A new outbreak of HIV infection among people who inject drugs during the COVID-19 pandemic in Greece.

BACKGROUND: Multiple HIV outbreaks have been recorded among people who inject drugs (PWID) since 2010. During an intervention for PWID in 2019-2021 in Thessaloniki, Greece, an increasing number of HIV cases was documented. Here, we provide an analysis of this new outbreak. METHODS: ALEXANDROS was a community-based program and participation included interviewing, rapid HIV/HCV tests, counselling and linkage to care. PWID were recruited through Respondent-Driven Sampling (RDS) in five sampling rounds. Crude and RDS-weighted HIV prevalence estimates were obtained. HIV incidence was estimated from data on 380 initially seronegative PWID with at least two tests. Multivariable Cox proportional hazards model was used to assess risk factors for HIV seroconversion. RESULTS: In total, 1,101 PWID were recruited. At first participation, 53.7% were current PWID, 20.1% homeless, 20.3% on opioid substitution treatment and 4.8% had received syringes in the past 12 months. HIV prevalence (95% CI) was 7.0% (5.6-8.7%) and an increasing trend was observed over 2019-2021 (p = 0.002). Two-thirds of the cases (67.5%) were new diagnoses. HIV incidence was 7.0 new infections/100 person-years (95% CI:4.8-10.2). Homelessness in the past 12 months (HR:2.68; 95% CI:1.24-5.81) and receptive syringe sharing (HR:3.86; 95% CI:1.75-8.51) were independently associated with increased risk of seroconversion. By the end of the program, 67.3% of the newly diagnosed cases initiated antiretroviral treatment. CONCLUSIONS: A new HIV outbreak among PWID was documented in Greece during the COVID-19 pandemic with homelessness and syringe sharing being associated with increased risk of HIV acquisition. Peer-driven programs targeting the population of high-risk underserved PWID can be used to early identify emerging outbreaks and to improve linkage to HIV care.

COVID-19 Burden in Long-Term Care Facilities in the Omicron Era: Public Health Action Not Yet Redundant.

Since the beginning of the pandemic, public health authorities have provided support to long-term care facilities (LTCFs) for the implementation of risk mitigation measures. Nevertheless, the necessity of these measures has been doubted, especially after vaccines and antiviral treatment became available. Here, we present the burden of COVID-19 infection in LTCFs during the first 9 months of 2022 across Greece. We tested the possible association of LTCF characteristics and public health response with the occurrence of clusters (two or more linked cases in LTCFs) with facilities recording one case as reference. After excluding LTCFs with sporadic cases, we tested the effect of the abovementioned variables on attack rate (cases/total number of persons in the LTCF). The disease burden in LTCFs was high and substantially varied among facilities, with hospitalization and case fatality rates ranging from 2 to 80% (median 14%, IQR 27%) and from 1 to 50% (median 5%, IQR 7%), respectively. The probability of transmission inside the facility increased when notification of public health authorities was delayed (p-Value < 0.001) after adjusting for vaccination status and phase of the pandemic. Results showed that active support from public health authorities is still important in reducing the burden in LTCFs.

Wastewater Levels of Respiratory Syncytial Virus Associated with Influenza-like Illness Rates in Children-A Case Study in Larissa, Greece (October 2022-January 2023).

The emergence of the COVID-19 pandemic has led to significant progress in the field of wastewater-based surveillance (WBS) of respiratory pathogens and highlighted its potential for a wider application in public health surveillance. This study aimed to evaluate whether monitoring of respiratory syncytial virus (RSV) in wastewater can provide a comprehensive picture of disease transmission at the community level. The study was conducted in Larissa (Central Greece) between October 2022 and January 2023. Forty-six wastewater samples were collected from the inlet of the wastewater treatment plant of Larissa and analyzed with a real-time reverse transcription polymerase chain reaction (RT-PCR) based method. RSV and SARS-CoV-2 wastewater viral loads (genome copies/100,000 inhabitants) were analyzed against sentinel surveillance data on influenza-like illness (ILI) to identify potential associations. Univariate linear regression analysis revealed that RSV wastewater viral load (lagged by one week) and ILI notification rates in children up to 14 years old were strongly associated (std. Beta: 0.73 (95% CI: 0.31-1.14), p = 0.002, R2 = 0.308). A weaker association was found between SARS-CoV-2 viral load and ILI rates in the 15+ age group (std. Beta: 0.56 (95% CI: 0.06-1.05), p = 0.032, R2 = 0.527). The results support the incorporation of RSV monitoring into existing wastewater-based surveillance systems.

Different Covid-19 Outcomes Among Systemic Rheumatic Diseases: A Nation-wide Cohort Study.

OBJECTIVES: To investigate Covid-19-associated risk of hospitalization and death in rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) in comparison with the general population during pandemic's first year and compare their overall mortality with 2019. METHODS: Interlinking nation-wide electronic registries, we recorded confirmed Covid-19-associated infections, hospitalizations and deaths, and all-cause deaths between 1-March-2020 and 28-February-2021 in all adults with RA, AS, PsA, SLE, and SSc under treatment (n = 74 970, median age 67.5, 51.2, 58.1, 56.2, 62.2 years, respectively) and in matched (1:5) on age, sex, and region of domicile random comparators from the general population. Deaths from all causes during 2019 were also recorded. RESULTS: Compared with the general population incidence rates (IR) for Covid-19-associated hospitalization were higher in RA [IR ratio (IRR):1.71(1.50-1.95)], SLE [2.0(1.4-2.7)] and SSc [2.28(1.29-3.90)], while Covid-19-associated death rates were higher in RA [1.91(1.46-2.49)]. When focusing only on SARS-CoV-2 infected subjects, after adjusting for age and gender, the odds ratio for Covid-19 associated death was higher in RA [1.47(1.11- 1.94)] and SSc [2.92(1.07-7.99)] compared with the general population. All-cause mortality rate compared with the general population increased in RA during the first pandemic year (IRR : 0.71) with reference to 2019 (0.59) and decreased in SSc (IRR : 1.94 vs 4.36). CONCLUSION: Covid-19 may have more severe impact in patients with systemic rheumatic disease than the general population. Covid-19-related mortality is increased in subgroups of patients with specific rheumatic diseases, underscoring the need for priority vaccination and access to targeted treatments.

Low circulation of respiratory syncytial and influenza viruses during autumn-winter 2021 in the industrial workplace and long-term healthcare facilities in Athens, Greece.

The emergence of SARS-CoV-2 has pinpointed the importance of non-pharmaceutical interventions (NPIs), which have been traditionally used for the prevention of the spread of respiratory viruses among individuals. The aim of our study was to capture the level of circulation of respiratory syncytial and influenza viruses during a period of medium severity NPIs due to SARS-CoV-2 pandemics in Greece. A total of 2,225 nasopharyngeal samples were received during the year 2021 as a part of the routine diagnostic service and were divided into two study groups: (a) January to September 2021 and (b) October to the end of December 2021. The latter is the time of the year when there is a peak of infections from most respiratory viruses, and thus, most of the samples were tested in that period. The samples were taken from three different sites, i.e., (a) industrial workers in a factory, (b) elderly homecare facilities, and c) people who actively asked to be tested for SARS-CoV-2. All the samples were tested simultaneously for SARS-CoV2, RSV, and influenza virus. A total of 2,110 samples were negative for either of the three viruses, 106 were SARS-CoV-2-positive, and 9 were RSV-positive from which 7 were found in the workers' group. None of the samples was found to be positive for the influenza virus, and no sample had co-infection. Our study shows the low-level circulation of RSV and influenza viruses during autumn-winter 2021 and will provide a reference for future studies of RSV and influenza in Greece.

Mapping the Early Dispersal Patterns of SARS-CoV-2 Omicron BA.4 and BA.5 Subvariants in the Absence of Travel Restrictions and Testing at the Borders in Europe.

The circulation of SARS-CoV-2 omicron BA.4 and BA.5 subvariants with enhanced transmissibility and capacity for immune evasion resulted in a recent pandemic wave that began in April-May of 2022. We performed a statistical phylogeographic study that aimed to define the cross-border transmission patterns of BA.4 and BA.5 at the earliest stages of virus dispersal. Our sample included all BA.4 and BA.5 sequences that were publicly available in the GISAID database through mid-May 2022. Viral dispersal patterns were inferred using maximum likelihood phylogenetic trees with bootstrap support. We identified South Africa as the major source of both BA.4 and BA.5 that migrated to other continents. By contrast, we detected no significant export of these subvariants from Europe. Belgium was identified as a major hub for BA.4 transmission within Europe, while Portugal and Israel were identified as major sources of BA.5. Western and Northern European countries exhibited the highest rates of cross-border transmission, as did several popular tourist destinations in Southern and Central/Western Europe. Our study provides a detailed map of the early dispersal patterns of two highly transmissible SARS-CoV-2 omicron subvariants at a time when there was an overall relaxation of public health measures in Europe.

Low circulation of respiratory syncytial and influenza viruses during autumn-winter 2021 in the industrial workplace and long-term healthcare facilities in Athens, Greece

The emergence of SARS-CoV-2 has pinpointed the importance of non-pharmaceutical interventions (NPIs), which have been traditionally used for the prevention of the spread of respiratory viruses among individuals. The aim of our study was to capture the level of circulation of respiratory syncytial and influenza viruses during a period of medium severity NPIs due to SARS-CoV-2 pandemics in Greece. A total of 2,225 nasopharyngeal samples were received during the year 2021 as a part of the routine diagnostic service and were divided into two study groups: (a) January to September 2021 and (b) October to the end of December 2021. The latter is the time of the year when there is a peak of infections from most respiratory viruses, and thus, most of the samples were tested in that period. The samples were taken from three different sites, i.e., (a) industrial workers in a factory, (b) elderly homecare facilities, and c) people who actively asked to be tested for SARS-CoV-2. All the samples were tested simultaneously for SARS-CoV2, RSV, and influenza virus. A total of 2,110 samples were negative for either of the three viruses, 106 were SARS-CoV-2-positive, and 9 were RSV-positive from which 7 were found in the workers' group. None of the samples was found to be positive for the influenza virus, and no sample had co-infection. Our study shows the low-level circulation of RSV and influenza viruses during autumn-winter 2021 and will provide a reference for future studies of RSV and influenza in Greece.

Molecular Epidemiology of SARS-CoV-2: The Dominant Role of Arginine in Mutations and Infectivity.

Background, Aims, Methods, Results, Conclusions: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global challenge due to its ability to mutate into variants that spread more rapidly than the wild-type virus. The molecular biology of this virus has been extensively studied and computational methods applied are an example paradigm for novel antiviral drug therapies. The rapid evolution of SARS-CoV-2 in the human population is driven, in part, by mutations in the receptor-binding domain (RBD) of the spike (S-) protein, some of which enable tighter binding to angiotensin-converting enzyme (ACE2). More stable RBD-ACE2 association is coupled with accelerated hydrolysis by proteases, such as furin, trypsin, and the Transmembrane Serine Protease 2 (TMPRSS2) that augment infection rates, while inhibition of the 3-chymotrypsin-like protease (3CLpro) can prevent the viral replication. Additionally, non-RBD and non-interfacial mutations may assist the S-protein in adopting thermodynamically favorable conformations for stronger binding. This study aimed to report variant distribution of SARS-CoV-2 across European Union (EU)/European Economic Area (EEA) countries and relate mutations with the driving forces that trigger infections. Variants' distribution data for SARS-CoV-2 across EU/EEA countries were mined from the European Centre for Disease Prevention and Control (ECDC) based on the sequence or genotyping data that are deposited in the Global Science Initiative for providing genomic data (GISAID) and The European Surveillance System (TESSy) databases. Docking studies performed with AutoDock VINA revealed stabilizing interactions of putative antiviral drugs, e.g., selected anionic imidazole biphenyl tetrazoles, with the ACE2 receptor in the RBD-ACE2 complex. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Epsilon, Kappa, Lambda, and Omicron variants, which stabilize the RBD-ACE2 complex, were investigated by computational approaches. Arginine is the critical amino acid in the polybasic furin cleavage sites S1/S2 (681-PRRARS-686) S2' (814-KRS-816). Critical mutations into arginine residues that were found in the delta variant (L452R, P681R) and may be responsible for the increased transmissibility and morbidity are also present in two widely spreading omicron variants, named BA.4.6 and BQ.1, where mutation R346T in the S-protein potentially contributes to neutralization escape. Arginine binders, such as Angiotensin Receptor Blockers (ARBs), could be a class of novel drugs for treating COVID-19.

Tracing the First Days of the SARS-CoV-2 Pandemic in Greece and the Role of the First Imported Group of Travelers.

The first SARS-CoV-2 case in Greece was confirmed on February 26, 2020, and since then, multiple strains have circulated the country, leading to regional and country-wide outbreaks. Our aim is to enlighten the events that took place during the first days of the SARS-CoV-2 pandemic in Greece, focusing on the role of the first imported group of travelers. We used whole-genome SARS-CoV-2 sequences obtained from the infected travelers of the group as well as Greece-derived and globally subsampled sequences and applied dedicated phylogenetics and phylodynamics tools as well as in-house-developed bioinformatics pipelines. Our analyses reveal the genetic variants circulating in Greece during the first days of the pandemic and the role of the group's imported strains in the course of the first pandemic wave in Greece. The strain that dominated in Greece throughout the first wave, bearing the D614G mutation, was primarily imported from a certain group of travelers, while molecular and clinical data suggest that the infection of the travelers occurred in Egypt. Founder effects early in the pandemic are important for the success of certain strains, as those arriving early, several times, and to diverse locations lead to the formation of large transmission clusters that can be estimated using molecular epidemiology approaches and can be a useful surveillance tool for the prioritization of nonpharmaceutical interventions and combating present and future outbreaks. IMPORTANCE The strain that dominated in Greece during the first pandemic wave was primarily imported from a group of returning travelers in February 2020, while molecular and clinical data suggest that the origin of the transmission was Egypt. The observed molecular transmission clusters reflect the transmission dynamics of this particular strain bearing the D614G mutation while highlighting the necessity of their use as a surveillance tool for the prioritization of nonpharmaceutical interventions and combating present and future outbreaks.

Global Distribution, Dispersal Patterns, and Trend of Several Omicron Subvariants of SARS-CoV-2 across the Globe.

Our study aims to describe the global distribution and dispersal patterns of the SARS-CoV-2 Omicron subvariants. Genomic surveillance data were extracted from the CoV-Spectrum platform, searching for BA.1*, BA.2*, BA.3*, BA.4*, and BA.5* variants by geographic region. BA.1* increased in November 2021 in South Africa, with a similar increase across all continents in early December 2021. BA.1* did not reach 100% dominance in all continents. The spread of BA.2*, first described in South Africa, differed greatly by geographic region, in contrast to BA.1*, which followed a similar global expansion, firstly occurring in Asia and subsequently in Africa, Europe, Oceania, and North and South America. BA.4* and BA.5* followed a different pattern, where BA.4* reached high proportions (maximum 60%) only in Africa. BA.5* is currently, by Mid-August 2022, the dominant strain, reaching almost 100% across Europe, which is the first continent aside from Africa to show increasing proportions, and Asia, the Americas, and Oceania are following. The emergence of new variants depends mostly on their selective advantage, translated as enhanced transmissibility and ability to invade people with existing immunity. Describing these patterns is useful for a better understanding of the epidemiology of the VOCs' transmission and for generating hypotheses about the future of emerging variants.

Interpretable Operations Research for High-Stakes Decisions: Designing the Greek COVID-19 Testing System

In the summer of 2020, in collaboration with the Greek government, we designed and deployed Eva-the first national-scale, reinforcement learning system for targeted COVID-19 testing. In this paper, we detail the rationale for three major design/algorithmic elements: Eva's testing supply chain, estimating COVID-19 prevalence, and test allocation. Specifically, we describe the design of Eva's supply chain to collect and process thousands of biological samples per day with special emphasis on capacity procurement. Then, we propose a novel, empirical Bayes estimation strategy to estimate COVID-19 prevalence among various passenger types with limited data and showcase how these estimates were instrumental in making a variety of downstream decisions. Finally, we propose a novel, multiarmed bandit algorithm that dynamically allocates tests to arriving passengers in a nonstationary environment with delayed feedback and batched decisions. All our design and algorithmic choices emphasize the need for transparent reasoning to enable human-in-the-loop analytics. Such transparency was crucial to building trust and acceptance among policymakers and public health experts in a period of global crisis.

Delta SARS-CoV-2 variant is entirely substituted by the omicron variant during the fifth COVID-19 wave in Attica region.

Wastewater analysis is the most attractive alternative way for the quantification and variant profiling of SARS-CoV-2. Infection dynamics can be monitored by RT-qPCR assays while NGS can provide evidence for the presence of existing or new emerging SARS-CoV-2 variants. Herein, apart from the infection dynamic in Attica since June 1st, 2021, the monitoring of 9 mutations of the omicron and 4 mutations of the delta SARS-CoV-2 variants, utilizing both novel Nested-Seq and RT-PCR, is reported and the substitution of the delta variant (B.1.617.2) by the omicron variant (B.1.1.529) in Attica, Greece within approximately one month is highlighted. The key difference between the two methodologies is discovery power. RT-PCR can only detect known sequences cost-effectively, while NGS is a hypothesis-free approach that does not require prior knowledge to detect novel genes. Overall, the potential of wastewater genomic surveillance for the early discovery and monitoring of variants important for disease management at the community level is underlined. This is the first study, reporting the SARS-CoV-2 infection dynamic for an extended time period and the first attempt to monitor two of the most severe variants with two different methodologies in Greece.

Protection of vaccination versus hybrid immunity against infection with COVID-19 Omicron variants among Health-Care Workers.

BACKGROUND AIM: The Omicron COVID-19 variants BA.1* and BA.2* evade immune system leading to increased transmissibility and breakthrough infections. We aim to test the hypothesis that immunity achieved post COVID-19 infection combined with vaccination (hybrid immunity), is more effective against Omicron infection than vaccination alone in a health-care setting. METHODS: Data on regular pre-emptive PCR testing from all Health-Care Workers (HCWs) at Laiko University Hospital from 29th December 2020, date on which the national COVID-19 immunization program began in Greece, until 24th May 2022, were retrospectively collected and recorded. The infection rate was calculated after December 21st, 2021, when Omicron was the predominant circulating variant in Greece, as the total number of infections (positive PCR COVID-19 test regardless of symptoms) divided by the total person-months at risk. RESULTS: Of 1,305 vaccinated HCWs who were included in the analysis [median age of 47 (IQR: 36, 56) years, 66.7 % women], 13 % and 87 % had received 2 or 3 vaccine doses (full and booster vaccination), respectively. A COVID-19 infection had occurred in 135 of 1,305 of participants prior to Omicron predominance. Of those 135 HCWs with hybrid immunity only 13 (9.6 %) were re-infected. Of the 154 and 1,016 HCWs with full and booster vaccination-induced immunity, respectively, 71 (46.1 %, infection rate 13.4/100 person-months) and 448 (44.1 %, infection rate 12.2/100 person-months) were infected during the follow up period. No association between gender or age and COVID-19 infection was found and none of the participants had a severe infection or died. CONCLUSIONS: Hybrid immunity confers higher protection by almost 5-fold compared to full or booster vaccination for COVID-19 infection with the Omicron variant among HCWs who are at high risk of exposure. This may inform public health policies on how to achieve optimal immunity in terms of the timing and mode of vaccination.

Time Lag between COVID-19 Diagnosis and Symptoms Onset for Different Population Groups: Evidence That Self-Testing in Schools Was Associated with Timely Diagnosis among Children.

Early identification of COVID-19 cases has been vital for reducing transmission and enabling treatment. In Greece, in autumn 2021 when Delta was the predominant circulating variant, unvaccinated citizens had to be tested before attending activities, and self-testing was required twice a week for students (5-17 years). Here, we describe the time of diagnosis by age group and possible exposure to assess testing strategies (September to November 2021). Information on the presence of symptoms at the time of diagnosis was available for 69,298 cases; 24,855 (36%) were asymptomatic or tested the same day as onset (early diagnosis), 21,310 (31%) reported testing one day after, and 23,133 (33%) did so two or more days after the onset of symptoms. The median lag was 2 days (1-14). Early diagnosis significantly differed among age groups (p-value < 0.001) and was higher among children. For every one-year increase of age, the odds of an early diagnosis were reduced by 1%. Cases exposed during training activities or in settings such as accommodation centers and hospitals were more frequently diagnosed early. The percentage of persons having a positive self-test before a rapid test/PCR diagnosis ranged from 7% in the age group of 60 years and above to 86% in the age group of 5-17 years. The provision of self-tests in schools and increased testing in closed settings led to an earlier diagnosis and probably to a decreased transmission of the virus in the period during which Delta was the predominant variant in Greece. However, more effort is needed for early diagnosis of adults in the community, especially after the onset of symptoms.

Development and Analytical Validation of a One-Step Five-Plex RT-ddPCR Assay for the Quantification of SARS-CoV-2 Transcripts in Clinical Samples.

Highly sensitive methodologies for SARS-CoV-2 detection are essential for the control of COVID-19 pandemic. We developed and analytically validated a highly sensitive and specific five-plex one-step RT-ddPCR assay for SARS-CoV-2. We first designed in-silico novel primers and probes for the simultaneous absolute quantification of three different regions of the nucleoprotein (N) gene of SARS-CoV-2 (N1, N2, N3), a synthetic RNA as an external control (RNA-EC), and Beta-2-Microglobulin (B2M) as an endogenous RNA internal control (RNA-IC). The developed assay was analytically validated using synthetic DNA and RNA calibrator standards and then was applied to 100 clinical specimens previously analyzed with a commercially available CE-IVD RT-qPCR assay. The analytical validation of the developed assay resulted in very good performance characteristics in terms of analytical sensitivity, linearity, analytical specificity, and reproducibility and recovery rates even at very low viral concentrations. The simultaneous absolute quantification of the RNA-EC and RNA-IC provides the necessary metrics for quality control assessment. Direct comparison of the developed one-step five-plex RT-ddPCR assay with a CE-IVD RT-qPCR kit revealed a very high concordance and a higher sensitivity [concordance: 99/100 (99.0%, Spearman's correlation coefficient: -0.850, p < 0.001)]. The developed assay is highly sensitive, specific, and reproducible and has a broad linear dynamic range, providing absolute quantification of SARS-COV-2 transcripts. The inclusion of two RNA quality controls, an external and an internal, is highly important for standardization of SARS-COV-2 molecular testing in clinical and wastewater samples.

The COVID-19 pandemic as inspiration to reconsider epidemic models: A novel approach to spatially homogeneous epidemic spread modeling.

Epidemic spread models are useful tools to study the spread and the effectiveness of the interventions at a population level, to an epidemic. The workhorse of spatially homogeneous class models is the SIR-type ones comprising ordinary differential equations for the unknown state variables. The transition between different states is expressed through rate functions. Inspired by -but not restricted to- features of the COVID-19 pandemic, a new framework for modeling a disease spread is proposed. The main concept refers to the assignment of properties to each individual person as regards his response to the disease. A multidimensional distribution of these properties represents the whole population. The temporal evolution of this distribution is the only dependent variable of the problem. All other variables can be extracted by post-processing of this distribution. It is noteworthy that the new concept allows an improved consideration of vaccination modeling because it recognizes vaccination as a modifier of individuals response to the disease and not as a means for individuals to totally defeat the disease. At the heart of the new approach is an infection age model engaging a sharp cut-off. This model is analyzed in detail, and it is shown to admit self-similar solutions. A hierarchy of models based on the new approach, from a generalized one to a specific one with three dominant properties, is derived. The latter is implemented as an example and indicative results are presented and discussed. It appears that the new framework is general and versatile enough to simulate disease spread processes and to predict the evolution of several variables of the population during this spread.

Effects of low molecular weight heparin and fondaparinux on mortality, hemorrhagic and thrombotic complications in COVID-19 patients.

Background: Coronavirus disease 2019 (COVID-19) is associated with increased thrombosis prevalence. However, there are insufficient data supporting the appropriate anticoagulation dose in COVID-19. Objective: We aim to systematically assess the currently available data regarding the effects of different dosing regimens of low molecular weight heparin and/or fondaparinux (LMWH/F) on mortality risk as well as the risk of arterial/venous thrombotic events and hemorrhagic complications in confirmed COVID-19 cases. Design: We conducted a living systematic review and meta-analysis on the effects of different LMWH/F doses on mortality, thrombotic and hemorrhagic events in COVID-19 patients. Data Sources and Methods: MEDLINE, Scopus, Embase, Cochrane Library, Cochrane COVID-19 study register, European Union Drug Regulating Authorities Clinical Trials Database, and ClinicalTrials.gov were searched to detect observational cohort studies and randomized-controlled clinical trials (RCTs) comparing difference doses of LMWH/F among confirmed COVID-19 cases. Results: Thirty-one eligible studies (6 RCTs and 25 cohort studies) with 11,430 hospitalized patients were included. No association was found between LMWH/F and mortality during the following comparisons: (1) no LMWH/F versus any LMWH/F; (2) prophylactic versus higher than prophylactic LMWH/F; (3) prophylactic versus therapeutic LMWH/F; (4) intermediate versus therapeutic LMWH/F; and (5) lower than therapeutic versus therapeutic LMWH/F. Mortality was higher in patients receiving prophylactic versus intermediate LMWH/F (OR = 2.01; 95% CI: 1.19-3.39). However, this effect was mostly driven by observational data. No associations were detected between the intensity of LMWH/F and the risk of thrombotic and hemorrhagic events, except the lower risk for hemorrhage in patients on prophylactic compared to higher LMWH/F doses. Conclusion: The risk for all-cause mortality was higher in patients receiving prophylactic LMWH/F compared to those on an intermediate dose of LMWH/F, based on observational data. These results should be interpreted in light of the moderate quality and heterogeneity of the included studies. Registration: The study protocol has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (Registration number: CRD42021229771).