Prevalence, severity and impacts of breathlessness in Indian adults: An exploratory, nationally representative, cross-sectional online survey.

There are no known estimates of the prevalence, severity and impacts from breathlessness in low- and middle-income countries. This study aimed to explore the prevalence, severity, self-attributed underlying conditions and impacts of breathlessness limiting exertion in community-dwelling adults in India. This exploratory, population-based online survey recruited a pre-planned sample of 3,000 adult respondents stratified by age, sex and rurality (quotas as per the 2011 Indian National Census). Measures included: demographics; breathlessness limiting exertion (modified Medical Research [mMRC] scale); health-related quality of life (EQ-5D-5L); and disability (World Health Organisation's Disability Assessment Schedule 2.0 12-item questionnaire [WHODAS-12]). Respondents (n = 3,046) had a mean age of 38 years (SD 15); 57% were male, 59% lived in rural areas and 33% had completed 12th grade. Breathlessness limiting exertion (mMRC ≥1) was reported by 44%, mostly attributed to poor nutrition (28%), lung conditions excluding tuberculosis (17%) or anaemia (13%). Compared to those without breathlessness, a higher proportion of people with breathlessness (mMRC ≥1) reported problems across all EQ-5D-5L dimensions. Most people reporting breathlessness (81%) indicated the symptom had adversely affected their normal activities. Disability scores (WHODAS-12 total and individual domains) increased as breathlessness worsened. To conclude, in India, conservative estimates indicate 626 million people live with breathlessness of whom 52 million people live with severe breathlessness. The symptom is associated with poorer health-related quality of life and marked disability, including reduced ability to perform daily activities.

Adaptive multi-interventional trial platform to improve patient care for fibrotic interstitial lung diseases.

BACKGROUND: Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD). METHODS: Description of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure. RESULTS: The target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results. CONCLUSION: By using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD.

Progressive pulmonary fibrosis: an expert group consensus statement.

This expert group consensus statement emphasises the need for standardising the definition of progressive fibrosing interstitial lung diseases (F-ILDs), with an accurate initial diagnosis being of paramount importance in ensuring appropriate initial management. Equally, case-by-case decisions on monitoring and management are essential, given the varying presentations of F-ILDs and the varying rates of progression. The value of diagnostic tests in risk stratification at presentation and, separately, the importance of a logical monitoring strategy, tailored to manage the risk of progression, are also stressed. The term "progressive pulmonary fibrosis" (PPF) exactly describes the entity that clinicians often face in practice. The importance of using antifibrotic therapy early in PPF (once initial management has failed to prevent progression) is increasingly supported by evidence. Artificial intelligence software for high-resolution computed tomography analysis, although an exciting tool for the future, awaits validation. Guidance is provided on pulmonary rehabilitation, oxygen and the use of non-invasive ventilation focused specifically on the needs of ILD patients with progressive disease. PPF should be differentiated from acute deterioration due to drug-induced lung toxicity or other forms of acute exacerbations. Referral criteria for a lung transplant are discussed and applied to patient needs in severe diseases where transplantation is not realistic, either due to access limitations or transplantation contraindications. In conclusion, expert group consensus guidance is provided on the diagnosis, treatment and monitoring of F-ILDs with specific focus on the recognition of PPF and the management of pulmonary fibrosis progressing despite initial management.

Home monitoring in interstitial lung diseases.

The widespread use of smartphones and the internet has enabled self-monitoring and more hybrid-care models. The COVID-19 pandemic has further accelerated remote monitoring, including in the heterogenous and often vulnerable group of patients with interstitial lung diseases (ILDs). Home monitoring in ILD has the potential to improve access to specialist care, reduce the burden on health-care systems, improve quality of life for patients, identify acute and chronic disease worsening, guide treatment decisions, and simplify clinical trials. Home spirometry has been used in ILD for several years and studies with other devices (such as pulse oximeters, activity trackers, and cough monitors) have emerged. At the same time, challenges have surfaced, including technical, analytical, and implementational issues. In this Series paper, we provide an overview of experiences with home monitoring in ILD, address the challenges and limitations for both care and research, and provide future perspectives. VIDEO ABSTRACT.

Perspectives of Respiratory Physicians toward Need and Integration of Palliative Care in Advanced Respiratory Diseases.

Objectives: Patients with chronic life-limiting or advanced respiratory diseases often suffer from high symptom burden, requiring palliative care to alleviate symptoms, improve quality of life and restore dignity. The present study explored the perception of respiratory physicians and their current practice of integrating palliative care for adult patients with chronic advanced respiratory diseases. Materials and Methods: An exploratory survey method using Google survey forms and SurveyMonkey was emailed to respiratory physicians between December 2020 and May 2021. Results: One hundred and seventy-two respiratory physicians responded to the survey. The majority of respiratory physicians (n = 153; 88.9%) thought that early integration of palliative care early was beneficial. They did not feel referring to palliative care would result in loss of control on patient care (n = 107; 62.21%) and 66 (38.37%) strongly disagreed that the referral would result in a loss of hope in patients. Further exploration into the training needs of respiratory physicians revealed that 121 (70.35%) felt the need for training in end-of-life care. Conclusion: Respiratory physicians in our study had an inclination toward palliative care integration into their routine clinical practice. A majority of them expressed the need to enhance their skills in palliative care. Therefore, concerted efforts at integration and a mutual exchange of knowledge between respiratory physicians and palliative care physicians will ensure that patients with advanced respiratory diseases are provided high-quality palliative care.

Integration and Application of Clinical Practice Guidelines for the Diagnosis of Idiopathic Pulmonary Fibrosis and Fibrotic Hypersensitivity Pneumonitis.

Recent clinical practice guidelines have addressed the diagnosis of idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (fHP). These disease-specific guidelines were developed independently, without clear direction on how to apply their respective recommendations concurrently within a single patient, where discrimination between these two fibrotic interstitial lung diseases represents a frequent diagnostic challenge. The objective of this review, created by an international group of experts, was to suggest a pragmatic approach on how to apply existing guidelines to distinguish IPF and fHP. Key clinical, radiologic, and pathologic features described in previous guidelines are integrated in a set of diagnostic algorithms, which then are placed in the broader context of multidisciplinary discussion to guide the generation of a consensus diagnosis. Although these algorithms necessarily reflect some uncertainty wherever strong evidence is lacking, they provide insight into the current approach favored by experts in the field based on currently available knowledge. The authors further identify priorities for future research to clarify ongoing uncertainties in the diagnosis of fibrotic interstitial lung diseases.

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.

Integrating Clinical Probability into the Diagnostic Approach to Idiopathic Pulmonary Fibrosis: An International Working Group Perspective.

Background: When considering the diagnosis of idiopathic pulmonary fibrosis (IPF), experienced clinicians integrate clinical features that help to differentiate IPF from other fibrosing interstitial lung diseases, thus generating a "pre-test" probability of IPF. The aim of this international working group perspective was to summarize these features using a tabulated approach similar to chest HRCT and histopathologic patterns reported in the international guidelines for the diagnosis of IPF, and to help formally incorporate these clinical likelihoods into diagnostic reasoning to facilitate the diagnosis of IPF. Methods: The committee group identified factors that influence the clinical likelihood of a diagnosis of IPF, which was categorized as a pre-test clinical probability of IPF into "high" (70-100%), "intermediate" (30-70%), or "low" (0-30%). After integration of radiological and histopathological features, the post-test probability of diagnosis was categorized into "definite" (90-100%), "high confidence" (70-89%), "low confidence" (51-69%), or "low" (0-50%) probability of IPF. Findings: A conceptual Bayesian framework was created, integrating the clinical likelihood of IPF ("pre-test probability of IPF") with the HRCT pattern, the histopathology pattern when available, and/or the pattern of observed disease behavior, into a "post-test probability of IPF." The diagnostic probability of IPF was expressed using an adapted diagnostic ontology for fibrotic interstitial lung diseases. Interpretation: The present approach will help incorporate the clinical judgment into the diagnosis of IPF, thus facilitating the application of IPF diagnostic guidelines and, ultimately improving diagnostic confidence and reducing the need for invasive diagnostic techniques.

The emerging role of mycophenolate mofetil in interstitial lung diseases.

INTRODUCTION: Mycophenolate mofetil (MMF), initially approved to prevent rejection in solid organ allograft, is now being increasingly used for other conditions. Over the last decade, MMF has emerged as a useful therapy for a variety of immune-mediated diseases. AREAS COVERED: There has been a growing interest in the clinical use of MMF in the treatment of ILDs due to its versatile anti-inflammatory, immunomodulatory, anti-fibrotic and anti-proliferative properties. In this focussed review, we summarize the available literature using the Pubmed, Science Direct and EMBASE databases published until June 2021 on the efficacy and tolerability of MMF in various ILDs. EXPERT OPINION: Other than idiopathic pulmonary fibrosis (IPF) and its broader category of progressive fibrosing ILD, there have been no drugs approved by relevant regulatory agencies for the treatment of the multiple other forms of ILD. Though results are limited, immunosuppressants such as MMF have shown promise as an effective and well-tolerated steroid-sparing agent, providing hope that the limited treatment armamentarium for ILDs can be expanded.

Placing the results of the SOLIDARITY trial with regards to remdesivir in perspective.

Remdesivir, a repurposed antiviral, was first accorded approval by the US Food Drug Administration (FDA) for the treatment of COVID-19 which necessitates hospitalization. However, the interim data of SOLIDARITY trial revealed no benefits with remdesivir for COVID-19 patients which led immediate debates in social media and the press about the utility of the drug. Both preclinical and clinical data demonstrated its efficacy in COVID-19. The recently concluded ACTT-1 trial showed its efficacy in reducing the duration of hospital stay which is of utmost importance for a country like India where reduction in bed occupancy can save lives of many and eases the financial burden of patient and government. Our benefit-risk analysis of ACTT-1 trial also favored the use of remdesivir over standard of care. The SOLIDARITY trial was fundamentally different from other clinical trials on remdesivir with respect to its design, adaptive nature, and selection of endpoints. Moreover, the success of antiviral therapy also depends on the timing of initiation and combination with other drugs. Hence we believe that drugs like Remdesivir are very important for countries like India where soft end points such as time to recovery and clinical improvement and early discharge become extremely significant during a pandemic.

Expert recommendations on the role of macrolides in chronic respiratory diseases.

BACKGROUND: India contributes to 32% of the total global disability-adjusted life years, due to chronic respiratory diseases. This has led to a high rate of health loss from these diseases. Antibiotics are commonly used in the management of respiratory disorders. With excellent tissue penetration, prolonged tissue persistence, and favorable side effect profile, macrolides are one of the best treatment options being recommended for respiratory, urogenital, dermal, and other bacterial infections. Still, there is a lack of clinical trial data on the use of macrolides in the management of respiratory chronic disease, and hence, there is a need for clinical guidance on their use in Indian setting. METHODS: A systematic review of the literature was conducted on PubMed, Cochrane database, and Google Scholar. Existing guidelines, meta-analyses, systematic reviews, randomized controlled trials (RCTs), non-RCTs, landmark studies, and key-cited articles were selected. Recommendations were based on available evidence and expert panel's logical empiricism and consensus. RESULTS AND DISCUSSION: This article discusses evidence-based and clinical practice based management of chronic respiratory conditions including chronic obstructive pulmonary disease, asthma, bronchiectasis, diffusive panbronchiolitis, and organizing pneumonia. The authors reviewed different respiratory conditions, role of macrolides in their management, adverse events and antimicrobial resistance associated with macrolides, evidence review of various clinical trials, guideline recommendations, and clinical recommendations.

Vaping associated lung injury (EVALI) as an organizing pneumonia pattern- A case report.

Electronic cigarettes use or vaping is popular but has not been proven to be an innocuous substitute for traditional smoking. Several patterns of vaping-associated lung injuries have been reported. We report a case of a 43-year-old female patient, who presented with productive cough and an organizing pneumonia pattern on computed tomography (CT) scan. Recognizing the various CT scan patterns of vaping-associated lung injury is important to make a diagnosis because the cessation of vaping is an important step in the treatment.

The global initiative for asthma guidelines (2019): change in the recommendation for the management of mild asthma based on the SYGMA-2 trial - A critical appraisal.

The Global Initiative for Asthma (GINA) recently released their updated Global Strategy for Asthma Management and Prevention Guide (2019). The pocket guide for practicing clinicians states that "the 2019 GINA strategy report represents the most important change in asthma management in 30 years." An important recommendation is the change in treatment strategy for the management of mild asthma where the guideline recommends that" all adults and adolescents with asthma should receive either symptom driven (in mild asthma) or daily low dose inhaled corticosteroid (ICS) containing controller treatment to reduce the risk of serious exacerbations." Our study critically appraises the SYGMA-2 trial, a key trial that largely formed the basis of this recommendation and discusses the potential consequences of using only long-acting beta-2-agonist + ICS as needed as against regular, daily low-dose ICS with as-needed short-acting beta-2-agonist. Our critique covers airway inflammation, disease heterogeneity, understanding the noninferiority margin and its consequences, the Hawthorne effect, and conflict of interest. It is our view that statement of this magnitude will have far-reaching implications for clinical practice which will be in the interests of some patients but also against the interests of others.

Device-handling study of a novel breath-actuated inhaler, Synchrobreathe®, versus a pMDI.

INTRODUCTION: Synchrobreathe®, a new-generation, novel breath-actuated inhaler (BAI) can address the key issues arising during the use of both pressurised metered dose inhalers ([pMDIs]; hand-breath coordination) and dry powder inhalers ([DPIs]; high inspiratory flow required) with respect to optimal drug deposition. MATERIALS AND METHODS: This was an open-label, prospective, 2-week, multicentre study that assessed device handling, ease of use, errors and participant perception regarding the use of Synchrobreathe® versus a pMDI in patients with chronic obstructive pulmonary disease (COPD) (n = 162) or asthma (n = 239) and inhaler-naïve healthy volunteers (n = 59). Ability to use the device without errors at the first attempt, total number of errors before and after training, time taken to use the device correctly and total number of training sessions, and number of attempts to perform the correct technique on Day 1 and Day 14 were evaluated. Device handling and preference questionnaires were also administered on Day 14. RESULTS: Of 460 participants, 421 completed the study. The number of participants using Synchrobreathe without any error after reading the patient information leaflet (PIL) was significantly low (p < 0.05) on Day 1. On Day 14, significantly more number of participants used Synchrobreathe without any error (p < 0.001). The total number of errors before and after training with Synchrobreathe was significantly less (p < 0.001). The average time required to perform the inhalation technique correctly (p < 0.01) and the total number of attempts (P < 0.001) with Synchrobreathe were significantly lower. The average number of attempts to inhale correctly was significantly (p < 0.001) less with Synchrobreathe on Day1 and Day 14. Most participants rated Synchrobreathe as their choice of inhaler. CONCLUSION: Synchrobreathe is an easy-to-use and easy-to-handle device with significantly less number of errors, which may have positive implications for disease control in asthma and COPD.

Salmeterol/fluticasone through breath-actuated inhaler versus pMDI: a randomized, double-blind, 12 weeks study.

OBJECTIVE: Salmeterol/fluticasone combination (SFC) formulated in a breath-actuated inhaler (BAI) overcomes the co-ordination problem associated with the pressurized-metered dose inhaler (pMDIs). Our aim was to compare the efficacy and the safety of SFC given through the BAI versus the conventional pMDI in moderate-to-severe asthmatics. METHODS: In this randomized, double-blind, double-dummy, prospective, active-controlled, parallel group, multicenter, 12 weeks study, 150 asthmatics were randomized to receive SFC (25/125 mcg) through either BAI or pMDI. The primary efficacy endpoint was mean change in pre-dose morning PEFR value at 12 weeks and the secondary efficacy endpoints included, mean change in FEV(1), pre-bronchodilator FVC, pre-dose morning and evening PEFR, symptom scores at 2, 4, 8, and 12 weeks. Patient preferences for device and safety were also assessed. RESULTS: At 12 weeks, the mean change in pre-dose morning PEFR in BAI and pMDI groups was 50.72 L/min and 48.82 L/min, respectively (p < 0.0001; both groups) and the difference between the two groups was not significant. Both the treatment groups showed a statistically significant improvement in secondary endpoints at all-time points compared with baseline. The usability questionnaire assessment results showed that the BAI device was preferred by 75% of patients as compared with 25% preferring pMDI. SFC in both BAI and pMDI devices was found to be safe and well tolerated. CONCLUSION: This is the first study to demonstrate that SFC given through the BAI produces comparable efficacy and safety endpoints as pMDI. Additionally, BAI was the preferred inhaler by patients compared to conventional pMDI.

Resistance patterns among multidrug-resistant tuberculosis patients in greater metropolitan Mumbai: trends over time.

BACKGROUND: While the high burden of multidrug-resistant tuberculosis (MDR-TB) itself is a matter of great concern, the emergence and rise of advanced forms of drug-resistance such as extensively drug-resistant TB (XDR-TB) and extremely drug-resistant TB (XXDR-TB) is more troubling. The aim of this study was to investigate the trends over time of patterns of drug resistance in a sample of MDR-TB patients in greater metropolitan Mumbai, India. METHODS: This was a retrospective, observational study of drug susceptibility testing (DST) results among MDR-TB patients from eight health care facilities in greater Mumbai between 2005 and 2013. We classified resistance patterns into four categories: MDR-TB, pre-XDR-TB, XDR-TB and XXDR-TB. RESULTS: A total of 340 MDR-TB patients were included in the study. Pre-XDR-TB was the most common form of drug-resistant TB observed overall in this Mumbai population at 56.8% compared to 29.4% for MDR-TB. The proportion of patients with MDR-TB was 39.4% in the period 2005-2007 and 27.8% in 2011-2013, while the proportion of those with XDR-TB and XXDR-TB was changed from 6.1% and 0% respectively to 10.6% and 5.6% during the same time period. During the same periods, the proportions of patients with ofloxacin, moxifloxacin and ethionamide resistance significantly increased from 57.6% to 75.3%, from 60.0% to 69.5% and from 24.2% to 52.5% respectively (p<0.05). DISCUSSION: The observed trends in TB drug-resistance patterns in Mumbai highlight the need for individualized drug regimens, designed on the basis of DST results involving first- and second-line anti-TB drugs and treatment history of the patient. A drug-resistant TB case-finding strategy based on molecular techniques that identify only rifampicin resistance will lead to initiation of suboptimal treatment regimens for a significant number of patients, which may in turn contribute to amplification of resistance and transmission of strains with increasingly advanced resistance within the community.

Ease-of-use, preference, confidence, and satisfaction with Revolizer(®), a novel dry powder inhaler, in an Indian population.

CONTEXT: While prescribing an inhaler device, it is important to take into account the usability, preference, confidence, and satisfaction of the patients. AIMS: The present study assessed these parameters with Revolizer(®), a novel dry powder inhaler (DPI), in patients with obstructive airway diseases and in device-naïve healthy participants. SETTINGS AND DESIGN: In this open-label, prospective, multicentre study with 100 participants [n = 50 healthy participants, n = 45 mild asthma patients, and n = 5 mild chronic obstructive pulmonary disease (COPD) patients], all participants were instructed and trained on the use of Revolizer and then the participants subsequently demonstrated the inhalation technique at two visits. MATERIALS AND METHODS: The average time required to execute three correct consecutive attempts and the number of errors (including critical errors) were recorded. Participants were asked about the ease of use, preference, confidence, and satisfaction by means of a questionnaire at each visit. RESULTS: The average time required by the participants to achieve three correct consecutive attempts at visit 1 was 3.75 ± 2.10 min, which significantly reduced at visit 2 (3.07 ± 1.32 min, P < 0.01). The number of errors decreased from visit 1 to visit 2. More than 85% participants found the Revolizer easy to use, and it was preferred by more than 75% participants. Revolizer scored high on the confidence and satisfaction of all participants at both visits. CONCLUSIONS: Revolizer is an easy-to-use and a preferred device in patients with mild asthma and COPD, as well as in healthy participants with no previous experience of using inhalation devices. The participants felt confident and satisfied using the Revolizer.