Drug-induced hypersensitivity syndrome (DIHS) or drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug reaction characterized by a range of clinical manifestations. These range from mild cases resolving upon cessation of the causative drug to severe cases involving complex disease progression and potential fatality. A hallmark of DIHS/DRESS is the sequential reactivation of herpesviruses, particularly human herpesvirus 6 (HHV-6), during the disease course, contributing to recurrent symptoms. Viral reactivation can lead to critical complications, including infectious DIHS/DRESS-associated complications (iDACs) and autoimmune sequelae (aDACs). Managing DIHS/DRESS remains challenging due to its complexity, requiring precise prediction and tailored treatment strategies. Recent studies suggest that early-stage classification using the DIHS/DRESS Severity (DDS) score may help identify refractory cases, including DACs. Furthermore, early intervention with anti-cytomegalovirus (anti-CMV) therapy can mitigate iDACs caused by CMV reactivation, preventing progression to severe CMV-related diseases. Long-term follow-up is crucial, as aDACs can manifest even 3 years postonset. Serial monitoring is recommended, particularly in patients treated with intravenous immunoglobulin or corticosteroid pulse therapy, which are recognized risk factors for aDAC development. This review highlights DIHS/DRESS management strategies, focusing on its clinical features, the role of viral reactivation, and therapeutic interventions.

Some skin conditions may require intensive care treatment. Early diagnosis can be challenging but is crucial to adequate patient management and decision making, since appropriate treatment influences prognosis. The following skin conditions will be reviewed: severe cutaneous drug reactions (drug reaction with eosinophilia and systemic symptoms [DRESS], Stevens-Johnson syndrome/toxic epidermal necrolysis [SJS/TEN]), acute cutaneous graft versus host disease (aGvHD) following allogeneic stem cell transplantation, infectious diseases (staphylococcal scalded skin syndrome [SSSS], toxic shock-syndrome [TSS], necrotizing fasciitis) and vascular disease (acute infectious purpura fulminans). We focus on the course of the diseases, describing clinical presentation and differential diagnosis as well as diagnostic and therapeutic strategies.

Some skin conditions may require intensive care treatment. Early diagnosis can be challenging but is crucial to adequate patient management and decision making, since appropriate treatment influences prognosis. The following skin conditions will be reviewed: severe cutaneous drug reactions (drug reaction with eosinophilia and systemic symptoms [DRESS], Stevens-Johnson syndrome/toxic epidermal necrolysis [SJS/TEN]), acute cutaneous graft versus host disease (aGvHD) following allogeneic stem cell transplantation, infectious diseases (staphylococcal scalded skin syndrome [SSSS], toxic shock-syndrome [TSS], necrotizing fasciitis) and vascular disease (acute infectious purpura fulminans). We focus on the course of the diseases, describing clinical presentation and differential diagnosis as well as diagnostic and therapeutic strategies.

Mucormycosis is a fungal infection typically affecting immunocompromised patients. Here, we report a severe case of invasive cutaneous and peritoneal mucormycosis caused by Rhizopus microsporus, successfully treated with a combination of antifungal therapy, PD-1 inhibitor, and interferon-gamma. We highlight the importance of personalized immunotherapy in refractory cases of invasive mucormycosis.

Besides reactions of the IgE-mediated immediate type, medicamentous therapies can cause a variety of different mucocutaneous adverse events. Exanthematous manifestations require a fast and certain diagnosis due to their extent, sometimes rapid progression, and mucous membrane or organ involvement.

The spectrum of non-IgE-mediated exanthematic drug reactions is covered.

The most relevant reactions are portrayed clinically and histopathologically.

Displayed are classical maculo-papular drug eruption, lichenoid drug reaction, acute generalized exanthematic pustulosis (AGEP), severe potentially life-threatening drug reactions such as Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) as well as generalized bullous fixed drug eruption (GBFDE), drug reaction with eosinophilia and systemic symptoms (DRESS), and some others.

Cutaneous drug-related side effects cover a broad spectrum. Important for the correct treatment is a reliable diagnosis. In the case of severe, life-threatening drug reactions, however, permanent discontinuation of the drug is essential.

Although rare, life-threatening dermatoses encompass various inflammatory, infectious, vasculitic/vasculopathy, paraneoplastic, and neoplastic skin diseases. Complications include skin barrier dysfunction, secondary infection, and internal organ involvement. Skin signs may serve as a critical window into systemic disease. Life-threatening dermatoses are typically associated with "red flag" clinical signs or symptoms, which inform the dermatologist about the severity of the disease and mandate a thorough history, review of systems, physical examination, and laboratory evaluation. This contribution highlights severe cutaneous adverse reactions, infections, vasculitides and vasculopathies, and paraneoplastic eruptions. Dermatologists should recognize life-threatening dermatoses and have a framework for rapid diagnosis and management.

Acute generalized exanthematous pustulosis (AGEP) is a rare, painful, and pruritic drug-induced rash characterized by sterile pustules on an erythematous base, followed by desquamation. While commonly induced by antibiotics, cases associated with antineoplastic drugs have become more frequent in recent years. Here, we report a 76-year-old Chinese male with lung large-cell neuroendocrine carcinoma who developed erythema and pustules on his left lower leg, which spread to the trunk and limbs after the fourth cycle of immunotherapy and chemotherapy. Despite initial treatments with antihistamines, antibiotics, and systemic glucocorticoids, the patient's condition worsened with the development of extensive pustules and fever. Histopathological and laboratory findings confirmed AGEP, with elevated IL-17 levels. Following the discontinuation of immunotherapy and administration of the anti-IL-17 monoclonal antibody ixekizumab, the patient showed rapid improvement within 5 days, marked by a significant reduction in pustules and normalization of body temperature. This case underscores the role of IL-17 in AGEP's pathogenesis and suggests that IL-17 inhibitors such as ixekizumab may provide an effective treatment option for severe, refractory cases.

Morbilliform eruptions, which are a clinical reaction pattern characterized by erythematous macules and papules coalescing into patches that cover most of the skin surface, are one of the most common cutaneous findings in the inpatient setting. In the hospital setting, most causes are benign and due to low-risk drug exanthems; however, morbilliform eruptions may also be a sign of high-risk diseases, including Stevens-Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome, acute generalized exanthematous pustulosis, and graft-versus-host disease. Proper identification of the etiology and risk stratification of a morbilliform eruption is critical to ensure proper management and optimize patient outcomes. In this review, we discuss the key features that differentiate high-risk from low-risk morbilliform eruptions, as well as specific characteristics that differentiate the different high-risk eruptions. Additionally, we offer a clinical algorithm that may be applied in the management of a patient who presents with a morbilliform rash.

Eosinophilia has not been highlighted in clozapine-induced adverse inflammatory events, as it is often asymptomatic and self-limiting, while drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome occurs rarely. This study aimed to reveal the temporal relationships between eosinophilia and other inflammatory events during clozapine initiation.

The temporal relationships between eosinophilia and other inflammatory events were evaluated among 241 patients with schizophrenia treated with clozapine for the first time at 7 hospitals. Risk factors for eosinophilia were investigated among preceding inflammatory events and other clinical characteristics. Furthermore, patients with eosinophilia were stratified by the severity of adverse inflammatory events and their clinical characteristics were compared.

Of the 54 patients who experienced inflammatory adverse events, 27 (50%) developed eosinophilia. In all but 1 patient, clinical symptoms of inflammatory adverse events preceded eosinophilia. In contrast, of the 187 patients without inflammatory events, 21 (11%) developed eosinophilia. Multivariate analysis revealed that more severe preceding inflammatory adverse events were associated with a greater risk of eosinophilia. The median time to the first detection of eosinophilia and peak eosinophil count occurred significantly earlier in patients with severe adverse events than in asymptomatic patients.

In most cases, eosinophilia developed after the onset of inflammatory symptoms. Preceding inflammation was associated with the development of clozapine-induced eosinophilia. Eosinophilia may not be suitable as an early detection marker of severe inflammatory adverse effects. These findings enhanced our understanding of the involvement of eosinophilia in clozapine-induced inflammatory events.

Drug rash with eosinophilia and systemic symptoms (DRESS) is a life-threatening severe cutaneous adverse reaction.

This study aims to study fatal DRESS cases using FAERS database and systematic review.

Data of the FDA Adverse Event Reporting System (FAERS) database were extracted and manipulated. Articles from Pubmed, Embase and CINAHL databases were screened.

0.13% of the adverse events submitted to FAERS was identified as DRESS and the percentage of fatal cases was up to 6.62%. The top five drugs calculated to induce DRESS with the highest number of reported cases were allopurinol, lamotrigine, vancomycin, amoxicillin and carbamazepine. The top five drugs statistically related to fatal outcome with the highest number of reported cases were allopurinol, vancomycin, trimethoprim, sulfamethoxazole and lamotrigine. Skin manifestations remained the main reason for admission and the average time from dose to rash onset was 27.19 days. The most commonly cited culprit medication type were antibiotics (50.00%), anti-gout agents (15.38%) and anti-epileptic drug (11.54%).

We discussed fatal cases of DRESS through FAERS system and case reports, hoping to raise awareness when using relevant drugs.

A 21-year-old female patient presented with fever, pharyngitis, lymphadenopathy and generalized exanthema that had started 2 weeks prior. Allergies were not known, the family and travel history were negative. Due to depression, Duloxetine had been taken for 1.5 years, and due to bipolar disorder, a treatment with Lamotrigine was started four weeks prior but was stopped because of increased transaminase levels. Laboratory findings on admission showed eosinophilia (1.327 /nl), lymphocytosis and acute hepatitis (GOT 428 U/l, GPT 438 U/l) with deranged coagulation. Inflammatory parameters were increased. Ultrasound revealed hepatosplenomegaly with ascites. Acute viral or parasitic infection was excluded serologically. A skin biopsy showed a perivascular inflammatory infiltrate, compatible with a drug reaction. An inflammatory infiltrate was found in the liver biopsy, consistent with drug-induced hepatitis. Cough, dyspnea and pleural effusion occurred. In summary of the findings and with the help of the RegiSCAR-Score, the diagnosis of drug reaction with eosinophilia and systemic symptoms (DRESS) could be made. Under high-dose prednisolone therapy, a gradual decrease of transaminases and reconstitution of liver synthesis could be observed.In patients with eosinophilia, lymphadenopathy, acute hepatitis and generalized exanthema, DRESS is a rare but-due to its potentially life-threatening consequences-important differential diagnosis. The most important measure is to stop the suspected inducing medication immediately. Severe cases should be treated with high-dose systemic corticosteroids.

Cutaneous adverse drug reactions (CADRs) remain a challenge for non-dermatologists. Medical-related applications to assist in learning about and managing patients with CADRs are scarce. We aimed to evaluate the efficacy of a web application for non-dermatologists in managing CADRs by comparing the knowledge scores of users and non-users.

A multicenter randomized controlled trial was conducted between January 2023 and May 2023. Clinician participants were randomized (1:1) into the application and control groups using a simple randomization method. Knowledge scores between the groups were compared to evaluate the efficacy of the web application, and participants' perspectives on the application were also collected.

A total of 44 clinician participants were included in the final analysis. The median age was 33.0 years (95% confidence interval (CI) 27.5-35.0) and predominantly female (56.8%). The score in the application group (median, 27.0; 95% CI, 25.0-28.0) was significantly higher than that in the control group (median, 14.0; 95% CI 13.0-17.0) (p < 0.001). There were no differences in scores between the sex groups (p = 0.695), between general practitioners (GPs) and non-GPs (p = 0.93), or among groups with different frequencies of evaluation of patients with CADRs (p = 0.266). In addition, the participants in the application group rated a high level of overall satisfaction.

The web application for CADRs is an effective and convenient tool for assisting non-dermatologist physicians in learning and providing initial management with a high level of satisfaction. However, prospective long-term randomized controlled studies are required to confirm the efficacy of this tool.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare severe cutaneous adverse drug reaction associated with multi-organ involvement and long-term sequelae. Human herpesviridae species reactivation has been observed, however, risk factors for reactivation and its impact on the clinical course and outcomes is unclear. We aimed to explore the impact of viral reactivation on DRESS on clinical outcomes and to identify potential risk factors for reactivation. This was a retrospective cohort study in an academic medical centre. Cases were validated in-hospital cases of DRESS from 2009 to 2017. Overall, 100 patients fulfilled the probable or definite DRESS case criteria. Ninety-three patients had at least one viral marker tested. Viral reactivation was positive in 39 patients (42%). HHV6, EBV and CMV reactivation occurred in 24 out of 85 cases (28%), 15 out of 87 (17%) cases, and 18 out of 89 (20%) cases respectively. Viral reactivation cases were associated with higher 1-year mortality, dialysis initiation, recurrent flares of disease, and longer hospital stay (all p < 0.05). Risk of inpatient mortality (OR, 5.8; 95% CI, 1.7-20.7; p < 0.01) and 1-year mortality (OR, 10.0, 95% CI, 2.9-34.9; p < 0.01) increased with multiple viral reactivations. Human herpesviridae viral reactivation in DRESS, particularly multiple viral reactivations, is associated with poorer clinical outcomes. Although this study is unable to prove a causal or pathogenic association, routine evaluation of herpesvirus in DRESS should be performed. Further work is needed to identify patients at risk of reactivation and the potential impact of treatment.

Diagnosing drug reaction with eosinophilia and systemic symptoms (DRESS) can be challenging.

We sought to identify clinical and laboratory features outside of the Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria that distinguish patients with probable DRESS (RegiSCAR ≥ 4) from those with drug rash and eosinophilia (DRE).

Using international coding classifications of drug-induced fever, generalized skin eruption due to medications, and eosinophilia, a retrospective audit from 2008 to 2023 of hospitalized patients was performed.

Forty-four cases of DRESS were compared to 80 cases of DRE. In addition to the RegiSCAR distinguishing factors for DRESS were longer drug latency before symptom onset (median 21 vs 5 days, P < .001) and higher alanine transaminase levels (increase by a factor of 2.49 [95% confidence interval, 1.56, 4.00; P = .009]). Follow-up (mean 5.67 years) revealed a low rate of statewide drug alert reporting (29.6%) and drug allergy testing in DRESS (20.5%). Inadvertent reexposure to a culprit or structurally related drug resulted in recurrent DRESS in 3 patients (7.5%), and tolerance of structurally related drugs occurred in 8 patients (17.5%).

In this large study evaluating DRE patients whose disease does not meet the RegiSCAR criteria for DRESS, we found that additional factors outside the RegiSCAR criteria may help clinicians differentiate DRESS, which is critical for optimal and timely patient management. Our study also highlights the need for development of local protocols to ensure appropriate allergy labeling and testing are performed to prevent recurrent DRESS.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially life-threatening adverse drug reaction characterized by extensive skin rash in association with hematological abnormalities, including eosinophilia and atypical lymphocytosis, lymphadenopathy, fever, and extensive visceral organ involvement. Here, we presented a rare case of vancomycin-induced DRESS syndrome in a male who was treated with IV vancomycin for a brain abscess.

We present a case of lamotrigine-triggered DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome with acute kidney injury stage 3. A 17-year-old girl with known epilepsy treated with lamotrigine presented with acute kidney injury as well as skin eruption, fever, and apathy. Extended diagnostics, considering infectious and autoimmune diseases, remained unremarkable. Lamotrigine blood levels were within the target range. Kidney biopsy showed acute interstitial nephritis with tubular necrosis. Methylprednisolone pulse therapy led to an improvement in kidney function; skin eruption and neurological symptoms resolved. During the hospital stay, the girl admitted to inconsistent and variable intake of lamotrigine, occasionally resulting in notable overdosing. This report demonstrates that acute kidney injury in lamotrigine-induced DRESS syndrome is an acute interstitial nephritis with tubular necrosis, an aspect that has not been deeply characterized so far. Additionally, we aim to elevate awareness towards non-adherence as cause of disease, especially among the adolescent population.

In high HIV prevalence settings, first-line antituberculosis drug (FLTD)-associated drug reaction with eosinophilia and systemic symptoms (DRESS) poses therapeutic challenges. A sequential and additive drug challenge (SADC) of FLTDs best identifies offending drug(s), avoids unnecessary exclusions, and optimizes reinitiation of nonoffending drugs. However, SADC-associated reaction complexities limit its utility.

We aimed to describe the characteristics of patients with FLTD-associated DRESS, their treatment-limiting SADC reactions, and related outcomes.

Patients hospitalized with FLTD-associated DRESS from 2013 to 2023 in a South African tertiary hospital and enrolled (retrospectively or prospectively) in an existing registry were eligible.

SADC was undertaken in 41 patients. Overall, 47 classifiable reactions occurred. 34/47 (72%) reactions in 29/41 (71%) patients were treatment-limiting and 12 of 41(29%) patients reinitiated FLTDs uneventfully. Fifteen single and 8 multiple drug reactors were identified. Rifampicin in 13 of 23(57%) reactors was the most common individual offender. Ethambutol was most frequently involved in multiple drug reactors. The median (interquartile range) time to a detectable reaction was 24(12-120) hours, 6 of 34(18%) being immediate (<6 hours). Itch (65%), eosinophilia (56%), fever (41%), atypical lymphocytosis (41%), rash (38%), transaminitis (32%), and facial edema (18%) singly or in combination were the most common features. Three reactions, 1 epidermal necrolysis and 2 liver derangements, were Common Terminology Criteria for Adverse Events grade 4 (life-threatening) events. No predictors of multiple drug reactivity were identified, but multiple reactors were hospitalized significantly longer, 125(100-134) days versus 60(45-80) days.

SADC optimizes FLTD reinitiation. However, timing, clinical presentation, and severity of SADC-associated reactions after FLTD-associated DRESS are markedly heterogeneous. Additionally, multiple drug reactors are a complex group that require longer hospitalization. There are no routine biomarkers available to distinguish true multiple drug hypersensitivity from nonspecific flare-ups and to guide long-term drug avoidance strategies.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is an illness which is difficult to diagnose because of its various symptoms. In our case, a patient with small spotted exanthema with nearly erythroderma and eosinophilia presented to the emergency room. Systemic steroid therapy was started on suspicion of a drug reaction. Over the course of time, the patient's general condition deteriorated significantly and the patient developed cholecystitis, Staphylococcus aureus bacteremia, pneumonitis and cytomegalovirus reactivation. With this case report, we want to show that DRESS is a disease that is difficult to treat and can develop after a long delay.

The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe cutaneous adverse reaction. Due to its unfamiliarity, non-specific diagnostic criteria, and delayed onset, this condition is frequently overlooked, which can sometimes result in life-threatening consequences. DRESS typically manifests as an extensive mucocutaneous rash with multi-organ involvement. This report aims to emphasize the varied presentation of the syndrome. Our patient was initially presented with acute onset vomiting, abdominal pain, fever for a couple of days with a minor skin rash. At first, she was treated for acute viral gastritis. However, on her second presentation within a week, she had a more extensive skin rash. Upon detailed history, it was found that this was linked to the initiation of sulfasalazine for ulcerative colitis. RegiSCAR (Registry of Severe Cutaneous Adverse Reactions) scoring suggested it as a definite case of DRESS. The primary manifestation of gastrointestinal symptoms led to a delayed diagnosis. Still, it is important to consider the possibility of drug hypersensitivity when there are skin changes and blood abnormalities present.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is an idiosyncratic severe cutaneous adverse reaction that may be potentially life-threatening. Recently, a simple scoring system for the early screening of DRESS patients was derived by combining hsCRP levels, the eosinophil count, and the total body surface area (CET score). The objectives of this study were validating the CET score, and calculating its lead time advantage and cost-benefits compared to RegiSCAR scoring.

This is a prospective observational case-control study, where 110 consecutive patients diagnosed with drug-induced maculopapular exanthema (MPE) were recruited during the 18 months of the study period. Patients were classified as cases (DRESS) and controls (MPE) using RegiSCAR score cut-off 2 (possible DRESS). They were also simultaneously screened using the CET score, based on which patients were classified as positive or negative. They were subsequently followed up on Day 15 for a second comparison and assessment of lead time and at 3 and 6 weeks to evaluate clinical response.

Seventy cases and 40 controls were recruited. At a cut-off of >2.12, the CET score had a sensitivity of 94.3%, a specificity of 60%, a positive predictive value (PPV) of 80.5%, and a negative predictive value (PPV) of 85.7%. The median delay in diagnosing DRESS using RegiSCAR was around 14.5 hours. There was a median cost benefit of 12.1 USD in favor of the CET score.

The CET score had good diagnostic performance in screening DRESS patients with a lead time of 14.5 hours and fewer costs incurred.

To investigate the safety and efficacy of subcutaneous tocilizumab (SC-TCZ) treatment in a long-term extension (LTE) of clinical trials in polyarticular or systemic juvenile idiopathic arthritis (pJIA or sJIA).

Patients with pJIA or sJIA from two open-label, 52-week phase 1b core trials of SC-TCZ who had adequate response per investigator assessment entered the LTE and continued SC-TCZ treatment according to body weight-based dosing regimens until commercial availability or up to 5 years. Pharmacokinetics, pharmacodynamics, and efficacy were assessed for up to 3 years, and safety for up to 5 years in the LTE.

Forty-four patients with pJIA and 38 patients with sJIA entered the LTE. Tocilizumab trough concentrations were maintained within the range expected to provide clinical benefit (mean values: pJIA, ∼10 μg/ml; sJIA, ∼75 μg/ml over 3 years). Pharmacodynamic parameters (interleukin-6, soluble interleukin-6 receptor, erythrocyte sedimentation rate, C-reactive protein) were maintained throughout the LTE at levels achieved in the core trials. Inactive disease per American College of Rheumatology provisional criteria was reported for 90% (17/19) and 53% (8/15) of patients with pJIA and 91% (10/11) and 92% (12/13) of patients with sJIA in the <30 and ≥30 kg body weight groups, respectively. Serious adverse events in the LTE were reported in six patients with pJIA (13.6%; five serious infections) and five patients with sJIA (13.2%; one serious infection).

Patients with pJIA or sJIA experienced long-term disease control with SC-TCZ treatment. Long-term safety was consistent with the known tocilizumab safety profile.

clinicaltrials.gov, NCT02165345.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is gaining attention in pharmacovigilance, but its association with antipsychotics, other than clozapine, is still unclear.

We conducted a case/non-case study with disproportionality analysis based on the World Health Organization (WHO) global spontaneous reporting database, VigiBase®. We analyzed individual case safety reports of DRESS syndrome related to antipsychotics compared to (1) all other medications in VigiBase®, (2) carbamazepine (a known positive control), and (3) within classes (typical/atypical) of antipsychotics. We calculated reporting odds ratio (ROR) and Bayesian information component (IC), with 95% confidence intervals (CIs). Disproportionate reporting was prioritized based on clinical importance, according to predefined criteria. Additionally, we compared characteristics of patients reporting with serious/non-serious reactions.

A total of 1534 reports describing DRESS syndrome for 19 antipsychotics were identified. The ROR for antipsychotics as a class as compared to all other medications was 1.0 (95% CI 0.9-1.1). We found disproportionate reporting for clozapine (ROR 2.3, 95% CI 2.1-2.5; IC 1.2, 95% CI 1.1-1.3), cyamemazine (ROR 2.3, 95% CI 1.5-3.5; IC 1.2, 95% CI 0.5-1.7), and chlorpromazine (ROR 1.5, 95% CI 1.1-2.1; IC 0.6, 95% CI 0.1-1.0). We found 35.7% of cases with co-reported anticonvulsants, and 25% with multiple concurrent antipsychotics in serious compared to 8.6% in non-serious cases (p = 0.03). Fatal cases were 164 (10.7%).

Apart from the expected association with clozapine, chlorpromazine and cyamemazine (sharing an aromatic heteropolycyclic molecular structure) emerged with a higher-than-expected reporting of DRESS. Better knowledge of the antipsychotic-related DRESS syndrome should increase clinicians' awareness leading to safer prescribing of antipsychotics.

RegiSCAR validation criteria for drug reaction with eosinophilia and systemic symptoms (DRESS) includes lymphadenopathy, a frequent feature of both tuberculosis (TB) and human immunodeficiency virus (HIV). TB is the most common HIV-associated coinfection. Advanced HIV is associated with lymph node (LN) fibrosis. It is not clear if this negatively affects case validation in HIV-associated DRESS. To answer this question, we designed a prospective descriptive study to assess lymphadenopathy in various combinations of comorbid HIV, TB, and DRESS.

We sought to describe the prevalence of DRESS-associated lymphadenopathy and characterize LN quality, size, and distribution in a high HIV-TB burden setting over time.

We prospectively and systematically examined LN in 25 consecutive acute DRESS cases hospitalized at a South African tertiary-care center and 10 hospitalized non-DRESS HIV-TB coinfected controls.

Fourteen (56%) of 25 patients were HIV infected, with a median (interquartile range) CD4 count of 254 (66-478) cells/mm³, and 7 of 14 were coinfected with TB. Using RegiSCAR criteria, 12 (46%) of 25 were definite DRESS cases, 8 (31%) of 25 probable, and 5 (23%) of 25 possible. Possible cases were excluded in the analysis. Fifteen (75%) of 20 subjects had LN in ≥2 anatomic sites, including all 7 patients with HIV-TB coinfection. In contrast, 1 (20%) of 5 hospitalized non-DRESS HIV-TB coinfected controls had LN. Cervical LN, in 15 (88%) of 17, was most common, followed by axillary (76%) and inguinal (59%). Cervical LN ranged between 1 and 2 cm in size. Among the 8 (32%) of 25 subjects with follow-up data, LN had regressed in all within 6 weeks of stopping the offending drug and initiating TB treatment. There was no correlation with CD4 cell count and LN.

Lymphadenopathy is a common feature of acute DRESS, even among HIV-TB-coinfected patients with advanced immunosuppression.

Severe cutaneous adverse reactions (SCARs) are rare but life-threatening, with antibiotics being the main cause. This retrospective study from a single center was designed to analyze the culprit drugs, clinical features and treatment outcomes of antibiotic-induced SCARs.

We analyzed cases of antibiotic-induced SCARs in a tertiary hospital in China between January 2013 and January 2024, including Steven-Johnson syndrome (SJS) or Stevens-Johnson syndrome-toxic epidermal necrolysis (SJS-TEN) overlap, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). Descriptive analysis of the demographic characteristics, clinical manifestations, treatment and prognosis were carried out.

Among 354 cases of SCARs, 63 validated antibiotic-related cases were included. Cephalosporins (31.7%), penicillins (25.4%), and quinolones (19.0%) were the most common triggers for SCARs. Overall, liver (50.8%), lungs (31.7%), and kidneys (23.8%) were the most frequently affected organ in SCARs cases. Eight patients (28.6%) in the SJS/SJS-TEN overlap group and 8 patients (80.0%) in the TEN group received combination therapy of corticosteroids and IVIG. Patients with SCARs caused by penicillins or cephalosporins could receive alternative treatments such as lincomamides, quinolones, and tetracyclines. The mortality rate in the TEN group was the highest at 20.0%, followed by the SJS/SJS-TEN overlap group (7.1%), and no deaths were observed in the DRESS and AGEP groups.

The identification of the culprit antibiotics and the application of alternative antibiotic therapies are crucial for the management of antibiotic-induced SCARs. If complicated underlying conditions and complications like advanced age, cancer and pneumonia coexist with SCARs, patients might be more at risk for mortality.

Drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS) is a life-threatening, multi-organ adverse drug reaction with a mortality rate of approximately 10 %-20 %. The most common culprit drugs are anticonvulsants, some antibiotics such as dapsone and minocycline, salazosulfapyridine, allopurinol and some antiretroviral molecules such as abacavir and nevirapine. Only one case of DRESS induced by sildenafil has been reported in the literature. Here we report a new case.

Higher frequencies of inflammatory adverse effects of clozapine have been reported in Japan. As the international titration protocol for Asians has set slower dose titration than the Japanese package insert, we hypothesized that a dose titration speed slower than the recommendation of the guideline would be associated with fewer inflammatory-related adverse events.

The medical records of all 272 patients who were first started on clozapine at seven hospitals between 2009 and 2023 were studied retrospectively. Of those, 241 were included in the analysis. The patients were divided into two groups regarding whether the titration speed was faster or slower than the guideline for Asians. The incidence of inflammatory adverse events with clozapine was compared between the groups.

The frequency of inflammatory adverse events was 34 % (37/110) in the faster titration group and 13 % (17/131) in the slower titration group, and a significant difference was observed by Fisher exact test (odds ratio 3.38; 95 % confidence interval 1.71-6.91; p < 0.001). Serious adverse effects, fever for more than five days, and clozapine discontinuation were significantly more frequent in the faster titration group. Logistic regression analysis indicated significantly more inflammatory adverse events in the faster titration group (adjusted odds ratio 4.01; 95 % confidence interval 2.02-7.87; p < 0.001) considering age, sex, body mass index, concomitant valproic acid, and smoking as confounding factors.

Clozapine-induced inflammatory adverse events were less frequent in Japanese individuals when a titration rate was more gradual than the protocol recommended in the Japanese package insert.

Drug-induced hypersensitivity syndrome, also known as drug reaction with eosinophilia and systemic symptoms, is a severe cutaneous adverse reaction characterized by an exanthem, fever, and hematologic and visceral organ involvement. The differential diagnosis includes other cutaneous adverse reactions, infections, inflammatory and autoimmune diseases, and neoplastic disorders. Three sets of diagnostic criteria have been proposed; however, consensus is lacking. The cornerstone of management is immediate discontinuation of the suspected drug culprit. Systemic corticosteroids remain first-line therapy, but the literature on steroid-sparing agents is expanding. Longitudinal evaluation for sequelae is recommended. Adjunctive tests for risk stratification and drug culprit identification remain under investigation. Part II of this continuing medical education activity begins by exploring the differential diagnosis and diagnosis of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms and concludes with an evidence-based overview of evaluation and treatment.

Background: The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome represents a severe form of drug hypersensitivity reaction characterized by significant morbidity, mortality, and long-term sequelae, coupled with limited therapeutic avenues. Accurate identification of the causative drug(s) is paramount for acute management, exploration of safe therapeutic alternatives, and prevention of future occurrences. However, the absence of a standardized diagnostic test and a specific causality algorithm tailored to DRESS poses a significant challenge in its clinical management. Methods: We conducted a retrospective case-control study involving 37 DRESS patients to validate a novel causality algorithm, the ALDRESS, designed explicitly for this syndrome, comparing it against the current standard algorithm, SEFV. Results: The ALDRESS algorithm showcased superior performance, exhibiting an 85.7% sensitivity and 93% specificity with comparable negative predictive values (80.6% vs. 97%). Notably, the ALDRESS algorithm yielded a substantially higher positive predictive value (75%) compared to SEFV (51.40%), achieving an overall accuracy rate of 92%. Conclusions: Our findings underscore the efficacy of the ALDRESS algorithm in accurately attributing causality to drugs implicated in DRESS syndrome. However, further validation studies involving larger, diverse cohorts are warranted to consolidate its clinical utility and broaden its applicability. This study lays the groundwork for a refined causality assessment tool, promising advancements in the diagnosis and management of DRESS syndrome.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and severe adverse drug reaction involving multiple organs. Data on DRESS syndrome among children are currently limited. The purpose of this study was to determine the clinical features, causative drugs, systemic organ involvement, laboratory findings, disease severity score, and treatment outcomes in pediatric DRESS patients. The medical records of all pediatric DRESS patients, based on the RegiSCAR diagnostic criteria and admitted to King Chulalongkorn Memorial Hospital, Bangkok, Thailand from January 2010 to December 2021, were reviewed. Twenty-two cases were identified (males 54.5%) with a median age of 9.5 years. Anticonvulsants (54.5%) and antibiotics (27.3%) were the leading culprit drugs. Skin rash was reported in all cases, followed closely by liver involvement (95.5%). Eosinophilia and atypical lymphocytosis were identified in 54.5% and 31.8% of cases, respectively. The median latency period was 17.5 days. Liver enzyme elevation was detected at an average onset of 20.0 days and hepatocellular type was the most common pattern of liver injury. Nineteen patients (86.4%) were treated with systemic corticosteroids with prednisolone being the most prescribed medication. One case developed Graves' disease after DRESS and multiple relapses of DRESS. One case (4.5%) died due to refractory status epilepticus that was unrelated to DRESS. Anticonvulsants were the major cause of DRESS in pediatric patients. High suspicion for DRESS is crucial in patients receiving these drugs and presenting with fever, rash, and internal organ involvement.

Allergic reactions to drugs caused by piperacillin-tazobactam are common in clinical practice. However, we also found a few cases of drug-induced hypersensitivity syndrome (DiHS)/Drug reaction with eosinophilia and systemic symptoms (DRESS) caused by piperacillin-tazobactam in our clinical work. We report a case of a 60-year-old female patient who was treated with piperacillin-tazobactam anti-infective therapy after the diagnosis of hematogenous lung abscess, developed fever, rash, and blood abnormalities after 26 days of application, and was later diagnosed as DIHS, which was improved after the administration of glucocorticoid and anti-allergic drugs. In addition, we also retrospectively analyzed 17 cases of DiHS caused by piperacillin-tazobactam from the PubMed databases between March 1980 and September 2023. The majority of the patients had an incubation period of more than 14 days, and the common clinical features included elevated eosinophil count/percentage, fever, rash, liver damage, and lymph node enlargement. After treatment with topical or systemic glucocorticoids, 16 of the 17 patients improved and one died because of the underlying condition. The clinical features of DiHS were diverse and included a long incubation period, skin rash, elevated eosinophils, and impaired organ function. Since some patients have atypical clinical features, clinicians should raise awareness of the disease, recognize these features early, and treat them promptly.

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.