Severe Cutaneous Adverse Drug Reactions in Paediatric Age: A Narrative Review

Fever, Rash, and Systemic Symptoms: Understanding the Role of Virus and HLA in Severe Cutaneous Drug Allergy

Severe cutaneous adverse drug reactions of Chinese inpatients: ameta-analysis*

Background: Severe cutaneous adverse reactions (SCARs) are rare but potentially life-threatening conditions leading to significant morbidity and mortality. They include Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), SJS-TEN complex, acute generalized exanthematous pustulosis (AGEP), and Exfoliative Dermatitis and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Objective: To study the clinical and epidemiological aspects of severe cutaneous adverse drug reactions (SCARS). Materials and Methods: A retrospective study at a tertiary care hospital in Western India reviewed SCARs cases from January 2018 to September 2021. Clinical and epidemiological data were extracted using a predesigned pro forma and analyzed. Data from case sheets, clinical charts, and treatment records were reviewed. Causality was assessed using WHO-Uppsala criteria and the Naranjo scale, while SCORTEN criteria evaluated SJS/TEN prognosis. Diagnoses were based on RegiSCAR criteria for DRESS and clinical history for AGEP, Exfoliative dermatitis, SJS, TEN, and SJS/TEN overlap. Investigations included CBC, urine examination, blood sugar, and liver/renal function tests. Key parameters analyzed were patient demographics, culprit drugs, latent period, systemic complications, treatment, and outcomes. Results and Analysis: The study included 13 patients with SCARs, accounting for 0.04% of hospital admissions and 0.13% of dermatology visits. Patients ranged from 6 to 81 years old (mean age 33.1). Diagnoses included seven cases of SJS-TEN complex, 4 of DRESS, 1 of exfoliative dermatitis, and 1 of AGEP. Implicated drugs were antibiotics (30.8%), antiepileptics (23.1%), nonsteroidal anti-inflammatory drugs NSAIDs (15.4%), anti-tuberculosis treatment (ATT) (15.4%), and antiretroviral therapy (ART) (15.4%). Latency between drug intake and symptoms varied between 4 and 33 days. Limitations: There maybe the selection bias or misidentification of certain offending drugs, as re-challenge tests were not performed in any cases due to ethical considerations. Consequently, we can only speculate about the identity of the causative drugs. Conclusion: SCARs impact health significantly, affecting all the ages and often males with SJS/TEN and exfoliative dermatitis. The common triggers are antibiotics, anticonvulsants, NSAIDs, ATT, and ART. Effective management involves early diagnosis, stopping the offending drug, and multidisciplinary care to prevent deterioration and aid recovery.

Introduction: Practically all physicians encounter a diverse range of suspected cutaneous adverse drug reactions (CADRs) in their daily clinical practice. The skin and mucosa are the most often encountered areas for the early presentation of numerous adverse drug reactions. Cutaneous adverse drug reactions are classified as benign or severe. The clinical manifestations of drug eruptions can range from mild maculopapular exanthema to severe cutaneous adverse drug reactions (SCARs).Objective: To determine the varied clinical and morphological presentations of CADRs and to identify the culprit drug and common drugs causing CADRs.Materials and methods: Patients with clinical features suspected of CADRs presenting to the outpatient department (OPD) of dermatology, venereology, and leprosy (DVL) between December 2021 to November 2022 at Great Eastern Medical School and Hospital (GEMS), Srikakulam, Andhra Pradesh, India, were considered for the study. This was a cross-sectional, observational study. The patient’s clinical history was taken in detail. This included chief complaints (symptoms, site of onset, duration, drug history, latency time between drug administration and the appearance of cutaneous lesions), family history, associated diseases, the morphology of lesions, and mucosal examination. Upon drug discontinuation, improvement in cutaneous lesions and systemic features were noted. A complete general examination, systemic examination, dermatological tests, and mucosal examination were performed.Results: A total of 102 patients were involved in the study, of whom 55 were males and 47 were females. The male-to-female ratio was 1.17:1, with a slight male majority. The most common age group was 31 to 40 years for both males and females. Itching was the predominant complaint in 56 patients (54.9%). The mean latency period was shortest in urticaria (2.13+/- 0.99 hours) and longest in lichenoid drug eruption (4.33+/- 3.93 months). Most patients developed symptoms after a week of taking the drug (53.92%). A history of similar complaints was present in 38.23% of patients. Analgesics and antipyretics (39.2%) were the most common culprit drugs followed by antimicrobials (29.4%). Among analgesics and antipyretics, aceclofenac (24.5%) was the commonest culprit drug. Benign CADRs were observed in 89 patients (87.25%), and severe cutaneous adverse reactions (SCARs) were observed in 13 patients (12.74%). The common CADRs presented were drug-induced exanthem (27.4%). Imatinib-induced psoriasis vulgaris and lithium-induced scalp psoriasis were observed in one patient each. Severe cutaneous adverse reactions were observed in 13 patients (12.74%). Anticonvulsants, nonsteroidal anti-inflammatory drugs (NSAIDs), and antimicrobials were the culprit drugs for SCARs. Eosinophilia was present in three patients, deranged liver enzymes was present in nine patients, a deranged renal profile was present in seven patients, and death occurred in one patient with toxic epidermal necrolysis (TEN) of SCARs.Conclusion: Before prescribing any drug to a patient, a detailed drug history and family history of drug reactions need to be obtained. Patients should be advised to avoid over-the-counter usage of medications and self-administration of drugs. If adverse drug reactions occur, it is advised to avoid readministration of the culprit drug. Drug cards must be prepared and given to the patient, mentioning the culprit drug as well as the cross-reacting drugs.

Severe cutaneous adverse drug reactions (SCARs), although rare, are known to be associated with significant morbidity and mortality. SCARs include drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and acute generalized exanthematous pustulosis (AGEP). Studies on SCARs are limited in Saudi Arabia. This study aims to characterize SCARs at a tertiary care center in Saudi Arabia. A cross-sectional study was conducted at King Abdulaziz Medical City, Riyadh, Saudi Arabia. All inpatient and emergency department consultations to dermatology were electronically reviewed during the period from January 2016 to December 2020. All patients who developed an adverse cutaneous drug reaction were enrolled. Detailed analysis was performed only for SCARs. The culprit medication was determined based on the latency period, history of previous intake of the medication, and drug notoriety. There were 3050 hospital consultations to dermatology during the study period. Cutaneous adverse drug reactions constituted 253 (8.3%) cases. A total of 41 patients with SCARs were identified, accounting for 16.2% of all cutaneous drug reactions. Antibiotics and anticonvulsants were the most common causative drug groups accounting for 28 (68.3%) and 9 (22%) cases, respectively. DRESS was the most common SCAR. The latency period was the longest for DRESS and shortest for AGEP. Vancomycin was responsible for approximately a third of DRESS cases. Piperacillin/tazobactam was the most common cause for SJS/TEN and AGEP. The majority of drugs causing AGEP were antibiotics. The mortality rate was the highest in SJS/TEN (5/11 (45.5%)), followed by DRESS (1/23 (4.4%)) and AGEP (1/7 (14.3%)). SCARs are rare in Saudis. DRESS appears to be the most common SCAR in our region. Vancomycin is responsible for most cases of DRESS. SJS/TEN had the highest mortality rate. More studies are required to further characterize SCARs in Saudi Arabia and Arabian Gulf countries. More importantly, thorough studies of HLA associations and lymphocyte transformation tests among Arabs with SCARs are likely to further improve patient care in the Arabian Gulf region.

SUMMARYSevere cutaneous adverse drug reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis and acute generalised exanthematous pustulosis. These eruptions are a type of delayed hypersensitivity reaction and can be life-threatening.The assessment of a severe cutaneous drug reaction requires a detailed clinical history and examination to identify the culprit drug and evaluate the allergy. Allopurinol, antibiotics and anticonvulsants are often implicated.Patch testing and delayed intradermal testing can assist in determining if the reaction was allergic, however there is limited evidence about the sensitivity and specificity of skin testing in severe cutaneous adverse drug reactions. If the testing is non-conclusive or negative, it is recommended to avoid the suspected culprit drug and any structurally similar drug in future.Any decision to reintroduce a drug should be made after considering the harm–benefit ratio. Caution is also needed if considering a possibly cross-reactive drug in a patient with a history of severe cutaneous adverse drug reactions.

Aromatic anticonvulsant-induced severe cutaneous adverse drug reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrosis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS), are fatal immune-mediated adverse drug reactions. CYP2C19, a cytochrome P450 isoform, plays a role in metabolic rate of aromatic anticonvulsant. HLA-B*1502 has also been demonstrated to be associated with carbamazepine-induced SJS-TEN. Forty case patients who were diagnosed with SCARs after initiation of phenobarbital (PB), phenytoin (PHT), or carbamazepine (CBZ) for 1-8wk and forty control patients who received PB, PHT, or CBZ at least 2months with no adverse drug reactions were enrolled in the study. The genotypes of CYP2C19*1, CYP2C19*2, and HLA-B*1502 were analyzed using allele-specific polymerase chain reaction technique. Clinical characteristics of SCARs patients who used different drugs were also analyzed. There was no significant difference in sex, onset of symptoms, laboratory results, treatment, and length of stay among patients with SCARs due to PB, PHT, or CBZ. The patients with CYP2C19*2 variant had a trend to have a likelihood to develop SCARs more than the patients with CYP2C19 wild type (OR=2.5, 95% CI (0.96-67.3) p=0.06). In subgroup analysis, the patients with CYP2C19*2 variant were at four times increased risk of SCARs from phenobarbital more than the patients with CYP2C19 wild type (OR=4.5, 95% CI (1.17-17.37) p<0.03). There was no association between the HLA-B*1502 and aromatic anticonvulsant-induced severe cutaneous adverse reactions (SCARs). CYP2C19*2 variant may play a role in the genetic predisposition of SCARs from phenobarbital.

Context:Cutaneous adverse drug reactions (CADRs) are the most frequent of all manifestations of drug sensitivity that present with varied and diverse morphology and therefore, awareness about them is essential for diagnosis and prevention. Aims: To evaluate the clinical spectrum, morphology, causality, severity and preventability of cutaneous adverse drug reactions in a tertiary care hospital.Setting and Design:Descriptive study for six months in the Dermatology Department of a tertiary care hospital in Kerala.Methods and Materials:All patients of any gender and age who presented with visible skin lesions and were diagnosed or suspected cases of cutaneous adverse drug reactions were included in the study. All the relevant information was recorded using pre-structured proforma and ADR reporting form.Statistical Analysis:Data were analyzed using descriptive statistics. The quantitative variables were expressed as mean ± standard deviation and qualitative variables as frequencies and percentages. Odds ratio (OR) was calculated to assess the risk factors for severe cutaneous adverse drug reactions using SPSS 16.Results:Total 124 cutaneous adverse drug reactions were reported with mean age 39.22 ± 20.47 years, male:female ratio being 1:1.4. Most common cutaneous adverse drug reaction was maculopapular rash. Antibiotics accounted for maximum cases, of which beta-lactams were the most common. About 55.6% cutaneous adverse drug reactions occurred within 24 hours of drug administration. Mean hospital stay duration was 4.89 ± 6.23 days. Most reactions were either mild or moderate. Risk analysis revealed that concomitant use of more than one drug, delayed onset, oral route, more generalized area of involvement and medications prescribed for CNS indications were risk factors for severe cutaneous adverse drug reactions. All reactions were preventable. Majority got fully recovered. No fatality was observed.Conclusion:Identification and reporting of cutaneous adverse drug reactions reduces their future occurrences and encourages rational prescribing. The study emphasizes on having a deeper understanding of risk factors for serious cutaneous adverse drug reactions that may contribute significantly in improving their outcomes.

Background:Various medications are used for the treatment of various diseases. Ironically, adverse drug reactions (ADRs) also accompany the use of these medications and are as old as the medicine itself. These drug reactions can range from mild transient erythema at one end of the spectrum to severe cutaneous ADRs (SCADRS) that include Steven–Johnson syndrome (SJS), toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and drug reaction with eosinophilia and systemic symptoms complex (DRESS).Aim:This study aims to study the clinical and epidemiological aspects of severe cutaneous adverse drug reactions (SCADRS) at a referral center of Jammu region, with special reference to the role of corticosteroids in the management.Materials and Methods:The study was carried out between July 2015 and December 2015, at a tertiary hospital after permission from Ethical Committee of the institution. A total of 44 patients were included in the study which included outpatients as well as inpatients admitted after written informed consent. The Naranjo ADR probability scale was applied to indicate the causality of the drug with the SCADRS.Results:In the study, a total of 44 patients were included in the study. Males outnumbered the females, and maximum patients were in the age group of 21–40 years. SJS was the most common SCARD found followed by DRESS. Antiepileptic class of drug was found to be most commonly implicated. Immediate withdrawal of the culprit drug and administration of systemic steroids reverted the SCARD in maximum patients.Conclusion:Severe cutaneous adverse drug reactions can be associated with serious morbidity as well as mortality. Their knowledge and prompt recognition are essential for clinicians as early recognition, and immediate withdrawal of the culprit drug/drugs with adequate management can be lifesaving.

Severe cutaneous adverse drug reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP) are high-mortality adverse drug reactions. The risk factors and prognosis of drug-induced liver injury (DILI) concomitant with SCAR warrant clarification. We aimed to evaluate the characteristics and outcomes of DILI with SCAR. We analysed the database of a 10-year multi-centre prospective study in Taiwan from 2011 to 2020. A total of 1415 patients with DILI were enrolled, including 81 cases combined with SJS/TEN, 74 with DRESS, 3 with AGEP and 1257 with pure DILI. Approximated 11.2% of patients had SCAR, of which allopurinol was the leading incriminated drug, followed by sulphonamides and carbamazepine. The SJS/TEN group had the highest mortality (34.6%). Jaundice, acute kidney injury and SJS/TEN were independent risk factors of mortality (odds ratio: 29.54, 4.43 and 4.86, respectively, P<.003). Chronic kidney disease with high-dose allopurinol also contributed to high mortality (78.9%) in cases of allopurinol-induced DILI with SCAR. The HLA-B*5801 was associated with a high risk and mortality of allopurinol-induced DILI with SCAR. Likewise, the HLA-B*1502 was closely related to carbamazepine-induced DILI with SCAR. DILI patients combined with SCAR are common and have a high mortality in Taiwan. Allopurinol is the leading incriminated drug. Jaundice, acute kidney injury and SJS/TEN are risk factors of mortality. HLA-B*5801, chronic kidney disease and high drug dosage also contribute to high mortality in allopurinol-induced DILI with SCAR.

PurposeAlthough severe cutaneous adverse drug reactions (SCARs) are rare, they are associated with high morbidity and mortality, and thus early diagnosis and treatment are critical for improving prognoses. However, few studies have reported the characteristics of SCARs in children. Thus, we aimed to evaluate the clinical characteristics, current management and prognosis of pediatric SCARs.MethodsWe analyzed pediatric data in the Korean SCARs registry, which was built retrospectively in 2016 with SCAR cases treated in 34 tertiary referral university hospitals during 2010–2015. Using these cases, we descriptively analyzed detailed data regarding etiology, clinical and laboratory features, treatment strategies, and prognosis.ResultsForty-seven pediatric SCAR cases from 15 tertiary referral hospitals were included. The median patient age was 10 (interquartile range, 3-15.5) years and 68.1% (n = 32) were males. The culprit drug was identified in 95.7% (n = 45) of the patients; antibiotics (44.7%) and antiepileptic drugs (19.1%) were the most common and second most common culprits, respectively. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) cases presented with the largest area of skin involvement without permanent sequelae. Stevens-Johnson syndrome (SJS) cases involved relatively small areas of skin but serious sequelae in two children. Of 4 patients with toxic epidermal necrolysis (TEN), 1 died. Of all patients assessed, 36 (76.6%) received systemic steroids and 21 (44.7%) received intravenous immunoglobulin (IVIG). Thirteen (27.7%) received both systemic steroids and IVIG. Cyclosporine was administered to only 1 patient along with a systemic steroid.ConclusionsIn patients with pediatric SCARs, including those with DRESS, SJS and TEN, clinical presentations were variable. Thus, there was no clear continuous disease spectrum. Although the mortality rate was low (2.1%), clinical suspicion may be the best tool for proactive SCAR management.

To investigate the general characteristics, economic burden, causative drugs and medical errors associated with litigation involving severe cutaneous adverse drug reactions (SCADRs) in China, with the aims of improving rational medication use and reducing the extent of damage from SCADRs. This study analysed 150 lawsuit judgements involving SCADRs from 2005 to 2019, collected from China Judgments Online. In total, 50% of lawsuits stemmed from SCADRs occurring in general hospitals. The average time elapsed from the date of occurrence of the SCADRs to the end of litigation procedures was 1055days. Of the patients involved, 51% were female and more than two thirds (69%) were under 60years old. The most common outcome of SCADRs was death (39%), followed by disabilities (30%). The average responsibility of the medical provider was 48±29%. The average amount of compensation was $43424. Of the cases studied, 51% of SCADRs were Stevens-Johnson syndrome or toxic epidermal necrolysis, which together accounted for 75% of cases with known clinical subtype. The overall average economic burden of SCADRs was $99178, of which indirect costs made up the largest proportion (more than 60%). The most common causative drug groups were antimicrobial drugs (49%), Chinese patent medicine and Chinese herbal medicine (17%), and antipyretic analgesics (16%). Finally, 61% of medical errors were found to stem from violation of duty of care, 20% from violation of informed consent and 18% from violations related to the medical record writing and management system. Severe cutaneous adverse drug reactions not only severely affect patient survival and quality of life, but also impose a heavy economic burden in terms of health care and societal costs. Medical providers should be better educated on strategies to reduce risk to patients and establish mechanisms of risk sharing and management.

Clinical features and prognostic factors of severe cutaneous adverse drug reactions: A single-center retrospective study of 209 cases in China.

Severe cutaneous adverse drug reactions (SCARs), including drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but severe life-threatening adverse drug reactions. Although their incidence is rare, the mortality rates are as high as 10% for DRESS, 1–5% for SJS and 25–50% for TEN. Recent studies have suggested that HLA genes are associated with SCARs during treatment with causative medicines. The HLA gene is located on chromosome 6p21.1–21.3 and consists of HLA class I, II and III. Interestingly, HLA-pharmacogenomic markers influence these mechanisms of immunopathogenesis in culprit drug-induced SCARs. However, due to genetic differences at the population level, drug-induced SCARs are varied; thus, the specific pharmacogenomic markers for ethnicity might differ among populations. For instance, the HLA-A*31:01 allele is associated with carbamazepine-induced SCARs in Europeans and Japanese individuals, while the HLA-B*15:02 allele is associated with carbamazepine-induced SJS-TEN among Thais, Han Chinese, Taiwanese and Southeast Asians populations. Such differences pose a major challenge to preventing SCARs. Therefore, knowledge of the pharmacogenomics, mechanisms of immunopathogenesis and ethnic-specific genetic variation related to drug-induced SCARs is needed.

Cutaneous immune-mediated adverse drug reactions are more prevalent in people with human immunodeficiency virus (PWH). Severe cutaneous adverse drug reactions (SCAR) are a life-threatening subset of cutaneous adverse drug reactions (CADRs) and a significant public health issue in settings endemic for human immunodeficiency virus and tuberculosis. However, limited data are available on CADR requiring hospitalisation in African settings. The aim of this study is to describe the epidemiology, offending drugs and outcomes of CADRs requiring admission to a South African tertiary dermatology service. Retrospective folder review was conducted on all CADRs requiring hospitalisation at Nelson Mandela Academic Hospital in Mthatha, Eastern Cape, South Africa between 30 July 2015 and 15 December 2022. This data was compared to prospective inclusion of CADR admissions between 03 March 2021 and 09 April 2024 as part of the Immune-Mediated Adverse Drug Reactions (IMARI) Registry and Biorepository and AFRISCAR consortium. Where possible, phenotype and drug causality assessment was performed through RegiSCAR, or Naranjo and/or ALDEN scoring respectively. CADR admissions included 122 cases: 89 and 33 in the retrospective and prospective cohorts respectively. The commonest SCAR phenotype was Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) at 59.8% (73/122), although other validated SCAR phenotypes included drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) and generalized fixed bullous drug eruption (GBFDE). Cutaneous presentations included typical and atypical SCAR features against a background Fitzpatrick skin tones of type IV and above. Amongst the retrospective cohort 16.9% (15/89) of phenotypes were unclassifiable due to lack of photographs. The overall median (IQR) age was 38 (25-50) years, 50.8% (62/122) were male and 60.7% (74/122) were PWH [median (IQR) CD4T-cell count of 267 (76-470) cells/mm3]. The commonest offending drugs included cotrimoxazole in 24.6% (30/122); and anti-retroviral therapy (ART) in 13.9% (17/122). No offending drug could be identified in 24.7% (22/89) of the retrospective cohort. The median (IQR) length of hospital stay for validated SCAR was 13 (8-21) days for the retrospective cohort and 19 (13-28) days for the prospective cohort (p = 0.03). The median (IQR) length of hospital stay for non-SCAR was 9 (5-13) days for the retrospective cohort and 11 (9-16) days for the prospective cohort. Typical and atypical presentations of SCAR were represented in this vulnerable South African cohort of predominantly PWH. SJS/TEN was the commonest phenotype, and cotrimoxazole the most frequent offending drug. This data emphasises the need for prospective data collection across a diverse African population for valid SCAR phenotyping and drug causality assessment.