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.

Occupational interstitial lung diseases.

Millions of workers are exposed to substances known to cause occupational interstitial lung diseases (ILDs), particularly in developing countries. However, the burden of the disease is likely to be underestimated due to under-recognition, under-reporting or both. The diagnosis of occupational ILD requires a high level of suspicion and a thorough occupational history, as occupational and non-occupational ILDs may be clinically, functionally and radiologically indistinguishable, leading to delayed diagnosis and inappropriate management. A potential occupational aetiology should always be considered in the differential diagnosis of ILD, as removal from the workplace exposure, with or without treatment, is a key therapeutic intervention and may lead to significant improvement. In this article, we provide an overview of the 'traditional' inorganic dust-related ILDs but also address idiopathic pulmonary fibrosis and the immunologically mediated chronic beryllium disease, sarcoidosis and hypersensitivity pneumonitis, with emphasis on the importance of surveillance and prevention for reducing the burden of these conditions. To this end, health-care professionals should be specifically trained about the importance of occupational exposures as a potential cause of ILD.

Low Body Mass Index at Treatment Initiation and Rifampicin-Resistant Tuberculosis Treatment Outcomes: An Individual Participant Data Meta-Analysis.

BACKGROUND: The impact of low body mass index (BMI) at initiation of rifampicin-resistant tuberculosis (RR-TB) treatment on outcomes is uncertain. We evaluated the association between BMI at RR-TB treatment initiation and end-of-treatment outcomes. METHODS: We performed an individual participant data meta-analysis of adults aged ≥18 years with RR-TB whose BMI was documented at treatment initiation. We compared odds of any unfavorable treatment outcome, mortality, or failure/recurrence between patients who were underweight (BMI <18.5 kg/m2) and not underweight. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using logistic regression, with matching on demographic, clinical, and treatment-related factors. We evaluated effect modification by human immunodeficiency virus (HIV) status and other variables using likelihood ratio tests. We also estimated cumulative incidence of mortality during treatment stratified by HIV. RESULTS: Overall, 5148 patients were included; 1702 (33%) were underweight at treatment initiation. The median (interquartile range) age was 37 years (29 to 47), and 455 (9%) had HIV. Compared with nonunderweight patients, the aOR among underweight patients was 1.7 (95% CI, 1.4-1.9) for any unfavorable outcome, 3.1 (2.4-3.9) for death, and 1.6 (1.2-2.0) for failure/recurrence. Significant effect modification was found for World Health Organization region of treatment. Among HIV-negative patients, 24-month mortality was 14.8% (95% CI, 12.7%-17.3%) for underweight and 5.6% (4.5%-7.0%) for not underweight patients. Among patients with HIV, corresponding values were 33.0% (25.6%-42.6%) and 20.9% (14.1%-27.6%). CONCLUSIONS: Low BMI at treatment initiation for RR-TB is associated with increased odds of unfavorable treatment outcome, particularly mortality.

Understanding the Potential Impact of Different Drug Properties on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Transmission and Disease Burden: A Modelling Analysis.

BACKGROUND: The public health impact of the coronavirus disease 2019 (COVID-19) pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear. METHODS: Using a mathematical model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, COVID-19 disease and clinical care, we explore the public-health impact of different potential therapeutics, under a range of scenarios varying healthcare capacity, epidemic trajectories; and drug efficacy in the absence of supportive care. RESULTS: The impact of drugs like dexamethasone (delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R = 1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalization) could have much greater benefits, particularly in resource-poor settings facing large epidemics. CONCLUSIONS: Advances in the treatment of COVID-19 to date have been focused on hospitalized-patients and predicated on an assumption of adequate access to supportive care. Therapeutics delivered earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.

Asia Pacific perspectives on the second year of the COVID-19 pandemic: A follow-up survey.

BACKGROUND: The Coronavirus disease 2019 (COVID-19) pandemic is currently in its third year. This follow-up survey was commissioned by the Asia Pacific Association of Allergy Asthma and Clinical Immunology (APAAACI) Task Force on COVID-19 to compare and contrast changes in the epidemiology, clinical profile, therapeutics and public health measures of the pandemic in the Asia Pacific region. METHODS: A questionnaire-based survey comprising 32 questions was electronically sent out to all 15 member countries of APAAACI using Survey Monkey® from 1 December 2021 to 28 February 2022. RESULTS: Seventeen responses were received from 14/15 (93.4%) member countries and 3 individual members. Mild-to-moderate COVID-19 predominated over severe infection, largely contributed by COVID-19 vaccination programmes in the region. The incidence of vaccine adverse reactions in particular anaphylaxis from messenger ribonucleic acid (mRNA) vaccines was no longer as high as initially anticipated, although perimyocarditis remains a concern in younger males. Novel therapeutics for mild-to-moderate disease including neutralizing antibodies casirivimab/imdevimab (REGEN-COV®) and sotrovimab (Xevudy®), anti-virals Paxlovid® (nirmatrelvir and ritonavir) and Molnupiravir pre-exposure prophylaxis for high-risk persons with Tixagevimab and Cilgavimab (Evusheld) are now also available to complement established therapeutics (e.g., remdesivir, dexamethasone and baricitinib) for severe disease. In the transition to endemicity, public health measures are also evolving away from containment/elimination strategies. CONCLUSIONS: With access to internationally recommended standards of care including public health preventive measures, therapeutics and vaccines among most APAAACI member countries, much progress has been made over the 2-year period in minimizing the morbidity and mortality from COVID-19 disease.

Genomics of postvaccination SARS-CoV-2 infections during the Delta dominated second wave of COVID-19 pandemic, from Mumbai Metropolitan Region (MMR), India.

The present study was initiated to understand the proportion of predominant variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in postvaccination infections during the Delta dominated second wave of coronavirus disease 2019 (COVID-19) in the Mumbai Metropolitan Region (MMR) in India and to understand any mutations selected in the postvaccination infections or showing association with any patient demographics. Samples were collected (n = 166) from severe/moderate/mild COVID-19 patients who were either vaccinated (COVISHIELD/COVAXIN-partial/fully vaccinated) or unvaccinated, from a city hospital and from home isolation patients in MMR. A total of 150 viral genomes were sequenced by Oxford Nanopore sequencing and the data of 136 viral genomes were analyzed for clade/lineage and for identifying mutations. The sequences belonged to three clades (21A, 21I, and 21J) and their lineage was identified as either Delta (B.1.617.2) or Delta+ (B.1.617.2 + K417N) or sub-lineages of Delta variant (AY.120/AY.38/AY.99). A total of 620 mutations were identified of which 10 mutations showed an increase in trend with time (May-October 2021). Associations of six mutations (two in spike, three in orf1a, and one in nucleocapsid) were shown with milder forms of the disease and one mutation (in orf1a) with partial vaccination status. The results indicate a trend toward reduction in disease severity as the wave progressed.

Aminoglycosides and Capreomycin in the Treatment of Multidrug-resistant Tuberculosis: Individual Patient Data Meta-analysis of 12 030 Patients From 25 Countries, 2009-2016.

BACKGROUND: As new drugs are developed for multidrug-resistant tuberculosis (MDR-TB), the role of currently used drugs must be reevaluated. METHODS: We combined individual-level data on patients with pulmonary MDR-TB published during 2009-2016 from 25 countries. We compared patients receiving each of the injectable drugs and those receiving no injectable drugs. Analyses were based on patients whose isolates were susceptible to the drug they received. Using random-effects logistic regression with propensity score matching, we estimated the effect of each agent in terms of standardized treatment outcomes. RESULTS: More patients received kanamycin (n = 4330) and capreomycin (n = 2401) than amikacin (n = 2275) or streptomycin (n = 1554), opposite to their apparent effectiveness. Compared with kanamycin, amikacin was associated with 6 more cures per 100 patients (95% confidence interval [CI], 4-8), while streptomycin was associated with 7 (95% CI, 5-8) more cures and 5 (95% CI, 4-7) fewer deaths per 100 patients. Compared with capreomycin, amikacin was associated with 9 (95% CI, 6-11) more cures and 5 (95% CI, 2-8) fewer deaths per 100 patients, while streptomycin was associated with 10 (95% CI, 8-13) more cures and 10 (95% CI, 7-12) fewer deaths per 100 patients treated. In contrast to amikacin and streptomycin, patients treated with kanamycin or capreomycin did not fare better than patients treated with no injectable drugs. CONCLUSIONS: When aminoglycosides are used to treat MDR-TB and drug susceptibility test results support their use, streptomycin and amikacin, not kanamycin or capreomycin, are the drugs of choice.

Management of drug-resistant tuberculosis.

Drug-resistant tuberculosis is a major public health concern in many countries. Over the past decade, the number of patients infected with Mycobacterium tuberculosis resistant to the most effective drugs against tuberculosis (ie, rifampicin and isoniazid), which is called multidrug-resistant tuberculosis, has continued to increase. Globally, 4·6% of patients with tuberculosis have multidrug-resistant tuberculosis, but in some areas, like Kazakhstan, Kyrgyzstan, Moldova, and Ukraine, this proportion exceeds 25%. Treatment for patients with multidrug-resistant tuberculosis is prolonged (ie, 9-24 months) and patients with multidrug-resistant tuberculosis have less favourable outcomes than those treated for drug-susceptible tuberculosis. Individualised multidrug-resistant tuberculosis treatment with novel (eg, bedaquiline) and repurposed (eg, linezolid, clofazimine, or meropenem) drugs and guided by genotypic and phenotypic drug susceptibility testing can improve treatment outcomes. Some clinical trials are evaluating 6-month regimens to simplify management and improve outcomes of patients with multidrug-resistant tuberculosis. Here we review optimal diagnostic and treatment strategies for patients with drug-resistant tuberculosis and their contacts.

Prognostic Factors for Adverse Outcomes in COVID-19 Infection.

Whilst COVID-19 infection generally run a mild course in up to 80% of those affected, a number of pre-existing co-morbidities determine the severity of infection and the outcome in an individual patient. The most important of these co-morbidities that have consistently emerged in studies from across the globe, are the patients age and sex. Other important co-morbidities that adversely affect outcomes include pre-existing diabetes, obesity, hypertension, chronic lung disease and malignancy. This comprehensive review discusses the impact of these co-morbidities and the role of laboratory predictors of poor patient outcomes.

Hydroxychloroquine for COVID-19: What is our Current State of Knowledge?

Chloroquine and Hydroxychloroquine are drugs which have been widely used in malaria and rheumatoid arthritis respectively for over 50 years. There was anecdotal evidence of their efficacy in the earlier SARS outbreak in 2003. This prompted physicians from across the world to use them in the present SARS-CoV- 2 pandemic that is currently sweeping the globe, with 5 million people already infected to date. These drugs are already in widespread use for the treatment of COVID-19 in India, mainly because they are cheap and easily available, and because of the absence of any readily available alternative therapy. This timely review discusses the pre-clinical evidence, and data from the eight available clinical trials. We emphasise that careful monitoring for cardiac toxicity is required when these drugs are used. Finally, we conclude that current data does not allow us to recommend for or against the use of these drugs. Results of two large RCTs, one from the NIH and the other from WHO (Solidarity) are eagerly awaited before the role of these drugs in COVID-19 can be definitively established.

Favipiravir: A new and emerging antiviral option in COVID-19.

With over 16 million cases reported from across the globe, the SARS-CoV-2, a mere 125 microns in diameter, has left an indelible impact on our world. With the paucity of new drugs to combat this disease, the medical community is in a race to identify repurposed drugs that may be effective against this novel coronavirus. One of the drugs which has recently garnered much attention, especially in India, is an anti-viral drug originally designed for influenza, called favipiravir. In this article, we have tried to provide a comprehensive, evidence-based review of this drug in the context of the present pandemic to elucidate its role in the management of COVID-19.

Delamanid Central Nervous System Pharmacokinetics in Tuberculous Meningitis in Rabbits and Humans.

Central nervous system tuberculosis (TB) is devastating and affects vulnerable populations. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculous meningitis (TBM) specifically are nearly uniformly fatal, with little information being available to guide the treatment of these patients. Delamanid (DLM), a nitro-dihydro-imidazooxazole, is a new, well-tolerated anti-TB drug with a low MIC (1 to 12 ng/ml) against Mycobacterium tuberculosis It is used for the treatment of pulmonary MDR-TB, but pharmacokinetic (PK) data for DLM in the central nervous system (CNS) of patients with TBM are not available. In the present study, we measured DLM concentrations in the brain and cerebrospinal fluid (CSF) of six rabbits with and without experimentally induced TBM receiving single-dose DLM. We report the steady-state CSF concentrations from three patients receiving DLM as part of multidrug treatment who underwent therapeutic drug monitoring. Drug was quantified using liquid chromatography-tandem mass spectrometry. In rabbits and humans, mean concentrations in CSF (in rabbits, 1.26 ng/ml at 9 h and 0.47 ng/ml at 24 h; in humans, 48 ng/ml at 4 h) were significantly lower than those in plasma (in rabbits, 124 ng/ml at 9 h and 14.5 ng/ml at 24 h; in humans, 726 ng/ml at 4 h), but the estimated free CSF/plasma ratios were generally >1. In rabbits, DLM concentrations in the brain were 5-fold higher than those in plasma (means, 518 ng/ml at 9 h and 74.0 ng/ml at 24 h). All patients with XDR-TBM receiving DLM experienced clinical improvement and survival. Collectively, these results suggest that DLM achieves adequate concentrations in brain tissue. Despite relatively low total CSF drug levels, free drug may be sufficient and DLM may have a role in treating TBM. More studies are needed to develop a fuller understanding of its distribution over time with treatment and clinical effectiveness.

Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report.

The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new (i.e. bedaquiline, delamanid) and repurposed (i.e. clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1-2) and 57 (11.3%) as serious (grade 3-5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.

Few eligible for the newly recommended short course MDR-TB regimen at a large Mumbai private clinic.

BACKGROUND: India has the world's highest tuberculosis burden, and Mumbai is particularly affected by multidrug resistant tuberculosis (MDR-TB). WHO recommends short, intensive treatment ("Short Course") for previously untreated pulmonary MDR-TB patients but does not require universal drug susceptibility testing (DST) before Short Course. DST would likely screen out many MDR-TB patients in places like Mumbai with significant drug resistance. METHODS: MDR-TB patients at a private clinic were recruited for a prospective observational cohort. Short Course eligibility was evaluated by clinical criteria and DST results. Eligibility by DST was classified as rifampin monoresistance (as tested by Xpert MTB/RIF), rifampin, fluoroquinolones, and 2nd-line injectable drugs resistance (as tested by line probe assays) and resistance to other drugs. RESULTS: Of 559 participants with MDR-TB, 33% met clinical eligibility for Short Course. DST for rifampin, fluoroquinolones, and 2nd-line injectable drugs excluded 74.7% of participants. Complete phenotypic DST excluded 96.6% of participants. Prior treatment with either 1st or 2nd-line drugs did not significantly affect eligibility. CONCLUSIONS: In a global MDR-TB hotspot, < 5% of participants with MDR-TB were appropriate for Short Course by clinical characteristics and DST results. Rapid molecular testing would not sufficiently identify drug resistance in this population. Eligibility rates were not significantly reduced by prior TB treatment.

Towards tailored regimens in the treatment of drug-resistant tuberculosis: a retrospective study in two Italian reference Centres.

BACKGROUND: The increased incidence of drug-resistant TB is a major challenge for effective TB control. Limited therapeutic options and poor treatment outcomes of DR-TB may increase drug-resistance rates. The objective of the study is to retrospectively compare MDR-TB and pre-XDR-TB treatment regimens and outcomes in two large TB reference centres in Italy from January 2000 to January 2015. METHODS: A retrospective, multicentre study was conducted at the Regional TB Reference Centre Villa Marelli Institute (Milan) and at the Reference Center for MDR-TB and HIV-TB, Eugenio Morelli Hospital (Sondalo). The supra-national Reference Laboratory in Milan performed DST. Inclusion criteria were: age ≥ 18 and culture-confirmed diagnosis of MDR- or pre-XDR TB. Chi-square or Fisher exact test was used to detect differences in the comparison between treatment outcomes, therapeutic regimens, and drug-resistances. Computations were performed with STATA 15. RESULTS: A total of 134 patients were selected. Median (IQR) age at admission was 33 (26-41) years and 90 patients (67.2%) were male. Pulmonary TB was diagnosed in 124 (92.5%) patients. MDR- and pre-XDR-TB cases were 91 (67.9%) and 43 (32.1%), respectively. The WHO shorter MDR-TB regimen could have been prescribed in 16/84 (19.1%) patients. Treatment success was not statistically different between MDR- and pre-XDR-TB (81.3% VS. 81.4%; P = 0.99). Mortality in MDR-TB and pre-XDR-TB groups was 4.4 and 9.3%, respectively (P = 0.2). Median duration of treatment was 18 months and a total of 110 different regimens were administered. Exposure to linezolid, meropenem, and amikacin was associated with a better outcome in both groups (P = 0.001, P < 0.001, and P = 0.004, respectively). CONCLUSIONS: Tailored treatment regimens based on DST results can achieve successful outcomes in patients with pre-XDR-TB.

Drug-resistant tuberculosis: An update on disease burden, diagnosis and treatment.

The emergence of antimicrobial resistance against Mycobacterium tuberculosis, the leading cause of mortality due to a single microbial pathogen worldwide, represents a growing threat to public health and economic growth. The global burden of multidrug-resistant tuberculosis (MDR-TB) has recently increased by an annual rate of more than 20%. According to the World Health Organization approximately only half of all patients treated for MDR-TB achieved a successful outcome. For many years, patients with drug-resistant tuberculosis (TB) have received standardized treatment regimens, thereby accelerating the development of MDR-TB through drug-specific resistance amplification. Comprehensive drug susceptibility testing (phenotypic and/or genotypic) is necessary to inform physicians about the best drugs to treat individual patients with tailor-made treatment regimens. Phenotypic drug resistance can now often, but with variable sensitivity, be predicted by molecular drug susceptibility testing based on whole genome sequencing, which in the future could become an affordable method for the guidance of treatment decisions, especially in high-burden/resource-limited settings. More recently, MDR-TB treatment outcomes have dramatically improved with the use of bedaquiline-based regimens. Ongoing clinical trials with novel and repurposed drugs will potentially further improve cure-rates, and may substantially decrease the duration of MDR-TB treatment necessary to achieve relapse-free cure.

Bedaquiline and Delamanid Combination Treatment of 5 Patients with Pulmonary Extensively Drug-Resistant Tuberculosis.

We report the experiences of 5 patients taking bedaquiline with delamanid in combination: 1 patient was cured; 3 culture converted, with 2 continuing and 1 changing therapy; and 1 died from respiratory insufficiency. For 2 patients, QT-interval prolongation but no arrhythmias occurred. Use of this therapy is justified for patients with limited options.