AllergoOncology: Biomarkers and refined classification for research in the allergy and glioma nexus-A joint EAACI-EANO position paper.

Epidemiological studies have explored the relationship between allergic diseases and cancer risk or prognosis in AllergoOncology. Some studies suggest an inverse association, but uncertainties remain, including in IgE-mediated diseases and glioma. Allergic disease stems from a Th2-biased immune response to allergens in predisposed atopic individuals. Allergic disorders vary in phenotype, genotype and endotype, affecting their pathophysiology. Beyond clinical manifestation and commonly used clinical markers, there is ongoing research to identify novel biomarkers for allergy diagnosis, monitoring, severity assessment and treatment. Gliomas, the most common and diverse brain tumours, have in parallel undergone changes in classification over time, with specific molecular biomarkers defining glioma subtypes. Gliomas exhibit a complex tumour-immune interphase and distinct immune microenvironment features. Immunotherapy and targeted therapy hold promise for primary brain tumour treatment, but require more specific and effective approaches. Animal studies indicate allergic airway inflammation may delay glioma progression. This collaborative European Academy of Allergy and Clinical Immunology (EAACI) and European Association of Neuro-Oncology (EANO) Position Paper summarizes recent advances and emerging biomarkers for refined allergy and adult-type diffuse glioma classification to inform future epidemiological and clinical studies. Future research is needed to enhance our understanding of immune-glioma interactions to ultimately improve patient prognosis and survival.

Characteristics of an ethnically diverse cohort of children with pediatric cutaneous mastocytosis: One institution's experience.

There has been limited research exploring how the demographic characteristics of children with pediatric cutaneous mastocytosis (PCM) may influence both the cutaneous and systemic symptoms. In this observational retrospective study of 51 children with PCM, we found a significantly higher rate of gastrointestinal (GI) symptoms in children of Hispanic ethnicity (4/21,19%) compared to non-Hispanics (0/30, 0%, p = 0.024). While this finding may reflect the high proportion of Hispanics in our population, a racial predisposition toward distinct systemic symptoms may be possible. We also found a significantly lower proportion of Hispanic children being diagnosed with PCM under the age of 3 years (47.6%) when compared with non-Hispanic children (76.7%, p = 0.03), suggesting that more data are needed to further assess the role of ethnicity and healthcare disparities in PCM diagnosis. Larger prospective studies are necessary to better evaluate the association between ethnicity, early diagnosis, and systemic symptoms in PCM and to describe its impact on long-term outcomes.

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.

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.

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

The impact of the COVID-19 pandemic on otolaryngologic emergency department visits at two major NYC hospital systems.

PURPOSE: Since the COVID-19 pandemic began, emergency departments (ED) across the country have seen a significant decrease in patient visits. We aim to evaluate the impact of COVID-19 on ED visits for acute otolaryngologic complaints in New York City, one of the first epicenters of the pandemic in the US. MATERIALS AND METHODS: We conducted a retrospective study of patients who presented to the ED with a primary diagnosis of an acute otolaryngologic complaint between March 1 and May 31 in 2019 and 2020. This was a multicenter study, including two tertiary care hospital systems encompassing Manhattan, Bronx, Queens, and Long Island. RESULTS: A total of 10,162 patients were identified. Significantly fewer patients presented to the ED for acute otolaryngologic complaints in 2020 (7332 vs 2830, p < 0.001). The rate of total otolaryngology-related ED visits was decreased by a factor of 0.635 (95% CI 0.6079 to 0.6634). In a subgroup analysis of each individual diagnosis, there was a significant decrease in rate of ED visits for 13 out of 18 diagnoses, including for life-threatening conditions, such as anaphylaxis. There was no significant difference based on which borough in New York City. Pediatric patients (age 0-17) were more significantly impacted by the pandemic compared to other age groups. CONCLUSION: The COVID-19 pandemic has led to a reduction in the utilization of ED for acute otolaryngologic complaints, including those requiring emergent management, and an even more significant reduction in the pediatric population. Healthcare providers should encourage patients to seek appropriate care, particularly for those illnesses with significant associated morbidity and mortality.

IgE deficiency and prior diagnosis of malignancy: Results of the 2005-2006 National Health and Nutrition Examination Survey.

BACKGROUND: Data on patients from tertiary-level health care facilities suggest that IgE-deficient (IgE <2.5 kU/L) patients have high rates of prior malignant tumors. OBJECTIVE: To investigate the association between IgE levels and diagnosis of malignancy in non-institution-associated patients using the 2005-2006 US National Health and Nutrition Examination Survey (NHANES) cohort. METHODS: All individuals with available IgE levels and known prior diagnosis of malignancy were divided into 4 groups: IgE deficient (IgE, <2.5 kU/L), normal IgE levels (2.5-100 kU/L), high IgE levels (100-1,000 kU/L), and very high IgE levels (≥1,000 kU/L). Rates of malignancy were compared among groups. RESULTS: Of 4,488 individuals with data on IgE levels and malignancy status, 7.4% had a prior diagnosis of cancer. The rate of prior malignancy was significantly higher in the IgE-deficient group (12.6%) compared with individuals with high (6.7%, P = .04) and very high IgE levels (5.3%, P = 0.04). In the IgE-deficient group, only 3 patients had a diagnosis of malignancy within 3 years of IgE measurement. A mean (SD) of 10.3 (9.6) years elapsed between the time of malignancy diagnosis and IgE collection time; therefore, active neoplasm or recent chemotherapy was less likely to explain the very low IgE levels. Types of malignancies in the IgE-deficiency group included breast cancer (n = 6), nonmelanoma or unknown skin cancer (n = 3), uterine cancer (n = 2), cervical cancer (n = 1), lung cancer (n = 1), prostate cancer (n = 1), and hematologic cancer (n = 1). CONCLUSION: In this non-institution-based cohort, IgE deficiency was associated with a higher rate of prior diagnosis of malignancies compared with individuals with high or very high IgE levels. Prospective studies are essential to better evaluate the association between IgE levels and risk of cancer.

Increased malignancy incidence in IgE deficient patients not due to concomitant Common Variable Immunodeficiency.

BACKGROUND: Immunoglobulin E (IgE) deficiency (<2.5 kU/L) has unclear clinical significance. Very little is known about the clinical characteristics of IgE deficiency in patients with Common Variable Immunodeficiency (CVID). OBJECTIVE: To evaluate the clinical and laboratory differences between patients with IgE deficiency and those with non-IgE deficiency with and without CVID diagnosis. METHODS: This is a retrospective study of adult patients who had total serum IgE levels measured at our facility from 2010 through 2015. Patients with IgE levels lower than 2.5 kU/L composed the IgE deficiency group. We used Clinical Looking Glass software to identify laboratory results and comorbid conditions including CVID and malignancy. RESULTS: The IgE levels were measured in 2,339 patients and 63 (2.7%) had IgE deficiency. Of those with IgE deficiency, 14 of 63 (22%) had CVID diagnosis compared with only 62 of 2,276 patients (2.7%) with non-IgE deficiency and CVID. A significantly higher rate of prior malignancy was found in patients with IgE deficiency (21 of 63, 33%) compared with those with non-IgE deficiency (197 of 2,276, 8.7%; P = .001; odds ratio 5.51, 95% confidence interval 3.07-9.88). Six of 14 patients with CVID and IgE deficiency (43%) had a prior malignancy diagnosis compared with 8 of 62 patients (13%) with CVID and non-IgE deficiency (P = .009; odds ratio 10.65, 95% confidence interval 1.79-63.19). In addition to the higher rate of malignancy, patients with CVID and IgE deficiency did not have more severe disease than those with CVID and non-IgE deficiency. CONCLUSION: The rate of prior malignancy is significantly higher in patients with IgE deficiency than in those without IgE deficiency. Similarly, patients with CVID and IgE deficiency have a higher frequency of prior malignancy than those with CVID and non-IgE deficiency. However, patients with IgE deficiency have higher frequency of malignancy than patients with normal IgE levels even in the absence of CVID.

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.

Discordance between aeroallergen specific serum IgE and skin testing in children younger than 4 years.

BACKGROUND: Atopic sensitization to aeroallergens in early life has been found to be a strong risk factor for the development of persisting asthma in young children with recurrent wheeze. OBJECTIVE: To assess the yield of skin prick test (SPT) compared with allergen specific serum IgE (sIgE) testing at identifying aeroallergen sensitization in atopic children younger than 4 years. METHODS: Concordance between SPT and allergen-specific sIgE testing for 7 common aeroallergens was analyzed in 40 atopic inner-city children 18 to 48 months of age (mean [SD], 36 [9] months) with recurrent wheezing and family history of asthma and/or eczema. RESULTS: In 80% of children one or more allergen sensitizations would have been missed if only SPT had been performed, and in 38% of children one or more sensitizations would have been missed if only sIgE testing had been performed. Agreement between the SPT and sIgE test was fair for most allergens (κ = -0.04 to 0.50), as was correlation between sIgE levels and SPT grade (ρ = 0.21 to 0.55). Children with high total sIgE (≥300 kU/L) were more likely to have positive sIgE test results, with negative corresponding SPT results (P = .02). CONCLUSION: Our study revealed a significant discordance between allergen-specific SPT and sIgE testing results for common aeroallergens, suggesting that both SPT and sIgE testing should be performed when diagnosing allergic sensitization in young children at high risk of asthma. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01028560.

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.

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.

The other side of the coin: IgE deficiency, a susceptibility factor for malignancy occurrence.

Since the discovery of IgE, almost all attention was given to conditions with elevated specific or total IgE levels such as atopy, type I hypersensitivity reactions, or parasitic infestations. Recent prospective and retrospective studies show that having very low IgE levels, such as those seen in IgE deficiency (IgE<2.5 kU/L), is not without clinical consequences. Patients with ultra-low IgE levels have an elevated risk of cancer of any type. These results are in agreement with murine models research which demonstrated that grafted tumors grow faster and bigger on an IgE knockout background. The novel finding that IgE deficiency is a susceptibility factor for cancer, fits very well with the AllergoOncology concept. The reports on a beneficial, cytotoxic function of IgE, in cooperation with its high (FcεRI) and low (FcεRII, CD23) affinity IgE receptors resulting in tumor cell phagocytosis, propose a role of IgE in cancer surveillance. It appears that not only deficiency of serum IgE, but also lack of tissue-bound IgE is important in malignancy susceptibility in these patients. As such, IgE deficient individuals with absent serum and cell-bound IgE as suggested by negative type I hypersensitivity skin tests, are at the highest risk for a malignancy diagnosis. In contrast, IgE deficient individuals with cell-bound IgE depicted through positive type I hypersensitivity skin tests, have lower rates of malignancy diagnosis. The present report discusses the evidence and potential role of ultra-low IgE as a novel biomarker for cancer susceptibility.

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.

Rapid Implementation of a Multidisciplinary COVID-19 Cytokine Storm Syndrome Task Force.

OBJECTIVE: Patients with coronavirus disease 2019 (COVID-19) can progress to a state of unregulated inflammation called cytokine storm syndrome (CSS). We describe formation and operation of a COVID-19 multidisciplinary consultation service that was allowed to individualize treatment for critically ill patients with COVID-19 during the pandemic. METHODS: Institutional experts from different subspecialties formed a COVID-19 CSS task force at Montefiore Medical Center, Bronx, NY. They agreed on a set of four clinical and six laboratory parameters that can help early identify COVID-19 CSS. We describe the formation and implementation of the COVID-19 task force. The case series description of the COVID-19 CSS consultation cohort highlights consultation volume, baseline characteristics, clinical and laboratory parameters, and how biologic treatments were allocated to these patients. RESULTS: Between April 4,2020, and May 7,2020, the COVID-19 CSS task force was formed, consisting of adult and pediatric rheumatologists and allergy and immunology physicians. The task force evaluated a total of 288 patients, of whom 197 (68%) were male, the median (interquartile range [IQR]) age was 62 (51-70) years, 122 (42%) were Hispanic, and 88 (31%) were Black or African American. The common presenting symptoms in all referred patients were dyspnea (85%) and diarrhea (80%). Thirty-one patients who received biologic therapy were younger, with a median (IQR) age of 53 (32-63) years, as opposed to 62.5 (52-70) years in the nonbiologic group (P = 0.008). A higher proportion receiving biologics was in the critical care setting (26 [84%] vs 151 [59%]; P = 0.006). CONCLUSION: To the best of our knowledge, this is the first multidisciplinary collaborative effort to provide individualized patient recommendations for evaluation and treatment of patients with COVID-19 who may have CSS. This working model helped to devise an approach that may have identified patients who were most likely to benefit from biologic therapy in the absence of evidence-based guidelines.