The common variable immunodeficiency IgM repertoire narrowly recognizes erythrocyte and platelet glycans.

BACKGROUND: Autoimmune cytopenias (AICs) regularly occur in profoundly IgG-deficient patients with common variable immunodeficiency (CVID). The isotypes, antigenic targets, and origin(s) of their disease-causing autoantibodies are unclear. OBJECTIVE: We sought to determine reactivity, clonality, and provenance of AIC-associated IgM autoantibodies in patients with CVID. METHODS: We used glycan arrays, patient erythrocytes, and platelets to determine targets of CVID IgM autoantibodies. Glycan-binding profiles were used to identify autoreactive clones across B-cell subsets, specifically circulating marginal zone (MZ) B cells, for sorting and IGH sequencing. The locations, transcriptomes, and responses of tonsillar MZ B cells to different TH- cell subsets were determined by confocal microscopy, RNA-sequencing, and cocultures, respectively. RESULTS: Autoreactive IgM coated erythrocytes and platelets from many CVID patients with AICs (CVID+AIC). On glycan arrays, CVID+AIC plasma IgM narrowly recognized erythrocytic i antigens and platelet i-related antigens and failed to bind hundreds of pathogen- and tumor-associated carbohydrates. Polyclonal i antigen-recognizing B-cell receptors were highly enriched among CVID+AIC circulating MZ B cells. Within tonsillar tissues, MZ B cells secreted copious IgM when activated by the combination of IL-10 and IL-21 or when cultured with IL-10/IL-21-secreting FOXP3-CD25hi T follicular helper (Tfh) cells. In lymph nodes from immunocompetent controls, MZ B cells, plentiful FOXP3+ regulatory T cells, and rare FOXP3-CD25+ cells that represented likely CD25hi Tfh cells all localized outside of germinal centers. In CVID+AIC lymph nodes, cellular positions were similar but CD25hi Tfh cells greatly outnumbered regulatory cells. CONCLUSIONS: Our findings indicate that glycan-reactive IgM autoantibodies produced outside of germinal centers may contribute to the autoimmune pathogenesis of CVID.

Benefits of Aeroallergen Testing on Oral Corticosteroid Bursts in Adults with Asthma.

BACKGROUND: Aeroallergen testing can improve precision care for persistent asthma and is recommended by the U.S. clinical guidelines. How testing benefits diverse populations of adults with asthma, and the importance of the testing modality used, are not fully understood. OBJECTIVE: We sought to evaluate whether receipt of aeroallergen testing was associated with a reduction in oral corticosteroid (OCS) bursts. METHODS: We used electronic health record data to conduct a retrospective, observational cohort study of adults with asthma who were prescribed an inhaled corticosteroid and had an Allergy/Immunology visit in a large health system between 1/1/2017-6/30/2022. Negative binomial regression models were used to evaluate whether OCS bursts in the 12-month period after an initial visit were reduced for patients who received aeroallergen testing. We also measured differences in benefit after excluding patients with chronic obstructive pulmonary disease (COPD) and smoking histories, and whether testing receipt was via skin prick or serum. RESULTS: 668/1,383 (48.3%) patients received testing. Receipt of testing was not associated with fewer bursts in all patients (incidence rate ratio (IRR)=0.83 versus no testing, p=0.059), but it was among never smokers without COPD (417/844 tested, IRR=0.68, p=0.004). The receipt of skin testing was associated with fewer bursts in all patients (418/1,383 tested, IRR=0.77, p=0.02) and among never smokers without COPD (283/844 tested, IRR=0.59 versus no testing, p=0.001). CONCLUSION: Guideline-concordant aeroallergen testing in the context of Allergy/Immunology care was associated with clinical benefit in a real-life, diverse cohort of adults with asthma. This benefit varied according to patient comorbidities and the testing modality.

Factors associated with aeroallergen testing among adults with asthma in a large health system.

Background: Aeroallergen testing informs precision care for adults with asthma, yet the epidemiology of testing in this population remains poorly understood. Objective: We sought to identify factors associated with receiving aeroallergen testing, the results of these tests, and subsequent reductions in exacerbation measures among adults with asthma. Methods: We used electronic health record data to conduct a retrospective, observational cohort study of 30,775 adults with asthma who had an office visit with a primary care provider or an asthma specialist from January 1, 2017, to August 26, 2022. We used regression models to identify (1) factors associated with receiving any aeroallergen test and tests to 9 allergen categories after the index visit, (2) factors associated with positive test results, and (3) reductions in asthma exacerbation measures in the year after testing compared with before testing. Results: Testing was received by 2201 patients (7.2%). According to multivariable models, receiving testing was associated with having any office visit with an allergy/immunology specialist during the study period (odds ratio [OR] = 91.3 vs primary care only [P < .001]) and having an asthma emergency department visit (OR = 1.62 [P = .004]) or hospitalization (OR = 1.62 [P = .03]) in the year before the index visit. Age 65 years or older conferred decreased odds of testing (OR = 0.74 vs age 18-34 years [P = .008]) and negative test results to 6 categories (P ≤ .04 for all comparisons). Black race conferred increased odds of testing (OR =1.22 vs White race [P = .01]) and positive test results to 8 categories (P < .04 for all comparisons). Exacerbation measures decreased after testing. Conclusion: Aeroallergen testing was performed infrequently among adults with asthma and was associated with reductions in asthma exacerbation measures.

Cyclosporine for omalizumab-refractory chronic urticaria: a report of five cases.

BACKGROUND: While both the AAAAI/ACAAI and the EAACI/GA2LEN/EuroGuiDerm/APAAACI guidelines recommend starting cyclosporine for patients with chronic urticaria who have had an inadequate response to omalizumab, many clinicians are hesitant to initiate cyclosporine due to paucity of clinical data. The objective of this study was to report real-life clinical outcomes in adult patients with chronic urticaria who had an inadequate response to omalizumab and were switched from omalizumab to cyclosporine. Medical records of adult patients with chronic urticaria who had an inadequate response with omalizumab and were later treated with cyclosporine were reviewed retrospectively. Data pertaining to treatment method, clinical response, and adverse effects were recorded. RESULTS/PRESENTATION OF CASES: Five patients with omalizumab-refractory chronic urticaria, three of whom also had angioedema and one with an inducible urticaria, were treated with low doses of oral cyclosporine (1-3 mg/kg/d). Four of five patients in this case series had complete resolution of symptoms with oral cyclosporine, while continuing other standard therapies. Systemic side effects occurred in three patients which prompted drug discontinuation in two patients. DISCUSSION: Cyclosporine alone was effective in inducing urticaria control in adult patients with chronic urticaria who had an inadequate response to omalizumab, though the impact of cyclosporine was limited by reversible adverse effects. Adverse effects were associated with pre-existing medical conditions. As novel chronic urticaria therapies are being investigated, this experience highlights the importance of uncovering chronic urticaria subtypes which tend to respond to cyclosporine, while providing alternative treatments with better tolerability.

Penicillin allergy evaluation in hospitalized patients with hematologic malignancy.

A penicillin allergy testing service (PATS) assessed penicillin allergy in patients with hematologic malignancies; 17 patients who met criteria had negative skin testing. Patients who underwent penicillin challenge passed and were delabeled. Of delabeled patients, 87% received and tolerated ß-lactams during follow-up. Providers found the PATS valuable.

Respiratory Viruses Associated With Acute Wheezing in Hospitalized Young Children in Jordan.

A cross-sectional viral surveillance study of hospitalized children less than 2 years of old in Amman, Jordan, noted that respiratory syncytial virus and human metapneumovirus, but not human rhinovirus, were associated with higher odds of acute wheezing. Future longitudinal studies are needed to evaluate the association between early childhood viral acute respiratory infections and recurrent wheezing later in childhood.

Common variable immunodeficiency-associated endotoxemia promotes early commitment to the T follicular lineage.

BACKGROUND: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. OBJECTIVE: We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. METHODS: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. RESULTS: Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. CONCLUSIONS: Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs.

Immune responses to pertussis antigens in infants and toddlers after immunization with multicomponent acellular pertussis vaccine.

Given the resurgence of pertussis despite high rates of vaccination with the diphtheria-tetanus-acellular pertussis (DTaP) vaccine, a better understanding of vaccine-induced immune responses to Bordetella pertussis is needed. We investigated the antibody, cell-mediated, and cytokine responses to B. pertussis antigens in children who received the primary vaccination series (at 2, 4, and 6 months) and first booster vaccination (at 15 to 18 months) with 5-component acellular pertussis (aP) vaccine. The majority of subjects demonstrated a 4-fold increase in antibody titer to all four pertussis antigens (pertussis toxin [PT], pertactin [PRN], filamentous hemagglutinin [FHA], and fimbriae [FIM]) following the primary series and booster vaccination. Following the primary vaccine series, the majority of subjects (52 to 67%) mounted a positive T cell proliferative response (stimulation index of ≥ 3) to the PT and PRN antigens, while few subjects (7 to 12%) mounted positive proliferative responses to FHA and FIM. One month after booster vaccination (age 16 to 19 months), our study revealed significant increase in gamma interferon (IFN-γ) production in response to the PT and FIM antigens, a significant increase in IL-2 production with the PT, FHA, and PRN antigens, and a lack of significant interleukin-4 (IL-4) secretion with any of the antigens. While previous reports documented a mixed Th1/Th2 or Th2-skewed response to DTaP vaccine in children, our data suggest that following the first DTaP booster, children aged 16 to 19 months have a cytokine profile consistent with a Th1 response, which is known to be essential for clearance of pertussis infection. To better define aP-induced immune responses following the booster vaccine, further studies are needed to assess cytokine responses pre- and postbooster in DTaP recipients.

Linezolid desensitization for a patient with multiple medication hypersensitivity reactions.

OBJECTIVE: To describe a case in which a linezolid desensitization protocol was successfully used for a polymicrobial surgical wound infection in a patient with multiple drug hypersensitivity reactions. CASE SUMMARY: A 24-year-old woman with vocal cord dysfunction requiring tracheostomy was admitted for a surgical wound infection following a tracheostomy fistula closure procedure. The patient reported multiple antibiotic allergies including penicillins (rash), sulfonamides (rash), vancomycin (anaphylaxis), azithromycin (rash), cephalosporins (anaphylaxis), levofloxacin (unspecified), clindamycin (unspecified), and carbapenems (unspecified). Gram stain of the purulent wound drainage demonstrated mixed gram-negative and gram-positive flora, and bacterial cultures were overgrown with Proteus mirabilis, which precluded identification of other pathogens. Following failed test doses of linezolid, tigecycline, and daptomycin, all of which resulted in hypersensitivity reactions, a 16-step linezolid desensitization protocol was developed and successfully implemented without adverse reactions. The patient completed a 2-week course of antibiotic therapy that included linezolid upon finishing the desensitization protocol. DISCUSSION: Linezolid is useful in treating complicated and uncomplicated skin and soft tissue infections caused by gram-positive bacteria. With precautions, including premedication, a monitored nursing unit, and immediate availability of an emergency anaphylaxis kit, drug desensitization allows patients the ability to safely use medications to which they may have an immediate hypersensitivity reaction. Minimal data exist on linezolid desensitization protocols. CONCLUSIONS: Linezolid desensitization can be a viable option in patients requiring antimicrobial therapy for complicated gram-positive skin infections.