Skin testing as a biomarker in drug allergy.

Despite the significant negative impact drug allergies can have on patient care, the diagnosis is largely based on clinical history, and there are limited diagnostic tests that can be done at the time of a reaction. Biomarkers are needed to improve the diagnosis and the identification of the culprit medication. Skin testing is the most useful biomarker for immediate- and delayed-type reactions available, but it is limited by its low sensitivity. To improve its accuracy and reproducibility, a standardized procedure must be used. For immediate-type reactions, penicillin skin testing is the most widely studied, and it can be used in patients with history of anaphylaxis or recent immunoglobulin E-mediated reaction or for whom there is a significant risk if a reaction were to occur, such as pregnancy. Skin testing is also important in allergy to platinum agents allowing for continued first-line therapy. For delayed-type reactions, patch testing and delayed intradermal testing, used in conjunction with clinical history, can help to improve identification of the culprit medication depending on the type of reaction. Other biomarkers including in vitro testing for specific immunoglobulin E, basophil activation test, lymphocyte transformation test, ELISpot, and genetic factors that increase the likelihood of reaction are under investigation, and they may be most helpful when used in combination with the clinical history and skin testing results.

Severe autoimmune hemolytic anemia following receipt of SARS-CoV-2 mRNA vaccine.

BACKGROUND: Large clinical trials have demonstrated the overall safety of vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, reports have emerged of autoimmune phenomena, including vaccine-associated myocarditis, immune thrombocytopenia, and immune thrombotic thrombocytopenia. CASE PRESENTATION: Here we present a novel case of a young woman who developed life-threatening autoimmune hemolytic anemia (AIHA) after her first dose of a SARS-CoV-2 mRNA vaccine. Notably, initial direct antiglobulin testing was negative using standard anti-IgG reagents, which are "blind" to certain immunoglobulin (IgG) isotypes. Further testing using an antiglobulin reagent that detects all IgG isotypes was strongly positive and confirmed the diagnosis of AIHA. The patient required transfusion with 13 units of red blood cells, as well as treatment with corticosteroids, rituximab, mycophenolate mofetil, and immune globulin. CONCLUSION: As efforts to administer SARS-CoV-2 vaccines continue globally, clinicians must be aware of potential autoimmune sequelae of these therapies.

Management of patients with nonaspirin-exacerbated respiratory disease aspirin hypersensitivity reactions.

Because of widespread use, nonsteroidal anti-inflammatory drugs (NSAIDs) are the second most common cause of all adverse drug reactions, with hypersensitivity reported in ∼1% of the population. NSAID hypersensitivity can be categorized into five types by the underlying disease, symptoms of reaction, and timing of reaction. These include rhinitis and asthma induced by NSAIDs (also known as aspirin-exacerbated respiratory disease), NSAID-exacerbated cutaneous disease (NECD), urticaria or angioedema induced by multiple NSAIDs, single NSAID-induced reactions, and delayed NSAID reactions. NECD occurs in one-third of patients with chronic urticaria who develop an exacerbation of their urticaria, sometimes with angioedema, typically beginning 30-90 minutes after ingestion of NSAIDs that inhibit cyclooxygenase (COX)-1. In urticaria or angioedema induced by multiple NSAIDs, patients without underlying disease develop urticaria or angioedema 30-90 minutes after ingestion of COX-1-inhibiting NSAIDs including aspirin. Single NSAID-induced reactions are immediate and specific to a single NSAID and are thought to occur because of an IgE-mediated reaction against a specific epitope of the NSAID. Delayed NSAID reactions occur days to weeks after initiating an NSAID. These are T-cell mediated and not amenable to desensitization or rechallenge. Classifying the type of NSAID hypersensitivity is important because many patients with a prior history of urticaria or angioedema induced by multiple NSAIDs will often tolerate aspirin test dose. This would allow the use of an aspirin for primary or secondary prevention in patients with coronary artery disease despite a presumed history of NSAID hypersensitivity.

Evaluation and management of a patient with multiple drug allergies.

Multiple drug allergy syndrome (MDAS) is a clinical diagnosis made in patients with adverse reactions to two or more structurally unrelated drugs with an underlying immune-mediated mechanism causing the reaction. The evaluation of a patient with MDAS begins with a comprehensive drug allergy history and consideration of the underlying immune mechanism for each reaction. Skin testing is a useful diagnostic tool; however, the only validated immediate hypersensitivity skin testing is for penicillin where the antigenic determinants have been identified. Skin testing to most other drugs, although not validated, can be considered using a nonirritating concentration (NIC). In general, skin test positivity using an NIC suggests that the drug should be avoided, but a negative result does not rule out an IgE-mediated allergy. A test dose, also called a drug provocation test, graded oral challenge, or incremental challenge, should be performed when there is a low likelihood of an IgE-mediated mechanism for the reaction. In patients with a recent IgE-mediated hypersensitivity reaction or positive skin testing with no reasonable alternative treatment options, desensitization protocols can be used to allow the patient to safely receive a necessary drug. The evaluation of patients with MDAS is both challenging and time-consuming for the practicing allergist, who must systematically evaluate each reaction to help determine which drugs can be safely used again in the future. The molecular mechanisms and risk factors for this condition remain poorly understood, but research to further understand this condition is ongoing.

Clinical Phenotypes of Immediate First-Dose Reactions to mRNA COVID-19: A Multicenter Latent Class Analysis.

BACKGROUND: Although immediate potentially allergic reactions have been reported after dose 1 of mRNA coronavirus disease 2019 (COVID-19) vaccines, comprehensively defined subtypes have not been clearly distinguished. OBJECTIVE: To define distinct clinical phenotypes of immediate reactions after dose 1 of mRNA COVID-19 vaccination, and to assess the relation of clinical phenotype to mRNA COVID-19 vaccine second dose tolerance. METHODS: This retrospective study included patients with 1 or more potentially allergic symptoms or signs within 4 hours of receiving dose 1 of an mRNA COVID-19 vaccine and assessed by allergy/immunology specialists from 5 U.S. academic medical centers (January-June 2021). We used latent class analysis-an unbiased, machine-learning modeling method-to define novel clinical phenotypes. We assessed demographic, clinical, and reaction characteristics associated with phenotype membership. Using log-binomial regression, we assessed the relation between phenotype membership and second dose tolerance, defined as either no symptoms or mild, self-limited symptoms resolving with antihistamines alone. A sensitivity analysis considered second dose tolerance as objective signs only. RESULTS: We identified 265 patients with dose-1 immediate reactions with 3 phenotype clusters: (1) Limited or Predominantly Cutaneous, (2) Sensory, and (3) Systemic. A total of 223 patients (84%) received a second dose and 200 (90%) tolerated their second dose. Sensory cluster (all patients had the symptom of numbness or tingling) was associated with a higher likelihood of second dose intolerance, but this finding did not persist when accounting for objective signs. CONCLUSIONS: Three novel clinical phenotypes of immediate-onset reactions after dose 1 of mRNA COVID-19 vaccines were identified using latent class analysis: (1) Limited or Predominantly Cutaneous, (2) Sensory, and (3) Systemic. Whereas these clinical phenotypes may indicate differential mechanistic etiologies or associations with subsequent dose tolerance, most individuals proceeding to their second dose tolerated it.

Allergy and immunology interest and exposure among US medical students and residents.

Background: Despite the immense burden of allergic disease, the allergy and immunology (AI) workforce in the United States continues to shrink. Fellowship applications for AI have declined sharply in contrast to those in more popular specialties. Objectives: Here we have sought to evaluate the current level of AI interest and exposure among early trainees in the United States, as well as their perspective on how to improve interest in the field. Methods: An 18-item questionnaire was sent via e-mail list-serve to 2 groups: (1) mostly residents in the American Academy of Allergy, Asthma & Immunology (AAAAI) with interest in AI and (2) medical students in the American Medical Student Association (AMSA) whose specialty interests were not known. Results: In the AAAAI group, 412 members were surveyed and 70 responses were received. In the AMSA group, 4778 members were surveyed and 47 responses were received. More individuals in the AAAAI group interacted with their AI division than in the AMSA group (73% vs 19% [P < .001]). On average, the AAAAI group would "probably" pursue AI whereas the AMSA group who would "definitely not" do so (P < .001). Almost all of the AMSA group (94%) had heard of AI before, but only 19% of them interacted with AI at their program. Regarding ways to increase interest in AI, the top responses for both groups were clinical exposure via electives and shadowing (a score of 4.69 on a 5-point scale) and didactic exposure via lectures and presentations (a score of 4.29). Conclusions: Our study suggests that increasing AI opportunities for didactics and clinical exposure may lead medical students to develop more interest in pursuing the field. Some strategies are also discussed.

Safety, Outcomes, and Recommendations for Two-Step Outpatient Nonsteroidal Anti-Inflammatory Drug Challenges.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) outpatient challenge protocols are not standardized. They vary in clinical practice and can be time- and resource-intensive to perform. OBJECTIVE: To investigate the safety and outcomes of two-step outpatient NSAID challenges to evaluate patients with non-aspirin-exacerbated respiratory disease (AERD)-related NSAID hypersensitivity. METHODS: We conducted a retrospective study of patients with a history of NSAID allergy who underwent outpatient NSAID challenges under allergist supervision. Individuals with AERD were excluded. Patient demographics, NSAID reaction history, and drug challenge details and outcomes were collected. RESULTS: A total of 249 patients (mean age, 51.6 years; 63.5% female) underwent 262 NSAID challenges. Of these, 224 challenges were negative (85.5%). Thirty challenges resulted in an immediate reaction during the challenge procedure (11.5%) and eight resulted in delayed reactions (3.1%). Three individuals with immediate reactions required treatment with intramuscular epinephrine. Factors associated with a positive NSAID challenge included a prior reaction occurring within 5 years of drug challenge (odds ratio [OR] = 3.66; 95% confidence interval [CI], 1.67-8.44), a prior immediate reaction within 3 hours of NSAID ingestion (OR = 2.45; 95% CI, 1.12-5.57), a history of cross-reactive NSAID hypersensitivity to multiple NSAIDs (OR = 2.97; 95% CI, 1.23-6.91), and the presence of comorbid chronic spontaneous urticaria (OR = 2.95; 95% CI, 1.35-6.41). CONCLUSIONS: More than 85% of two-step non-AERD NSAID drug challenges were negative for an immediate or delayed reaction, which allowed patients to use at least one clinically indicated NSAID. Challenge reactions were generally mild. Two-step NSAID challenge protocols can be safely performed in the outpatient setting.

Response to Severe Acute Respiratory Syndrome Coronavirus 2 Initial Series and Additional Dose Vaccine in Patients With Predominant Antibody Deficiency.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with predominant antibody deficiency (PAD) is associated with high morbidity, yet data regarding the response to SARS-CoV-2 immunization in PAD patients, including additional dose vaccine, are limited. OBJECTIVE: To characterize antibody response to SARS-CoV-2 vaccine in PAD patients and define correlates of vaccine response. METHODS: We assessed the levels and function of anti-SARS-CoV-2 antibodies in 62 PAD patients compared with matched healthy controls at baseline, at 4 to 6 weeks after the initial series of immunization (a single dose of Ad26.COV2.S [Janssen] or two doses of BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]), and at 4 to 6 weeks after an additional dose immunization, if received. RESULTS: After the initial series of SARS-CoV-2 vaccination, PAD patients had lower mean anti-spike antibody levels compared with matched healthy controls (140.1 vs 547.3 U/mL; P = .02). Patients with secondary PAD (eg, B-cell depletion therapy was used) and those with severe primary PAD (eg, common variable immunodeficiency with autoinflammatory complications) had the lowest mean anti-spike antibody levels. Immune correlates of a low anti-spike antibody response included low CD4+ T helper cells, low CD19+ total B cells, and low class-switched memory (CD27+IgD/M-) B cells. In addition, a low (<100 U/mL) anti-spike antibody response was associated with prior exposure to B-cell depletion therapy, both at any time in the past (odds ratio = 5.5; confidence interval, 1.5-20.4; P = .01) and proximal to vaccination (odds ratio = 36.4; confidence interval, 1.7-791.9; P = .02). Additional dose immunization with an mRNA vaccine in a subset of 31 PAD patients increased mean anti-spike antibody levels (76.3 U/mL before to 1065 U/mL after the additional dose; P < .0001). CONCLUSIONS: Patients with secondary and severe primary PAD, characterized by low T helper cells, low B cells, and/or low class-switched memory B cells, were at risk for low antibody response to SARS-CoV-2 immunization, which improved after an additional dose vaccination in most patients.

Immunogenicity and Reactogenicity of SARS-CoV-2 Vaccines in Patients With Cancer: The CANVAX Cohort Study.

PURPOSE: The immunogenicity and reactogenicity of SARS-CoV-2 vaccines in patients with cancer are poorly understood. METHODS: We performed a prospective cohort study of adults with solid-organ or hematologic cancers to evaluate anti-SARS-CoV-2 immunoglobulin A/M/G spike antibodies, neutralization, and reactogenicity ≥ 7 days following two doses of mRNA-1273, BNT162b2, or one dose of Ad26.COV2.S. We analyzed responses by multivariate regression and included data from 1,638 healthy controls, previously reported, for comparison. RESULTS: Between April and July 2021, we enrolled 1,001 patients; 762 were eligible for analysis (656 had neutralization measured). mRNA-1273 was the most immunogenic (log10 geometric mean concentration [GMC] 2.9, log10 geometric mean neutralization titer [GMT] 2.3), followed by BNT162b2 (GMC 2.4; GMT 1.9) and Ad26.COV2.S (GMC 1.5; GMT 1.4; P < .001). The proportion of low neutralization (< 20% of convalescent titers) among Ad26.COV2.S recipients was 69.9%. Prior COVID-19 infection (in 7.1% of the cohort) was associated with higher responses (P < .001). Antibody titers and neutralization were quantitatively lower in patients with cancer than in comparable healthy controls, regardless of vaccine type (P < .001). Receipt of chemotherapy in the prior year or current steroids were associated with lower antibody levels and immune checkpoint blockade with higher neutralization. Systemic reactogenicity varied by vaccine and correlated with immune responses (P = .002 for concentration, P = .016 for neutralization). In 32 patients who received an additional vaccine dose, side effects were similar to prior doses, and 30 of 32 demonstrated increased antibody titers (GMC 1.05 before additional dose, 3.17 after dose). CONCLUSION: Immune responses to SARS-CoV-2 vaccines are modestly impaired in patients with cancer. These data suggest utility of antibody testing to identify patients for whom additional vaccine doses may be effective and appropriate, although larger prospective studies are needed.

First-Dose mRNA COVID-19 Vaccine Allergic Reactions: Limited Role for Excipient Skin Testing.

BACKGROUND: The Centers for Disease Control and Prevention state that a severe or immediate allergic reaction to the first dose of an mRNA COVID-19 vaccine is a contraindication for the second dose. OBJECTIVE: To assess outcomes associated with excipient skin testing after a reported allergic reaction to the first dose of mRNA COVID-19 vaccine. METHODS: We identified a consecutive sample of patients with reported allergic reactions after the first dose of mRNA COVID-19 vaccine who underwent allergy assessment with skin testing to polyethylene glycol (PEG) and, when appropriate, polysorbate 80. Skin testing results in conjunction with clinical phenotyping of the first-dose mRNA COVID-19 vaccine reaction guided second-dose vaccination recommendation. Second-dose mRNA COVID-19 vaccine reactions were assessed. RESULTS: Eighty patients with reported first-dose mRNA COVID-19 vaccine allergic reactions (n = 65; 81% immediate onset) underwent excipient skin testing. Of those, 14 (18%) had positive skin tests to PEG (n = 5) and/or polysorbate 80 (n = 12). Skin testing result did not affect tolerance of the second dose in patients with immediate or delayed reactions. Of the 70 patients who received the second mRNA COVID-19 vaccine dose (88%), 62 had either no reaction or a mild reaction managed with antihistamines (89%), but 2 patients required epinephrine treatment. Three patients with positive PEG-3350 intradermal (methylprednisolone) testing tolerated second-dose mRNA COVID-19 vaccination. Refresh Tears caused nonspecific skin irritation. CONCLUSIONS: Most individuals with a reported allergic reaction to the first dose of mRNA COVID-19 vaccines, regardless of skin test result, received the second dose safely. More data are needed on the value of skin prick testing to PEG (MiraLAX) in evaluating patients with mRNA COVID-19 vaccine anaphylaxis. Refresh Tears should not be used for skin testing.

mRNA Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions: Current Evidence and Suggested Approach.

The U.S. Food and Drug Administration (FDA) has recently issued an Emergency Use Authorization (EUA) for 2 highly effective coronavirus disease 2019 (COVID-19) vaccines from Pfizer-BioNTech and Moderna. This has brought hope to millions of Americans in the midst of an ongoing global pandemic. The FDA EUA guidance for both vaccines is to not administer the vaccine to individuals with a known history of a severe allergic reaction (eg, anaphylaxis) to any component of the COVID-19 vaccine. The Centers for Disease Control and Prevention (CDC) additionally advises individuals with a history of an immediate allergic reaction to a vaccine or injectable or any history of anaphylaxis be observed for 30 minutes after COVID-19 vaccination. All other individuals should be observed for 15 minutes after COVID-19 vaccination. Staff at vaccine clinics must be able to identify and manage anaphylaxis. Post-FDA EUA, despite very strong safety signals in both phase 3 trials, reports of possible allergic reactions have raised public concern. To provide reassurance and support during widespread global vaccination, allergists must offer clear guidance to individuals based on the best information available, but also in accordance with the broader recommendations of regulatory agencies. This review summarizes vaccine allergy epidemiology and proposes drug and vaccine allergy expert opinion informed risk stratification for Allergy specialist use in conjunction with guidance of public health and regulatory authorities. The risk stratification schema guide care for (1) individuals with different allergy histories to safely receive their first mRNA COVID-19 vaccine and (2) individuals who develop a reaction to their first dose of mRNA COVID-19 vaccine.

Natural Language Processing Combined with ICD-9-CM Codes as a Novel Method to Study the Epidemiology of Allergic Drug Reactions.

BACKGROUND: Allergic drug reaction epidemiologic data are sparse because it remains difficult to identify true cases in large data sets using manual chart review. OBJECTIVE: To develop and validate a novel informatics method based on natural language processing (NLP) in combination with International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes that identifies allergic drug reactions in the electronic health record. METHODS: Previously studied and high-yield ICD-9-CM codes were used to screen for possible allergic drug reactions among all inpatients admitted in 2007 and 2008. A random sample was selected for manual chart review to identify true cases of allergic drug reactions. A rule-based NLP algorithm was then developed to identify allergic drug reactions using free-text clinical notes and discharge summaries from the filtered cases. The performance of using manual chart review of ICD-9-CM codes alone was compared with ICD-9-CM codes in combination with NLP. RESULTS: Of 3907 cases identified by ICD-9-CM codes, 725 (19%) were randomly selected for manual chart review; 335 were confirmed as allergic drug reactions, resulting in a positive predictive value (PPV) of 46% (range: 18%-79%) when using ICD-9-CM codes alone. Our NLP algorithm in combination with ICD-9-CM codes achieved a PPV of 86% (range: 69%-100%). Among the 335 confirmed positive cases, NLP identified 259 true cases, resulting in a recall/sensitivity of 77% (range: 26%-100%). Among the 390 negative cases, NLP achieved a specificity of 89% (range: 69%-100%). CONCLUSION: Using NLP with ICD-9-CM codes improved identification of allergic drug reactions. The resulting decrease in manual chart review effort will facilitate large epidemiology studies of this understudied area.

Identification of Inpatient Allergic Drug Reactions Using ICD-9-CM Codes.

BACKGROUND: The study of allergic drug reactions has been limited because of challenges in identifying and confirming cases. OBJECTIVE: To determine the utility of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for identifying inpatient allergic drug reactions and to compare findings with previous data in the emergency department. METHODS: By reviewing medical records of inpatients with ICD-9-CM codes and E codes suggestive of allergic drug reactions at a large urban academic medical center, we determined codes that yielded the most drug allergy cases and identified culprit drugs. RESULTS: In 2005 and 2010, 3337 and 5282 possible allergic drug reactions during hospitalization were identified and 1367 were reviewed. Allergic drug reactions were found in 409 (30.1%) of the reviewed charts, with 172 (29.7%) in 2005 and 237 (30.5%) in 2010. The codes that identified the highest percentage of true allergic drug reactions were dermatitis due to drug (693.0), allergic urticaria (708), angioneurotic edema (995.1), and anaphylaxis (995.0). Antibiotics were the most common cause (44.4%); however, multiple drug classes were often identified as likely culprit drugs. CONCLUSION: Specific ICD-9-CM codes can identify patients with allergic drug reactions, with antibiotics accounting for almost half of true reactions. Most patients with codes 693.0, 995.1, 708, and 995.0 had allergic drug reactions, with 693.0 as the highest yield code. An aggregate of multiple specific codes consistently identifies a cohort of patients with confirmed allergic drug reactions.

Utility of ICD-9-CM Codes for Identification of Allergic Drug Reactions.

BACKGROUND: The epidemiology of allergic drug reactions is poorly understood due, in large part, to difficulty in identifying true cases in population data sets. Use of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes is a potentially valuable approach that requires formal evaluation. OBJECTIVE: To better understand the utility of ICD-9-CM codes for identification of allergic drug reactions, including the validation of specific codes by chart review. METHODS: We reviewed randomly sampled medical records of patients treated in the emergency department (ED) between January 1, 2001, and December 31, 2006, with ICD-9-CM codes for drug allergy and E codes (E930-949) for adverse drug reactions. RESULTS: During the 6-year period, 11,130 charts were identified by ICD-9-CM and E codes and 1,634 were reviewed. Allergic drug reactions were found in 444 (27%) of the reviewed ED visits. The codes that identified the highest percentage of true allergic drug reactions were dermatitis due to drug (693.0; 87%), adverse reaction to drug (995.2; 52%), and anaphylaxis (995.0; 38%). Patients with both an ICD-9-CM code and an E code had a high likelihood of having an allergic drug reaction (76%). Most allergic drug reactions were attributed to antibiotics (42%), intravenous contrast (7%), and nonsteroidal anti-inflammatory drugs (6%). The estimated frequency of allergic drug reactions increased from 0.49% of ED visits in 2001 to 0.94% in 2012. CONCLUSIONS: Specific ICD-9-CM and E codes can be used in combination to identify allergic drug reactions. Further study of these codes in the inpatient and outpatient settings is necessary to better understand the utility of diagnosis codes for improving epidemiologic research on drug allergy.