New considerations of health disparities within allergy and immunology.

The pandemic, political upheavals, and social justice efforts in our society have resulted in attention to persistent health disparities and the urgent need to address them. Using a scoping review, we describe published updates to address disparities and targets for interventions to improve gaps in care within allergy and immunology. These disparities-related studies provide a broad view of our current understanding of how social determinants of health threaten patient outcomes and our ability to advance health equity efforts in our field. We outline next steps to improve access to care and advance health equity for patients with allergic/immunologic diseases through actions taken at the individual, community, and policy levels, which could be applied outside of our field. Key among these are efforts to increase the diversity among our trainees, providers, and scientific teams and enhancing efforts to participate in advocacy work and public health interventions. Addressing health disparities requires advancing our understanding of the interplay between social and structural barriers to care and enacting the needed interventions in various key areas to effect change.

Health disparities in allergic and immunologic conditions in racial and ethnic underserved populations: A Work Group Report of the AAAAI Committee on the Underserved.

Health disparities are health differences linked with economic, social, and environmental disadvantage. They adversely affect groups that have systematically experienced greater social or economic obstacles to health. Renewed efforts are needed to reduced health disparities in the United States, highlighted by the disparate impact on racial minorities during the coronavirus pandemic. Institutional or systemic patterns of racism are promoted and legitimated through accepted societal standards, and organizational processes within the field of medicine, and contribute to health disparities. Herein, we review current evidence regarding health disparities in allergic rhinitis, asthma, atopic dermatitis, food allergy, drug allergy, and primary immune deficiency disease in racial and ethnic underserved populations. Best practices to address these disparities involve addressing social determinants of health and adopting policies to improve access to specialty care and treatment for the underserved through telemedicine and community partnerships, cross-cultural provider training to reduce implicit bias, inclusion of underserved patients in research, implementation of culturally competent patient education, and recruitment and training of health care providers from underserved communities. Addressing health disparities requires a multilevel approach involving patients, health providers, local agencies, professional societies, and national governmental agencies.

Lost in Translation: Lack of CD4 Expression due to a Novel Genetic Defect.

CD4 expression identifies a subset of mature T cells primarily assisting the germinal center reaction and contributing to CD8+ T-cell and B-cell activation, functions, and longevity. Herein, we present a family in which a novel variant disrupting the translation-initiation codon of the CD4 gene resulted in complete loss of membrane and plasma soluble CD4 in peripheral blood, lymph node, bone marrow, skin, and ileum of a homozygous proband. This inherited CD4 knockout disease illustrates the clinical and immunological features of a complete deficiency of any functional component of CD4 and its similarities and differences with other clinical models of primary or acquired loss of CD4+ T cells. The first inherited loss of any functional component of CD4, including soluble CD4, is clinically distinct from any other congenital or acquired CD4 T-cell defect and characterized by compensatory changes in T-cell subsets and functional impairment of B cells, monocytes, and natural killer cells.

Specific IgG4 antibodies to cow's milk proteins in pediatric patients with eosinophilic esophagitis.

BACKGROUND: Allergen-specific IgG4 (sIgG4) antibodies are often associated with tolerance, but sIgG4 antibodies to causally relevant foods have been reported recently in adults with eosinophilic esophagitis (EoE). Prevalence and levels of food sIgG4 are not well established in the general pediatric population. OBJECTIVE: We sought to investigate serum food sIgG4 with component diagnostics in children with EoE and children from an unselected birth cohort and to explore the effects of sex, age, and milk consumption on sIgG4 levels. METHODS: Sera from 71 pediatric patients with EoE and 210 early adolescent children from an unselected birth cohort (Project Viva) were assayed for sIgG4 and specific IgE (sIgE) to major cow's milk (CM) proteins (α-lactalbumin, ß-lactoglobulin, and caseins) and to wheat, soy, egg, and peanut proteins. RESULTS: In the EoE cohort high-titer sIgG4 (≥10 µg/mL) to CM proteins was more common than in control sera and achieved odds ratios for EoE ranging from 5.5 to 8.4. sIgE levels to CM proteins were mostly 4 IU/mL or less in patients with EoE, such that sIgG4/sIgE ratios were often 10,000 or greater. When adjusted for age and milk consumption, high-titer sIgG4 to CM proteins was strongly associated with EoE, with an odds ratio of greater than 20 to all 3 CM proteins in boys. CONCLUSIONS: sIgG4 to CM proteins are common and high titer in children with EoE. Although it is not clear that this response is pathogenic, sIgG4 levels imply that these antibodies are an important feature of the local immune response that gives rise to EoE.

Serum vitamin D levels in a cohort of adult and pediatric patients with eosinophilic esophagitis.

BACKGROUND: Vitamin D deficiency has been associated with increased risk for severe asthma, challenge-proven food allergy, and severe atopic dermatitis. Vitamin D levels have not been reported in patients with eosinophilic esophagitis (EoE). OBJECTIVE: To determine levels of 25-hydroxyvitamin D in a cohort of patients with EoE. METHODS: Total serum 25-hydroxyvitamin D was measured using liquid chromatography with tandem mass spectroscopy in adults (n = 35) and children (n = 34) with EoE. Results were compared with patient demographics, EoE-specific disease parameters, markers of sensitization, and features of severity using multivariable logistic regression. RESULTS: The median vitamin D level was 28.9 ng/mL. Patients with insufficient vitamin D (<30 ng/mL) were older (median 25.5 vs 16.2 years) and had a higher body mass index (median 25.2 vs 19.8 kg/m(2)). Peak median esophageal eosinophil counts were not significantly different for vitamin D insufficient and sufficient patient groups; however, higher vitamin D levels correlated with higher histologic eosinophil counts (R = 0.61, P = .03). Although there were no statistical differences in total IgE or levels of specific IgE between patients with vitamin D insufficiency and those with sufficiency, a positive skin prick test reaction to peanut was more common in patients who had vitamin D insufficiency (adjusted odds ratio 7.57, P = .009). Vitamin D insufficiency was not associated with surrogate markers of severity (dilation in adults or hospitalization or emergency visits in children). CONCLUSION: In these patients with EoE, vitamin D levels were low overall (median <30 ng/mL). The only marker of sensitization associated with insufficient vitamin D in these patients with EoE was a positive skin prick test reaction to peanut.

Factors Influencing Career Choice of Allergy and Immunology Fellows-in-Training: A Work Group Report of the AAAAI Program Directors Assembly Executive Committee.

BACKGROUND: As the burden of allergic and immunologic disease continues to increase, there is increased demand for a larger Allergy and Immunology (AI) subspecialty workforce. The field must prioritize the expansion of our workforce and the recruitment of exceptional and diverse trainees to ensure the vitality of the specialty. Although the AI fellowship match has traditionally been competitive, recent trends in fellowship applications have demonstrated fewer applicants per fellowship position. This trend has made recruitment a priority on the agenda of the national AI societies. OBJECTIVE: To elucidate key factors influencing the decision to choose the field of AI by querying fellows-in-training. METHODS: A survey was created and distributed yearly to fellows-in-training from 2017 to 2021 to identify factors influencing a career choice in AI. RESULTS: Approximately 59% of respondents rotated with AI in residency and 35% in both medical school and residency. Most respondents reported having a mentor in the field before fellowship, and many had their first exposures to AI during medical school (40%) or residency (32%). Most respondents decided to pursue AI during residency. The most common factors that influenced the decision to pursue AI were work/life balance, clinical aspects of the field, mentorship, and research opportunities. CONCLUSIONS: Our data suggest that the decision to pursue a career in AI often occurs during residency training and is motivated primarily by work/life balance, clinical aspects of the field, and clinician mentorship. Our survey results could provide guidance to AI training programs on strategies to recruit exceptional and diverse trainees.

Understanding Health Equity in Patient-Reported Outcomes.

Patient-reported outcomes (PROs) are measures of patients' health that are conveyed directly by individual patients. These measures serve as instruments to evaluate the impact of interventions on any aspect of patients' health, from specific symptoms to broader quality of life indicators. However, their effectiveness relies on capturing relevant factors accurately. Whereas they are commonly used in clinical trials, PROs extend their influence across health care settings, informing clinicians, health care payers, regulators, and administrators to guide quality improvement and reimbursement decisions. Neglecting health equity considerations in PRO development and implementation widens health disparities, leading to biased interpretations, medical mismanagement, and poor health outcomes among marginalized groups. To foster equitable health care, efforts must focus on considering the values of underrepresented populations in PRO design, addressing barriers to completion, enhancing representation in research, providing cultural competency training for clinicians, and allocating research funding to support health equity research. By addressing these issues, advances can be made toward fostering inclusive, equitable health care for all individuals.

Biologic Therapy in Rare Eosinophil-Associated Disorders: Remaining Questions and Translational Research Opportunities.

Rare eosinophil-associated disorders (EADs), including hypereosinophilic syndrome, eosinophilic granulomatosis with polyangiitis and eosinophilic gastrointestinal disorders, are a heterogeneous group of conditions characterized by blood and/or tissue hypereosinophilia and eosinophil-related clinical manifestations. Although the recent availability of biologic therapies that directly and indirectly target eosinophils has the potential to dramatically improve treatment options for all EADs, clinical trials addressing their safety and efficacy in rare EADs have been relatively few. Consequently, patient access to therapy is limited for many biologics, and the establishment of evidence-based treatment guidelines has been extremely difficult. In this regard, multicenter retrospective collaborative studies focusing on disease manifestations and treatment responses in rare EADs have provided invaluable data for physicians managing patients with these conditions and helped identify important questions for future translational research. During the Clinical Pre-Meeting Workshop held in association with the July 2023 biennial meeting of the International Eosinophil Society in Hamilton, Ontario, Canada, the successes and limitations of pivotal multicenter retrospective studies in EADs were summarized, and unmet needs regarding the establishment of guidelines for use of biologics in rare EADs were discussed. Key topics of interest included: 1) clinical outcome measures, 2) minimally invasive biomarkers of disease activity, 3) predictors of response to biologic agents, and 4) long-term safety of eosinophil depletion. Herein, we report a summary of these discussions, presenting a state-of-the-art overview of data currently available for each of these topics, the limitations of the data, and avenues for future data generation through implementation of multidisciplinary and multicenter studies.

Autoantibodies in chronic idiopathic urticaria and nonurticarial systemic autoimmune disorders.

BACKGROUND: Chronic idiopathic urticaria (CU) has been associated with other autoimmune diseases and basophil-activating autoantibodies to FcεRI or IgE. It is unknown whether patients with systemicautoimmune diseases have a similar prevalence of these autoantibodies. OBJECTIVE: To compare the prevalences of basophil-activating autoantibodies (elevated CU Index) in patients with CU, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Clinical characteristics and laboratory studies were examined for an association with the CU Index. METHODS: Adult patients, 27 with CU, 27 with RA, and 26 with SLE, and 20 healthy controls were compared on the basis of the CU Index panel, anti-IgE, and antithyroid antibodies. RESULTS: The CU Index values were significantly higher in the CU group when compared with the RA group but not when compared with the SLE group. 33% of CU, 23% of SLE, 3.7% of RA, and 15% of controls had apositive CU Index. Elevated antithyroid antibody levels did not correlate with a positive CU Index in any of the groups. An elevated CU Index in the SLE group was not associated with age, sex, ethnicity, disease severity, or history of atopy. CONCLUSION: The CU Index values were elevated in patients with CU and SLE. The presence of these autoantibodies did not correlate with disease activity or presence of thyroid antibodies. Functional autoantibodies may not be specific for chronic idiopathic urticaria, and their role in nonurticarial systemic autoimmune diseases requires further investigation.

Avapritinib versus Placebo in Indolent Systemic Mastocytosis.

BACKGROUND: Indolent systemic mastocytosis (ISM) is a clonal mast-cell disease driven by the KIT D816V mutation. We assessed the efficacy and safety of avapritinib versus placebo, both with best supportive care, in patients with ISM. METHODS: We randomized patients with moderate to severe ISM (total symptom score [TSS] of ≥28; scores range from 0 to 110, with higher numbers indicating more severe symptoms) two to one to avapritinib 25 mg once daily (n=141) or placebo (n=71). The primary end point was mean change in TSS based on the 14-day average of patient-reported severity of 11 symptoms. Secondary end points included reductions in serum tryptase and blood KIT D816V variant allele fraction (≥50%), reductions in TSS (≥50% and ≥30%), reduction in bone marrow mast cells (≥50%), and quality of life measures. RESULTS: From baseline to week 24, avapritinib-treated patients had a decrease of 15.6 points (95% CI, −18.6 to −12.6) in TSS compared to a decrease of 9.2 points (−13.1 to −5.2) in the placebo group; P<0.003. From baseline to Week 24, 76/141 patients (54%; 45% to 62%) in the avapritinib group compared to 0/71 patients in the placebo group achieved a ≥50% reduction in serum tryptase level; P<0.001. Edema and increases in alkaline phosphatase were more common with avapritinib than placebo; there were few treatment discontinuations because of adverse events. CONCLUSIONS: In this trial, avapritinib was superior to placebo in reducing uncontrolled symptoms and mast-cell burden in patients with ISM. The long-term safety and efficacy of this approach for patients with ISM remain the focus of the ongoing trial. (Funded by Blueprint Medicines Corporation; ClinicalTrials.gov number, NCT03731260.)

Methods for Cross-Cultural Communication in Clinic Encounters.

Successful cross-cultural communication is critical for adequate exchange of ideas with our patients. Our communities have become more diverse, and thus, the necessity has increased. The murder of George Floyd and other atrocities have sparked recognition of the need to address social injustice and racism and as we fight the ongoing coronavirus disease 2019 (COVID-19) pandemic. Allergist-immunologists are uniquely trained to explain the complex immunology of COVID-19 to patients, but they have less experience discussing issues of health equity. Here, we explore critical components of patient-provider communication: communicating with those for whom English is a second language, advising patients with limited health literacy, and understanding nonbiomedical views of health and wellness. Two barriers to communication are discussed: implicit bias and structural racism. Finally, we consider how the recent innovations in technology, the electronic health record including its patient portal and the use of telemedicine, have both impeded and improved communication. We offer suggestions as to what we could do to address these in our own local communities that would ensure better understanding and exchange of health information. This perspective grew out of an effort by the American Academy of Allergy, Asthma, and Immunology (AAAAI) Committee on the Underserved to provide training in cross-cultural communication.

Deconstructing the Way We Use Pulmonary Function Test Race-Based Adjustments.

Race is a social construct. It is used in medical diagnostic algorithms to adjust the readout for spirometry and other diagnostic tests. The authors review historic evidence about the origins of race adjustment in spirometry, and recent attention to the lack of scientific evidence for their continued use. Existing reference values imply that White patients have better lung function than non-White patients. They perpetuate the historical assumptions that human biological functions of the lung should be calculated differently on the basis of racial-skin color without considering the difficulty of using self-identified race. More importantly, they fail to consider the important effects of environmental exposures, socioeconomic differences, health care access, and prenatal factors on lung function. In addition, the use of "race adjustment" implies a White standard to which other non-White values need "adjustment." Because of the spirometric guidelines in place, the current diagnostic prediction adjustment practice may have untoward effects on patients not categorized as "White," including underdiagnosis in asthma and restrictive lung disease, undertreatment with lung transplant, undercompensation in workers compensation cases, and other unintended consequences. Individuals, institutions, national organizations, and policymakers should carefully consider the historic basis, and reconsider the current role of an automated, race-based adjustment in spirometry.

An International, Retrospective Study of Off-Label Biologic Use in the Treatment of Hypereosinophilic Syndromes.

BACKGROUND: Treatment of hypereosinophilic syndrome (HES) often requires the use of immunomodulators with substantial side effect profiles. The emergence of biologics offers an alternative treatment modality. OBJECTIVE: To examine real-world practice data to describe the safety and consequences of various biologics suspected to directly or indirectly affect eosinophilic inflammation for the treatment of HES. METHODS: Retrospective data from 13 centers were collected via an online Research Electronic Data Capture repository. Inclusion criteria included (1) peripheral eosinophil count of 1,500/mm3 or greater without a secondary cause; (2) clinical manifestations attributable to the eosinophilia; and (3) having received mepolizumab (anti-IL-5), benralizumab (afucosylated anti-IL-5 receptor α), omalizumab (anti-IgE), alemtuzumab (anti-CD52), dupilumab (anti-IL-4 receptor α), or reslizumab (anti-IL-5) outside a placebo-controlled clinical trial. RESULTS: Of the 151 courses of biologics prescribed for 121 patients with HES, 59% resulted in improved HES symptoms and 77% enabled tapering of other HES medications. Overall, 105 patients were receiving daily systemic glucocorticoids at the time of a biologic initiation and were able to reduce the glucocorticoid dose by a median reduction of 10 mg of daily prednisone equivalents. Biologics were generally safe and well-tolerated other than infusion reactions with alemtuzumab. Thirteen of 24 patients had clinical improvement after switching biologics and nine patients responded to increasing the dose of mepolizumab after a lack of response to a lower dose. CONCLUSIONS: Biologics may offer a safer treatment alternative to existing therapies for HES, although the optimal dosing and choice for each subtype of HES remain to be determined. Limitations of this study include its retrospective nature and intersite differences in data collection and availability of each biologic.

Disparities in Asthma and Allergy Care: What Can We Do?

The coronavirus disease pandemic and the growing movements for social and racial equality have increased awareness of disparities in American health care that exist on every level. Social determinants of health, structural racism, and implicit bias play major roles in preventing health equity. We begin with the larger picture and then focus on examples of systemic and health inequities and their solutions that have special relevance to allergy-immunology. We propose a 4-prong approach to address inequities that requires (1) racial and ethnic inclusivity in research with respect to both participants and investigators, (2) diversity in all aspects of training and practice, (3) improvement in communication between clinicians and patients, and (4) awareness of the social determinants of health. By communication we mean sensitivity to the role of language, cultural background, and health beliefs in physician-patient interactions and provision of training and equipment so that the use of telecommunication can be a resource for all patients. The social determinants of health are the social factors that affect health and the success of health care, such as adequacy of housing and access to nutritious foods. Using this 4-prong approach we can overcome health disparities.

Severity of COVID-19 in hospitalized patients with and without atopic disease.

BACKGROUND: Data from the 2009 influenza pandemic suggested asthma might protect from severe disease in hospitalized patients. Asthma does not appear to increase risk for hospitalization or mortality with COVID-19. OBJECTIVE: This study was undertaken to see if atopy actually protected those hospitalized with COVID-19. METHODS: Retrospective chart review on all patients testing positive for SARS-CoV-2 over 2 months at a major adult and pediatric tertiary referral center hospital. Charts were evaluated for history of atopic disease, as were the need for ICU admission, requirement for supplemental oxygen and/or intubation, and in hospital mortality. RESULTS: No significant differences in outcomes for patients (n = 275) based on atopic disease were noted: ICU admission, 43% versus 44.7% (atopic versus no atopic disease, respectively; p = 0.84); supplemental oxygen use, 79.1% versus 73.6% (p = 0.36); intubation rate, 35.8% versus 36.5% (p = 0.92); and mortality rate, 13.4% versus 20.7% (p = 0.19). More patients with atopic disease had COPD listed as a diagnosis in their chart (38.8% versus 17.3%, p < 0.001). COPD was associated with an increased rate of ICU admission (aOR = 2.22 (1.15, 4.30) p = 0.02) and intubation (aOR = 2.05 (1.07, 3.92) p = 0.03). After adjusting for COPD, patients with atopic disease had a trend for reduced mortality (aOR 0.55 (0.23, 1.28), p = 0.16), but those with asthma did not (p > 0.2). CONCLUSION: Severity of COVID-19 in hospitalized patients does not differ based on atopic status. However, adjusting for presence of COPD led to a suggestion of possible reduced severity in patients with atopy but not asthma.