The Association Between Malignancy, Immunodeficiency, and Atopy in IgE-Deficient Patients.

BACKGROUND: Studies show that IgE-deficient patients (IgE <2.5 kU/L) have a high prevalence of malignancy, but relevant clinical and laboratory characteristics associated with this susceptibility have never been well characterized. OBJECTIVE: To evaluate if there is an association between a malignancy diagnosis and other immunological parameters (atopy or other immune abnormalities) in IgE-deficient patients. METHODS: We retrospectively analyzed medical records of 408 IgE-deficient adults seen at our institution between 2005 and 2020. RESULTS: A malignancy diagnosis was found in 23.5% (96 of 408) of IgE-deficient patients. Among those who had allergy skin testing performed for allergic rhinitis-like symptoms, the nonatopic IgE-deficient patients (negative environmental skin tests) were more likely to have a malignancy diagnosis than the atopic group (odds ratio [OR] = 4.36, 95% confidence interval [CI]: 1.11-17.13, P = .03). The IgE-deficient individuals with an additional non-common variable immunodeficiency (non-CVID) humoral abnormality (n = 75; with low IgG, IgA, or IgM without meeting criteria for CVID) were more likely to have a malignancy diagnosis than those with only a selective IgE deficiency (n = 134; with normal IgA, IgM, and IgG) (OR = 2.79, 95% CI: 1.37-5.68, P = .005). Among the IgE-deficient patients, certain less well-defined immune abnormalities such as IgM deficiency (OR = 2.46, 95% CI: 1.13-5.36, P = .02), IgG2 deficiency (OR = 10.14, 95% CI: 1.9-54.1, P = .007), and CD4 lymphopenia (OR = 7.81, 95% CI: 2.21-27.63, P = .001) were associated with higher malignancy odds than those without these abnormalities. CONCLUSION: The odds of a malignancy diagnosis are not shared equally by all IgE-deficient patients. Prospective studies are needed to determine the utility of performing skin testing and measuring additional immunological parameters in assessing the long-term malignancy risk in IgE-deficient patients.

Adult-onset IgE-mediated cow's milk allergy-a rare phenotype.

Cow's milk allergy has been studied extensively in infants and young children and has public health importance around the globe. We describe the clinical and demographic characteristics of 3 cases of a rare presentation of adult-onset IgE-mediated cows' milk allergy.

Safety and efficacy of graded dosing of Pfizer-BioNTech mRNA COVID-19 vaccine after an immediate hypersensitivity reaction to first dose.

Current guidelines do not recommend subsequent mRNA COVID-19 vaccination in patients who experience immediate allergic reactions to the first dose. Our findings indicate that graded dosing of this vaccine is safe, efficacious, and useful for treating these individuals with allergy.

Relationship between low serum immunoglobulin E levels and malignancies in 9/11 World Trade Center responders.

BACKGROUND: Individuals with very low immunoglobulin E (IgE) levels have a high risk of developing malignancy. Previous studies have revealed that World Trade Center (WTC) responders exposed to carcinogens have an elevated risk of some cancers. OBJECTIVE: To evaluate the association between low-serum IgE levels and cancer development in WTC-exposed responders. METHODS: IgE levels were measured in 1851 WTC responders after September 11, 2001. This is the first pilot study in humans comparing the odds of developing cancer in this high-risk population, between the "low-IgE" (IgE in the lowest third percentile) vs "non-low-IgE" participants. RESULTS: A significantly higher proportion of hematologic malignancies was found in low-IgE (4/55, 7.3%) compared with non-low-IgE (26/1796, 1.5%, P < .01) responders. The proportion of solid tumors were similar in both groups (5.5% vs 11.4%, P > .05). After adjustment for relevant confounders (race, sex, age at blood draw, WTC arrival time, smoking status), the low-IgE participants had 7.81 times greater odds (95% confidence interval, 1.77-29.35) of developing hematologic cancer when compared with non-low-IgE participants. The hematologic cancers found in this cohort were leukemia (n = 1), multiple myeloma (n = 1), and lymphoma (n = 2). No statistical significance was found when estimating the odds ratio for solid tumors in relation to IgE levels. CONCLUSION: WTC responders with low serum IgE levels had the highest odds of developing hematologic malignancies. This hypothesis-generating study suggests that low serum IgE levels might be associated with the development of specific malignancies in at-risk individuals exposed to carcinogens. Larger, multicenter studies with adequate follow-up of individuals with different IgE levels are needed to better evaluate this relationship.

AllergoOncology: Danger signals in allergology and oncology: A European Academy of Allergy and Clinical Immunology (EAACI) Position Paper.

The immune system interacts with many nominal 'danger' signals, endogenous danger-associated (DAMP), exogenous pathogen (PAMP) and allergen (AAMP)-associated molecular patterns. The immune context under which these are received can promote or prevent immune activating or inflammatory mechanisms and may orchestrate diverse immune responses in allergy and cancer. Each can act either by favouring a respective pathology or by supporting the immune response to confer protective effects, depending on acuity or chronicity. In this Position Paper under the collective term danger signals or DAMPs, PAMPs and AAMPs, we consider their diverse roles in allergy and cancer and the connection between these in AllergoOncology. We focus on their interactions with different immune cells of the innate and adaptive immune system and how these promote immune responses with juxtaposing clinical outcomes in allergy and cancer. While danger signals present potential targets to overcome inflammatory responses in allergy, these may be reconsidered in relation to a history of allergy, chronic inflammation and autoimmunity linked to the risk of developing cancer, and with regard to clinical responses to anti-cancer immune and targeted therapies. Cross-disciplinary insights in AllergoOncology derived from dissecting clinical phenotypes of common danger signal pathways may improve allergy and cancer clinical outcomes.

Skin Testing Is Useful in Assessing Aeroallergen Sensitization in IgE Deficient Patients with Environmental Allergy-Like Symptoms.

BACKGROUND: The value of aeroallergen skin testing is not known in IgE deficient individuals (IgE<2.5 kU/L). OBJECTIVE: To investigate the utility of skin prick (SPT), intradermal skin testing (IDST) and measuring serum specific IgE (ssIgE) in IgE deficient patients presenting with environmental allergy-like symptoms. METHODS: Individuals with IgE deficiency who had both SPT and IDST performed between 2010 to 2020 were matched (age and gender) to three different groups of non-IgE deficient patients with IgE≥2.5 kU/L (normal IgE [2.5 ≤ IgE<100], high IgE [100≤IgE<1000] and very high IgE levels [≥1000 kU/L]) who also had skin testing performed for evaluation of environmental allergy-like symptoms. RESULTS: Among 34 IgE deficient patients who completed SPT and IDST, 52.9% (18/34) had at least one positive skin test (4 ± 3 positive tests/patient), compared with 91.2% in those with normal, 94.1% with high or 97.1% with very high IgE levels (p < 0.01). In contrast, only one of the IgE deficient patients had detectable ssIgE, while ssIgE levels were significantly higher in all other IgE subgroups. Allergic immunotherapy was prescribed for 22.2% of the IgE-deficient patients with positive skin tests, similar to those with normal (2/31, 6.5%, p = 0.21), high IgE (9/32, 28.1%, p = 0.25) and very high IgE levels (8/33, 23.5%, p = 0.07), with similar efficacy in their symptoms control. CONCLUSION: Individuals with IgE deficiency may present with environmental allergy-like symptoms. A combination of SPT and IDST is useful for diagnosing aeroallergen sensitizations in these patients, indicating the presence of skin mast cell-bound IgE in some of these individuals, despite very low serum IgE levels. Further studies are needed to assess the exact significance of positive skin tests and the benefits of immunotherapy in this group.

Severe asthma in adult, inner-city predominantly African-American and latinx population: demographic, clinical and phenotypic characteristics.

INTRODUCTION: The burden of asthma morbidity with co-existing atopy among the racial/ethnic minorities in the socio-economically disadvantaged NYC borough of the Bronx is unusually high. The multidisciplinary Montefiore Asthma Center (MAC) provides guideline-based treatment to this high-risk population through the joint efforts of Allergists/Immunologists, Pulmonologists, and on-site health educators. METHODS: The objective of this prospective, observational study was to define the demographic and clinical characteristics of severe asthma, evaluate improvement in asthma severity and lung function through the course of treatment at the MAC, and describe the asthma phenotypes of the patients managed at the MAC. Adults with severe asthma receiving treatment at the MAC were followed from their first to their last visit at the MAC. Patient demographics, along with asthma severity and co-existing allergies, were assessed. Possible phenotypes were defined (based on presence or absence of atopy, age at asthma onset, and blood eosinophil counts). RESULTS: 227 patients were included in the final analysis, of which 55.5% were Hispanic and 33.9% identified as non-Hispanic Black. Ninety-one percent (91%) of our cohort was found to be atopic and allergic rhinoconjunctivitis (ARC) was the most commonly identified co-existing allergic condition (86.3%). Mean Asthma Control Test (ACT) scores improved from 11.1 (± 4.9) at the initial visit to 14.8 (± 6.1) at the last visit. The spirometric values did not improve despite treatment at MAC. CONCLUSION: A multidisciplinary severe asthma center is an ideal setting to phenotype patients and offer personalized guideline-based management and education to adults with severe asthma.

Eosinophilia in Asthma Patients Is Protective Against Severe COVID-19 Illness.

BACKGROUND: There is a paucity of information on coronavirus disease 2019 (COVID-19) outcomes in asthmatics. OBJECTIVE: To identify risk factors associated with admission and subsequent mortality among COVID-19-infected asthmatics. METHODS: Adults at our institution with a positive polymerase chain reaction for COVID-19 between March 14 and April 27, 2020, were retrospectively identified. Comorbidities, laboratory results, and mortality rates during hospitalization were recorded. RESULTS: In total, 737 of 951 (77.5%) asthma patients with COVID-19 were seen in the emergency department (ED), and 78.8% of these ED patients (581 of 737) were admitted. Individuals with previously measured mean absolute eosinophil counts (AEC) ≥150 cells/µL were less likely to be admitted (odds ratio [OR] = 0.46, 95% confidence interval [CI]: 0.21-0.98, P = .04), whereas concomitant heart failure (CHF), chronic kidney disease (CKD), and chronic obstructive pulmonary disease (COPD) were risk factors for admission. Hospitalized patients with asthma with peak hospital-measured AEC ≥150 cells/µL (n = 104) were less likely to die compared with those whose AEC remained <150 cells/µL (n = 213) (mortality rate 9.6% vs 25.8%; OR = 0.006, 95% CI: 0.0001-0.64, P = .03). This group had also higher preadmission mean AEC (237 ± 181 vs 163 ± 147 cells/µL, P = .001, OR = 2012, 95% CI: 27.3-14,816). The mortality rate in patients with asthma alone (no associated CHF, CKD, COPD, diabetes, or hypertension) was similar to that of patients without asthma or any of these comorbidities. CONCLUSIONS: In asthmatics, pre-existing eosinophilia (AEC ≥150 cells/µL) was protective from COVID-19-associated admission, and development of eosinophilia (AEC ≥150 cells/µL) during hospitalization was associated with decreased mortality. Preadmission AEC influenced the AEC trend during hospitalization. Having a Th2-asthma phenotype might be an important predictor for reduced COVID-19 morbidity and mortality that should be further explored in prospective and mechanistic studies.

A randomized trial of subcutaneous allergy immunotherapy in inner-city children with asthma less than 4 years of age.

BACKGROUND: Allergic sensitization to environmental allergens in the first years of life is a strong predictor of asthma morbidity in children. Allergy immunotherapy can improve asthma and allergy outcomes, but its efficacy in inner-city, atopic children of less than 4 years of age with recurrent wheezing has not yet been established. OBJECTIVE: To determine whether subcutaneous allergy immunotherapy improves asthma in a population of US inner-city children when started at less than 4 years of age. METHODS: In a randomized controlled, open-label phase I-II single-center trial in the Bronx, New York, 58 children with recurrent wheezing or physician-diagnosed asthma were randomized to receive asthma standard of care treatment with or without a 3-year course of multiple allergen subcutaneous immunotherapy. RESULTS: A total of 23 children in the control group and 27 children in the immunotherapy group began the study. A total of 20 of 27 children commencing immunotherapy completed at least 2 years of immunotherapy. There was no difference in asthma medication and symptom scores between the treatment or control groups over time. Similarly, naso-ocular symptoms and allergy medication use were similar in both groups over time. Nevertheless, asthma-related quality of life improved in the immunotherapy group compared with the control group (P = .03). CONCLUSION: With the exception of asthma-related quality of life, allergy immunotherapy was ineffective in improving asthma outcomes in this population of inner-city children of less than 4 years of age. These findings suggest that the effects of allergy immunotherapy depend on population-specific factors and highlight the importance of precise predictors of immunotherapy efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01028560.

Increased Malignancy Rate in Children With IgE Deficiency: A Single-center Experience.

BACKGROUND: Immunoglobulin (Ig) E-deficient adults (IgE<2.5 kU/L) have increased susceptibility for developing malignancy. We evaluated the association between IgE deficiency and cancer diagnosis in children (age younger than 18 y), compared with those non-IgE-deficient (IgE≥2.5 kU/L). MATERIALS AND METHODS: Information about malignancy diagnosis were compared between 4 cohorts of children who had IgE levels measured at our institution: IgE-deficient (IgE<2.5 kU/L), normal IgE (2.5

Developing and pilot testing ASTHMAXcel, a mobile app for adults with asthma.

Objective: We sought to compare the impact of ASTHMAXcel, a novel, guideline-based, patient-facing mobile app to human-delivered asthma education.Methods: We conducted a focus group with asthma patients in the Bronx to identify desired mobile app features. ASTHMAXcel was designed based on patient feedback and consistent with NAEPP, BTS/SIGN, and GINA guidelines. The app was reviewed by internists, allergist/immunologists, and pulmonologists specializing in asthma treatment, asthma educators, and a behavioral scientist, and iteratively refined. The refined version of ASTHMAXcel was administered once via tablet at our outpatient Montefiore Asthma Center (MAC). Asthma knowledge was measured through the Asthma Knowledge Questionnaire (AKQ) pre and post-intervention. We also recorded process outcomes including completion time and patient satisfaction. In parallel, human-delivered education was delivered once at MAC. These outcomes were similarly collected.Results: 60 patients were enrolled with 30 in the ASTHMAXcel and 30 in the human-educator group. Mean AKQ in the ASTHMAXcel group vs human-educator group pre-intervention was 9.9 vs 10.5, p = 0.27. Mean AKQ post-intervention in the ASTHMAXcel group vs human-educator group was 12.3 vs 14.4, p = 0.0002. The mean AKQ improvement for both groups were 2.4 vs 3.9, p = 0.007. Patients were highly satisfied in the ASTHMAXcel group scoring on average 27.9 out of 30 maximum points on the satisfaction survey. There was no difference in satisfaction scores or completion times (minutes) of either intervention.Conclusion: ASTHMAXcel was associated with an increase in AKQ, but the human-educator group experienced a greater improvement. ASTHMAXcel demonstrated no differences in process outcomes vs human-delivered education.

Endoscopic sinus surgery improves aspirin treatment response in aspirin-exacerbated respiratory disease patients.

BACKGROUND: Aspirin desensitization and treatment benefits most patients with aspirin-exacerbated respiratory disease (AERD), although some patients fail therapy. Our objective was to assess whether recent endoscopic sinus surgery (ESS) improved aspirin treatment outcomes in AERD patients who initially failed aspirin therapy. METHODS: Outcomes of aspirin desensitization and treatment in AERD patients prospectively enrolled were assessed preoperatively and at 4, 12, and 24 weeks after ESS by determining changes in Asthma Control Test (ACT) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores and respiratory function. Biomarkers, including fractional excretion of nitric oxide (FeNO), spirometry, nasal inspiratory peak flow (NPF), immunoglobulin E (IgE), and eosinophil count, were measured. RESULTS: Nineteen patients who benefited (responders) and 21 patients who failed (nonresponders) preoperative aspirin treatment with a distant history of ESS (mean, 48 months) were identified. Nonresponders were more likely to be African American (71%, p < 0.01) and have higher baseline IgE levels (252 kU/L vs 87 kU/L in responders, p < 0.01). 24 of the 40 patients (nine responders and 15 non-responders) required subsequent ESS and underwent another aspirin desensitization 3-4 weeks after ESS. All 24 patients tolerated a second round of aspirin desensitization and treatment. The primary aspirin therapy was associated with a significant increase in IgE in nonresponders, but there was no significant increase in IgE after the second aspirin desensitization and treatment. CONCLUSION: Antecedent ESS enhances aspirin treatment responses in AERD patients and may convert patients who failed aspirin treatment before surgery to a more responsive phenotype after ESS. Patients with higher baseline serum IgE levels may benefit from ESS performed shortly before aspirin desensitization and therapy.

The association of environmental, meteorological, and pollen count variables with asthma-related emergency department visits and hospitalizations in the Bronx.

Objective: To better understand how meteorological variables, air quality variables, and pollen counts collectively contribute to asthma-related emergency department visits (AREDV) and asthma-related hospitalizations (ARH) among pediatric and adult patients in the New York City borough of the Bronx. Methods: The numbers of daily adult and pediatric AREDV and ARH from 2001 to 2008 were obtained from three Bronx hospitals. After removing outliers, interpolating missing data, and standardizing variable values by scaling the data using z-scores, data were analyzed using Spearman rank tests and linear regression models for the full year and each season. Results: There were a total of 42,065 AREDV and 1,664 ARH at both Bronx hospitals. With the exception of a spring peak in AREDVs, AREDVs and ARHs follow a cyclical pattern, climbing in the fall, plateauing in the winter, dropping in the spring, and reaching a low in the summer. Among the 11 air quality, meteorological, and pollen count variables, temperature and tree pollen made the greatest contribution to AREDV with scaled coefficients of -0.337 and 0.311 respectively; equating to an additional AREDV for every 5.0-unit decrease in temperature and an additional AREDV for every 186.0-unit increase in tree pollen. These two variables were confirmed to have independent associations with AREDV prior to the data interpolation. Grass pollen was also found to have a relatively large contribution to AREDV during the summer with a scaled coefficient of 0.314, equating to an additional AREDV for every 2.3-unit increase in grass pollen. Conclusion: There are distinct peaks of increased AREDVs that are closely associated with increased tree pollen counts in the spring and decreasing temperatures in the fall. Early anticipation of these air quality, meteorological, and pollen factor changes based on ongoing surveillance could potentially guide clinical practice and minimize AREDVs in the Bronx.

Sinus Surgery Is Associated with a Decrease in Aspirin-Induced Reaction Severity in Patients with Aspirin Exacerbated Respiratory Disease.

BACKGROUND: Nasal polyps influence the burden of aspirin-exacerbated respiratory disease (AERD) by contributing to eicosanoid production. AERD is diagnosed through graded aspirin challenges. It is not known how sinus surgery affects aspirin challenge outcomes. OBJECTIVE: To investigate the effects of endoscopic sinus surgery (ESS) on aspirin-induced reaction severity and on the levels of eicosanoids associated with these reactions. METHODS: Twenty-eight patients with AERD were challenged with aspirin before and 3 to 4 weeks after ESS. Respiratory parameters and plasma and urine levels of eicosanoids were compared before and after challenges. RESULTS: Before ESS, AERD diagnosis was confirmed in all study patients by aspirin challenges that resulted in hypersensitivity reactions. After ESS, reactions to aspirin were less severe in all patients and 12 of 28 patients (43%, P < .001) had no detectable reaction. A lack of clinical reaction to aspirin was associated with lower peripheral blood eosinophilia (0.1 K/µL [interquartile range (IQR) 0.1-0.3] vs 0.4 K/µL [IQR 0.2-0.8]; P = .006), lower urinary leukotriene E4 levels after aspirin challenge (98 pg/mg creatinine [IQR 61-239] vs 459 pg/mg creatinine [IQR 141-1344]; P = .02), and lower plasma prostaglandin D2 to prostaglandin E2 ratio (0 [±0] vs 0.43 [±0.2]; P = .03), compared with those who reacted. CONCLUSIONS: Sinus surgery results in decreased aspirin sensitivity and a decrease in several plasma and urine eicosanoid levels in patients with AERD. Diagnostic aspirin challenges should be offered to patients with suspected AERD before ESS to increase diagnostic accuracy. Patients with established AERD could undergo aspirin desensitizations after ESS as the severity of their aspirin-induced hypersensitivity reactions lessens.