An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes S100A3 and S100A13.

BACKGROUND: Pulmonary fibrosis is one of the leading indications for lung transplantation. The disease, which is of unknown aetiology, can be progressive, resulting in distortion of the extracellular matrix (ECM), inflammation, fibrosis and eventual death. METHODS: 13 patients born to consanguineous parents from two unrelated families presenting with interstitial lung disease were clinically investigated. Nine patients developed respiratory failure and subsequently died. Molecular genetic investigations were performed on patients' whole blood or archived tissues, and cell biological investigations were performed on patient-derived fibroblasts. RESULTS: The combination of a unique pattern of early-onset lung fibrosis (at 12-15 years old) with distinctive radiological findings, including 1) traction bronchiectasis, 2) intralobular septal thickening, 3) shrinkage of the secondary pulmonary lobules mainly around the bronchovascular bundles and 4) early type 2 respiratory failure (elevated blood carbon dioxide levels), represents a novel clinical subtype of familial pulmonary fibrosis. Molecular genetic investigation of families revealed a hypomorphic variant in S100A3 and a novel truncating mutation in S100A13, both segregating with the disease in an autosomal recessive manner. Family members that were either heterozygous carriers or wild-type normal for both variants were unaffected. Analysis of patient-derived fibroblasts demonstrated significantly reduced S100A3 and S100A13 expression. Further analysis demonstrated aberrant intracellular calcium homeostasis, mitochondrial dysregulation and differential expression of ECM components. CONCLUSION: Our data demonstrate that digenic inheritance of mutations in S100A3 and S100A13 underlie the pathophysiology of pulmonary fibrosis associated with a significant reduction of both proteins, which suggests a calcium-dependent therapeutic approach for management of the disease.

Anti-IgE therapy for asthma: an audit at atertiary care centre in Saudi Arabia.

BACKGROUND: Although anti-IgE therapy has been shown to offer numerous benefits, we suspect it is underutilized locally. To date, there are no studies on any aspect of its use in the Arab region. There is also no information on whether physicians follow current guidelines nor on patient response to this form of therapy. OBJECTIVE: Assess the use of omalizumab for patients with difficult asthma at a tertiary care center. DESIGN: Retrospective, descriptive. SETTING: Tertiary care hospital. PATIENTS AND METHODS: Information was collected from medical records and interviews of all patients who received a minimum of 6 months of omalizumab, including data on practices of the prescribing physician (pulmonary versus allergy), indications, dose, subjective response, number of emergency room visits and hospitalizations, changes in asthma medications, adverse effects, and the setting for delivery of therapy. MAIN OUTCOME MEASURES: Extent to which current guidelines for prescribing omalizumab were followed. Patient subjective and objective responses to treatment as reflected by changes in the use of medications and lung function before and after therapy. SAMPLE SIZE: 50 patients. RESULTS: Of the 50 consecutive patients, 35 were female and the mean (SD) age was 46.3 (9.2) years. Only 28 patients (56 %) met all the criteria for the prescription of omalizumab as per current guidelines; 18 (64%) by pulmonary and 10 (36%) by allergy physicians (P less than .05). Pulmonary physicians performed more tests for conditions complicating or simulating asthma (P less than .05). The mean (SD) duration of treatment by omalizumab of 35 (22) months was longer in patients managed by allergists (42 [24] months) than pulmonary physicians (30 [21] months) (P greater than .05). Both physician groups prescribed a lower initial dose than recommended (P less than .05 recommended vs. prescribed). Patients reported a significant improvement in symptoms, reduction in the use of broncho-dilators and oral steroids and in the use of healthcare services (from 16.28 [7.9] to 2.08 [1.78], P less than .0001) mean values from sum of hospitalizations/year, ER visits/year, exacerbations/year, but not in other medications or pulmonary function tests (P greater than .05). CONCLUSION: Despite several benefits, notably a reduction in utilization of health services and asthma medication, anti-IgE therapy is probably underutilized locally. Pulmonary physicians are more likely to follow the guidelines than allergy physicians. This study suggests that there is room for improvement in the prescription practices, particularly in dosing and the setting for delivery. Further multicenter prospective studies are required to identify gaps in the current practices and improve asthma management. LIMITATIONS: Too few patients met inclusion criteria, lack of control group, and use of a subjective assessment for patient symptoms as opposed to validated questionnaires. CONFLICT OF INTEREST: None.