Hana Alachkar

Response to pneumococcal polysaccharide vaccination in patients with chronic and allergic aspergillosis

INTRODUCTION Pneumococcal infection causes significant morbidity in patients with underlying lung disease, and vaccination has been associated with reduced disease rates. Response to vaccination has not been studied in chronic lung conditions characterised by ongoing infection or inflammation like chronic pulmonary aspergillosis (CPA). METHODS In a prospective observational study, consecutive patients with CPA, allergic aspergillosis and bronchiectasis attending a national referral centre received pneumococcal 23-valent polysaccharide vaccine (PPV-23) and had pre- and post-vaccination antibody concentrations quantified as part of routine clinical care. Serotype-specific pneumococcal IgG antibodies were quantified for 12 serotypes using a multiplex microsphere assay. A protective response was defined as a level of >1.3μg/mL or a ≥ fourfold rise in concentration for ≥70% of serotypes, pre to post-vaccination. C-reactive protein, Immunoglobulins and mannose binding lectin (MBL) levels were measured and correlated to vaccine response. RESULTS A total of 318 patients were enrolled. In vaccine-naïve patients (n=127), the lowest pre-vaccination levels were seen with serotypes 1 and 4 and the highest with serotype 19A. A protective response post-vaccination was seen in 50% of patients. The poorest responses were observed with serotypes 1, 3 and 4. Levels of C-reactive protein did not affect efficacy. Profound MBL deficiency was found in 28.8%; there were no significant differences in response to vaccination in patients with or without MBL deficiency. Post-vaccination serotype-specific concentrations waned gradually, however they were still elevated compared to pre-vaccination after 2-5 years. CONCLUSIONS Patients with chronic and allergic aspergillosis exhibited a poor response to PPV-23 vaccination compared to healthy adults. An alternative vaccination strategy or delay of vaccination until their underlying condition is better controlled, e.g. after treatment with antifungals may result in better response.

Bronchiectasis and deteriorating lung function in agammaglobulinemia despite immunoglobulin replacement therapy

Immunoglobulin replacement therapy enhances survival and reduces infection risk in patients with agammaglobulinaemia. We hypothesized that despite regular immunoglobulin therapy, some patients will experience ongoing respiratory infections and develop progressive bronchiectasis with deteriorating lung function. One hundred and thirty‐nine (70%) of 199 patients aged 1–80 years from nine cities in the United Kingdom with agammaglobulinaemia currently listed on the UK Primary Immune Deficiency (UKPID) registry were recruited into this retrospective case study and their clinical and laboratory features analysed; 94% were male, 78% of whom had Bruton tyrosine kinase (BTK) gene mutations. All patients were on immunoglobulin replacement therapy and 52% had commenced therapy by the time they were 2 years old. Sixty per cent were also taking prophylactic oral antibiotics; 56% of patients had radiological evidence of bronchiectasis, which developed between the ages of 7 and 45 years. Multivariate analysis showed that three factors were associated significantly with bronchiectasis: reaching 18 years old [relative risk (RR) = 14·2, 95% confidence interval (CI) = 2·7–74·6], history of pneumonia (RR = 3·9, 95% CI = 1·1–13·8) and intravenous immunoglobulin (IVIG) rather than subcutaneous immunoglobulin (SCIG) = (RR = 3·5, 95% CI = 1·2–10·1), while starting immunoglobulin replacement after reaching 2 years of age, gender and recent serum IgG concentration were not associated significantly. Independent of age, patients with bronchiectasis had significantly poorer lung function [predicted forced expiratory volume in 1 s 74% (50–91)] than those without this complication [92% (84–101)] (P < 0·001). We conclude that despite immunoglobulin replacement therapy, many patients with agammaglobulinaemia can develop chronic lung disease and progressive impairment of lung function.

Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease

Background Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor &kgr;B, c‐Jun N‐terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B‐cell expansion with nuclear factor &kgr;B and T‐cell anergy (heterozygous, gain‐of‐function mutations), and severe atopic disease (loss‐of‐function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole‐exome sequencing. Objectives We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss‐of‐function alleles. Methods Cell transfections and primary T‐cell assays were used to evaluate signaling and function of CARD11 variants. Results Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X‐linked–like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled‐coil domains of the CARD11 protein. Conclusion These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.

Clinical and laboratory features of seventy-eight UK patients with Good’s syndrome (thymoma and hypogammaglobulinaemia): Good’s syndrome in the UK

Good’s syndrome (thymoma and hypogammaglobulinaemia) is a rare secondary immunodeficiency disease, previously reported in the published literature as mainly individual cases or small case series. We use the national UK‐Primary Immune Deficiency (UKPID) registry to identify a large cohort of patients in the UK with this PID to review its clinical course, natural history and prognosis. Clinical information, laboratory data, treatment and outcome were collated and analysed. Seventy‐eight patients with a median age of 64 years, 59% of whom were female, were reviewed. Median age of presentation was 54 years. Absolute B cell numbers and serum immunoglobulins were very low in all patients and all received immunoglobulin replacement therapy. All patients had undergone thymectomy and nine (12%) had thymic carcinoma (four locally invasive and five had disseminated disease) requiring adjuvant radiotherapy and/or chemotherapy. CD4 T cells were significantly lower in these patients with malignant thymoma. Seventy‐four (95%) presented with infections, 35 (45%) had bronchiectasis, seven (9%) chronic sinusitis, but only eight (10%) had serious invasive fungal or viral infections. Patients with AB‐type thymomas were more likely to have bronchiectasis. Twenty (26%) suffered from autoimmune diseases (pure red cell aplasia, hypothyroidism, arthritis, myasthenia gravis, systemic lupus erythematosus, Sjögren’s syndrome). There was no association between thymoma type and autoimmunity. Seven (9%) patients had died. Good’s syndrome is associated with significant morbidity relating to infectious and autoimmune complications. Prospective studies are required to understand why some patients with thymoma develop persistent hypogammaglobulinaemia.