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.

Sarcoidosis at the Pulmonary Medicine Department of a tertiary care hospital in Mumbai. Our experience and The New Modified Criteria Clinical Radiological Physiological (TNMC CRP) score for sarcoidosis: A novel proposition to assess the functional status.

Sarcoidosis is a multisystemic granulomatous disease most commonly involving the pulmonary system and having a myriad of manifestations. However literature is scanty pertaining to the profile and scoring system in sarcoidosis. This study was undertaken to understand the profile of sarcoidosis and an endeavor to assess the functional status with a simplified scoring system. This was an observational study undertaken in the department of Pulmonary Medicine at a tertiary care. The profile of these patients was studied in terms of clinical features, radiological findings, the New Modified Criteria Clinical Radiological Physiological (TNMC CRP) score, six-minute walk distance (6MWD), spirometry, arterial blood gas parameters, serum angiotensin converting enzyme (ACE) levels and tissue biopsy histopathology. The 68 patients included 41 women and 27 men with a mean age of 42.7 years. They comprised of 18 (27%), 39 (57%), 4 (6%), 7 (10%) cases of stage 1, 2, 3, 4 sarcoidosis respectively. Most common presenting symptom and sign was progressive dyspnea 49 (72%), and peripheral lymphadenopathy 15 (22%). Serum ACE was elevated in 57 (83%). The average 6MWD was 360 meters. Most common high resolution computed tomography (HRCT) finding was mediastinal lymphadenopathy and peri-bronchovascular nodules. Spirometry was restrictive abnormality in 48 (96%) patients. Evidence of pulmonary hypertension (PH) was present in 32 (47%) patients. Tissue diagnosis revealed granulomatous inflammation in 51 biopsies with a transbronchial lung biopsy (TBLB) yield of 62%. The average TNMC CRP score was 5. There was a positive correlation between this score and 6MWD which was statistically significant. The score correlated with the functional status. Diagnosis of sarcoidosis warrants a comprehensive and multimodality approach. HRCT and tissue biopsy are the most important diagnostic armamentariums. Modified simplified scores help assess the functional status of the disease.

Prevalence and profile of sleep-disordered breathing and obstructive sleep apnea in patients with interstitial lung disease at the pulmonary medicine department of a tertiary care hospital in Mumbai.

BACKGROUND: Sleep-disordered breathing (SDB), predominantly obstructive sleep apnea (OSA), is a frequent phenomenon in interstitial lung disease (ILD) and may be associated with significant morbidity and mortality. METHODOLOGY: A prospective, observational, hospital-based study was conducted in a tertiary care hospital after ethics committee permission. The study group consisted of 100 consecutive ILD patients diagnosed by a multidisciplinary diagnosis. They were evaluated for the prevalence of SDB with a polysomnography after a comprehensive history, detailed clinical examination, calculation of various pretest probability scores, and relevant prerequisite workup. RESULTS: Out of the total 100 ILD patients, 44 were male (44%) and 56 were female (56%). SDB was present in 57 (57%) patients. Of these, 29 (29%) were found to have only nocturnal oxygen desaturation (NOD), while 28 (28%) had OSA. The 28 cases of OSA were distributed as 15 mild OSA (53.57%), 10 moderate OSA (35.71%), and 3 severe OSA (10.71%). The patients were divided into the following four groups: total study Group (A), patients with OSA (Group B), patients with NOD without OSA (Group C), and no SDB (Group D). The mean forced vital capacity values predicted in the four groups were 53.67%, 50%, 45.56%, and 57.87%, respectively. The mean body mass index in the four groups was 24.56, 27, 26.98, and 24.89 kg/m2, respectively. The mean 6-min walk distance in the four groups was 280.7, 250, 256.65, and 311.4 m, respectively. The mean partial pressure of oxygen in the four groups was 65.65, 60, 62.10, and 75.66 mmHg, respectively. The mean apnea-hypopnea index in the study group was 2.98/h, 8.6/h with mild OSA, 21.69/h with moderate OSA, 48.78/h with severe OSA, 3.89/h in patients having NOD without OSA, and 2.54/h in patients with no SDB. CONCLUSION: SDB in ILD is associated with a significant impact on the cardinal determinants of functional capacity, lung function, and quality of life.

"Esophagomediastinal fistula presenting as drug resistant tuberculosis".

Esophageal tuberculosis is one of the rarest forms of tuberculosis with higher incidence in immunocompromised cases. In majority of cases it is seen associated with esophagomediastinal and esophagotracheal fistulas. Diagnosis is established with the help of esophagoscopy followed by histopathology and microbiological analysis of biopsy sample. Treatment with antituberculous therapy alone is sufficient in majority of cases, however surgical management is mandatory in severe and non resolving cases. We thereby report an interesting case of esophagomediastinal fistula presenting as drug resistant tuberculosis with retroviral disease.

Management of interstitial lung diseases: A consensus statement of the Indian Chest Society (ICS) and National College of Chest Physicians (NCCP).

BACKGROUND: Interstitial lung disease (ILD) is a complex and heterogeneous group of acute and chronic lung diseases of several known and unknown causes. While clinical practice guidelines (CPG) for idiopathic pulmonary fibrosis (IPF) have been recently updated, CPG for ILD other than IPF are needed. METHODS: A working group of multidisciplinary clinicians familiar with clinical management of ILD (pulmonologists, radiologist, pathologist, and rheumatologist) and three epidemiologists selected by the leaderships of Indian Chest Society and National College of Chest Physicians, India, posed questions to address the clinically relevant situation. A systematic search was performed on PubMed, Embase, and Cochrane databases. A modified GRADE approach was used to grade the evidence. The working group discussed the evidence and reached a consensus of opinions for each question following face-to-face discussions. RESULTS: Statements have been made for each specific question and the grade of evidence has been provided after performing a systematic review of literature. For most of the questions addressed, the available evidence was insufficient and of low to very low quality. The consensus of the opinions of the working group has been presented as statements for the questions and not as an evidence-based CPG for the management of ILD. CONCLUSION: This document provides the guidelines made by consensus of opinions among experts following discussion of systematic review of evidence pertaining to the specific questions for management of ILD other than IPF. It is hoped that this document will help the clinician understand the accumulated evidence and help better management of idiopathic and nonidiopathic interstitial pneumonias.

Tuberculosis in 2019.

Tuberculosis (TB) updates and guidelines have been published rapidly in last few years. The WHO and RNTCP have recommended suggestions that have changed the diagnostics and therapeutics paradigm in 2019. The rapid nature of these changes need to be appraised at the pulmonologist end. We conducted a google survey to study these gaps and subsequently review TB in 2019 focusing on the gaps in the survey. We narrate a short review covering the important diagnostic and therapeutic aspects in brief. We discuss the results of our google survey to address the knowledge gaps. Diagnosis, principles and rationale of therapy and treatment of drug sensitive and drug resistant tuberculosis including the shorter regimen and regrouping of drugs are important considerations of our review.

Malignant Mesothelioma - Report of Two Cases with Different Presentations.

Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm that stems from the mesothelial cells lining the visceral cavities, namely, the pleura, peritoneum, pericardium, and tunica vaginalis of the testes. MPM is the most common variant of these and constitutes up to 80% of all malignant mesotheliomas. It is usually associated with asbestos exposure and is a locally invasive neoplasm that spreads along pleura and can involve lungs with locoregional metastasis. Diagnosis remains challenging due to the latency between asbestos exposure and clinical presentation and the variable clinicoradiological manifestations. Meticulous history taking, high index of, suspicion and multimodality approach toward diagnosis are the keys to better prognosis. We hereby present two interesting cases of MPM with different presentations.

Impulse oscillometry.

Pulmonary function testing involves a battery of tests from the simple pulse oximetry to the cardiopulmonary exercise testing. Impulse oscillometry (IOS) is one of the newly described pulmonary function tests. It is based on the old principle of forced oscillatory technique modified and refined as per research and advances. It involves the use of sound waves during normal tidal breathing, which gives information on oscillatory pressure-flow relationships and eventually resistance and reactance. The resistance at 20 Hz (R20) represents the resistance of the large airways. The resistance at 5 Hz (R5) means the total airway resistance. (R5-R20) reflects resistance in the small airways. The reactance at 5 Hz (X5) indicates the elastic recoil of the peripheral airways. Resonant frequency and area of reactance are also measured. IOS has major uses in diagnosis and control of asthma in children and the elderly, where spirometry is otherwise normal. IOS has been studied in other respiratory diseases like COPD, ILD and supraglottic stenosis.

Pulmonary Vocal Syndrome.

Vocal cord paralysis is a common entity with diverse causes clinically manifesting as dysphonia. Vocal cord paralysis due to respiratory cause is due to involvement of left recurrent laryngeal nerve usually secondary to bronchogenic carcinoma. However, it can also be seen in association with other less well recognised causes such as pulmonary tuberculosis. We present to you a patient with hoarseness of voice due to left recurrent laryngeal nerve paralysis secondary to endobronchial tuberculosis.

The clinico-radiological profile of obliterative bronchiolitis in a tertiary care center.

BACKGROUND: Obliterative bronchiolitis (OB) forms a major proportion of chronic airway diseases (CADs). OB is often misdiagnosed and included under the umbrella term 'chronic obstructive pulmonary disease'. We set out to identify the proportion of OB cases among the CADs and study the clinical profile of OB. MATERIALS AND METHODS: This prospective, observational study noted all patients with Chronic airway obstruction (CAO), of which patients with OB were included and the clinical profile was studied. Data were subjected to statistical analysis. RESULTS: Five hundred patients with CAO were noted in the study period, of which 115 patients were found to be OB amounting to a prevalence of 23%. The mean age of presentation was 51.8 years (standard deviation 12.1) with a male-female ratio of 1:1. The most common etiology for OB was as sequelae to past treated pulmonary tuberculosis (PTB) seen in 82 patients (71%) of cases. Dyspnea in 114 patients (99%) and productive cough in 110 patients (95%) were the predominant symptoms. Postexercise desaturation was seen in all 115 patients (100%). Forty-six patients (43%) presented with either Type 1 or Type 2 respiratory failure. Spirometry showed obstructive pattern in 68 patients (59%) with forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio of <70% and FEV1 <70% postbronchodilator and mixed pattern in 47 patients (41%) with a reduction in both FEV1 and FVC and normal FEV1/FVC ratio. There was the presence of mosaic attenuation on high-resolution computerized tomography (HRCT) of the chest with expiratory scans in all 115 patients (100%). Pulmonary hypertension was documented in 109 patients (95%). CONCLUSION: OB is one of the major causes of CAO. HRCT of the chest with expiratory scans plays a important role in the diagnosis. Early diagnosis can prevent irrevocable complications.

Hermansky-Pudlak syndrome with interstitial lung disease: A holistically worked up couplet.

Hermansky-Pudlak syndrome (HPS) is an extremely subtile autosomal recessive disorder characterized by tyrosinase-positive oculocutaneous albinism (Ty-pos OCA), bleeding tendencies, and systemic complications associated to lysosomal dysfunction. The most grave complication of disease is interstitial lung disease (ILD) leading to irrevocable pulmonary fibrosis. Patients with HPS-1, HPS-2, and HPS-4 variants have a penchant to develop pulmonary fibrosis. The pulmonary involvement is characterised by progressive dyspnea hypoxemia respiratory failure and corpulmonale. The disease has an unfortunate prognosis with a high mortality rate and a poor quality of life. The options currently available in the therapeutic armamentarium are dismal with a dire need for opportune research. We hereby narrate an intriguing case scenario of a pair of siblings affected with this rare disorder with its associated ILD.

Extrapulmonary drug-resistant tuberculosis at a drug-resistant tuberculosis center, Mumbai: Our experience - Hope in the midst of despair!

BACKGROUND: Drug-resistant tuberculosis (DR-TB) is a global problem with only 52% reported cure rate. Extrapulmonary (EP) DR-TB poses a formidable diagnostic, therapeutic challenge. We aimed to study their clinical profile and treatment outcomes under the programmatic setting. MATERIALS AND METHODS: This retrospective observational study included the database of consecutive EPDR-TB cases enrolled at the DR-TB center from 2012 to 2014. The demographic, clinical details, drug susceptibility tests (DSTs), follow-up, therapy, adverse events (AEs), and outcome were reviewed. Statistical analysis was done using percentages and mean. RESULTS: Of total 1743 DR-TB patients, 76 (4.4%) EPDR-TB cases were included. These consisted of 53 (69.7%) adults and 23 (30.3%) children, with female preponderance. The mean age in adults and children was 27.96 (9.63) and 12.56 (3.83), respectively. EP sites involved were lymph nodes in 39 (51.3%), spine in 15 (19.7%), other bones in 6 (7.9%), pleural effusion in 9 (11.9%), central nervous system in 2 (2.6%), and disseminated EP disease in 5 (6.6%). Forty-one (53.9%) had multi-DR-TB (MDR-TB), 29 (38.2%) MDR-TB with fluoroquinolone resistance {preextensively DR-TB (Pre-XDR-TB (FQ)), 1 (1.3%) MDR-TB with aminoglycoside resistance (Pre-XDR-TB (AM)), and 5 (6.6%) extensively DR-TB (XDR-TB) on DST. Thirteen (17.11%) had comorbidities. None had HIV. Two (2.63%) had DM. Patients were treated as per the revised TB control program - programmatic management of DR-TB guidelines. Duration of intensive (IP) was 6.55 (1.22) months. Ten (13.2%) received shorter regimens, wherein therapy was stopped at 12-18 months due to severe adverse drug reactions and treatment response. Sixty-two (81.6%) completed treatment, 8 (10.5%) defaulted, 3 (4%) died, 2 (2.6%) failed, and 1 (1.3%) was transferred out. Two-third of patients reported AE. CONCLUSION: The prevalence of EP cases in DR-TB was 4.4%. Treatment completion rate was very high (81.6%). Shorter regimens were efficacious.

Utility of para-aminosalicylic acid in drug-resistant tuberculosis: Should it be classified as Group D3 or Group C?

BACKGROUND: The World Health Organization drug-resistant tuberculosis (DR-TB) 2016 guidelines reclassified para-aminosalicylic acid (PAS) as Group D3 "add-on" drug. We studied our DR-TB data wherein PAS was widely and preferably used as a substitute in the standardized regimen in varied situations and report its utility in DR-TB. METHODOLOGY: This retrospective observational study enrolled both pulmonary and extrapulmonary DR-TB patients receiving PAS in the programmatic management of DR-TB from March 2012 to June 2013. They were divided into seven subgroups on the basis of indication for PAS substitution in the standardized regimen for DR-TB cases. The clinical profile and outcomes were analyzed. RESULTS: PAS was substituted in 250 cases (225 - pulmonary DR-TB and 25 - extrapulmonary DR-TB). PAS was used in (1) pre-extensively drug-resistant TB (XDR-TB) fluoroquinolones (FQs) - 136 (54.4%), (2) XDR-TB - 15 (6%), (3) substitute drug for serious adverse events - 3 (1.2%), (4) pregnant DR-TB patients - 5 (2%), (5) patients on successful private-based second-line therapy adopted under the Revised National Tuberculosis Control Program - 10 (4%), (6) substitute drug for previous FQ exposure - 5 (2%), and (7) Category V - 76 (30.4%). Although 51.2% had an unfavorable response (UFR) against 48.8% with FR, wide disparity was noted in subgroups. FR was observed in 68.4% pre-XDR-TB (FQ), 80% pregnant patients, 90% adopted from private on successful second-line therapy, 80% previous FQ exposure against 40% XDR-TB, 7.9% Category V, and 0% PAS substitution for adverse drug reactions (ADRs). UFR was seen in 31.6% pre-XDR-TB (FQ), 20% pregnant patients, 10% adopted from private on successful second-line therapy, 20% of previous FQ exposure against 60% XDR-TB, 92.1% Category V, and 100% on PAS substitution for ADR. CONCLUSION: In view of the safety and efficacy of PAS in our DR-TB patients except for XDR and Category V group, we recommend larger studies with PAS and consider its reclassification into Group C rather than Group D3.

Use of pigtail catheter and urosac: Numero uno for ambulatory chest drainage!

BACKGROUND: Intercostal chest drainage is required for varied lung diseases with the pleural involvement. While the conventional method of intercostal drainage (ICD) insertion with the bulky underwater drain (UWD) was the gold standard for management, it had numerous disadvantages. It was time and again challenged with better ambulatory methods, although the documentation and continued use of the same are rare in practice. We studied the efficacy of ambulatory chest drainage (ACD) with pigtail and urosac against the conventional drainage methods (ICD-UWD) at a tertiary care center. MATERIALS AND METHODS: This prospective, observational study included the patients requiring chest drainage grouping them as per the intervention they underwent, i.e., (1) Pigtail-Urosac (ACD group) and (2) ICD-UWD (Non-ACD group). The clinical data were recorded and analyzed for the difference in the hospital stay, the total duration of drainage, successful outcome, residual disease, and pain in both groups using unpaired t-test and Chi-square test. RESULTS: Of the 85 patients included in the study; 45 had pigtail-urosac and 40 had ICD-UWD, consisting of 34 pleural effusions and 51 pneumothoraces. The ACD and non-ACD groups were similar in etiology. Of the 85 patients, 50 had complete lung expansion, 18 pleural thickening, 15 loculated residual disease, and two pleurocutaneous fistulae. In the ACD group, the hospital stay was less as compared to the non-ACD group, i.e., 4.06 (4.42) versus 19.68 (31.39) days (P = 0.0008). The duration of chest drainage showed a similar trend, i.e., 19.29 (66.91) versus 52.18 (46.38) days (P = 0.006). Pain (P < 0.0001) recorded was significantly less with better expansion (P < 0.0001), less pleural thickening (P = 0.0067), and residual disease (P = 0.0087) in the ACD group. CONCLUSION: The use of pigtail-urosac is a safe, effective, and preferred method for ACD.

Cryptococcosis with bird's eye manifestation: A case report.

Cryptococcosis is a menacing opportunistic infection most commonly affecting immunocompromised individuals. Its occurrence in immunocompetant individuals is uncustomary. Disseminated cryptococcosis is subtile in immunocompetent individuals. Cryptococcosis presenting with myriad of symptoms with involvement of lung, meninges, hematological system is rare. We present to you a unique case of disseminated cryptococcosis presenting as bilateral pulmonary nodular opacities with peripheral eosinophilia and meningitis along with a narration of the enthralling diagnostic process.

A perplexing primary novel hilar lesion: Remember the pneumonic PPNHL!

A 60-year-old female presented with dyspnea, cough, and chest pain with a left hilar mass lesion. In our case, clinicoradiological correlation, bronchoscopy, and computed tomography-guided biopsy revealed the diagnosis of primary pulmonary non-Hodgkin's lymphoma (PPNHL) on histopathology and immunohistochemistry. We discuss the approach to hilar masses. PPNHL is a rare malignant lymphoma most common being mucosa-associated lymphoid tissue lymphoma. Various therapeutic options are available. The chemotherapy regimen consisting of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) is preferred.

Systemic thrombosis due to pulmonary tuberculosis.

Pulmonary tuberculosis (TB) is an established cause of venous thrombosis. A few instances have been described with arterial thrombosis as well. It has been speculated that TB causes systemic hypercoagulability, which may lead to venous thrombosis. This may be the presenting phenomenon, may occur shortly after diagnosis of TB, or even after starting antitubercular therapy. We describe a patient of pulmonary TB, who presented with pulmonary thromboembolism, with both arterial as well as venous thrombosis, which resolved on antitubercular therapy.