Post TB Lung
Post TB Lung
Post TB Lung
Post-tuberculosis lung disease (PTLD) is emerging as a significant area of global interest. As the number of patients surviving
tuberculosis (TB) increases, the subsequent long-term repercussions have drawn increased attention due to their profound
clinical and socioeconomic impacts. A primary obstacle to its comprehensive study has been its marked heterogeneity. The
disease presents a spectrum of clinical manifestations which encompass tracheobronchial stenosis, bronchiectasis, granulo-
mas with fibrosis, cavitation with associated aspergillosis, chronic pleural diseases, and small airway diseases—all persistent
consequences of PTLD. The spectrum of symptoms a patient may experience varies based on the severity of the initial infec-
tion and the efficacy of the treatment received. As a result, the long-term management of PTLD necessitates a detailed and
specific approach, addressing each manifestation individually—a tailored strategy. In the immediate aftermath (0–12 months
after anti-TB chemotherapy), there should be an emphasis on monitoring for relapse, tracheobronchial stenosis, and smoking
cessation. Subsequent management should focus on addressing hemoptysis, managing infection including aspergillosis, and
TB-associated chronic obstructive pulmonary disease or restrictive lung function. There remains a vast expanse of knowledge
to be discovered in PTLD. This review emphasizes the pressing need for comprehensive, consolidated guidelines for manage-
ment of patients with PTLD.
agement, supplemented with additional narrative reviews secretion can induce an intensified inflammatory response,
incorporating search terms like “pulmonary tuberculosis”, further damaging lung tissues [19]. A study comparing TB
“tracheobronchial stenosis”, “endobronchial tuberculosis”, patient sera indicated elevated TNF-α levels in severe cases
“pulmonary function”, “bronchiectasis”, “pulmonary as- than in mild-to-moderate ones (p < 0.05) [20]. Matrix metal-
pergillosis”, “cavitation”, “hemoptysis”, “rehabilitation”, loproteinases (MMPs), encompassing 25 potent proteases,
and “vaccination” enabled us to gain a holistic understand- play a pivotal role in lung remodeling during TB. Elevated
ing of PTLD. This methodology was particularly necessary MMP-1 gene expression in sputum and bronchoalveolar
given that emphasis on PTLD has only recently increased. lavage fluid samples was found to correlate with alveolar
We found that there is a limited number of systematic re- destruction in lung granulomas and increased collagen
views available for quality assessment or comparison, and breakdown [21]. Interestingly, MMP-1 concentrations were
there is a notable shortage of randomized controlled trials 8.5-fold higher in patients with pronounced lung disease
that address the various subtypes of PTLD, including bron- compared to those with milder afflictions [21]. Additional-
chiectasis, cavitation, aspergillosis, chronic obstructive pul- ly, a study showed that the median value of serum MMP-1
monary disease (COPD), and tracheobronchial stenosis—all was significantly higher in post-TB patients with sequelae
persistent outcomes of PTLD [4,11-16]. This review delves than in post-TB patients without sequelae [22]. Owing to
into the multifaceted nature of PTLD, its personalized as- the distinctive characteristics of granulomas, cavitations,
sessment and management strategies, and points towards and fibrosis, which are further influenced by unique healing
future research directions. capacities and external environmental factors such as tobac-
co smoking, pollution, and concomitant viral/bacterial infec-
tions, the pathogenesis of TB exhibits pronounced hetero-
PATHOGENESIS OF TB AND THE geneity. The subsequent section delves into the prevalent
HETEROGENEITY OF PTLD features of PTLD, given its diverse clinical manifestations.
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Seo W, et al. Post-tuberculosis lung disease
attributable at least in part to previous pulmonary tuberculo- and remains an area awaiting further elucidation.
sis” [6]. This suggests that PTLD encompasses a spectrum of
post-infectious sequelae, and TB survivors potentially fall un-
der the PTLD category [15]. According to Menzies et. al.[23], DIFFERENT CLINICAL CHARACTERISTICS OF
the estimated disability-adjusted life-years stood at 12.1 per PTLD
TB case, with 28% spanning 15 or more years following the
initial TB episode. A systemic review on long-term, all-cause Complications in large airways
mortality in PTLD indicated that the combined standardized Airway-related morbidities can be classified into those af-
mortality ratios for individuals with confirmed treatment fecting the large airways, including the trachea, main bron-
completions or cures, in comparison to controls, stood at chi, and bronchi, and those involving the small airways,
3.76 [7]. Remarkably, even in high-income countries, fully specifically those less than 2 millimeters in diameter. In the
treated TB remained associated with a heightened mortality acute phase of infection, the anatomy of these airways may
risk. There was a marked increase in all-cause deaths among be stenotic, distorted, or enlarged due to extensive wall in-
post-treatment TB patients compared to controls (20.7 vs. juries. Damage to the small airways often results in airflow
3.1%) [24]. A recent cohort study involving 82,098 adult TB limitation, which can be quantified using spirometry (Table 1).
survivors showed a 1.62-fold higher mortality risk in TB survi-
vors compared to controls, even after adjusting for potential Tracheobronchial stenosis
confounders [25]. Given that TB pathophysiology implicates Endobonchial tuberculosis (EBTB) incidence is reported to
both the small and large airways, lung parenchyma, pleura, range from 10% to 38.8% among TB patients [28]. Intrigu-
and even pulmonary vessels, the clinical manifestations of ingly, in South Korea, EBTB demonstrates a predilection for
PTLD are varied. This variation can even be discerned from younger female TB patients, specifically those in their 20s
one lobe to another within a single patient, adding layers and 30s [28-30]. To establish a diagnosis, bronchoscopic
of complexity to the disease profile [26,27]. Consequently, examination, complemented by microbial and histopatho-
understanding the epidemiology of PTLD proves challenging logical confirmations, is essential. Subsequent computed
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The Korean Journal of Internal Medicine Vol. 39, No. 1, January 2024
tomography (CT) scans are also recommended, as EBTB (Table 1) [35]. While the predominant infectious causes of
often eludes detection in plain chest radiographs [31]. bronchiectasis differ globally, TB stands out as one of the
Hallmark bronchoscopic features encompass actively case- principal post-infectious etiologies, especially in countries
ating, edematous-hyperemic, fibrostenotic, tumorous, and with a high prevalence of TB [36-39]. A cross-sectional
ulcerative types (Fig. 1). While most lesions demonstrated study, drawing on data from the Korean National Health
improvement within a 5-month treatment period, around and Nutrition Examination Survey from 2007–2009, re-
two-thirds of those with actively caseating and edema- vealed 43.5% of bronchiectasis patients had a prior history
tous-hyperemic types metamorphosed into the fibrostenot- of pulmonary TB (Fig. 3A). To put this into perspective, ap-
ic type after anti-TB therapy [32]. The concomitant use of proximately half of bronchiectasis patients in Korea can be
corticosteroids with anti-TB treatment to avert tracheobron-
chial stenosis remains a subject of debate for adult EBTB
patients. However, initiating corticosteroid treatment during
the early phase (symptoms lasting less than 3 months) may
Trachea 50%
offer therapeutic benefits [33,34]. Upper 27%
RUL 65%
Despite therapeutic efforts, between 60 and 95% of cas-
es exhibited tracheobronchial stenosis or strictures to vary- Right main 26% Left main 26%
bronchi (87%), right upper lobe bronchus (65%), and the Lingular 5%
trachea (50%) (Fig. 2). Conducting bronchoscopic assess-
RML 17%
ments during and after anti-TB therapy can aid clinicians in
identifying further progression of stenotic complications.
When irreversible EBTB complications manifest, clinicians
might consider interventional bronchoscopy and surgical in-
terventions, as discussed in subsequent sections.
A B C
Figure 1. Hallmark bronchoscopic features of endobronchial tuberculosis patients. (A) Actively caseating type with a whitish cheese-like
material (arrow heads), edematous-hyperemic type with swollen and hyperemic mucosal features (solid arrow), (B) fibrostenotic type with
narrowing of the bronchial lumen due to fibrosis, and (C) ulcerative type with mucus secretion collected.
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Seo W, et al. Post-tuberculosis lung disease
classified as PTLD patients with subsequent complications. 1.03–2.69; p = 0.038) [41]. The increased prevalence of he-
Bronchiectasis, like EBTB, is also recognized as an evolving moptysis in post-TB bronchiectasis isn’t yet fully understood.
manifestation during the course of TB infection. Notably, However, this group often exhibits marked reductions in
CT scans have shown emergent bronchiectasis in roughly lung function, as demonstrated by diminished forced expi-
a quarter of active TB patients [40]. Bronchiectasis develops ratory volume in one second (FEV1) and greater evidence of
secondary to adjacent parenchymal destruction and fibrosis, bronchial artery hypertrophy—a major hemoptysis contrib-
leading to traction bronchiectasis (Fig. 3A). However, it can utor [41-44]. It’s conceivable that severe symptoms, such as
also develop in conjunction with EBTB due to tracheobron- consistent coughing and sputum production, could intensify
chial stenosis with its distal bronchial dilatation, which sub- pressures on nearby blood vessels. This may heighten the
sequently becomes bronchiectasis. likelihood of vessel rupture, leading to hemoptysis.
Hemoptysis is frequently associated with bronchiectasis,
occurring in 22–25% of afflicted patients [36,37]. A mark- Small airway complications
edly higher proportion of bronchiectasis patients admitted Obstruction of small airways can be quantified post-bron-
due to hemoptysis have a history of pulmonary TB, with chodilator using spirometry. A population-based multi-
an odds ratio (OR) of 1.66 (95% confidence interval [CI], center, cross-sectional study, the Burden of Obstructive
A B C
Figure 3. Computed tomography scans of post-tuberculosis lung disease patients with various clinical and radiologic features. (A) Post-tu-
berculosis lung disease patient with bronchiectasis (arrows) and fibrotic changes, (B) post-tuberculosis lung disease patients with multiple
granulomas, remaining small nodularity, and fibrotic changes with traction of pleural, and (C) totally destroyed left upper lung with sur-
rounding pleural wall thickenings (arrows).
a)
Table 2. The similarities and differences between PTLD and S-COPD
Differences
Characteristic Similarities
PTLD S-COPD
Host Mostly in old people Become patients after episode of pulmonary Gradually worsens while smoking
TB for many years or by aging
Clinical symptoms Mostly respiratory symptoms: Hemoptysis Dyspnea
cough, sputum, and/or dyspnea
Imaging Emphysema and chronic Very heterogeneous: granulomas/fibrosis, Overall hyperinflated
bronchitis calcification, bronchiectsis, gas-trapping,
tracheobronchial stenosis, pleural thickenings
Lung pathology Chronic airway obstruction, Airflow obstruction, restriction, or mixed Airflow obstruction
and pulmonary Decreased diffusion capacity patterns
function
COPD, chronic obstructive pulmonary disease; PTLD, post-tuberculosis lung disease; S-COPD, smoking-associated COPD.
a)
Adapted from Gai et al. [45].
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The Korean Journal of Internal Medicine Vol. 39, No. 1, January 2024
Lung Disease (BOLD) with 14,050 participants, established a years following the completion of anti-TB therapy (Fig. 3B).
significant association between a history of TB and spirome- As TB progresses, mononuclear inflammatory cells form the
try-verified airflow obstruction (adjusted OR, 2.51; 95% CI, core structure of granulomas, undergoing cellular metamor-
1.83–3.42) and also restriction (adjusted OR, 2.13; 95% CI, phosis to yield epithelioid cells, multinucleated giant cells,
1.42–3.19) [16]. There is a broad spectrum of residual spi- and foamy macrophages [46]. Furthermore, granulomas
rometric abnormalities among people with PTLD, often dis- incorporate other immune cells, including T and B lympho-
playing a combined obstructive and restrictive pattern [10]. cytes and fibroblasts. While much remains to be elucidated,
Because spirometry results simply represent the combined animal studies infected with TB suggest that each individual
expiratory airflows from the entire lungs, measured at the granulomatous lesion may uniquely respond to the host’s
end of the blowing tip by the flow detector, COPD patients immune reaction, potentially leading to varied disease tra-
with PTLD and those with COPD due to tobacco smoking jectories [47,48]. The fibrotic transformation of granulomas
might exhibit similar spirometric outcomes despite their an- is believed to involve collagen-producing fibroblasts and
atomical and pathophysiological differences (Table 2) [45]. pro-fibrotic cytokines such as transforming growth factor
While tobacco-induced COPD typically affects all lung lobes beta 1 (TGF-β1) [49]. This fibrotic encapsulation of granu-
uniformly, TB-associated COPD may afflict a selective num- lomas can benefit the host by segregating infected tissues
ber of lobes based on the primary infection site and its pro- from healthy ones [50]. Nonetheless, excessive fibrotic pro-
gression during the infectious phase and treatment duration gression can be detrimental, with traction bronchiectasis as
(Fig. 4). a good example.
Subsequent to completing anti-TB treatment, character-
Lung parenchyma complications istic CT imaging of early TB manifestations like marginated
linear branching centrilobular nodules (referred to as the
Granulomas and fibrosis “tree-in-bud” pattern) and poorly defined heterogeneous
Granulomas are the hallmark of TB, and multiple granu- consolidations resolve and diminish both in size and density
lomas are frequently observed in TB patients, even several [51]. During treatment, the “tree-in-bud” lesions disappear,
A B C
Figure 4. (A) A COPD patient with no history of TB and a 40 pack-year smoking history. CT imaging reveals signs of emphysema, bron-
chial wall thickening, and post-bronchodilator spirometry demonstrates an FEV1/FVC ratio of 0.46, FEV1 at 58% (1.73 L) of the predicted
value, TLC at 5.46 L (84%), and DLco at 13.2 (65%) mL/min/mmHg. (B) A PTLD patient with no smoking history. CT imaging displays TB
sequelae predominantly in the right upper lobe with minimal involvement in the other lobes. Pulmonary function tests do not indicate any
decline, with a post-bronchodilator spirometry showing an FEV1/FVC ratio of 0.76, and FEV1 at 93% (3.02 L). (C) A PTLD patient with no
smoking history. CT imaging shows a completely destroyed left lung, calcified granulomas, and fibrotic scars in the right upper lobe with
pulmonary function significantly diminished, with an FEV1/FVC ratio of 0.55, FEV1 at 25% (0.59 L), TLC at 60% (2.81 L), and DLco at 12.0
(68%) mL/min/mmHg. COPD, chronic obstructive pulmonary disease; TB, tuberculosis; CT, computed tomography; FEV1, forced expirato-
ry volume in one second; FVC, forced vital capacity; TLC, total lung capacity, DLco, diffusing capacity of the lungs for carbon monoxide;
PTLD, pulmonary-TB lung disease.
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Seo W, et al. Post-tuberculosis lung disease
leaving tiny discrete dots. Lobular consolidations resolve and burden at the inner cavity edge [52-54]. Both higher rates
turn to centrilobular nodules, which then further diminish, of bacterial replication and poorly vascularized and shielded
resulting in residual fibrotic alterations (Fig. 5). In PTLD, structure of the cavity can elevate the risk of treatment failure
radiological findings often include bronchial wall thicken- and the emergence of drug resistance [18,55-57]. Though
ing, emphysematous changes, fibrocalcific changes, bron- most cavities heal and close after anti-TB chemotherapy,
cho-vascular distortion, and bronchiectasis [51]. some persist beyond treatment. Persisting cavities post six
months of treatment can double the relapse rate in compar-
Cavitation and chronic pulmonary aspergillosis ison to healed cavities [55]. Incomplete healing might leave
According to the widely cited experimental rabbit model, a the cavity’s inner space exposed to the primary airway sys-
TB cavity initially forms when the necrotic core of a granulo- tem, raising the susceptibility for secondary colonization by
matous abscess erodes an adjacent airway, creating an oxy- pathogens such as Aspergillus fumigatus.
gen-rich environment optimal for TB bacilli proliferation. This When inhaled, Aspergillus species from the environment
environment manifests as a significantly increased bacillary can lead to invasive fungal pneumonia and inflammatory
A B
Figure 5. Pair of the same section of computed tomography scans of a pulmonary tuberculosis patient at the commencement of antitu-
berculosis treatment (A) and after 3 months of the treatment (B).
A B
Figure 6.A PTLD patient with cavitation in the LUL presented with dyspnea, sputum, and cough. The recent CT scan revealed a newly
observed mass-like lesion with an air crescent sign (A) in the previously empty cavitation seen on a CT scan 17 years ago (B), confirming
newly developed Aspergillosis with suspected invasive aspergillosis. PTLD, pulmonary-TB lung disease; LUL, left upper lung; CT, computed
tomography.
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The Korean Journal of Internal Medicine Vol. 39, No. 1, January 2024
necrosis, culminating in chronic pulmonary aspergillosis hemoptysis. Furthermore, untreated CPA can evolve into
(CPA) [13,58]. The most prevalent type of CPA is chronic chronic fibrotic pulmonary aspergillosis (CFPA), a severe
cavitary pulmonary aspergillosis (CCPA), characterized by form marked by extensive fibrosis and the destruction of
one or more lung cavities, which may contain aspergillo- at least two lung lobes, causing significant lung function
mas, commonly referred to as a “fungal ball” (Fig. 6) [59]. impairment [59]. CPA patients who have diabetes mellitus,
If left untreated, CPA can lead to increased vascularization malnutrition, alcoholism, are of advanced age, have un-
of adjacent bronchial arteries, resulting in potentially fatal dergone prolonged corticosteroid treatment, have certain
Figure 7. Flow chart of long-term management of people with post-tuberculosis lung disease. There is limited evidence to choose vac-
cination recommendation differently to individuals with PTLD from rest of CRD patients. TB, tuberculosis; CT, computed tomography;
mMRC, modified medical research council dyspnea scale; CAT, chronic obstructive pulmonary disease assessment test; 6MWT, 6-minute
walk test; SpO2, peripheral oxygen saturation; BMI, body mass index; TB-PCR, tuberculosis-polymerase chain reaction; AFB, acid-fast ba-
cilli; COVID-19, coronavirus disease 2019; NTM, non-tuberculous mycobacterium; COPD, chronic obstructive pulmonary disease; LAMA,
long-acting muscarinic antagonist; LABA, long-acting beta agonist; ICS, inhaled corticosteroids; IV, intravenous; CCPA, chronic cavitary
pulmonary aspergillosis; CFPA, chronic fibrosing pulmonary aspergillosis; SAIA, subacute invasive aspergillosis.
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Seo W, et al. Post-tuberculosis lung disease
immune deficiencies, connective tissue disorders, or have underlying issue [9]. Conversely, reinfection refers to a pre-
received radiation therapy require close medical monitoring. viously cured patient becoming infected with a new strain of
This is because their condition can worsen to subacute in- M. tuberculosis, leading to the development of pulmonary
vasive aspergillosis (SAIA), a fast-progressing type of CPA TB again. Differentiating between reinfection and relapse
where hyphae are seen invading lung tissues [13,60,61]. necessitates genotyping, which, unfortunately, is not uni-
Conversely, in hyper-reactive (or allergic) individuals, pulmo- versally accessible across countries [62]. Recognized risk fac-
nary aspergillosis might result in allergic bronchopulmona- tors for relapse encompass: 1) pre-existing drug resistance,
ry aspergillosis or asthma coupled with fungal sensitization 2) adoption of alternative therapeutic regimens excluding
[13]. rifampicin, 3) extensive residual radiological abnormalities,
such as cavitations or the presence of scars in three or more
zones, 4) advanced age, 5) being male, and 6) habits like
MANAGEMENT OF PTLD smoking or alcohol consumption [63-68]. Studies indicate
that relapses predominantly arise within 6–12 months
Understanding post-TB patients is crucial, as these individu- post-treatment completion [69]. Therefore, it is imperative
als may encounter complications not just in the lungs, but for people with PTLD to undergo more frequent follow-ups
also cardiovascular/pericardial, neurological, psychological, during the initial year. Subsequent clinical visits should be
and even developmental issues when the TB patient is an strategically scheduled based on the specific sequelae war-
adolescent or child. A recent review article by Nightingale ranting attention in the patient.
et al. highlighted the significance of post-TB management
and provided comprehensive suggestions for overseeing the Tracheobronchial stenosis management
health and wellbeing of these patients [8]. Our review aims TB, a leading cause of benign tracheobronchial stenosis, of-
to focus on the specific management of post-TB patients ten results in life-threatening and life-long complications in
dealing with impaired lung anatomy and physiology (or PTLD patients. Mild luminal narrowing may not mandate rig-
PTLD), following the successful completion of their anti-TB orous intervention beyond the administration of mucolytics.
regimen. A predominant challenge in providing appropri- In contrast, complete obliteration, which leads to a signifi-
ate long-term care for PTLD patients is the heterogeneity of cant reduction in airflow and subsequent respiratory failure,
the disease. As demonstrated in Table 1, we advocate for a has the potential to be lethal [12]. The left main bronchus
management strategy that categorizes PTLD into subtypes and left bronchi are typically more prone to involvement,
such as: 1) mild abnormal X-rays features like granulomas largely attributed to the added anatomical compression ex-
and fibrosis, 2) bronchiectasis, 3) cavities, 4) tracheobron- erted by the aortic arch (Fig. 2) [70-72]. Historically, prior
chial stenosis, 5) pleural complications, and 6) small airway to the 1990s, surgical resection and bronchoplastic recon-
diseases. It is common for patients to exhibit multiple sub- struction were the standard treatments for tracheobronchial
types. Our proposed flowchart (Fig. 7) aims to guide clini- stenosis [71]. The advent of the late 1990s saw the intro-
cians through each subtype, ensuring comprehensive and duction of less invasive techniques utilizing rigid bronchos-
thorough long-term management of PTLD. We delve into copy. These can be broadly categorized into dilatation and
these in the subsequent sections. ablation. These techniques emerged as superior alternatives
for patients with multiple stenosis sites, especially when
Monitoring the TB recurrence accompanied by severe comorbidities such as heart failure
TB recurrence is identifiable when a patient, after receiving or chronic renal disease. Although no studies have directly
at least 6 months of anti-TB drugs and confirmed smear or contrasted the efficacy of these diverse bronchoscopic pro-
sputum culture negative after the treatment, manifests ac- cedures, the balloon dilation technique has gained prefer-
tive TB again. The two primary causes for TB recurrence are ence. Its minimally invasive nature, coupled with the need
relapse and reinfection. A true relapse occurs when TB bacil- for fewer specialized skills and the widespread availability of
li, having survived a course of anti-TB treatment confirmed bronchoscopes, makes it the often-chosen treatment. The
as successful, re-emerge. Thus, relapse and treatment fail- procedure entails positioning a deflated balloon within the
ure can be considered distinct manifestations of a similar stenotic bronchus, which is then inflated radially for several
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The Korean Journal of Internal Medicine Vol. 39, No. 1, January 2024
seconds to minutes (Fig. 8) [73]. variant. It’s noteworthy that while 99% of lung blood flow
Recently, the dilation process has incorporated multiple originates from pulmonary arteries, primarily facilitating gas
modalities, including laser resection and mechanical bou- exchange, an overwhelming 90% of life-threatening he-
gienation, typically performed under general anesthesia moptysis instances are attributable to the bronchial arteries
[74]. Because balloon dilation often prove ineffective, stent [82]. In PTLD patients, factors such as bronchiectasis, pulmo-
insertion is typically the subsequent preferred intervention. nary hypertension, chronic infection, and an aberrant vascu-
Airway stenting is valuable not only post balloon dilation lature elevate the risk of bronchial artery rupture. These con-
failure but also in scenarios complicated by tracheobron- ditions may precipitate a redirection of blood flow from the
chomalacia or fistulas, conditions not suitable for balloon pulmonary to bronchial arteries, ensuing in bronchial artery
dilation [12]. Given the complications associated with me- dilation, hypervascularization, and the genesis of collateral
tallic stents (e.g., metal fracture, granulation tissue pro- vessels that are rupture-prone [83].
liferation), there is a shift towards favoring silicone stents For instances where hemoptysis is quiescent and minimal,
[71,75-77]. Research centered on silicone stents highlights administration of tranexamic acid, an antifibrinolytic agents,
that a majority of patients (ranging from 63.6 to 100%) is often deemed appropriate. This can be delivered via neb-
experience immediate symptom alleviation post-placement ulization, intravenous infusion, or oral intake. While robust
[72,78]. A recent study analyzed 381 post-TB tracheobron- evidence remains pending, certain studies suggest potential
chial stenosis patients who underwent silicone stenting. The benefits, such as reductions in hemoptysis volume, shorter
results revealed that 75% (or 285 patients) successfully had hospitalization durations, and diminished needs for invasive
their stents removed after a median duration of 25 months, interventions, all with minimal side effects compared to
achieving a 70% stent-free rate [74]. However, prolonged controls [84-86]. Moreover, should the hemoptysis source
placement of silicone stents can also lead to granulation for- be pinpointed, positioning the patient in a decubitus stance
mation [72,79,80]. with the afflicted side downward can deter the aspiration of
blood into the unaffected lung [14]. In the event of signifi-
Hemoptysis management cant or life-endangering hemoptysis, immediate referral to
Hemoptysis can often prove fatal. PTLD patients, especially an emergency setting is imperative. Intensive care interven-
those with bronchiectasis or cavitation, are particularly sus- tions could encompass endotracheal intubation, broncho-
ceptible to hemoptysis [81]. Although previously discussed, scopic management, and the more decisive measure of an-
the precise mechanism underlying the increased incidence giography followed by bronchial artery embolization. Upon
of hemoptysis in post-TB bronchiectasis remains elusive. Fur- angiographic identification of the bleeding vessel, arterial
thermore, the current therapeutic approach to hemoptysis embolization is typically executed utilizing microparticle em-
in bronchiectasis does not specifically address its post-TB bolic agents such as polyvinyl alcohol particles or tris-acryl
A B C
Figure 8. Balloon dilation procedure on the annular cicatrical stenosis at the left main bronchus of an endobronchial tuberculosis patient
after two years of antituberculosis chemotherapy (A) and chest X-rays before (B) and after the dilation procedure (C).
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Seo W, et al. Post-tuberculosis lung disease
gelatin microspheres [87,88]. cavities, which can either contain a fungal ball or not, or
demonstrate the presence of nodules. Second, there should
Management of infective exacerbation be direct evidence of an Aspergillus infection, as determined
Infective exacerbation is another complication frequent- by either microscopy or a culture derived from a biopsy. Al-
ly observed in PTLD patients with bronchiectasis. A robust ternatively, there can be a clear immunological response to
correlation exists between chronic bacterial infection and Aspergillus species. Third, other potential diagnoses must
exacerbation of bronchiectasis [89-91]. Notably, Pseudomo- be excluded. Lastly, these symptoms or findings should have
nas aeruginosa has been identified in numerous bronchi- been consistent for at least three months [59]. For example,
ectasis patients, showing a prevalence rate of 15.0%. This a PTLD patient’s CT scan showing a fungal ball present for
bacterium has also been independently linked with height- over three months, coupled with a positive Aspergillus IgG
ened mortality (hazard ratio [HR], 2.03; 95% CI, 1.36–3.03; or precipitins test (noted in over 90% of cases), suffices for
p = 0.001) among those experiencing regular exacerbations CPA and, more specifically, CCPA confirmation. CFPA refers
[92]. A reduction in microbiome diversity that leads to Pseu- to CPA with extensive fibrosis affecting at least two lobes,
domonas dominance is also associated with greater disease while SAIA denotes rapidly-progressing CPA, usually within
severity and higher risk of mortality [93]. Consequently, three months, with histologic evidence of invasive hyphae in
antibiotics emerge as a pivotal therapeutic intervention for lung tissue, especially among the immunocompromised or
infective exacerbations of bronchiectasis. PTLD patients with severely debilitated as previously described.
bronchiectasis should thus receive similar treatment. Typi- Simple aspergilloma, rounded accumulations of fungal
cally, a 14-day antibiotic regimen is administered to counter hyphae, fibrin, mucus, and cellular debris, poses a 15–20%
exacerbations involving P. aeruginosa [11,94,95]. Recently, risk of development in cavities larger than 2 cm [13]. For
guidelines and reports have highlighted the importance of PTLD patients with cavities exceeding 2 cm, regular moni-
comprehensive management of bronchiectasis to prevent toring for the emergence of aspergilloma is advised. Upon
exacerbations using non-pharmacological treatments, such confirmation of a simple aspergilloma, surgical resection be-
as airway clearance techniques and pulmonary rehabilita- comes the often-recommended intervention to counter and
tion (PR) [96]. While comprehensive research is necessary treat potentially lethal hemoptysis [59]. On the other hand,
to fully understand the specifics of PTLD exacerbation, we CCPA generally demands oral triazoles therapy to prevent
suggest that PTLD patients with bronchiectasis be managed both its clinical and radiological symptoms, notably fibrosis
analogously when experiencing infective exacerbations. and severe hemoptysis [99-105]. For non-severe symptoms,
outpatient oral azole therapy (e.g., itraconazole 200 mg or
Cavitation and chronic pulmonary aspergillosis voriconazole 150–200 mg twice daily for a minimum of 4–6
management months) can be considered. In cases where SAIA is suspect-
Surgical resection of cavitary TB, a potential precursor to ed, PTLD patients should be immediately referred to a tertia-
drug-resistant TB, remains an option but typically presents ry care hospital for prompt diagnosis, utilizing tools like CT
a poor prognosis. The majority of surgical treatments were scans and bronchoscopy. The condition should be treated
explored in the early 20th century, prior to the advent of similarly to acute invasive aspergillosis because of its rapid
effective chemotherapy [97]. The WHO consolidated guide- progression and high mortality rate.
lines advocate for elective partial lung resection in patients
with rifampicin-/multidrug-resistant-TB [98]. Management of small airway obstruction
A cavity with fungal ball, particularly due to Aspergil- Although smoking is the traditional risk factor for COPD,
lus, can lead to symptoms such as hemoptysis, chest pain, TB or PTLD has been identified as another significant and
cough, and fever. The management strategies for CPA dif- independent risk factor for airflow obstruction. Conversely,
fer based on the disease’s severity and type, encompassing smoking is also a risk factor for TB development and can
simple aspergilloma, CPPA, CFPA, and SAIA. Before initiat- exacerbate its severity [106]. A comprehensive cross-sec-
ing treatment for CPA, obtaining a definitive diagnosis is tional survey from China in 2021 demonstrated that of
crucial. This diagnosis is based on several key criteria. First, 610 confirmed PTLD patients, 21.3% experienced airflow
thoracic imaging must show the presence of one or more obstruction. Even after accounting for confounding factors,
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The Korean Journal of Internal Medicine Vol. 39, No. 1, January 2024
a history of TB remained a significant correlate of airflow crease in trough FEV1 by 140 mL (p < 0.001) in comparison
obstruction (OR, 1.31), and compromised lung function per- to a placebo at the 8-week mark [112]. Though the sample
sisted [107]. A prospective study from Malawi on PTLD en- was limited (n = 29), a study on the impact of LAMA on
compassed 301 patients (60.4% HIV positive) who, post-ac- PTLD indicated that 8-week daily inhaled tiotropium bro-
tive TB treatment and a subsequent 3-year follow-up, mide administration improved their lung function [113].
27.9% maintained compromised lung function, with a However, the pulmonary function patterns in many TB-as-
median FEV1 decline of 180 mL (or 60 mL/yr) [108]. Interest- sociated COPD cases are varied, and which specific pheno-
ingly, the post-hoc analysis revealed a marked improvement types respond best to long-acting bronchodilator therapies
in lung function during the first 9 months following treat- remains undetermined.
ment completion, with fewer changes observed thereafter. Conversely, the use of inhaled corticosteroids (ICS) is dis-
Hence, the importance of baseline lung function assessment couraged in TB-associated COPD. While ICS/LABA therapies
and subsequent annual follow-ups is emphasized to identify have demonstrated efficacy in certain COPD populations,
deteriorating subgroups for timely intervention. numerous studies have highlighted the potential long-term
What predisposes individuals to compromised lung func- adverse effects of ICS, specifically increased risks of TB and
tion and airflow obstruction? A landmark study conducted mycobacterial diseases in this demographic [114]. ICS use
in Hong Kong, incorporating 16,345 active TB patients, re- in COPD patients may increase the risk of pneumonia by
vealed that both current and former smokers were associ- suppressing both cellular and humoral immunity, altering
ated with more pronounced lung disease, cavitation, and a the bactericidal effect of macrophages, and reducing nitric
1.5–2 times increased likelihood of remaining smear- and oxide production [115]. Such risks seem contingent on the
culture-positive following two months of treatment. These specific ICS type. Research from Taiwan involving TB-asso-
individuals were also less probable to attain a cure or com- ciated COPD patients revealed that those in the fluticasone/
plete treatment within two years and had elevated relapse salmeterol cohort exhibited nearly a 50% increased likeli-
rates compared to non-smokers [109]. This underscores the hood of developing active TB relative to the budesonide/
pressing need for physicians to advocate for smoking cessa- formoterol group (adjusted HR, 1.45; 95% CI, 1.14–1.85)
tion among PTLD patients. [116]. Again, further investigations are warranted to eluci-
A pivotal question emerges: Are the COPD cases induced date the fundamental mechanisms relating ICS use to TB
by smoking and TB, both resulting in chronic airflow ob- relapse.
struction, distinct pathological entities? As previously de-
scribed, these COPD subtypes manifest unique physiological PR
and radiological attributes (Table 2). In recent years, there’s PR has established itself as a cornerstone in the manage-
a shifting perspective to view COPD as a continuum of air- ment of chronic respiratory diseases (CRD) including asth-
flow obstruction with various endotypes, of which TB is ma, COPD, cystic fibrosis, and others [117,118]. It should be
one [110]. This aligns with the contemporary stances ad- a personalized, multidisciplinary program tailored to individ-
opted by both the Global Initiative for Chronic Obstructive ual patient needs [117]. Furthermore, PR has been demon-
Lung Disease and Lancet committees [111]. While further strated to be more cost-effective than pharmacotherapy in
research is essential to discern the optimal treatment modal- patients with CRD [119]. However, it’s pivotal to emphasize
ities for PTLD versus conventional smoking-induced COPD, that for a program to be classified as PR, it must encompass
inhaler therapies appear comparably efficacious in PTLD. comprehensive baseline and subsequent post-PR outcome
Despite the absence of long-term randomized trials con- measurements to validate its efficacy. While there is a robust
firming efficacy, both long-acting bronchodilator therapies body of evidence supporting PR in general CRD, specific re-
(like long‐acting β‐agonist [LABA] and long‐acting musca- search addressing PTLD remains more limited [120]. None-
rinic antagonist [LAMA]) have shown promise in alleviating theless, there is emerging evidence regarding PR programs
TB-associated COPD symptoms and improving lung func- uniquely tailored for PTLD patients [121-124].
tion. A trial of LABA (inhaled indacaterol 150 µg once daily) We list recommendations for PTLD-specific PR as follows
targeting PTLD with moderate-to-severe airflow restriction [125-130]. Firstly, aerobic exercise is advised, using either
revealed enhanced symptom scores and a significant in- a treadmill or cycle-ergometer for 30 minutes, 2–5 times
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The Korean Journal of Internal Medicine Vol. 39, No. 1, January 2024
for the diagnosis of malnutrition - A consensus report from CRedit authorship contributions
the global clinical nutrition community. Clin Nutr 2019;38:1-9. Wan Seo: conceptualization, methodology, investigation, writing -
original draft, visualization; Hyung Woo Kim: conceptualization, meth-
odology, supervision; Ju Sang Kim: conceptualization, methodology,
supervision; Jinsoo Min: conceptualization, methodology, validation,
Received : September 19, 2023 writing - review & editing, supervision, funding acquisition
Revised : October 24, 2023
Accepted : Novermber 8, 2023 Conflicts of interest
The authors disclose no conflicts.
Correspondence to
Jinsoo Min, M.D., M.P.H., Ph.D. Funding
Division of Pulmonary and Critical Care Medicine, Department of In- This work was supported by the Research Program funded by the Ko-
ternal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The rea National Institute of Health (grant number 2022E200100).
Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul
06591, Korea
24 www.kjim.org https://doi.org/10.3904/kjim.2023.395