Cutaneous adverse drug reactions.

Cutaneous adverse drug reactions (ADRs) represent a heterogeneous field including various clinical patterns without specific features suggesting drug causality. Maculopapular exanthema and urticaria are the most common types of cutaneous ADR. Serious cutaneous ADRs, which may cause permanent sequelae or have fatal outcome, may represent 2% of all cutaneous ADR and must be quickly identified to guide their management. These serious reactions include bullous manifestations (epidermal necrolysis i.e. Stevens-Johnson syndrome and toxic epidermal necrolysis), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). Some risk factors for developing cutaneous ADRs have been identified, including immunosuppression, autoimmunity or genetic variants. All drugs can cause cutaneous ADRs, the most commonly implicated being antibiotics (especially aminopenicillins and sulfonamides), anticonvulsants, allopurinol, antineoplastic drugs, non-steroidal anti-inflammatory drugs and iodinated contrast media. Pathophysiology is related to immediate or delayed "idiosyncratic" immunologic mechanisms, i.e., usually not related to dose, and pharmacologic/toxic mechanisms, commonly dose-dependent and/or time-dependent. If an immuno-allergic mechanism is suspected, allergological explorations (including epicutaneous patch testing and/or intradermal test) are often possible to clarify drug causality, however these have a variable sensitivity according to the drug and to the ADR type. No in vivo or in vitro test can consistently confirm the drug causality. To determine the origin of a rash, a logical approach based on clinical characteristics, chronologic factors and elimination of differential diagnosis (especially infectious etiologies) is required, completed with a literature search. Reporting to pharmacovigilance system is therefore essential both to analyze drug causality at individual level, and to contribute to knowledge of the drug at population level, especially for serious cutaneous ADRs or in cases involving newly marketed drugs.

Acute generalized exanthematous pustulosis: Analysis of cases managed in a Tunisian tertiary hospital.

Acute generalized exanthematous pustulosis (AGEP) is a severe and life-threatening cutaneous adverse reaction. Drug-induced AGEP is mainly related to antibiotics. More recently, AGEP following spider bites has been increasingly described. Treatment includes withdrawal of the offending drug and supportive care. In Tunisia, data concerning severe cutaneous adverse reactions (SCARs) in general and especially AGEP is lacking. Herein, we conducted a retrospective study to investigate the epidemiological, clinical characteristics and etiologies of AGEP referred to the Dermatology department. Our study included 32 cases of AGEP. AGEP cases occurred in overall 8.9% of all SCARs referred to the department during the same period study. The majority were females (24 women and 7 men). The median age of the patients was 33 years. A history of psoriasis was reported in 16.1% of patients. All patients presented with an extensive erythematous rash with pinhead pustules. Neutrophil hyperleukocytosis (greater than 7000/mm3) was noted in 17 patients (63% of cases). It was associated with hypereosinophilia exceeding 500 elements/mm3 in 8 cases (29.6%). Drug-induced AGEP was reported in 53% of cases. Antibiotics were implicated in the majority of cases. Delay in onset ranged from 15hours to 7 days, with an average of 2.8 days. A non-drug-induced etiology was considered if the pharmacological investigation was negative, or if a clear non-drug trigger was found. It was retained in ten cases (48.4% of all observations). Spider bites were revealed in 8 cases. AGEP represents a severe, usually drug-related skin reaction. It is classified as a type IVd reaction mediating T cell-related sterile neutrophilic inflammatory response. It typically occurs within 24-48 h of ingestion of the offending drug. Antibiotics are the most common drug family to cause AGEP. Spider bites were involved in 25.8% of cases in our study, as important as antibiotic-induced AGEP. Analysis of the particularities of AGEP according to etiology, whether drug-induced or not, revealed the presence of an initial escarotic lesion (P=0.01) and the finding of blood hypereosinophilia (P=0.014) in the non-drug AGEP group were the distinguishing features. Blood hyperesoniophilia, more frequent in the non-drug AGEP group, suggests a pathophysiology probably different from that of the drug AGEP group. Clinicians should be aware of both etiologies. Our study focuses on the importance of AGEP associated with spider bite as a potential triggering factor in Tunisia.

A retrospective, 5-year, clinicoepidemiological study of severe cutaneous adverse reactions (SCARs).

BACKGROUND: A severe cutaneous adverse reaction (SCAR) is a rare, clinically heterogeneous, life-threatening phenomenon that results in serious skin damage, systemic complications, and significant morbidity or mortality comprising of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or SJS-TEN overlap, acute generalized exanthematous pustulosis (AGEP), exfoliative dermatitis, and drug rash with eosinophilia and systemic symptoms (DRESS). MATERIALS AND METHODS: A retrospective study was conducted on all cases of SCARs admitted in a tertiary care referral hospital from January 2015 to December 2019. Clinical and epidemiological details were retrieved from the records of patients as per predesigned proforma. The data collected were analyzed and statistically evaluated. RESULTS AND ANALYSIS: A total of 142 patients (67 males, 75 females) with SCARs, constituting 0.08% of total hospital admission and 0.027% of total dermatology outpatient department (OPD), were studied. Age group ranged from 2 to 61 years, with the mean age of 33.6 years (SD = 17.43). Most patients belonged to SJS-TEN complex (75 cases; SJS 48, SJS-TEN 18, TEN nine) followed by exfoliative dermatitis (27 cases/19%), AGEP (26 cases/18.3%), and DRESS (14 cases/9.8%). Anticonvulsants were most commonly implicated (22%) followed by antibiotics (20%), nonsteroidal anti-inflammatory drugs (NSAIDs) (17%), and ayurvedic (7%). There was only single mortality in a DRESS patient. CONCLUSION: SCAR has considerable disease burden with marginal female preponderance in SJS/TEN and exfoliative dermatitis and can involve even the pediatric population. Anticonvulsants followed by antibiotics, NSAIDs, and ayurvedic medicines are common groups known to cause SCARs. To date, there are no definitive recommendations regarding their optimal treatment regimen, hence early diagnosis, prompt withdrawal of culprit drug, high standard of nursing care, and interdisciplinary consultations are vital steps to avoid disease progression and restore health.

Acute generalized exanthematous pustulosis in children and adolescents in Singapore: A ten-year retrospective review.

BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is a rare, severe, cutaneous adverse reaction. Although most commonly caused by drugs, it can also be triggered by infections, especially in children. METHODS: This is a retrospective study involving children and adolescents aged 16 years or younger, diagnosed with AGEP between January 2010 and March 2020 in our tertiary pediatric hospital. Information pertaining to the patient's demographics, clinical presentation and progress, biochemical, microbiological, and histopathological investigations, treatment, and outcomes was analyzed. RESULTS: Eight patients were diagnosed with AGEP with mean age 8.2 years (range: 1.7-16.0 years). None of the patients had a personal or family history of psoriasis. Almost all patients had fever (n = 7, 87.5%). Although all 8 patients had intercurrent illness, 5 cases were attributed to infection, while the other 3 were likely precipitated by drugs. Abnormal hematological and biochemical parameters included a raised absolute neutrophil count (mean: 11.5 × 109 /L, range: 5.0-30.9 × 109 /L), C-reactive protein (mean: 52.5 mg/L, range: 5.0-143.7 mg/L), and erythrocyte sedimentation rate (mean: 38.6 mm/h, range: 6-64 mm/h). All patients developed post-pustular desquamation and subsequently recovered. The mean duration from onset to cessation of acute pustulation was 5.6 days (range: 3.0-10.0 days). One patient developed a recurrent episode of AGEP. CONCLUSION: AGEP is rare and may be more commonly caused by infections in children. The condition is self-limiting with overall good outcomes in this age-group. In cases with concomitant infection and drug use, formal allergy testing should be arranged after resolution of the infection to confirm the underlying etiology.

Aetiopathogenesis of severe cutaneous adverse reactions (SCARs) in children: A 9-year experience in a tertiary care paediatric hospital setting.

BACKGROUND: Severe cutaneous adverse reactions (SCARs) are delayed-type hypersensitivity reactions to drugs including as follows: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP). Incidence, triggers and management of SCARs have not been investigated in large-scale epidemiological studies on children. OBJECTIVE: The aim of our study was to collect epidemiological, clinical and aetiological data from children with SCARs referred to our tertiary care paediatric hospital of Florence. METHODS: From 2010 to 2018 charts of children with diagnosis of SCAR were reviewed, and data collected during the acute phase and/or the subsequent allergy evaluation. Patients underwent patch tests, intradermal tests and lymphocyte transformation tests. All children were investigated for infectious diseases. RESULTS: Incidence of SCARs in hospitalized children was 0.32% over a 9-year period. Fifty-four children were enrolled (31 M; 23 F; median age 6.5 years): 17 cases of DRESS, 30 SJS, 3 TEN, 2 AGEP, 1 linear immunoglobulin A bullous disease (LABD) and 1 pemphigus. Twenty-eight out of 54 patients underwent drug allergy investigations, and 50% of them resulted positive. Combining clinical history and results of allergy work-up, 74% SCARs seem to be caused by drugs, 18.6% by both drugs and infections, 3.7% by infections, and 3.7% remained idiopathic. No deaths occurred. CONCLUSIONS: In this study, SCARs incidence is in line with literature data. Drugs were most commonly the leading cause. Management of SCARs requires cooperation among professional figures for an early diagnosis and a prompt treatment. Mortality rate seems to be lower in children.

Acute generalized exanthematous pustulosis and psoriasis: what can be learned from comorbidities.

BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is a rare pustular severe cutaneous adverse reaction. Differentiating between AGEP and pustular psoriasis may represent a diagnostic challenge. We sought to evaluate the prevalence of comorbidities in a series of patients with AGEP compared to a series of patients with psoriasis vulgaris and to a series of patients with drug-related psoriasis. METHODS: Medical records of 14 patients with AGEP, 33 patients with psoriasis vulgaris, and 18 patients with drug-related psoriasis were reviewed. The presence of comorbidities was recorded, and a comparative analysis was performed. RESULTS: A personal history of psoriasis was present in 4 (28%) patients with AGEP compared to 12 (66%) patients with drug-related psoriasis (Pv=0.03). The prevalence of psoriasis-related morbidities was significantly lower in the AGEP group compared to the psoriasis group and to the drug-related psoriasis group (Pv<0.01, 0.05, respectively). Each of the psoriasis-related morbidities had significantly lower prevalence in the AGEP group compared to the psoriasis group and to the drug-related psoriasis group (Pv<0.01). CONCLUSIONS: In conclusion, differences between AGEP, psoriasis vulgaris, and drug-related psoriasis regarding the prevalence of psoriasis-related morbidities may assist differentiation in borderline cases.

Cefixime-associated acute generalized exanthematous pustulosis: Rare cases in India.

BACKGROUND: Cefixime is a widely used third-generation cephalosporin schedule H1 drug, which is prescribed for the treatment of otitis media, respiratory tract infections, and uncomplicated urinary tract infections and is effective against infections caused by Enterobacteriaceae and Haemophilus influenzae species in India. The National Coordination Centre (NCC)-Pharmacovigilance Programme of India (PvPI), Indian Pharmacopoeia Commission (IPC), has received rare individual case safety reports (ICSRs) for acute generalized exanthematous pustulosis (AGEP) associated with the use of cefixime. MATERIALS AND METHODS: IPC, NCC-PvPI also acts as a national collaborating center for pharmacovigilance activities under the aegis of Ministry of Health and Family Welfare, Government of India; moreover, it is a member country in global pharmacovigilance system, World Health Organization-Uppsala Monitoring Centre, Sweden. There are more than 250 government/corporate medical colleges and hospitals acting as regional adverse drug reaction monitoring centers, actively functioning under PvPI. Furthermore, various stakeholders including consumers and pharmaceutical industries also play a significant contribution. NCC-PvPI receives spontaneous ICSRs from various stakeholders. RESULTS: NCC-PvPI, IPC has received a total of four spontaneous ICSRs for cefixime-induced AGEP. After clinical evaluation of reported ICSRs, a strong causal relationship was established between AGEP and cefixime and was supported by published literature and histopathological examination of skin. Based on the statistics with positive information component (IC025 Value: 0.17) and proportionality relative risk (PRR:3.4), PvPI considered cefixime-associated AGEP may be a potential signal. CONCLUSION: Hence, initially, AEGP is considered by PvPI as drug safety alert in July 2016. Therefore, to enhance the safety of population in rational usage of medication, as a result, there is a need for physicians and health-care professionals to sensitize about serious adverse reaction while prescribing the cefixime as signal in India.

Severe cutaneous adverse reactions to drugs.

During the past decade, major advances have been made in the accurate diagnosis of severe cutaneous adverse reactions (SCARs) to drugs, management of their manifestations, and identification of their pathogenetic mechanisms and at-risk populations. Early recognition and diagnosis of SCARs are key in the identification of culprit drugs. SCARS are potentially life threatening, and associated with various clinical patterns and morbidity during the acute stage of Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reactions with eosinophilia and systemic symptoms, and acute generalised exanthematous pustulosis. Early drug withdrawal is mandatory in all SCARs. Physicians' knowledge is essential to the improvement of diagnosis and management, and in the limitation and prevention of long-term sequelae. This Seminar provides the tools to help physicians in their clinical approach and investigations of SCARs.

Severe Cutaneous Adverse Drug Reactions in Pediatric Patients: A Multicenter Study.

BACKGROUND: The severe cutaneous adverse drug reactions (SCARs) are rare but could be life-threatening. These include drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis. OBJECTIVE: The purpose of this study was the evaluation of the clinical characteristics of patients with the diagnosis of SCARs. METHODS: Patients who were diagnosed with SCARs between January 2011 and May 2016 by pediatric allergy clinics in the provinces of Ankara, Trabzon, Izmir, Adana, and Bolu were included in this multicenter study. Clinical and laboratory findings, the time between suspected drug intake and development of clinical findings, treatments they have received, and length of recovery time were recorded. RESULTS: Fifty-eight patients with SCARs were included in this study. The median age of the patients was 8.2 years (interquartile range, 5.25-13 years) and 50% (n = 29) were males. Diagnosis was Stevens-Johnson syndrome/TEN in 60.4% (n = 35), DRESS in 27.6% (n = 16), and acute generalized exanthematous pustulosis in 12% (n = 7) of the patients. In 93.1% of the patients, drugs were the cause of the reactions. Antibiotics ranked first among the drugs (51.7%) and antiepileptic drugs were the second (31%) most common. A patient who was diagnosed with TEN developed lagophthalmos and a patient who was diagnosed with DRESS developed secondary diabetes mellitus. Only 1 patient with the diagnosis of TEN died. CONCLUSIONS: SCARs in children are not common but potentially serious. Early diagnosis and appropriate treatment of SCARs will reduce the incidence of morbidity and mortality.

Acute generalised exanthematous pustulosis (AGEP)-a potential pitfall for the acute physician.

Acute generalised exanthematous pustulosis is a rare drug-induced dermatosis with an incidence of 1-5 cases per million cases per year, characterised by the appearance of hundreds of sterile pustules over erythematous and oedematous skin. Fever and neutrophilia are usually present. It has a rapid course and usually resolves following discontinuation of the precipitating drug or as a result of topical corticosteroid treatment. A patient with AGEP, who presented with generalized pustulosis lesions after the use of Flucloxacillin for cellulitis is described, along with the management and differential diagnosis of this condition.

[Acute localized exanthematous pustulosis on the face: 6 cases in Tunisia]. / Pustulose exanthématique aiguë localisée de la face : six cas tunisiens.

BACKGROUND: Acute localized exanthematous pustulosis (ALEP) is a rare and localized variant of acute generalized exanthematous pustulosis (AGEP). Only 15 cases of ALEP have been reported to date in the literature, with all cases following drug administration. We report 6 paediatric cases of ALEP occurring in springtime, with no associated drug administration in any case. PATIENTS AND METHODS: Over the last three years (2011, 2012 and 2013), we observed 6 cases of ALEP in 6 Tunisian children aged between 9 and 14 years. All cases were observed during the spring months. Diagnosis of ALEP was based in all cases on the EuroSCAR criteria and on the definition of ALEP proposed by Prange et al. A drug-related aetiology was ruled out in all cases, with exposure to a specific planned plant (Thapsia garganica) being retained as an aetiological factor in one case. DISCUSSION: Drug administration is the most frequent though not the sole cause of ALEP. The seasonal nature of this dermatosis may suggest other causes, mainly viral infection, plant contact or airborne allergens.

[Surveillance of severe cutaneous drug reactions: experience REACT-Lombardia]. / Sorveglianza di reazioni gravi cutanee da farmaco: l'esperienza REACT-Lombardia.

Adverse drug reactions affecting the skin have particular relevance as they may cause significant mortality and a possible modification of the benefit/risk profile of the concerned drug. The following entities are of special importance: Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP) and drug rash with eosinophilia and systemic symptoms (DRESS). On the above mentioned reactions we focused our surveillance programme in the Lombardy region, the REACT-Lombardia project. The REACT registry involved 22 hospital-based dermatological centres, collecting, from April 2009 up to March 2014, a total of 72 cases of SJS-TEN, 17 cases of AGEP and 9 cases of DRESS. Allopurinol was the drug associated with the largest number of cases of SJS/TEN (21 cases) followed by paracetamol (8 cases), levofloxacine (6 cases) and carbamazepine (4 cases). The risk for specific drug exposures was estimated by employing drug utilization data expressed as Defined Daily Doses (DDD). Mortality rate from SJS-TEN was 21%. Together with the registry, a "hub and spoke" clinical network for the management of severe cutaneous reactions was established with the Burn Unit of Niguarda Ca' Granda Hospital as the reference center for the most critical patients.

Epidemiology of severe drug hypersensitivity.

Epidemiological studies of severe drug hypersensitivities are important to understanding the morbidity and mortality of this heterogeneous group of disorders. These insights also allow greater identification of at-risk patient groups. However, epidemiological studies of drug hypersensitivity reactions are challenging due to the variable diagnostic criteria applied and incomplete data sets studied. We review the epidemiology of severe drug hypersensitivity reactions with a particular focus on severe cutaneous adverse reactions (SCARs). SCAR diseases include: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash eosinophilia and systemic symptoms, serum-sickness-like reaction and acute generalized exanthematous pustulosis.

Epidemiology of cutaneous adverse drug reactions.

Epidemiologic investigations of cutaneous adverse drug reactions (cADR) are important to evaluate their impact in dermatology and health care in general as well as their burden for affected patients. Few epidemiologic studies have been performed on frequent non-life-threatening cADR including reactions of both delayed and immediate hypersensitivity, such as maculopapular exanthema, fixed drug eruption and urticaria. Concerning rare but life-threatening severe cutaneous adverse reactions, e.g. toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis and drug reaction with eosinophilia and systemic symptoms, several epidemiologic studies have been performed to date, some of which are still ongoing. Such studies enabled the calculation of reliable incidence rates and demographic data, but also allowed to perform risk estimation for drugs. The spectrum of drugs causing cADR differs substantially when separating the various clinical conditions. Whereas antibiotics are by far the most frequent inducers of milder cADR like maculopapular exanthema, they have a much lower risk to induce SJS/TEN, for which high-risk drugs are anti-infective sulfonamides, allopurinol, certain anti-epileptic drugs, nevirapine and nonsteroidal anti-inflammatory drugs (NSAIDS) of the oxicam type. In contrast, acute generalized exanthematous pustulosis is predominantly caused by the antibiotics pristinamycin and aminopenicillins, followed by quinolones, (hydroxy-)chloroquine and sulfonamides. Drug reaction with eosinophilia and systemic symptoms can be induced by a number of drugs known to cause SJS/TEN, such as certain antiepileptics and allopurinol, but also other medications (e.g. minocyclin).