Abstract

BACKGROUND The early COVID-19 literature suggested that people with cancer may be more likely to be infected with SARS-CoV-2 or develop COVID-19 than people without cancer, due to increased health services contact and/or immunocompromise. While some studies were criticised due to small patient numbers and methodological limitations, they created or reinforced concerns of clinicians and people with cancer. These risks are also important in COVID-19 vaccine prioritisation decisions. We performed a systematic review to critically assess and summarise the early literature. METHODS AND FINDINGS We conducted a systematic search of Medline/Embase/BioRxiv/MedRxiv/SSRN databases including peer-reviewed journal articles, letters/commentaries, and non-peer-reviewed pre-print articles for 1 January-1 July 2020. The primary endpoints were diagnosis of COVID-19 and positive SARS-CoV-2 test. We assessed risk of bias using a tool adapted from the Newcastle-Ottawa Scale. Twelve studies were included in the quantitative synthesis. All four studies of COVID-19 incidence (including 24,181,727 individuals, 125,649 with pre-existing cancer) reported that people with cancer had higher COVID-19 incidence rates. Eight studies reported SARS-CoV-2 test positivity for >472,000 individuals, 48,370 with pre-existing cancer. Seven of these studies comparing people with any and without cancer, were pooled using random effects [pooled odds ratio 0.91, 95%CI:0.57-1.47; unadjusted for age, sex, or comorbidities]. Two studies suggested people with active or haematological cancer had lower risk of a positive test. All 12 studies had high risk of bias; none included universal or random COVID-19/SARS-CoV-2 testing. CONCLUSIONS The early literature on susceptibility to SARS-CoV-2/COVID-19 for people with cancer is characterised by pervasive biases and limited data. To provide high-quality evidence to inform decision-making, studies of risk of SARS-CoV-2/COVID-19 for people with cancer should control for other potential modifiers of infection risk, including age, sex, comorbidities, exposure to the virus, protective measures taken, and vaccination, in addition to stratifying analyses by cancer type, stage at diagnosis, and treatment received.

Abstract

BACKGROUND During the COVID-19 pandemic, there are growing concerns about the safety of administering immunotherapy in cancer patients with COVID-19. However, current clinical guidelines provided no clear recommendation. METHODS Studies were searched and retrieved from electronic databases. The meta-analysis was performed by employing the generic inverse-variance method. A random-effects model was used to calculate the unadjusted odds ratios (ORs) and adjusted ORs with the corresponding 95% CIs. RESULTS This meta-analysis included 20 articles with 6,042 cancer patients diagnosed with COVID-19. According to the univariate analysis, the acceptance of immunotherapy within 30 days before COVID-19 diagnosis did not increase the mortality of cancer patients (OR: 0.92; 95% CI: 0.68-1.25; P=0.61). Moreover, after adjusting for confounders, the adjusted OR for mortality was 0.51, with borderline significance (95% CI: 0.25-1.01; P=0.053). Similarly, the univariate analysis showed that the acceptance of immunotherapy within 30 days before COVID-19 diagnosis did not increase the risk of severe/critical disease in cancer patients (OR: 1.07; 95% CI: 0.78-1.47; P=0.66). No significant between-study heterogeneity was found in these analyses. CONCLUSIONS Accepting immunotherapy within 30 days before the diagnosis of COVID-19 was not significantly associated with a higher risk of mortality or severe/critical disease of infected cancer patients. Further prospectively designed studies with large sample sizes are required to evaluate the present results.

Abstract

BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV-2 virus has resulted in significant mortality and burdening of healthcare resources. While initially noted as a pulmonary pathology, subsequent studies later identified cardiovascular involvement with high mortalities reported in specific cohorts of patients. While cardiovascular comorbidities were identified early on, the exact manifestation and etiopathology of the infection remained elusive. This systematic review aims to investigate the role of inflammatory pathways, highlighting several culprits including neutrophil extracellular traps (NETs) which have since been extensively investigated. METHOD A search was conducted using three databases (MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations and EMBASE). Data from randomized controlled trials (RCT), prospective series, meta-analyses, and unmatched observational studies were considered for the processing of the algorithm and treatment of inflammatory response during SARS-CoV-2 infection. Studies without the SARS-CoV-2 Infection period and case reports were excluded. RESULTS A total of 47 studies were included in this study. The role of the acute inflammatory response in the propagation of the systemic inflammatory sequelae of the disease plays a major part in determining outcomes. Some of the mechanisms of activation of these pathways have been highlighted in previous studies and are highlighted. CONCLUSION NETs play a pivotal role in the pathogenesis of the inflammatory response. Despite moving into the endemic phase of the disease in most countries, COVID-19 remains an entity that has not been fully understood with long-term effects remaining uncertain and requiring ongoing monitoring and research.

Abstract

PURPOSE Cancer patients with COVID-19 likely express biomarker changes in circulation. However, the biomarkers used in SARS-CoV-2 infected cancer patients for COVID-19 severity and prognosis are largely unclear. Therefore, this systematic review aims to determine what biomarkers were measured in cancer patients with COVID-19 and their prognostic utility. METHODS A systematic literature review in PubMed, Embase, and Scopus was performed on June 16th, 2021. The search keywords coronavirus, neoplasm, biomarkers, and disease progression were used to filter out 17 eligible studies, which were then carefully evaluated. RESULTS A total of 4,168 patients, 16 types of cancer, and 60 biomarkers were included. Seven up-regulated markers, including CRP, d-dimer, ferritin, IL-2R, IL-6, LDH, and PCT, were identified in eligible studies. Albumin and hemoglobin were significantly down-regulated in cancer patients with COVID-19. Moreover, we observed that the SARS-CoV-2 infected cancer patients with lower CRP, ferritin, and LDH levels successfully survived from COVID-19 treatments. CONCLUSION Several important clinical biomarkers, such as CRP, ferritin, and LDH, may serve as the prognostic markers to predict the outcomes following COVID-19 treatment and monitor the deterioration of COVID-19 in cancer patients.

Abstract

BACKGROUND Convalescent plasma has been proposed as an early treatment to interrupt the progression of early COVID-19 to severe disease, but there is little definitive evidence. We aimed to assess whether early treatment with convalescent plasma reduces the risk of hospitalisation and reduces SARS-CoV-2 viral load among outpatients with COVID-19. METHODS We did a multicentre, double-blind, randomised, placebo-controlled trial in four health-care centres in Catalonia, Spain. Adult outpatients aged 50 years or older with the onset of mild COVID-19 symptoms 7 days or less before randomisation were eligible for enrolment. Participants were randomly assigned (1:1) to receive one intravenous infusion of either 250-300 mL of ABO-compatible high anti-SARS-CoV-2 IgG titres (EUROIMMUN ratio ≥6) methylene blue-treated convalescent plasma (experimental group) or 250 mL of sterile 0·9% saline solution (control). Randomisation was done with the use of a central web-based system with concealment of the trial group assignment and no stratification. To preserve masking, we used opaque tubular bags that covered the investigational product and the infusion catheter. The coprimary endpoints were the incidence of hospitalisation within 28 days from baseline and the mean change in viral load (in log(10) copies per mL) in nasopharyngeal swabs from baseline to day 7. The trial was stopped early following a data safety monitoring board recommendation because more than 85% of the target population had received a COVID-19 vaccine. Primary efficacy analyses were done in the intention-to-treat population, safety was assessed in all patients who received the investigational product. This study is registered with ClinicalTrials.gov, NCT04621123. FINDINGS Between Nov 10, 2020, and July 28, 2021, we assessed 909 patients with confirmed COVID-19 for inclusion in the trial, 376 of whom were eligible and were randomly assigned to treatment (convalescent plasma n=188 [serum antibody-negative n=160]; placebo n=188 [serum antibody-negative n=166]). Median age was 56 years (IQR 52-62) and the mean symptom duration was 4·4 days (SD 1·4) before random assignment. In the intention-to-treat population, hospitalisation within 28 days from baseline occurred in 22 (12%) participants who received convalescent plasma versus 21 (11%) who received placebo (relative risk 1·05 [95% CI 0·78 to 1·41]). The mean change in viral load from baseline to day 7 was -2·41 log(10) copies per mL (SD 1·32) with convalescent plasma and -2·32 log(10) copies per mL (1·43) with placebo (crude difference -0·10 log(10) copies per mL [95% CI -0·35 to 0·15]). One participant with mild COVID-19 developed a thromboembolic event 7 days after convalescent plasma infusion, which was reported as a serious adverse event possibly related to COVID-19 or to the experimental intervention. INTERPRETATION Methylene blue-treated convalescent plasma did not prevent progression from mild to severe illness and did not reduce viral load in outpatients with COVID-19. Therefore, formal recommendations to support the use of convalescent plasma in outpatients with COVID-19 cannot be concluded. FUNDING Grifols, Crowdfunding campaign YoMeCorono.

Abstract

BACKGROUND Casirivimab and imdevimab are non-competing monoclonal antibodies that bind to two different sites on the receptor binding domain of the SARS-CoV-2 spike glycoprotein, blocking viral entry into host cells. We aimed to evaluate the efficacy and safety of casirivimab and imdevimab administered in combination in patients admitted to hospital with COVID-19. METHODS RECOVERY is a randomised, controlled, open-label platform trial comparing several possible treatments with usual care in patients admitted to hospital with COVID-19. 127 UK hospitals took part in the evaluation of casirivimab and imdevimab. Eligible participants were any patients aged at least 12 years admitted to hospital with clinically suspected or laboratory-confirmed SARS-CoV-2 infection. Participants were randomly assigned (1:1) to either usual standard of care alone or usual care plus casirivimab 4 g and imdevimab 4 g administered together in a single intravenous infusion. Investigators and data assessors were masked to analyses of the outcome data during the trial. The primary outcome was 28-day all-cause mortality assessed by intention to treat, first only in patients without detectable antibodies to SARS-CoV-2 infection at randomisation (ie, those who were seronegative) and then in the overall population. Safety was assessed in all participants who received casirivimab and imdevimab. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS Between Sept 18, 2020, and May 22, 2021, 9785 patients enrolled in RECOVERY were eligible for casirivimab and imdevimab, of which 4839 were randomly assigned to casirivimab and imdevimab plus usual care and 4946 to usual care alone. 3153 (32%) of 9785 patients were seronegative, 5272 (54%) were seropositive, and 1360 (14%) had unknown baseline antibody status. 812 (8%) patients were known to have received at least one dose of a SARS-CoV-2 vaccine. In the primary efficacy population of seronegative patients, 396 (24%) of 1633 patients allocated to casirivimab and imdevimab versus 452 (30%) of 1520 patients allocated to usual care died within 28 days (rate ratio [RR] 0·79, 95% CI 0·69-0·91; p=0·0009). In an analysis of all randomly assigned patients (regardless of baseline antibody status), 943 (19%) of 4839 patients allocated to casirivimab and imdevimab versus 1029 (21%) of 4946 patients allocated to usual care died within 28 days (RR 0·94, 95% CI 0·86-1·02; p=0·14). The proportional effect of casirivimab and imdevimab on mortality differed significantly between seropositive and seronegative patients (p value for heterogeneity=0·002). There were no deaths attributed to the treatment, or meaningful between-group differences in the pre-specified safety outcomes of cause-specific mortality, cardiac arrhythmia, thrombosis, or major bleeding events. Serious adverse reactions reported in seven (<1%) participants were believed by the local investigator to be related to treatment with casirivimab and imdevimab. INTERPRETATION In patients admitted to hospital with COVID-19, the monoclonal antibody combination of casirivimab and imdevimab reduced 28-day mortality in patients who were seronegative (and therefore had not mounted their own humoral immune response) at baseline but not in those who were seropositive at baseline. FUNDING UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

Abstract

OBJECTIVE To assess the effect of statin treatment versus placebo on clinical outcomes in patients with covid-19 admitted to the intensive care unit (ICU). DESIGN INSPIRATION/INSPIRATION-S was a multicenter, randomized controlled trial with a 2×2 factorial design. Results for the anticoagulation randomization have been reported previously. Results for the double blind randomization to atorvastatin versus placebo are reported here. SETTING 11 hospitals in Iran. PARTICIPANTS Adults aged ≥18 years with covid-19 admitted to the ICU. INTERVENTION Atorvastatin 20 mg orally once daily versus placebo, to be continued for 30 days from randomization irrespective of hospital discharge status. MAIN OUTCOME MEASURES The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all cause mortality within 30 days from randomization. Prespecified safety outcomes included increase in liver enzyme levels more than three times the upper limit of normal and clinically diagnosed myopathy. A clinical events committee blinded to treatment assignment adjudicated the efficacy and safety outcomes. RESULTS Of 605 patients randomized between 29 July 2020 and 4 April 2021 for statin randomization in the INSPIRATION-S trial, 343 were co-randomized to intermediate dose versus standard dose prophylactic anticoagulation with heparin based regimens, whereas 262 were randomized after completion of the anticoagulation study. 587 of the 605 participants were included in the primary analysis of INSPIRATION-S, reported here: 290 were assigned to atorvastatin and 297 to placebo (median age 57 years (interquartile range 45-68 years); 256 (44%) women). The primary outcome occurred in 95 (33%) patients assigned to atorvastatin and 108 (36%) assigned to placebo (odds ratio 0.84, 95% confidence interval 0.58 to 1.21). Death occurred in 90 (31%) patients in the atorvastatin group and 103 (35%) in the placebo group (odds ratio 0.84, 95% confidence interval 0.58 to 1.22). Rates for venous thromboembolism were 2% (n=6) in the atorvastatin group and 3% (n=9) in the placebo group (odds ratio 0.71, 95% confidence interval 0.24 to 2.06). Myopathy was not clinically diagnosed in either group. Liver enzyme levels were increased in five (2%) patients assigned to atorvastatin and six (2%) assigned to placebo (odds ratio 0.85, 95% confidence interval 0.25 to 2.81). CONCLUSIONS In adults with covid-19 admitted to the ICU, atorvastatin was not associated with a significant reduction in the composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all cause mortality compared with placebo. Treatment was, however, found to be safe. As the overall event rates were lower than expected, a clinically important treatment effect cannot be excluded. TRIAL REGISTRATION ClinicalTrials.gov NCT04486508.

Abstract

INTRODUCTION Patients affected with severe forms of coronavirus disease 2019 (COVID-19) suffer from a wide range of sequelae, from limited airway diseases to multiple organ failure. These sequelae may create exercise limitation, impair the daily activity and thus impact the mental health and the social life. However, the extent of functional limitations and depressive symptoms are understudied especially in patients with COVID-19 after intensive care unit (ICU) hospitalization. METHODS The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) was a clinical trial that randomized ICU patients with COVID-19 to intermediate-dose vs standard-dose anticoagulation. In the current study, we assessed the interval change in 30-day and 90-day functional limitations based on the post-COVID-19 functional status scale (PCFS) and depressive symptoms based on the Patient Health Questionnaire-2 (PHQ-2) in the trial participants. We also assessed the effect of intermediate-dose vs standard-dose prophylactic anticoagulation on the functional outcomes and depressive symptoms. RESULTS Of 600 randomized patients in INSPIRATION, 375 (age: 62 years; 42% women) participated in the functional status study. 195 patients died during the 90-day follow up (191 by day 30). Among survivors, between day 30 and day 90, the proportion of patients with moderate-to-severe functional limitation (PCSF grade 3-or-4) decreased from 20.0% to 4.8% (P <0.001) and PHQ-2 ≥ 3 decreased from 25.5% to 16.6% (P = 0.05). The proportion of patients with no functional limitations (PCFS grade 0) increased (4.2% to 15.4%, P<0.001). Intermediate-dose compared with standard-dose prophylactic anticoagulation did not impact the 90-day proportion of patients with PCFS grade 3-or-4 (5.3% vs 4.2%; odds ratio (OR), 1.20, [95% CI, 0.46-3.11]; P = 0.80) or PHQ-2 ≥ 3 (17.9% vs 15.3%; OR, 1.14, [95% CI, 0.79-1.65]; P = 0.14), with similar results when accounting for study center. CONCLUSION In patients with COVID-19 admitted to the ICU, functional limitations and depressive symptoms were common at 30-day follow-up and had some improvement by 90-day follow-up among survivors. Intermediate-dose compared to standard-dose prophylactic anticoagulation did not improve functional outcomes.

Abstract

BACKGROUND Pulmonary embolisms are frequently and prognostically in individuals infected by coronavirus disease 2019 (COVID-19); the incidence of pulmonary embolisms is varied across numerous studies. This study aimed to assess the pooled incidence of pulmonary embolic events and the prognostic value of such events in intensive care unit (ICU) admissions of patients with COVID-19. METHODS The Cochrane Library, PubMed, and EmBase were systematically searched for eligible studies published on or before October 20, 2021. The pooled incidence of pulmonary embolism was calculated using the random-effects model. Moreover, the prognostic value was assessed by measuring the sensitivity, specificity, positive and negative likelihood ratio (PLR and NLR), diagnostic odds ratio (DOR), and the area under the receiver operating characteristic curve (AUC). RESULTS Thirty-six studies involving 10,367 COVID-19 patients were selected for the final meta-analysis. The cumulative incidence of pulmonary embolism in patients with COVID-19 was 21% (95% confidence interval [95%CI]: 18-24%; P<0.001), and the incidence of pulmonary embolism in ICU and non-ICU patients was 26% (95%CI: 22-31%; P<0.001) and 17% (95%CI: 14-20%; P<0.001), respectively. The predictive role of pulmonary embolism in ICU admission was also assessed, and the sensitivity, specificity, PLR, NLR, DOR, and AUC were 0.31 (95%CI: 0.21-0.42), 0.84 (95%CI: 0.75-0.90), 1.88 (95%CI: 1.45-2.45), 0.83 (95%CI: 0.75-0.91), 2.25 (95%CI: 1.64-3.08), and 0.61 (95%CI: 0.57-0.65), respectively. CONCLUSION This study found that the incidence of pulmonary embolism was relatively high in COVID-19 patients, and the incidence of pulmonary embolism in ICU patients was higher than that in non-ICU patients.

Abstract

A reliable estimate of SARS-CoV-2-specific antibodies is increasingly important to track the spread of infection and define the true burden of the ongoing COVID-19 pandemic. A systematic review and a meta-analysis were conducted with the objective of estimating the seroprevalence of SARS-CoV-2 infection in Africa. A systematic search of the PubMed, Scopus, Web of Science and Google Scholar electronic databases was conducted. Thirty-five eligible studies were included. Using meta-analysis of proportions, the overall seroprevalence of anti-SARS-CoV-2 antibodies was calculated as 16% (95% CI 13.1-18.9%). Based on antibody isotypes, 14.6% (95% CI 12.2-17.1%) and 11.5% (95% CI 8.7-14.2%) were seropositive for SARS-CoV-2 IgG and IgM, respectively, while 6.6% (95% CI 4.9-8.3%) were tested positive for both IgM and IgG. Healthcare workers (16.3%) had higher seroprevalence than the general population (11.7%), blood donors (7.5%) and pregnant women (5.7%). The finding of this systematic review and meta-analysis (SRMA) may not accurately reflect the true seroprevalence status of SARS-CoV-2 infection in Africa, hence, further seroprevalence studies across Africa are required to assess and monitor the growing COVID-19 burden.