Results of a systematic review and meta-analysis of early studies on ivermectin in SARS-CoV-2 infection.

Ivermectin, an antiparasitic drug, has been repurposed for COVID-19 treatment during the SARS-CoV-2 pandemic. Although its antiviral efficacy was confirmed early in vitro and in preclinical studies, its clinical efficacy remained ambiguous. Our purpose was to assess the efficacy of ivermectin in terms of time to viral clearance based on the meta-analysis of available clinical trials at the closing date of the data search period, one year after the start of the pandemic. This meta-analysis was reported by following the PRISMA guidelines and by using the PICO format for formulating the question. The study protocol was registered on PROSPERO. Embase, MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), bioRvix, and medRvix were searched for human studies of patients receiving ivermectin therapy with control groups. No language or publication status restrictions were applied. The search ended on 1/31/2021 exactly one year after WHO declared the public health emergency on novel coronavirus. The meta-analysis of three trials involving 382 patients revealed that the mean time to viral clearance was 5.74 days shorter in case of ivermectin treatment compared to the control groups [WMD = -5.74, 95% CI (-11.1, -0.39), p = 0.036]. Ivermectin has significantly reduced the time to viral clearance in mild to moderate COVID-19 diseases compared to control groups. However, more eligible studies are needed for analysis to increase the quality of evidence of ivermectin use in COVID-19.

Investigating the association between IL-6 antagonist therapy and blood coagulation in critically ill patients with COVID-19: a protocol for a prospective, observational, multicentre study.

INTRODUCTION: Hypercoagulation is one the main features of COVID-19. It is induced by the hyperinflammatory response that shifts the balance of haemostasis towards pro-coagulation. Interleukin-6 (IL-6) antagonist therapy has been recommended in certain subgroups of critically ill patients with COVID-19 to modulate inflammatory response. The interaction between immune response and haemostasis is well recognised. Therefore, our objective is to evaluate whether the modulation of the inflammatory response by IL-6 antagonist inflicts any changes in whole blood coagulation as assessed by viscoelastic methods in critically ill patients with COVID-19. METHODS AND ANALYSIS: In this prospective observational study, we are going to collect data on inflammatory parameters and blood coagulation using the ClotPro^® device. The primary outcome is the change of the fibrinolytic system measured by the Lysis Time and Lysis onset time before and after immunomodulation therapy. Data will be collected before the IL-6 antagonist administration at baseline (T₀) then after 24, 48 hours, then on day 5 and 7 (T_1-4, respectively). Secondary outcomes include changes in other parameters related to inflammation, blood coagulation and biomarkers of endothelial injury. ETHICS AND DISSEMINATION: Ethical approval was given by the Medical Research Council of Hungary (1405-3/2022/EÜG). All participants provided written consent. The results of the study will be disseminated through peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05218369; Clinicaltrials.gov.

Effectiveness and safety of fibrinolytic therapy in critically ill patients with COVID-19 with ARDS: protocol for a prospective meta-analysis.

INTRODUCTION: The use of fibrinolytic therapy has been proposed in severe acute respiratory distress syndrome (ARDS). During the COVID-19 pandemic, anticoagulation has received special attention due to the frequent findings of microthrombi and fibrin deposits in the lungs and other organs. Therefore, the use of fibrinolysis has been regarded as a potential rescue therapy in these patients. In this prospective meta-analysis, we plan to synthesise evidence from ongoing clinical trials and thus assess whether fibrinolytic therapy can improve the ventilation/perfusion ratio in patients with severe COVID-19-caused ARDS as compared with standard of care. METHODS AND ANALYSIS: This protocol was registered in PROSPERO. All randomised controlled trials and prospective observational trials that compare fibrinolytic therapy with standard of care in adult patients with COVID-19 and define their primary or secondary outcome as improvement in oxygenation and/or gas exchange, or mortality will be considered eligible. Safety outcomes will include bleeding event rate and requirement for transfusion. Our search on 25 January 2022 identified five eligible ongoing clinical trials. A formal search of MEDLINE (via PubMed), Embase, CENTRAL will be performed every month to identify published results and to search for further trials that meet our eligibility criteria. DISSEMINATION: This could be the first qualitative and quantitative synthesis summarising evidence of the efficacy and safety of fibrinolytic therapy in critically ill patients with COVID-19. We plan to publish our results in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42021285281.

Higher Dose Anticoagulation Cannot Prevent Disease Progression in COVID-19 Patients: A Systematic Review and Meta-Analysis.

Implementation of higher dose (HD) thromboprophylaxis has been considered in patients infected with coronavirus disease 2019 (COVID-19). Our aim was to compare HD to standard dose (SD) thromboprophylaxis in COVID-19 patients. The protocol is registered on PROSPERO (CRD42021284808). We searched for randomised controlled studies (CENTRAL, Embase, Medline and medRxviv) that compared HD to SD anticoagulation in COVID-19 and analysed outcomes such as mortality, thrombotic events, bleedings, and disease progression. The statistical analyses were made using the random effects model. Fourteen articles were included (6253 patients). HD compared with SD showed no difference in mortality (OR 0.83 [95% CI 0.54-1.28]). The use of HD was associated with a decreased risk of thrombosis (OR 0.58 [95% CI 0.44-0.76]), although with an increased risk of major bleeding (OR 1.64 [95% CI 1.25-2.16]). The cohort with D-dimer < 1 mg/mL showed no effect (OR 1.19 [95% CI 0.67-2.11]), but in the case of D-dimer > 1 mg/mL, a tendency of lower risk in the HD group was observed (OR 0.56 [95% CI 0.31-1.00]). The need for intubation in moderately ill patients showed a nonsignificant lower likelihood in the HD group (OR 0.82 [95% CI 0.63-1.08]). We cannot advocate for HD in all COVID-19 patients, although it shows some nonsignificant benefits on disease progression in those with elevated D-dimer who do not need ICU admission.

Immunoglobulin Response and Prognostic Factors in Repeated SARS-CoV-2 Positive Patients: A Systematic Review and Meta-Analysis.

With repeated positivity being an undiscovered and major concern, we aimed to evaluate which prognostic factors may impact repeated SARS-CoV-2 positivity (RSP) and their association with immunoglobulin detectability among recovered patients. A systematic literature search was performed on 5 April 2021. Cohort studies with risk factors for repeated RSP or information about the immunoglobulin response (immunoglobulin M (IgM) and/or immunoglobulin G (IgG)) were included in this analysis. The main examined risk factors were severity of the initial infection, body mass index (BMI), length of hospitalization (LOH), age, and gender, for which we pooled mean differences and odds ratios (ORs). Thirty-four cohort studies (N = 9269) were included in our analysis. We found that increased RSP rate might be associated with IgG positivity; IgG presence was higher in RSP patients (OR: 1.72, CI: 0.87-3.41, p = 0.117). Among the examined risk factors, only mild initial disease course showed a significant association with RSP (OR: 0.3, CI: 0.14-0.67, p = 0.003). Age, male gender, BMI, LOH, and severity of the first episode do not seem to be linked with repeated positivity. However, further prospective follow-up studies focusing on this topic are required.

Metabolic Associated Fatty Liver Disease Is Associated With an Increased Risk of Severe COVID-19: A Systematic Review With Meta-Analysis.

Background: The most common pre-existing liver disease, the metabolic dysfunction-associated fatty liver disease (MAFLD) formerly named as non-alcoholic fatty liver disease (NAFLD), may have a negative impact on the severity of COVID-19. This meta-analysis aimed to evaluate if MAFLD or NAFLD are associated with a more severe disease course of COVID-19. Methods: A systematic search was performed in five databases for studies comparing severity, the rate of intensive care unit (ICU) admission, and mortality of COVID-19 patients with and without MAFLD or NAFLD. In meta-analysis, pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: Altogether, we included nine studies in our quantitative and qualitative synthesis. MAFLD was associated with an increased risk of severe COVID-19 compared to the non-MAFLD group (28 vs. 13%, respectively; OR = 2.61, CI: 1.75-3.91). Similarly, in the NAFLD vs. non-NAFLD comparison, NAFLD proved to be a risk factor as well (36 vs. 12%, respectively; OR = 5.22, CI: 1.94-14.03). On the other hand, NAFLD was not associated with an increased risk of ICU admission (24 vs. 7%, respectively; OR = 2.29, CI: 0.79-6.63). We were unable to perform meta-analysis to investigate the association of MAFLD with the rate of ICU admission and with mortality. Conclusion: In conclusion, patients with MAFLD and NAFLD showed a more severe clinical picture in COVID-19. Our results support the importance of close monitoring of COVID-19 patients with MAFLD. Further research is needed to explore the cause of increased severity of COVID-19 in MAFLD.

Repeated SARS-CoV-2 Positivity: Analysis of 123 Cases.

Repeated positivity and reinfection with severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) is a significant concern. Our study aimed to evaluate the clinical significance of repeatedly positive testing after coronavirus disease 2019 (COVID-19) recovery. We performed a systematic literature search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. With available individual patient data reporting on repeatedly SARS-CoV-2 positive (RSP) patients, case reports, and case series were included in this analysis. We performed a descriptive analysis of baseline characteristics of repeatedly positive cases. We assessed the cases according to the length of their polymerase chain reaction (PCR) negative interval between the two episodes. Risk factors for the severity of second episodes were evaluated. Overall, we included 123 patients with repeated positivity from 56 publications, with a mean repeated positivity length of 47.8 ± 29.9 days. Younger patients were predominant in the delayed (>90 days) recurrent positive group. Furthermore, comparing patients with RSP intervals of below 60 and above 60 days, we found that a more severe disease course can be expected if the repeated positivity interval is shorter. Severe and critical disease courses might predict future repeatedly positive severe and critical COVID-19 episodes. In conclusion, our results show that the second episode of SARS-CoV-2 positivity is more severe if it happens within 60 days after the first positive PCR. On the other hand, the second episode's severity correlates with the first.

Visceral Adiposity Elevates the Risk of Critical Condition in COVID-19: A Systematic Review and Meta-Analysis.

OBJECTIVE: A higher BMI has become acknowledged as one of the important risk factors for developing critical condition in coronavirus disease 2019 (COVID-19). In addition to BMI, body composition, and particularly visceral adiposity, might be an even more accurate measure to stratify patients. Therefore, the aim of this study was to evaluate the association between the distributions of computed-tomography-quantified fat mass and critical condition of patients with COVID-19. METHODS: A systematic search was conducted in five databases for studies published until November 17, 2020. In the meta-analysis, pooled mean difference (standardized mean difference [SMD]) of visceral fat area (VFA; in square centimeters) was calculated between patients in the intensive care unit and those in general ward and between patients with the requirement for invasive mechanical ventilation (IMV) and those without the IMV requirement. RESULTS: The quantitative synthesis revealed that patients requiring intensive care had higher VFA values (SMD = 0.46, 95% CI: 0.20-0.71, P < 0.001) compared with patients on the general ward. Similarly, patients requiring IMV had higher VFA values (SMD = 0.38, 95% CI: 0.05-0.71, P = 0.026) compared with patients without the IMV requirement. CONCLUSIONS: VFA values were found to be significantly higher in patients with critical condition. Therefore, abdominal adiposity seems to be a risk factor in COVID-19, and patients with central obesity might need special attention.

Early changes in laboratory parameters are predictors of mortality and ICU admission in patients with COVID-19: a systematic review and meta-analysis.

Despite the growing knowledge of the clinicopathological features of COVID-19, the correlation between early changes in the laboratory parameters and the clinical outcomes of patients is not entirely understood. In this study, we aimed to assess the prognostic value of early laboratory parameters in COVID-19. We conducted a systematic review and meta-analysis based on the available literature in five databases. The last search was on July 26, 2020, with key terms related to COVID-19. Eligible studies contained original data of at least ten infected patients and reported on baseline laboratory parameters of patients. We calculated weighted mean differences (WMDs) for continuous outcomes and odds ratios (ORs) with 95% confidence intervals. 93 and 78 studies were included in quantitative and qualitative syntheses, respectively. Higher baseline total white blood cell count (WBC), C-reactive protein (CRP), lactate-dehydrogenase (LDH), creatine kinase (CK), D-dimer and lower absolute lymphocyte count (ALC) (WMDALC = - 0.35 × 109/L [CI - 0.43, - 0.27], p < 0.001, I2 = 94.2%; < 0.8 × 109/L, ORALC = 3.74 [CI 1.77, 7.92], p = 0.001, I2 = 65.5%) were all associated with higher mortality rate. On admission WBC, ALC, D-dimer, CRP, LDH, and CK changes could serve as alarming prognostic factors. The correct interpretation of laboratory abnormalities can guide therapeutic decisions, especially in early identification of potentially critical cases. This meta-analysis should help to allocate resources and save lives by enabling timely intervention.

Personalised health education against health damage of COVID-19 epidemic in the elderly Hungarian population (PROACTIVE-19): protocol of an adaptive randomised controlled clinical trial.

BACKGROUND: Early reports indicate that COVID-19 may require intensive care unit (ICU) admission in 5-26% and overall mortality can rise to 11% of the recognised cases, particularly affecting the elderly. There is a lack of evidence-based targeted pharmacological therapy for its prevention and treatment. We aim to compare the effects of a World Health Organization recommendation-based education and a personalised complex preventive lifestyle intervention package (based on the same WHO recommendation) on the outcomes of the COVID-19. METHODS: PROACTIVE-19 is a pragmatic, randomised controlled clinical trial with adaptive "sample size re-estimation" design. Hungarian population over the age of 60 years without confirmed COVID-19 will be approached to participate in a telephone health assessment and lifestyle counselling voluntarily. Volunteers will be randomised into two groups: (A) general health education and (B) personalised health education. Participants will go through questioning and recommendation in 5 fields: (1) mental health, (2) smoking habits, (3) physical activity, (4) dietary habits, and (5) alcohol consumption. Both groups A and B will receive the same line of questioning to assess habits concerning these topics. Assessment will be done weekly during the first month, every second week in the second month, then monthly. The composite primary endpoint will include the rate of ICU admission, hospital admission (longer than 48 h), and mortality in COVID-19-positive cases. The estimated sample size is 3788 subjects per study arm. The planned duration of the follow-up is a minimum of 1 year. DISCUSSION: These interventions may boost the body's cardiovascular and pulmonary reserve capacities, leading to improved resistance against the damage caused by COVID-19. Consequently, lifestyle changes can reduce the incidence of life-threatening conditions and attenuate the detrimental effects of the pandemic seriously affecting the older population. TRIAL REGISTRATION: The study has been approved by the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (IV/2428- 2 /2020/EKU) and has been registered at clinicaltrials.gov ( NCT04321928 ) on 25 March 2020.

Obesity is a risk factor for developing critical condition in COVID-19 patients: A systematic review and meta-analysis.

The disease course of COVID-19 varies from asymptomatic infection to critical condition leading to mortality. Identification of prognostic factors is important for prevention and early treatment. We aimed to examine whether obesity is a risk factor for the critical condition in COVID-19 patients by performing a meta-analysis. The review protocol was registered onto PROSPERO (CRD42020185980). A systematic search was performed in five scientific databases between 1 January and 11 May 2020. After selection, 24 retrospective cohort studies were included in the qualitative and quantitative analyses. We calculated pooled odds ratios (OR) with 95% confidence intervals (CIs) in meta-analysis. Obesity was a significant risk factor for intensive care unit (ICU) admission in a homogenous dataset (OR = 1.21, CI: 1.002-1.46; I2 = 0.0%) as well as for invasive mechanical ventilation (IMV) (OR = 2.05, CI: 1.16-3.64; I2 = 34.86%) in COVID-19. Comparing body mass index (BMI) classes with each other, we found that a higher BMI always carries a higher risk. Obesity may serve as a clinical predictor for adverse outcomes; therefore, the inclusion of BMI in prognostic scores and improvement of guidelines for the intensive care of patients with elevated BMI are highly recommended.