Predictors of unfavorable responses to therapy in rifampicin-sensitive pulmonary tuberculosis using an integrated approach of radiological presentation and sputum mycobacterial burden

Introduction Despite the exalted status of sputum mycobacterial load for gauging pulmonary tuberculosis treatment and progress, Chest X-rays supplement valuable information for taking instantaneous therapeutic decisions, especially during the COVID-19 pandemic. Even though literature on individual parameters is overwhelming, few studies have explored the interaction between radiographic parameters denoting severity with mycobacterial burden signifying infectivity. By using a sophisticated approach of integrating Chest X-ray parameters with sputum mycobacterial characteristics, evaluated at all the three crucial time points of TB treatment namely pre-treatment, end of intensive phase and completion of treatment, utilizing the interactive Cox Proportional Hazards model, we aimed to precisely deduce predictors of unfavorable response to TB treatment. Materials and method We extracted de-identified data from well characterized clinical trial cohorts that recruited rifampicin-sensitive Pulmonary TB patients without any comorbidities, taking their first spell of anti-tuberculosis therapy under supervision and meticulous follow up for 24 months post treatment completion, to accurately predict TB outcomes. Radiographic data independently obtained, interpreted by two experienced pulmonologists was collated with demographic details and, sputum smear and culture grades of participants by an independent statistician and analyzed using the Cox Proportional Hazards model, to not only adjust for confounding factors including treatment effect, but also explore the interaction between radiological and bacteriological parameters for better therapeutic application. Results Of 667 TB patients with data available, cavitation, extent of involvement, lower zone involvement, smear and culture grade at baseline were significant parameters predisposing to an unfavorable TB treatment outcome in the univariate analysis. Reduction in radiological lesions in Chest X-ray by at least 50% at 2 months and 75% at the end of treatment helped in averting unfavorable responses. Smear and Culture conversion at the end of 2 months was highly significant as a predictor (p<0.001). In the multivariate analysis, the adjusted hazards ratios (HR) for an unfavorable response to TB therapy for extent of involvement, baseline cavitation and persistence (post treatment) were 1.21 (95% CI: 1.01–1.44), 1.73 (95% CI: 1.05–2.84) and 2.68 (95% CI: 1.4–5.12) respectively. A 3+ smear had an HR of 1.94 (95% CI: 0.81–4.64). Further probing into the interaction, among patients with 3+ and 2+ smears, HRs for cavitation were 3.26 (95% CI: 1.33–8.00) and 1.92 (95% CI: 0.80–4.60) while for >2 zones, were 3.05 (95% CI: 1.12–8.23) and 1.92 (95% CI: 0.72–5.08) respectively. Patients without cavitation, zonal involvement <2, and a smear grade less than 2+ had a better prognosis and constituted minimal disease. Conclusion Baseline Cavitation, Opacities occupying >2 zones and 3+ smear grade individually and independently forecasted a poorer TB outcome. The interaction model revealed that Zonal involvement confined to 2 zones, without a cavity and smear grade up to 2+, constituting “minimal disease”, had a better prognosis. Radiological clearance >50% along with smear conversion at the end of intensive phase of treatment, observed to be a reasonable alternative to culture conversion in predicting a successful outcome. These parameters may potentially take up key positions as stratification factors for future trials contemplating on shorter TB regimens.


A brief summary of the two clinical trials that were aimed at
shortening of TB treatment to 4 months, from which the cohort has been taken for analysis is given below in order to have a bird's eye view of the characteristics of patients enrolled.
Reference 1: Jawahar MS et.al (2013)  This was a randomised control clinical trial that attempted to shorten tuberculosis (TB) treatment to 4 months using gatifloxacin or moxifloxacin in combination with other antitubercular treatment (ATT) drugs. Newly diagnosed, sputum-positive HIV-negative adult pulmonary TB patients were randomly allocated to receive gatifloxacin or moxifloxacin, along with isoniazid and rifampicin for 4 months with pyrazinamide for first 2 months (G or M) or isoniazid and rifampicin for 6 months with ethambutol and pyrazinamide for first 2 months (C). All regimens were administered thrice-weekly. Clinical and bacteriological assessments were done monthly during treatment and for up to 24 months post-treatment. The mean weight of the participants was 43.6 kilogram and, the sputum culture was 3+ and the number of zones in X-ray was >2 in 79% of the study participants signifying extensive disease. Second month culture negativity was 83% in the gatifloxacin arm, 88% in the moxifloxacin arm and 78% in the control arm (standard of care Section 2.0: Chest X-ray (CXR) interpretation.

Selection of X-rays and interpretation
The cohort analyzed in this study was limited to those participants whose Chest X-rays were available serially for all the three decisive time points of treatment period, namely baseline or pre-treatment, 2 nd month or end of intensive phase and end of treatment. All the patients were exposed to a standard Chest X-ray PA view taken in Akimbo's position, at a distance of 6 feet between the tube and the screen. All the soft copy images were of DICOM format (Digital Imaging and communications in Medicine). For valid comparison, each patient needed to have X-rays either as soft or hard copies uniformly throughout for that particular patient at all crucial time points. X-rays of poor quality were excluded.
To minimize inaccuracies in interpretation, the visual estimation was done in such a way that, those lesions with definite evidence of zonal involvement and those with visibly apparent reduction in lesion size were considered. The readers were totally blinded to the clinical data and their observations were captured in separate files and sent to the independent statistician for amalgamation. Two Readers who were pulmonologists managing TB for at least 20 years interpreted the X-rays independently with an umpire reader who had at least 25 years' experience interpreting in cases of discrepancies. ❖ The Mid zone is bordered from the lower zone by a horizontal line drawn from the anterior lower end of the fourth rib.

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❖ The zones have no relationship with the lobes of the Lung in the chest Xray.
Simple visual estimation was used, mimicking the way patients are managed at hospitals, by characterizing the lesions as shown in the table and assigning a number to each type of lesion.
The zones were denoted as alphabets.
A simple picture to denote the description of zones is given below.

Measurement of reduction or clearance of radiological lesion
We used a slightly modified Ralph scoring for calculating the reduction percentage of radiological lesions or radiological clearance by comparing the CXR's at two consecutive points i.e., baseline and the end of intensive phase, End of intensive phase and end of treatment.
At baseline, definitive lesions in each of the zones were counted at 100% (dichotomous scoring was used, presence was 100, and absent was 0). In a similar way, the lesions in the follow-up serial X-rays at end of intensive phase (IP) and end of treatment or continuation phase (CP) were also read and recorded. An increase in size of a lesion roughly 50% from baseline size was considered deterioration (D), a visual decrease in size of a lesion by at least 50% from baseline as improvement (I), with similar picture as previous one -status quo (S). If the lesion at baseline disappeared completely in the follow-up X-ray reading at end of IP, it was termed as resolved (R). If any new lesion arises in one of the zones or any lesion extends into other neighboring zones in the follow-up X-ray at end of IP, and was previously not detected in the baseline CXR, then it was coined as newly appeared (A). This R-I-S-D-A classification and coding was followed for each lesion in each zone in the follow up X-rays and numerically represented as R (+100%), I (+50%), S (0), D (-50%) and A (-100%). Going by the pathophysiology of pulmonary TB, lesions that signified healing process of the TB disease such as fibrosis and calcifications were scored as improvement as would be deciphered by a treating clinician and given a score of 50% in the follow up X-rays. An opacity breaking down into cavitation was given a score of -100% (minus 100%) as it signified deterioration for practical estimation, paying due heed to the Ralph scoring method. After assigning the individual scores to the topographical lesions in each zone, a simple reduction percentage was calculated by dividing the sum of the scores of each lesion in the X-ray at end of IP or end of treatment, by the number of lesions accounted for, to arrive at the overall reduction percentage.
We felt that this kind of scoring exactly adapts itself to the practical way in which clinicians decipher improvement or deterioration.