United States Drug Allergy Registry (USDAR) grading scale for immediate drug reactions.

BACKGROUND: There is no accepted grading system classifying the severity of immediate reactions to drugs. OBJECTIVE: The purpose of this article is to present a proposed grading system developed through the consensus of drug allergy experts from the United States Drug Allergy Registry (USDAR) Consortium. METHODS: The USDAR investigators sought to develop a consensus severity grading system for immediate drug reactions that is applicable to clinical care and research. RESULTS: The USDAR grading scale scores severity levels on a scale of 0 to 4. A grade of no reaction (NR) is used for patients who undergo challenge without any symptoms or signs, and it would confirm a negative challenge result. A grade 0 reaction is indicative of primarily subjective complaints that are commonly seen with both historical drug reactions and during drug challenges, and it would suggest a low likelihood of a true drug allergic reaction. Grades 1 to 4 meet the criteria for a positive challenge result and may be considered indicative of a drug allergy. Grade 1 reactions are suggestive of a potential immediate drug reaction with mild symptoms. Grade 2 reactions are more likely to be immediate drug reactions of moderate severity. Grade 3 reactions have features suggestive of a severe allergic reaction, whereas grade 4 reactions are life-threatening reactions such as anaphylactic shock and fatal anaphylaxis. CONCLUSION: This proposed grading schema for immediate drug reactions improves on prior schemata by being developed specifically for immediate drug reactions and being easy to implement in clinical and research practice.

High-titer post-vaccine COVID-19 convalescent plasma for immunocompromised patients during the first omicron surge.

BACKGROUND: Transplant and hematologic malignancy patients have high Coronavirus disease 2019 (COVID-19) mortality and impaired vaccination responses. Omicron variant evades several monoclonal antibodies previously used in immunocompromised patients. Polyclonal COVID-19 convalescent plasma (CCP) may provide broader neutralizing capacity against new variants at high titers. Vaccination increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) titer in convalescent donors. METHODS: We conducted a retrospective chart review of hospitalized immunocompromised patients with COVID-19 who received high-titer CCP during the first omicron surge, collected from vaccinated donors within 6 months of pre-omicron COVID-19. Data on safety and outcomes were extracted. RESULTS: A total of 44 immunocompromised patients were included, 59.1% with solid organ transplant, 22.7% with hematopoietic cell transplant, 11.4% with hematologic malignancy, and 6.8% with autoimmune disease. Overall, 95% of CCP units transfused were from recently recovered and vaccinated donors and had SARS-CoV-2 antibody results 8- to 37-fold higher than the Food and Drug Administration's cutoff for high-titer CCP. There were two mild transfusion reactions. A total of 30-day mortality was 4.5%. There were no differences in 100-day mortality by underlying diagnosis, levels of immunosuppression, and timing of CCP administration. Patients with higher immunosuppression had significantly higher mean World Health Organization clinical progression scores at 30-day post-CCP compared to those with lower immunosuppression. CONCLUSIONS: CCP is a safe, globally available treatment for immunocompromised patients with COVID-19. Mortality was lower in our cohort than that of COVID-19 patients with similar immunocompromising conditions. Post-vaccine CCP with very high titers should be prioritized for study in immunocompromised patients. Post-vaccine CCP has the potential to keep pace with new variants by overcoming mutations at sufficiently high titer.

Digital Antibiotic Allergy Decision Support Tool Improves Management of ß-Lactam Allergies.

BACKGROUND: Frontline providers frequently make time-sensitive antibiotic choices, but many feel poorly equipped to handle antibiotic allergies. OBJECTIVE: We hypothesized that a digital decision support tool could improve antibiotic selection and confidence when managing ß-lactam allergies. METHODS: A digital decision support tool was designed to guide non-allergist providers in managing patients with ß-lactam allergy labels. Non-allergists were asked to make decisions in clinical test cases without the tool, and then with it. These decisions were compared using paired t tests. Users also completed surveys assessing their confidence in managing antibiotic allergies. RESULTS: The tool's algorithm was validated by confirming its recommendations aligned with that of five allergists. Non-allergist providers (n = 102) made antibiotic management decisions in test cases, both with and without the tool. Use of the tool increased the proportion of correct decisions from 0.41 to 0.67, a difference of 0.26 (95% CI, 0.22-0.30; P < .001). Users were more likely to give full-dose antibiotics in low-risk situations, give challenge doses in medium-risk situations, and avoid the antibiotic and/or consult allergy departments in high-risk situations. A total of 98 users (96%) said the tool would increase their confidence when choosing antibiotics for patients with allergies. CONCLUSIONS: A point-of-care clinical decision tool provides allergist-designed guidance for non-allergists and is a scalable system for addressing antibiotic allergies, irrespective of allergist availability. This tool encouraged appropriate antibiotic use in low- and medium-risk situations and increased caution in high-risk situations. A digital support tool should be considered in quality improvement and antibiotic stewardship efforts.

Penicillin Allergy Evaluation and Health Equity: A Call to Action.

Allergists have been at the forefront of addressing the burden of unverified penicillin allergy labels. Coordinated national efforts with infectious diseases, antimicrobial stewardship experts, and pharmacy societies to advocate for formal evaluation of patient-reported penicillin allergy have resulted in improvements in delabeling efforts. Given the poorer health outcomes associated with the penicillin allergy label and the potential health benefits that can be gained with delabeling, improving access to penicillin allergy evaluation is of the utmost importance. Health disparities are widely recognized to impact all aspects of health care, and multilevel interventions at the patient, clinician, and systems level are required to ensure equitable care delivery. Structural racism underpins many social determinants of health and is a key driver of racial and ethnic health disparities. In this Rostrum, we use a conceptual framework from the 2015 National Academy of Medicine report Improving Diagnosis in Health Care to explore how inequities are related to the evaluation of penicillin allergy. We use the National Institute on Minority Health and Health Disparities Strategies to Advance Health Disparities to elucidate areas of important study. Building upon existing efforts to address disparities in Allergy/Immunology, we highlight the urgent importance of understanding and eliminating health disparities in penicillin allergy evaluation and delabeling.

Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones, Vancomycin, Tetracyclines, and Macrolides.

While fluoroquinolones, vancomycin, macrolides, and tetracyclines are generally safe antibiotics, they can induce both immediate and delayed hypersensitivity reactions (HSRs). Historically, less has been published on allergies to these antibiotics compared to beta lactams, but the prevalence of non-beta lactam HSRs is increasing. To fluoroquinolones, immediate HSRs are more common than delayed reactions. Both IgE and non-IgE mechanisms, such as the mast cell receptor Mas-related G protein-coupled receptor X2 (MRGPRX2), have been implicated in fluoroquinolone-induced anaphylaxis. Skin testing for fluoroquinolones is controversial, and the gold standard for diagnosis is a graded dose challenge. To vancomycin, the most common reaction is vancomycin infusion reaction (previously called "red man syndrome"), which is caused by infusion rate-dependent direct mast cell degranulation. Severity can range from flushing and pruritis to angioedema, bronchospasm, and hypotension that mimic type I HSRs. MRGPRX2 has been implicated in vancomycin infusion reactions. IgE-mediated HSRs to vancomycin are rare. Vancomycin skin testing yields high false positive rates. Thus, direct provocation challenge with slower infusion rate and/or antihistamine pre-treatment is preferred if symptoms are mild to moderate, and desensitization can be considered if symptoms are severe. To tetracyclines, non-IgE-mediated and delayed HSRs predominate with cutaneous reactions being the most common. There is no standardized skin testing for tetracyclines, and avoidance is generally recommended after a severe reaction because of the paucity of data for testing. Graded dose challenges and desensitizations can be considered for alternative or index tetracyclines if there are no alternatives. With macrolides, urticaria/angioedema is the most common immediate HSR, and rash is the most common delayed HSR. The predictive value for skin testing to macrolides is similarly poorly defined. In general, HSRs to fluroquinolones, vancomycin, macrolides, and tetracyclines are challenging to diagnose given the lack of validated skin testing and in vitro testing. Direct provocation challenge remains the gold standard for diagnosis, but the benefits of confirming an allergy may not outweigh the risk of a severe reaction. Skin testing, direct provocation challenge, and/or desensitization to the index non-beta lactam antibiotic or alternatives in its class may be reasonable approaches depending on the clinical context and patient preferences.

Nocardiosis in Immunocompromised Patients on Alternative Pneumocystis Prophylaxis.

Prophylactic trimethoprim/sulfamethoxazole (TMP/SMX) prevents Pneumocystis jirovecii pneumonia and nocardiosis in immunocompromised patients but sometimes is avoided because of purported allergies or side effects. Of 25 immunocompromised patients receiving alternative prophylaxis in whom nocardiosis developed, 16 subsequently tolerated TMP/SMX treatment. Clinicians should consider TMP/SMX allergy evaluation and rechallenging to assess patient tolerance.

Infectious Implications of Interleukin-1, Interleukin-6, and T Helper Type 2 Inhibition.

Targeting interleukins that drive innate inflammation has expanded treatments of autoinflammatory and autoimmune disorders. Interleukin (IL)-1 inhibition has proven useful for monogenic autoinflammatory syndromes, and IL-6 inhibition for autoimmune arthritides. Biological therapies impeding these pathways impair detection and containment of pathogens, particularly invasive bacteria, reflecting the importance of IL-1 and IL-6 in communicating danger throughout the immune system. Biologics targeting T helper type 2 inflammation are used to treat specific allergic, atopic, and eosinophilic diseases. They may impair protections against local herpesvirus reactivations while augmenting antiviral responses to respiratory viruses. Their risks with helminth exposures have yet to be defined.

Case series of sebelipase alfa hypersensitivity reactions and successful sebelipase alfa rapid desensitization.

Allergic immune-mediated hypersensitivity reactions are known potential complications of enzyme replacement therapy. Sebelipase alfa, recombinant lysosomal acid lipase (LAL), is a potentially life-altering treatment for patients with LAL deficiency. There is very little information on the diagnosis and management of immediate hypersensitivity reactions to this drug. Here we present three unique cases of hypersensitivity reactions to sebelipase alfa, spanning a broad age spectrum from infancy to adulthood, each managed with successful rapid desensitization.

Successful eradication of chronic symptomatic Candida krusei urinary tract infection with increased dose micafungin in a liver and kidney transplant recipient: Case report and review of the literature.

Treatment of symptomatic candiduria is notoriously challenging because of the limited repository of antifungals that achieve adequate urinary concentrations. Fluconazole, amphotericin B-based products, and flucytosine are established treatment options for most Candida species. Candida krusei exhibits intrinsic resistance to fluconazole and decreased susceptibility to amphotericin B and flucytosine. In transplant patients, both amphotericin B-based products and flucytosine are less desirable because of their toxicities. Other triazole antifungals are unappealing because they do not achieve adequate urinary concentrations, have multiple toxicities, and interact with transplant-related immunosuppressive medications. Echinocandins are well-tolerated but have been traditionally deferred in the treatment of symptomatic funguria because of their poor urinary concentrations but there is a small but emerging body of literature supporting their use. Here, we present a case of successful eradication of chronic symptomatic C krusei urinary tract infection with micafungin 150 milligrams daily in a liver and kidney transplant recipient, and we review the literature on treatment of symptomatic candiduria.

Eremothecium coryli bloodstream infection in a patient with acute myeloid leukemia: first case report of human infection.

Eremothecium coryli is a dimorphic fungus of the Saccharomycetes class. While species within this class are known to cause human infection, Eremothecium species have previously only been known as phytopathogens and never been isolated from a human sample. Here, we report the first known case of human E. coryli infection.

West Nile virus encephalitis in GATA2 deficiency.

We report a male with longstanding warts who presented with severe West Nile virus encephalitis (WNVE) and recovered after interferon alfa-2b and intravenous immunoglobulin. He was later found to have GATA2 deficiency and underwent successful hematopoietic stem cell transplant.

A novel outpatient desensitization protocol for recombinant human erythropoietin allergy in a pediatric patient.

BACKGROUND: Recombinant human erythropoietin, such as epoetin alfa and darbepoetin alfa, is an important therapy for anemia due to chronic renal failure. Allergy to recombinant human erythropoietin and the need for desensitization are rare. CASE PRESENTATION: We report here a novel epoetin alfa outpatient desensitization protocol in a girl who developed delayed cutaneous hypersensitivity to subcutaneous epoetin alfa and intravenous darbepoetin alfa. An initial attempt at traditional epoetin alfa desensitization failed, so we created a slower 17-day outpatient desensitization that succeeded and allowed treatment continuation. CONCLUSIONS: This case highlights the notion that delayed-type hypersensitivity to recombinant human erythropoietin can occur as evident by reproducible reactions after repeated exposures and slow outpatient desensitization can be considered when a trial of more rapid induction of tolerance is unsuccessful.

Scedosporium apiospermum infection of the urinary system with a review of treatment options and cases in the literature.

Infection with Scedosporium species is associated with a significant morbidity and mortality and is becoming increasingly common, especially in immunocompromised patients. We describe the presentation and successful management of an immunocompromised patient with Scedosporium apiospermum infection of the upper urinary tract system, a rare disease manifestation. The current literature on urinary tract scedosporiosis is further reviewed with emphasis on treatment options and limitations of current antifungal therapy.

Mast cells recruited to mesenteric lymph nodes during helminth infection remain hypogranular and produce IL-4 and IL-6.

Mast cells (MC) and basophils share expression of the high-affinity receptor for IgE (FcεRI) but can be distinguished by their divergent expression of KIT and CD49b. In BALB/c mice, MC lineage cells expressing high levels of FcεRI by flow cytometry were seen only in bone marrow whereas those expressing intermediate levels of FcεRI were present in bone marrow and spleen of naive mice and in mesenteric lymph nodes (mLN) of Trichinella spiralis-infected mice. These FcεRI(+)KIT(+)CD49b(-) cells had a membrane phenotype similar to i.p. connective tissue-type MC, but were smaller and hypogranular by flow cytometry forward and side scatter profiles, respectively. Consistent with this, they lacked the prominent secretory granules identified by histochemistry and immunodetection for the MC-specific granule proteases that are readily seen in mature jejunal mucosal MC that also are induced by the infection and present at the same time. The concentration of these MC lineage cells in mLN determined by flow cytometry was comparable to that of MC progenitors (MCp) measured by limiting dilution and clonal expansion with maturation. We observed upregulation of IL-4 transcription by MCp in mLN and spleens of helminth-infected 4get mice, and we demonstrated by intracellular cytokine staining production of IL-4 and IL-6 by the mLN MCp in helminth-infected mice. Furthermore, treatment of helminth-infected mice with anti-FcεRI mAb, a protocol known to deplete basophils, also depleted mLN MCp. Thus, this study identifies a hypogranular subset of MCp recruited to mLN by helminth infection that may be an important unrecognized source of cytokines.