Genetic insight into Birt-Hogg-Dubé syndrome in Indian patients reveals novel mutations at FLCN.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is a rare monogenic condition mostly associated with germline mutations at FLCN. It is characterized by either one or more manifestations of primary spontaneous pneumothorax (PSP), skin fibrofolliculomas and renal carcinoma (chromophobe). Here, we comprehensively studied the mutational background of 31 clinically diagnosed BHDS patients and their 74 asymptomatic related members from 15 Indian families. RESULTS: Targeted amplicon next-generation sequencing (NGS) and Sanger sequencing of FLCN in patients and asymptomatic members revealed a total of 76 variants. Among these variants, six different types of pathogenic FLCN mutations were detected in 26 patients and some asymptomatic family members. Two of the variants were novel mutations: an 11-nucleotide deletion (c.1150_1160delGTCCAGTCAGC) and a splice acceptor mutation (c.1301-1G > A). Two variants were Clinvar reported pathogenic mutations: a stop-gain (c.634C > T) and a 4-nucleotide duplication (c.1329_1332dupAGCC). Two known variants were: hotspot deletion (c.1285delC) and a splice donor mutation (c.1300 + 1G > A). FLCN mutations could not be detected in patients and asymptomatic members from 5 families. All these mutations greatly affected the protein stability and FLCN-FNIP2 interaction as observed by molecular docking method. Family-based association study inferred pathogenic FLCN mutations are significantly associated with BHDS. CONCLUSION: Six pathogenic FLCN mutations were detected in patients from 10 families out of 15 families in the cohort. Therefore, genetic screening is necessary to validate the clinical diagnosis. The pathogenic mutations at FLCN affects the protein-protein interaction, which plays key roles in various metabolic pathways. Since, pathogenic mutations could not be detected in exonic regions of FLCN in 5 families, whole genome sequencing is necessary to detect all mutations at FLCN and/or any undescribed gene/s that may also be implicated in BHDS.

Anti-p-benzoquinone antibody level as a prospective biomarker to identify smokers at risk for COPD.

BACKGROUND AND OBJECTIVE: Identification of smokers having predisposition to COPD is important for early intervention to reduce the huge global burden of the disease. Using a guinea pig model, we have shown that p-benzoquinone (p-BQ) derived from cigarette smoke (CS) in the lung is a causative factor for CS-induced emphysema. p-BQ is also derived from CS in smokers and it elicits the production of anti-p-BQ antibody in humans. We therefore hypothesized that anti-p-BQ antibody might have a protective role against COPD and could be used as a predictive biomarker for COPD in smokers. The objective of this study was to compare the serum anti-p-BQ antibody level between smokers with and without COPD for the evaluation of the hypothesis. METHODS: Serum anti-p-BQ antibody concentrations of current male smokers with (n=227) or without (n=308) COPD were measured by an indirect enzyme-linked immunoabsorbent assay (ELISA) developed in our laboratory. COPD was diagnosed by spirometry according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. RESULTS AND DISCUSSION: A significant difference was observed in the serum anti-p-BQ antibody level between smokers with and without COPD (Mann-Whitney U-test =4,632.5, P=0.000). Receiver operating characteristic (ROC) curve analysis indicated that the ELISA had significant precision (area under the curve [AUC] =0.934, 95% confidence interval [CI]: 0.913-0.935) for identifying smokers with COPD from their low antibody level. The antibody cutoff value of 29.4 mg/dL was constructed from the ROC coordinates to estimate the risk for COPD in smokers. While 90.3% of smokers with COPD had a low antibody value (≤29.4 mg/dL), the majority (86.4%) of smokers without COPD had a high antibody value (≤29.4 mg/dL); 13.6% of current smokers without COPD having an antibody level below this cutoff value (odds ratio [OR] =59.3, 95% CI: 34.15-101.99) were considered to be at risk for COPD. CONCLUSION AND FUTURE DIRECTIONS: Our results indicate that serum anti-p-BQ antibody level may be used as a biomarker to identify asymptomatic smokers at risk for COPD for early intervention of the disease.

Spectrum of diffuse parenchymal lung diseases with special reference to idiopathic pulmonary fibrosis and connective tissue disease: An eastern India experience.

OBJECTIVE: To evaluate the clinical spectrum of diffuse parenchymal lung diseases (DPLD) encountered in the Indian setting and to compare idiopathic pulmonary fibrosis (IPF) and connective tissue disease associated DPLD (CTD-DPLD), the two commonest aetiologies. MATERIALS AND METHODS: A prospective study of clinical, imaging and laboratory parameters of patients diagnosed as DPLD and followed up in the Pulmonary Medicine Department of a tertiary-care teaching institution in eastern India was conducted over a period of one year. RESULTS: 92 patients of DPLD were diagnosed in the study period with IPF (n = 35, 38.04%), CTD-DPLD (n = 29, 31.5%), hypersensitivity pneumonitis (n = 10, 10.9%), sarcoidosis (n = 5, 5.4%) and silicosis (n = 5, 5.4%) being the common causes. The CTD-DPLD group had a lower mean age (39.5 ± 1.86 vs 56.9 ± 1.12 years), a longer duration of symptoms (3.5 ± 0.27 vs 2.5 ± 0.26 years), more extra pulmonary manifestations, significantly more base line FVC and 6-minute-walk-distance than the IPF patients. 19 patients of IPF (54%) opted for treatment. All the IPF patients had a significant fall in FVC after six months (mean change -0.203 ± 0.01 litres) compared to the CTD-DPLD group (mean change - 0.05 ± 0.04 litres.). CONCLUSION: CTD-DPLD patients belong to a younger age group, with longer duration of symptoms, more extrapulmonary features, better physiological parameters and better response to therapy than IPF patients. Larger prospective epidemiological studies and enrolment in clinical trials are necessary for better understanding of the spectrum of diffuse parenchymal lung disorders and their therapeutic options.

Pulmonary disease due to Mycobacterium massiliense.

We report a case of a patient suffering from multidrug-resistant pulmonary tuberculosis (MDR-PTB) who later developed an invasive infection of the respiratory tract with a rapidly growing non-tuberculous mycobacteria (NTM), recently identified as Mycobacterium massiliense, closely related to M. abscessus. To the best of our knowledge, this is the first case of M. massiliense infection being reported from India.

Metastatic pleural effusion: a rare presentation of salivary gland adenoid cystic carcinoma.

Adenoid cystic carcinoma, an uncommon malignant salivary gland neoplasm, is known for its long clinical course, indolent growth, local recurrence and late distant metastasis. We report an unusual case of adenoid cystic carcinoma of the palate in a 64-year-old woman, undiagnosed for more than 15 years, who presented as malignant pleural effusion.

Adult thoracic empyema: A comparative analysis of tuberculous and nontuberculous etiology in 75 patients.

BACKGROUND: Thoracic empyema is a disease of significant morbidity and mortality, especially in the developing world where tuberculosis remains a common cause. Clinical outcomes in tuberculous empyema are complicated by the presence of concomitant fibrocavitary parenchymal disease and frequent bronchopleural fistulae. We performed a prospective study over a one-and-a-half-year period with the objective of comparing the clinical profiles and outcomes of patients with tuberculous and nontuberculous empyema. MATERIALS AND METHODS: A prospective study of adult cases of nonsurgical thoracic empyema admitted in a tertiary care hospital in eastern India was performed over a period of 18 months. A comparative analysis of clinical characteristics, treatment modalities, and outcomes of patients with tuberculous and nontuberculous empyema was carried out. RESULTS: Seventy-five cases of empyema were seen during the study period, of which 46 (61.3%) were of nontuberculous etiology while tuberculosis constituted 29 (38.7%) cases. Among the nontuberculous empyema patients, Staphylococcus aureus (11, 23.93%) was the most frequent pathogen isolated, followed by Gram-negative bacilli. Tuberculous empyema was more frequent in younger population compared to nontuberculous empyema (mean age of 32.7 years vs. 46.5 years). Duration of illness and mean duration of chest tube drainage were longer (48.7 vs. 23.2 days) in patients with tuberculous empyema. Also the presence of parenchymal lesions and bronchopleural fistula often requiring surgical drainage procedures was more in tuberculous empyema patients. CONCLUSION: Tuberculous empyema remains a common cause of empyema thoracis in a country like India. Tuberculous empyema differs from nontuberculous empyema in the age profile, clinical presentation, management issues, and has a significantly poorer outcome.

Occurrence of allergic bronchopulmonary mycosis in patients with asthma: An Eastern India experience.

BACKGROUND: Allergic bronchopulmonary mycosis (ABPM) is a clinical syndrome associated with immune sensitivity to various fungi notably Aspergillus spp. that colonize the airways of asthmatics. Early diagnosis and treatment with systemic corticosteroids is the key in preventing the progression of the disease to irreversible lung fibrosis. AIMS: To study the occurrence of ABPM among asthma patients with fungal sensitization attending a chest clinic of a tertiary hospital of eastern India. The clinico-radiological and aetiological profiles are also described. MATERIALS AND METHODS: All consecutive patients with asthma presenting to the chest clinic over a period of one year were screened for cutaneous hypersensitivity to 12 common fungal antigens. The skin test positive cases were further evaluated for ABPM using standard criteria. RESULTS: One hundred and twenty-six asthma patients were screened using twelve common fungal antigens; forty patients (31.74%) were found to be skin test positive, and ABPM was diagnosed in ten patients (7.93%). Of the 10 cases of ABPM, nine cases were those of allergic bronchopulmonary aspergillosis (ABPA) and one case was identified as caused by sensitization to Penicillium spp. A majority of the cases of ABPM had advanced disease and had significantly lower FEV1 compared to non-ABPM skin test positive asthmatics. Central bronchiectasis on high resolution CT scan was the most sensitive and specific among the diagnostic parameters. CONCLUSION: There is a significant prevalence of ABPM in asthma patients attending our hospital and this reinforces the need to screen asthma patients for fungal sensitisation. This will help in early diagnosis and prevention of irreversible lung damage.

Life-threatening haemothorax: a rare presentation of pulmonary arteriovenous malformation.

Arteriovenous malformations of the lung are rare pulmonary vascular disorders which can suddenly lead to life threatening complications. Haemothorax due to rupture of a pulmonary arteriovenous malformation (PAVM) is very rare. We report here a case of a 39 year-old lady who presented with an acute onset of shortness of breath due to right-sided massive haemothorax and was subsequently detected to have pulmonary as well as cerebral arteriovenous malformation (CAVM).

Pregnancy unmasking lymphangioleiomyomatosis.

A 30 year-old housewife presented with cough and shortness of breath which progressed during her ensuing pregnancy, culminating in a still-birth at 9 months of gestation and requiring her hospitalisation in the immediate postpartum period. HRCT scan of the thorax showed thin-walled cysts and open lung biopsy confirmed the clinical impression of lymphangioleiomyomatosis. She was put on oral medroxyprogesterone acetate. After disease flare-up in the postpartum period her symptoms have stabilised.