Post-Tuberculosis Lung Disease: Clinical Review of an Under-Recognised Global Challenge
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Thematic Review Series
Respiration 2021;100:751–763 Received: July 17, 2020
Accepted: October 20, 2020
DOI: 10.1159/000512531 Published online: January 5, 2021
Post-Tuberculosis Lung Disease:
Clinical Review of an Under-Recognised
Global Challenge
Brian W. Allwood a Anthony Byrne b Jamilah Meghji c Andrea Rachow d, e
Marieke M. van der Zalm f Otto Dagobert Schoch g, h
aDivisionof Pulmonology, Department of Medicine, Stellenbosch University, Stellenbosch, South Africa;
bHeart
Lung Clinic, St Vincent’s Hospital Clinical School, University of New South Wales, St. Vincent, NSW, Australia;
cDepartment of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK; dDivision of Infectious
Diseases and Tropical Medicine, Medical Centre of the University of Munich (LMU), Munich, Germany;
eGerman Centre for Infection Research (DZIF), Partner Site, Munich, Germany; fDesmond Tutu TB Centre,
Department of Paediatrics and Child Health, Stellenbosch University, Stellenbosch, South Africa; gLung Center,
Cantonal Hospital St. Gallen and University of Zurich, St. Gallen, Switzerland; hTuberculosis Competence Center,
Swiss Lung Association, Berne, Switzerland
Keywords smoking. Due to a lack of controlled trials in this population,
Post-tuberculosis lung disease · Chronic obstructive no evidence-based recommendations for the investigation
pulmonary disease · Restrictive lung disease · and management of PTLD are currently available. Empirical
Bronchiectasis · Aspergillosis · Haemoptysis expert opinion advocates pulmonary rehabilitation, smok-
ing cessation, and vaccinations (pneumococcal and influen-
za). Exacerbations in PTLD remain both poorly understood
Abstract and under-recognised. Among people with PTLD, the prob-
An estimated 58 million people have survived tuberculosis ability of tuberculosis recurrence must be balanced against
since 2000, yet many of them will suffer from post-tubercu- other causes of symptom worsening. Unnecessary courses
losis lung disease (PTLD). PTLD results from a complex inter- of repeated empiric anti-tuberculosis chemotherapy should
play between organism, host, and environmental factors be avoided. PTLD is an important contributor to the global
and affects long-term respiratory health. PTLD is an overlap- burden of chronic lung disease. Advocacy is needed to in-
ping spectrum of disorders that affects large and small air- crease recognition for PTLD and its associated economic, so-
ways (bronchiectasis and obstructive lung disease), lung pa- cial, and psychological consequences and to better under-
renchyma, pulmonary vasculature, and pleura and may be stand how PTLD sequelae could be mitigated. Research is
complicated by co-infection and haemoptysis. People af- urgently needed to inform policy to guide clinical decision-
fected by PTLD have shortened life expectancy and in- making and preventative strategies for PTLD.
creased risk of recurrent tuberculosis, but predictors of long- © 2021 S. Karger AG, Basel
term outcomes are not known. No data are available on PTLD
in children and on impact throughout the life course. Risk- From the Thematic Review Series: “Tuberculosis”
factors for PTLD include multiple episodes of tuberculosis, Series Editors: Coenraad F. Koegelenberg, Christoph Lange, Otto D.
drug-resistant tuberculosis, delays in diagnosis, and possibly Schoch.
karger@karger.com © 2021 S. Karger AG, Basel Otto Dagobert Schoch
www.karger.com/res Division of Pulmonary Medicine
Kantonsspital St. Gallen
CH–9007 St. Gallen (Switzerland)
otto.schoch @ kssg.chIntroduction general population [5–7]. According to Romanowski et
al. [5], cardiovascular disease is the leading cause of the
Post-tuberculosis lung disease (PTLD) has been over- excess deaths after tuberculosis treatment completion,
looked as a significant cause of chronic lung disease for while, in contrast, a large Brazilian cohort study found
the last 50 years. In the first half of the last century, much respiratory disease to be the most frequent cause of excess
was written about post-tuberculosis complications. How- deaths in the first year after tuberculosis diagnosis [7].
ever, with the advent of effective chemotherapeutic agents The number of PTLD-related publications has increased
to treat tuberculosis, the focus of the international tuber- significantly in recent years [1] and includes data from large
culosis research and clinical community shifted towards international population-based studies investigating the
diagnostics and anti-tuberculosis treatment, with the aim global burden of chronic respiratory diseases in low- and
of improving disease survival. middle-income countries (LMICs). Taken together, there
This is now changing: the last decade has seen a re- is now convincing evidence for the existence of chronic
newed focus on the high burden and damaging impact of lung disease after pulmonary tuberculosis, which contrib-
the long-term sequelae of tuberculosis disease, for indi- utes to excess morbidity after treatment completion. Find-
vidual patients, their households, and their communities ings from the Burden of Obstructive Lung Disease (BOLD)
[1]. The first International Post-Tuberculosis Sympo- study and the PLATINO study [8, 9], together with other
sium was held in 2019 (www.post-tuberculosis.com) to clinical studies and systematic reviews, have consistently
bring together patients, clinicians, and researchers work- demonstrated an association between previous tuberculo-
ing in this area, in order to advocate for patients suffering sis disease and abnormal lung structure and function [10–
from post-tuberculosis complications and to identify ex- 13]. Several large, prospective cohort studies are underway,
isting knowledge and evidence gaps [2, 3]. PTLD was an evaluating the clinical spectrum, characteristics, and sever-
area of particular interest at the symposium and was de- ity of PTLD and its evolution over time, with their early
fined as “evidence of chronic respiratory abnormality, data supporting previous findings [14].
with or without symptoms, attributable at least in part to Despite this growing body of data, accurate estimates
previous pulmonary tuberculosis.” of the global burden and morbidity associated with PTLD
In this review, we summarise current thinking about remain limited. Such estimates have been hampered by
PTLD and highlight research priority areas. However, we the diverse clinical spectrum of PTLD presentations (see
caution that PTLD must be viewed as only one of several below), limited correlation between physiological, radio-
possible consequences that may occur after tuberculosis. logical, symptom, and outcome data with different ways
Many other organ systems can be permanently affected by of measuring disease, and heterogeneous case definitions.
tuberculosis and may result in significant disability, and Current estimates of residual spirometric abnormalities
the importance of economic, social, and psychological im- after tuberculosis vary widely according to the population
pacts, including stigmatization, cannot be overstated. under study and range from 34 to 74%, with estimates for
obstructive and restrictive physiology ranging from 18.4
to 86% and 16.1 to 29.7%, respectively [12–15]. Spirom-
Epidemiology etry alone may underestimate post-tuberculosis lung
damage when measured against either radiology or ex-
Last year, an estimated 10 million people worldwide tended physiology (e.g., diffusing capacity and plethys-
suffered from active tuberculosis disease, and the vast mography) [14, 16].
majority of these cases involved the lung. Among patients Consensus achieved at the first International Post-Tu-
who receive antimycobacterial treatment, global treat- berculosis Symposium regarding these patterns and defi-
ment success rates average 85%, and the World Health nitions, in conjunction with a number of ongoing pro-
Organisation (WHO) estimates some 58 million lives spective cohorts, will hopefully help to clarify these esti-
were saved through tuberculosis diagnosis and treatment mates. However, even with improved definitions,
between 2000 and 2018 alone [4]. post-tuberculosis patients in both high- and low-income
Emerging data suggest a high burden of residual mor- settings are frequently exposed to multiple concurrent re-
bidity and mortality among tuberculosis survivors, even spiratory exposures, including smoking, cannabis use, in-
after treatment completion. Even in high-income coun- door biomass fuels, and occupational exposures, such
tries, the observed mortality rates of tuberculosis survi- that it may remain challenging to attribute the burden of
vors are significantly higher (3–6 times) than those of the lung disease due to tuberculosis alone within this group.
752 Respiration 2021;100:751–763 Allwood/Byrne/Meghji/Rachow/
DOI: 10.1159/000512531 van der Zalm/SchochPathogenesis tor alpha and interleukins, (3) transcription factors in-
cluding hypoxia-inducible factor, and (4) enzymes such
PTLD is a result of the interplay between direct dam- as the matrix metalloproteinases (MMP) [13]. Granulo-
age caused by the tuberculosis organism in the lower re- mas are complex structures containing natural killer cells,
spiratory tract and the host immune response [13, 17]. neutrophils, and T and B lymphocytes surrounding a ne-
These processes result in airway distortion, reduced elas- crotic core of infected alveolar macrophages. The granu-
ticity, destruction of the muscular components of bron- loma may contain many or few bacilli, and rather than
chial walls, or damage to the lung parenchyma and vas- being protective to the host, it may aid mycobacterial pro-
culature, which lead to structural pathology and anatom- liferation and lung destruction [22]. Animal studies sug-
ical distortion on imaging, and abnormal respiratory gest tumour necrosis factor alpha may perpetuate necro-
physiology with abnormal spirometry, altered lung vol- sis; however; low levels may reduce macrophage activity
umes and impaired diffusing capacity [17]. The host-im- [23]. The MMPs are a group of 28 different proteases im-
mune relationship in tuberculosis is extremely complex plicated in lung injury and remodelling through the deg-
and beyond the scope of this review. However, the hetero- radation of extracellular matrix components. Hypoxic
geneity of lung damage observed between pulmonary tu- conditions have been shown to upregulate MMP-1 via
berculosis patients may be explained by variation in the hypoxia-inducible factor, which may partly explain the
nature and severity of the host immune response, patho- greater tissue destruction seen in patients with tubercu-
gen characteristics, and the host-pathogen interaction losis disease and cavities [24]. A greater understanding of
[13]. We highlight a few key concepts relevant to the de- the immunopathogenesis and of the underlying genetic
velopment of PTLD here. factors that regulate genetic factors that regulate these im-
Following inhalation, Mycobacterium tuberculosis mune responses will lead to improved respiratory out-
must evade the innate immune defences of the respira- comes in PTLD, through integration of immune-modu-
tory tract in order to progress to disease. After negotiating lating host-directed therapies in the treatment of pulmo-
airway epithelial cells, the organism may infect phago- nary tuberculosis. Finally, environmental and inhaled
cytes such as dendritic cells and alveolar macrophages, factors (e.g., smoking) may play an as-yet undetermined
where it not only survives but replicates [18]. This initi- modifying role in the host-pathogen interaction, worsen-
ates an anti-inflammatory response that blocks reactive ing outcomes after treatment completion.
oxygen and nitrogen intermediate production and reduc-
es the acidity of the phagosome, tasked with attempting
to contain the bacilli [19]. The alveolar macrophage is Clinical Patterns of PTLD
subsequently destroyed by the escaping organisms after
replication, which in turn attracts other inflammatory Patients after tuberculosis present with a wide range of
cells such as neutrophils. Meanwhile, antigen-presenting consequences from completely asymptomatic to severe
dendritic cells have travelled to lymph nodes by 6–8 weeks disability. PTLD is heterogeneous and includes pathology
to activate and recruit T lymphocytes that migrate to the affecting the airways, parenchyma, pleural, and pulmo-
site of infection to proliferate and form early granulomas nary vascular compartment. Multiple patterns of pathol-
[20]. The heterogeneity of lung damage observed between ogy can be seen within a single patient, between or within
individuals with (treated) pulmonary tuberculosis may be areas of the lung (Table 1). Post-tuberculosis bronchiec-
explained by the host-pathogen interaction and perhaps tasis can range from simple traction to actual disease of
the variability in gene coding for the complex array of the bronchi, and the natural history of this disease may be
host immune responses [13]. It is important to mention different from other forms of non-CF bronchiectasis.
at this point that the prompt initiation of (effective) anti-
tuberculosis treatment may mitigate host damage by Airway Pathology
eradication of the initiating stimulus [21]. Nonetheless, Large population-based studies, systematic reviews,
despite appropriate treatment, some patients develop and clinical cohort work suggest that previous tuberculo-
cavitation, bronchiectasis, fibrosis, and other irreversible sis disease is associated with chronic airway obstruction
structural changes. While the precise mechanisms are not [8, 10, 11, 25–29], reduced lung volumes [8, 15, 30], and
yet fully understood, there are 4 important components: mixed patterns of disease. Few data are available describ-
(1) the process of granuloma formation and resolution, ing the trajectory of spirometry volumes over time from
(2) cytokines production including tumour necrosis fac- the point of tuberculosis diagnosis, through to treatment
Post-Tuberculosis Lung Disease Respiration 2021;100:751–763 753
DOI: 10.1159/000512531a b
Fig. 1. Two patients with post-tuberculosis lung disease, exhibiting bronchiectasis predominantly in the right
lower lobe with residual nodularity bilaterally (a) and bronchiectasis predominantly in the left upper lobe, lin-
gula (b).
Table 1. Clinical patterns of PTLD
Compartment Clinical patterns Suggested definition
Airways Tuberculosis-associated obstructive Airway obstruction (FEV1/FVC ratioa b
c d
Fig. 2. Post-tuberculosis lung disease in 4 individuals demonstrating residual cavitation and bronchiectasis in the
right lung, with volume loss (a); complete left lung destruction with relatively preserved left lung volume (b);
mosaicism, residual nodularity and lobar destruction/collapse (c); and complete collapse of the left lung with
compensatory hyperinflation (d).
[11, 14, 32, 33] (Fig. 1, 2). A high burden of residual in- More data on the incidence and prognostic implications
flammatory changes including consolidation, ground of pulmonary hypertension among tuberculosis survi-
glass change, and nodules have been observed at tubercu- vors are required to elucidate the pathophysiology, out-
losis treatment completion, with metabolic activity in comes, and potential therapeutic options.
these lesions appearing to fluctuate over time on PET-CT
imaging – the clinical significance of this ongoing inflam- Aspergillus-Related Disease and Haemoptysis
mation is not yet clear [34, 35]. Bronchiectasis and fungal diseases with subsequent
haemoptysis are severe, potentially life-threatening com-
Pulmonary Vascular Disease plications after successful tuberculosis treatment, and
The burden of pulmonary vascular disease among the form an important part of the PTLD spectrum. Data on
post-tuberculosis population remains poorly defined but the burden of aspergillosis disease among tuberculosis
is thought to be secondary to lung damage and may be survivors in LMICs are limited, with mixed results, large-
common in the context of extensive pulmonary disease ly due to the challenge in containing the imaging, serol-
[36, 37], with clinicians in high-burden settings frequent- ogy, and microbiology required for diagnosis. In a recent
ly encountering patients with advanced cor pulmonale. cohort of 405 survivors of a successfully treated first epi-
Post-Tuberculosis Lung Disease Respiration 2021;100:751–763 755
DOI: 10.1159/000512531sode of pulmonary tuberculosis from Malawi, examined 50]. Data suggest that alveoli continue to increase in
at treatment completion with high-resolution computed number, size, and complexity into early adulthood [51],
tomography, some form of post-tuberculosis bronchiec- and early lung insults have been shown to lead to altera-
tasis was found in 170 (44.2%) [14]. Moderate-to-severe tions in lung growth and development and potentially
cystic bronchiectasis were found in 49 patients (12.7%), permanent loss of lung function [49, 52]. The extent to
with a higher prevalence in HIV-negative (18.9%) as which insults to the developing lung are associated with
compared to HIV-positive (8.5%) patients. Mycetoma increased risk of chronic respiratory illnesses in later life
was present in 5 (1.3%) patients, and Aspergillus IgG was depends on the underlying cause, timing, and signifi-
found in 2 (0.8%) [14]. cance of such insults [53]. Numerous cohort studies have
After inhalation of Aspergillus species, early innate im- shown that there is an association between lung function
mune reaction activates alveolar macrophages and epi- in childhood and adulthood [54, 55], and lower respira-
thelial cells to trigger neutrophil recruitment and reduce tory tract infections during infancy have been shown to
fungal burden [38]. In pre-existing structural lung dam- reduce lung function in childhood [56, 57]. A longitudi-
age, for example, persistent cavitary lesions after healed nal study by Githinji and colleagues [58] in HIV-infected
tuberculosis, chronic necrotizing pulmonary aspergillo- adolescents recently found that prior history of tubercu-
sis with slowly progressing invasive fungal pneumonia losis or severe lower respiratory tract infections were in-
and inflammatory necrosis are classical sequelae [38, 39]. dependently associated with consistent lower lung func-
On a world-wide scale, it has been recognized that previ- tion trajectories. This finding suggest tuberculosis has an
ous tuberculosis is by far the most common risk factor for impact on lung function; however, prospective and more
chronic pulmonary aspergillosis (CPA), with some re- detailed data about type and severity of tuberculosis epi-
searchers estimating 5-year prevalence rate of 18% after sode and its impact on lung health are required.
tuberculosis treatment [40]; however, estimates vary The pathophysiology of paediatric pulmonary tuber-
widely, and evolution over time may be an important fac- culosis is different from adult-type tuberculosis disease,
tor [14, 41, 42]. In cases of CPA, chronic inflammation with less destructive cavitary disease as seen in adults and
leading to increased vascularization with bronchial arter- adolescents. Nevertheless, paediatric pulmonary tuber-
ies and the feared complication of profound haemoptysis culosis represents a wide disease spectrum, both in terms
and asphyxia may result. Diagnostic criteria for CPA in- of severity and typical patterns, which is often related to
clude the presence of respiratory or constitutional symp- age at disease presentation. Children may present with
toms for at least 3 months, suggestive radiological find- uncomplicated lymph node disease, complicated lymph
ings and serological or microbiological evidence of Asper- node disease with airway compression and lobar col-
gillus[43]. lapse, bronchopneumonia, miliary tuberculosis, adult-
type cavitary disease, pleural effusion, or a peripheral
opacity with associated lymph node enlargement [59,
Childhood PTLD and Lung Development 60]. Young infants are particularly at risk for severe in-
trathoracic and disseminated tuberculosis associated
An estimated 1.1 million childrenPeak FEV1
Impact TB on developing lung?
? Symptomatic respiratory illness
Further division and growth alveoli
Alveolar
Birth 5 10 15 20 25 30 35 40 50
Age, years
Fig. 3. Lungs develop throughout childhood until they reach a pla- time. Early life insults can cause de-tracking of lung function. We
teau around the age of 20 years. Alveoli appear from week 29 of hypothesize that tuberculosis disease early in life might cause de-
gestation and continue to form until 2–4 years after birth. After tracking of lung function, which might remain diminished
that, alveoli continue to increase in number, size, and complexity throughout childhood. This could mean that these individuals will
until early adulthood. It is known that lung function tracks be prone to symptomatic respiratory disease earlier in life. FEV1,
throughout life, meaning that it remains in similar percentile over forced expiratory volume in 1 s.
include lung function measurements regardless of symp- Adults previously treated for tuberculosis in high tu-
toms and social determinants for lung health. berculosis-burden settings have an increased risk of de-
veloping incident tuberculosis, compared to those who
are tuberculosis naive, including both disease relapse and
Clinical Outcomes Associated with PTLD recurrence [68]. The extent to which this is driven by un-
derlying impaired immune function in damaged lung tis-
Prospective data on the long-term outcomes of PTLD sue or underlying socioeconomic risk factors and sus-
remain limited, and no validated prognostic scores are yet tained increased exposure also remains unclear [69]. Al-
available. However, cross-sectional data from tuberculo- though population-level data suggest increased mortality
sis survivors suggest a high prevalence of chronic respira- among tuberculosis survivors compared to tuberculosis-
tory symptoms some years after treatment completion, naive adults [5–7], the extent to which PTLD contributes
including breathlessness and chronic cough [62, 63]. to this excess mortality remains unclear.
These symptoms can be stigmatizing and lead to repeated
investigation or perhaps empirical re-treatment for sus-
pected recurrent tuberculosis disease [64, 65]. The fre- Risk Factors for PTLD
quency and severity of respiratory exacerbations among
those with residual structural and physiological abnor- As described above, reasons for the heterogeneity of
malities are poorly described, but many face reduced pattern and severity of PTLD between tuberculosis pa-
quality of life and impaired functional capacity [66], and tients are not known, but likely involve host, pathogen,
those with extensive PTLD and destroyed lung tissue ex- and environmental factors [13]. Investigation of these
perience high rates of hospitalization and respiratory-re- risk factors is ongoing. HIV co-infection is anticipated as
lated mortality [67]. a key effect-modifier in the relationship between tubercu-
Post-Tuberculosis Lung Disease Respiration 2021;100:751–763 757
DOI: 10.1159/000512531losis disease and residual lung damage, and the extent of tions should evaluate impact on residual lung pathology
PTLD in HIV co-infected patients likely reflects a balance as well as their effect on reducing TB-related mortality.
of the protective effect of low CD4 counts and impaired
immune responses to mycobacterial infection at tubercu- Minimising Tuberculosis-Related Lung Damage
losis diagnosis [70–72], with the impact of immune re- Once tuberculosis disease is established, early diagno-
constitution for those initiated on antiretroviral therapy sis and effective treatment are crucial for limiting the lung
concurrently with tuberculosis treatment [13]. Prelimi- damage caused [21]. Delayed diagnosis and longer dis-
nary findings suggest that HIV co-infection may be asso- ease durations in multidrug-resistant tuberculosis are
ciated with reduced severity of PTLD [14, 73], but these likely important factors in the observed greater pulmo-
data are limited and require confirmation in further stud- nary function impairment in drug-resistant compared to
ies. drug-susceptible tuberculosis [79].
More severe lung damage is observed in the context of Smoking cessation interventions have proven efficacy
multidrug-resistant tuberculosis [74, 75], with recurrent for asthma and COPD. In a non-randomized study from
episodes of disease [72], and where tuberculosis diagnosis Malaysia, tuberculosis patients who received smoking
is delayed [70, 71, 76]. The influence of concurrent respi- cessation advice and nicotine replacement therapy had
ratory exposures is less clear. Tobacco smoking has been earlier sputum smear conversion and better quit rates and
shown to have a positive association with PTLD in few treatment outcomes at 6 months [80]. Even though no
studies [72, 77]. Environmental factors such as indoor air specific study for the PTLD population exists, smoking
pollution or occupational risks and their distribution in cessation should be an integral part in the management
the respective populations may worsen PTLD and/or may of PTLD.
lead to concurrent lung damage, thereby explaining the Because excessive inflammation may contribute to
severity, heterogeneity, and inconsistency of respiratory lung damage, corticosteroids during tuberculosis treat-
outcome data, which were observed in specific subgroups ment have been hypothesized to reduce lung function
such as females [71, 73] and miners [72, 76]. loss. However, among 118 patients with pulmonary tu-
berculosis given systemic corticosteroids in addition to
tuberculosis treatment, there was no change in airflow
Management obstruction at 1 year follow-up, compared to tuberculosis
treatment alone [81]. Thus, corticosteroids cannot be ad-
The lack of clinical intervention studies in this patient vocated for. Given the broad immunosuppressive action
population means that there are currently no evidence- of steroids and their adverse metabolic and cardiovascu-
based international guidelines for the management of lar effects, a more precise method of immunomodulation
PTLD [1]. This represents a challenge for both treating may still hold promise. Preliminary studies show that
clinicians and patients who experience persistent and dis- metformin use among patients on tuberculosis treatment
abling respiratory symptoms despite mycobacteriological resulted in a reduction to the levels of MMP 1, 2, 3, 9, and
cure. While evidence-driven guidelines are urgently 12, which correlate to the degree of pulmonary involve-
needed, expert opinions must be sought to bridge the ment and degree of cavity formation [82]. To date, there
management gap. We discuss below some of the treat- are no randomized trials that assess lung function out-
ment options available and identify the (many) gaps in comes following the use of metformin among patients
the published literature to date. with pulmonary tuberculosis; however, other host-di-
rected therapies are underway.
Tuberculosis Disease Prevention
Undoubtedly, the most important step in the manage- Managing Established PTLD
ment of PTLD should be its prevention. Where possible, For those with established PTLD, treatments that are
providing prophylactic tuberculosis treatment to those widely used for other chronic lung diseases such as COPD,
people with latent infection at high risk of progression to bronchiectasis, asthma, and pulmonary fibrosis may be of
disease including household contacts and people living benefit; however, specific evidence in PTLD remains
with HIV [78] has potential benefits for population lung lacking. Outpatient pulmonary rehabilitation has been
health as well as tuberculosis control. The upstream social shown to be widely accepted by patients and results in
determinants of tuberculosis disease must also be ad- improved symptom scores and health-related quality of
dressed. Studies evaluating the impact of such interven- life in tuberculosis survivors [83].
758 Respiration 2021;100:751–763 Allwood/Byrne/Meghji/Rachow/
DOI: 10.1159/000512531 van der Zalm/SchochInhaled bronchodilators may be useful in the manage- Exacerbations of PTLD are a priority area for research. ment of PTLD in patients with airflow obstruction to re- Little data exist to inform management, or policy deci- duce symptoms of breathlessness and improve (or pre- sions, yet exacerbations are likely to both identify individ- vent) a decline in lung function. However, there are no uals at increased risk and those who disproportionally ac- long-term randomised trials to inform efficacy, effect cess medical care. As noted above, patients previously size, or medication choice. A single randomized trial of treated for tuberculosis are at increased risk of recurrence, PTLD patients with moderately severe disease found that and this should be actively excluded with exacerbations. daily use of the long-acting beta agonist inhaler, inda- However, exacerbations of PTLD are frequently and erro- caterol (dose 150 μg), resulted in a significant improve- neously re-treated with empiric treatment for “recurrent ment in lung function (trough FEV1) and dyspnoea score tuberculosis” without microbiological evidence, exposing at 8 weeks compared to placebo, but no improvement in patients to harm [65]. Adding complexity, Xpert nucleic quality of life was achieved [84]. A smaller, non-random- amplification tests yield a 14% (1 in 7) false-positive rate in ized study demonstrated significant improvements in re-treatment cases and may remain positive for years after lung function from baseline among tuberculosis survi- successful tuberculosis treatment completion [91]. Thus, vors with destroyed lung and FEV1
daily practice in LMICs with a high PTLD burden, many compared to those with similar pulmonary risk factors or
of these therapeutic and surgical options are either un- healthy controls [30, 100–103]. Preliminary modelling
available or unaffordable, limiting clinician’s choices. data suggest that inclusion of post-tuberculosis morbid-
Major haemoptysis, defined by a loss of 300–600 mL ity and mortality may increase estimates of disability-ad-
of blood within 24 h and/or blood causing airway ob- justed life years by at least 54% (and potentially as much
struction, is a major life-threatening emergency [94]. It is as 174%), when permanent disability and early mortality
not only a well-known and feared complication of active are also considered [69]. Further, social stressors such as
pulmonary tuberculosis and of chronic bronchiectasis of discrimination and stigma are common among people
any cause, but often the presenting syndrome of an un- with tuberculosis and increasingly recognized as factors
recognized CPA. Under these circumstances, clinicians that compromise mental health, quality of life, and tuber-
frequently use bronchial artery embolization to address culosis treatment outcomes long term [2, 3, 104]. There
active bleeding, although recurrence is common [95, 96]. is an urgent need for robust epidemiological and large
Other interventional or complex surgical options have multi-country cohort studies on the economic and psy-
also been applied with good results [97, 98]. Unfortunate- chosocial impact beyond tuberculosis cure.
ly, for many patients with PTLD-associated haemoptysis,
surgical resection is not an option due to either the over-
whelming extent of disease or poor physiological reserve. Future and Conclusion
For now, it seems reasonable that, as in other forms of
chronic lung diseases, smoking cessation, vaccination, It is true to say that currently we have more questions
and pulmonary rehabilitation should be considered in a than answers around PTLD, its determinants, natural his-
PTLD management plan. However, well-designed ran- tory, and management. Yet in recent years, there has been
domized trials are urgently required to identify feasible an expansion of interest in this complex condition, with
and scalable interventions to improve the outcomes of the realization that the high prevalence of PTLD in
PTLD patients. In order for these trials to move forward, LMICs, where 80% of the world’s population resides, may
consensus is needed on how patterns and severity of in fact make it an extremely important form of chronic
PTLD are defined, how disease is measured, and out- lung disease and respiratory impairment worldwide.
comes to be evaluated over time. Several priority research areas have been identified.
First, epidemiological research is needed to better define
the risk factors and predictors for PTLD, as well as long-
Economic, Social, and Psychological Impact term functional outcomes, and most importantly causes
and predictors of the observed premature mortality in tu-
It is well known that tuberculosis is driven by poverty berculosis survivors. This includes the burden and nature
and is associated with a catastrophic financial burden on of PTLD in children, and its long-term effects on the in-
affected, mostly low-income, households [99]. High pa- dividual’s lung health throughout life. Second, a better
tient costs not only worsen the financial situation of house- understanding of the immunological drivers of PTLD is
holds but also negatively influence tuberculosis treatment needed, combined with prevention and host-directed
outcomes [100]. The need to mitigate catastrophic costs strategies during treatment, to avoid or minimize damage
associated with tuberculosis disease has been prioritized during tuberculosis disease. Third, research into effective
within The End TB agenda. People cured of tuberculosis treatment of the various PTLD phenotypes is urgently
may find themselves with long-term socio-psychological needed, for those with established PTLD in whom pri-
consequences of the acute disease episode, and PTLD may mary prevention is too late. Finally, it must be remem-
result in ongoing economic, social, and psychological dis- bered that PTLD is only one of many complications after
tress. However, data on these impacts of tuberculosis, be- tuberculosis, which significantly affects the economic, so-
yond treatment completion, remain limited and their im- cial, and psychological well-being of individuals, families,
pact on long-term well-being is poorly defined. and societies. This broader impact needs to be defined
There are currently no recommendations for the eval- with a view to designing effective intervention strategies
uation of mental or health-related quality of life in people to minimise this impact.
beyond tuberculosis treatment. There is limited evidence In conclusion, PTLD, for many decades forgotten, is
that people who are microbiologically cured of tubercu- now being recognised as an important cause of chronic
losis have substantially lower health-related quality of life lung disease globally, particularly in LMICs. While there
760 Respiration 2021;100:751–763 Allwood/Byrne/Meghji/Rachow/
DOI: 10.1159/000512531 van der Zalm/Schochis an emerging literature on PTLD, collaborative research Funding Sources
is urgently needed to inform our understanding of the
There was no funding related to the preparation of the manu-
natural history, prevention, and treatment of PTLD and script.
to allow for the development of much needed evidence-
based management guidelines.
Author Contributions
Conflict of Interest Statement All authors contributed equally to the writing and preparation
of the manuscript.
B.W.A. has received honoraria from Novartis. M.M.Z. is part
of the EDCTP2 programme supported by the European Union
(Grant No. 99726 TB-Lung FACT TMA 2015 CDF – 1012). All
other authors have no conflicts of interest to declare.
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