ABSTRACT
RationalePulmonary aspergillosis may complicate COVID-19 and contribute to excess mortality in intensive care unit (ICU) patients. The incidence is unclear because of discordant definitions across studies. ObjectiveWe sought to review the incidence, diagnosis, treatment, and outcomes of COVID-19-associated pulmonary aspergillosis (CAPA), and compare research definitions. MethodsWe systematically reviewed the literature for ICU cohort studies and case series including [≥] patients with CAPA. We calculated pooled incidence. Patients with sufficient clinical details were reclassified according to 4 standardized definitions (Verweij, White, Koehler, and Bassetti). MeasurementsCorrelations between definitions were assessed with Spearmans rank test. Associations between antifungals and outcome were assessed with Fishers Exact test. Main Results38 studies (35 cohort studies and 3 case series) were included. Among 3,297 COVID-19 patients in ICU cohort studies, 313 were diagnosed with CAPA (pooled incidence 9.5%). 197 patients had patient-level data allowing reclassification. Definitions had limited correlation with one another ({rho}=0.330 to 0.621, p<0.001). 38.6% of patients reported to have CAPA did not fulfil any research definitions. Patients were diagnosed after a median of 9 days (interquartile range 5-14) in ICUs. Tracheobronchitis occured in 5.3% of patients examined with bronchoscopy. The mortality rate (50.0%) was high, irrespective of antifungal use (p=0.28); this remained true even when the analysis was restricted to patients meeting standardized definitions for CAPA. ConclusionsThe reported incidence of CAPA is exaggerated by use of non-standard definitions. Further research should focus on identifying patients likely to benefit from antifungals.
ABSTRACT
BackgroundInvasive mould disease (IMD) - most commonly pulmonary aspergillosis - is reported to affect up to a third of critically ill COVID-19 patients. Most reported cases are diagnosed with probable/putative COVID-19 associated pulmonary aspergillosis (CAPA) based on a combination of non-specific clinical, radiographic, and mycological findings, but the clinical significance - and whether these cases represent true invasive disease - is unresolved. MethodsWe performed a systematic review of autopsy series of decedents with COVID-19 for evidence of IMD. We searched PubMed, Web of Science, OVID (Embase) and MedRxiv for English- or French-language case series published between January 1, 2019 to September 26, 2020. We included series describing lung histology of [≥]3 decedents, and authors were contacted for missing information as necessary. FindingsWe identified 51 case series describing autopsies of 702 decedents. Individual-level data was available for 430 decedents. The median age was 72 (IQR 61 to 80) years. Diabetes mellitus, pre-existing lung disease, and immunocompromising conditions were reported for 129 (32%), 95 (22%), and 25 (6%) decedents, respectively. The median hospitalization length was 10 (IQR 5-22) days. 51.6% of decedents had received mechanical ventilation for a median of nine (IQR 5-20) days. Treatment included immunomodulation in 60 (most often steroids or tocilizumab) and antifungals in 41 decedents. Eleven decedents (1{middle dot}6%) had autopsy-confirmed IMD (6 with CAPA, 4 with invasive pulmonary mycosis not specified and 1 with disseminated mucormycosis). Among 173 decedents who received mechanical ventilation, 5 had IMD (2{middle dot}9%). InterpretationAutopsy-proven IMD, including CAPA, is uncommon in fatal COVID-19. FundingThis study is unfunded CategoryReview
ABSTRACT
IntroductionUse of hydroxychloroquine in hospitalized patients with COVID-19, especially in combination with azithromycin, has raised safety concerns. Here, we report safety data from three outpatient randomized clinical trials. MethodsWe conducted three randomized, double-blind, placebo-controlled trials investigating hydroxychloroquine as pre-exposure prophylaxis, post-exposure prophylaxis and early treatment for COVID-19. We excluded individuals with contraindications to hydroxychloroquine. We collected side effects and serious adverse events. We report descriptive analyses of our findings. ResultsWe enrolled 2,795 participants. The median age of research participants was 40 (IQR 34-49) years, and 59% (1633/2767) reported no chronic medical conditions. Overall 2,324 (84%) participants reported side effect data, and 638 (27%) reported at least one medication side effect. Side effects were reported in 29% with daily, 36% with twice weekly, 31% with once weekly hydroxychloroquine compared to 19% with placebo. The most common side effects were upset stomach or nausea (25% with daily, 18% with twice weekly, 16% with weekly, vs. 10% for placebo), followed by diarrhea, vomiting, or abdominal pain (23% for daily, 16% twice weekly, 12% weekly, vs. 6% for placebo). Two individuals were hospitalized for atrial arrhythmias, one on placebo and one on twice weekly hydroxychloroquine. No sudden deaths occurred. ConclusionData from three 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 can safely investigate whether hydroxychloroquine is efficacious for COVID-19. Short SummaryData from three randomized clinical trials using hydroxychloroquine for the prevention and treatment of COVID-19 did not suggest significant safety concerns. Gastrointestinal side effects were common but arrhythmias were rare. There were no sudden deaths in any trial.
