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Highlights from the American Thoracic Society International Congress 2019 – Focus on Respiratory Infections

Authors: Alex Lowe, Senior Medical Writer, Touch Medical Media, UK

Respiratory infections are associated with the development of symptoms and exacerbations in a range of respiratory conditions, including asthma and chronic obstructive pulmonary disease (COPD).1,2 Consequently, there is great interest in developing therapeutic agents that can mitigate the effects of respiratory infections, as well as in the improved testing of pathogens to direct treatment. Additionally, there is a need to improve our understanding of the impact of factors such as e-cigarettes on patient outcomes. These themes were focuses of the 104th American Thoracic Society international congress, held in Dallas, Texas, United States on 17–22 May, 2019.

resTORbio Inc. presented data on a randomised, double-blind, placebo-controlled Phase IIb trial of 652 patients at high-risk of respiratory infection. Patients were treated with the target of rapamycin complex 1 (TORC1) inhibitor, dactolisib, either alone or in combination with everolimus, or were given matched placebo.3 Building on previous research suggesting that TORC1 inhibition may upregulate antiviral immune defenses, it was demonstrated that dactolisib decreased the incidence of laboratory confirmed respiratory tract infections by 67% (p=0.007) in high-risk adults greater than 85 years of age and by 69% (p=0.0001) in patients 65 years of age with asthma versus placebo during the winter cold and influenza season. Additionally, the incidence of all respiratory infections, confirmed and unconfirmed, in patients greater than 65 years of age with asthma, was reduced by 67% (p=0.003) with dactolisib compared with placebo. Dactolisib was found to be well tolerated, with a safety profile similar to placebo.3

The initial results of a prospective, randomised, controlled proof-of-concept trial evaluating the potential of four candidate therapies for tuberculosis were presented.4 Current treatments for tuberculosis leave most patients with lung injury and at risk of developing COPD; the adjunctive host-directed therapies evaluated in this trial have the potential to mitigate injury and shorten tuberculosis treatment. The 200 enrolled patients with human immunodeficiency virus-1 (HIV-1) and rifampin-susceptible pulmonary tuberculosis received either the phosphodiesterase-4 inhibitor CC-11050, everolimus, the oral gold salt auranofin, vitamin D2 or a control for the first 4 months of rifabutin-substituted standard treatment. Initial results suggest trends towards improved lung function and accelerated culture conversion with CC-11050 and everolimus, but not auranofin or vitamin D, with forced expiratory volume in 1 second (FEV1) improvements from baseline of 280 ml with CC-11050 versus the control group. We await the final results from this trial with interest.4

Also presented were the results of a single-centre, randomised controlled study using new molecular point-of-care testing (POCT), the FilmArray® Respiratory Panel (BioFire™ Diagnostics, Inc., Salt Lake City, UT, USA), for the identification of viruses and atypical pathogens.5 The study enrolled 761 hospitalised adults with lower respiratory tract infections (LRTI) diagnosed as pneumonia, acute COPD exacerbation, or acute bronchiectasis exacerbation, to determine if POCT reduced antibiotic use compared to routine clinical care. Compared with routine care, POCT significantly reduced the duration of antibiotic use (mean difference: −1.6 days; p<0.0001), the length of hospital stays (median: 9 versus 8 days) and the cost of hospitalisation ($2017 versus $1761). Although further work is required, POCT testing for patients with LRTI could help optimise antibiotics use, an issue of particular importance given the growing incidence of antibiotic resistance, while improving clinical outcomes in patients.5

New data on the effect of e-cigarettes on influenza vaccination response were also presented, building on previous research indicating a link between e-cigarettes and respiratory tract immune suppression.6 In the study, the responses of healthy volunteers who were non-smokers, and cigarette or e-cigarette smokers vaccinated with a live attenuated influenza vaccine were determined. Patient response to the vaccine differed with smoking status; e-cigarette smokers demonstrated suppressed interferon-gamma pathway gene expression, which is important for antiviral responses. Additionally, e-cigarette smokers had lower levels of influenza-specific immunoglobulin-A compared with other groups. Further research to determine whether these effects translate into a greater incidence of influenza in e-cigarette smokers could help inform physicians who advise patients on the risks of smoking.6

Finally, results of a study investigating the long-term effects of bacterial pneumonia in children less than two years of age were also presented and may be informative of supportive care measures that should be taken after hospital discharge.7 In this prospective study, predictors of chronic pulmonary dysfunction (CPD) 6 and 12 months after hospital discharge were assessed in 259 children who had required mechanical ventilation for acute respiratory failure. A positive bacterial culture was found to confer a 4.3-fold higher risk of pulmonary dysfunction at discharge (i.e. requiring mechanical ventilation, supplemental oxygen, bronchodilators or steroids) and continued to confer a 3.7-fold and 3.4-fold risk of CPD at 6 and 12 months, respectively.7

In summary, new agents for boosting anti-viral defenses and treating tuberculosis demonstrated reductions in the incidence and duration of respiratory infections, respectively. Additionally, POCT for severe LRTI enabled reductions in antibiotic use and improved patient outcomes, which may allow for a more nuanced approach to treatment. Initial results suggest an impact of e-cigarette smoke on vaccine response. Finally, the long-term impact of pneumonia on children demonstrates the need for further supportive care measures in these patients post-discharge.

References
1. Busse WW, Lemanske RF, Jr., Gern JE. Role of viral respiratory infections in asthma and asthma exacerbations. Lancet. 2010;376:826–34.

2. Linden D, Guo-Parke H, Coyle PV, et al. Respiratory viral infection: a potential “missing link” in the pathogenesis of COPD. Eur Respir Rev. 2019;28(151). pii:180063.

3. Mannick J, Shergill S, Teo G. A2623 Oral TORC1 inhibitor dactolisib enhances immune function and reduces the incidence of respiratory tract infections in elderly subjects with asthma. Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.

4. Wallis RS, Ginindza S, Beattie T, et al. A7388/319 – Preliminary results of an experimental medicine trial of adjunctive host-directed therapy in adults with moderately or far-advanced rifampin-susceptible pulmonary tuberculosis. Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.

5. Duan S, Gu X, Fan G, et al. A4209/401 The clinical value of a new molecular point-of-care testing in hospitalized lower respiratory tract infection patients: a randomized controlled study. Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.

6. Rebuli ME, Glista-Baker E, Speen AM, et al. A4170/702 Nasal mucosal immune response to infection with live-attenuated influenza virus (LAIV) is altered with exposure to e-cigarettes and cigarettes. Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.

7. Keim G, Yehya N, Spear D, et al. A1197/917 Bacterial pneumonia predicts ongoing chronic pulmonary dysfunction in previously healthy infants. Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.

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