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1.
JAMMI: Journal of the Association of Medical Microbiology & Infectious Disease Canada ; 6(4):241-244, 2021.
Article in English | CINAHL | ID: covidwho-1566625
2.
Open forum infectious diseases ; 8(12), 2021.
Article in English | EuropePMC | ID: covidwho-1563852

ABSTRACT

Coronavirus disease 2019 (COVID-19) can become complicated by secondary invasive fungal infections (IFIs), stemming primarily from severe lung damage and immunologic deficits associated with the virus or immunomodulatory therapy. Other risk factors include poorly controlled diabetes, structural lung disease and/or other comorbidities, and fungal colonization. Opportunistic IFI following severe respiratory viral illness has been increasingly recognized, most notably with severe influenza. There have been many reports of fungal infections associated with COVID-19, initially predominated by pulmonary aspergillosis, but with recent emergence of mucormycosis, candidiasis, and endemic mycoses. These infections can be challenging to diagnose and are associated with poor outcomes. The reported incidence of IFI has varied, often related to heterogeneity in patient populations, surveillance protocols, and definitions used for classification of fungal infections. Herein, we review IFI complicating COVID-19 and address knowledge gaps related to epidemiology, diagnosis, and management of COVID-19–associated fungal infections.

3.
Lancet Microbe ; 2(8): e405-e414, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1286408

ABSTRACT

Invasive mould disease (IMD) might affect up to a third of critically ill patients with COVID-19. COVID-19-associated pulmonary aspergillosis (CAPA) is typically diagnosed on the basis of a combination of non-specific clinical, radiographical, and mycological findings, but whether most cases represent invasive disease is unresolved. We systematically reviewed autopsy series of three or more decedents with COVID-19 for evidence of IMD. We searched PubMed, Web of Science, OVID (Embase), and medRxiv for studies in English or French published from Jan 1, 2019, to Sept 26, 2020. We identified 1070 references, of which 50 studies met the criteria. These studies described autopsies from 677 decedents, with individual-level data for 443 decedents. The median age was 70·0 years (IQR 57·0-79·0). Of decedents with individual-level data, 133 (30%) had diabetes, 97 (22%) had pre-existing lung disease, and 27 (6%) had immunocompromising conditions. Of 548 decedents with such data, 320 (58%) received invasive mechanical ventilation; among 140 decedents for whom this was known, ventilation was for a median of 9·0 days (IQR 5·0-20·0). Treatment included immunomodulation in 60 decedents and antifungals in 50 decedents. Autopsy-proven IMD occurred in 11 (2%) of 677 decedents, including eight CAPA, two unspecified IMD, and one disseminated mucormycosis. Among 320 decedents who received mechanical ventilation, six (2%) had IMD. We conclude that IMD, including CAPA, is an uncommon autopsy finding in COVID-19.

4.
CMAJ Open ; 9(2): E693-E702, 2021.
Article in English | MEDLINE | ID: covidwho-1278708

ABSTRACT

BACKGROUND: Identification of therapies to prevent severe COVID-19 remains a priority. We sought to determine whether hydroxychloroquine treatment for outpatients with SARS-CoV-2 infection could prevent hospitalization, mechanical ventilation or death. METHODS: This randomized controlled trial was conducted in Alberta during the first wave of the COVID-19 pandemic without direct contact with participants. Community-dwelling individuals with confirmed SARS-CoV-2 infection (by reverse transcription polymerase chain reaction [RT-PCR] viral ribonucleic acid test) within the previous 4 days, and symptom onset within the previous 12 days, were randomly assigned to oral hydroxychloroquine or matching placebo for 5 days. Enrolment began Apr. 15, 2020. The primary outcome was the composite of hospitalization, invasive mechanical ventilation or death within 30 days. Secondary outcomes included symptom duration and disposition at 30 days. Safety outcomes, such as serious adverse events and mortality, were also ascertained. Outcomes were determined by telephone follow-up and administrative data. RESULTS: Among 4919 individuals with a positive RT-PCR test, 148 (10.2% of a planned 1446 patients) were randomly assigned, 111 to hydroxychloroquine and 37 to placebo. Of the 148 participants, 24 (16.2%) did not start the study drug. Four participants in the hydroxychloroquine group met the primary outcome (4 hospitalizations, 0 mechanical ventilation, 4 survived to 30 days) and none in the placebo group. Hydroxychloroquine did not reduce symptom duration (hazard ratio 0.77, 95% confidence interval 0.49-1.21). Recruitment was paused on May 22, 2020, when a since-retracted publication raised concerns about the safety of hydroxychloroquine for hospitalized patients with COVID-19. Although we had not identified concerns in a safety review, enrolment was slower than expected among those eligible for the study, and cases within the community were decreasing. Recruitment goals were deemed to be unattainable and the trial was not resumed, resulting in a study underpowered to assess the effect of treatment with hydroxychloroquine and safety. INTERPRETATION: There was no evidence that hydroxychloroquine reduced symptom duration or prevented severe outcomes among outpatients with proven COVID-19, but the early termination of our study meant that it was underpowered. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT04329611.


Subject(s)
Ambulatory Care , COVID-19 , Hospitalization/statistics & numerical data , Hydroxychloroquine , Respiration, Artificial/statistics & numerical data , Ambulatory Care/methods , Ambulatory Care/statistics & numerical data , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/mortality , Early Termination of Clinical Trials , Female , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Independent Living/statistics & numerical data , Male , Middle Aged , Mortality , Outcome Assessment, Health Care , Preventive Health Services/methods , SARS-CoV-2/isolation & purification , Severity of Illness Index
5.
Infect Dis Clin North Am ; 35(2): 261-277, 2021 06.
Article in English | MEDLINE | ID: covidwho-1232974

ABSTRACT

Various uncommon fungal pathogens have been increasingly identified as causes of disseminated and invasive fungal disease (IFD) worldwide. Growing recognition and clinical knowledge of these emerging fungal pathogens has occurred through improved molecular diagnostics, nucleic sequence databases, and taxonomic reclassification of medically significant fungi. However, emerging fungal diseases carry significant morbidity and mortality and, due to a paucity of published literature, the collective clinical experience with these fungi is often limited. In this review, we focus on unusual emerging fungal pathogens not extensively covered elsewhere in this issue of Infectious Diseases Clinics of North America.

6.
Med Mycol Case Rep ; 31: 1, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1078095
7.
Open Forum Infect Dis ; 8(3): ofab065, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1069304

ABSTRACT

Background: Limited clinical data suggest a ~16% prevalence of bacterial superinfections among critically ill patients with coronavirus disease 2019 (COVID-19). Methods: We reviewed postmortem studies of patients with COVID-19 published in English through September 26, 2020, for histopathologic findings consistent with bacterial lung infections. Results: Worldwide, 621 patients from 75 studies were included. The quality of data was uneven, likely because identifying superinfections was not a major objective in 96% (72/75) of studies. Histopathology consistent with a potential lung superinfection was reported in 32% (200/621) of patients (22-96 years old; 66% men). Types of infections were pneumonia (95%), abscesses or empyema (3.5%), and septic emboli (1.5%). Seventy-three percent of pneumonias were focal rather than diffuse. The predominant histopathologic findings were intra-alveolar neutrophilic infiltrations that were distinct from those typical of COVID-19-associated diffuse alveolar damage. In studies with available data, 79% of patients received antimicrobial treatment; the most common agents were beta-lactam/beta-lactamase inhibitors (48%), macrolides (16%), cephalosoprins (12%), and carbapenems (6%). Superinfections were proven by direct visualization or recovery of bacteria in 25.5% (51/200) of potential cases and 8% of all patients in postmortem studies. In rank order, pathogens included Acinetobacter baumannii, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Lung superinfections were the cause of death in 16% of potential cases and 3% of all patients with COVID-19. Conclusions: Potential bacterial lung superinfections were evident at postmortem examination in 32% of persons who died with COVID-19 (proven, 8%; possible, 24%), but they were uncommonly the cause of death.

8.
Ann Intern Med ; 173(8): 623-631, 2020 10 20.
Article in English | MEDLINE | ID: covidwho-981646

ABSTRACT

BACKGROUND: No effective oral therapy exists for early coronavirus disease 2019 (COVID-19). OBJECTIVE: To investigate whether hydroxychloroquine could reduce COVID-19 severity in adult outpatients. DESIGN: Randomized, double-blind, placebo-controlled trial conducted from 22 March through 20 May 2020. (ClinicalTrials.gov: NCT04308668). SETTING: Internet-based trial across the United States and Canada (40 states and 3 provinces). PARTICIPANTS: Symptomatic, nonhospitalized adults with laboratory-confirmed COVID-19 or probable COVID-19 and high-risk exposure within 4 days of symptom onset. INTERVENTION: Oral hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days) or masked placebo. MEASUREMENTS: Symptoms and severity at baseline and then at days 3, 5, 10, and 14 using a 10-point visual analogue scale. The primary end point was change in overall symptom severity over 14 days. RESULTS: Of 491 patients randomly assigned to a group, 423 contributed primary end point data. Of these, 341 (81%) had laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or epidemiologically linked exposure to a person with laboratory-confirmed infection; 56% (236 of 423) were enrolled within 1 day of symptoms starting. Change in symptom severity over 14 days did not differ between the hydroxychloroquine and placebo groups (difference in symptom severity: relative, 12%; absolute, -0.27 point [95% CI, -0.61 to 0.07 point]; P = 0.117). At 14 days, 24% (49 of 201) of participants receiving hydroxychloroquine had ongoing symptoms compared with 30% (59 of 194) receiving placebo (P = 0.21). Medication adverse effects occurred in 43% (92 of 212) of participants receiving hydroxychloroquine versus 22% (46 of 211) receiving placebo (P < 0.001). With placebo, 10 hospitalizations occurred (2 non-COVID-19-related), including 1 hospitalized death. With hydroxychloroquine, 4 hospitalizations occurred plus 1 nonhospitalized death (P = 0.29). LIMITATION: Only 58% of participants received SARS-CoV-2 testing because of severe U.S. testing shortages. CONCLUSION: Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19. PRIMARY FUNDING SOURCE: Private donors.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Outpatients , Pandemics , Pneumonia, Viral/drug therapy , Adult , Antimalarials/therapeutic use , COVID-19 , Coronavirus Infections/epidemiology , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Middle Aged , Pneumonia, Viral/epidemiology , Retrospective Studies , Risk Factors , SARS-CoV-2 , Time Factors
10.
Open Forum Infect Dis ; 7(11): ofaa500, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-873054

ABSTRACT

Background: Use of hydroxychloroquine in hospitalized patients with coronavirus disease 2019 (COVID-19), especially in combination with azithromycin, has raised safety concerns. Here, we report safety data from 3 outpatient randomized clinical trials. Methods: We conducted 3 randomized, double-blind, placebo-controlled trials investigating hydroxychloroquine as pre-exposure prophylaxis, postexposure prophylaxis, and early treatment for COVID-19 using an internet-based design. We excluded individuals with contraindications to hydroxychloroquine. We collected side effects and serious adverse events. We report descriptive analyses of our findings. Results: We enrolled 2795 participants. The median age of research participants (interquartile range) was 40 (34-49) years, and 59% (1633/2767) reported no chronic medical conditions. Overall 2544 (91%) participants reported side effect data, and 748 (29%) reported at least 1 medication side effect. Side effects were reported in 40% with once-daily, 36% with twice-weekly, 31% with once-weekly hydroxychloroquine, compared with 19% with placebo. The most common side effects were upset stomach or nausea (25% with once-daily, 19% with twice-weekly, and 18% with once-weekly hydroxychloroquine, vs 11% for placebo), followed by diarrhea, vomiting, or abdominal pain (23% for once-daily, 17% twice-weekly, and 13% once-weekly hydroxychloroquine, vs 7% for placebo). Two individuals were hospitalized for atrial arrhythmias, 1 on placebo and 1 on twice-weekly hydroxychloroquine. No sudden deaths occurred. Conclusions: Data from 3 outpatient COVID-19 trials demonstrated that gastrointestinal side effects were common but mild with the use of hydroxychloroquine, while serious side effects were rare. No deaths occurred related to hydroxychloroquine. Randomized clinical trials, in cohorts of healthy outpatients, can safely investigate whether hydroxychloroquine is efficacious for COVID-19. ClinicalTrialsgov Identifier: NCT04308668 for postexposure prophylaxis and early treatment trials; NCT04328467 for pre-exposure prophylaxis trial.

11.
Open Forum Infect Dis ; 7(8): ofaa304, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-733363

ABSTRACT

Knowledge dissemination during COVID19 has been notable for the rise of pre-prints and publication by press release, favoring speed over accuracy. We stress the importance of journals in this landscape and highlight the value of editorial judgment and peer review.

12.
N Engl J Med ; 383(6): 517-525, 2020 08 06.
Article in English | MEDLINE | ID: covidwho-505858

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are exposed, the standard of care is observation and quarantine. Whether hydroxychloroquine can prevent symptomatic infection after SARS-CoV-2 exposure is unknown. METHODS: We conducted a randomized, double-blind, placebo-controlled trial across the United States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis. We enrolled adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Within 4 days after exposure, we randomly assigned participants to receive either placebo or hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days. RESULTS: We enrolled 821 asymptomatic participants. Overall, 87.6% of the participants (719 of 821) reported a high-risk exposure to a confirmed Covid-19 contact. The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); the absolute difference was -2.4 percentage points (95% confidence interval, -7.0 to 2.2; P = 0.35). Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported. CONCLUSIONS: After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure. (Funded by David Baszucki and Jan Ellison Baszucki and others; ClinicalTrials.gov number, NCT04308668.).


Subject(s)
Coronavirus Infections/prevention & control , Hydroxychloroquine/therapeutic use , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Post-Exposure Prophylaxis , Adult , Betacoronavirus , COVID-19 , Canada , Double-Blind Method , Female , Humans , Hydroxychloroquine/adverse effects , Inhalation Exposure , Male , Middle Aged , Occupational Exposure , SARS-CoV-2 , Treatment Failure , United States
13.
Can J Anaesth ; 67(9): 1201-1211, 2020 09.
Article in English | MEDLINE | ID: covidwho-275845

ABSTRACT

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 causing the coronavirus disease (COVID-19) pandemic. Currently, there is a lack of evidence-based therapies to prevent COVID-19 following exposure to the virus, or to prevent worsening of symptoms following confirmed infection. We describe the design of a clinical trial of hydroxychloroquine for post-exposure prophylaxis (PEP) and pre-emptive therapy (PET) for COVID-19. METHODS: We will conduct two nested multicentre international double-blind randomized placebo-controlled clinical trials of hydroxychloroquine for: 1) PEP of asymptomatic household contacts or healthcare workers exposed to COVID-19 within the past four days, and 2) PET for symptomatic outpatients with COVID-19 showing symptoms for less than four days. We will recruit 1,500 patients each for the PEP and PET trials. Participants will be randomized 1:1 to receive five days of hydroxychloroquine or placebo. The primary PEP trial outcome will be the incidence of symptomatic COVID-19. The primary PET trial outcome will be an ordinal scale of disease severity (not hospitalized, hospitalized without intensive care, hospitalization with intensive care, or death). Participant screening, informed consent, and follow-up will be exclusively internet-based with appropriate regulatory and research ethics board approvals in Canada and the United States. DISCUSSION: These complementary randomized-controlled trials are innovatively designed and adequately powered to rapidly answer urgent questions regarding the effectiveness of hydroxychloroquine to reduce virus transmission and disease severity of COVID-19 during a pandemic. In-person participant follow-up will not be conducted to facilitate social distancing strategies and reduce risks of exposure to study personnel. Innovative trial approaches are needed to urgently assess therapeutic options to mitigate the global impact of this pandemic. TRIALS REGISTRATION: clinicaltrials.gov (NCT04308668); registered 16 March, 2020.


Subject(s)
Coronavirus Infections/prevention & control , Hydroxychloroquine/administration & dosage , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Post-Exposure Prophylaxis/methods , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/transmission , Double-Blind Method , Humans , Pneumonia, Viral/transmission , SARS-CoV-2 , Severity of Illness Index
14.
Open Forum Infect Dis ; 7(4): ofaa130, 2020 Apr.
Article in English | MEDLINE | ID: covidwho-60353

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging viral infection causing coronavirus disease 2019 (COVID-19). Hydroxychloroquine and chloroquine have garnered unprecedented attention as potential therapeutic agents against COVID-19 following several small clinical trials, uncontrolled case series, and public figure endorsements. While there is a growing body of scientific data, there is also concern for harm, particularly QTc prolongation and cardiac arrhythmias. Here, we perform a rapid narrative review and discuss the strengths and limitations of existing in vitro and clinical studies. We call for additional randomized controlled trial evidence prior to the widespread incorporation of hydroxychloroquine and chloroquine into national and international treatment guidelines.

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