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Pathogenic Mycobacterium tuberculosis complex organisms (MTBC) primarily cause pulmonary tuberculosis (PTB); however, MTBC are also capable of causing disease in extrapulmonary (EP) organs, which pose a significant threat to human health worldwide. Extrapulmonary tuberculosis (EPTB) accounts for about 20–30% of all active TB cases and affects mainly children and adults with compromised immune systems. EPTB can occur through hematogenous, lymphatic, or localized bacillary dissemination from a primary source, such as PTB, and affects the brain, eye, mouth, tongue, lymph nodes of neck, spine, bones, muscles, skin, pleura, pericardium, gastrointestinal, peritoneum, and the genitourinary system as primary and/or disseminated disease. EPTB diagnosis involves clinical, radiological, microbiological, histopathological, biochemical/immunological, and molecular methods. However, only culture and molecular techniques are considered confirmatory to differentiate MTBC from any non-tuberculous mycobacteria (NTM) species. While EPTB due to MTBC responds to first-line anti-TB drugs (ATD), drug susceptibility profiling is an essential criterion for addressing drug-resistant EPTB cases (DR-EPTB). Besides antibiotics, adjuvant therapy with corticosteroids has also been used to treat specific EPTB cases. Occasionally, surgical intervention is recommended, mainly when organ damage is debilitating to the patient. Recent epidemiological studies show a striking increase in DR-EPTB cases ranging from 10–15% across various reports. As a neglected disease, significant developments in rapid and accurate diagnosis and better therapeutic interventions are urgently needed to control the emerging EPTB situation globally. In this review, we discuss the recent advances in the clinical diagnosis, treatment, and drug resistance of EPTB.

Pulmonary disease due to Mycobacterium abscessus (Mab) has become an increasing cause of health concern, particularly among individuals infected with nontuberculous mycobacteria. Since Mab is intrinsically resistant to many antibiotics, it is very challenging to treat patients with symptomatic disease. In this case series, we report four patients with symptomatic pulmonary Mab who had prior history of antituberculosis treatment intake and declared cured at the end of treatment. The current episode was confirmed to be due to Mab infection by molecular and clinical diagnosis and received species specific-antibiotics therapy. All were periodically monitored for the sputum smear and culture conversions throughout the treatment period. The clinical course was variable though all received similar antibiotic regimen and showed varied treatment outcomes. The time of diagnosis and the treatment outcome indicate that a better understanding of host-pathogen interactions is essential for the successful treatment of pulmonary Mab infection.

Diseases due to pathogenic mycobacteria cause significant health and economic impact on humans worldwide. Although mycobacterial diseases primarily affect the lungs, the involvement of extrapulmonary organs has also gained ground, particularly among individuals with co‐existing medical conditions. Besides Mycobacterium tuberculosis complex organisms, non‐tuberculous mycobacteria (NTM) are also known to cause pulmonary and extrapulmonary diseases. Primary and disseminated extrapulmonary mycobacterial infections affect the brain, eye, mouth, tongue, lymph nodes of the neck, spine, bones, muscles, skin, pleura, pericardium, gastro‐intestinal, peritoneum and genito‐urinary system. The clinical presentation of extrapulmonary mycobacterial diseases, including systemic symptoms, of M. tuberculosis‐infected cases and NTM‐infected cases is similar. Moreover, extrapulmonary mycobacterial diseases are complicated by the involvement of diverse bacterial species as aetiological agents. Culture and molecular techniques are used to differentiate NTM from Mycobacterium tuberculosis and to classify sub‐species of the pathogens. As sub‐speciation and drug susceptibility profiling are critical factors in treating extrapulmonary NTM diseases, there are often significant delays in initiating treatment and customising the therapeutic regimen. Here, we summarise the clinical symptoms of NTM diseases in various extrapulmonary organs, and discuss the recent trends in diagnosing and treating these diseases. We also highlight the complications associated with the management of extrapulmonary NTM disease.

COVID-19, caused by a novel coronavirus, SARS-CoV-2, contributes significantly to the morbidity and mortality in humans worldwide. In the absence of specific vaccines or therapeutics available, COVID-19 cases are managed empirically with the passive immunity approach and repurposing of drugs used for other conditions. Recently, a concept that bacilli Calmette–Guerin (BCG) vaccination could confer protection against COVID-19 has emerged. The foundation for this widespread attention came from several recent articles, including the one by Miller et al. submitted to MedRxiv, a pre-print server. The authors of this article suggest that a correlation exists between countries with a prolonged national BCG vaccination program and the morbidity/mortality due to COVID-19. Further, clinical BCG vaccination trials are currently ongoing in the Netherlands, Australia, the UK, and Germany with the hope of reducing mortality due to COVID-19. Although BCG vaccination helps protect children against tuberculosis, experimental studies have shown that BCG can also elicit a non-specific immune response against viral and non-mycobacterial infections. Here, we summarize the pros and cons of BCG vaccination and critically analyze the evidence provided for the protective effect of BCG against COVID-19 and highlight the confounding factors in these studies.

Pulmonary diseases due to mycobacteria cause significant morbidity and mortality to human health. In addition to tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), recent epidemiological studies have shown the emergence of non-tuberculous mycobacteria (NTM) species in causing lung diseases in humans. Although more than 170 NTM species are present in various environmental niches, only a handful, primarily Mycobacterium avium complex and M. abscessus, have been implicated in pulmonary disease. While TB is transmitted through inhalation of aerosol droplets containing Mtb, generated by patients with symptomatic disease, NTM disease is mostly disseminated through aerosols originated from the environment. However, following inhalation, both Mtb and NTM are phagocytosed by alveolar macrophages in the lungs. Subsequently, various immune cells are recruited from the circulation to the site of infection, which leads to granuloma formation. Although the pathophysiology of TB and NTM diseases share several fundamental cellular and molecular events, the host-susceptibility to Mtb and NTM infections are different. Striking differences also exist in the disease presentation between TB and NTM cases. While NTM disease is primarily associated with bronchiectasis, this condition is rarely a predisposing factor for TB. Similarly, in Human Immunodeficiency Virus (HIV)-infected individuals, NTM disease presents as disseminated, extrapulmonary form rather than as a miliary, pulmonary disease, which is seen in Mtb infection. The diagnostic modalities for TB, including molecular diagnosis and drug-susceptibility testing (DST), are more advanced and possess a higher rate of sensitivity and specificity, compared to the tools available for NTM infections. In general, drug-sensitive TB is effectively treated with a standard multi-drug regimen containing well-defined first- and second-line antibiotics. However, the treatment of drug-resistant TB requires the additional, newer class of antibiotics in combination with or without the first and second-line drugs. In contrast, the NTM species display significant heterogeneity in their susceptibility to standard anti-TB drugs. Thus, the treatment for NTM diseases usually involves the use of macrolides and injectable aminoglycosides. Although well-established international guidelines are available, treatment of NTM disease is mostly empirical and not entirely successful. In general, the treatment duration is much longer for NTM diseases, compared to TB, and resection surgery of affected organ(s) is part of treatment for patients with NTM diseases that do not respond to the antibiotics treatment. Here, we discuss the epidemiology, diagnosis, and treatment modalities available for TB and NTM diseases of humans.

Tuberculosis (TB), a bacterialinfectious disease caused by Mycobacterium tuberculosis (M.tb), which causes significant mortality in humans worldwide. Current treatment regimen involve the administration of multiple antibiotics over the course of several months that contributes to patient non-compliance leading to relapse and the development of drug-resistant M.tb (MDR and XDR) strains. Together, these facts highlight the need for the development of shorter TB treatment regimens. Host-directed therapy (HDT) is a new and emerging concept that aims to augment host immune response using drugs/compounds with or without adjunct antibiotics against M.tb infection. Autophagy is a natural catabolic mechanism of the cell that involves delivering the cytosolic constituents to the lysosomes for degradation and recycling the components; thereby maintaining the cellular and energy homoeostasis of a cell. However, over the past decade, an improved understanding of the role of autophagy in immunity has led to autophagy activation by using drugs or agents. This autophagy manipulation may represent a promising host-directed therapeutic strategy for human TB. However, current clinical knowledge on implementing autophagy activation by drugs or agents, as a stand-alone HDT or as an adjunct with antibiotics to treat human TB is insufficient. In recent years, many reports on high-throughput drug screening and measurement of autophagic flux by fluorescence, high-content microscopy, flow cytometry, microplate reader and immunoblotting have been published for the discovery of drugs that modulate autophagy. In this review, we discuss the commonly used chemical screening approaches in mammalian cells for the discovery of autophagy activating drugs against M.tbinfection. We also summarize the various autophagy-activating agents, both pre-clinical candidates and compounds approved for advanced clinical investigation during mycobacterial infection. Finally, we discuss the opportunities and challenges in using autophagy activation as HDT strategy to improve TB outcome and shorten treatment regimen.

The Mycobacterium tuberculosis (Mtb) Lineage 4 strains CDC1551 and H37Rv develop tolerance to multiple antibiotics upon macrophage residence. Genetic mutation of the efflux pump Rv1258c in CDC1551 abolishes rifampin tolerance but not isoniazid tolerance. Here we show that clinical isolates from the other predominant Mtb lineages developed macrophage-induced isoniazid tolerance. Furthermore, all lineages developed rifampin tolerance except Lineage 2 Beijing strains, which are natural Rv1258c mutants. Thus macrophage-induced antibiotic tolerance is featured across the majority of Mtb lineages. Our findings further link Rv1258c to rifampin tolerance among clinical isolates.