Journal of Clinical Tuberculosis and Other Mycobacterial Diseases 3 (2016) 1012

Contents lists available at ScienceDirect

Journal of Clinical Tuberculosis and Other

Mycobacterial Diseases
journal homepage: www.elsevier.com/locate/jctube

Long term complications after completion of pulmonary tuberculosis

treatment: A quest for a public health approach

Background
Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis, remains a major public health problem globally. In 2014,
more than 9.6 million people are estimated to have fallen ill with
TB while 1.5 million people died of the disease [1]. The disease
is closely associated with poverty, which explains the high rates
of TB in countries or in geographic areas within countries where
poverty rates are high. The disease is also closely linked with HIV
which has been the major driver for the high rates of TB in many
countries of Sub Saharan Africa [25]. TB is also associated with
other immunosuppressive states such as diabetes mellitus and tobacco smoking and it is currently postulated that the next wave
of the global TB epidemic will be driven by these emerging health
threats [68].
Over the last two decades treatment of TB has signicantly improved and 61 million patients were successfully treated for TB
globally since 1995 [1]. However such successful treatment of TB
based on either documentation of bacteriological clearance of Mycobacterium tuberculosis bacilli from the involved site or completion of the prescribed drug dose does not assess structural and
functional effects on the involved organ which is the hallmark
of the pathology of TB [9]. While any part of the body may be
affected by TB, pulmonary TB is the most common site of disease primarily because the Mycobacterium tuberculosis transmits
through the respiratory route. Thus TB is a major contributor to
the overall burden of lung disease in the world. It may be that the
majority of patients with pulmonary TB, the resulting structural
and functional damage is small and will not pose any signicant
long term lung health risk, however, for some patients an episode
of pulmonary TB may herald the beginning of chronic respiratory
disease and pose a signicant risk of reduced longevity despite the
successful treatment of their disease [10]. In this paper we argue on the importance of a programmatic approach to address the
long term complications of PTB and suggest mechanisms to prevent, rapidly identify and provide appropriate long term care for
patients with post TB chronic lung disease.
Long term complications of pulmonary TB
Of the 6.3 million notied cases of TB that occurred in 2014,
81% had lung TB [1]. Based on recent trends in treatment outcomes, about 86% of the new and relapse PTB cases notied
in 2014 were successfully treated. However, several studies have
http://dx.doi.org/10.1016/j.jctube.2016.03.001
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demonstrated persistence of symptoms, reduced quality of life,

abnormal radiological ndings and impaired pulmonary function
tests in patients successfully treated for PTB [1114]. Pulmonary
TB is associated with various long term lung complications including lung scarring (brosis), bronchiectasis, Chronic Pulmonary
Aspergillosis (CPA), air way stenosis and Chronic Obstructive Pulmonary Disease (COPD) [15] and it may even be a risk factor for
lung cancer [16]. There is however very limited data on the full
spectrum of these complications in cohorts of patients treated for
PTB. For many of these complications the published literature is
based mostly on case reports and small case series. In one such
study, Neeta Singh et al report on 51 multidrug resistant TB patients who were successful treated. Of these, 78% had persistent
respiratory symptoms, 98% had residual radiological sequelae, 96%
had ventilatory defects with 66% of those with ventilatory defects
exhibiting a mixed type of ventilatory abnormality while 19% had
pure restriction and 11% had pure obstruction after completion of
treatment [17]. In a similar small prospective study among 25 patients with drug susceptible TB, the investigators observed resolution of exudative lesions and adenopathy at completion of treatment while leaving permanent features that included emphysematous change (36%), bronchiectasis (40%), bronchovascular distortion(56%), and brotic bands (64%). Structural and functional residual changes were more common in patients with cavitary than
non-cavitary disease [18].
Towards the end of the days of the sanatoria treatment for TB,
high rates of obstructive airways disease were observed in patients
exiting sanatoria. In one study as much as 62% of white men exiting a sanatorium were found to have spirometric evidence of obstructive airways disease [19]. Other studies have replicated these
ndings in addition to documenting restrictive and combined restrictive and obstructive ventilatory defects and a higher frequency
of lung function impairment with repeated episodes of lung TB
[2022]. In a study among South African miners with a history of
tuberculosis, lung function impairment was identied in 18%, 27%,
and 35% of subjects after one, two, or three episodes of the disease
[21]. In a case-control study using pulmonary function tests of patients with culture-conrmed pulmonary tuberculosis and a comparison group with latent tuberculosis infection, survivors of TB
were 5.4 times more likely to have a decline in Forced Expiratory
Volume in 1 s (FEV1) and Forced Vital Capacity (FVC) than were
subjects with Latent Tuberculosis Infection (LTBI) after adjusting
for risk factors such as age, Body Mass Index, country of birth, gender, and smoking [22]. In a population based Latin American study

/ Journal of Clinical Tuberculosis and Other Mycobacterial Diseases 3 (2016) 1012

that investigated obstructive Lung disease in the community, the

overall prevalence of airow obstruction dened as FEV1/FVC ratio
post-bronchodilator of less than 0.7 was 30.7% among those with
a history of tuberculosis, compared with 13.9% among those without this history [23]. A recent systematic review examining the relationship between pulmonary TB and COPD in community based
studies found a consistent association across the two community
based studies identied with odds ratios ranging from 1.78 to 6.31,
between a reported history of TB and Spirometry conrmed COPD
among people aged 40 years and above. The risk of COPD was correlated to the TB incidence of the country [24]. This subject has
recently received a lot of attention in the realm of the Burden of
Lung Disease (BOLD) initiative [25,26]. Thus the experience of an
episode or more of lung TB poses a signicant risk of obstructive,
restrictive and combined ventilatory lung defects which may be
progressive leading to progressive deterioration of quality of life
and early mortality.
Bronchiectasis is dened as the permanent dilatation and distortion of the airways. It is clinically characterized by persistent
cough with the production of sputum which in untreated patients
is often copious, purulent and associated with recurrent episodes
of hemoptysis. Bronchiectasis is a risk factor for community acquired pneumonia. Robust studies on the incidence of post TB
bronchiectasis are unavailable, however in a review of this subject Toni Jordan et al indicated that the incidence of bronchiectasis
post PTB was in the range of 1965% and in etiological studies of
bronchiectasis, TB is often the most common identied cause especially in TB endemic settings [27]. The systematic review conducted by Byrne Al et al found a signicant association between
lung TB and bronchiectasis [24].
Aspergillus lung disease may present in three ways: invasive
Aspergillosis, a serious life threatening lung disease that presents
as severe pneumonia; Allergic Bronchopulmonary Aspergillosis
(ABPA) presenting as the syndrome of severe asthma with fungal
sensitization often with central Bronchiectasis and CPA which in
post TB patients commonly presents as an Aspergilloma/mycetoma.
In post TB CPA, the fungus, most commonly Aspergillus fumigatus,
colonizes cavities in the lung left behind by the TB. Precise estimates of the proportion of PTB patients who eventually develop
CPA are not available and neither have the risk factors for this
disease been fully identied. Based on studies conducted in the
United Kingdom in the 1960s where rates of radiologically identied Aspergilloma of up to 22% were found in patients with residual cavities following treatment for TB, Denning et al estimated
that the incidence of CPA in patients previously treated for PTB
globally was 372,0 0 0 in 2007. The cumulative ve year prevalence
was estimated to be 1, 174 0 0 0, 852 0 0 0 and 1 372 0 0 0 cases at
15%, 25% and 10% annual attrition rates, respectively implying that
CPA post PTB is a major global public health threat [28]. However,
it is evident that the inputs into this modeling need to be updated
with more recent clinical observations.
Characteristically CPA, presenting as a simple Aspergilloma will
manifest with the symptoms of prolonged malaise, cough and recurrent hemoptysis which can be massive and life threatening. The
diagnosis of CPA is dependent on clinical suspicion, availability and
access to chest imaging with plain chest x-rays and CT scans and
availability of serological testing for Aspergillus precipitins (IgG antibodies). In many parts of the world where TB is endemic these
diagnostic necessities are not routinely available. Similarly, itraconazole, which has in recent studies been found to be ecacious
in attenuating the clinical disease associated with CPA [29], may
also not be available in low resource, high TB burden settings. The
denitive treatment of CPA presenting as a simple Aspergilloma
is surgical excision. The availability of cardiothoracic surgical services may also be severely limited in low resourced and high TB
endemic settings.

11

Other long term complications of PTB include airway stenosis

(tracheal or bronchial stenosis) and stulae formations (tracheaesophageal stula) all of which threaten life. These complications
have mostly been reported as case reports or small case series and
therefore their incidence in patients who suffer PTB is currently
unknown.

What needs to be done?

Robust epidemiological studies to determine rates of occurrence
and risk factors for these complications are lacking which has contributed to the lack of attention given to these problems by national TB control programs. Of the many possible complications of
PTB, COPD, Bronchiectasis and CPA stand out as the most common
problems that occur in signicant numbers to require public health
attention at the global and country level.
The WHOs ambitious End TB Strategy approved by all countries
[30] targets to reduce TB deaths by 90% in 2030 with intermediate milestones of reduction by 35% in 2020 and 75% in 2025. We
argue that TB mortality must take into account deaths that occur
following successful bacteriological treatment of PTB which means
that deaths due to the long term complications of PTB will need
to be factored into the quantication of deaths from TB. We therefore propose that the public health implications of the long term
complications of PTB with a special emphasis on COPD, bronchiectasis and CPA, should be explored and appropriate public health
measures to deal with them elaborated and implemented. Here
we propose a list of actions that the global TB community including national TB programmes need to undertake to elaborate
and evolve appropriate public health programs to confront these
problems.
Firstly, we propose that the spectrum and magnitude of post
TB chronic lung disease with a special focus on COPD, Bronchiectasis and CPA should be clearly established through the conduct of
robust epidemiological studies. Large multi country cohort studies
may be used for this purpose. This could in the long run help to
establish the cumulative incidence and the full spectrum of chronic
respiratory disease post PTB and to characterize patients likely to
suffer these clinical problems. Such understanding of the magnitude and spectrum of chronic respiratory disease post PTB can be
used to advocate for resources to manage PTB beyond cure of TB
as currently dened.
Secondly, we suggest that the minimum set of clinical evaluations and interventions that need to be carried out at the end
of treatment for PTB be dened. As discussed above the current
practice of using bacteriological clearance of Mycobacterium tuberculosis or completion of treatment as a measure of treatment success is likely to be missing a signicant proportion of patients who
need to continue to remain in care as a result of the episode of
PTB. This evaluation should include assessment of structural and
functional integrity of the lungs and associated symptoms and
how these changes are impacting the quality of life of affected
individuals. It is also important to assess patients for risk of and
presence of fungal colonization or infection at the end of their
treatment in order to identify those who need additional care for
CPA.
Lastly, we propose that implementation science should be used
to develop and assess the ecacy, effectiveness and costs of public health approaches for the delivery of care packages for post
TB chronic respiratory disease. These care programs may be modeled along those currently elaborated for other chronic respiratory
and non- respiratory diseases. Lessons learnt from the provision of
chronic care using the Practical Approach to Lung Health (PAL [31]
may be used to inform the design of care programs for chronic
respiratory disease resulting from PTB.

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/ Journal of Clinical Tuberculosis and Other Mycobacterial Diseases 3 (2016) 1012

Conclusion
Exploring mechanisms to address the long term complications
that follow treatment of pulmonary TB is long overdue and will
signicantly contribute to the quality of care for TB patients. In
many PTB patients successful completion of TB treatment or bacteriological cure is not the end of the need for care. Systematic
generation of data is needed to develop approaches for the prevention, care and treatment of patients with post TB chronic lung
disease. The global TB community cannot afford to continue ignoring this facet of TB care and control and needs to act with urgency
to address what is likely to be a huge public health burden.

Jeremiah Chakaya
Department of Medicine, Therapeutics, Dermatology and Psychiatry,
Kenyatta University, Nairobi, Kenya
Bruce Kirenga
Division of pulmonary medicine & lung institute Makerere
University, Kampala, Uganda
Haileyesus Getahun
Global TB Programme, WHO, Geneva, Switzerland.
Corresponding author:
E-mail address: chakaya.jm@gmail.com (J. Chakaya)

Received 9 February 2016

Accepted 4 March 2016
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