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.

The Role of Early Subspeciality Consultation in the Timing of Hemophagocytic Lymphohistiocytosis Diagnosis and Management.

OBJECTIVE: The aim of this study was to investigate the relation between timing of subspeciality consult and hemophagocytic lymphohistiocytosis (HLH) consideration, immunosuppression initiation, and in-hospital mortality in patients with HLH. METHODS: We conducted a medical records review study of patients 18 years or older with definite or probable HLH at Montefiore Medical Center between 2006 and 2019. Earlier subspeciality consultation (rheumatology, hematology, and infectious disease) was defined as consultation in less than or equal to 18 hours from time of admission. Demographic, clinical characteristics, and outcomes were compared between patients with early and later subspecialty consultation. RESULTS: A total of 28 patients were included. The median age was 40 years, and 61% of patients were male. Infection was identified as a cause of HLH in 13 patients (46%). Fifteen patients (54%) were classified as having an earlier subspeciality consultation with a median time (interquartile range) to HLH consideration of 1.0 day (0.3-4.2 days) compared with 7.9 days (3.1-9.9 days) for the later consultation group (p = 0.002). The median time (interquartile range) to immunosuppression initiation was 4.6 days (1.7-7.8 days) versus 10.9 days (5.1-13.4 days) (p = 0.01), respectively. Five patients (33%) had in-hospital deaths in the early consultation group compared with 7 patients (54%) in later consultation group (p = 0.27). Among the subset of patients who survived to discharge, the 90-day readmission rate was higher in the later consultation group (83% vs 30%, p = 0.12). CONCLUSIONS: In patients with HLH, earlier subspeciality consultation may play a role in earlier HLH consideration and treatment initiation.

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.

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.

New modalities of allergen immunotherapy.

Allergen immunotherapy is a rapidly evolving field. Although subcutaneous immunotherapy has been practiced for over a hundred years, improved understanding of the underlying immunological mechanisms has led to the development of new, efficacious and better tolerated allergen-derivatives, adjuvants and encapsulated allergens. Diverse routes of allergen immunotherapy - oral, sublingual, epicutanoeus and intralymphatic - are enabling immunotherapy for anaphylactic food allergies and pollen-food allergy syndrome, while improving the tolerability and effectiveness of aeroallergen immunotherapy. The addition of Anti-IgE therapy decreases adverse effects of subcutaneous and oral immunotherapy.

Clonal and constricted T cell repertoire in Common Variable Immune Deficiency.

We used high throughput sequencing to examine the structure and composition of the T cell receptor ß chain in Common Variable Immune Deficiency (CVID). TCRß CDR3 regions were amplified and sequenced from genomic DNA of 44 adult CVID subjects and 22 healthy adults, using a high-throughput multiplex PCR. CVID TCRs had significantly less junctional diversity, fewer n-nucleotide insertions and deletions, and completely lacked a population of highly modified TCRs, with 13 or more V-gene nucleotide deletions, seen in healthy controls. The CVID CDR3 sequences were significantly more clonal than control DNA, and displayed unique V gene usage. Despite reduced junctional diversity, increased clonality and similar infectious exposures, DNA of CVID subjects shared fewer TCR sequences as compared to controls. These abnormalities are pervasive, found in out-of-frame sequences and thus independent of selection and were not associated with specific clinical complications. These data support an inherent T cell defect in CVID.

Hyper IgM Syndrome: a Report from the USIDNET Registry.

PURPOSE: The United States Immunodeficiency Network (USIDNET) patient registry was used to characterize the presentation, genetics, phenotypes, and treatment of patients with Hyper IgM Syndrome (HIGM). METHODS: The USIDNET Registry was queried for HIGM patient data collected from October 1992 to July 2015. Data fields included demographics, criteria for diagnosis, pedigree analysis, mutations, clinical features, treatment and transplant records, laboratory findings, and mortality. RESULTS: Fifty-two physicians entered data from 145 patients of ages 2 months to 62 years (median 12 years); 131 were males. Using patients' age at last entry, data from 2072 patient years are included. Mutations were recorded for 85 subjects; 82 were in CD40LG. Eighteen subjects had non-X-linked HIGM. 40 % had a normal serum IgM and 15 %, normal IgA. Infections were reported for 91 %, with pulmonary, ear, and sinus infections being the most common. 42 % had Pneumocystis jirovecii pneumonia; 6 % had Cryptosporidium. 41 % had neutropenia. 78 % experienced non-infectious complications: chronic diarrhea (n = 22), aphthous ulcers (n = 28), and neoplasms (n = 8) including colon cancer, adrenal adenoma, liver adenocarcinoma, pancreatic carcinoid, acute myeloid leukemia, hepatoma, and, in a female with an autosomal dominant gain of function mutation in PIK3CD, an ovarian dysgerminoma. Thirteen patients had a hematopoietic marrow or stem cell transplant; three had solid organ transplants. Thirteen were known to have died (median age = 14 years). CONCLUSIONS: Analysis of the USIDNET Registry provides data on the common clinical features of this rare syndrome, and in contrast with previously published data, demonstrates longer survival times and reduced gastrointestinal manifestations.

Peanut T-cell epitope discovery: Ara h 1.

BACKGROUND: Identification of potential T-cell epitopes in the peanut major allergens is essential for development of peptide-based immunotherapy. Traditional methods of T-cell epitope discovery use overlapping short peptides spanning the full length of the protein in T-cell proliferation assays. Because large proteins, such as Ara h 1, require a large number of peptides, this limits screening to a small number of allergic subject-derived T-cell lines. OBJECTIVE: We sought to identify candidate peptides of Ara h 1 that display promiscuous binding to MHC class II and induce TH2 cytokine production by T cells. METHODS: In silico MHC class II binding prediction was performed with NetMHCIIpan 2.0 (peptide length, 15; 1-mer offset) and the most abundant class II alleles in the North American population and with an in vitro MHC class II peptide reporter assay performed in parallel, which used synthetic 15-mer peptides offset by 5 mer spanning the protein. High-resolution MHC class II typing and a T-cell proliferation assay using preselected peptides were performed with PBMCs from 98 subjects with peanut allergy and 14 healthy control subjects. IL-4, IL-13, IL-5, IFN-γ, and TNF-α levels were measured in culture supernatants. RESULTS: Thirty-six Ara h 1 peptides were identified by using in silico predictions and MHC class II binding assays. In combination with T-cell proliferation and cytokines secreted in T-cell assays, we have identified 4 vaccine candidate Ara h 1 peptides. CONCLUSIONS: Preselection of peptides by using in silico and in vitro approaches in combination with conventional methods appears to be an effective strategy for identifying peanut T-cell peptide vaccine candidates.

High-throughput sequencing reveals an altered T cell repertoire in X-linked agammaglobulinemia.

To examine the T cell receptor structure in the absence of B cells, the TCR ß CDR3 was sequenced from DNA of 15 X-linked agammaglobulinemia (XLA) subjects and 18 male controls, using the Illumina HiSeq platform and the ImmunoSEQ analyzer. V gene usage and the V-J combinations, derived from both productive and non-productive sequences, were significantly different between XLA samples and controls. Although the CDR3 length was similar for XLA and control samples, the CDR3 region of the XLA T cell receptor contained significantly fewer deletions and insertions in V, D, and J gene segments, differences intrinsic to the V(D)J recombination process and not due to peripheral T cell selection. XLA CDR3s demonstrated fewer charged amino acid residues, more sharing of CDR3 sequences, and almost completely lacked a population of highly modified Vß gene segments found in control DNA, suggesting both a skewed and contracted T cell repertoire in XLA.

Growth comparison in children with and without food allergies in 2 different demographic populations.

OBJECTIVE: To examine the effects of food avoidance on the growth of children with food allergies. STUDY DESIGN: A retrospective chart review was performed for children with and without food allergies followed at 2 New York City general pediatric practices. Charts were selected based on codes from the International Classification of Diseases, 9th Revision, for well child visit, food allergy, anaphylaxis, and/or epinephrine autoinjector prescriptions. Heights and weights were obtained to calculate body mass index, height, and weight z-scores. RESULTS: Of the 9938 children seen, 439 (4.4%) were avoiding one or more foods. Of those with commercial insurance, children with food allergies were significantly shorter (mean height z-score = 0.06; P = .01) and weighed less (mean weight z-score -0.1; P = .006) than children without food allergies (mean height z-score = 0.42; mean weight z-score = 0.07). In contrast, children with food allergies and state insurance were not smaller in height or weight compared with children without food allergies. Among white subjects, there was a significant effect of food allergies on height and weight (ANOVA for height P = .012, for weight P = .0036) that was not observed for Hispanic/Latino, black, or Asian subjects. Children with allergies to milk weighed significantly less than children without milk allergies (P = .0006). CONCLUSIONS: Children with food allergies and commercial insurance have significant impairment in growth compared with those without food allergies. Additionally, children avoiding all forms of milk are shorter and weigh less than matched counterparts. Therefore, height and weight measurements should be assessed routinely in children with food allergies because there is risk for growth impairment in this population.

Phellinus tropicalis abscesses in a patient with chronic granulomatous disease.

Chronic Granulomatous Disease (CGD), caused by genetic defects in components of the phagocyte NADPH oxidase pathway, leads to recurrent life-threatening bacterial and invasive fungal infections. While a number of unique pathogens have been associated with this disease, the causative organisms may be difficult to identify. Here, we present a 24 year old male with known X-linked CGD who concurrently developed a cervical abscess and an abscess in the subcutaneous tissues of the right hip, both of which were surgically drained. Cultures failed to identify any organisms. He was treated empirically with ertapenem but the hip abscess recurred at the original site and in contiguous dependent areas in the posterior thigh and knee. A filamentous organism was observed microscopically, initially considered a contaminant, but on culture yielded a mold growth, identified as Phellinus tropicalis (synonym: Inonotus tropicalis) based on phenotypic and molecular methods. This is the third case report of human infection with P. tropicalis, all in subjects with CGD. The patient was treated with voriconazole with resolution of his symptoms.

Granuloma formation around filarial larvae triggered by host responses to an excretory/secretory antigen.

In previous studies using a murine model of filarial infection, granuloma formation was found to be a most important host-protective mechanism. We have also shown that in vitro cytoadherence is a surrogate for the formation of antifilarial granulomas in vivo and that it requires "alternatively activated" host cells and a source of antifilarial antibody. We show here that antibodies against L3 excretory/secretory (E/S) products can facilitate in vitro cytoadherence. We generated a set of hybridomas reactive with filarial E/S products and screened them for their ability to mediate in vitro cytoadherence. One clone (no. 1E9) was positive in this assay. We then screened a novel expression library of filarial antigens displayed on the surface of T7 bacteriophage for reactivity with 1E9. Phage expressing two filarial antigens (TCTP and BmALT-2) reacted with 1E9. Immunization of mice showed that the cohort immunized with BmALT-2 cleared a challenge infection with infective Brugia pahangi L3 in an accelerated manner, whereas cohorts immunized with TCTP cleared larvae with the same kinetics as in unimmunized mice. These data confirm that BmALT-2 is the antigenic target of granuloma-mediated killing of B. pahangi L3. Our findings also confirm previous studies that BmALT-2 is a potential vaccine candidate for filarial infection. Our data reinforce the work of others and also provide a possible mechanism by which immune responses to BmALT-2 may provide host protection.

cPLA2 is protective against COX inhibitor-induced intestinal damage.

Cytosolic phospholipase A(2) (cPLA(2)) is the rate-limiting enzyme responsible for the generation of prostaglandins (PGs), which are bioactive lipids that play critical roles in maintaining gastrointestinal (GI) homeostasis. There has been a long-standing association between administration of cyclooxygenase (COX) inhibitors and GI toxicity. GI injury is thought to be induced by suppressed production of GI-protective PGs as well as direct injury to enterocytes. The present study sought to determine how pan-suppression of PG production via a genetic deletion of cPLA(2) impacts the susceptibility to COX inhibitor-induced GI injury. A panel of COX inhibitors including celecoxib, rofecoxib, sulindac, and aspirin were administered via diet to cPLA(2)(-/-) and cPLA(2)(+/+) littermates. Administration of celecoxib, rofecoxib, and sulindac, but not aspirin, resulted in acute lethality (within 2 weeks) in cPLA(2)(-/-) mice, but not in wild-type littermates. Histomorphological analysis revealed severe GI damage following celecoxib exposure associated with acute bacteremia and sepsis. Intestinal PG levels were reduced equivalently in both genotypes following celecoxib exposure, indicating that PG production was not likely responsible for the differential sensitivity. Gene expression profiling in the small intestines of mice identified drug-related changes among a panel of genes including those involved in mitochondrial function in cPLA(2)(-/-) mice. Further analysis of enterocytic mitochondria showed abnormal morphology as well as impaired ATP production in the intestines from celecoxib-exposed cPLA(2)(-/-) mice. Our data demonstrate that cPLA(2) appears to be an important component in conferring protection against COX inhibitor-induced enteropathy, which may be mediated through affects on enterocytic mitochondria.