	Leukocytosis (>11×109/L) or atypical lymphocytosis (>5%) or eosinophilia (1.5×109/L)	Lymphocytes are above or below laboratory limits Eosinophils above laboratory limits (in% or absolute count) Platelets below laboratory standards
Adenopathy or hepatitis ≥ 2 cm in diameter (hepatic aminotransferase value > 2 times normal) or interstitial nephritis or interstitial pneumonia or myocarditis	Fever > 38°C lymph node Abnormal liver function (ALT>100U/L) or other organ damage HHV6 reactivation	Fever > 38°C ≥ 2 enlarged lymph nodes Involvement ≥ 1 viscera
3/3 for DRESS	7/7 is typical DiHS and 5/7 is atypical DiHS	≥3/7为DiHS/DRESS; The RegiSCAR scoring system classifies them as no case, probable, suspected, or definitive

Notes: ALT, alanine aminotransferase, DiHS, drug-induced allergic syndrome, DRESS, drug reaction with eosinophilia and systemic symptoms, HHV, human herpes virus

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The RegiSCAR scoring system classifies cases into four categories: no case, probable case, suspected case, or confirmed case (Table 2).

Table 2 RegiSCAR scoring system for DiHS/DRESS

Grading Criteria	be	No	Unknown
Fever > 38°C	-1
淋巴结肿大（≥2处，＞1cm）	1
Eosinophilia:
0.7 to 1.499 ×109/L (or 10 to 19.9% if leukocytes < 4.0×109/L)	1
≥ 1.5×109/L (or ≥20% if leukocytes < 4.0×109/L)	2
Atypical lymphocytes	1
Cumulative Skin:	1
The rash ranges > 50% BSA	1
Rash Prompt DRESS*	1	-1
Biopsy suggests DRESS	-1
Organ involvement †:
1 viscera	1
≥ 2 organs	2
Resolution≥ 15 days	-1	-1
Other potential causes††	1
The final score < 2 points with no cases, the final score is 2-3 points with probable cases, the final score is 4-5 points with suspicious cases, and the final score is > 5 points with confirmed cases.

Remarks: *≥ 2 symptoms: purpuric lesions (except legs), infiltrates, facial edema, psoriasis desquamation

† liver (ALT>2×UNL twice in a row or D-bibl >2×UNL twice in a row, or AST, T-bili, and ALP >2× UNL once), renal (creatinine > 1.5× at baseline or proteinuria >1 g/day, hematuria, decreased creatinine clearance, or low GFR), lung (evidence of interstitial lung disease (CT, CXR) or abnormal BAL or abnormal biopsy specimen or blood gases), muscle/heart (elevated serum CPK, >). 2× elevated UNL or isoenzyme fractions: elevated CPK-MM (skeletal muscle), CPK-MB (myocardium), or troponin T (>0.01 ug/L) or imaging abnormalities including cardiogram, echocardiography, electrocardiogram, electromyography, CT, or MRI), pancreas (amylase and/or lipase >2×UNL), other organs (spleen, thyroid, central nervous system, gastrointestinal tract), after other causes have been ruled out.

†† ANA, blood culture, HAV/HBV/HCV testing, chlamydia/mycoplasma testing; if no positive and more than 3 ≥ are negative.

ALP, alkaline phosphatase, ALT, alanine aminotransferase, ANA, antinuclear antibody, AST, aspartate aminotransferase, BAL, bronchoalveolar lavage, BSA, body surface area, CNS, central nervous system, CPK, creatine phosphokinase, CPK-MB, creatine phosphokinase - muscle/brain, CPK-MM, creatine phosphokinase - muscular, CT, computed tomography, CXR, chest x-ray, D-bili, direct bilirubin, DRESSDrug reactions with eosinophilia and systemic symptoms, ECG, ECG, EMG, electromyography, GFR, glomerular filtration rate, HAV, hepatitis A virus, HBV, hepatitis B virus, HCV, hepatitis C virus, MRI, magnetic resonance imaging, T-bili, total bilirubin, UNL, upper limit of normal

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PART TWO

Diagnostics and management processes for DiHS/DRESS

1

diagnosis

Consider using the Bocquet, J-SCAR, or RegiSCAR criteria/scoring systems.

Diagnostic biomarkers, such as thymus and activation-regulating chemokine 159 (TARC), are needed for further study.

Skin biopsy, although included in the RegiSCAR scoring system, is not required to meet diagnostic criteria.

2

Identification of drug causative factors

Develop a comprehensive medication use chart to assess drug exposure to prescription drugs, over-the-counter drugs, supplements, recreational drugs, toxins, contrast agents, and vaccines in at least 6 weeks prior to the onset of illness.

03

Initial Assessment*

Hematology: complete blood count with differential, peripheral blood smear for atypical lymphocytes

Liver function tests

Renal function: BUN, creatinine, urine test, proteinuria/creatinine ratio

Additional tests:

Hematology: C-reactive protein, hemophilic lymphohistiocytosis screening†

Renal function: urine eosinophil test (Wright staining)

Cardiac function: ECG, troponin T, echocardiography

Endocrine: thyroid-stimulating hormone (TSH), free thyroxine, fasting blood glucose, and lipase

Rheumatology: Creatine kinase (CK)

Consider human herpesvirus type 6 (HHV6), HHV7,

Quantitative polymerase chain reaction (PCR) detection of human herpesvirus type 4 (EBV) and cytomegalovirus (CMV).

04

Initial treatment

Discontinuation of suspected causative medications and all non-essential medications

Label suspected causative drugs in cases

Supportive care

Consider topical corticosteroids for symptomatic relief††

Consider systemic corticosteroids (usually 1 to 2 mg/kg/day of prednisone or equivalent)

Consider steroid-sparing therapy

05

Ongoing Assessment*

Twice-weekly complete blood count with differential, liver function tests, BUN, creatinine, urine, and CK may be considered when appropriate

In severe or refractory cases, consider PCR testing for HHV6, HHV7, EBV, and CMV

06

Ongoing treatment

When the skin and systemic condition improves, the dose of systemic corticosteroids and/or steroid-sparing agents can be tapered.

Take appropriate measures to monitor, prevent and manage iatrogenic adverse events.

07

Longitudinal assessment of sequelae*

Organ dysfunction: consider complete blood count with differential, liver function tests, BUN, creatinine, urine, and CK for at least one year in the appropriate clinical setting.

Autoimmune disease: at 3 months, 1 year, and 2 years, TSH and free thyroxine are measured.

Psychiatric symptoms: monitor for PTSD, depression, and anxiety symptoms for at least one year.

08

Ancillary tests for risk stratification and identification of drug causative factors

Pharmacogenomics testing: HLA genotyping, CYP genotyping

In vivo test: patch test, delayed intradermal test

In vitro and in vivo assays: lymphocyte conversion rate, ELISpot assays, gene expression profile

Remark:

*Further evaluation of each organ system, including subspecialty consultation, should be performed based on symptoms and test results

† if HLH is suspected, hematological evaluation should include fasting triglycerides, fibrinogen, histopathologic assessment of bone marrow, spleen, and/or lymph nodes, NK cell activity, ferritin, and soluble CD25 (IL-2 receptor).

†† some patients may recover spontaneously after stopping the drug and only need supportive care and topical corticosteroids to relieve symptoms

PART THREE

conclusion

The clinical diagnosis of DiHS/DRESS is complex, and more high-quality studies are needed to optimize risk stratification, assessment, and evidence-based treatment strategies. Specific research directions include investigating diagnosis and prognosis, biomarkers, conducting randomized, double-blind, placebo-controlled clinical trials, and determining the clinical utility of ancillary tests in risk stratification and determination of drug pathogenic factors. Advances in gene expression profiling and multi-omics analysis may help identify new therapeutic targets and open the door to personalized medicine for DiHS/DRESS.

Bibliography:

Wei BM, Fox LP, Kaffenberger BH, Korman AM, Micheletti RG, Mostaghimi A, Noe MH, Rosenbach M, Shinkai K, Kwah JH, Phillips EJ, Bolognia JL, Damsky W, Nelson CA. Drug-induced Hypersensitivity Syndrome / Drug Reaction with Eosinophilia and Systemic Symptoms. Part II. Diagnosis and Management. J Am Acad Dermatol. 2023 Jul 27:S0190-9622(23)02403-9. doi: 10.1016/j.jaad.2023.02.073.

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