One Health Perspectives on New Emerging Viral Diseases in African Wild Great Apes.

The most recent emerging infectious diseases originated in animals, mainly in wildlife reservoirs. Mutations and recombination events mediate pathogen jumps between host species. The close phylogenetic relationship between humans and non-human primates allows the transmission of pathogens between these species. These pathogens cause severe impacts on public health and impair the conservation of habituated or non-habituated wild-living apes. Constant exposure of great apes to human actions such as hunting, deforestation, the opening of roads, and tourism, for example, contributes to increased interaction between humans and great apes. In spite of several studies emphasizing the risks of pathogen transmission between animals and humans, outbreaks of the reverse transmission of infectious agents threatening wildlife still occur on the African continent. In this context, measures to prevent the emergence of new diseases and conservation of primate species must be based on the One Health concept; that is, they must also ensure the monitoring of the environment and involve political and social aspects. In this article, we review and discuss the anthropological aspects of the transmission of diseases between people and wild primates and discuss new anthropozoonotic diseases in great apes in Africa from studies published between 2016 and 2020. We conclude that the health of great apes also depends on monitoring the health of human populations that interact with these individuals.

Severe COVID-19 patients show a dysregulation of the NLRP3 inflammasome in circulating neutrophils.

SARS-CoV-2 triggers inflammasome-dependent release of pro-inflammatory cytokine IL-1ß and pyroptosis, therefore, contributes to the huge inflammatory response observed in severe COVID-19 patients. Less is known about the engagement of inflammasome in neutrophils, main players in tissue injury and severe infection. We studied the activation of the inflammasome in neutrophils from severe COVID-19 patients and assessed its consequence in term of cells contribution to disease pathogenesis. We demonstrated that NLRP3 inflammasome is dramatically activated in neutrophils from severe COVID-19 patients and that the specific inhibition of NLRP3 reverts neutrophils' activation. Next, the stimulation of severe patients' neutrophils with common NLRP3 stimuli was not able to further activate the inflammasome, possibly due to exhaustion or increased percentage of circulating immature neutrophils. Collectively, our results demonstrate that the NLRP3 inflammasome is hyperactivated in severe COVID-19 neutrophils and its exhaustion may be responsible for the increased susceptibility to subsequent (and possibly lethal) infections. Our findings thus include a novel piece in the complex puzzle of COVID-19 pathogenesis.

A common variant close to the "tripwire" linker region of NLRP1 contributes to severe COVID-19.

OBJECTIVE AND DESIGN: The heterogeneity of response to SARS-CoV-2 infection is directly linked to the individual genetic background. Genetic variants of inflammasome-related genes have been pointed as risk factors for several inflammatory sterile and infectious disease. In the group of inflammasome receptors, NLRP1 stands out as a good novel candidate as severity factor for COVID-19 disease. METHODS: To address this question, we performed an association study of NLRP1, DPP9, CARD8, IL1B, and IL18 single nucleotide variants (SNVs) in a cohort of 945 COVID-19 patients. RESULTS: The NLRP1 p.Leu155His in the linker region, target of viral protease, was significantly associated to COVID-19 severity, which could contribute to the excessive cytokine release reported in severe cases. CONCLUSION: Inflammasome genetic background contributes to individual response to SARS-CoV-2.

A common variant close to the “trip-wire” linker region of NLRP1 contributes to severe COVID-19 (preprint)

Objective and design: The heterogeneity of response to SARS-COV-2 infection is directly linked to the individual genetic background. Genetic variants of inflammasome related genes have been pointed as risk factors for several inflammatory sterile and infectious disease. In the group of inflammasome receptors, NLRP1 stand out as a good novel candidate as severity factor for Covid-19 disease. Methods: To address this question, we performed an association study of NLRP1, DPP9, CARD8, IL1B and IL18 single nucleotide variants (SNVs) in a cohort of 945 Covid-19 patients. Results: The NLRP1 p.Leu155His in the linker region, target of viral protease, was significantly associated to Covid-19 severity, which could contribute to the excessive cytokine release reported in severe cases. 

Machine Learning Approaches to Analyze MALDI-TOF Mass Spectrometry Protein Profiles.

Machine learning is being employed for the development of diagnostic methods for several diseases, but prognostic techniques are still poorly explored. The development of such approaches is essential to assist healthcare workers to ensure the most appropriate treatment for patients. In this chapter, we demonstrate a detailed protocol for the application of machine learning to MALDI-TOF MS spectra of COVID-19-infected plasma samples for risk classification and biomarker identification.

Identification of Circulating Biomarkers of COVID-19 Using MALDI-TOF Mass Spectrometry.

Matrix-assisted laser desorption/ionization source coupled with time-of-flight mass analyzer mass spectrometry (MALDI-TOF MS) is being widely used to obtain proteomic profiles for clinical purposes, as a fast, low-cost, robust, and efficient technique. Here we describe a method for biofluid analysis using MALDI-TOF MS for rapid acquisition of proteomic signatures of COVID-19 infected patients. By using solid-phase extraction, the method allows the analysis of biofluids in less than 15 min.

Impact of the COVID-19 Pandemic on Pediatric Elbow Fractures: Marked Change in Management and Resource Utilization, Without a Change in Incidence.

BACKGROUND: Elbow fractures are the most common pediatric fractures requiring operative treatment. Although recent reports have suggested that the COVID-19 pandemic has markedly reduced the incidence of pediatric fractures, no study has specifically evaluated the impact on pediatric elbow fractures. This study aimed to evaluate changes in the incidence, severity, and resource utilization for managing pediatric elbow fractures during the COVID-19 pandemic, compared with prepandemic years. METHODS: A prepandemic (2007 to 2017) cohort and a COVID-19 pandemic period (March 2020 to March 2021) cohort of pediatric elbow injuries from a single tertiary hospital were retrospectively examined and compared. Exclusion criteria included outside treatment or lack of diagnosis by an orthopedist. Presentation information, injury patterns, transport, and treatment requirements were collected. RESULTS: Although the incidence of pediatric elbow fractures and rate of neurovascular injury were comparable, seasonal patterns were not sustained and the rate of fracture displacement was found to be significantly elevated in the COVID-19 period compared with nonpandemic years. Likewise, marked changes to where patients first presented (emergency department vs. Clinic), how the patients were transported, and the distance traveled for care were observed. Specifically, patients were more likely to present to the clinic, were more likely to self-transport instead of using emergency medical service transportation, and traveled a greater distance for care, on average. Aligning with these changes, the resources utilized for the treatment of pediatric elbow fracture markedly changed during the COVID-19 period. This study found that there was an increase in the overall number of surgeries performed, the total operative time required to treat elbow fractures, and the number of patients requiring admission during the COVID-19 period. CONCLUSIONS: These data provide a contrasting viewpoint to prior reports, illustrating that the incidence of elbow fractures remained consistent during the COVID-19 period, whereas the operative volume and need for hospital admission increased compared with years prior. Furthermore, this study demonstrated how the COVID-19 pandemic altered the interface between pediatric patients with elbow fractures and our institution regarding the location of presentation and transportation. LEVEL OF EVIDENCE: Level III-retrospective cohort study.

Bacterial Co-Infection in Patients with COVID-19 Hospitalized (ICU and Not ICU): Review and Meta-Analysis.

The prevalence of patients hospitalized in ICUs with COVID-19 and co-infected by pathogenic bacteria is relevant in this study, considering the integrality of treatment. This systematic review assesses the prevalence of co-infection in patients admitted to ICUs with SARS-CoV-2 infection, using the PRISMA guidelines. We examined the results of the PubMed, Embase, and SciELO databases, searching for published English literature from December 2019 to December 2021. A total of 542 rec ords were identified, but only 38 were eligible and, and of these only 10 were included. The tabulated studies represented a sample group of 1394 co-infected patients. In total, 35%/138 of the patients were co-infected with Enterobacter spp., 27% (17/63) were co-infected with methicillin-sensitive Staphylococ cus aureus, 21% (84/404) were co-infected with Klebsiella spp., 16% (47/678) of patients were co-infected with coagulase-negative Staphylococcus, 13% (10/80) co-infected with Escherichia coli (ESBL), and 3% (30/1030) of patients were co-infected with Pseudomonas aeruginosa. The most common co-infections were related to blood flow; although in the urinary and respiratory tracts of patients Streptococcus pneumoniae was found in 57% (12/21) of patients, coagulase negative Staphylococcus in 44% (7/16) of patients, and Escherichia coli was found in 37% (11/29) of patients. The present research demonstrated that co-infections caused by bacteria in patients with COVID-19 are a concern.

Impact of the lockdown on children with physical disabilities and their parents facing the COVID-19 pandemic: The ECHO French survey

Objective: During the COVID-19 pandemic, the daily lives of children with physical disabilities and their families have significantly been affected. This study aimed at identifying potential healthcare issues through child wellbeing, continuity of rehabilitation and medical care, and parental concerns during the first full lockdown in France. Design: Cross-sectional study. Method: The French national survey ECHO was developed by a multidisciplinary group and disseminated in France from the 6th of April 2020, via internet. This online survey was addressed to the parents of children with physical disabilities, aged from zero to 18 years. It explored the experiences of children and their families during lockdown. Information regarding the child's well-being, rehabilitation and family organisation was collected. Results: The children (mean age 9.5 ±4.8 years) mostly had cerebral palsy (42%). Negative effects on morale (43% of the children), behaviour (38% of the children) and social interactions (no contact with other children for 62%) were reported. Sixty-five percent of the children stopped physical activities. Medical follow-up was maintained for 49%. Of the rehabilitation disciplines, physiotherapy and occupational therapy were continued for 49% and 27% of children respectively. Physiotherapy was performed by the parents for 40% of children. The main parental concern was the lack of rehabilitation (70%) and they complained of a lack of help (60%). Conclusion: This study highlighted substantial effects on the health of children with physical disabilities and loss of opportunity with massive interruption of medical follow up and rehabilitation. Regular assessment of the health benefit/ risk is essential to support families and ensure continuity of care during the pandemic.

TGF-β SIGNALING PATHWAY SHAPES ADAPTIVE IMMUNITY in EARLY SARS-CoV-2 INFECTION

Background: SARS-CoV-2 induces cytokine response dysregulation and immune dysfunction. What remains unclear is how cytokine signaling shapes immune responses during early SARS-CoV-2 infection when adaptive immunity is developing. Our goal is to identify immune pathways that shape the early development of adaptive immune responses in COVID-19 patients. We performed paired single-cell transcriptomic and epigenomic profiling at two time-points of early SARS-CoV-2 infection to determine immune signatures of acute infection and epigenetic drivers that underpin immune response dynamics. Methods: PBMC samples were collected from four moderate to severe COVID-19 patients at two early time-points (n = 3 for Week 1 and n = 3 for Week 2 after symptom onset, including 2 participants having paired blood sampling at both time points) and from two healthy controls (n = 2). Using paired scRNA-Seq and scATAC-Seq, we captured transcriptomic and epigenomic profiles in the same single cells to identify chromatin accessibility changes as a potential mechanism for the surge and decline of immune responses elicited during acute SARS-CoV-2 infection. Using bioinformatic approaches, we identified heterogeneous immune cell populations, modeled cell differentiation trajectories, determined dysregulated immune pathways through gene set enrichment analysis, and connected chromatin co-accessible landscapes. Results: We captured transcriptomic and epigenomic profiles of 43,726 single cells and identified paired transcriptional and epigenetic landscapes in six major immune cell types: CD4+ T cells, CD8+ T cells, B cells, dendritic cells, monocytes, and NK cells. We found that early SARS-CoV-2 infection induced a surge in IL-2, IL-6, IFN-α, IFN-γ, TNF-α, and NF-κB responses at Week 1 that declined at Week 2 in adaptive immune cells (CD4+ T, CD8+ T, and B cells). In contrast, TGF-β responses surged early at Week 1 and continued to increase at Week 2 in these cells. In B cells and plasmablasts, we found early surges of IGHA1 (encoding IgA heavy chain) and SOX4 (an essential transcription factor for B cell development) expressions that correlated with expression of SMAD-dependent TGF-β signaling pathway. Further, we found a notable increase in chromatin accessibility at the SMAD binding regulatory element 150 kb upstream of SOX4 in B cells of infected patients. Conclusion: Our data suggest a significant increase in TGF-β activity that instructs dynamic B cell-associated protective immunity during early SARS-CoV-2 infection.

Complicaciones neurológicas en pacientes críticos por SARS-CoV-2 Neurological complications in critical patients with COVID-19

Introducción Nos proponemos analizar las complicaciones neurológicas de los pacientes con infección grave por SARS-CoV-2 que han requerido ingreso en unidad de cuidados intensivos (UCI). Pacientes y métodos Estudio descriptivo retrospectivo, observacional, de pacientes consecutivos ingresados en UCI por infección respiratoria grave por SARS-CoV-2 desde el 1 de abril hasta el 1 de junio de 2020. Resultados Registramos 30 pacientes con síntomas neurológicos, 21 hombres (72,40%), edad media: 57,41 años ± 11,61 desviación estándar (DE). Estancia media en UCI: 18,83 ± 14,33 DE. A nivel sindrómico: 28 pacientes (93,33%) con síndrome confusional agudo, 15 (50%) con patología neuromuscular, 5 (16,66%) con cefalea, 4 (13,33%) con patología cerebrovascular y 4 (13,33%) con encefalopatías/encefalitis. Punción lumbar normal en 6 pacientes (20%). La RMN craneal o TAC craneal mostró alteraciones en 20 casos (66,6%). Se realizó EEG en todos los pacientes (100%), alterado en 8 pacientes (26,66%). En 5 de los 15 pacientes con miopatía clínica se ha podido confirmar con ENMG. Hemos encontrado relación entre la mayor edad y los días de ingreso en UCI (p = 0,002;IC 95%: 4,032-6,022;OR: 3,594). Conclusiones La infección grave por COVID-19 afecta mayoritariamente a hombres, similar a lo descrito en otras series. La mitad de nuestros pacientes presenta una miopatía aguda, y casi la totalidad de los pacientes salen de la UCI con síndromes confusionales agudos que evolucionan a una resolución completa, sin correlacionarse con los resultados del EEG o de pruebas de neuroimagen. La mayor edad se asocia con un mayor número de días de estancia en UCI.

Cancer patients display diminished viral RNA clearance and altered T cell responses during SARS-CoV-2 infection

Cancer patients display immunomodulation related to malignancy and anti-cancer therapies, but how these factors impact COVID-19 remains unknown. To investigate immune responses in cancer patients with COVID-19, we undertook a prospective case-control study, enrolling hospitalized solid tumor patients with acute COVID-19, as well as age-, gender-, and comorbidity-matched COVID-19 patients without cancer as controls. Using biospecimens collected during hospitalization, we performed virologic measurements as well as in-depth immunophenotyping of cellular, antibody and cytokine responses. We enrolled 17 cancer patients (cases) admitted to Yale-New Haven Hospital between March 15 and June 30, 2020 with COVID-19, as well as 17 matched non-cancer patients (controls) admitted with COVID-19. No significant differences were observed between cases and controls based on patient characteristics (age, gender, race, co-morbidities, smoking history, days from symptom onset to COVID-19 diagnosis) or outcomes (COVID-19 severity, length of hospital stay, rate of intubation or mortality). The most common primary tumor sites were lung (4/17) and gastrointestinal (4/17);all cases had received cancer-directed therapy within 6 months of COVID-19 diagnosis, with 13/17 receiving treatment less than 1 month prior to hospitalization. Three of 17 cases had received immune checkpoint inhibitor therapies. Despite having similar SARS-CoV-2 viral RNA loads at the time of COVID-19 diagnosis when compared with controls, cancer cases had increased viral RNA abundance during hospitalization, suggesting slower clearance. Antibody responses against SARS-CoV-2 were preserved in cancer cases, with cases displaying similar levels of IgM and IgG antibodies directed against SARS-CoV-2 epitopes compared to controls. Cytokine profiling revealed higher plasma levels of CCL3, IL1A and CXCL12 in cancer cases compared to controls. Using flow cytometric immunophenotyping, we found that innate immune and non-T cell adaptive immune parameters were similar between cases and controls hospitalized with COVID-19. However, among cancer cases on conventional therapies, T cell lymphopenia was more profound, and these cases demonstrated higher levels of CD8+ exhausted (CD8+CD45RA-PD1+TIM3+ ), CD8+GranzymeB+ and CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ activated T cells when compared with controls;interestingly, these differences were not observed in patients who had received immune checkpoint inhibition. Thus, we found reduced viral RNA clearance and specific alterations in T cell and cytokine responses in cancer patients hospitalized with COVID-19 compared with matched controls with COVID-19. This dysregulated T cell response in cancer patients, which may reflect immune modulation due to chronic antigen stimulation as well as cancer therapies, may lead to altered virologic and clinical outcomes in this population.

Safety and immunogenicity of CoronaVac in people living with HIV: a prospective cohort study.

BACKGROUND: People living with HIV might have a poor or delayed response to vaccines, mainly when CD4 cell counts are low, and data concerning COVID-19 vaccines in this population are scarce. This prospective cohort study assessed the safety and immunogenicity of the inactivated SARS-CoV-2 vaccine CoronaVac in people with HIV compared with people with no known immunosuppression. METHODS: In this prospective cohort study, adults (aged ≥18 years) living with HIV who were regularly followed up at the University of Sao Paulo HIV/AIDS outpatient clinic in Sao Paulo, Brazil, were included in the study. Eligibility for people with HIV was independent of antiretroviral use, HIV viral load, or CD4 cell count. Adults with no known immunosuppression with CoronaVac vaccination history were included as a control group. CoronaVac was given intramuscularly in a two-dose regimen, 28 days apart. Blood was collected before vaccine administration and 6 weeks after the second dose (day 69). Immunogenicity was assessed at baseline (day 0), before second vaccine (day 28), and 6 weeks after second vaccine dose (day 69) through SARS-CoV-2 IgG titre and seroconversion, neutralising antibody (NAb) positivity and percentage activity, and factor increase in IgG geometric mean titres (FI-GMT). We investigated whether HIV status and CD4 count (<500 or ≥500 cells per µL) were associated with CoronaVac immunogenicity by use of multivariable models adjusted for age and sex. FINDINGS: Between Feb 9, 2021, and March 4, 2021, 776 participants were recruited. Of 511 participants included, 215 (42%) were people with HIV and 296 (58%) were people with no known immunosuppression. At 6 weeks after the second vaccine dose (day 69), 185 (91%) of 204 participants with HIV and 265 (97%) of 274 participants with no known immunosuppression had seroconversion (p=0·0055). 143 (71%) of 202 participants with HIV were NAb positive compared with 229 (84%) of 274 participants with no known immunosuppression (p=0·0008). Median IgG titres were 48·7 AU/mL (IQR 26·6-88·2) in people with HIV compared with 75·2 AU/mL (50·3-112·0) in people with no known immunosuppression (p<0·0001); and median NAb activity was 46·2% (26·9-69·7) compared with 60·8% (39·8-79·9; p<0·0001). In people with HIV who had CD4 counts less than 500 cells per µL seroconversion rates, NAb positivity, and NAb activity were lower than in those with CD4 counts of at least 500 cells per µL. In multivariable models for seroconversion, NAb positivity, IgG concentration, and NAb activity after a complete two-dose regimen, adjusted for age and sex, people with HIV who had CD4 counts of at least 500 cells per µL and people with no known immunosuppression had higher immunogenicity than did people with HIV with CD4 counts less than 500 cells per µL. No serious adverse reactions were reported during the study. INTERPRETATION: Immunogenicity following CoronaVac in people with HIV seems strong but reduced compared with people with no known immunosuppression. Our findings highlight the need for strategies to improve vaccine immunogenicity in people with HIV. FUNDING: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and B3-Bolsa de Valores do Brasil.

Atovaquone for Treatment of COVID-19 (Ataq COVID-19) Trial

Background. Our group performed an in-silico screen to identify FDA approved drugs that inhibit SARS-C0V-2 main protease (Mpro), followed by in vitro viral replication assays, and in vivo pharmacokinetic studies in mice. These studies identified atovaquone as a promising candidate for inhibiting viral replication. Methods. Enrolled patients were randomized in a 2:1 fashion to atovaquone 1500 mg twice daily versus matched placebo. Patients received standard of care treatment including remdesivir, dexamethasone, or convalescent plasma as deemed necessary by the treating team. Patients agreed to allow collection of saliva at baseline and twice a day while hospitalized or up to 10 days. Saliva was collected and RNA extracted for viral load (VL) measurement by Real-time PCR. Our primary outcome was to examine the between group differences in log transformed VL(copies/mL) using generalized linear mixed-effect models of repeated measures from all samples. Additional analysis of Atovquone plasma concentrations were examined and correlated with viral load and body mass index (BMI). Results. Of the 61 patients enrolled;41 were received atovaquone and 19 placebo. Overall the population was predominately male Hispanic with a mean age of 51 years. The two groups were balanced (Table 1) with regard to age, gender, race, co-morbidities, days from onset of symptoms, baseline oxygen requirements, and receipt of COVID-19 specific standard of care treatment. A higher proportion with diabetes was noted in the Atovaquone arm. The log10 VL was 5.25 copies/mL vs. 4.79 copies/mL at baseline in the atovaquone vs. placebo group. Although there was a decrease in VL over time, there was no differences between the atovaquone plus standard of care arm versus the standard of care arm (Figure 1). Additional analysis of atovaquone plasma concentration demonstrated a wide variation in atovaquone levels, inverse association between atovaquone levels and BMI (rho -0.44, p=0.03), and Day 5 concentrations and VL (rho -0.54, p=0.005). Conclusion. Although atovaquone showed promising in vitro antiviral properties for COVID-19, in this pilot study we did not detect a change in VL in patients who received atovaquone compared to placebo, possibly due to failure of patients achieve adequate drug levels.

SARS-CoV-2 (COVID-19)-specific T cell and B cell responses in convalescent rheumatoid arthritis: Monozygotic twins pair case observation.

Rheumatoid arthritis (RA) patients present higher risk of SARS-CoV-2 infection (COVID-19), and proper management of the disease in this population requires a better understanding of how the immune system controls the virus. We analyzed the T cell and B cell phenotypes, and their repertoire in a pair of monozygotic twins with RA mismatched for COVID-19 infection. Twin- was not infected, while Twin+ was infected and effectively controlled the infection. We found no significant changes on the αß T cell composition, while γδ T cells and B cells presented considerable expansion of memory population in Twin+ and robust T/B cell responses to several SARS-CoV-2 peptides. T cell receptor ß/γ-chain and immunoglobulin heavy chain next-generation sequencing depicted a remarkable higher diversity in Twin+ compared with Twin-, despite no significant changes being found in variable/joining family usage. Repertoire overlap analyses showed that, although being identical twins, very few clones were shared between them, indicating that COVID-19 may lead to deep changes on the immune cell repertoire in RA patients. Altogether, our results indicate that RA patients may develop robust and persistent COVID-19-specific T/B cell responses; γδ T cells and B cells may play a key role in the management of COVID-19 in RA, and the infection may lead to a profound reshaping of immune cell receptor specificities.

MALDI-TOF mass spectrometry of saliva samples as a prognostic tool for COVID-19.

BACKGROUND: The SARS-CoV-2 infections are still imposing a great public health challenge despite the recent developments in vaccines and therapy. Searching for diagnostic and prognostic methods that are fast, low-cost and accurate are essential for disease control and patient recovery. The MALDI-TOF mass spectrometry technique is rapid, low cost and accurate when compared to other MS methods, thus its use is already reported in the literature for various applications, including microorganism identification, diagnosis and prognosis of diseases. METHODS: Here we developed a prognostic method for COVID-19 using the proteomic profile of saliva samples submitted to MALDI-TOF and machine learning algorithms to train models for COVID-19 severity assessment. RESULTS: We achieved an accuracy of 88.5%, specificity of 85% and sensitivity of 91.5% for classification between mild/moderate and severe conditions. When we tested the model performance in an independent dataset, we achieved an accuracy, sensitivity and specificity of 67.18, 52.17 and 75.60% respectively. CONCLUSION: Saliva is already reported to have high inter-sample variation; however, our results demonstrates that this approach has the potential to be a prognostic method for COVID-19. Additionally, the technology used is already available in several clinics, facilitating the implementation of the method. Further investigation using a larger dataset is necessary to consolidate the technique.

Anticoagulation in Patients With COVID-19: JACC Review Topic of the Week.

Clinical, laboratory, and autopsy findings support an association between coronavirus disease-2019 (COVID-19) and thromboembolic disease. Acute COVID-19 infection is characterized by mononuclear cell reactivity and pan-endothelialitis, contributing to a high incidence of thrombosis in large and small blood vessels, both arterial and venous. Observational studies and randomized trials have investigated whether full-dose anticoagulation may improve outcomes compared with prophylactic dose heparin. Although no benefit for therapeutic heparin has been found in patients who are critically ill hospitalized with COVID-19, some studies support a possible role for therapeutic anticoagulation in patients not yet requiring intensive care unit support. We summarize the pathology, rationale, and current evidence for use of anticoagulation in patients with COVID-19 and describe the main design elements of the ongoing FREEDOM COVID-19 Anticoagulation trial, in which 3,600 hospitalized patients with COVID-19 not requiring intensive care unit level of care are being randomized to prophylactic-dose enoxaparin vs therapeutic-dose enoxaparin vs therapeutic-dose apixaban. (FREEDOM COVID-19 Anticoagulation Strategy [FREEDOM COVID]; NCT04512079).