Use of anticoagulants in patients with COVID-19: a living systematic review and meta-analysis.

OBJECTIVE: To answer questions related to the use of anticoagulants in the treatment of COVID-19 patients. METHODS: This was a systematic review and meta-analysis of phase 3 randomized controlled trials comparing the use of anticoagulants in non-hospitalized and hospitalized COVID-19 patients. We searched the following databases: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to January 22, 2022. The risk of bias was assessed by the Cochrane risk-of-bias tool, and the quality of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: A total of 401 studies were initially selected. Of those, 9 met the inclusion criteria and were therefore analyzed (a total of 6,004 patients being analyzed). In non-hospitalized COVID-19 patients, no significant difference was found between post-discharge prophylactic anticoagulation and no intervention regarding venous thromboembolism or bleeding at 30 days. In hospitalized COVID-19 patients, full anticoagulation resulted in a slight reduction in thrombotic events at 30 days (risk difference, -0.03; 95% CI, -0.06 to -0.00; p = 0.04; I2 = 78%), the quality of evidence being moderate. However, no significant difference was found between full anticoagulation and no intervention regarding the risk of major bleeding, the quality of evidence being very low. No significant difference was found between intermediate- and standard-dose prophylactic anticoagulation (risk difference, -0.01; 95% CI, -0.07 to 0.06; p = 0.81; I2 = 0%), the quality of evidence being very low. CONCLUSIONS: Therapeutic anticoagulation appears to have no effect on mortality in COVID-19 patients, resulting in a slight reduction in venous thromboembolism in hospitalized patients.

Use of remdesivir in patients with COVID-19: a systematic review and meta-analysis.

OBJECTIVE: Studies in the literature regarding the use of remdesivir to treat COVID-19 patients have shown conflicting results. This study sought to answer questions related to the use of remdesivir for the treatment of patients hospitalized with moderate to severe COVID-19. METHODS: This was a systematic review and meta-analysis including phase 3 randomized clinical trials (RCTs) and observational cohort studies selected from various databases, comparing patients hospitalized with moderate to severe COVID-19 receiving remdesivir and controls. RESULTS: A total of 207 studies were retrieved, 9 of which met the eligibility criteria and were included in the study. The meta-analysis using RCTs alone showed no statistically significant differences regarding mortality or use of mechanical ventilation/extracorporeal membrane oxygenation between remdesivir and control groups, and the quality of evidence was moderate and low, respectively. The use of remdesivir increased the recovery rate by 6% (95% CI, 3-9); p = 0.004) and the clinical improvement rate by 7% (95% CI, 1-14); p = 0.02). Additionally, no significant differences in mortality were found between remdesivir and control groups when the meta-analysis used observational cohort studies alone (risk difference = -0.01 (95% CI, -0.02 to 0.01; p = 0.32), the quality of evidence being moderate, and the risk of adverse events was 4% ([95% CI, -0.08 to 0.01]; p = 0.09). CONCLUSIONS: The use of remdesivir for the treatment of patients with moderate to severe COVID-19 had no significant impact on clinically important outcomes.

Use of remdesivir in patients with COVID-19: a systematic review and meta-analysis / Uso de remdesivir em pacientes com COVID-19: revisão sistemática e meta-análise

ABSTRACT Objective: Studies in the literature regarding the use of remdesivir to treat COVID-19 patients have shown conflicting results. This study sought to answer questions related to the use of remdesivir for the treatment of patients hospitalized with moderate to severe COVID-19. Methods: This was a systematic review and meta-analysis including phase 3 randomized clinical trials (RCTs) and observational cohort studies selected from various databases, comparing patients hospitalized with moderate to severe COVID-19 receiving remdesivir and controls. Results: A total of 207 studies were retrieved, 9 of which met the eligibility criteria and were included in the study. The meta-analysis using RCTs alone showed no statistically significant differences regarding mortality or use of mechanical ventilation/extracorporeal membrane oxygenation between remdesivir and control groups, and the quality of evidence was moderate and low, respectively. The use of remdesivir increased the recovery rate by 6% (95% CI, 3-9); p = 0.004) and the clinical improvement rate by 7% (95% CI, 1-14); p = 0.02). Additionally, no significant differences in mortality were found between remdesivir and control groups when the meta-analysis used observational cohort studies alone (risk difference = −0.01 (95% CI, −0.02 to 0.01; p = 0.32), the quality of evidence being moderate, and the risk of adverse events was 4% ([95% CI, −0.08 to 0.01]; p = 0.09). Conclusions: The use of remdesivir for the treatment of patients with moderate to severe COVID-19 had no significant impact on clinically important outcomes.

RESUMO Objetivo: Estudos na literatura sobre o uso de remdesivir no tratamento de pacientes com COVID-19 têm apresentado resultados divergentes. O objetivo deste estudo foi responder a perguntas a respeito do uso de remdesivir no tratamento de pacientes hospitalizados com COVID-19 moderada a grave. Métodos: Trata-se de uma revisão sistemática e meta-análise de ensaios clínicos controlados randomizados (ECR) de fase 3 e estudos observacionais de coorte recuperados de diversos bancos de dados, comparando pacientes hospitalizados com COVID-19 moderada a grave recebendo remdesivir a controles. Resultados: Foram recuperados 207 estudos, dos quais 9 preencheram os critérios de elegibilidade e foram incluídos no estudo. A meta-análise somente dos ECR não mostrou diferenças estatisticamente significativas entre os grupos remdesivir e controle quanto à mortalidade ou ao uso de ventilação mecânica/oxigenação por membrana extracorpórea, e a qualidade das evidências foi moderada e baixa, respectivamente. O uso de remdesivir aumentou a taxa de recuperação em 6% (IC95%: 3-9; p = 0,004) e a taxa de melhora clínica em 7% (IC95%: 1-14; p = 0,02). Além disso, não foram observadas diferenças significativas entre os grupos remdesivir e controle quanto à mortalidade quando a meta-análise concentrou-se apenas nos estudos observacionais de coorte [diferença de risco = −0,01 (IC95%: −0,02 a 0,01); p = 0,32; qualidade das evidências: moderada], e o risco de eventos adversos foi de 4% (IC95%: −0,08 a 0,01; p = 0,09). Conclusões: O uso de remdesivir no tratamento de pacientes com COVID-19 moderada a grave não teve impacto significativo em desfechos clinicamente importantes.

Use of anticoagulants in patients with COVID-19: a living systematic review and meta-analysis / Uso de anticoagulantes em pacientes com COVID-19: revisão sistemática "viva" e meta-análise

ABSTRACT Objective: To answer questions related to the use of anticoagulants in the treatment of COVID-19 patients. Methods: This was a systematic review and meta-analysis of phase 3 randomized controlled trials comparing the use of anticoagulants in non-hospitalized and hospitalized COVID-19 patients. We searched the following databases: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to January 22, 2022. The risk of bias was assessed by the Cochrane risk-of-bias tool, and the quality of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation system. Results: A total of 401 studies were initially selected. Of those, 9 met the inclusion criteria and were therefore analyzed (a total of 6,004 patients being analyzed). In non-hospitalized COVID-19 patients, no significant difference was found between post-discharge prophylactic anticoagulation and no intervention regarding venous thromboembolism or bleeding at 30 days. In hospitalized COVID-19 patients, full anticoagulation resulted in a slight reduction in thrombotic events at 30 days (risk difference, −0.03; 95% CI, −0.06 to −0.00; p = 0.04; I2 = 78%), the quality of evidence being moderate. However, no significant difference was found between full anticoagulation and no intervention regarding the risk of major bleeding, the quality of evidence being very low. No significant difference was found between intermediate- and standard-dose prophylactic anticoagulation (risk difference, −0.01; 95% CI, −0.07 to 0.06; p = 0.81; I2 = 0%), the quality of evidence being very low. Conclusions: Therapeutic anticoagulation appears to have no effect on mortality in COVID-19 patients, resulting in a slight reduction in venous thromboembolism in hospitalized patients.

RESUMO Objetivo: Responder a perguntas relacionadas ao uso de anticoagulantes no tratamento de pacientes com COVID-19. Métodos: Revisão sistemática e meta-análise de ensaios clínicos controlados randomizados de fase 3 comparando o uso de anticoagulantes em pacientes com COVID-19 não hospitalizados e hospitalizados. Os bancos de dados MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials e ClinicalTrials.gov foram investigados desde sua criação até 22 de janeiro de 2022. O risco de viés foi avaliado pela ferramenta de risco de viés da Cochrane, e a qualidade das evidências foi avaliada pelo sistema Grading of Recommendations Assessment, Development and Evaluation. Resultados: Inicialmente foram selecionados 401 estudos. Destes, 9 preencheram os critérios de inclusão e, portanto, foram analisados (num total de 6.004 pacientes analisados). Em pacientes com COVID-19 não hospitalizados, não se observou diferença significativa entre anticoagulação profilática pós-alta e nenhuma intervenção no que tange a tromboembolismo venoso ou sangramento em 30 dias. Em pacientes com COVID-19 hospitalizados, a anticoagulação plena resultou em ligeira redução de eventos trombóticos em 30 dias (diferença de risco: −0,03; IC95%: −0,06 a −0,00; p = 0,04; I2 = 78%); a qualidade das evidências foi moderada. No entanto, não se observou diferença significativa entre anticoagulação plena e nenhuma intervenção quanto ao risco de sangramento maior; a qualidade das evidências foi muito baixa. Não se observou diferença significativa entre anticoagulação profilática com dose intermediária e dose-padrão (diferença de risco: −0,01; IC95%: −0,07 a 0,06; p = 0,81; I2 = 0%); a qualidade das evidências foi muito baixa. Conclusões: A anticoagulação terapêutica parece não ter efeito na mortalidade em pacientes com COVID-19, resultando em ligeira redução do tromboembolismo venoso em pacientes hospitalizados.

Use of hydroxychloroquine to prevent SARS-CoV-2 infection and treat mild COVID-19: a systematic review and meta-analysis.

OBJECTIVE: Chloroquine or hydroxychloroquine has demonstrated no effect on the treatment of hospitalized COVID-19 patients. This study aimed to answer questions related to the use of hydroxychloroquine for pre-exposure or post-exposure prophylaxis of SARS-CoV-2 infection and in the treatment of patients with mild COVID-19 in terms of hospitalization, adverse events, and mortality. METHODS: This was a systematic review and meta-analysis of phase 3 randomized clinical trials, selected from various databases, which compared patients who received hydroxychloroquine for SARS-CoV-2 prophylaxis or treatment of mild COVID-19 cases with controls. RESULTS: A total number of 1,376 studies were retrieved. Of those, 9 met the eligibility criteria and were included in the study. No statistically significant differences were found between the hydroxychloroquine and control groups in terms of pre- or post-exposure prophylaxis of SARS-CoV-2 infection. The use of hydroxychloroquine increased the risk of adverse events by 12% (95% CI, 6-18%; p < 0.001), and the number needed to harm was 9. In addition, no significant differences were found between the hydroxychloroquine and control groups regarding hospitalization (risk difference [RD] = -0.02; 95% CI, -0.04 to 0.00; p = 0.14) or mortality (RD = 0.00; 95% CI, -0.01 to 0.02; p = 0.98) in the treatment of mild COVID-19. CONCLUSIONS: The use of hydroxychloroquine for prophylaxis of SARS-CoV-2 infection or treatment of patients with mild COVID-19 is not recommended.

Use of hydroxychloroquine to prevent SARS-CoV-2 infection and treat mild COVID-19: a systematic review and meta-analysis / Uso de hidroxicloroquina para prevenir a infecção por SARS-CoV-2 e tratar COVID-19 leve: revisão sistemática e meta-análise

ABSTRACT Objective: Chloroquine or hydroxychloroquine has demonstrated no effect on the treatment of hospitalized COVID-19 patients. This study aimed to answer questions related to the use of hydroxychloroquine for pre-exposure or post-exposure prophylaxis of SARS-CoV-2 infection and in the treatment of patients with mild COVID-19 in terms of hospitalization, adverse events, and mortality. Methods: This was a systematic review and meta-analysis of phase 3 randomized clinical trials, selected from various databases, which compared patients who received hydroxychloroquine for SARS-CoV-2 prophylaxis or treatment of mild COVID-19 cases with controls. Results: A total number of 1,376 studies were retrieved. Of those, 9 met the eligibility criteria and were included in the study. No statistically significant differences were found between the hydroxychloroquine and control groups in terms of pre- or post-exposure prophylaxis of SARS-CoV-2 infection. The use of hydroxychloroquine increased the risk of adverse events by 12% (95% CI, 6-18%; p < 0.001), and the number needed to harm was 9. In addition, no significant differences were found between the hydroxychloroquine and control groups regarding hospitalization (risk difference [RD] = −0.02; 95% CI, −0.04 to 0.00; p = 0.14) or mortality (RD = 0.00; 95% CI, −0.01 to 0.02; p = 0.98) in the treatment of mild COVID-19. Conclusions: The use of hydroxychloroquine for prophylaxis of SARS-CoV-2 infection or treatment of patients with mild COVID-19 is not recommended.

RESUMO Objetivo: A cloroquina ou hidroxicloroquina não apresentou nenhum efeito no tratamento de pacientes hospitalizados com COVID-19. O objetivo deste estudo foi responder a questões a respeito do uso de hidroxicloroquina na profilaxia da infecção por SARS-CoV-2 pré ou pós-exposição e no tratamento de pacientes com COVID-19 leve no tocante à hospitalização, eventos adversos e mortalidade. Métodos: Trata-se de uma revisão sistemática e meta-análise de ensaios clínicos controlados aleatórios de fase 3 que foram selecionados por meio de buscas em diversos bancos de dados e que compararam controles e pacientes que receberam hidroxicloroquina para profilaxia de SARS-CoV-2 ou tratamento de COVID-19 leve. Resultados: Foram identificados 1.376 estudos. Destes, 9 preencheram os critérios de elegibilidade e foram incluídos no estudo. Não foram encontradas diferenças significativas entre os grupos hidroxicloroquina e controle quanto à profilaxia da infecção por SARS-CoV-2 pré ou pós-exposição. O uso de hidroxicloroquina aumentou o risco de eventos adversos em 12% (IC95%: 6-18%; p < 0,001), e o número necessário para prejudicar foi 9. Não foram encontradas diferenças significativas entre os grupos hidroxicloroquina e controle quanto à hospitalização [diferença de risco (DR) = −0,02; IC95%: −0,04 a 0,00; p = 0,14] e mortalidade (DR = 0,00; IC95%: −0,01 a 0,02; p = 0,98) no tratamento de COVID-19 leve. Conclusões: Não é recomendado o uso de hidroxicloroquina nem na profilaxia da infecção por SARS-CoV-2 nem no tratamento de pacientes com COVID-19 leve.

Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data

BACKGROUND: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI. METHODS: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022. FINDINGS:We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per µL (the median for the cohort) was 45% (95% CI 38­52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63­87), increasing to 89% (80­94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05­3·08) but not after 30 days (1·25, 0·84­2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16­8·84). INTERPRETATION:In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients

Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data.

BACKGROUND: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI. METHODS: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022. FINDINGS: We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per µL (the median for the cohort) was 45% (95% CI 38-52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63-87), increasing to 89% (80-94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05-3·08) but not after 30 days (1·25, 0·84-2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16-8·84). INTERPRETATION: In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients. FUNDING: This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A.

Concomitância de leishmanioses e infecçäo pelo vírus da imunodeficiência humana (HIV): estudo de quatro casos / Concurrent leishmaniasis and human immunodeficiency virus infection: a study of four cases

Säo apresentados quatro casos de leishmaniose em pacientes com SIDA, sendo dois de leishmaniose visceral e dois com forma cutâneo-mucosa. Lesöes cutâneas e de mucosa oral, disseminadas, estavam presentes nos pacientes com a forma tegumentar da doença. Febre prolongada, hepatoesplenomegalia e pancitopenia foram as manifestaçöes principais da forma visceral. A contagem de linfócitos TCD4+ era baixa em todos os casos. A pesquisa de leishmanias foi positiva no aspirado de medula óssea e na biópsia de lesöes cutâneas e mucosas. Os pacientes responderam ao tratamento com antimoniais pentavalentes e com a anfotericina B. Poucos casos de coinfecçäo leishmaniose e HIV têm sido descritos em nosso meio. Apesar da ampla expansäo de ambas, até agora suas áreas de distribuiçäo geográfica teve pouca superposiçäo. Os autores recomendam a inclusäo desta parasitose no diagnóstico diferencial das doenças oportunistas que acometem indivíduos com SIDA