Identification of 22 novel BTK gene variants in B cell deficiency with hypogammaglobulinemia.

X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by pathogenic variants in the BTK gene, resulting in impaired B cell differentiation and maturation. Over 900 variants have already been described in this gene, however, new pathogenic variants continue to be identified. In this report, we describe 22 novel variants in BTK, associated with B cell deficiency with hypo- or agammaglobulinemia in male patients or in asymptomatic female carriers. Genetic data was correlated with BTK protein expression by flow cytometry, and clinical and family history to obtain a comprehensive assessment of the clinico-pathologic significance of these new variants in the BTK gene. For one novel missense variant, p.Cys502Tyr, site-directed mutagenesis was performed to determine the impact of the sequence change on protein expression and stability. Genetic data should be correlated with protein and/or clinical and immunological data, whenever possible, to determine the clinical significance of the gene sequence alteration.

Pneumococcal serotype-specific cut-offs based on antibody responses to pneumococcal polysaccharide vaccination in healthy adults.

Antibody responses to pneumococcal polysaccharide vaccination are frequently used as a diagnostic tool for humoral immunodeficiencies, part of the larger collection of inborn errors of immunity. Currently, arbitrary criteria, such as a serotype specific titer of >/= 1.3 µg/mL is most often used as a cut-off for interpretation of pneumococcal antibody responses. The magnitude of the antibody response to each of the 23 serotypes in Pneumovax®, and serotype-specific cut-offs in healthy pneumococcal vaccine-naïve adults has not been previously characterized. IgG antibody concentrations were measured prospectively for 23 pneumococcal serotypes pre and 4-6 weeks post-Pneumovax® vaccination in 100 healthy adults, using a multiplex bead-based assay. Antibodies to 19 of 23 serotypes were informative for distinguishing subjects who responded to vaccination, and the serotype threshold was determined to be 9 of 19 serotypes, which characterized an antibody response to pneumococcal vaccination. While this study may facilitate classification of IgG serotype-specific antibody responses post-pneumococcal vaccination in adult patients undergoing diagnostic immunological evaluation for antibody immunodeficiencies or other relevant contexts, additional studies in healthy children and S. pneumoniae protein-conjugate-vaccinated healthy adults will need to be undertaken in the future.

Effects of secondhand smoke exposure on asthma morbidity and health care utilization in children: a systematic review and meta-analysis.

BACKGROUND: Secondhand smoke (SHS) exposure can trigger asthma exacerbations in children. Different studies have linked increased asthma symptoms, health care use, and deaths in children exposed to SHS, but the risk has not been quantified uniformly across studies. OBJECTIVE: To perform a systematic review and meta-analysis to evaluate and quantify asthma severity and health care use from SHS exposure in children. METHODS: A systematic review was undertaken to assess the association between asthma severity and SHS in children. Inclusion criteria included studies that evaluated children with SHS exposure and reported outcomes of interest with asthma severity including exacerbations. Random effect models were used to combine the outcomes of interest (hospitalization, emergency department or urgent care visits, severe asthma symptoms, wheeze symptoms, and pulmonary function test results) from the included studies. RESULTS: A total of 1,945 studies were identified and 25 studies met the inclusion criteria. Children with asthma and SHS exposure were twice as likely to be hospitalized for asthma (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.20-2.86, P = .01) than children with asthma but without SHS exposure. SHS exposure also was significantly associated with emergency department or urgent care visits (OR 1.66, 95% CI 1.02-2.69, P = 0.04), wheeze symptoms (OR 1.32, 95% CI 1.24, 1.41, P < .001), and lower ratio of forced expiratory volume in 1 second to forced vital capacity (OR -3.34, 95% CI -5.35 to -1.33, P = .001). CONCLUSION: Children with asthma and SHS exposure are nearly twice as likely to be hospitalized with asthma exacerbation and are more likely to have lower pulmonary function test results.

Asthma-associated comorbidities in children with and without secondhand smoke exposure.

BACKGROUND: Secondhand smoke (SHS) exposure is known to trigger asthma, but asthma disease severity and comorbidities in children exposed to SHS are not very well quantified. OBJECTIVE: To identify comorbidities and understand health care usage in children with asthma exposed to SHS (cases) compared with children with asthma but without SHS exposure (controls). METHODS: A retrospective nested matched case-and-control study was conducted with children 5 to 18 years old who were enrolled in the Pediatric Asthma Management Program. Pulmonary function testing (spirometry, methacholine challenges, and exhaled nitric oxide) and body mass index were reviewed. Influenza vaccination rates, oral steroid usage, emergency department visits, and hospitalizations were assessed. Network analysis of the 2 groups also was conducted to evaluate for any associations between the variables. RESULTS: Cases had significantly higher body mass index percentiles (>75%, odds ratio [OR] 1.64, 95% confidence interval [CI] 1.22-2.2, P = .001). Cases were less likely to have had a methacholine challenge (OR 0.49, 95% CI 0.36-0.68, P < .001) and an exhaled nitric oxide (OR 0.6, 95% CI 0.37-0.97, P = .04) performed than controls. The ratio of forced expiration volume in 1 second to forced vital capacity and forced expiration volume in 1 second were lower in cases than in controls (P < .05). Cases were less likely to have received an influenza vaccination (OR 0.61, 95% CI 0.45-0.82, P = .001) than controls. Unsupervised multivariable network analysis suggested a lack of discrete and unique subgroups between cases and controls. CONCLUSION: Children with asthma exposed to SHS are more likely to have comorbid conditions such as obesity, more severe asthma, and less health care usage than those not exposed to SHS. Smoking cessation interventions and addressing health disparities could be crucial in this vulnerable population.

Successful outpatient graded administration of trimethoprim-sulfamethoxazole in patients without HIV and with a history of sulfonamide adverse drug reaction.

BACKGROUND: The outcomes of trimethoprim-sulfamethoxazole (TMP-SMX) desensitization have been widely reported in the HIV literature but less so in the non-HIV literature. OBJECTIVE: To evaluate the safety and efficacy of graded administration of TMP-SMX in patients without HIV and with a history of TMP-SMX adverse drug reaction (ADR). METHODS: A retrospective chart review, 2004-2012, of all the patients without HIV seen in the Division of Allergic Diseases and with a history of TMP-SMX ADR who underwent outpatient graded administration of TMP-SMX was conducted. The medical record was reviewed for age, sex, details of the initial ADR to TMP-SMX, an indication for TMP-SMX administration, and outcome. Patients also were contacted by telephone, and medical records were reviewed to determine long-term outcomes. RESULTS: Seventy-two patients (46 women [64%]; mean [SD] age, 57.7 ± 13.89 years]) were included. The most common patient-reported reactions to TMP-SMX were rash 39 (54%), and hives 9 (13%). TMP-SMX administration was needed for the following indications: prophylaxis (62 [86%]) and treatment of infection (10 [14%]). Forty-three of the patients (60%) underwent a 1-day TMP-SMX administration protocol. Thirty-five of the 43 (81%) underwent a 6-step (90 minutes to 6 hours) protocol and 7 of the 43 (16%) underwent a novel 14-step TMP-SMX protocol. Twenty-nine (40%) underwent a >1-day TMP-SMX administration protocol. Our overall success rate was 90% (mean duration of 11 months). Ninety-eight percent of the patients successfully completed a 1-day graded administration protocol, and 76% successfully completed a >1-day protocol. TMP-SMX was stopped in 8 patients because of the ADR. CONCLUSION: We report the largest case series of successful outpatient graded administration of TMP-SMX with both 1-day and >1-day protocols, which have shown to be safe and well tolerated in patients without HIV and with a history of sulfonamide ADR.

An Apple-core Lesion in the Colon: An Infectious Etiology.

Gastrointestinal involvement occurs in about 70% to 90% of histoplasmosis cases but is usually not the initial manifestation. We present the case of a 52-yearold HIV-positive woman who presented with gastrointestinal symptoms and an apple-core lesion on CT scan of the abdomen. The patient had been diagnosed with histoplasma colitis eight months earlier and was started on long-term itraconazole therapy. However, she prematurely discontinued treatment. A colonoscopy during the present hospitalization revealed a 3.5-cm mass, biopsies of which revealed Histoplasma capsulatum. In the present report, we discuss the differential diagnosis of apple-core lesions in the colon and the importance of keeping histoplasmosis on the differential diagnosis, especially in endemic areas like the Ohio River valley. It is equally important to ensure compliance with treatment of histoplasmosis, as well as close follow-up, as progression to colonic obstruction while on medical management has been reported.