Successfully Treated but Not Fit for Purpose: Paying Attention to Chronic Lung Impairment

Successfully treated but not fit for purpose: paying attention to chronic lung impairment after TB treatment

Authors and Institutions:

Anthony D Harries 1, 2

Serge Ade 1, 3

Peter Burney 4

Nguyen Binh Hoa 1,5

Neil W Schluger 6,7

Jose Luis Castro 1, 7

1. International Union Against Tuberculosis and Lung Disease, Paris, France

2. Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine , London, UK

3. National Tuberculosis Programme, Cotonou, Benin

4. National Heart and Lung Institute, Imperial College, London, UK

5. National Tuberculosis Control Programme, Hanoi, Vietnam

6. Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University Medical Center, USA

7. Vital Strategies, New York, USA Address for correspondence:

Professor Anthony D Harries,

Old Inn Cottage,

Vears Lane,

Colden Common,

Winchester, SO21 1TQ,

Email = [email protected]

Paper Content:

Narrative word count – 1504

Abstract word count = 99

References = 30

Tables / Figures = none

Running Head:

Tuberculosis and chronic lung impairment

Key Words:

Tuberculosis; chronic restrictive lung disease; chronic airway obstruction; respiratory physicians; sustainable development goals ABSTRACT

In 2013, 86% of patients with newly diagnosed tuberculosis successfully completed treatment and were discharged from care. However, long term studies in industrialised and resource-poor countries all point to a higher risk of death in TB survivors compared with the general population. The likely explanation is chronic restrictive and obstructive lung disease consequent upon tuberculosis. We call for better linkages between tuberculosis control programmes and respiratory medicine services, a better understanding of the burden of respiratory disability at the end of anti-tuberculosis treatment and political, programmatic, clinical and research action to improve the quality of life of affected patients. Mr Phiri, a 35 year old subsistence farmer, from rural Southern Malawi has just completed 6 months of anti-tuberculosis treatment for presumed drug-susceptible tuberculosis (TB). He was HIV-negative when tested at the time of registration for his TB, he attended all his clinic visits, he adhered to his fixed-dose medication, his final sputum smear was negative for acid-fast bacilli and he is pronounced cured. In due course he will contribute to that impressive global statistic of 85% or higher treatment success for people newly diagnosed with TB.1 He no longer has TB. He was not known to have HIV-infection six months previously and is therefore discharged from care. Yet do we really know how healthy he is? Will he now be able to live a normal life with a life expectancy equivalent to someone who has never had TB?

The answer is probably no. In 1995, a cohort of 827 African patients diagnosed with

TB in Zomba district, Malawi, was carefully followed up over 7 years from the time of registration with visits paid to the village homes to ascertain whether patients were alive or dead.2-4 At the time of registration, the mean age (SD) of the cohort was 35 (12) years and

77% of the cohort was HIV-positive. There were 181 patients who were registered with HIV- negative TB. At 12 months, 124 (68.5%) were recorded as having completed treatment. Six years later, only 62 (50%) of these 124 patients were found alive. There were 57 (46%) known to have died during this six years, death having been ascertained by a visit to the patient’s home. The remaining five patients were lost to follow-up. Most of the deaths post- treatment occurred at home, so there was no information about causes of death and verbal autopsy was not carried out. Much was made at that time about the HIV-associated deaths, as

Malawi was grappling to deal with a burgeoning HIV-driven TB epidemic. However, the

National TB Programme in Malawi did express surprise at the high mortality in HIV-negative patients with nearly half of a relatively young cohort being dead within six years of completing anti-tuberculosis treatment. Risk of death and lung impairment following ant-tuberculosis treatment

Long term follow-up studies in industrialised countries such as UK, Denmark, USA and Israel have also found that the risk of death in patients completing TB treatment is high, with mortality rates consistently above what are observed in the general population.5-8 In these studies, the relative risk of death was higher in males and in younger individuals with

TB compared with the general population. As the authors pointed out though, the explanation for these higher mortality rates was speculative and included premature death from chronic lung impairment, super-infections including from bronchopulmonary aspergilloma, lung cancer, liver disease and other co-morbidities known to be associated with TB such as HIV infection and diabetes mellitus.

Post-tuberculous lung impairment is one obvious cause of morbidity and mortality following successful anti-tuberculosis treatment. Nearly one hundred years ago, lung function studies on men and women with TB showed evidence of restrictive lung disease.9,10 More recent studies have shown that pulmonary TB is associated with largely irreversible changes to bronchial and parenchymal structures leading to distortion of bronchial vasculature, bronchiectasis, emphysema and fibrosis.11-16 A restrictive pattern of lung disease is common and is independent of tobacco smoking.17 Although pulmonary impairment is more likely after extensive parenchymal involvement, significant declines may also be observed in patients with localised pulmonary TB.18 Chronic airway obstruction can also be a result of pulmonary TB, and this association has been known about for over 50 years.19,20 A recent study in Mexico found that just over one third of patients with a history of pulmonary TB had non-reversible chronic airway obstruction, which was independent of smoking history and which impacted significantly on quality of life.21 Airway obstruction in these patients was significantly associated with extensive pulmonary radiographic changes, residual lung cavities and mediastinal retraction. However, similar to patients with restrictive airways disease, TB patients with no sequelae on chest radiography may also show chronic airway obstruction and persistent respiratory symptoms.22 In a recently published, large international, population-based, Burden of Obstructive Lung Disease (BOLD) study, the risk of restrictive airways disease and airflow obstruction in people with a history of TB was more than twice as high as that found in people with no history of TB, and this was particularly apparent in people from low- and middle-income countries.23

TB and chronic lung impairment within the End TB Strategy and Sustainable

Development Goals

The aims of anti-tuberculosis treatment, as stated by the World Health Organization in their 2010 Treatment Guidelines, are to cure the patient, prevent death, prevent relapse, reduce transmission of TB to others and prevent the development and transmission of drug resistance.24 The Stop TB (and now the End TB) strategy generally does a good job in achieving these aims with treatment success for new patients with TB registered globally in

2013 reaching 86%.1 However, within these broad aims there are also explicit statements about restoring quality of life and productivity and preventing death from the late effects of

TB.24 Responsibility towards patients with pulmonary TB should not therefore end with attainment of microbiological cure.

The last two decades have seen an inexorable rise in non-communicable diseases in all countries of the world, with the global number of deaths from these diseases rising from an estimated 27 million in 1990 to nearly 35 million by 2010.25 Non-communicable diseases consist of a vast group of conditions, but in terms of what to focus on to prevent premature mortality, the emphasis has been on four main clusters – cardiovascular disease, cancer, diabetes and chronic respiratory disease. In the new Sustainable Development Goals (SDG), which are set to dominate global health policy from 2016 to 2030, the fourth target of the only SDG focused on health (SDG 3.4) is “to reduce by one third premature mortality from non-communicable diseases through prevention and treatment by 2030”.26 A lot of the recent attention has been focused on cardiovascular disease and diabetes, although chronic obstructive pulmonary disease is the third leading cause of mortality worldwide.27

Bronchodilators (short- acting and long-acting beta-2 agonists and anti-muscarinics) and anti- inflammatory drugs (inhaled corticosteroids and phosphodiesterase inhibitors) either singly or in combination can provide symptomatic relief, with effects further augmented by persuading patients to quit smoking.28

Linking National TB Programmes to Respiratory medicine services

With this strong association between TB and impaired lung function, there needs to be more thought and discussion about how to better link TB control programmes with respiratory medicine services and a better understanding of the burden of respiratory disability at the end of anti-tuberculosis treatment. Approximately 5 million TB patients successfully complete treatment each year,1 but we have no information about what proportion of these patients has respiratory disability, the severity of lung impairment, the impact on quality of life or whether the respiratory dysfunction is amenable to treatment. This needs to change. Already we are seeing connections, synergies and benefits of integrating care between communicable and non-communicable diseases with notable examples being diabetes and tuberculosis and HIV and cardiovascular disease.29 TB and chronic respiratory disease need to follow suit.

For a start, National TB Control Programmes need to systematically reach out to respiratory physicians, and respiratory physicians with an interest in TB need to link up with

National TB Control Programmes. Together these two groups need to work out simple strategies for assessing patients for lung function at the end of treatment. In countries with a high burden of TB, there will need to be sufficient numbers of trained respiratory physicians who have the necessary skills to handle the large patient load. This outreach between TB

Control Programmes and respiratory physicians must be coupled with significant advocacy and awareness efforts to ensure that the rhetoric about linkage is matched with action.

If lung function is impaired, then appropriate treatment needs to be instituted, and, ideally, patients then should be regularly followed up. Based on the cohort analysis reports of case finding and treatment outcomes, the respiratory disease burden at the end of TB treatment can be measured and plans made as to how patients can be treated and managed.

Post-treatment connections are not new to TB control programmes: for example, patients with HIV-associated TB are often discharged from TB care at the end of anti-tuberculosis treatment and referred to long term HIV care and treatment with antiretroviral therapy. Much useful research could be carried out in this context particularly in terms of understanding baseline risk factors that predict long-term lung damage which may then be prevented by earlier diagnosis and possible judicious use of anti-inflammatory drugs or immune- therapeutic approaches during anti-tuberculosis treatment.30

TB and chronic lung disease are two examples of a communicable and non- communicable disease occurring within the same patient population, although temporarily related, and we should not ignore the long term consequences of this infectious disease. To be effective we will need to harness and secure political, programmatic, clinical and research commitment for integrated and sustainable action. REFERENCES

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