Mycobacterium tuberculosis complex (MTBC), the causative organisms of tuberculosis (TB), has afflicted man for millennia. TB was declared a global health emergency by the World Health Organization in 1993. Before the 2020 Covid pandemic, it was responsible for 10 million new cases annually and was the leading infectious disease killer worldwide. MTBC strain typing represents an important complementary tool to guide TB control measures. TB programmes can use genotyping results in combination with epidemiological information to determine if recent transmission has likely occurred, and hence identify outbreaks that require targeted public health action. MTBC genotyping also can differentiate between relapse or re-infection, detect false-positive cases, and identify and monitor the circulating TB strains in the population over time. Restriction Fragment Length Phenotyping (RFLP), introduced in the 1990s, was labour intensive, required large amounts of DNA and was not easily comparable between laboratories. These disadvantages are overcome by the PCR-based MIRU-VNTR and spoligotyping methods. More recently, whole genome sequencing (WGS) of MTBC has been shown to provide high resolution identification of recent transmission chains and their direction, as well as drug resistance prediction. Its increasing reliability and affordability has enabled this technology to transition from the research arena to clinical care and public health functions. Its application in high TB burden countries will hopefully revitalize global TB control efforts which have set back by the Covid pandemic.

BACKGROUND:Little is known about the joint associations of multiple lifestyle risk factors including smoking, low body mass index, physical inactivity, alcohol consumption, and low diet quality with risk of active tuberculosis.METHODS:We analyzed data from the Singapore Chinese Health Study, a prospective cohort study of 63 257 Chinese adults aged 45-74 years enrolled between 1993 and 1998. Incident cases of active tuberculosis were identified via linkage with the National TB Registry through 31 December 2016. Cox proportional hazards regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) of tuberculosis risk in relation to the combined scores of lifestyle risk factors.RESULTS:Compared with participants with none of the risk factors, the adjusted HRs (95% CI) of active tuberculosis for participants with 1, 2, 3, 4, and 5 risk factors were 1.24 (1.02-1.51), 1.84 (1.51-2.23), 2.52 (2.03-3.14), 4.07 (3.07-5.41), and 9.04 (5.44-15.02), respectively (Ptrend < .0001). The HR for those with 5 factors was ~1.5 times the product of individual risk estimates from the 5 factors on a multiplicative scale. The stepwise increase in risk of active tuberculosis with increasing number of lifestyle risk factors was significantly stronger in participants with diabetes than their counterparts without diabetes at recruitment (Pinteraction = .01).CONCLUSIONS:Multiple lifestyle risk factors were associated with risk of active tuberculosis in a synergistic manner. Our findings highlight the importance of public health programs and interventions targeting these factors simultaneously to reduce the tuberculosis burden among the general population.

Objective: To describe the molecular epidemiology of Mycobacterium tuberculosis complex (MTBC) and factors associated with its transmission in Singapore. Methods: Spoligotyping, 24-loci mycobacterial interspersed repetitive units - variable number of tandem repeats (MIRU-VNTR) typing and demographic data from the national TB notification registry of MTBC culture-positive cases notified from January 2011 to December 2017 were analysed. Results: Of the 12,046 culture-positive cases notified, complete spoligotyping and MIRU-VNTR typing results were available for 8690 (72.1%) belonging to 4950 (57.0%) local-born and 3740 (43.0%) foreign-born persons. From these, 4810 (55.3%) were identified in 883 clusters. The proportion of recent transmission was 45.2%. The East-Asian Lineage 2 accounted for 4045 (47.1%) of isolates, and disproportionately accounted for large clusters. Clustered cases were more likely to be older than 50 years, male, Malay, local-born, Singapore citizens or Permanent Residents, of lower socioeconomic status, imprisoned; to harbour East-Asian Lineage 2 strain; to have cavitary pulmonary TB, positive sputum smear or be recalcitrant treatment defaulters. They were less likely to have multidrug-resistant, or isoniazid or rifampicin mono-resistant TB. Conclusion: We demonstrated the diversity of MTBC strains and, notwithstanding the likely over-estimation of clustering using these genotyping methods, elucidated factors associated with TB transmission in Singapore.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT. METHODS: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement. RESULTS: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care. CONCLUSION: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI.

BACKGROUND: Adipokines are emerging mediators of immune response, and may affect susceptibility to active TB.OBJECTIVE: To examine the associations between adipokines and the risk of active TB.METHODS: In a case-control study nested within a prospective cohort of middle-aged and older adults in Singapore, 280 incident active TB cases who donated blood for research before diagnosis were matched with 280 controls. Serum levels of adiponectin, resistin, leptin and ghrelin were measured. Multivariable logistic regression models were used to compute the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between adipokines and the risk of active TB.RESULTS: Higher levels of leptin and resistin were associated with reduced risk of TB in a dose-dependent manner. Compared to those in the lowest quartile of leptin levels, those in the highest quartile had an OR of 0.46 (95%CI 0.26-0.82; P for trend = 0.009). Similarly, compared to those in the lowest quartile of resistin levels, those in the highest quartile had an OR of 0.46 (95%CI 0.24-0.90; P for trend = 0.03). Adiponectin and ghrelin levels were not associated with TB risk.CONCLUSION: Increased serum levels of leptin and resistin may be associated with reduced susceptibility to active TB infection.

OBJECTIVES:WHO recommends that low burden countries consider systematic screening and treatment of latent tuberculosis infection (LTBI) in migrants from high incidence countries. We aimed to determine LTBI prevalence and risk factors and evaluate cost-effectiveness of screening and treating LTBI in migrants to Singapore from a government payer perspective.DESIGN:Cross-sectional study and cost-effectiveness analysis.SETTING:Migrants in Singapore.PARTICIPANTS:3618 migrants who were between 20 and 50 years old, have not worked in Singapore previously and stayed in Singapore for less than a year were recruited.PRIMARY AND SECONDARY OUTCOME MEASURES:Costs, quality-adjusted life-years (QALYs), threshold length of stay, incremental cost-effectiveness ratios (ICERs), cost per active TB case averted.RESULTS:Of 3584 migrants surveyed, 20.4% had positive interferon-gamma release assay (IGRA) results, with the highest positivity in Filipinos (33.2%). Higher LTBI prevalence was significantly associated with age, marital status and past TB exposure. The cost-effectiveness model projected an ICER of S$57 116 per QALY and S$12 422 per active TB case averted for screening and treating LTBI with 3 months once weekly isoniazid and rifapentine combination regimen treatment compared with no screening over a 50-year time horizon. ICER was most sensitive to the cohort's length of stay in Singapore, yearly disease progression rates from LTBI to active TB, followed by the cost of IGRA testing.CONCLUSIONS:For LTBI screening and treatment of migrants to be cost-effective, migrants from high burden countries would have to stay in Singapore for ~50 years. Risk-stratified approaches based on projected length of stay and country of origin and/or age group can be considered.

BACKGROUND. Matrix metalloproteinases (MMPs) are key regulators of tissue destruction in tuberculosis (TB) and may be targets for host-directed therapy. We conducted a phase II double-blind, randomized, controlled trial investigating doxycycline, a licensed broad-spectrum MMP inhibitor, in patients with pulmonary TB. METHODS. Thirty patients with pulmonary TB were enrolled within 7 days of initiating anti-TB treatment and randomly assigned to receive either 100 mg doxycycline or placebo twice a day for 14 days, in addition to standard care. RESULTS. Whole blood RNA-sequencing demonstrated that doxycycline accelerated restoration of dysregulated gene expression in TB towards normality, rapidly down-regulating type I and II interferon and innate immune response genes, and up-regulating B-cell modules relative to placebo. The effects persisted for 6 weeks after doxycycline discontinuation, concurrent with suppressed plasma MMP-1. Doxycycline significantly reduced sputum MMP-1,-8,-9,-12 and-13, suppressed type I collagen and elastin destruction, reduced pulmonary cavity volume without altering sputum mycobacterial loads, and was safe. CONCLUSION. Adjunctive doxycycline with standard anti-TB treatment suppressed pathological MMPs in PTB patients. Larger studies on adjunctive doxycycline to limit TB immunopathology are merited.

Abstract Background Previously treated (ie, recurrent) tuberculosis (TB) cases account for approximately 7%–8% of incident TB globally and in Singapore. Molecular fingerprinting has enabled the differentiation of these patients into relapsed or reinfection cases. Methods Patient demographics, disease characteristics, and treatment information were obtained from the national TB notification registry and TB Control Unit. We performed a retrospective, case-control study to evaluate factors associated with recurrent TB disease in Singapore citizens and permanent residents with culture-positive TB from 2006 to 2013 and who developed a second episode of culture-positive TB up to 2016 using multivariable logistic regression analyses. Results Ninety-one cases with culture-positive first and recurrent TB disease episodes were identified. Recurrent TB was associated with age ≥60 years (adjusted odds ratio [aOR], 1.98 [95% confidence interval {CI}, 1.09–3.61), male sex (aOR, 2.29 [95% CI, 1.22–4.51]), having concomitant pulmonary and extrapulmonary TB (aOR, 3.10 [95% CI, 1.59–6.10]) and extrapulmonary TB alone (aOR, 3.82 [95% CI, 1.12–13.31]), and was less likely in non-Malays (aOR, 0.52 [95% CI, .27–.99]). DNA fingerprinting results for both episodes in 49 cases differentiated these into 28 relapsed and 21 reinfection cases. Relapse was associated with having concomitant pulmonary and extrapulmonary TB (aOR, 9.24 [95% CI, 2.50–42.42]) and positive sputum acid-fast bacilli smear (aOR, 3.95 [95% CI, 1.36–13.10]). Conclusions Relapse and reinfection contributed to 57% and 43%, respectively, of recurrent TB in Singapore. Our study highlights the underappreciated association of concomitant pulmonary and extrapulmonary TB as a significant risk factor for disease relapse.

There were 290 multidrug-resistant (MDR)-TB cases diagnosed in Singapore from 2006 to 2018. Eighty-one percent were foreign-born. Spoligotyping and MIRU-VNTR methods identified 108 patients in 24 clusters. The Beijing spoligotype accounted for 22 clusters. Whole genome sequencing (WGS) analysis reduced the number of clustered patients and clusters to 43 and nine respectively. One MIRU cluster was redefined into three WGS clusters. All the clusters had foreign-born source cases. Forty percent of local-born, versus 9% of foreign-born, MDR-TB cases belonged to WGS clusters. WGS more accurately elucidated potential MDR-TB transmission which was overestimated by conventional genotyping methods in Singapore.

World Health Organization Regional Office for Europe – Tuberculosis, Copenhagen, Denmark; Department of Medical, Surgical and Experimental Sciences, University of Sassari Sassari, Italy; Independent Consultant, Atlanta, GA, USA; International Union Against Tuberculosis and Lung Disease, Paris, France; Respiratory Medicine, Tan Tock Seng Hospital, Singapore; Maugeri Care and Research Institute, WHO Collaborating Center, Tradate, Italy

SETTING: Although diabetes (DM) and low body mass index (BMI) are established risk factors for active tuberculosis (TB), the joint effect of type 2 diabetes (T2D) and BMI is unclear. DESIGN: A prospective cohort of 63,257 adults aged 45–74 years were recruited from 1993 to 1998 in Singapore. Active TB cases were identified via linkage with the National TB Registry up to December 2014. Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the relations of T2D and BMI, independently and jointly, with TB risk. RESULTS: T2D was associated with increased TB risk (HR 2.31, 95% CI 1.93–2.78). Conversely, BMI was inversely associated with TB risk: HR for underweight (BMI < 18.5 kg/m 2 ) was 2.87 (95% CI 2.15–3.82) compared to obese (BMI ≥ 27.5 kg/m 2 ) individuals. Compared to obese individuals without T2D, HR for active TB among underweight individuals with T2D was 8.30 (95% CI 4.43–15.54). There was no statistically significant interaction between BMI and T2D on TB risk ( P interaction = 0.85). CONCLUSION: Underweight and T2D are independent determinants for active TB. This has important public health implications in Asia where prevalence of tuberculous infection is high, and T2D occurs at lower levels of BMI.

BACKGROUND: Although asthma is associated with impaired lung immunity, it is unclear whether asthma affects the risk of active tuberculosis (TB). Because the upper and lower airways are immunologically related, sinonasal disease may also modify susceptibility to TB disease. OBJECTIVES: To evaluate whether asthma and sinonasal disease prospectively modulate the risk of active TB in the Singapore Chinese Health Study. METHODS: In this population-based prospective cohort, we recruited 63,257 Chinese adults aged 45 to 74 years from 1993 to 1998 in Singapore, and conducted follow-up I interviews among 52,325 surviving participants from 1999 to 2004. Data on self-reported history of physician-diagnosed sinonasal disease were collected at baseline, and data on asthma and chronic bronchitis were collected at follow-up I interviews. Active TB cases were identified by linkage with the National TB Notification Registry through December 2014. Multivariable Cox proportional hazards regression models were used to estimate the risk of active TB. RESULTS: During a mean follow-up of 17 years from recruitment, there were 1249 cases of active TB, and among them, 678 cases were diagnosed in the 12-year period from follow-up I interviews. We observed reduced risk of active TB in those with a history of asthma at follow-up I (hazard ratio [HR], 0.55; 95% CI, 0.32-0.93) or sinonasal disease at baseline (HR, 0.59; 95% CI, 0.36-0.95). Conversely, history of chronic bronchitis was not associated with risk of TB (HR, 0.95; 95% CI, 0.68-1.31). CONCLUSIONS: Asthma or sinonasal disease may modulate immunological response to reduce the incidence of active TB in the adult population. (C) 2018 American Academy of Allergy, Asthma & Immunology

Acute respiratory infections such as influenza and community-acquired pneumonia (CAP) are leading causes of hospitalization with significant morbidity and mortality. Tuberculosis (TB) is one of the top 10 global causes of death and the leading cause from a single infectious agent. As part of Respirology's 25-year celebration, we present an opinion on advances in diagnosis and treatment of these common respiratory infections. Influenza and CAP continue to be important. The availability of pneumococcal vaccines and multiplex polymerase chain reactions (PCR) has led to a decreasing incidence of pneumococcal pneumonia and detection of more viral aetiologies in CAP. In recent years, rapid and automated molecular tests based on nucleic acid amplification have become available, with high sensitivity for detection of influenza A, influenza B and respiratory syncytial virus (RSV).1 Fibroblast growth factor 21 was shown in a secondary analysis of two randomized controlled trials (RCT) to be an effective biomarker in discriminating patients with moderate to severe CAP, predicting longer hospital length of stay (LOS) and 30-day mortality (adjusted odds ratio (OR): 1.61 (95% CI: 1.21–2.14; P = 0.001)) in comparisons to procalcitonin and C-reactive protein.2 Implementation of rapid diagnostics and biomarkers in healthcare settings may facilitate management of acute respiratory infections and decision-making on appropriate use of antiviral or antibiotic therapy, hospital LOS and prevention of nosocomial transmission with infection control measures. Cardiovascular events, such as atrial fibrillation, acute myocardial infarction (AMI), ischaemic stroke and deep venous thrombosis, complicate the course of approximately one-third of patients hospitalized for CAP. These events are associated with a fivefold increase in CAP-associated 30-day mortality.3 A self-controlled case series in Canada has shown a significant association between respiratory infections (especially influenza) and AMI. Incidence ratios for AMI within 1 week after detection of influenza B, influenza A, RSV and other viruses were 10.11 (95% CI: 4.37–23.38), 5.17 (95% CI: 3.02–8.84), 3.51 (95% CI: 1.11–11.12) and 2.77 (95% CI: 1.23–6.24), respectively.4 Studies of strategies to reduce these cardiovascular complications are of interest. Oseltamivir is currently the sole influenza antiviral on the World Health Organization (WHO) Essential Medicines list. Intravenous zanamivir has been recommended in the European Union for treating complicated and potentially life-threatening influenza caused by either the influenza A or B virus in adults and children from 6 months of age if the virus is resistant to other antiviral treatments, or inhaled zanamivir is not suitable. A meta-analysis of data from 18 309 patients in 70 clinical centres has shown that initiation of a neuraminidase inhibitor (NAI) treatment on admission, regardless of time since illness onset, is associated with a 19% reduction in LOS (incidence rate ratio: 0.81; 95% CI: 0.78–0.85) versus no or later initiation of treatment among patients hospitalized with non-fatal 2009 influenza A(H1N1).5 Baloxavir is an inhibitor of polymerase acidic protein endonuclease enzyme, with strong antiviral activity against diverse influenza A and B viruses. It has broad potency against various clinically relevant subtypes of influenza A viruses (H1N2, H5N1, H5N2, H5N6, H7N9 and H9N2). In a phase III study comparing a single dose of baloxavir 40–80 mg versus placebo or oseltamivir 75 mg twice daily (bd) in otherwise healthy influenza patients with uncomplicated influenza, baloxavir significantly reduced time to alleviation of symptoms by >24 h versus placebo and was comparable to oseltamivir. In addition, baloxavir significantly reduced viral titres versus placebo or oseltamivir from 1 day post dose.6 In another phase III study of high-risk patients with influenza comparing a single dose of baloxavir 40–80 mg versus placebo or oseltamivir 75 mg bd, baloxavir is superior to placebo in shortening the time to improvement of influenza symptoms with fewer influenza-related complications. Baloxavir is superior to placebo and oseltamivir in shortening the duration of symptoms and reducing viral titres in influenza B infection. However, emergence of A/H3N2 viral mutants with polymerase/I38X substitutions in up to 10% of adolescents and adults and 23.4% of young children is of concern.7 Clinical trials comparing the adjunctive role of baloxavir in two to three doses in addition to oseltamivir against oseltamivir and placebo are in progress. Systemic corticosteroids are frequently used for the treatment of acute respiratory distress syndrome. In comparison to controls who did not receive systemic corticosteroids, high-dose systemic corticosteroids (defined as >150 mg/day methylprednisolone equivalent) was associated with increased risks of 30-day mortality (38.5% vs 7.7%, P = 0.021) and 60-day mortality (50% vs 15.4%, P = 0.022) and longer viral shedding (15 vs 13 days, P = 0.039) among patients with influenza A(H7N9) viral pneumonia. There was no difference between low dose (25–150 mg/day methylprednisolone) and controls.8 A bundled intervention including adjunctive systemic corticosteroids in the form of prednisolone acetate 50 mg/day for 7 days for patients with CAP demonstrated no evidence of effectiveness (with regard to hospital LOS, mortality and readmission) and resulted in a higher incidence of gastrointestinal bleeding in comparison with controls who did not receive systemic corticosteroids (9 (2.2%) vs 3 (0.7%)).9 The updated guideline of the American Thoracic Society and Infectious Diseases Society of America has recommended not to prescribe systemic corticosteroids routinely for CAP except for those with refractory septic shock.10 Personal protective equipment is important for healthcare workers treating patients with acute respiratory infections. In a cluster randomized real-world effectiveness study among outpatient healthcare workers from 2011 to 2015, N95 respirators versus medical masks resulted in no significant difference between the two types of masks in the incidence of laboratory-confirmed influenza (8.2% vs 7.2% healthcare personnel-seasons, respectively) (difference: 1.0% (95% CI: −0.5% to 2.5%); P = 0.18) (adjusted OR: 1.18 (95% CI: 0.95 to 1.45)).11 The declaration of TB as a global public health emergency by the WHO in 1993 proved the catalyst for governments, donor agencies and the private sector to prioritize funding for the research and development of TB diagnostics, drugs and vaccines. Development of rapid molecular-based tests to detect resistance-conferring mutations in the Mycobacterium tuberculosis (MTB) genome has been a key advance. The Xpert MTB/rifampicin (RIF) (Cepheid, Sunnyvale, CA, USA), a near point-of-care test endorsed by the WHO in 2010, has shortened the time to detection of MTB and rifampicin resistance (as a surrogate for multidrug-resistant (MDR) TB) from weeks/months to less than 2 h. It has recently been replaced by a more sensitive version, the Xpert MTB/RIF Ultra. A new cartridge, run on GeneXpert software, which detects resistance to isoniazid, fluoroquinolones and second-line injectables will be available soon. Whole-genome sequencing (WGS) is expected to expand the range of drugs for which resistance can be tested without reliance on the slower phenotypic method. Using WGS, a high degree of correlation of genotypic predictions of susceptibility of MTB to first-line drugs with their phenotypic susceptibility has been shown. Public health laboratories in England, the Netherlands and New York State have replaced phenotypic first-line drug susceptibility testing with WGS to guide clinical practice.12 Since rifampicin was approved in 1968, no new drug or drug class has been approved for TB until 2012, when bedaquiline attained accelerated US Food and Drug Administration (FDA) approval for MDR-TB treatment. In 2019, pretomanid became the third TB drug in 50 years to be FDA-approved for its use in combination with bedaquiline and linezolid for the treatment of extensively drug-resistant, treatment-intolerant or non-responsive pulmonary MDR-TB. In 2019, the first RCT on MDR-TB treatment showed non-inferiority of the shorter WHO 9–11 month (‘Bangladesh’) regimen compared to the WHO 20-month regimen in eligible patients.13 An individual patient data meta-analysis showed the treatment outcome and mortality benefit of bedaquiline, later-generation fluoroquinolones and linezolid in the longer MDR-TB treatment regimen, providing the evidence base which shaped key changes to the 2019 WHO guidelines on MDR-TB treatment.14 An injection-free MDR-TB treatment regimen is now recommended, and the second-line drugs have been re-grouped such that levofloxacin/moxifloxacin, bedaquiline and linezolid are designated high-priority drugs to be included in the longer WHO MDR-TB treatment regimen.15 Research to identify biomarkers for incipient TB and to develop tests with higher positive predictive value for progression of latent TB infection (LTBI) to active TB than that of the tuberculin skin test (TST) and interferon-gamma release assays (IGRA) is ongoing. In the last decade, evidence for the efficacy and safety of shorter LTBI treatment regimens (i.e. 12 weeks of weekly rifapentine and isoniazid; 4 months of rifampicin; and 4 weeks of daily rifapentine and isoniazid, the latter in human immunodeficiency virus (HIV)-infected persons) as alternatives to 6–9 months of isoniazid has emerged.16-18 The only licensed TB vaccine, BCG (bacille Calmette–Guerin), has been in use since 1920 and does not confer substantial protection against pulmonary TB in adults. Progress in TB vaccine development has been hampered by limited understanding of the protective immune response, lack of immune correlates for protection and the uncertain predictive value of preclinical animal models. There are currently 14 vaccine candidates in clinical trials. Recently, a phase 2b trial of the M72/AS01E vaccine in Africa showed vaccine efficacy of 50% at 3 years for MTB-infected, HIV-negative adults against active pulmonary TB, representing a major breakthrough.19 TB control programmes and health services need to be strengthened to realize the potential of these recent scientific advances. Political leadership and accountability, sustainable funding and investment in research and development, and, not least, addressing the societal and poverty-related drivers of the TB epidemic will be vital in order to achieve WHO's ambitious goal to ‘End TB by 2030’. D.S.C.H. has attended Roche advisory board meetings related to the discussion of baloxavir data and research, but there was no remuneration involved. C.B.E.C. has no conflict of interest.

In this Tuberculosis Updates 2018 series, experts from various parts of the world review important innovations and developments in a global effort to end the tuberculosis (TB) epidemic.1-9 Major gaps remain in reaching, diagnosing and effectively managing TB patients in many parts of the world.1 Social inequities continue to hamper TB control, especially in resource-limited settings.10 Universal health coverage and social protection are necessary to remove the barriers to the access to quality TB care. Antimicrobial resistance represents a growing threat to public health and economic growth worldwide.11, 12 Standardized treatment regimens, while having facilitated large-scale programmatic implementation, could have inadvertently accelerated the development of multidrug-resistant (MDR) TB and extensively drug-resistant (XDR) TB through drug-specific resistance amplification.2, 3 Although the End-TB Strategy advocates universal access to drug susceptibility testing (DST), this is not widely available.4 The slow growth of Mycobacterium tuberculosis complicates phenotypic DST, and the long turn round time severely limits its clinical utility in guiding the initial choice of drugs. Unlike the regular reporting of minimal inhibitory concentration (MIC) for other bacterial infections, the use of a single critical concentration that inhibits the growth of 99% of phenotypically wild-type strains to classify phenotypical susceptibility or resistance to TB drugs may not bear a direct relationship with either achievable serum drug level or clinical response of a mutant strain.4 Clinical breakpoint, or MIC at or below which the relevant strain is likely to respond to treatment, may be useful for drugs that can be used at higher doses, such as isoniazid, rifampicin and fluoroquinolones. However, with the intrinsic difficulty in delineating the effect of individual drugs in a combination regimen, suggested values for the clinical breakpoint are given only for moxifloxacin in the recently published technical report from the World Health Organization (WHO).13 Commercial rapid molecular tests are now available for direct application to clinical specimens to detect mutations associated with resistance to key first- and second-line drugs, such as rifampicin, isoniazid, pyrazinamide, fluoroquinolones and second-line injectables, but their drug target coverage is still too limited to guide the formulation of individualized treatment regimens.2, 4 Whole-genome sequencing holds promise for revolutionizing the coverage and predictive power of genotypical DST,14 but cost, throughput, facility requirement, background noises and replicative errors still remain important hurdles preventing its direct application to clinical specimens. The preliminary results of the STREAM Stage 1 Trial showed marginally lower favourable outcome (78.1% vs 80.6%) for the standardized 9–12-month shorter MDR-TB regimen as compared to the conventional 18–24-month regimen.2, 15 The difference could neither demonstrate non-inferiority of the shorter regimen nor superiority of the longer regimen. The trial end-point may not fully reflect the operational advantages of the much shorter regimen. Following an expedited review, the WHO continues to conditionally recommend the shorter regimen for adults and children with pulmonary MDR/rifampicin-resistant (RR) TB who were not previously treated with second-line TB drugs and in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered highly unlikely.15 However, no more than 4–50% of patients in some MDR-TB hotspots, such as Eastern Europe, South East Asia, Pakistan and Brazil, are likely to be eligible for the shorter regimen because of the high prevalence of drug resistance to one or more of the drugs used in the regimen,2 thus raising concern of its longer-term sustainability. TB drugs used in the longer conventional regimen for MDR-TB have been regrouped into three different categories by the WHO in August 2018.16 Group A drugs, including levofloxacin/moxifloxacin, bedaquiline and linezolid, are to be prioritized. Group B drugs, including clofazimine and cycloserine/terizidone, are to be added next. Group C drugs (ethambutol, delamanid, pyrazinamide, imipenem-cilastatin, meropenem, amikacin/streptomycin, ethionamide/prothionamide, p-aminosalicylic acid) are included when drugs from Groups A and B cannot be used. Judicious use of repurposed and new drugs is essential to avoid the emergence of resistance to these drugs, which would further set global TB control efforts back, in view of the relatively slow rate of TB drug development. With the reasonably favourable outcomes achievable with an optimized background regimen in both the STREAM Stage 1 Trial15 and Delamanid Trial 213,17 there may be a valid question as to whether the relatively toxic drug, linezolid, and the expensive new drug, bedaquiline, with very short and incompletely established safety record, are needed in the treatment of MDR-TB in the absence of fluoroquinolone resistance. Kanamycin and capreomycin are no longer recommended by WHO based on their associated risk of treatment failure and relapse in a recent individual data meta-analysis.18 However, retrospective observational data on treatment outcomes are often subject to confounding by indication as well as non-comparability between cases and controls. In that meta-analysis, the overall treatment success rate was only 61% (or 71% after excluding those who died during treatment). Use of kanamycin and capreomycin were associated, respectively, with very good treatment success rates of 2192 of 2523 (86.9%) and 821 of 938 (87.5%) in drug-susceptible cases, even though they still fell short of the exceptionally high success rate of 406 of 455 (89.2%) observed in a possibly non-comparable control group not using injectables. Furthermore, in vitro susceptibility to second-line injectables has been consistently associated with better treatment outcomes in MDR-TB.18, 19 The disparate effects between amikacin and the other two injectables may not be expected from their shared mechanisms of action. Kanamycin has been successfully used in the shorter MDR-TB regimen for adults.2, 3 Intermittent dosing of the injectable after a daily phase may also help to reduce side effects and improve tolerance. In February 2018, the WHO updated the guidelines for programmatic management of latent TB infection (LTBI).20 Either tuberculin skin test (TST) or interferon-gamma release assay (IGRA) can be used to diagnose LTBI, but such testing is not a strict requirement for initiating preventive treatment in people living with HIV or child household contacts aged <5 years, particularly in resource-constrained areas with high ongoing risk of TB transmission. IGRA works better than TST among people vaccinated with Bacillus Calmette-Guerin (BCG), particularly when the prevalence of true infection is low relative to BCG-induced cross-reaction.5 LTBI tests and biomarkers for predicting TB are subject to a generic limitation imposed on the positive predictive value by the generally low absolute disease risks.5, 6 A 16-gene host transcription signature has been reported to predict TB in the 12 months in the validation cohort with a sensitivity of 53.7% and a specificity of 82.8%.21 However, with an absolute disease risk below 2%, the reported sensitivity and specificity would only translate into a positive predictive value in the region of 5%, still suboptimal for informing clinical decisions on an individual basis. Shorter, better tolerated treatments using rifamycins (weekly rifapentine plus isoniazid for 12 weeks,22 daily rifampicin for 4 months,23 daily rifapentine and isoniazid for 1 month24) are proving safe and effective alternatives to isoniazid, especially in terms of lower risk of hepatotoxicity. However, the risks of other adverse effects (e.g. hypersensitivity reaction to rifamycins) remain considerable relative to the number of TB averted, thereby necessitating a targeted approach to optimize benefit versus risk ratio, although at the expense of reduced population coverage. In selected high-risk household contacts of MDR-TB, preventive treatment may be considered.20 Limited data suggested the protective efficacy of fluoroquinolone-based regimens for contacts of fluoroquinolone—susceptible MDR-TB.25 Most cases of TB in the intermediate burden countries are caused by endogenous reactivation of LTBI among the aging population.7 Although the extended family structure is breaking down in many of these Asian cultures, grandparents may still play an important role in caring of young kids, raising a question of whether cross-generation transmission could further sustain the TB epidemic. On the other hand, while family contacts have higher risk of being infected, most TB transmission appears to occur outside the households in ill-characterized community settings.8 Before novel tools, such as molecular epidemiology, geospatial analyses and ventilation studies, can be successfully deployed to inform targeted interruption of such transmission in the general community, alternative population-based interventions are desirable to reinforce the current approach of controlling TB at the source through early diagnosis and effective treatment. Highly predictive correlates of vaccine-induced protection are yet to be identified to de-risk TB vaccine research and development as well as human testing at an early stage.6, 9 Notwithstanding this current hurdle, various novel TB vaccine candidates are being developed, with at least 12 of them now in clinical trials.9 With the high global burden of LTBI, vaccines capable of preventing pulmonary TB in infected individuals will be needed to exert a quick impact on TB incidence. A sub-unit vaccine, M72/AS01E, demonstrated 54% protection against active pulmonary TB in HIV-negative adults with a positive IGRA in a recently published phase IIb trial.26 This proof-of-concept study brings fresh hope for new and possibly transformative TB vaccines in the near future. Heads of state and government, who are meeting on 26 September 2018 at the United Nations General Assembly, have committed to mobilize US$ 13 billion a year by 2022 to implement TB prevention and care and US$ 2 billion for research.27 Substantial advances have been made, especially in the diagnostic and treatment tools for drug-resistant TB and LTBI. However, careful planning is required in their field deployment. In particular, screening for TB and LTBI needs to be properly targeted at clearly defined high-risk groups within the specific epidemiological, social and health systems contexts to optimize the potential impact against the opportunity costs.28 Further breakthroughs, especially in highly predictive biomarkers for disease development and more effective vaccines for those already infected, are required to maximize the population impact.

The Ministry of Health (MOH) has updated the Clinical Practice Guidelines on Chronic Obstructive Pulmonary Disease (COPD) to provide doctors and patients in Singapore with evidence-based treatment for COPD. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH Clinical Practice Guidelines on COPD, for the information of SMJ readers. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: https://www.moh.gov.sg/content/moh_web/healthprofessionalsportal/doctors/guidelines/cpg_medical.html. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

Background: Singapore is an intermediate TB incidence country with a stagnant TB incidence rate of ~ 40/100,000 population since 2008. Its population is 5.61 million of which 40% are foreign-born long-stay residents. The local-born demographic is that of an ageing population. The population density is 7,796 / sq km. Universal MTb genotyping is performed at the Central TB Laboratory and we present the data herein. Methods: There were 12,047 MTb isolates for unique case-episodes of TB nation-wide from Jan 2011 to Dec 2017. Valid genotyping (Spoligotyping and 24 loci MIRU-VNTR) data were available for 8,768 isolates (72%). Analysis for clustering was done using software (Bionumerics 6.6 Applied Maths NV). A cluster was defined when 2 or more isolates had an identical spoligotype and MIRU-VNTR. Results: The majority were Beijing (46%) and EAI (24%) strains. Fifty-three percent (n= 4,679) were clustered into 872 clusters (size ranging from 2 to 210) implying a transmission rate of 43% of the cases within this period. Clustered cases were more likely to be male (OR1.21, p=0.007), persistent treatment defaulters (OR 1.42, p=0.03), local-born (OR 2.33, p<0.001) or infected with the Beijing strain (OR 4.03, p<0.001). Conclusions: We found a high rate of clustering, but a high proportion belonged to the Beijing strain. Whole genome sequencing will be useful to better discriminate and define the clusters.

The 2013 tuberculosis (TB) review series ‘Tuberculosis: Current state of knowledge’ highlighted important gaps in our existing knowledge on the complex interactions between the pathogen and the host. We also detailed major limitations in current control strategies.1 Since then, there have been major developments in new diagnostic tools and drugs/regimens for TB and latent TB infection (LTBI), some of which have modified clinical practice in both high- and low-burden countries.2 In 2014, the World Health Assembly approved the ‘End TB Strategy’, which set ambitious targets to achieve a 95% reduction in TB death and 90% reduction in TB incidence rate by 2035.3 To consolidate developments and to meet the upcoming challenges, we have invited a panel of international experts to critically re-examine the relevant issues in a new series of themed reviews focused on TB. Despite over two decades of effort to find and treat infectious sources, there were still an estimated 10.4 million incident TB cases with 1.7 million deaths in 2016.2 The annual decline of TB incidence remained at around 2%, not much higher than the annual decline of TB mortality of 1.71% in the United Kingdom in the pre-chemotherapeutic era.4 Resistance has also emerged to most of the medications used to treat TB, and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB is threatening TB control in many high-burden areas.2 Against this background, there is a need to critically examine how we can turn the vision of the End TB Strategy into reality. Pursuing social protection, universal health coverage and optimizing the use of new tools from the development pipelines are necessary to achieve the priority targets of over 90% treatment coverage, treatment success rate and preventive treatment coverage, and accelerate the annual decline of TB incidence from 2% to 10% in the coming decade. With the current estimate that one quarter of the global population has been infected with the tubercle bacillus,5 critical breakthroughs in either the screening and treatment of LTBI or the development of new TB vaccines are indispensable to further accelerate the annual decline of TB incidence to 17% beyond 2025. A high burden of LTBI is observed in rising elderly populations in many Asia-Pacific areas. This is largely as a result of the heightened transmission arising from the high TB incidence that peaked alongside rapid urbanization in the last century.6 Older people often have a TB incidence several fold higher than younger people in these areas.2, 6 With frequent co-morbidities, TB in older people is often more difficult to diagnose and treat, posing a critical challenge in TB control. Wing Wai Yew et al. will discuss the epidemiological, clinical and mechanistic perspectives of TB in older people, highlighting the colliding epidemics of smoking, diabetes mellitus and TB, and how unravelling the underlying mechanisms might potentially help to prevent and better manage TB in this group. Vaccines are often regarded as a first-line tool in controlling infectious diseases because they are more readily applied on a population scale. However, the existing Bacillus Calmette–Guerin (BCG) vaccine gives only partial and variable protection against pulmonary TB, the major source of infection, in adults.7 Bingdong Zhu et al. will highlight the challenges in the development of new TB vaccines. As natural infection by the tubercle bacillus fails to prevent reinfection,8 simple inactivation or attenuation of the organism is unlikely to produce a fully protective vaccine. However, quite a number of candidate vaccines developed using new approaches and/or delivery vectors have entered different phases of clinical trials. Slow but steady progress has also been made to discern the complex immunological mechanisms underlying vaccine protection. Hopefully, suitable immunological correlates could be identified to serve as biomarkers or surrogate end points for selecting promising candidates for further advancement in the development pipeline, thereby minimizing the need for large and protracted clinical trials using disease as the primary end point. Delia Goletti et al. will review efforts to identify biomarkers for disease development, treatment response and outcome. Similar to immunological correlates, biomarkers with good predictive power on a group basis may circumvent the need to use disease or failure/relapse as primary end points in protracted clinical trials in new drug or regimen development for either LTBI or active TB disease. Biomarkers with high predictive power on an individual basis will be needed to inform clinical decision on who, when and how to treat either condition. As humans are the predominant hosts for Mycobacterium tuberculosis complex, selection pressure from clinical use of TB drugs necessarily accounts for the initial emergence of drug resistance associated with various naturally occurring chromosomal mutations.9 However, most of the MDR-TB cases now arise through secondary transmission of drug-resistant strains emerging from suboptimal use of these drugs in the past few decades.2 Christoph Lange et al. will explore how we can combat the evolving epidemic of drug-resistant TB with the help of new diagnostic and treatment tools. The relative contributions of non-adherence and pharmacokinetic variabilities to the progressive acquisition of drug resistance will also be examined together with the ongoing controversies on the role of directly observed therapy. Paolo Miotto et al. will examine the roles and limitations of genotypic and phenotypic drug susceptibility tests in the management of drug-resistant TB. As the available rapid molecular tests cover only a limited number of TB drugs,2 they cannot fully replace phenotypic tests in guiding the treatment of MDR/XDR-TB. However, the choice of critical concentrations in the latter tests remains a contentious issue as the 95th percentile minimum inhibitory concentration (MIC) of the wild TB strains bears little relationship to either the achievable serum drug concentration or the actual MIC of the mutant strain.10 Furthermore, genotypic and phenotypic mismatches are not uncommon.10, 11 Infection by multiple strains may also pose a problem for either type of drug susceptibility tests.12 Kwok-Chiu Chang et al. will examine the pertinent issues related to the development and clinical application of new drugs and regimens in the treatment of drug-susceptible and drug-resistant TB. Treatment duration substantially shorter than the current 6-month standard short-course regimen is desirable to promote adherence. However, in recent clinical trials,13-15 for reasons as yet unclear, standard short-course regimens failed to reproduce the high treatment efficacy observed in earlier trials conducted by the British Medical Research Council.16 Either a regimen superior to the 6-month short-course regimen or an innovative approach to optimize the treatment duration to minimize relapse may, therefore, be required to meet the priority target for over 90% treatment success under the ‘End TB Strategy’. Suitable measures to protect new and repurposed drugs and accelerated efforts in new drug development are required to manage the continuing emergence of resistance17 and the problem of mycobacterial persistence.18 With the successful control of ongoing transmission by the directly observed therapy-short course (DOTS) strategy in intermediate TB burden countries, further acceleration in the decline of TB incidence would hinge on preventing the reactivation of LTBI.19 Robert Belknap et al. will review the challenges and opportunities in the management of LTBI. Current diagnostic tests for LTBI (i.e. the tuberculin skin test and interferon gamma assays) have low predictive values for the development of disease. A targeted approach is necessary to reduce the number needed to treat to prevent a single case of TB.19, 20 Current regimens for preventive therapy are not without risk of adverse effects and their treatment duration of 3–9 months also pose challenges in patient acceptability and adherence. While mass screening and treatment programme for LTBI has helped to reduce the high TB risk in a small Alaskan community,21, 22 better diagnostic and treatment tools than those currently available are required for the implementation of this TB control strategy on a population-wide scale. In the last review of this series, Neel R. Gandhi et al. will re-examine the transmission of TB in both nosocomial and household settings. New investigation tools, such as whole genome sequencing, are reshaping our knowledge on the transmission of this old human pathogen.23 Despite the heightened TB infection risks among household contacts, household transmission appears to account only for a small portion of the overall transmission in the ongoing TB epidemic.23, 24 With changing patterns of urbanization, innovations and new approaches to curb TB transmission at multiple levels may be needed to impact TB in the coming decades.