Clinical Profile and Quality of Life of Patients With Post-pulmonary Tuberculosis Sequelae Presenting to a Tertiary Care Hospital

Background and objective There is a dearth of studies on the clinical presentation of patients with post-pulmonary tuberculosis (PTB) sequelae and its impact on their quality of life (QoL). In light of this, we conducted this study to analyze the clinical profile and QoL in patients with post-PTB sequelae. Methods Patients with a history of treated PTB and evidence of radiological damage were enrolled prospectively from November 2018 till June 2020 to study their clinical profile and QoL as per the eligibility criteria. A detailed clinical history was taken along with posteroanterior-view chest X-rays and CT scans of the thorax with bronchial angiography in patients with hemoptysis. QoL was assessed using the Hindi version of St. George's Respiratory Questionnaire (SGRQ) for which permission was obtained from the St. George’s University of London. SGRQ scores were calculated using score calculation algorithms (Microsoft Excel-based) and missing data imputation as recommended by its developer. Results A total of 174 patients were included in the analysis. The analyzed population was relatively younger (mean age: 44.27 years) with BMIs leaning toward the lower side of normal (median: 19.6 kg/m²); the majority of the patients were males (59%) and non-smokers (77%). PTB had been diagnosed clinico-radiologically in the majority (68%) of patients with non-compliance to antitubercular treatment (ATT) being reported by only 9% of patients. Multiple courses of ATT were received by about one-third of patients, mainly on a clinico-radiologic basis. Systemic hypertension (HTN) (11%) and diabetes mellitus (DM) (9%) were the most common comorbidities. The most common symptom complex found was cough, expectoration, and dyspnea (n=102, 59%). At least one incidence of massive hemoptysis was reported by 20% of patients. Bronchial artery embolization (BAE) was performed for moderate to massive hemoptysis in 26% of patients with a success rate of >90%. One-fifth of the study participants required hospitalization for exacerbation of respiratory symptoms with more than half of these (59%) requiring ventilatory support. Health-related QoL was significantly impaired as reflected by a median SGRQ total score of 45.53. The most affected domain of QoL was the activity domain (mean score: 45.47). Females had worse QoL as compared to males (p=0.0062), and so did underweight patients (p=0.048). The prolonged duration of the illness also significantly impaired the QoL (p<0.001, r=0.313). Conclusion The sequelae of PTB are under-recognized even among physicians and are frequently misdiagnosed as active PTB. The QoL is more severely affected due to residual damage. This study highlights the clinical profile of this patient population and underscores the need to recognize post-PTB sequelae as a separate entity. An important remedy to mitigate its long-term consequences is its inclusion and recognition in national and international TB guidelines to facilitate its early identification and promote further research to address its evidence-based management.


Introduction
Pulmonary tuberculosis (PTB) can lead to irreversible lung damage, manifesting as scarring, fibrosis, cavitation, or other types of damage on radiological images. This damage can lead to loss of lung function, long-term respiratory symptoms, and eventually, chronic respiratory disease, including chronic obstructive 1 2 2 3 1 pulmonary disease (COPD), bronchiectasis, and aspergillosis [1][2][3][4][5]. However, the current WHOrecommended TB registries only focus on mortality and morbidity during TB treatment and, as a result, patients are not followed up beyond the cure of the disease [6]. Out of hundreds of international TB guidelines, only a few mention TB sequelae, and none describe how to identify or manage the condition. This could be attributed to the lack of studies focusing on post-PTB sequelae.
Although smoking remains the most crucial risk factor for COPD, a considerable burden of the disease in developing countries cannot be explained by smoking alone. TB and other non-smoking-related risk factors of COPD have been well described [7]. The relationship between TB and COPD in non-smokers is supported by data from the Burden of Obstructive Lung Disease (BOLD) and Proyecto Latinoamericano de Investigación en Obstrucción Pulmonar (PLATINO) studies, which performed sub-group analyses and found even more robust associations between TB and COPD in people who were never-smokers [8,9]. A systematic review and meta-analysis found that the association between prior history of TB and the presence of COPD was strongest in never-smokers and younger people (<40 years of age) [10].
As the patients of PTB are rarely followed up upon completion of the treatment, there is scarce data on their sociodemographic parameters and symptomatology of post-PTB sequelae. It is unknown how physicians usually approach such patients. It is not uncommon to find such patients being managed as active PTB cases on clinico-radiologic grounds, particularly by primary care practitioners due to a lack of awareness about post-PTB sequelae. The presentation of respiratory failure and management in such patients has rarely been documented in the literature. The effect of impaired pulmonary function on health-related quality of life (QoL) has been studied sparingly. A few studies have observed a correlation between spirometry measures and components of St. George's Respiratory Questionnaire (SGRQ) scores as well as overall [11,12].
Globally, good quality data on the clinical profile and QoL of patients with post-PTB sequelae are sparse, particularly from India where TB is endemic. Hence, this study was planned to perform a comprehensive evaluation of the clinical profile and QoL of patients with post-PTB sequelae.

Materials And Methods
This was an observational cross-sectional study involving patients attending the Department of Pulmonary Medicine, All India Institute of Medical Sciences (AIIMS), New Delhi between November 2018 and June 2020 who were selected based on the eligibility criteria. All patients who had microbiologically or clinicoradiologically proven and treated PTB as per national guidelines with radiological evidence of sequelae were defined as post-PTB sequelae cases. They would undergo a detailed evaluation, including clinical history, posteroanterior-view chest X-rays, and CT scans of the thorax with bronchial angiography in patients with hemoptysis. All patients would undergo sputum for acid-fast bacillus (AFB) and cartridge-based nucleic acid amplification test (CB-NAAT) to rule out active PTB. As per the clinico-radiological assessment, bronchoalveolar lavage (BAL) was done to rule out active TB, wherever indicated. The QoL was assessed using the Hindi version of SGRQ for which permission was obtained from the St. George's University of London. SGRQ scores were calculated using score calculation algorithms (Microsoft Excel-based) and missing data imputation as recommended by its developer (P.W. Jones, St Georges Hospital Medical School, London, UK). Patients with active PTB, prior diagnosis of asthma or COPD, bronchiectasis due to nontubercular causes, interstitial lung disease, pneumoconiosis (like silicosis, coal miner's pneumoconiosis, and asbestosis), and other causes of pulmonary fibrosis, history of thoracotomy, and patients unwilling to give consent were excluded from the study.

Data management and statistical analysis
Data entry was done as per the designed proforma. Study data were collected and managed using REDCap electronic data capture tools hosted at AIIMS, New Delhi. Data management and analysis software Stata, version 14.2 was used for analysis. We used mean and standard deviation (SD) to represent the continuous variables when the variable followed a normal distribution. In the case of non-normal continuous variables, we used the median and interquartile range (IQR). The categorical variables were represented as frequencies with percentages. Categorical variables were compared between the groups by Chi-square/Fisher's exact test.
Wilcoxon rank-sum test was applied when the continuous variable did not follow a normal distribution. A pvalue <0.05 was considered statistically significant.

Results
A total of 181 patients were enrolled in the study. Of these, 174 were included in the analysis (Figure 1). We excluded five patients who were found to have a recurrence of active PTB, one patient who had allergic bronchopulmonary aspergillosis-central bronchiectasis (ABPA-CB), and one patient who had suspected intrabronchial foreign body with left lower lobe bronchiectasis.   Smear and culture +ve 1 Smear and CB-NAAT +ve 1 The duration between the first ATT completion and the appearance of symptoms, months, median (IQR) 36 (1-120) Duration of ATT received per patient, months, median (IQR) 9 (6)(7)(8)(9)(10)(11)(12) No. of ATT courses received, n (%)  The diagnosis of PTB was on a clinico-radiologic basis in the majority of the participants (67.8%) with a median (IQR) duration between the first antitubercular treatment (ATT) completion and the appearance of symptoms being 36 (1-120) months. The median (IQR) duration of ATT received per patient was nine (6-12) months; 15 (9%) patients reported a history of ≥3 courses of ATT intake whereas 41 (23.56%) participants reported an intake of two courses of ATT. The most commonly used initial regimen at the time of diagnosis of TB was category I in 166 (95%) participants; 44 (25%) patients had been prescribed category I followed by category II treatment after varying intervals of time. Non-compliance to the first ATT intake was reported by only 15 (9%) participants.
Modified Medical Research Council (mMRC) grade 2 was the most common grade of dyspnea present (n=71, 53%) in patients; massive hemoptysis of at least one episode was present in 34 (20%) patients; two (1%) patients also had hoarseness of voice. Seasonal worsening of symptoms and wheezing were reported by 22% and 17% of participants respectively. Dull aching chest pain was present in 12% of patients. Table 4 summarizes the symptomatic presentations among the study participants.  Among the treatments prescribed for dyspneic patients, the combination of long-acting beta-agonist (LABA) + inhaled corticosteroid (ICS) and long-acting muscarinic antagonist (LAMA) was received by 75 (56%) patients; LABA + LAMA combination was administered to 10 (07%) participants while LAMA alone to 17 (13%) participants. Symptomatic relief of dyspnea with inhalers was reported by 126 out of 135 (93%) dyspneic patients. Bronchial artery embolization (BAE) was performed in 46 (26.4%) participants, resulting in the control of hemoptysis in 42 (91%) patients. Hospitalization for exacerbation of respiratory symptoms due to post-tubercular chronic lung disease was reported in 34 (20%) patients with 20 (59%) of them requiring mechanical ventilatory support during exacerbation. Vaccination against pneumococcus and influenza, at least once, was reported by 21 (12%) participants. The treatment profile is presented in Table 5.

Quality of life (QoL)
Of the 174 patients, QoL was assessed in 157 patients (90%). It could not be assessed in three patients who expired while on invasive ventilation for respiratory failure, six patients due to CAD with left ventricular (LV) dysfunction, two patients due to congenital heart disease (CHD), and two patients due to valvular heart disease (VHD); four patients did not return the questionnaire (Figure 1). The median (IQR) total score was 45.53 (24.65-55.65). Table 6 shows the various components of SGRQ.  The QoL depicted by the mean total score of SGRQ was analyzed in terms of gender, smoking status, exposure to biomass, and BMI ( Tables 7, 8, 9, 10 respectively); females had a significantly worse QoL as compared to males (p=0.0062); The was a significant difference in QoL between patients with BMI <18.5

Parameter Mean ± SD Median (IQR)
Kg/m 2 and those with BMI ≥18.5 Kg/m 2 (p=0.048) with undernourished individuals having a worse QoL. A significant positive correlation was found between the total score of SGRQ and the duration of being symptomatic, implying that a more prolonged duration of illness is associated with a worse QoL for the patients (Figure 2).

Discussion
This was a tertiary care hospital-based cross-sectional study to assess the clinical profile and estimate the long-term effects of treated PTB on the QoL of patients. Despite having no evidence of active PTB, patients treated for PTB had substantial impairment in QoL. In our study, the affected population predominantly belonged to the younger, economically productive age group (mean age: 44 years) with 59% of the participants being males. The median BMI was 19.6 kg/m 2 with about one-third (33.90%) of the participants being underweight; smoking history was given by 23% of patients with 35 (87.5%) of them being bidi smokers, thus reflecting the lower socioeconomic status of the affected population. Among female participants in the study, more than half (54.92%) had biomass fuel exposure for varying duration. The preponderance of post-PTB sequelae in the younger age group is in line with other studies [8,13]. The predominance of males was also reported in the studies by Akkara et al. and Radovic et al., where males accounted for 74 and 62.5% of cases respectively [13,14]. Also, in the study by Mbatchou Ngahane et al., 146 (54%) of the study participants were males; 242 (90%) of their cases were never-smokers; however, only eight (3%) patients in their study were underweight with 63% of patients having a normal BMI [15].
HTN (11%) and DM (9%) were the two most common comorbidities in our study participants followed by CAD (5%). Multiple comorbidities were present in 11 (6%) participants with the combination of HTN and CAD being the most common combination found. Mbatchou Ngahane et al. in their study reported HTN and DM in 12 (4.5%) and eight (3%) cases respectively [15].
Multiple courses (≥2) of ATT were given to 56 patients (32%) for treating suspected relapse of PTB on a clinic-radiologic basis without microbiologic confirmation, possibly due to the failure of recognizing healed PTB sequelae as a separate disease entity, thereby unnecessarily increasing potential of drug-related adverse events with no mitigation of morbidity in patients, for which the patient had presented to the physician. Van Kampen et al. also highlighted this problem of misdiagnosing post-PTB sequelae as active PTB in resourcelimited settings [16]. This is particularly relevant in cases of chronic cavitary pulmonary aspergillosis (CCPA), which has clinico-radiologic similarity with PTB, and which, if left untreated, can progress to chronic fibrosing pulmonary aspergillosis (CFPA) with permanent loss of lung function. The median interval between the first ATT completion and the appearance of symptoms attributable to post-PTB sequelae was 36 months (IQR: 1-120); the median duration of ATT received per patient was nine months (IQR: 6-12).
The majority of the patients reported being compliant (91%) to ATT when they were diagnosed with PTB. Persistence of symptoms after the completion of ATT was reported by 56 patients (32%) in our study. Other studies have shown that PTB patients who have completed treatment continue to have respiratory symptoms at the end of treatment (30-47%), after one year of treatment (40%), and after two and a half years of treatment completion (15.9%) [17,18]. Banu Rekha et al. also documented the persistence of symptoms in 58 (29%) of their patients [11]. Another study has reported 53.62% of patients developing respiratory symptoms >72 months after the completion of their ATT [19].
Akkara et al. [13] in their study have documented that most of the patients (85%) presented with respiratory complaints such as cough, expectoration, or breathlessness after a mean duration of 8.9 months following the cure of TB; hemoptysis was present in 12% of the participants. Singla et al. in their study on sequelae in 46 patients with multidrug-resistant (MDR) PTB, after completion of two years of treatment, found dyspnea to be the most common residual symptom (87%) with mMRC grade 2 dyspnea present in 65% of cases [20]. In another study, cough (94%) was also a dominant symptom followed by chest pain (63%) and expectoration (51%) with dyspnea and hemoptysis reported in 34% and 28% of cases respectively [15]. QoL was assessed using the Hindi version of SGRQ validated in the Indian population [22]. The median (IQR) total score was 45.53 (24.65-55.65), reflecting significant impairment in health-related QoL. We did not find any effect on QoL due to smoking or biomass exposure; however, patients who had BMI <18.5 kg/m 2 had significantly worse QoL compared to patients with BMI ≥18.5 kg/m 2 . This emphasizes the need to improve the nutritional status of patients suffering from post-PTB sequelae. A significant positive correlation was found between the total SGRQ score and the duration of being symptomatic, implying that a more prolonged duration of illness is associated with worse QoL in patients. This reflects the need to recognize the entity at the earliest. Pasipanodya et al. [23], in their study of 106 patients with post-PTB sequelae, did not find any effect of smoking on QoL. We also did not find any effect of smoking on QoL. However, another study by Banu Rekha et al. did find a significant effect of smoking on QoL in their patients with smokers faring worse [11]. They also found significantly higher total scores of SGRQ in females as compared to males, reflecting a worse QoL, which is in line with our study [11]. Among the three components of SGRQ, the score for the impact component was lower than that for the symptom and activity components in our study, which is in line with earlier SGRQ-based studies in treated PTB patients [11]. While evaluating SGRQ in our study population, we noted some of its limitations. Hemoptysis is not mentioned in SGRQ, which was present in 108 (62%) patients in our study and was sometimes the dominant symptom, and hence its effects on QoL could not be evaluated. The age group affected was younger (mean age: 44.27 ± 14.63 years) and, as a result, the effect on impact score and activity score components of SGRQ may not be reflective of the actual effect as young people are generally more healthy and active. A dull aching chest pain (12%), which was as common as wheezing (17%) in our study participants, is not mentioned in the SGRQ score, and hence its impact on QoL could not be assessed.
The strengths of our study include its location, which is one of the TB-endemic regions. Moreover, our study focused on the clinical presentation of the disease in detail as well as the approach by clinicians, which no other study has reported to date to the best of our knowledge. The study also assessed the impact on QoL, which has received scarce attention in the literature so far. The main limitation of the study is that it was hospital-based rather than community-based, and hence the extrapolation of its data can be misleading given the burden of PTB. Another limitation of the study is that the majority of our patients had their PTB diagnosed on a clinico-radiologic basis instead of having a microbiologic diagnosis that is confirmatory.

Conclusions
The sequelae of healed PTB are under-recognized even among physicians, with consequent misdiagnosis as active PTB, which leads to erroneous management involving repeated courses of ATT, thereby predisposing patients to drug-induced toxicity. This increases morbidity and mortality, which can be further aggravated by the undetected progression of post-PTB sequelae. The QoL is also affected due to residual damage. This study highlights the clinical profile of these patients and underscores the need to recognize post-PTB sequelae as a separate entity. The best way to mitigate its long-term consequences is by inclusion and recognition of post-PTB sequelae in national and international TB guidelines to facilitate its early identification and promote further research to address its management.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Institute Ethics Committee for Post Graduate Research, AIIMS, Ansari Nagar, New Delhi issued approval IECPG -31/ 23.01.2019. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.