An unusual complication secondary to kanamycin use in a patient of multidrug-resistant pulmonary tuberculosis.

Gitelman syndrome (GS) is a rare genetic renal disease characterized by hypomagnesemia, hypokalemia, hypocalciuria, and metabolic alkalosis. It usually presents in late childhood or early adulthood. A 30-year-old female diagnosed case of multidrug-resistant (MDR-TB) pulmonary tuberculosis 2 months ago presented to our outpatient department with intermittent painful spasms in all four limb muscles. Her treatment regimen consisted of kanamycin, levofloxacin, cycloserine, and ethionamide. On further evaluation, her investigations revealed hypokalemia, hypocalcemia, hypomagnesemia, metabolic alkalosis with normal serum creatinine level. She was initially treated with intravenous calcium and potassium. However, the electrolyte abnormalities and metabolic alkalosis persisted. All her lab parameters became normal after discontinuing kanamycin and electrolyte replacement for 4 weeks. She was discharged and advised to continue her antituberculosis treatment. There was no recurrence of symptoms on further follow up.

Lipid mediators of inflammation and Resolution in individuals with tuberculosis and tuberculosis-Diabetes.

Individuals with concurrent tuberculosis (TB) and Type 2 diabetes (DM) have a higher risk of adverse outcomes. To better understand potential immunological differences, we utilized a comprehensive panel to characterize pro-inflammatory and pro-resolving (i.e., mediators involved in the resolution of inflammation) lipid mediators in individuals with TB and TB-DM. A nested cross-sectional study of 40 individuals (20 newly diagnosed DM and 20 without DM) was conducted within a cohort of individuals with active drug-susceptible treatment-naïve pulmonary TB. Lipid mediators were quantified in serum samples through lipid mediator profiling. We conducted correlation-based analysis of these mediators. Overall, the arachidonic acid-derived leukotriene and prostaglandin families were the most abundant pro-inflammatory lipid mediators, while lipoxins and maresins families were the most abundant pro-resolving lipid mediators in individuals with TB and TB-DM. Individuals with TB-DM had increased correlations and connectivity with both pro-inflammatory and pro-resolving lipid mediators compared to those with TB alone. We identified the most abundant lipid mediator metabolomes in circulation among individuals with TB and TB-DM; in addition, our data shows a substantial number of significant correlations between both pro-inflammatory and pro-resolving lipid mediators in individuals with TB-DM, delineating a molecular balance that potentially defines this comorbidity.

Effect of Diabetes Mellitus on the Pharmacokinetics and Pharmacodynamics of Tuberculosis Treatment.

Diabetes mellitus (DM) and tuberculosis (TB) are two common diseases with increasing geographic overlap and clinical interactions. The effect of DM and hemoglobin A1c (HbA1c) values on the pharmacokinetics (PK) and pharmacodynamics (PD) of anti-TB drugs remains poorly characterized. Newly diagnosed TB patients with and without DM starting fixed-dose, thrice-weekly treatment underwent sampling for PK assessments (predose and 0.5, 2, and 6 h postdose) during the intensive and continuation phases of treatment. The effect of DM and HbA1c values on the maximum concentration (Cmax) of rifampin, isoniazid, and pyrazinamide and the association between drug concentrations and microbiologic and clinical outcomes were assessed. Of 243 patients, 101 had DM. Univariate analysis showed significant reductions in the Cmax of pyrazinamide and isoniazid (but not rifampin) with DM or increasing HbA1c values. After adjusting for age, sex, and weight, DM was associated only with reduced pyrazinamide concentrations (adjusted geometric mean ratio = 0.74, P = 0.03). In adjusted Cox models, female gender (adjusted hazards ratio [aHR] = 1.75, P = 0.001), a lower smear grade with the Xpert assay (aHR = 1.40, P < 0.001), and the pyrazinamide Cmax (aHR = 0.99, P = 0.006) were independent predictors of sputum culture conversion to negative. Higher isoniazid or rifampin concentrations were associated with a faster time to culture conversion in patients with DM only. A pyrazinamide Cmax above the therapeutic target was associated with higher unfavorable outcomes (treatment failure, relapse, death) (odds ratio = 1.92, P = 0.04). DM and higher HbA1c values increased the risk of not achieving therapeutic targets for pyrazinamide (but not rifampin or isoniazid). Higher pyrazinamide concentrations, though, were associated with worse microbiologic and clinical outcomes. DM status also appeared to influence PK-PD relationships for isoniazid and rifampin.

Glycated Hemoglobin Trajectories and Their Association With Treatment Outcomes Among Patients With Pulmonary TB in India: A Prospective Cohort Study.

BACKGROUND: Transient hyperglycemia is seen commonly during TB treatment, yet its association with unfavorable treatment outcomes is unclear. RESEARCH QUESTION: Does an association exist between glycated hemoglobin (HbA1c) trajectories and TB treatment outcomes? STUDY DESIGN AND METHODS: Adults with pulmonary TB were evaluated prospectively for 18 months after the second HbA1c measurement. HbA1c trajectories during the initial 3 months of treatment were defined as follows: persistent euglycemia, HbA1c < 6.5% at baseline and 3-month follow-up; persistent hyperglycemia, HbA1c ≥ 6.5% at baseline and 3-month follow-up; transient hyperglycemia, HbA1c ≥ 6.5% at baseline and < 6.5% at 3-month follow-up; incident hyperglycemia, HbA1c < 6.5% at baseline and ≥ 6.5% at 3-month follow-up. Multivariable Poisson regression was used to measure the association between HbA1c trajectories and unfavorable treatment outcomes of failure, recurrence, and all-cause mortality. RESULTS: Of the 587 participants, 443 participants (76%) had persistent euglycemia, 118 participants (20%) had persistent hyperglycemia, and 26 participants (4%) had transient hyperglycemia. One participant had incident hyperglycemia and was excluded. Compared with participants with persistent euglycemia, those with transient hyperglycemia showed a twofold higher risk of experiencing an unfavorable treatment outcome (adjusted incidence rate ratio [aIRR], 2.07; 95% CI, 1.04-4.15) after adjusting for confounders including diabetes treatment, and BMI; we did not find a significant association with persistent hyperglycemia (aIRR, 1.64; 95% CI, 0.71-3.79). Diabetes treatment was associated with a significantly lower risk of unfavorable treatment outcomes (aIRR, 0.38; 95% CI, 0.15-0.95). INTERPRETATION: Transient hyperglycemia and lack of diabetes treatment was associated with a higher risk of unfavorable treatment outcomes in adults with pulmonary TB.

T-cell responses in COVID-19 survivors 6-8 months after infection: A longitudinal cohort study in Pune.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune response is crucial for disease management, although diminishing immunity raises the possibility of reinfection. METHODS: We examined the immunological response to SARS-CoV-2 in a cohort of convalescent COVID-19 patients in matched samples collected at 1 and 6-8 months after infection. The peripheral blood mononuclear cells were isolated from enrolled study participants and flow cytometry analysis was done to assess the lymphocyte subsets of naive, effector, central memory, and effector memory CD4+ or CD8+ T cells in COVID-19 patients at 1 and 6-8 months after infection. Immunophenotypic characterization of immune cell subsets was performed on individuals who were followed longitudinally for 1 month (n = 44) and 6-8 months (n = 25) after recovery from COVID infection. RESULTS: We observed that CD4 +T cells in hospitalized SARS-CoV-2 patients tended to decrease, whereas CD8+ T cells steadily recovered after 1 month, while there was a sustained increase in the population of effector T cells and effector memory T cells. Furthermore, COVID-19 patients showed persistently low B cells and a small increase in the NK cell population. CONCLUSION: Our findings show that T cell responses were maintained at 6-8 months after infection. This opens new pathways for further research into the long-term effects in COVID-19 immunopathogenesis.

Sex Differences in TB Clinical Presentation, Drug Exposure, and Treatment Outcomes in India.

BACKGROUND: The role of sex differences in clinical presentation, TB drug pharmacokinetic variables, and treatment outcomes is unclear. RESEARCH QUESTION: What is the effect of sex on TB disease severity, drug exposure, and treatment outcome? STUDY DESIGN AND METHODS: This study was a prospective cohort study conducted in India. It assessed TB disease severity; risk of unfavorable treatment outcomes (failure, recurrence, and death) according to sex; and risk factors for unfavorable outcomes stratified according to sex. Effects of sex on the pharmacokinetic variables (maximum concentration and area under the curve) of rifampicin, isoniazid, and pyrazinamide were estimated by using noncompartmental analyses. RESULTS: Of 1,541 people with microbiologically confirmed TB, 567 (37%) were women. Women had a lower risk of high mycobacterial burden (smear grade ≥ 2 and/or time to detection < 7 days) with an adjusted OR of 0.70 (95% CI, 0.56-0.87). Among the 744 participants who were followed up prospectively, 261 (35%) were women. Women had a lower risk of unfavorable treatment outcomes (adjusted incidence risk ratio, 0.60; 95% CI, 0.43-0.85), mostly because recurrence was lower (adjusted incidence risk ratio, 0.45; 95% CI, 0.23-0.86). Isoniazid (but not rifampicin and pyrazinamide) maximum concentration and area under the curve were significantly higher among women (P < .01) than men. Among women, unfavorable outcomes were more likely among those with cavitary disease, but among men, increased risk of unfavorable outcomes was associated with alcohol use, higher BMI, and lower glycated hemoglobin level. INTERPRETATION: Women present with lower mycobacterial burden, achieve higher TB drug exposure, and are less likely to have unfavorable treatment outcomes than men. Strategies to improve TB treatment success should take into account sex differences in risk factors for unfavorable outcomes.

Lymphopenia with Altered T Cell Subsets in Hospitalized COVID-19 Patients in Pune, India.

The cellular immune cell subsets affecting COVID-19 disease severity are being studied by researchers from many countries. The current study was carried out to investigate the alteration of peripheral blood mononuclear cells (PBMCs) and their subsets in hospitalized COVID-19 patients in a tertiary care center in Pune, India. The PBMCs were isolated from enrolled study participants, and flow cytometry analysis was done to assess peripheral white blood cell alterations. The lymphocyte subsets of naive, effector, central memory, and effector memory CD4+ or CD8+ T cells were then evaluated in COVID-19 patients with different disease categories and compared to healthy controls. The immunophenotypic characterization of the immune cell subset was done for 139 COVID-19 patients and 21 healthy controls. These data were evaluated based on the disease severity. A total of 139 COVID-19 patients were classified as mild (n = 30), moderate (n = 57), or severe (n = 52) cases. The decreased percentages of total lymphocytes, CD3+ T cells, CD4+ T cells, naive T cells, central memory T cells, and Natural Killer (NK) cytotoxic cells were found, and there was increase in effector T (TEf) cells and effector memory T cells in patients with severe COVID-19 compared to healthy controls. The severity of SARS-CoV-2 infection has an effect on lymphocyte subsets, resulting in reduced T memory cells and NK cells but increased TEf cells in severe cases. Clinical Trial Registration: CTRI ID-CTRI/2021/03/032028.

Early Microbiologic Markers of Pulmonary Tuberculosis Treatment Outcomes.

Rationale: Earlier biomarkers of pulmonary tuberculosis (PTB) treatment outcomes are critical to monitor shortened anti-TB treatment (ATT). Objectives: To identify early microbiologic markers of unfavorable TB treatment outcomes. Methods: We performed a subanalysis of 2 prospective TB cohort studies conducted from 2013 to 2019 in India. We included participants aged ⩾18 years who initiated 6-month ATT for clinically or microbiologically diagnosed drug-sensitive PTB and completed at least one follow-up visit. Sputum specimens were subjected to a baseline Xpert Mycobacterium tuberculosis/rifampin (MTB/RIF) assay, acid-fast bacilli (AFB) microscopy and liquid and solid cultures, and serial AFB microscopy and liquid and solid cultures at weeks 2, 4, and 8. Poisson regression was used to assess the impact of available microbiologic markers (test positivity, smear grade, time to detection, and time to conversion) on a composite outcome of failure, recurrence, or death by 18 months after the end of treatment. Models were adjusted for age, sex, nutritional status, diabetes, smoking, alcohol consumption, and regimen type. Results: Among 1,098 eligible cases, there were 251 (22%) adverse TB treatment outcomes: 127 (51%) treatment failures, 73 (29%) recurrences, and 51 (20%) deaths. The primary outcome was independently associated with the Xpert MTB/RIF assay (medium-positive adjusted incidence rate ratio [aIRR], 1.91; 95% confidence interval [CI], 1.07-3.40; high-positive aIRR, 2.51; 95% CI, 1.41-4.46), positive AFB smear (aIRR, 1.48; 95% CI, 1.06-2.06), and positive liquid culture (aIRR, 1.98; 95% CI, 1.21-3.23) at baseline; Week 2 positive liquid culture (aIRR, 1.47; 95% CI, 1.04-2.09); and Week 8 positive AFB smear (aIRR, 1.63; 95% CI, 1.06-2.50) and positive liquid culture (aIRR, 1.54; 95% CI, 1.07-2.22). There was no evidence of Mycobacterium tuberculosis growth in the Mycobacterium Growth Indicator Tube at Week 4 conferring a higher risk of adverse outcomes (aIRR, 1.25; 95% CI, 0.89-1.75). Conclusions: Our analysis identifies Week 2 respiratory mycobacterial culture as the earliest microbiologic marker of unfavorable PTB treatment outcomes.

Tuberculosis notification: An inquiry among private practitioners in Pimpri-Chinchwad municipal corporation area of Maharashtra, India.

BACKGROUND: The Government of India implemented mandatory TB notification policy since 2012. After that India's TB notifications from the private sector steadily increased; however, less is known about private practitioners' (PP's) experiences with TB notification. The present study aims to fulfil this gap. METHODS: We conducted a cross-sectional study during November 2019 to March 2020 in Pimpri-Chinchwad Municipal Corporation (PCMC) area of Maharashtra State. We used a mixed methods approach which involved a survey of 200 PPs and in-depth interviews (IDIs) with 7 PPs and 8 National TB Elimination Program (NTEP) staff. The data were presented in the form of frequencies and percentages and thematic analysis was performed on the qualitative data. RESULTS: The study revealed that most PPs (194 of 200; 97%) were aware of TB notification and 75% reported that they notify TB cases to the NTEP. Of those who notify, majority (129 of 145; 89%) reported that they use paper-based notification being the convenient method due to in-person visit and help by the NTEP staff. Only a third of PPs were aware of electronic notification methods. The main reasons behind low utilization of web based and mobile application were unfamiliarity and technical issues such as poor network connectivity. A third of PPs were aware about monetary incentives for notification and only 17% reported actual receipt of incentive at some point. CONCLUSIONS: Our study identifies several areas where the NTEP can undertake interventions to strengthen the implementation of mandatory TB notification policy. Low awareness about electronic notification methods and preference for paper-based notification in this Study area suggest that more efforts are necessary for successful transitioning from paper-based to electronic notification system.

Tuberculosis (TB) Aftermath: study protocol for a hybrid type I effectiveness-implementation non-inferiority randomized trial in India comparing two active case finding (ACF) strategies among individuals treated for TB and their household contacts.

BACKGROUND: Approximately 7% of all reported tuberculosis (TB) cases each year are recurrent, occurring among people who have had TB in the recent or distant past. TB recurrence is particularly common in India, which has the largest TB burden worldwide. Although patients recently treated for TB are at high risk of developing TB again, evidence around effective active case finding (ACF) strategies in this population is scarce. We will conduct a hybrid type I effectiveness-implementation non-inferiority randomized trial to compare the effectiveness, cost-effectiveness, and feasibility of two ACF strategies among individuals who have completed TB treatment and their household contacts (HHCs). METHODS: We will enroll 1076 adults (≥ 18 years) who have completed TB treatment at a public TB unit (TU) in Pune, India, along with their HHCs (averaging two per patient, n = 2152). Participants will undergo symptom-based ACF by existing healthcare workers (HCWs) at 6-month intervals and will be randomized to either home-based ACF (HACF) or telephonic ACF (TACF). Symptomatic participants will undergo microbiologic testing through the program. Asymptomatic HHCs will be referred for TB preventive treatment (TPT) per national guidelines. The primary outcome is rate per 100 person-years of people diagnosed with new or recurrent TB by study arm, within 12 months following treatment completion. The secondary outcome is proportion of HHCs < 6 years, by study arm, initiated on TPT after ruling out TB disease. Study staff will collect socio-demographic and clinical data to identify risk factors for TB recurrence and will measure post-TB lung impairment. In both arms, an 18-month "mop-up" visit will be conducted to ascertain outcomes. We will use the RE-AIM framework to characterize implementation processes and explore acceptability through in-depth interviews with index patients, HHCs and HCWs (n = 100). Cost-effectiveness will be assessed by calculating the incremental cost per TB case detected within 12 months and projected for disability-adjusted life years averted based on modeled estimates of morbidity, mortality, and time with infectious TB. DISCUSSION: This novel trial will guide India's scale-up of post-treatment ACF and provide an evidence base for designing strategies to detect recurrent and new TB in other high burden settings. TRIAL REGISTRATION: NCT04333485 , registered April 3, 2020. CTRI/2020/05/025059 [Clinical Trials Registry of India], registered May 6 2020.

Diabetes Mellitus and Tuberculosis Treatment Outcomes in Pune, India.

BACKGROUND: Diabetes mellitus (DM) increases the risk of tuberculosis (TB) disease. Knowledge of the impact of DM on TB treatment outcomes is primarily based on retrospective studies. METHODS: We conducted a prospective cohort study of new pulmonary TB patients with and without DM (TB-DM and TB only) in India. The association of DM with a composite unfavorable TB treatment outcome (failure, recurrence, mortality) over 18 months was determined, and the effect of DM on all-cause mortality and early mortality (death during TB treatment) was assessed. RESULTS: Of 799 participants, 574 (72%) had TB only and 225 (28%) had TB-DM. The proportion of patients with DM who experienced the composite outcome was 20%, as compared with 21% for TB-only participants (adjusted hazard ratio [aHR], 1.13; 95% CI, 0.75-1.70). Mortality was higher in participants with DM (10% vs 7%), and early mortality was substantially higher among patients with DM (aHR, 4.36; 95% CI, 1.62-11.76). CONCLUSIONS: DM was associated with early mortality in this prospective cohort study, but overall unfavorable outcomes were similar to participants without DM. Interventions to reduce mortality during TB treatment among people with TB-DM are needed.

Pyopneumothorax of rare cause.

Rupture of pyriform sinus due to forced effort with closed glottis has been reported but is extremely rare. We report a case of rupture of pyriform sinus following multiple episodes of vomiting with subsequent development of pyopneumothorax.