Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Provider reported barriers and solutions to improve testing among tuberculosis patients 'eligible for drug susceptibility test': A qualitative study from programmatic setting in India.

BACKGROUND:In a study conducted in Bhopal district (a setting with facility for molecular drug susceptibility testing (DST)) located in central India in 2014-15, we found high levels of pre-diagnosis attrition among patients with presumptive multi drug-resistant tuberculosis (MDR-TB)-meaning TB patients who were eligible for DST, were not being tested. OBJECTIVES:In this study, we explored the health care provider perspectives into barriers and suggested solutions for improving DST. METHODS:This was a descriptive qualitative study. One to one interviews (n = 10) and focus group discussions (n = 2) with experienced key informants involved in programmatic management of DR-TB were conducted in April 2017. Manual descriptive thematic analysis was performed. RESULTS:The key barriers reported were a) lack of or delay in identification of patients eligible for DST because of using treatment register as the source for identifying patients b) lack of assured specimen transport after patient identification and c) lack of tracking. Extra pulmonary TB patients were not getting identified as eligible for DST. Solutions suggested by the health care providers were i) generation of unique identifier at identification in designated microscopy center (DMC), immediate intimation of unique identifier to district and regular monitoring by senior TB laboratory and senior treatment supervisors of patients eligible for DST that were missed; ii) documentation of unique identifier at each step of cascade; iii) use of human carriers/couriers to transport specimen from DMCs especially in rural areas; and iv) routine entry of all presumptive extra-pulmonary TB specimen, as far as possible, in DMC laboratory register. CONCLUSION:Lack of assured specimen transport and lack of accountability for tracking patient after identification and referral were the key barriers. The identification of patients eligible for DST among microbiologically confirmed TB at the time of diagnosis and among clinically confirmed TB at the time of treatment initiation is the key. Use of unique identifier at identification and its use to ensure cohort wise tracking has to be complemented with specimen transport support and prompt feedback to the DMC. The study has implications to improve detection of MDR-TB among diagnosed/notified TB patients

Cascade of care of patients with presumptive MDR-TB (eligible for DST) in the diagnosis pathway, district Bhopal, India*.

<p>TB–Tuberculosis; DST–drug susceptibility testing; MDR-TB–multi drug-resistant tuberculosis; DMC–designated microscopy center; DTC–district tuberculosis center; DOTS–directly observed treatment short course; NRL–national reference laboratory; IRL–Intermediate reference laboratory; DR-TB–drug-resistant TB; LT–laboratory technician; TB-HV–TB health visitor.</p

Attrition of patients with presumptive MDR-TB (eligible for DST) in the diagnosis pathway, district Bhopal, India (2014)* [16].

<p>MDR-TB: Multi drug-resistant tuberculosis, DST: Drug susceptibility testing, NRL: national reference laboratory *reproduced with permission, original publisher BioMed Central [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196162#pone.0196162.ref016" target="_blank">16</a>].</p

Suggested solutions as perceived by programme staff to increase drug susceptibility testing among patients with presumptive MDR-TB in Bhopal district, India (2017).

<p>Suggested solutions as perceived by programme staff to increase drug susceptibility testing among patients with presumptive MDR-TB in Bhopal district, India (2017).</p

Study participants (health care providers involved in programmatic management of drug-resistant TB) characteristics and duration of each data collection activity in Bhopal district, India (2017).

<p>Study participants (health care providers involved in programmatic management of drug-resistant TB) characteristics and duration of each data collection activity in Bhopal district, India (2017).</p

Case definitions as per revised national tuberculosis control programme (RNTCP), India [24].

<p>Case definitions as per revised national tuberculosis control programme (RNTCP), India [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196162#pone.0196162.ref024" target="_blank">24</a>].</p

Providers’ perspectives into barriers and suggested solutions to improve DST among presumptive MDR-TB (eligible for DST) in Bhopal district, India (2017), in relation to the care pathway for diagnosis*.

<p>TB–Tuberculosis; DST–drug susceptibility testing; MDR-TB–multi drug-resistant tuberculosis; DMC–designated microscopy center (sputum collection center); DTC–district tuberculosis center; DOTS–directly observed treatment short course; NRL–national reference laboratory; IRL–Intermediate reference laboratory; DR-TB–drug-resistant TB; LT–laboratory technician of DMC; TB-HV–TB health visitor; NGO–non-Governmental organization; STLS–senior tuberculosis laboratory supervisor.</p

High pre-diagnosis attrition among patients with presumptive MDR-TB: an operational research from Bhopal district, India

Abstract Background Pre-diagnosis attrition needs to be addressed urgently if we are to make progress in improving MDR-TB case detection and achieve universal access to MDR-TB care. We report the pre-diagnosis attrition, along with factors associated, and turnaround times related to the diagnostic pathway among patient with presumptive MDR-TB in Bhopal district, central India (2014). Methods Study was conducted under the Revised National Tuberculosis Control Programme setting. It was a retrospective cohort study involving record review of all registered TB cases in Bhopal district that met the presumptive MDR-TB criteria (eligible for DST) in 2014. In quarter 1, Line Probe Assay (LPA) was used if sample was smear/culture positive. Quarter 2 onwards, LPA and Cartridge-based Nucleic Acid Amplification Test (CbNAAT) was used for smear positive and smear negative samples respectively. Pre-diagnosis attrition was defined as failure to undergo DST among patients with presumptive MDR-TB (as defined by the programme). Results Of 770 patients eligible for DST, 311 underwent DST and 20 patients were diagnosed as having MDR-TB. Pre-diagnosis attrition was 60% (459/770). Among those with pre-diagnosis attrition, 91% (417/459) were not identified as ‘presumptive MDR-TB’ by the programme. TAT [median (IQR)] to undergo DST after eligibility was 4 (0, 10) days. Attrition was more than 40% across all subgroups. Age more than 64 years; those from a medical college; those eligible in quarter 1; patients with presumptive criteria ‘previously treated – recurrent TB’, ‘treatment after loss-to-follow-up’ and ‘previously treated-others’; and patients with extra-pulmonary TB were independent risk factors for not undergoing DST. Conclusion High pre-diagnosis attrition was contributed by failure to identify and refer patients. Attrition reduced modestly with time and one factor that might have contributed to this was introduction of CbNAAT in quarter 2 of 2014. General health system strengthening which includes improvement in identification/referral and patient tracking with focus on those with higher risk for not undergoing DST is urgently required