Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions (SCARs), which include Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (also known as drug-induced hypersensitivity syndrome), acute generalized exanthematous pustulosis, and generalized bullous fixed drug eruption, are life-threatening conditions. The pathogenesis of SCARs involves T cell receptors recognizing drug antigens presented by human leukocyte antigens, triggering the activation of distinct T cell subsets. These cells interact with keratinocytes and various immune cells, orchestrating cutaneous lesions and systemic manifestations. Genetic predisposition, impaired drug metabolism, viral reactivation or infections, and heterologous immunity influence SCAR development and clinical presentation. Specific genetic associations with distinct SCAR phenotypes have been identified, leading to the implementation of genetic screening before prescription in various countries to prevent SCARs. Whilst systemic corticosteroids and conventional immunomodulators have been the primary therapeutic agents, evolving strategies, including biologics and small molecules targeting tumour necrosis factor, different cytokines, or Janus kinase signalling pathways, signify a shift towards a precision management paradigm that considers individual clinical presentations.

Examining cefazolin utilization and perioperative anaphylaxis in patients with and without a penicillin allergy label: A cross-sectional study.

STUDY OBJECTIVE: To compare the occurrence of cefazolin perioperative anaphylaxis (POA) in patients with and without a penicillin allergy label (PAL) to determine whether the prevalence of cefazolin POA differs based on the presence of a PAL. DESIGN: Cross-sectional study. SETTING: A large U.S. healthcare system in the Baltimore-D.C. region, July 2017 to July 2020. PATIENTS: 112,817 surgical encounters across inpatient and outpatient settings in various specialties, involving 90,089 patients. Of these, 4876 (4.3%) encounters had a PAL. INTERVENTIONS: Perioperative cefazolin administration within 4 h before surgery to 4 h after the procedure began. MEASUREMENTS: The primary outcome was cefazolin POA in patients with and without PALs. Potential POA cases were identified based on tryptase orders or diphenhydramine administrations within the initial cefazolin administration to 6 h postoperatively. Verification included two validation steps. The first checked for hypersensitivity reaction (HSR) documentation, and the second, led by Allergy specialists, identified POA and the probable culprit. The secondary outcome looked at cefazolin use trends in patients with a PAL, stratified by setting and specialty. MAIN RESULTS: Of 112,817 encounters, 1421 (1.3%) had possible cefazolin HSRs. Of these, 22 (1.5%) had POA, resulting in a 0.02% prevalence. Of these, 13 (59.1%) were linked to cefazolin and 9 (40.9%) attributed to other drugs. Only one cefazolin POA case had a PAL, indicating no significant difference in cefazolin POA prevalence between patients with and without PALs (p = 0.437). Perioperative cefazolin use in patients with PALs steadily increased from 2.6% to 6.0% between 2017 and 2020, specifically in academic settings. CONCLUSIONS: The prevalence of cefazolin POA does not exhibit significant differences between patients with and without PALs, and notably, the incidence remains remarkably low. Based on these findings, it is advisable to view cefazolin as an acceptable choice for prophylaxis in patients carrying a PAL.

Successful Treatment of Delayed Localized Necrotizing Inflammatory Myositis After Severe Acute Respiratory Syndrome Coronavirus 2 mRNA-1273 Vaccine: A Case Report.

Reported adverse reactions to the mRNA-1273 vaccine (Spikevax, Moderna Inc) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) range from mild, local delayed cutaneous reactions to rarer, more serious reactions such as myocarditis. Here, we describe the presentation and successful treatment of delayed, localized necrotizing inflammatory myositis following a third dose of the mRNA-1273 SARS-CoV-2 vaccine. To our knowledge, this is the first report of biopsy-confirmed, delayed inflammatory myositis after administration of an mRNA-1273 SARS-CoV-2 vaccine booster.

Stevens-Johnson syndrome and toxic epidermal necrolysis: A systematic review of PubMed/MEDLINE case reports from 1980 to 2020.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, life-threatening immunologic reactions. Prior studies using electronic health records, registries or reporting databases are often limited in sample size or lack clinical details. We reviewed diverse detailed case reports published over four decades. Methods: Stevens-Johnson syndrome and toxic epidermal necrolysis-related case reports were identified from the MEDLINE database between 1980 and 2020. Each report was classified by severity (i.e., SJS, TEN, or SJS-TEN overlap) after being considered a "probable" or "definite" SJS/TEN case. The demographics, preconditions, culprit agents, clinical course, and mortality of the cases were analyzed across the disease severity. Results: Among 1,059 "probable" or "definite" cases, there were 381 (36.0%) SJS, 602 (56.8%) TEN, and 76 (7.2%) SJS-TEN overlap cases, with a mortality rate of 6.3%, 24.4%, and 21.1%, respectively. Over one-third of cases had immunocompromised conditions preceding onset, including cancer (n = 194,18.3%), autoimmune diseases (n = 97, 9.2%), and human immunodeficiency virus (HIV) (n = 52, 4.9%). During the acute phase of the reaction, 843 (79.5%) cases reported mucous membrane involvement and 210 (19.8%) involved visceral organs. Most cases were drug-induced (n = 957, 90.3%). A total of 379 drug culprits were reported; the most frequently reported drug were antibiotics (n = 285, 26.9%), followed by anticonvulsants (n = 196, 18.5%), analgesics/anesthetics (n = 126, 11.9%), and antineoplastics (n = 120, 11.3%). 127 (12.0%) cases reported non-drug culprits, including infections (n = 68, 6.4%), of which 44 were associated with a mycoplasma pneumoniae infection and radiotherapy (n = 27, 2.5%). Conclusion: An expansive list of potential causative agents were identified from a large set of literature-reported SJS/TEN cases, which warrant future investigation to understand risk factors and clinical manifestations of SJS/TEN in different populations.

Humoral and cellular immunogenicity of SARS-CoV-2 vaccines in chronic lymphocytic leukemia: a prospective cohort study.

Chronic lymphocytic leukemia (CLL), the most common leukemia worldwide, is associated with increased COVID-19 mortality. Previous studies suggest only a portion of vaccinated CLL patients develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibodies. Whether the elicited antibodies are functional and/or accompanied by functional T-cell responses is unknown. This prospective cohort study included patients with CLL who received SARS-CoV-2 and PCV13 vaccines (not concurrently). The primary cohort included adults with CLL off therapy. Coprimary outcomes were serologic response to SARS-CoV-2 (receptor binding domain [RBD] immunoassay) and PCV13 vaccines (23-serotype IgG assay). Characterization of SARS-CoV-2 antibodies and their functional activity and assessment of functional T-cell responses was performed. Sixty percent (18/30) of patients demonstrated serologic responses to SARS-CoV-2 vaccination, appearing more frequent among treatment-naïve patients (72%). Among treatment-naïve patients, an absolute lymphocyte count ≤24 000/µL was associated with serologic response (94% vs 14%; P < .001). On interferon-γ release assays, 80% (16/20) of patients had functional spike-specific T-cell responses, including 78% (7/9) with a negative RBD immunoassay, a group enriched for prior B-cell-depleting therapies. A bead-based multiplex immunoassay identified antibodies against wild-type and variant SARS-CoV-2 (α, ß, γ, and δ) in all tested patients and confirmed Fc-receptor binding and effector functions of these antibodies. Of 11 patients with negative RBD immunoassay after vaccination, 6 (55%) responded to an additional mRNA-based vaccine dose. The PCV13 serologic response rate was 29% (8/28). Our data demonstrate that SARS-CoV-2 vaccination induces functional T-cell and antibody responses in patients with CLL and provides the framework for investigating the molecular mechanisms and clinical benefit of these responses. This trial was registered at www.clinicaltrials.gov as #NCT05007860.

COVID-19 severity in asthma patients: a multi-center matched cohort study.

OBJECTIVE: The evidence pertaining to the effects of asthma on Coronavirus disease 2019 outcomes has been unclear. To improve our understanding of the clinically important association of asthma and Coronavirus disease 2019. METHODS: A matched cohort study was performed using data from the Mass General Brigham Health Care System (Boston, MA). Adult (age ≥18 years) patients with confirmed Coronavirus disease 2019 and without chronic obstructive pulmonary disease, cystic fibrosis, or interstitial lung disease between March 4, 2020 and July 2, 2020 were analyzed. Up to five non-asthma comparators were matched to each asthma patient based on age (within 5 years), sex, and date of positive test (within 7 days). The primary outcomes were hospitalization, mechanical ventilation, and death, using multivariable Cox-proportional hazards models accounting for competing risk of death, when appropriate. Patients were followed for these outcomes from diagnosis of Coronavirus disease 2019 until July 2, 2020. RESULTS: Among 562 asthma patients, 199 (21%) were hospitalized, 15 (3%) received mechanical ventilation, and 7 (1%) died. Among the 2686 matched comparators, 487 (18%) were hospitalized, 107 (4%) received mechanical ventilation, and 69 (3%) died. The adjusted Hazard Ratios among asthma patients were 0.99 (95% Confidence Internal 0.80, 1.22) for hospitalization, 0.69 (95% Confidence Internal 0.36, 1.29) for mechanical ventilation, and 0.30 (95% Confidence Internal 0.11, 0.80) for death. CONCLUSIONS: In this matched cohort study from a large Boston-based healthcare system, asthma was associated with comparable risk of hospitalization and mechanical ventilation but a lower risk of mortality.

Assessment of the Frequency of Dual Allergy to Penicillins and Cefazolin: A Systematic Review and Meta-analysis.

Importance: Cefazolin is the preoperative antibiotic of choice because it is safer and more efficacious than second-line alternatives. Surgical patients labeled as having penicillin allergy are less likely to prophylactically receive cefazolin and more likely to receive clindamycin or vancomycin, which results in higher rates of surgical site infections. Objective: To examine the incidence of dual allergy to cefazolin and natural penicillins. Data Sources: MEDLINE/PubMed, Web of Science, and Embase were searched without language restrictions for relevant articles published from database inception until July 31, 2020. Study Selection: In this systematic review and meta-analysis, a search of MEDLINE/PubMed, Web of Science, and Embase was performed for articles published from database inception to July 31, 2020, for studies that included patients who had index allergies to a natural penicillin and were tested for tolerability to cefazolin or that included patients who had index allergies to cefazolin and were tested for tolerability to a natural penicillin. A total of 3228 studies were identified and 2911 were screened for inclusion. Data Extraction and Synthesis: Data were independently extracted by 2 authors. Bayesian meta-analysis was used to estimate the frequency of allergic reactions. Main Outcomes and Measures: Dual allergy to cefazolin and a natural penicillin. Results: Seventy-seven unique studies met the eligibility criteria, yielding 6147 patients. Cefazolin allergy was identified in 44 participants with a history of penicillin allergy, resulting in a dual allergy meta-analytical frequency of 0.7% (95% credible interval [CrI], 0.1%-1.7%; I2 = 74.9%). Such frequency was lower for participants with unconfirmed (0.6%; 95% CrI, 0.1%-1.3%; I2 = 54.3%) than for those with confirmed penicillin allergy (3.0%; 95% CrI, 0.01%-17.0%; I2 = 88.2%). Thirteen studies exclusively assessed surgical patients (n = 3884), among whom 0.7% (95% CrI, 0%-3.3%; I2 = 85.5%) had confirmed allergy to cefazolin. Low heterogeneity was observed for studies of patients with unconfirmed penicillin allergy who had been exposed to perioperative cefazolin (0.1%; 95% CrI, 0.1%-0.3%; I2 = 13.1%). Penicillin allergy was confirmed in 16 participants with a history of cefazolin allergy, resulting in a meta-analytical frequency of 3.7% (95% CrI, 0.03%-13.3%; I2 = 64.4%). The frequency of penicillin allergy was 4.4% (95% CrI, 0%-23.0%; I2 = 75%) for the 8 studies that exclusively assessed surgical patients allergic to cefazolin. Conclusions and Relevance: These findings suggest that most patients with a penicillin allergy history may safely receive cefazolin. The exception is patients with confirmed penicillin allergy in whom additional care is warranted.

Association of ß-Lactam Allergy Documentation and Prophylactic Antibiotic Use in Surgery: A National Cross-Sectional Study of Hospitalized Patients.

Alternative antibiotics for surgical prophylaxis are associated with increased adverse events and surgical site infection compared to cefazolin. In a sample of perioperative inpatients from 100 hospitals in the United States, cefazolin was 9-fold less likely to be used in patients with a documented ß-lactam allergy whereas clindamycin was 45-fold more likely.

Preoperative penicillin allergy testing in patients undergoing cardiac surgery.

BACKGROUND: Cefazolin is a first-line prophylactic antibiotic used to prevent surgical site infections (SSIs) in cardiac surgery. Patients with a history of penicillin allergy often receive less effective second-line antibiotics, which is associated with an increased SSI risk. OBJECTIVE: To describe the impact of preoperative penicillin allergy evaluation on perioperative cefazolin use in patients undergoing cardiac surgery. METHODS: We performed a retrospective cohort study of patients with a documented penicillin allergy who underwent cardiac surgery at the Massachusetts General Hospital from September 2015 to December 2018. We describe penicillin allergy evaluation assessment and outcomes. We evaluated the association between preoperative penicillin allergy evaluation and first-line perioperative antibiotic use using a multivariable logistic regression model. RESULTS: Of 3802 cardiac surgical patients, 510 (13%) had a documented penicillin allergy; 165 (33%) were referred to allergy and immunology practitioners. Of 160 patients (31%) who underwent penicillin allergy evaluation (ie, penicillin skin testing and, if results were negative, an amoxicillin challenge), 154 (97%) were found not to have a penicillin allergy. Patients who underwent preoperative penicillin allergy evaluation were more likely to receive the first-line perioperative antibiotic (92% vs 38%, P < .001). After adjusting for potential confounders, patients who underwent preoperative penicillin allergy evaluation had higher odds of first-line perioperative antibiotic use (adjusted odds ratio, 26.6; 95% CI, 12.8-55.2). CONCLUSION: Integrating penicillin allergy evaluation into routine preoperative care ensured that almost all evaluated patients undergoing cardiac surgery received first-line antibiotic prophylaxis, a critical component of SSI risk reduction. Further efforts are needed to increase access to preoperative allergy evaluation.

Drug-Induced Anaphylaxis Documented in Electronic Health Records.

BACKGROUND: Although drugs represent a common cause of anaphylaxis, few large studies of drug-induced anaphylaxis have been performed. OBJECTIVE: To describe the epidemiology and validity of reported drug-induced anaphylaxis in the electronic health records (EHRs) of a large United States health care system. METHODS: Using EHR drug allergy data from 1995 to 2013, we determined the population prevalence of anaphylaxis including anaphylaxis prevalence over time, and the most commonly implicated drugs/drug classes reported to cause anaphylaxis. Patient risk factors for drug-induced anaphylaxis were assessed using a logistic regression model. Serum tryptase and allergist visits were used to assess the validity and follow-up of EHR-reported anaphylaxis. RESULTS: Among 1,756,481 patients, 19,836 (1.1%) reported drug-induced anaphylaxis; penicillins (45.9 per 10,000), sulfonamide antibiotics (15.1 per 10,000), and nonsteroidal anti-inflammatory drugs (NSAIDs) (13.0 per 10,000) were most commonly implicated. Patients with white race (odds ratio [OR] 2.38, 95% CI 2.27-2.49), female sex (OR 2.20, 95% CI 2.13-2.28), systemic mastocytosis (OR 4.60, 95% CI 2.66-7.94), Sjögren's syndrome (OR 1.94, 95% CI 1.47-2.56), and asthma (OR 1.50, 95% CI 1.43-1.59) had an increased odds of drug-induced anaphylaxis. Serum tryptase was performed in 135 (<1%) anaphylaxis cases and 1,587 patients (8.0%) saw an allergist for follow-up. CONCLUSIONS: EHR-reported anaphylaxis occurred in approximately 1% of patients, most commonly from penicillins, sulfonamide antibiotics, and NSAIDs. Females, whites, and patients with mastocytosis, Sjögren's syndrome, and asthma had increased odds of reporting drug-induced anaphylaxis. The low observed frequency of tryptase testing and specialist evaluation emphasize the importance of educating providers on anaphylaxis management.

Racial/ethnic variation and risk factors for allopurinol-associated severe cutaneous adverse reactions: a cohort study.

OBJECTIVES: To examine associations of race/ethnicity and purported risk factors with hospitalised allopurinol-associated severe cutaneous adverse reactions (AASCARs). METHODS: We used US Medicaid data to identify incident allopurinol users between 1999 and 2012. We examined the risk of hospitalised AASCARs according to race/ethnicity and purported key risk factors and calculated relative risks (RR). RESULTS: Among 400 401 allopurinol initiators, we documented 203 hospitalised AASCAR cases (1 in 1972 initiators). The average AASCAR hospitalisation was 9.6 days and 43 individuals (21%) died. The multivariable-adjusted RRs for AASCARs among blacks, Asians and Native Hawaiians/Pacific Islanders compared with whites or Hispanics were 3.00 (95% CI 2.18 to 4.14), 3.03 (95% CI 1.72 to 5.34) and 6.68 (95% CI 4.37 to 10.22), respectively. Female sex, older age (≥60 years), chronic kidney disease and initial allopurinol dose (>100 mg/day) were independently associated with a 2.5-fold, 1.7-fold, 2.3-fold and 1.9-fold higher risk of AASCAR, respectively. In our combined demographic analysis, older women (≥60 years) of a high-risk race/ethnicity (blacks, Asians or Native Hawaiians/Pacific Islanders) had over a 12-fold higher risk of hospitalised AASCARs than younger men of a low-risk race/ethnicity (whites or Hispanics) (multivariable-adjusted RR, 12.25; 95% CI 6.46 to 23.25). CONCLUSIONS: This racially diverse (yet mostly white) cohort study indicates that the risk of hospitalised AASCAR is rare overall, although blacks, Asians and Native Hawaiians/Pacific-Islanders have a substantially higher risk of hospitalised AASCARs, particularly among older women. These data also support the practice of initiating allopurinol at a low dose (eg, ≤100 mg/day).

The Impact of a Reported Penicillin Allergy on Surgical Site Infection Risk.

Background: A reported penicillin allergy may compromise receipt of recommended antibiotic prophylaxis intended to prevent surgical site infections (SSIs). Most patients with a reported penicillin allergy are not allergic. We determined the impact of a reported penicillin allergy on the development of SSIs. Methods: In this retrospective cohort study of Massachusetts General Hospital hip arthroplasty, knee arthroplasty, hysterectomy, colon surgery, and coronary artery bypass grafting patients from 2010 to 2014, we compared patients with and without a reported penicillin allergy. The primary outcome was an SSI, as defined by the Centers for Disease Control and Prevention's National Healthcare Safety Network. The secondary outcome was perioperative antibiotic use. Results: Of 8385 patients who underwent 9004 procedures, 922 (11%) reported a penicillin allergy, and 241 (2.7%) had an SSI. In multivariable logistic regression, patients reporting a penicillin allergy had increased odds (adjusted odds ratio, 1.51; 95% confidence interval, 1.02-2.22) of SSI. Penicillin allergy reporters were administered less cefazolin (12% vs 92%; P < .001) and more clindamycin (49% vs 3%; P < .001), vancomycin (35% vs 3%; P < .001), and gentamicin (24% vs 3%; P < .001) compared with those without a reported penicillin allergy. The increased SSI risk was entirely mediated by the patients' receipt of an alternative perioperative antibiotic; between 112 and 124 patients with reported penicillin allergy would need allergy evaluation to prevent 1 SSI. Conclusions: Patients with a reported penicillin allergy had a 50% increased odds of SSI, attributable to the receipt of second-line perioperative antibiotics. Clarification of penicillin allergies as part of routine preoperative care may decrease SSI risk.

Decision-Making in Critical Limb Ischemia: A Markov Simulation.

BACKGROUND: Critical limb ischemia (CLI) is a feared complication of peripheral vascular disease that often requires surgical management and may require amputation of the affected limb. We developed a decision model to inform clinical management for a 63-year-old woman with CLI and multiple medical comorbidities, including advanced heart failure and diabetes. METHODS: We developed a Markov decision model to evaluate 4 strategies: amputation, surgical bypass, endovascular therapy (e.g. stent or revascularization), and medical management. We measured the impact of parameter uncertainty using 1-way, 2-way, and multiway sensitivity analyses. RESULTS: In the base case, endovascular therapy yielded similar discounted quality-adjusted life months (26.50 QALMs) compared with surgical bypass (26.34 QALMs). Both endovascular and surgical therapies were superior to amputation (18.83 QALMs) and medical management (11.08 QALMs). This finding was robust to a wide range of periprocedural mortality weights and was most sensitive to long-term mortality associated with endovascular and surgical therapies. Utility weights were not stratified by patient comorbidities; nonetheless, our conclusion was robust to a range of utility weight values. CONCLUSIONS: For a patient with CLI, endovascular therapy and surgical bypass provided comparable clinical outcomes. However, this finding was sensitive to long-term mortality rates associated with each procedure. Both endovascular and surgical therapies were superior to amputation or medical management in a range of scenarios.

Ceftaroline desensitization procedure in a pregnant patient with multiple drug allergies.

Validated skin testing is lacking for many drugs, including ceftaroline. The cross-reactivity between ceftaroline and other ß-lactam antibiotics is unknown. We report a case of a pregnant patient with cystic fibrosis and multiple drug allergies who required ceftaroline for methicillin-resistant Staphylococcus aureus pneumonia and underwent an uncomplicated empiric desensitization procedure.

Comprehensive allergy evaluation is useful in the subsequent care of patients with drug hypersensitivity reactions during anesthesia.

BACKGROUND: For patients with a history of drug hypersensitivity reaction (HSR) during anesthesia, strategies to minimize risk with subsequent anesthesia are unclear. Identification of the cause of HSR during anesthesia remains challenging. OBJECTIVE: To determine the success of a comprehensive allergy evaluation and management plan for patients with HSR during anesthesia, including identification of the causative agent and review of outcomes during subsequent anesthesia exposure. METHODS: We performed chart reviews of patients referred for the evaluation of HSR during anesthesia between 2003 and 2012. Data collection included patient characteristics, signs/symptoms of HSR during anesthesia, and subsequent outcomes. Patients underwent comprehensive allergy evaluation including skin testing for identifying potential culprit agents, and the results were used to provide recommendations for any subsequent anesthesia. RESULTS: Over the 10-year study period, 73 patients with HSR during anesthesia were referred for further evaluation. Thirteen patients (18%) had positive skin test results to a drug received during anesthesia. One patient with a positive skin test result was diagnosed with mastocytosis. The causative agents identified in these 13 patients included latex, ß-lactam antibiotics, neuromuscular blockers, tetracaine, odansetron, and fentanyl. On follow-up, 47 of the 73 patients (64%) subsequently underwent procedures requiring anesthesia. Using our recommendations from evaluation and testing, 45 of these 47 patients (96%) successfully tolerated subsequent anesthesia. The 2 patients who developed recurrent HSR during anesthesia were later diagnosed with mast cell disorders. CONCLUSIONS: Our comprehensive evaluation and management plan minimizes risk with subsequent anesthesia even when the cause of HSR could not be identified. Baseline tryptase levels may be helpful in this patient population to diagnose mast cell disorders.