Twenty‐five years of Respirology: Advances in respiratory infections and tuberculosis

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.