Astrocyte

THE EVOLUTION - THE BRONCHOSCOPY LAB
Year
: 2017  |  Volume : 4  |  Issue : 1  |  Page : 45--52

Newer approaches in diagnostic and therapeutic bronchoscopy in pulmonary tuberculosis


Pavankumar Biraris, S Lakshmipriya, Rajani Bhat, Ravindra Mehta 
 Institute of Pulmonary Medicine and Interventional Pulmonology, Apollo Hospitals, Bengaluru, Karnataka, India

Correspondence Address:
Ravindra Mehta
Institute of Pulmonary Medicine and Interventional Pulmonology, Apollo Hospitals, Bengaluru - 560 011, Karnataka
India

Abstract

Tuberculosis (TB), true to its description as the “Captain of the men of death,” is now an uncontrolled epidemic of global proportions. Inherent to controlling this looming threat, is a high-end diagnostic and therapeutic approach, with conventional tools, and out of the box approaches. The diagnostic approach to TB has seen accelerated development in an attempt to tackle the epidemic of resistance. On the therapeutic front, progress is slow, and beyond chemotherapy and occasional surgery, hardly any therapeutic approaches to TB have been described. With the advent of newer bronchoscopic techniques such as endobronchial ultrasound (EBUS) and therapeutic bronchoscopy, a host of new options are available to the physician, both in the diagnostic and therapeutic arena. This review focuses on bronchoscopic diagnostic and therapeutic methods in TB and its sequelae. We highlight both the established and cutting edge role of bronchoscopy in the management of specific aspects of TB. In addition, this discussion incorporates the introduction of innovative therapeutic modalities in the disease, and is an overview into the growing role of pulmonary procedures in all aspects of TB.



How to cite this article:
Biraris P, Lakshmipriya S, Bhat R, Mehta R. Newer approaches in diagnostic and therapeutic bronchoscopy in pulmonary tuberculosis.Astrocyte 2017;4:45-52


How to cite this URL:
Biraris P, Lakshmipriya S, Bhat R, Mehta R. Newer approaches in diagnostic and therapeutic bronchoscopy in pulmonary tuberculosis. Astrocyte [serial online] 2017 [cited 2020 Jul 16 ];4:45-52
Available from: http://www.astrocyte.in/text.asp?2017/4/1/45/217659


Full Text



 Introduction



Mycobacterium tuberculosis (MTB) is a leading cause of death from infectious diseases in our country. India accounts for one fourth of the global tuberculosis (TB) burden. In 2015, an estimated 28 lakh cases occurred, and 4.8 lakh people died due to TB. India has the highest burden of both TB and multi-drug resistant (MDR) TB, based on the 2016 Global TB report. An estimated 1.3 lakh MDR-TB patients are diagnosed annually in India.[1]

The bronchoscopy is an important tool in the diagnostic approach to TB, and has also made inroads into the therapeutic arena. The bronchoscopic procedures in pulmonary tuberculosis (PTB) can be classified into two major categories [Table 1].{Table 1}

 Diagnostic Applications



Bronchoalveolar lavage in smear negative PTB

As per the Revised National Tuberculosis Control Program (RNTCP), sputum smear microscopy is one of the main surveillance and diagnostic methods for PTB. However, though the positive predictive value (PPV) of sputum smear microscopy is 95%, the sensitivity is 40–60%, and 30% of patients in the early stage of the disease cannot spontaneously expectorate.[2] If smear-negative PTB is left untreated, about 50% of patients need chemotherapy by 12 months.[3] Sputum smear-negative, culture positive cases are potential source of spread of TB in community. The early diagnosis of smear-negative PTB is important, as mortality rate for smear-negative, culture-positive cases is significantly high at 14.1%.[4]

Among the various bronchoscopic procedures described in the diagnosis of smear-negative PTB, bronchoalveolar lavage (BAL) is superior to bronchial washings. The bronchial washings are obtained by bronchoscopically instilling 10 mL to 20 mL of sterile saline followed by quick aspiration. BAL is a more detailed procedure, which samples the distal air spaces (a few million alveoli), with larger aliquots of saline (≥100 mL). BAL also allows the recovery of both cellular and non-cellular components of the alveolar lining fluid and epithelial surface of the lower respiratory tract, and has a higher yield for the diagnosis of TB. The larger quantity of saline used in BAL helps to enhance the yield by lowering the concentration of the local anesthetic used, which can inhibit the growth of MTB.[5],[6] BAL not only facilitates early diagnosis, but is also reliable for the assessment of drug-resistant TB, using gene-based tools. BAL fluid Xpert MTB/RIF in sputum-negative PTB has a sensitivity and specificity of 79.1% and 93.1% respectively. Considering the TB culture as the gold standard for diagnosis of smear-negative PTB, the sensitivity of BAL Acid fast bacilli (AFB) smear and Xpert MTB/RIF is 22.2% and 81.4% respectively.[7]

Bronchial brushings

In a study of 50 patients with suspected PTB, comparison of bronchial washings, brushings, and biopsy for diagnosis of PTB was done. The positive cultures of material with bronchial brushings taken from abnormal looking mucosa was significantly higher than with bronchial washings.[8]

Endobronchial tuberculosis

Although computerized tomography (CT) of the chest provides reliable evidence of endobronchial tuberculosis (EBTB), bronchoscopy [Figure 1] is essential for accurate diagnosis, and to define the type and extent of disease. EBTB accounts for 3–90% of cases of TB in autopsy studies, and is more common in females in the second to third decade of life. It can involve any part of the tracheobronchial tree. In terms of distribution in the main airways, the disease appears in the trachea in 17%, left main bronchus in 18%, right upper lobe in 15%, right lower lobe in 15%, and multisite and bilateral in 15%.[9] On the basis of the bronchoscopic appearance, EBTB is classified into seven types [Table 2].[10]{Figure 1}{Table 2}

The commonest form of EBTB is the “actively caseating” type (43.0%), and the least common is the “ulcerative” type (2.7%), with other subtypes falling in between.[11] Among the different bronchoscopic sampling techniques like washings, brushings, and biopsy, bronchial biopsy is the most reliable method for confirming the diagnosis, with a positive yield of 30% to 84%.[12] In the various subtypes of EBTB, the positivity of BAL AFB smear and culture is highest in the granular type (75%), and the least in the fibro-stenotic type. Due to varying stages of involvement, there can be a limited yield of microbiologic methods in early EBTB, and histopathology using endobronchial biopsy is very important to establish the diagnosis.[9],[13]

Transbronchial lung biopsy

Transbronchial lung biopsy [TBLB, [Figure 2] is an important bronchoscopic procedure to establish a diagnosis in smear-negative PTB, when there is parenchymal involvement. TBLB is an outpatient procedure that can be performed under conscious sedation and local anesthesia. It not only provides additional sample for diagnosis, but also helps to rule out mimics of TB such as malignancy and fungal infections. In immunocompromised individuals, TBLB plays vital role to rule out other opportunistic infections.{Figure 2}

In most patients, combining BAL and TBLB can maximize the diagnostic yield of bronchoscopy. TBLB provides a rapid diagnosis in 17–60% of cases with active TB.[14],[15] TBLB also provides a rapid diagnosis in miliary TB. In smear-negative miliary TB, the yield of TBLB ranges between 60% and 80%.[16],[17] Culture of TBLB and bronchial brushing specimens further enhances the yield.

Radial probe endobronchial ultrasound guided TBLB

Delayed diagnosis and empiric anti-TB treatment in an era of drug resistance is a threat for global TB control.[18] Radial EBUS-TBLB (Radial probe guided endobronchial ultrasound guided TBLB [Figure 3]) is a step ahead of conventional TBLB, to get a definitive diagnosis in parenchymal involvement. In this modality, the parenchymal lesion can be further localized using an ultrasound at the tip of a tiny probe, which goes through the bronchoscope, and this adds a component of visualization to regular TBLB. Radial EBUS-TBLB is a safe and reliable diagnostic method with minimal complications. In a recent study, radial EBUS-TBLB was done in 123 patients with peripheral lung lesions in high endemic TB settings. Twenty two patients had a final diagnosis of PTB. The diagnostic sensitivity for PTB was 77.3%, with a PPV, negative predictive value (NPV), and diagnostic accuracy of 100%, 95.2%, and 95.8% respectively. In 58.8% cases, the diagnosis of PTB relied on histology.[19]{Figure 3}

Transbronchial needle aspiration for mediastinal lymphadenopathy in tuberculosis

Lymph node TB constitutes 20–40% of extrapulmonary TB.[20] Mediastinal lymphadenopathy (MLN) is a clinically challenging condition, and tissue diagnosis is recommended in most cases, to prove TB or alternative Diagnosis, and obtain samples for culture and resistance analysis. It is of paramount importance in immunocompromised individuals to guide accurate management, and in malignancy where exclusion of TB is essential prior to instituting chemotherapy.

Transbronchial needle aspiration (TBNA) is a technique in which a cytology or histology specimen is obtained from the MLN using flexible bronchoscopy. Conventional TBNA or EBUS-TBNA (EBUS guided TBNA) are the two safe and effective options available for the diagnosis of MLN. TBNA/EBUS-TBNA play an important role to resolve the diagnostic dilemma of TB versus sarcoidosis in TB endemic settings such as India.

Conventional TBNA (C-TBNA)

In a study of 84 HIV-negative, sputum smear-negative patients with MLN, the sensitivity, specificity, PPV and NPV of TBNA [Figure 4] for the diagnosis of TB were 83%, 100%, 100%, and 38% respectively. TBNA was done with a 19-gauge histology needle, and overall accuracy was 85%. TBNA provided an immediate diagnosis in 78%, and it was the sole source of diagnosis in 68% patients. Additionally, acid-fast bacilli were isolated in culture of the TBNA specimen in 27% patients.[21]{Figure 4}

In another study of 41 HIV-infected patients with MLN, TBNA was done with a 19-gauge histology needle. A diagnosis of TB was established in 20 of 23 (87%), an immediate diagnosis was achieved in 74%, and the culture was positive in 61% subjects.[22]

A recent study by Mehta et al. highlights the high prevalence of TB in MLN in India, and the utility of conventional TBNA (C-TBNA). This is one of the largest series in literature of 400 patients with MLN sampled with C-TBNA. The diagnostic yield of C-TBNA for MLN sampling was 347/400 (86.75%), with TB being 43%, and C-TBNA was the sole diagnostic modality in 215/400 (53.75%) patients. The other diagnoses included sarcoidosis (25.5%) and malignancy (18.25%), highlighting the important role of C-TBNA is both diagnosing TB in MLN accurately, and ruling out other differential diagnoses such as sarcoidosis and malignancy.[23]

EBUS-TBNA

EBUS-TBNA [Figure 5] has revolutionized the diagnostic algorithm of MLN. There is no direct comparison between conventional TBNA and EBUS-TBNA in the available literature for TB MLN enlargement. EBUS-TBNA was shown to have a high sensitivity for diagnosis of isolated mediastinal TB lymphadenitis, which can occur in 9% of all cases.[24] In a study of 156 patients done by Navani et al., a diagnosis of TB was established in 146 (94%) patients, and the study identified 74 (47%) culture positive cases and eight patients with MDR-TB.[25] In another study, the overall diagnostic yield of EBUS-TBNA for TB was 85%.[26]{Figure 5}

TB lymphadenopathy is considered to be a paucibacillary disease. EBUS-TBNA samples can provide additional information regarding MDR-TB. Among microbiologically confirmed 80 cases, an Xpert MTB/RIF assay demonstrated overall sensitivity for culture-positive TB of 72.6%. Xpert MTB/RIF was positive in 100% (14/14) of smear positive and 67.6% of smear-negative cases (48 of 71). Among the cases that were culture positive by TBNA, Xpert identified two-thirds of the MDR-TB cases, leading to an immediate regimen change 5 weeks ahead of culture. The diagnostic yield of TBNA for detection of TB increases when Xpert MTB/RIF results are combined with cytology, with a sensitivity of 96.6%.[27]

 Therapeutic Applications



Tuberculosis bronchostenosis

In EBTB, tracheobronchial stenosis (TBS, [Figure 6]) and stricture are the most common complications with long-term sequalae, and may develop in 60–95% cases despite adequate anti-TB therapy. About two-thirds of patients with caseating and edematous-hyperemic type of EBTB progress to the fibrostenotic stage.[28] The armamentarium of bronchoscopic interventions available to manage TB bronchostenosis include balloon dilatation, APC (argon plasma coagulation), laser, cryosurgery, and stent insertion.{Figure 6}

Balloon dilatation

The dilatation of a stenotic area helps in improving drainage of the distal involved lobe, and in palliation of symptoms. The dilatation of a stenotic segment can be achieved with flexible or rigid bronchoscopy, using a balloon (balloon bronchoplasty, [Figure 6]), or dilating instruments. The rigid and flexible bronchoscopy are often combined to obtain better endoscopic outcomes.[29] Cohen et al. first described balloon dilatation in 1984.[30] It is especially indicated for annular cicatric stenosis, and may be more effective in fixed fibrotic stenosis, than in patients with active inflammation and calcification.[31] The advantages of balloon bronchoplasty is that it is simple, rapid, well-tolerated, minimally invasive, and provides immediate symptomatic relief.[32] The complications associated with dilatation are dehiscence of the bronchial wall due to excessive stretching, with pneumothorax, pneumomediastinum, and subcutaneous emphysema. The patients who require more than one session of balloon dilatation usually need stenting or ablative procedures.

Ablative techniques

Ablative techniques are also used to re-establish the patency of the airway, singly or in combination with other techniques.

Mu et al. have analyzed the effect of cryotherapy in granular EBTB that did not have luminal narrowing of the bronchus at the time of diagnosis. The rate of disappearance of the lesions was faster in patients who received bronchoscopic cryotherapy and anti-TB chemotherapy, compared to the patients who received only anti-TB treatment.[33]

In a controlled trail of 115 patients with sputum smear-positive, culture sensitive TB, 41 patients received bronchoscopic APC plus routine anti-TB chemotherapy (APC group) and the other 74 patients received only routine anti-TB chemotherapy (chemotherapy group). The complete resolution of endobronchial lesions was seen in 100% of the APC group and 84.6% in chemotherapy group. The rate of resolution of lesions in the APC group was faster than that of the chemotherapy group. There were no significant complications in the APC group. APC can be a potential complementary therapy to Anti tuberculosis treatment (ATT) in endobronchial TB, with more studies required to define its exact role.[34] Use of endobronchial laser in the management of pulmonary TB has also been described in literature for post-TB fibrous stenosis of large bronchi.[35]

The surgical resection may be indicated for patients not responding to interventional bronchoscopic techniques. However, diffuse and eccentric involvement, with significant malacia often precludes surgical intervention.

Tracheobronchial stents

Before considering stents in TB, the possibility of active TB lesions have to be ruled by any of the above discussed diagnostic modalities. In TB fibrostenosis [Figure 6] without active TB (smear-negative/histopathology negative) with significant main airway obstruction, tracheobronchial stenting can be very useful. Currently, airway stenting is mainly possible only in the trachea and main bronchi, due to the smaller nature of distal bronchi.

Stenting is usually performed after balloon dilatation with recurrent stenosis, or if there is lack of cartilaginous support which needs stenting. Tracheobronchial stents can be broadly divided into silicone or metal stents. Silicone stents like Dumon stent (Novatech), Hood stent (Hood laboratories) are recommended over metallic stents because of their ease of placement and removal, and the relative contraindication to metallic stents in benign disease.[36] If metallic stents are used, only the completely covered metallic stents are recommended. The old generation self-expanding metallic stents (SEMS) are the Gianturco-z and the Wallstent, and the newer generation SEMS include the Ultraflex stents, Niti-s covered stents and the Microtech tracheobronchial stents. The silicone stents can be left in place for several years.

The complications related to stenting include airway wall perforation, stent migration leading to obstruction, granulation at either end that can worsen the obstruction, and hemoptysis. The SEMS remain relatively stable in position, but the disadvantage is excessive granulation tissue formation and difficulty removing once the stent gets epithelialized, and should be used only if all other options are exhausted.[37]

In series of 80 patients with post-tuberculous tracheobronchial stenosis, use of silicone stents in addition to other modalities of management has been reported. The silicone stents were required in 94% (75/80) of patients. In 88% patients, bronchoscopic intervention provided immediate symptomatic relief and improved lung function. Post insertion, with median of 14 months, stents were successfully removed in 65% (49/75) patients. Definitive surgical management was required in 4% (3/75) patients. During the median follow-up of 41 months, stent related acute complications reported were excessive bleeding (N = 1); pneumothorax (N = 5), pneumomediastinum without mortality (N = 2). Stent-related chronic complications described in the study were migration (51%), granuloma formation (49%), mucostasis (19%), and restenosis (40%).[38] In a similar study seven patients underwent a total of 11 dilatations with placement of 10 straight and 1 Y stent. The stents were left in situ for a mean of 32 months.[39]

There is definitive role of advanced therapeutic bronchoscopy (balloon bronchoplasty and stenting) in patients with TB - bronchostenosis. However, prospective studies with guidelines are needed to define the candidates for stenting, duration for which stents should be left in situ, and management of stent-related complications.

Bronchoscopic management of air leaks (case with illustration of bronchopleural fistula)

Prolong air leak (PAL) is defined as persistent air leak for more than 5 days. It contributes to significant mortality and morbidity in TB. PAL can be due to bronchopleural fistula (BPF) or alveolarpleural fistula (APF).[40] An APF is defined as a communication between the pulmonary parenchyma distal to a segmental bronchus and the pleural space. BPF is a communication between a main-stem/segmental bronchus and the pleural space.[41] The bronchoscopic interventions represent a viable option when these conventional methods fail or are not feasible. Though several innovative options are described for BPF and APF, their specific application in TB has not been well-defined. Briefly, the bronchoscopic management options for PAL include application of sealants, or occlusive devices. Sealants are adhesive-like substances, which close the air leak, and include collagen matrix plugs,[42] collagen screw plugs,[43] synthetic hydrogel,[44] and bio-glues,[45] with variable efficiency.

Endobronchial occlusive devices are used to occlude the bronchus leading to BPF. Various devices are described in literature, including stents and their modifications, endobronchial valves (EBV), Amplatzer devices,[46] and the endoscopic Watanabe spigot (EWS).[47]

In our experience, an innovative second-generation spigot-blocker, named as “customized endobronchial silicone blocker (CESB)” [Figure 7]a and [Figure 7]b can be used for refractory BPF/APF in TB, when other options include surgery are exhausted. In a recent abstract, 21 CESBs were placed in 15 patients with BPF related to TB. The BPFs included four post-surgical (lobectomy/pneumonectomy) main bronchial dehiscences and in 11 patients, secondary/tertiary bronchial dehiscences. The BPF resolved in 12/15 patients (80%), which lead to successful chest tube removal. The complications included migration in 3/15 (20%) patients, with persistence of the BPF.[48] This innovative CESB option can be useful in these situations with TB related PAL, when all other options are exhausted.{Figure 7}{Figure 8}

Bronchoscopic management of hemoptysis

Hemoptysis is a common complication of TB, and is usually related to an active tuberculous cavity, sequelae of TB like bronchiectasis, or an aspergilloma in a tubercular cavity.[49]

An integrated management of TB-related hemoptysis is recommended and includes conservative management, bronchial artery embolization (BAE), surgical management, and bronchoscopic interventions. Scarce literature is available on bronchoscopic management of TB-associated hemoptysis. In our experience, the principles of management of hemoptysis in TB are similar to that of any other disease. Bronchoscopic options are briefly discussed below, especially for massive hemoptysis.

In massive hemoptysis, the most important initial step to protect the non-diseased side from flooding with blood (concept of “hypoxic flooding”) is to keep the diseased lung in the dependent position. After initial hemodynamic stabilization of patients, bronchoscopy serves to localize the bleeding site, if not apparent by earlier investigations. For local control, several flexible or rigid bronchoscopic options are discussed in literature. These are classified according to whether the source of bleed is endobronchial or parenchymal. In TB-related bleeding, most bleeds are parenchymal in origin. The general strategies include cold saline lavage, topical vasoconstrictive agents, fibrinogen/thrombin, balloon tamponade, stent tamponade, and endo-bronchial airway blockers, all of which are useful mainly for parenchymal etiologies. For endobronchial bleeding, APC (argon photo-coagulation), electrocautery, laser, and cryotherapy have been described. These are most often temporary measures for emergency management; however, in some cases, bronchoscopic management provides a long-lasting hemostatic effect.

The rigid bronchoscopy clearly has an advantage for airway control and management in patients with massive life-threatening hemoptysis. It offers improved visualization of the airways, secures airway patency, and ventilation, and allows better suction of blood clots and secretions. It also provides effective tamponade of accessible bleeding sites. In addition, various other complementary endobronchial procedures described below can be done using the rigid scope. Lack of ready availability of rigid bronchoscopy and training is the limiting factor.

In mild to moderate hemoptysis, topical instillation of the agents like cold-Saline,[50] vasoactive agents [51] like diluted epinephrine, thrombin and fibrinogen-thrombin infusion [52], and n-butyl cyanoacrylate,[53] a biocompatible adhesive have been effective in temporary control of hemoptysis.

The biggest challenge in TB bleeds is massive hemoptysis, which may require out of the box therapies. Innovations such as endobronchial embolization with silicone spigots have been successfully used in case of massive hemoptysis, based on blocking the bleeding segment to prevent “hypoxic flooding”. Dutau et al. reported the first case of its successful use in massive hemoptysis. Following this procedure, the patient underwent BAE, and the spigot was removed 2 hours later.[54] Adachi et al., has recently described the use of Endobronchial Watanabe Spigots (EWS) for the management of massive hemoptysis associated with Mycobacterium avium complex infection. There was no worsening of infection, and later the patient had definitive BAE.[55]

On similar lines, we have extended the use of the spigot to massive hemoptysis in TB. The customized endobronchial silicon spigot (CESB) described above, reinforced with bio-glue to prevent migration, has been successfully used for the management of TB-related massive hemoptysis in seven patients. In this series, four had active TB, three had old inactive TB. Three patients were taken for rescue CESB insertion after failed BAE. Of the remaining four, three were not suitable for BAE due to azotemia and one was hemodynamically unstable, and these were taken directly for CESB placement. Immediate success was achieved in all (100%) patients, which allowed time for elective procedures later as needed. After stabilization, BAE was done successfully in one patient and one patient had elective lobectomy. No further intervention was required in the other other patients. The CESB was removed after a mean duration of 45 days. The complications included migration in one case. No significant infection was noted.[56]

Future aspects: Tuberculosis therapy and the expanding role of interventional bronchoscopy

An anaerobic environment is unfavorable for growth of MTB. The historic treatment options like of “collapse therapy” or “thoracoplasty” was based on the hypothesis that hypoventilation and atelectasis results in an anaerobic environment and prevents the growth of MTB. Following a similar hypothesis, Corbetta et al. described lobar collapse therapy using EBV (EBV, Zephyr, PulmonX Inc., Redwood City, CA, USA) as a new complementary approach to treat cavities in MDR-TB and difficult-to-treat TB.[57] In 5 patients unfit for surgical resection, with an unsatisfactory response to drug therapy, lobar occlusion therapy to target collapse was done using EBV's, in addition to anti-TB drug therapy. The study included two patients with MDR/XDR TB, and two patients with difficult-to-treat TB. These two patients included a patient with a persistent cavity and symptoms despite treatment, and one patient with a TB cavity and treatment related DRESS syndrome (drug reaction, eosinophilia, and systemic side effects). One patient had an atypical mycobacterial infection. At the time of EBV placement, four out of five patients had positive sputum smear microscopy, with average 1 to 5 months of treatment. Targeted “lobar volume reduction” with reduction in cavity size was achieved in four patients within 1 month of EBV implantation. The sputum TB smears and cultures turned negative 3–5 months after EBV placement and remained negative till the end of follow-up (mean follow-up: 23 ± 12 months, range 6–40), in combination with anti-TB chemotherapy.

Complications reported included pneumothorax in one patient, which is described with EBV therapy, and did not requiring drainage. EBV induced collapse is a potential therapy for patients who have otherwise refractory mycobacterial pulmonary disease, and needs larger prospective control studies to establish safety and effectiveness.

 Conclusions



This article describes the latest advances in the bronchoscopic diagnostic and therapeutic approach to TB in 2017. This heralds a new era in the multimodality approach to TB. On the diagnostic front, bronchoscopic procedures are complementary to traditional diagnostic tools in getting accurate samples, for both accurately identifying TB and defining drug resistance. These include bronchoscopy with BAL, endobronchial biopsy and transbronchial biopsy, and the expanded spectrum of bronchoscopy with EBUS and radial EBUS. In the therapeutic arena, bronchoscopic procedures go hand-in-hand with other tools and chemotherapy, and are offering innovative solutions in difficult situations. These procedures offer minimally invasive options in both emergent and elective situations such as TB airway stenosis, massive hemoptysis, BPF, and drug-resistant TB.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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