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

The use of mosquito repellents at three sites in India with declining malaria transmission: surveys in the community and clinic

BACKGROUND: Repellents such as coils, vaporizers, mats and creams can be used to reduce the risk of malaria and other infectious diseases. Although evidence for their effectiveness is limited, they are advertised as providing an additional approach to mosquito control in combination with other strategies, e.g. insecticide-treated nets. We examined the use of repellents in India in an urban setting in Chennai (mainly Plasmodium vivax malaria), a peri-urban setting in Nadiad (both P. vivax and P. falciparum malaria), and a more rural setting in Raurkela (mainly P. falciparum malaria). METHODS: The use of repellents was examined at the household level during a census, and at the individual level in cross-sectional surveys and among patients visiting a clinic with fever or other symptoms. Factors associated with their use were examined in a multivariate analysis, and the association between malaria and the use of repellents was assessed among survey- and clinic participants. RESULTS: Characteristics of participants differed by region, with more people of higher education present in Chennai. Use of repellents varied between 56-77 % at the household level and between 32-78 % at the individual level. Vaporizers were the main repellents used in Chennai, whereas coils were more common in Nadiad and Raurkela. In Chennai and Nadiad, vaporizers were more likely to be used in households with young male children. Vaporizer use was associated with higher socio-economic status (SES) in households in Chennai and Nadiad, whereas use of coils was greater in the lower SES strata. In Raurkela, there was a higher use of coils among the higher SES strata. Education was associated with the use of a repellent among survey participants in Chennai and clinic study participants in Chennai and Nadiad. Repellent use was associated with less malaria in the clinic study in Chennai and Raurkela, but not in the surveys, with the exception of the use of coils in Nadiad. CONCLUSIONS: Repellents are widely used in India. Their use is influenced by the level of education and SES. Information on effectiveness and guidance on choices may improve rational use

The burden of submicroscopic and asymptomatic malaria in India revealed from epidemiology studies at three varied transmission sites in India.

Malaria in India, while decreasing, remains a serious public health problem, and the contribution of submicroscopic and asymptomatic infections to its persistence is poorly understood. We conducted community surveys and clinic studies at three sites in India differing in their eco-epidemiologies: Chennai (Tamil Nadu), Nadiad (Gujarat), and Rourkela (Odisha), during 2012-2015. A total of 6,645 subject blood samples were collected for Plasmodium diagnosis by microscopy and PCR, and an extensive clinical questionnaire completed. Malaria prevalence ranged from 3-8% by PCR in community surveys (24 infections in Chennai, 56 in Nadiad, 101 in Rourkela), with Plasmodium vivax dominating in Chennai (70.8%) and Nadiad (67.9%), and Plasmodium falciparum in Rourkela (77.3%). A proportional high burden of asymptomatic and submicroscopic infections was detected in community surveys in Chennai (71% and 71%, respectively, 17 infections for both) and Rourkela (64% and 31%, 65 and 31 infections, respectively). In clinic studies, a proportional high burden of infections was identified as submicroscopic in Rourkela (45%, 42 infections) and Chennai (19%, 42 infections). In the community surveys, anemia and fever were significantly more common among microscopic than submicroscopic infections. Exploratory spatial analysis identified a number of potential malaria hotspots at all three sites. There is a considerable burden of submicroscopic and asymptomatic malaria in malarious regions in India, which may act as a reservoir with implications for malaria elimination strategies

Age-dependent breadth and intensity of response to <i>P</i>. <i>vivax</i> and <i>P</i>. <i>falciparum</i>.

<p>Age-dependent A) breadth of response to 265 <i>P</i>. <i>vivax</i> and 373 <i>P</i>. <i>falciparum</i> antigens in children (n = 61) and adults (n = 129) from Raurkela and Nadiad. The box indicates the first and third quartiles, the line inside the box indicates the median, and whiskers represent the minimum and maximum values. B) Average of mean intensity of antibody binding to the same subset of <i>P</i>. <i>vivax</i> and <i>P</i>. <i>falciparum</i> antigens in children and adults, top of bars indicate the mean value and error bars represent 95% confidence interval of the mean. Kruskal–Wallis/Dunn adjusted p-values for pairwise comparison of groups are shown as asterisks: 0.03 (*), 0.002 (**), 0.0002 (***), <0.0001 (****).</p

Summary of 353 samples collected at three sites in India.

<p>Summary of 353 samples collected at three sites in India.</p

Breadth of antibody response to <i>P</i>. <i>vivax</i> and <i>P</i>. <i>falciparum</i>.

<p>Breadth of response to A) 265 <i>P</i>. <i>vivax</i> and B) 373 <i>P</i>. <i>falciparum</i> antigens in samples collected from malaria-positive (Chennai = 45; Nadiad = 55; Raurkela = 74) and malaria-negative adults (Chennai = 25; Nadiad = 34; Raurkela = 32) at three sites in India. The box indicates the first and third quartiles, the line inside the box indicates the median, and whiskers represent the minimum and maximum values. Kruskal–Wallis/Dunn adjusted p-values for pairwise comparison of groups are shown as asterisks: 0.03 (*), 0.002 (**), 0.0002 (***), <0.0001 (****).</p

Comparison of individuals with symptomatic and asymptomatic malaria.

<p>A) Breadth of response to 265 <i>P</i>. <i>vivax</i> antigens, and 373 <i>P</i>. <i>falciparum</i> antigens in symptomatic (<i>P</i>. <i>vivax</i> = 58; <i>P</i>. <i>falciparum</i> = 38) and asymptomatic (<i>P</i>. <i>vivax</i> = 16; <i>P</i>. <i>falciparum</i> = 9) malaria-positive adults at three sites in India. The box indicates the first and third quartiles, the line side of the box indicates the median, and whiskers represent the minimum and maximum values. B) Average of mean intensity of antibody binding to 265 <i>P</i>. <i>vivax</i> and 373 <i>P</i>. <i>falciparum</i> antigens in symptomatic and asymptomatic malaria-positive adults, top of bars indicate the mean value and error bars represent 95% confidence interval of the mean. C) Average of <i>P</i>. <i>vivax</i> and <i>P</i>. <i>falciparum</i> asexual parasitemia (number of asexual parasites per microliter) in symptomatic and asymptomatic malaria-positive adults. Kruskal–Wallis/Dunn adjusted p-values for pairwise comparison of groups are shown as asterisks: 0.03 (*), 0.002 (**), 0.0002 (***), <0.0001 (****).</p