Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

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

Presence of protozoan parasite Ophryocystis elektroscirrha (Neogregarinda: Ophryocystidae) in populations of butterflies in Monteverde, Costa Rica

Ophryocystis elektroschirrha (Neogregarinda: Ophryocystidae), is a parasite found in populations of monarch (Danaus plexippus) and queen (Danuas gilippus) butterflies (Lepidoptera Nymphalidae Danainae) (Altizer & Oberhauser 1997, Altizer et al. 2000, Leong et al. 1997, Vickerman et al. 1999). The parasite has both asexual and sexual stages in its lifecycle, and produces spores while the butterfly is pupating (Yixian Yueh 2005). Larvae become infected when they consume leaves or egg shells contaminated with spores. High densities of spores restrict body size and can reduce fecundity and life span in male adults (Altizer & Oberhauser 1999). This study investigates whether the parasite occurs on other species of butterflies. One hundred and fifty-two butterflies were caught in Monteverde, Costa Rica, and sampled for spores. A one cm squared piece of transparent sticky tape was pressed against the abdomen, and then adhered to a microscope slide. Slides were examined under 40 X magnification, and all spores were counted. The butterflies represented the families Pieridae and Papilionidae and also seven sub-families of Nymphalidae: Charaxinae, Danainae, Ithomiinae, Melitaeinae, Nymphalinae and Morphinae. Five individuals were infected, all D. plexippus. The spore counts ranged between 590 and more than 1000 per square centimetre. These intensities were much higher than in a previous study in the Monteverde region which found only seven and three spores on two monarch butterflies (Hsu 2004). The absence of the parasite in the other families and sub-families sampled may be due to inadequate sample sizes, or alternatively may be explained if the parasite host relationship is an obligate one. Future studies could more extensively research the occurrence of O. elektroscirrha in monarch and queen populations in Monteverde. It would also be worthwhile to focus on Danaine and Ithomiine butterflies closely related to D. plexippus and D. gilippus in case phylogenetic relatedness controls susceptibility to infection. Elektroscirrha ophryocystis (Neogregarinda: Ophryocystidae) es un parásito que se encuentra en poblaciones de mariposas monarca (Danaus plexippus) y reina (Danaus gilippus) (Lepidoptera Nymphalidae Danainae) (Altizer et al. 2000 Altizer et al. 2000, Leong et al. 1997, Vickerman et al. 1999) y que presenta un ciclo de vida que alterna etapas sexuales y asexuales, produciendo esporas mientras la mariposa se encuentra en estado de pupa (Yixian Yueh 2005). Las orugas se infectan cuando consumen hojas o cáscaras de huevo contaminadas con esporas. Las densidades altas de esporas pueden restringir el tamaño corporal y reducir la fecundidad y longevidad de los machos adultos (Altizer & Oberhauser 1999). Se investigó la posibilidad de que este parásito ocurriese en otras especies. Ciento cincuenta y dos mariposas fueron atrapadas y muestreadas en Monteverde, Costa Rica, y examinadas para encontrar esporas. Un pedazo de cinta adhesiva transparente de un cm2 se puso en el abdomen de las mariposas para sacar las esporas y luego se examinó esta cinta bajo el microscopio. Los portaobjetos fueron examinados a una magnificación de 40 X y las esporas se contaron. Las familias presentes en esta muestra incluyeron Pieridae y Papilionidae y también las siguientes subfamilias de Nymphalidae: Charaxinae, Danainae, 2 Ithomiinae, Melitaeinae, Nymphalinae y Morphinae. Se encontraron cinco individuos infectados con conteos de esporas de entre 530 y más de 1,000 por centímetro cuadrado; estos cinco individuos pertenecían a la especie D. plexippus. Las concentraciones de esporas fueron mucho más altas que las encontradas en un estudio anterior en el que se reportaron solamente siete y tres esporas en dos mariposas monarca (Hsu 2004). La ausencia del parásito en las otras familias y subfamilias puede ser debido al tamaño pequeño de la muestra, o puede ser atribuido a una relación obligatoria entre el parásito y el anfitrión. Se sugiere una investigación más amplia de la ocurrencia de O. elektroscirrha en poblaciones de mariposas monarca y reina en Monteverde en estudios futuros, así como un enfoque en las mariposas de las subfamilias Danaine e Ithomiinae - estrechamente relacionados a D. plexippus y D. gilippus – en caso de que la cercanía filogenética controle la susceptibilidad a la infección.https://digitalcommons.usf.edu/tropical_ecology/1599/thumbnail.jp

Presence of protozoan parasite Ophryocystis elektroscirrha (Neogregarinda: Ophryocystidae) in populations of butterflies in Monteverde, Costa Rica

Ophryocystis elektroschirrha (Neogregarinda: Ophryocystidae), is a parasite found in populations of monarch (Danaus plexippus) and queen (Danuas gilippus) butterflies (Lepidoptera Nymphalidae Danainae) (Altizer & Oberhauser 1997, Altizer et al. 2000, Leong et al. 1997, Vickerman et al. 1999). The parasite has both asexual and sexual stages in its lifecycle, and produces spores while the butterfly is pupating (Yixian Yueh 2005). Larvae become infected when they consume leaves or egg shells contaminated with spores. High densities of spores restrict body size and can reduce fecundity and life span in male adults (Altizer & Oberhauser 1999). This study investigates whether the parasite occurs on other species of butterflies. One hundred and fifty-two butterflies were caught in Monteverde, Costa Rica, and sampled for spores. A one cm squared piece of transparent sticky tape was pressed against the abdomen, and then adhered to a microscope slide. Slides were examined under 40 X magnification, and all spores were counted. The butterflies represented the families Pieridae and Papilionidae and also seven sub-families of Nymphalidae: Charaxinae, Danainae, Ithomiinae, Melitaeinae, Nymphalinae and Morphinae. Five individuals were infected, all D. plexippus. The spore counts ranged between 590 and more than 1000 per square centimetre. These intensities were much higher than in a previous study in the Monteverde region which found only seven and three spores on two monarch butterflies (Hsu 2004). The absence of the parasite in the other families and sub-families sampled may be due to inadequate sample sizes, or alternatively may be explained if the parasite host relationship is an obligate one. Future studies could more extensively research the occurrence of O. elektroscirrha in monarch and queen populations in Monteverde. It would also be worthwhile to focus on Danaine and Ithomiine butterflies closely related to D. plexippus and D. gilippus in case phylogenetic relatedness controls susceptibility to infection. Elektroscirrha ophryocystis (Neogregarinda: Ophryocystidae) es un parásito que se encuentra en poblaciones de mariposas monarca (Danaus plexippus) y reina (Danaus gilippus) (Lepidoptera Nymphalidae Danainae) (Altizer et al. 2000 Altizer et al. 2000, Leong et al. 1997, Vickerman et al. 1999) y que presenta un ciclo de vida que alterna etapas sexuales y asexuales, produciendo esporas mientras la mariposa se encuentra en estado de pupa (Yixian Yueh 2005). Las orugas se infectan cuando consumen hojas o cáscaras de huevo contaminadas con esporas. Las densidades altas de esporas pueden restringir el tamaño corporal y reducir la fecundidad y longevidad de los machos adultos (Altizer & Oberhauser 1999). Se investigó la posibilidad de que este parásito ocurriese en otras especies. Ciento cincuenta y dos mariposas fueron atrapadas y muestreadas en Monteverde, Costa Rica, y examinadas para encontrar esporas. Un pedazo de cinta adhesiva transparente de un cm2 se puso en el abdomen de las mariposas para sacar las esporas y luego se examinó esta cinta bajo el microscopio. Los portaobjetos fueron examinados a una magnificación de 40 X y las esporas se contaron. Las familias presentes en esta muestra incluyeron Pieridae y Papilionidae y también las siguientes subfamilias de Nymphalidae: Charaxinae, Danainae, 2 Ithomiinae, Melitaeinae, Nymphalinae y Morphinae. Se encontraron cinco individuos infectados con conteos de esporas de entre 530 y más de 1,000 por centímetro cuadrado; estos cinco individuos pertenecían a la especie D. plexippus. Las concentraciones de esporas fueron mucho más altas que las encontradas en un estudio anterior en el que se reportaron solamente siete y tres esporas en dos mariposas monarca (Hsu 2004). La ausencia del parásito en las otras familias y subfamilias puede ser debido al tamaño pequeño de la muestra, o puede ser atribuido a una relación obligatoria entre el parásito y el anfitrión. Se sugiere una investigación más amplia de la ocurrencia de O. elektroscirrha en poblaciones de mariposas monarca y reina en Monteverde en estudios futuros, así como un enfoque en las mariposas de las subfamilias Danaine e Ithomiinae - estrechamente relacionados a D. plexippus y D. gilippus – en caso de que la cercanía filogenética controle la susceptibilidad a la infección.https://digitalcommons.usf.edu/tropical_ecology/1599/thumbnail.jp