Joyce E. Yu

Memory B cells in common variable immunodeficiency: Clinical associations and sex differences

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired antibody responses, recurrent infections, inflammatory, autoimmune and malignancy-related conditions. We evaluated the relationship between memory B cell phenotype, sex, age at diagnosis, immunologic and clinical conditions in 105 CVID subjects from one medical center. Reduced numbers of switched memory B cells (cutoff <or=0.55% of B cells) were an independent risk factor of granulomas, autoimmune diseases and splenomegaly (p<0.001). Not previously noted, CVID females had significantly more switched memory cells (p=0.007) than males. Splenectomized subjects did not have fewer IgM memory B cells and these numbers were not related to the development of lung disease, as previously proposed. Lower baseline serum IgG was an independent predictor of pneumonia (p=0.007) and severe infections (p=0.001). We conclude that outcomes in CVID depend on an interplay of factors including sex, numbers of switched memory B cells, and baseline serum IgG and IgA levels.

Toll-like receptor 7 and 9 defects in common variable immunodeficiency.

BACKGROUND Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia, reduced numbers of peripheral blood isotype-switched memory B cells, and loss of plasma cells. OBJECTIVE Because Toll-like receptor (TLR) activation of B cells can initiate and potentially sustain normal B cell functions, we examined functional outcomes of TLR7 and TLR9 signaling in CVID B cells. METHODS TLR7-mediated, TLR7/8-mediated, and TLR9-mediated cell proliferation, isotype switch, and immunoglobulin production by control and CVID B cells or isolated naive and memory B cell subsets were examined. We quantitated TNF-alpha, IL-6, and IL-12 production in response to TLR1-9 ligands and measured IFN-alpha production by TLR7-stimulated PBMCs and isolated plasmacytoid dendritic cells (pDCs). IFN-beta mRNA expression by TLR3-stimulated fibroblasts was assessed. RESULTS Unlike CD27(+) B cells of controls, TLR7-activated, TLR7/8-activated, or TLR9-activated CVID B cells or isolated CD27(+) B cells did not proliferate, upregulate CD27, or shed surface IgD. TLR-stimulated CVID B cells failed to upregulate activation-induced cytosine deaminase mRNA or produce IgG and IgA. TLR7-stimulated PBMCs and pDCs produced little or no IFN-alpha. Reconstituting IFN-alpha in TLR7-stimulated CVID B-cell cultures facilitated proliferation, CD27 upregulation, and isotype switch. These TLR defects are restricted because CVID PBMCs stimulated with TLR ligands produced normal amounts of TNF-alpha, IL-6, and IL-12; TLR3-mediated expression of IFN-beta by CVID fibroblasts was normal. CONCLUSION Defective TLR7 and TLR9 signaling in CVID B cells and pDCs, coupled with deficient IFN-alpha, impairs CVID B cell functions and prevents TLR-mediated augmentation of humoral immunity in vivo.

High levels of Crohn's disease-associated anti-microbial antibodies are present and independent of colitis in chronic granulomatous disease

Chronic granulomatous disease (CGD) and inflammatory bowel disease (IBD) have overlapping gastrointestinal manifestations. Serum antibodies to intestinal microbial antigens in IBD are thought to reflect a loss of tolerance in the setting of genetically encoded innate immune defects. CGD subjects studied here, with or without colitis, had considerably higher levels of ASCA IgA, ASCA IgG, anti-OmpC, anti-I2, and anti-CBir1, but absent to low pANCA, compared to IBD-predictive cutoffs. Higher antibody levels were not associated with a history of colitis. Except for higher ASCA IgG in subjects <18 years, antibody levels were not age-dependent. In comparison, 7 HIES subjects expressed negative to low antibody levels to all of these antigens; none had colitis. Our results suggest that markedly elevated levels of antimicrobial antibodies in CGD do not correlate with a history of colitis but may reflect a specific defect in innate immunity in the face of chronic antigenic stimulation.

Development of a food allergy education resource for primary care physicians

BackgroundFood allergy is estimated to affect 3–4% of adults in the US, but there are limited educational resources for primary care physicians. The goal of this study was to develop and pilot a food allergy educational resource based upon a needs survey of non-allergist healthcare providers.MethodsA survey was undertaken to identify educational needs and preferences for providers, with a focus on physicians caring for adults and teenagers, including emergency medicine providers. The results of the survey were used to develop a teaching program that was subsequently piloted on primary care and emergency medicine physicians. Knowledge base tests and satisfaction surveys were administered to determine the effectiveness of the educational program.ResultsEighty-two physicians (response rate, 65%) completed the needs assessment survey. Areas of deficiency and educational needs identified included: identification of potentially life-threatening food allergies, food allergy diagnosis, and education of patients about treatment (food avoidance and epinephrine use). Small group, on-site training was the most requested mode of education. A slide set and narrative were developed to address the identified needs. Twenty-six separately enrolled participants were administered the teaching set. Pre-post knowledge base scores increased from a mean of 38% correct to 64% correct (p < 0.001). Ability to correctly demonstrate the use of epinephrine self injectors increased significantly. Nearly all participants (>95%) indicated that the teaching module increased their comfort with recognition and management of food allergy.ConclusionOur pilot food allergy program, developed based upon needs assessments, showed strong participant satisfaction and educational value.

Epinephrine Concentrations in EpiPens After the Expiration Date

FL Cantrell, P Cantrell, A Wen, R Gerona. Ann Intern Med. 2017;166(12):918–919 To determine if EpiPens are still potent up to 50 months after the labeled expiration date. Unused, expired EpiPens were collected from patients and practitioners at a community clinic. Patients and practitioners provided unused, expired EpiPens over a 2-week period. All units were examined for color changes and expiration date. The concentration of epinephrine in two aliquots from each unit was quantified by liquid chromatography and tandem mass spectrometry. Epinephrine-d6 …

Inhaled Corticosteroids and Bone Mineral Density at School Age: A Follow-up Study After Early Childhood Wheezing

VH Sidoroff, MK Ylinen, LM Kroger, HP Kroger, MO Korppi. Pediatr Pulmonol. 2015;50(1):1–7 The goal of this study was to evaluate the association between inhaled corticosteroid (ICS) use and bone mineral density (BMD) in school-age children with a history of early childhood wheezing. This study cohort included 89 children who were part of a larger, prospectively followed group who had been hospitalized for infection-induced wheezing at <24 months of age. Exclusion criteria included prematurity and chronic lung or heart disease. At the follow-up visit 12 years after hospitalization, corticosteroid use was assessed by patient-completed questionnaires and retrospective chart …

Reduced Lung Function at Birth and the Risk of Asthma at 10 Years of Age

Håland G, Carlsen KC, Sandvik L, et al. N Engl J Med. 2006;355:1682–1689 PURPOSE OF THE STUDY. To evaluate whether reduced lung function at birth predicts the development of asthma and markers of obstructive airway diseases by 10 years of age. STUDY POPULATION. A prospective cohort of 616 10-year-old Norwegian children from the Environmental and Childhood Asthma (ECA) study who were initially enrolled as healthy term infants and had undergone lung-function testing and passive respiratory mechanics evaluation shortly after birth. METHODS. Lung function at birth was measured by calculating the fraction of time to peak expiratory flow to total expiratory time (tPTEF/tE) on the basis of tidal breathing flow-volume loops. Respiratory mechanics at birth were assessed by calculating respiratory system compliance and resistance during passive maneuvers. Data at the 10-year follow-up were collected during 2 clinical visits including forced expiratory flow-volume loops, methacholine-challenge tests, a treadmill exercise test, and skin-prick testing for common inhalant and food allergens. Parents also completed a validated International Study of Asthma and Allergies in Childhood questionnaire on airway symptoms, asthma-medication use, and previous physician-diagnosed asthma. The follow-up assessments and interviews were blinded with regard to the lung-function measurements at birth. RESULTS. In this cohort, the prevalence of a history of asthma was 20.2%, and prevalence of current asthma was 11.1%. Children with a tPTEF/tE at or below the median at birth were more likely at 10 years of age to have a history of asthma (24.3% vs 16.2%; P = .01), current asthma (14.6% vs 7.5%; P = .005), severe bronchial hyperresponsiveness (9.1% vs 4.9%; P = .05), and inhaled corticosteroid use (5.9% vs 2.4%; P = .02). Children with respiratory system compliance at or below the median were more likely to have a history of asthma (27.4% vs 14.8%; P = .001) and current asthma (15.0% vs 7.7%; P = .009). Decreased lung-function measurements did not consistently correlate with percent predicted forced flow-volume loops and exercise testing. CONCLUSIONS. Reduced lung function at birth may be a risk factor for the development of asthma by 10 years of age. REVIEWER COMMENTS. Other studies to date have shown that infants with reduced lung function have an increased risk for wheezing and asthma in the first few years of life. This study suggests that measuring lung function at birth may be useful in predicting which infants will develop asthma by late childhood. Knowing these risks may allow for directed therapy and prevention.

Neonatal-Onset Multisystem Inflammatory Disease Responsive to Interleukin-1β Inhibition

Goldbach-Mansky R, Dailey NJ, Canna SW, et al. N Engl J Med. 2006;355:581–592 PURPOSE OF THE STUDY. Neonatal-onset multisystem inflammatory disease (NOMID) is a chronic inflammatory disease that develops in infancy and is characterized by an urticarial rash, arthropathy, and central nervous system disease, including aseptic meningitis, cerebral atrophy, mental retardation, seizures, and vision and hearing loss. Approximately 60% of patients have a mutation in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, which is involved in the interleukin 1β (IL-1β) pathway. This study evaluated the effect of anakinra (Kineret, Amgen), an IL-1 receptor antagonist, on the various clinical and laboratory aspects of NOMID. STUDY POPULATION. A cohort of 18 patients aged 4 to 32 years with clinical NOMID (67% with mutations in CIAS1) who had active disease despite treatment with other antiinflammatory agents. METHODS. Patients were given a daily subcutaneous dose of anakinra. The drug was withdrawn from 11 patients at 3 months with the development of a clinical flare. Thereafter, all patients were continued on daily treatments up to 24 months. Clinical and laboratory assessments were made at 1, 3, and 6 months during therapy with anakinra. Primary end points included changes in a disease-specific daily diary score and changes in the serum levels of acute-phase reactants. RESULTS. All patients had an immediate response to anakinra with resolution of rash and conjunctivitis. There was an improvement in diary scores at 3 months that was maintained at 6 months. Serum amyloid A, C-reactive protein, and the erythrocyte sedimentation rate significantly declined with treatment. All the patients had headache at baseline, which resolved or improved with therapy, and cochlear and leptomeningeal lesions were improved on MRI. Serum levels of IL-1β, which were initially higher than those in healthy controls, decreased over the first 6 months of therapy. All the patients who underwent a treatment withdrawal experienced rapid improvement of their symptoms after resuming anakinra. Other than injection-site reactions, which resolved with continued treatment, there were no serious adverse events. CONCLUSIONS. Anakinra may be a safe and effective treatment for patients with NOMID. REVIEWER COMMENTS. This study suggests that anakinra may have a role in the treatment of other diseases in which IL-1β mediates inflammation (eg, systemic juvenile rheumatoid arthritis). Additional studies are needed to determine its long-term effects and clinical application. This study is an example of how specific immunomodulatory therapy may be useful in treating those diseases that have a defined molecular pathophysiologic profile.

Immunotherapy With a Ragweed-Toll-Like Receptor 9 Agonist Vaccine for Allergic Rhinitis

Creticos PS, Schroeder JT, Hamilton RG, et al. N Engl J Med. 2006;355:1445–1455 PURPOSE OF THE STUDY. The conjugate compound of the ragweed antigen, Amba1, and an immunostimulatory DNA sequence containing a CpG motif is associated with a suppression of T-helper 2 cellular and cytokine responses via binding to toll-like receptor 9 (TLR9). This study investigated whether Amba1-immunostimulatory oligodeoxyribonucleotide conjugate (AIC) is a safe and effective immunotherapy for ragweed-sensitized patients. STUDY POPULATION. A randomized, double-blind, placebo-controlled, phase 2 clinical trial in which 25 participants with a history of fall allergic rhinitis aged 23 to 60 years were assigned to receive a vaccine containing either AIC or placebo. METHODS. Participants received a total of 6 weekly injections before the ragweed season. The primary clinical end point was the change in albumin level in nasal secretions assessed by a posttreatment nasal allergen challenge. Postchallenge rhinitis symptoms were also scored. Secondary clinical end points included the rhinitis visual analog score, daily nasal symptom diary score, use of relief medication, a rhinoconjunctivitis quality-of-life questionnaire, and skin-test sensitivity. Immunologic evaluation included measuring Amba1- and ragweed-specific immunoglobulin (Ig) G and IgE and cytokine levels. RESULTS. There was no affect on the primary end point with AIC treatment. However, during the 2 posttreatment ragweed seasons, subjects in the group that received AIC had better peak-season rhinitis visual analog scores, peak-season daily nasal-symptom diary scores, and midseason rhinoconjunctivitis quality-of-life scores. Those in the AIC group also had decreased peak-season use of relief medications and antihistamine and decongestant use in the second season posttherapy. AIC was associated with a rise in the Amba1-specific IgE level after treatment but was not associated with an increase in the Amba1-specific IgE level during either posttreatment ragweed season. There were no vaccine-associated serious adverse reactions. CONCLUSIONS. AIC may have a potential therapeutic role in the treatment of ragweed-allergic individuals. REVIEWER COMMENTS. Current allergen immunotherapy involves frequent dosing over 3 to 5 years, which can lead to compliance issues, and may be associated with systemic allergic reactions. The described vaccine is devised to be less likely to trigger allergic reactions during therapy and to enhance nonallergic immune responses to increase efficacy. This study was limited by the small number of patients and the lack of long-term follow-up. However, it suggests that conjugated allergen vaccines may be an option in the future as shorter, safe, and effective immunotherapy regimens that may warrant consideration for use in children.