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1.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-337927

ABSTRACT

Although the antimicrobial potential of nitric oxide (NO) is widely published, it is little used clinically. NO is a key signalling molecule modulating vascular, neuronal, inflammatory and immune responses. Endogenous antimicrobial activity is largely mediated by high local NO concentrations produced by cellular inducible nitric oxide synthase, and by derivative reactive nitrogen oxide species including peroxynitrite and S-nitrosothiols. NO may be taken as dietary substrate (inorganic nitrate, L-arginine), and therapeutically as gaseous NO, and transdermal, sublingual, oral, intranasal and intravenous nitrite or nitrate. Numerous preclinical studies have demonstrated that NO has generic static and cidal activities against viruses (including β-coronaviruses such as SARS-CoV-2), bacteria, protozoa and fungi/yeasts  in vitro. Therapeutic effects have been seen in animal models  in vivo, and phase II trials have demonstrated that NO donors can reduce microbial infection. Nevertheless, excess NO, as occurs in septic shock, is associated with increased morbidity and mortality. In view of the dose-dependent positive and negative effects of NO, safety and efficacy trials of NO and its donors are needed for assessing their role in the prevention and treatment of infections. Trials should test dietary inorganic nitrate for pre- or post-exposure prophylaxis and gaseous NO or oral, topical or intravenous nitrite and nitrate for treatment of mild-to-severe infections, including due to SARS-CoV-2 (COVID-19). This review summarises the evidence base from  in vitro, in vivo and early phase clinical studies of NO activity in viral, bacterial, protozoal and fungal infections.

2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-334304

ABSTRACT

Background: Infections cause considerable care home morbidity and mortality. Nitric oxide (NO) has broad-spectrum anti-viral, bacterial and yeast activity in vitro . We assessed the feasibility of supplementing dietary nitrate (NO substrate) intake in care home residents.MethodsWe performed a cluster-randomised placebo-controlled trial in UK residential and nursing care home residents and compared nitrate containing (400 mg) versus free (0 mg daily) beetroot juice given for 60 days. Outcomes comprised feasibility of recruitment, adherence, salivary and urinary [nitrate], and ordinal infection/clinical events.ResultsOf 30 targeted care homes in late 2020, 16 expressed interest and only 6 participated. 49 residents were recruited (median 8 [interquartile range 7–12] per home), mean (standard deviation) age 82 (8) years, with proxy consent 41 (84%), advance directive for hospital non-admission 8 (16%) and ≥ 1 doses of COVID-19 vaccine 37 (82%). Background dietary nitrate was < 30% of acceptable daily intake. 34 (76%) residents received > 50% of juice. Residents randomised to nitrate vs placebo had higher urinary nitrate levels, median 50 [18–175] v 18 [10–50] mg/L, difference 25 [0–90]. Data paucity precluded clinical between-group comparisons;the outcome distribution was: no infection 32 (67%), uncomplicated infection 0, infection requiring healthcare support 11 (23%), all-cause hospitalisation 5 (10%), all-cause mortality 0. Urinary tract infections were most common.ConclusionsRecruiting UK care homes during the COVID-19 pandemic was partially successful. Supplemented dietary nitrate was tolerated and elevated urinary [nitrate]. Together, infections, hospitalisations and deaths occurred in 33% of residents over 60 days. A larger trial is now required. Registration ISRCTN51124684

3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329063

ABSTRACT

Background: We evaluated the use of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, for the treatment of patients admitted to hospital because of COVID-19. Methods: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was conducted that included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. Findings: Between 2 February 2021 and 29 December 2021, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% receiving tocilizumab (with planned use within the next 24 hours recorded for a further 9%). Overall, 513 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0.87;95% CI 0.77-0.98;p=0.026). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of 8 previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths) in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0.57;95% CI 0.45-0.72). Including the results from RECOVERY into an updated meta-analysis of all 9 completed trials (involving 11,888 randomised patients and 1484 deaths) allocation to baricitinib or other JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0.80;95% CI 0.71-0.89;p<0.001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no excess of thrombosis, or other safety outcomes. Interpretation: In patients hospitalised for COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth.

4.
Age Ageing ; 51(3)2022 03 01.
Article in English | MEDLINE | ID: covidwho-1692262

ABSTRACT

The COVID-19 pandemic resulted in catastrophic levels of morbidity and mortality for care home residents. Despite this, research platforms for COVID-19 in care homes arrived late in the pandemic compared with other care settings. The Prophylactic Therapy in Care Homes Trial (PROTECT-CH) was established to provide a platform to deliver multi-centre cluster-randomized clinical trials of investigational medicinal products for COVID-19 prophylaxis in UK care homes. Commencing set-up in January 2021, this involved the design and development of novel infrastructure for contracting and recruitment, remote consent, staff training, research insurance, eligibility screening, prescribing, dispensing and adverse event reporting; such infrastructure being previously absent. By the time this infrastructure was in place, the widespread uptake of vaccination in care homes had changed the epidemiology of COVID-19 rendering the trial unfeasible. While some of the resources developed through PROTECT-CH will enable the future establishment of care home platform research, the near absence of care home trial infrastructure and nationally linked databases involving the care home sector will continue to significantly hamper progress. These issues are replicated in most other countries. Beyond COVID-19, there are many other research questions that require addressing to provide better care to people living in care homes. PROTECT-CH has exposed a clear need for research funders to invest in, and legislate for, an effective care home research infrastructure as part of national pandemic preparedness planning. Doing so would also invigorate care home research in the interim, leading to improved healthcare delivery specific to those living in this sector.


Subject(s)
COVID-19 , COVID-19/epidemiology , Delivery of Health Care , Humans , Pandemics/prevention & control
5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-306475

ABSTRACT

Although the antimicrobial potential of nitric oxide (NO) is widely published, it is little used clinically. NO is a key signalling molecule modulating vascular, neuronal, inflammatory and immune responses. Endogenous antimicrobial activity is largely mediated by high local NO concentrations produced by cellular inducible nitric oxide synthase, and by derivative reactive nitrogen oxide species including peroxynitrite and S-nitrosothiols. NO may be taken as dietary substrate (inorganic nitrate, L-arginine), and therapeutically as gaseous NO, and transdermal, sublingual, oral, intranasal and intravenous nitrite or nitrate. Numerous preclinical studies have demonstrated that NO has generic static and cidal activities against viruses (including β-coronaviruses such as SARS-CoV-2), bacteria, protozoa and fungi/yeasts in vitro. Therapeutic effects have been seen in animal models in vivo, and phase II trials have demonstrated that NO donors can reduce microbial infection. Nevertheless, excess NO, as occurs in septic shock, is associated with increased morbidity and mortality. In view of the dose-dependent positive and negative effects of NO, safety and efficacy trials of NO and its donors are needed for assessing their role in the prevention and treatment of infections. Trials should test dietary inorganic nitrate for pre- or post-exposure prophylaxis and gaseous NO or oral, topical or intravenous nitrite and nitrate for treatment of mild-to-severe infections, including due to SARS-CoV-2 (COVID-19). This review summarises the evidence base from in vitro, in vivo and early phase clinical studies of NO activity in viral, bacterial, protozoal and fungal infections.

6.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-291740

ABSTRACT

Although the antimicrobial potential of nitric oxide (NO) is widely published, it is little used clinically. NO is a key signalling molecule modulating vascular, neuronal, inflammatory and immune responses. Endogenous antimicrobial activity is largely mediated by high local NO concentrations produced by cellular inducible nitric oxide synthase, and by derivative reactive nitrogen oxide species including peroxynitrite and S-nitrosothiols. NO may be taken as dietary substrate (inorganic nitrate, L-arginine), and therapeutically as gaseous NO, and transdermal, sublingual, oral, intranasal and intravenous nitrite or nitrate. Numerous preclinical studies have demonstrated that NO has generic static and cidal activities against viruses (including β-coronaviruses such as SARS-CoV-2), bacteria, protozoa and fungi/yeasts  in vitro . Therapeutic effects have been seen in animal models  in vivo , and phase II trials have demonstrated that NO donors can reduce microbial infection. Nevertheless, excess NO, as occurs in septic shock, is associated with increased morbidity and mortality. In view of the dose-dependent positive and negative effects of NO, safety and efficacy trials of NO and its donors are needed for assessing their role in the prevention and treatment of infections. Trials should test dietary inorganic nitrate for pre- or post-exposure prophylaxis and gaseous NO or oral, topical or intravenous nitrite and nitrate for treatment of mild-to-severe infections, including due to SARS-CoV-2 (COVID-19). This review summarises the evidence base from  in vitro, in vivo  and early phase clinical studies of NO activity in viral, bacterial, protozoal and fungal infections.

7.
Lancet Reg Health Eur ; 8: 100186, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1397545

ABSTRACT

BACKGROUND: This study sought to establish the long-term effects of Covid-19 following hospitalisation. METHODS: 327 hospitalised participants, with SARS-CoV-2 infection were recruited into a prospective multicentre cohort study at least 3 months post-discharge. The primary outcome was self-reported recovery at least ninety days after initial Covid-19 symptom onset. Secondary outcomes included new symptoms, disability (Washington group short scale), breathlessness (MRC Dyspnoea scale) and quality of life (EQ5D-5L). FINDINGS: 55% of participants reported not feeling fully recovered. 93% reported persistent symptoms, with fatigue the most common (83%), followed by breathlessness (54%). 47% reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24% of participants. The EQ5D-5L summary index was significantly worse following acute illness (median difference 0.1 points on a scale of 0 to 1, IQR: -0.2 to 0.0). Females under the age of 50 years were five times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age. INTERPRETATION: Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present in young, previously healthy working age adults, and were most common in younger females. FUNDING: National Institute for Health Research, UK Medical Research Council, Wellcome Trust, Department for International Development and the Bill and Melinda Gates Foundation.

8.
J Med Microbiol ; 70(4)2021 Apr.
Article in English | MEDLINE | ID: covidwho-1189541

ABSTRACT

Introduction. During previous viral pandemics, reported co-infection rates and implicated pathogens have varied. In the 1918 influenza pandemic, a large proportion of severe illness and death was complicated by bacterial co-infection, predominantly Streptococcus pneumoniae and Staphylococcus aureus.Gap statement. A better understanding of the incidence of co-infection in patients with COVID-19 infection and the pathogens involved is necessary for effective antimicrobial stewardship.Aim. To describe the incidence and nature of co-infection in critically ill adults with COVID-19 infection in England.Methodology. A retrospective cohort study of adults with COVID-19 admitted to seven intensive care units (ICUs) in England up to 18 May 2020, was performed. Patients with completed ICU stays were included. The proportion and type of organisms were determined at <48 and >48 h following hospital admission, corresponding to community and hospital-acquired co-infections.Results. Of 254 patients studied (median age 59 years (IQR 49-69); 64.6 % male), 139 clinically significant organisms were identified from 83 (32.7 %) patients. Bacterial co-infections/ co-colonisation were identified within 48 h of admission in 14 (5.5 %) patients; the commonest pathogens were Staphylococcus aureus (four patients) and Streptococcus pneumoniae (two patients). The proportion of pathogens detected increased with duration of ICU stay, consisting largely of Gram-negative bacteria, particularly Klebsiella pneumoniae and Escherichia coli. The co-infection/ co-colonisation rate >48 h after admission was 27/1000 person-days (95 % CI 21.3-34.1). Patients with co-infections/ co-colonisation were more likely to die in ICU (crude OR 1.78,95 % CI 1.03-3.08, P=0.04) compared to those without co-infections/ co-colonisation.Conclusion. We found limited evidence for community-acquired bacterial co-infection in hospitalised adults with COVID-19, but a high rate of Gram-negative infection acquired during ICU stay.


Subject(s)
Bacterial Infections/epidemiology , COVID-19/epidemiology , Coinfection/epidemiology , Adult , Aged , Aged, 80 and over , Bacteria/classification , Bacteria/isolation & purification , Bacterial Infections/microbiology , COVID-19/microbiology , Coinfection/microbiology , Critical Illness , Cross Infection/epidemiology , Cross Infection/microbiology , England/epidemiology , Female , Hospitalization , Humans , Intensive Care Units , Male , Middle Aged , Odds Ratio , Retrospective Studies , SARS-CoV-2 , Young Adult
9.
BMJ Open ; 11(3): e043887, 2021 03 10.
Article in English | MEDLINE | ID: covidwho-1127585

ABSTRACT

INTRODUCTION: Very little is known about possible clinical sequelae that may persist after resolution of acute COVID-19. A recent longitudinal cohort from Italy including 143 patients followed up after hospitalisation with COVID-19 reported that 87% had at least one ongoing symptom at 60-day follow-up. Early indications suggest that patients with COVID-19 may need even more psychological support than typical intensive care unit patients. The assessment of risk factors for longer term consequences requires a longitudinal study linked to data on pre-existing conditions and care received during the acute phase of illness. The primary aim of this study is to characterise physical and psychosocial sequelae in patients post-COVID-19 hospital discharge. METHODS AND ANALYSIS: This is an international open-access prospective, observational multisite study. This protocol is linked with the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) and the WHO's Clinical Characterisation Protocol, which includes patients with suspected or confirmed COVID-19 during hospitalisation. This protocol will follow-up a subset of patients with confirmed COVID-19 using standardised surveys to measure longer term physical and psychosocial sequelae. The data will be linked with the acute phase data. Statistical analyses will be undertaken to characterise groups most likely to be affected by sequelae of COVID-19. The open-access follow-up survey can be used as a data collection tool by other follow-up studies, to facilitate data harmonisation and to identify subsets of patients for further in-depth follow-up. The outcomes of this study will inform strategies to prevent long-term consequences; inform clinical management, interventional studies, rehabilitation and public health management to reduce overall morbidity; and improve long-term outcomes of COVID-19. ETHICS AND DISSEMINATION: The protocol and survey are open access to enable low-resourced sites to join the study to facilitate global standardised, longitudinal data collection. Ethical approval has been given by sites in Colombia, Ghana, Italy, Norway, Russia, the UK and South Africa. New sites are welcome to join this collaborative study at any time. Sites interested in adopting the protocol as it is or in an adapted version are responsible for ensuring that local sponsorship and ethical approvals in place as appropriate. The tools are available on the ISARIC website (www.isaric.org). PROTOCOL REGISTRATION NUMBER: osf.io/c5rw3/ PROTOCOL VERSION: 3 August 2020 EUROQOL ID: 37035.


Subject(s)
COVID-19/diagnosis , COVID-19/psychology , Colombia , Ghana , Humans , Italy , Longitudinal Studies , Norway , Prospective Studies , Risk Factors , Russia , South Africa , United Kingdom
11.
N Engl J Med ; 384(8): 693-704, 2021 Feb 25.
Article in English | MEDLINE | ID: covidwho-1101722

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. METHODS: In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment. RESULTS: A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55). CONCLUSIONS: In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.).


Subject(s)
COVID-19/drug therapy , Dexamethasone/therapeutic use , Glucocorticoids/therapeutic use , Oxygen Inhalation Therapy , Respiration, Artificial , Administration, Oral , Aged , Aged, 80 and over , Anti-Infective Agents/therapeutic use , COVID-19/mortality , COVID-19/therapy , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Drug Therapy, Combination , Female , Glucocorticoids/administration & dosage , Glucocorticoids/adverse effects , Hospitalization , Humans , Injections, Intravenous , Kaplan-Meier Estimate , Length of Stay , Male , Odds Ratio , United Kingdom
13.
N Engl J Med ; 383(21): 2030-2040, 2020 Nov 19.
Article in English | MEDLINE | ID: covidwho-990092

ABSTRACT

BACKGROUND: Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (Covid-19) on the basis of in vitro activity and data from uncontrolled studies and small, randomized trials. METHODS: In this randomized, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19, we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care. The primary outcome was 28-day mortality. RESULTS: The enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, after an interim analysis determined that there was a lack of efficacy. Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P = 0.15). Consistent results were seen in all prespecified subgroups of patients. The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to 1.27). There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine. CONCLUSIONS: Among patients hospitalized with Covid-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. (Funded by UK Research and Innovation and National Institute for Health Research and others; RECOVERY ISRCTN number, ISRCTN50189673; ClinicalTrials.gov number, NCT04381936.).


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Aged , Aged, 80 and over , Antiviral Agents/adverse effects , Betacoronavirus , COVID-19 , Coronavirus Infections/mortality , Female , Hospitalization , Humans , Hydroxychloroquine/adverse effects , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Respiration, Artificial , SARS-CoV-2 , Treatment Failure
15.
Medicine (Abingdon, England : UK Ed.) ; (1357-3039 (Print))2020.
Article in English | PMC | ID: covidwho-850319

ABSTRACT

Some newly emerging viral lung infections have the potential to cause large outbreaks of severe respiratory disease amongst humans. In this contribution we discuss infections by influenza A (H5N1), SARS and Hanta virus. The H5N1 subtype of avian influenza (bird flu) has crossed the species barrier and causes severe illness in humans. So far, 328 humans in twelve countries have contracted the disease and 200 have died. The young are particularly affected. Oseltamivir is the antiviral drug of choice and should be given as early as possible. Patients require supportive care, often including invasive ventilation. If H5N1 develops the ability to transmit efficiently between humans, an influenza pandemic is likely. Severe acute respiratory syndrome (SARS) was first seen in China in 2002. The outbreak was finally contained in 2003, by which time 8098 probable SARS cases had been identified with at least 774 deaths. The virus was identified in 2003 as belonging to the coronaviridae family. SARS is transmitted between humans and clusters have been seen. The mainstay of treatment is supportive. Various antiviral agents and adjunctive therapies were tried but none were conclusively effective. Hanta virus is an emerging cause of viral lung disease. In 1993, a new species of Hanta virus was recognized, after an outbreak of a new rapidly progressive pulmonary syndrome in the US, 465 cases of ‘Sin Nombre’ virus have now been seen in the US with a mortality rate of 35%. Many of the confirmed cases had contact with rodents (the major host of hanta viruses). Treatment is supportive, as there is no specific therapy. FAU - Roberts, Helen

16.
JAMA ; 324(13): 1330-1341, 2020 10 06.
Article in English | MEDLINE | ID: covidwho-739604

ABSTRACT

Importance: Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support. Objective: To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality. Design, Setting, and Participants: Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance-weighted fixed-effect analysis using risk ratios. Exposures: Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients). Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events. Results: A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as "low" for 6 of the 7 mortality results and as "some concerns" in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo. Conclusions and Relevance: In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Coronavirus Infections/drug therapy , Glucocorticoids/therapeutic use , Pneumonia, Viral/drug therapy , Betacoronavirus , COVID-19 , Cause of Death , Coronavirus Infections/mortality , Critical Illness , Dexamethasone/therapeutic use , Humans , Hydrocortisone/therapeutic use , Methylprednisolone/therapeutic use , Pandemics , Pneumonia, Viral/mortality , Randomized Controlled Trials as Topic , SARS-CoV-2
18.
J Infect ; 81(2): 266-275, 2020 08.
Article in English | MEDLINE | ID: covidwho-401261

ABSTRACT

OBJECTIVES: In previous influenza pandemics, bacterial co-infections have been a major cause of mortality. We aimed to evaluate the burden of co-infections in patients with COVID-19. METHODS: We systematically searched Embase, Medline, Cochrane Library, LILACS and CINAHL for eligible studies published from 1 January 2020 to 17 April 2020. We included patients of all ages, in all settings. The main outcome was the proportion of patients with a bacterial, fungal or viral co-infection. . RESULTS: Thirty studies including 3834 patients were included. Overall, 7% of hospitalised COVID-19 patients had a bacterial co-infection (95% CI 3-12%, n=2183, I2=92·2%). A higher proportion of ICU patients had bacterial co-infections than patients in mixed ward/ICU settings (14%, 95% CI 5-26, I2=74·7% versus 4%, 95% CI 1-9, I2= 91·7%). The commonest bacteria were Mycoplasma pneumonia, Pseudomonas aeruginosa and Haemophilus influenzae. The pooled proportion with a viral co-infection was 3% (95% CI 1-6, n=1014, I2=62·3%), with Respiratory Syncytial Virus and influenza A the commonest. Three studies reported fungal co-infections. CONCLUSIONS: A low proportion of COVID-19 patients have a bacterial co-infection; less than in previous influenza pandemics. These findings do not support the routine use of antibiotics in the management of confirmed COVID-19 infection.


Subject(s)
Bacterial Infections/virology , Coinfection/microbiology , Coinfection/virology , Coronavirus Infections/virology , Pneumonia, Viral/virology , Bacterial Infections/complications , Bacterial Infections/epidemiology , Betacoronavirus , COVID-19 , Coinfection/epidemiology , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Humans , Mycoses/complications , Mycoses/epidemiology , Mycoses/virology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Virus Diseases/complications , Virus Diseases/epidemiology , Virus Diseases/microbiology
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