Chakaya, J

Ehtesham, NZ

Fox, GJ

Marais, BJ

Maurer, M

Ntoumi, F

Swaminathan, S

Zijenah, L

Zumla, A

UCL Discovery

 1 Invited Comment for Lancet Infectious Diseases (World TB Day) Title: Tackling long-term morbidity and mortality after successful tuberculosis treatment    Authors: Ben J Marais FRACP*, Jeremiah Chakaya MD, Soumya Swaminathan MD, Greg J. Fox FRACP, Nasreen Ehtesam PhD, Francine Ntoumi FRCP, Lynn Zijenah PhD, Markus Maurer FRCP and Alimuddin Zumla FRCP  Institutional Affiliations: BM Faculty of Medicine and Health, The University of Sydney, Sydney, Australia                    Email: <ben.marais@health.nsw.gov.au> JK Department of Medicine, Therapeutics, Dermatology and Psychiatry, Kenyatta University, Nairobi, Kenya. Email: <chakaya.jm@gmail.com> SS World Health Organization, Geneva, Switzerland. Email: doctorsoumya@yahoo.com GF The University of Sydney Central Clinical School, Faculty of Medicine and Health, The University of Sydney, NSW, Australia 2006.   Email: greg.fox@sydney.edu.au. ORCID ID. https://orcid.org/0000-0002-4085-1411 NE Jamia Hamdard-Institute of Molecular Medicine, Hamdard Nagar, New Delhi, India Email: Nasreen Ehtesham <nzehtesham@gmail.com> FN Université Marien NGouabi, Fondation Congolaise pour la Recherche Médicale (FCRM), Brazzaville, Congo. Institute for Tropical Diseases, University of Tübingen, Germany.  Email: <fntoumi@fcrm-congo.com LZ Department of Immunology, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe. Email: <lzijenah@gmail.com>  MM Immunosurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal, and Department of Oncology and Haematology, Krankenhaus Nordwest, Frankfurt, Germany. Email: <markus.maeurer@fundacaochampalimaud.pt> AZ Department of Infection, Division of Infection and Immunity, University College London, and  NIHR Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, United Kingdom. Email: a.i.zumla@gmail.com  Keywords: Tuberculosis, post-treatment morbidity, bronchiectasis, COPD, drug-resistance  Word Count: 806 (References 15)  2  Conflict of interests to declare: None  *Correspondence to:  Professor Ben J Marais FCP.PhD Clinical School, The Children’s Hospital at Westmead,  Locked Bag 4001, Westmead,  NSW, 2145 Sydney, Australia Tel: +61-2-9845 3433;  Email: ben.marais@health.nsw.gov.au     3 Tuberculosis (TB) is a curable disease, but the number of cases with difficult to cure drug resistant disease is rising (1). Even among patients in whom bacteriological cure is achieved, long-term functional impairment is common.(2)  This is especially true for cases with a late diagnosis, in whom the initiation of appropriate treatment is delayed and in young children or immunocompromised individuals in whom disease progression can be rapid and early symptoms maybe non-specific.   Post-TB morbidity Pulmonary TB, the commonest form of the disease, is an important, but under-appreciated, cause of chronic lung disease that is associated with substantial global morbidity and mortality.(3) Post-TB pulmonary morbidity includes functional disability due to reduced lung function, bronchiectasis with recurrent bacterial infections, and extensive cavitation with opportunistic infections such as Aspergillus.(3) A survey done in the United States identified lung function impairment in more than 50% of cured TB patients, with 10% suffering severe compromise.(2)  A systematic review found a significant association between a history of TB and the presence of chronic obstructive lung disease (COPD) in older adults (pooled odds ratio 3.05; 95% confidence interval 2.42-3.85).(4) Among individual studies the strongest association between TB and chronic lung disease was found in high TB-incidence countries, especially in younger people not smoking cigarettes, since it is difficult to untangle confounding effect of cigarette smoking.   The TB treatment period provides an important opportunity to promote strategies that will optimise long-term lung health, including smoking cessation and general lung health education. This is even more important in patients with drug resistant-TB, who frequently experience increased adverse lung health impacts due to delays in commencing effective treatment.(5) Given that the treatment of drug resistant-TB is complex, costly and often toxic, an important lung health strategy is to prevent disease progression among close contacts of drug resistant-TB cases. The outcome of on-going prevention trials are eagerly awaited.(6) The prolonged engagement of patients with the health care system during TB treatment also offers an opportunity to consider other interventions that may improve their long-term health outcome, such as screening for common non-communicable diseases.(7) Person-centred care that includes pragmatic screening for diseases such as diabetes, hypertension and renal disease is feasible in TB patients and provides an opportunity to link those detected on initial screening to appropriate care pathways.(8)   4 Although children usually respond very well to TB treatment, young children (under 2-3 years of age) are particularly vulnerable to develop severe disseminated forms of the disease.(9)  By the time TB meningitis becomes clinically apparent, it is often associated with permanent neurological sequellae, which emphasizes the need for better protection strategies and earlier diagnosis. Clinical deterioration due to hydrocephalus, stroke or tuberculoma formation is common following the initiation of effective TB meningitis treatment, highlighting the need for novel immune modulatory approaches to reduce the steroid-resistant inflammatory cascade that underlies these adverse outcomes.(10)  Post-TB mortality TB is the leading infectious killer on the planet, despite the fact that current death estimates do not consider post-TB mortality. Accurate mortality estimates following discharge from TB care are not available, but a prospective cohort study among adults treated for pulmonary TB in Vietnam found that TB patients had a markedly elevated risk of death, particularly in the post-treatment period.  In total, 9% of patients died within 2-3 years of treatment initiation; 3.1% during treatment and 5.8% after discharge. The standardized mortality ratio compared to population controls, in a setting with a low prevalence of human immunodeficiency virus (HIV) infection, was 4.0 (95% CI 3.7-4.2).(11)    A systematic review of 6922 deaths in 40 781 TB cases and community controls calculated a pooled standardised mortality ratio of 2·91 (95% CI 2·21–3·84), which increased to 3.76 (95% CI 3·04–4·66) when restricted to TB cases with confirmed treatment completion or cure.(12)  Study heterogeneity was pronounced, and few confounding factors could be considered. However, the direction of the effect and effect estimates were similar when stratified by tuberculosis type, sex, age, and country-income category. Cardiovascular disease was the most common cause of death among those in whom this could be assessed, and mechanisms linking the TB and cardiovascular disease epidemics have been considered.(13)  TB is not only pro-inflammatory but it also induces thrombophilia. However, studies exploring potential interventions to reduce post-TB cardiac mortality, such as the use of low-dose aspirin or statins during and after TB treatment have not been performed.    Other co-morbidities influencing health outcomes following TB treatment include alcohol and drug misuse, HIV co-infection, diabetes, malnutrition, the detrimental effects of stigma and social exclusion, as well socio-economic disadvantage, which has a bi-directional effect.(14) While these challenges have no easy solutions, it is essential that health systems recognise the continuing morbidity following TB. A greater focus upon the biomedical and  5 social interventions to reduce post-treatment morbidity and mortality will be essential if the long-term prognosis of patients with TB is to be improved (15).    6 References 1) 2019 Global Report 2) Pasipanodya JG, McNabb SJ, Hilsenrath P, et al. Pulmonary impairment after tuberculosis and its contribution to TB burden. BMC Public Health 2010; 10: 259 3) Byrne AL, Marais BJ, Mitnick CD, Lecca L, Marks GB. Risk factors for and origins of COPD. Lancet 2015; 385: 1723-1724 4) Byrne AL, Marais BJ, Mitnick CD, Lecca L, Marks GB. Tuberculosis and chronic respiratory disease: a systematic review and meta-analysis. Int J Infect Dis 2015; 32: 138-46 5) Byrne AL, Marais BJ, Mitnick CD, Garden F, Lecca L, Contreras C, Garcia F, Marks GB. Chronic airflow obstruction after successful treatment of tuberculosis in Lima, Peru. Eur Resp J Open Research 2017; 3: 00026-2017 6) Fox G, Nguyen CB, Nguyen TA et.al. Levofloxacin versus placebo for the treatment of latent tuberculosis among contacts of patients with multidrug-resistant tuberculosis (The VQUIN MDR Trial): a protocol for a randomized controlled trial. BMJ Open 2020; 10: e033945 7) Marais B, Lönnroth K, Lawn S, Migliori GB, Mwaba P, Glaziou P et.al. Tuberculosis co-morbidity with communicable and non-communicable diseases: integrating health services and control efforts. Lancet Infect Dis 2013; 13: 436-48 8) Byrne AL, Marais BJ, Mitnick CD, Garden FL, Lecca L, Contreras C, Yauri Y, Garcia F, Marks GB. Feasibility and yield of screening for common non-communicable diseases in a cohort of patients treated for TB in Lima, Peru. Int J Tuberc Lung Dis 2018; 22; 86-92 9) Perez-Velez CM, Marais BJ. Tuberculosis in children. N Engl J Med 2012: 367: 348-61 10) Seddon JA, Thwaites GE; International Tuberculous Meningitis Research Consortium. Tuberculous meningitis: new tools and new approaches required. Wellcome Open Res 2019; 4: 181 11) Fox GJ, Nguyen VN, Dinh NS, Nghiem LPH, Le TNA, Nguyen TA et.al. Post-treatment Mortality Among Patients With Tuberculosis: A Prospective Cohort Study of 10 964 Patients in Vietnam. Clin Infect Dis 2019; 68: 1359-1366 12) Romanowski K, Baumann B, Basham CA, Ahmad Khan F, Fox GJ, Johnston JC. Long-term all-cause mortality in people treated for tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2019; 19: 1129-1137 13) Lönnroth K, Jaramillo E, Williams BG, Dye C, Raviglione M. Drivers of tuberculosis epidemics: the role of risk factors and social determinants. Soc Sci Med 2009; 68: 2240–46 14) Huaman MA, Henson D, Ticona E, Sterling TR, Garvy BA. Tuberculosis and cardiovascular disease: linking the epidemics.Trop Dis Travel Med Vaccines 2015; 1: 10.  7 15) Iberi S, du Plessis N, Walzl G, et al. Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies. Lancet Infect Dis 2018; 18: e183–e198 

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Tackling long-term morbidity and mortality after successful tuberculosis treatment

https://discovery.ucl.ac.uk/id/eprint/10096723/

Tackling long-term morbidity and mortality after successful tuberculosis treatment

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