COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials

BackgroundMonoclonal antibody and antiviral treatments for COVID-19 disease remain largely unavailable worldwide, and existing monoclonal antibodies may be less active against circulating omicron variants. Although treatment with COVID-19 convalescent plasma (CCP) is promising, randomized clinical trials (RCTs) among outpatients have shown mixed results. MethodsWe conducted an individual participant data meta-analysis from all outpatient CCP RCTs to assess the overall risk reduction for all-cause hospitalizations by day 28 in all participants who had transfusion initiated. Relevant trials were identified by searching MEDLINE, Embase, MedRxiv, WHO, Cochrane Library, and Web of Science from January 2020 to September 2022. ResultsFive included studies from four countries enrolled and transfused 2,620 adult patients. Comorbidities were present in 1,795 (69%). The anti-Spike or virus neutralizing antibody titer range across all trials was broad. 160 (12.2%) of 1315 control patients were hospitalized, versus 111 (8.5%) of 1305 CCP-treated patients, yielding a 3.7% (95%CI: 1.3%-6.0%; p=.001) ARR and 30.1% RRR for all-cause hospitalization. The effect size was greatest in those with both early transfusion and high titer with a 7.6% ARR (95%CI: 4.0%-11.1%; p=.0001) accompanied by at 51.4% RRR. No significant reduction in hospitalization was seen with treatment > 5 days after symptom onset or in those receiving CCP with antibody titers below the median titer. ConclusionsAmong outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization. CCP may be most effective when given within 5 days of symptom onset and when antibody titer is higher. Key PointsWhile the outpatient COVID-19 randomized controlled trial meta-analysis indicated heterogeneity in participant risk factors and convalescent plasma, the combined CCP efficacy for reducing hospitalization was significant, improving with transfusion within 5 days of symptom onset and high antibody neutralization levels.

Convalescent plasma for outpatients with early COVID-19

BackgroundConvalescent plasma (CP) for hospitalized patients with COVID-19 has not demonstrated clear benefits. However, data on outpatients with early symptoms are scarce. We aimed to assess whether treatment with CP administered during the first 7 days of symptoms reduced the disease progression or risk of hospitalization of outpatients. MethodsTwo double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when <20% of their predefined sample size had been recruited. A Bayesian adaptive individual patient data meta-analysis was implemented. Analyses were done with Bayesian proportional odds and logistic models, where odds ratios (OR)<1.0 indicate a favorable outcome for CP. Fourteen study sites across the Netherlands and Catalonia in Spain participated in the trial. The two studies included outpatients aged [≥]50 years and diagnosed with COVID-19 and symptomatic for [≤]7days. The intervention consisted of one unit (200-300mL) of CP with a predefined minimum level of antibodies. The two primary endpoints were (a) a 5-point disease severity scale (fully recovered by day 7 or not, hospital or ICU admission and death) and (b) a composite of hospitalization or death. ResultsOf 797 patients included, 390 received CP and 392 placebo. At baseline, they had a median age of 58 years, 1 comorbidity, symptoms for 5 days and 93% tested negative for SARS-CoV-2 S-protein IgG antibodies. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The OR of CP for an improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311). The OR for hospitalization or death was 0.919 (CI 0.592-1.416). The effect of CP on hospital admission or death was largest in patients with [≤]5 days of symptoms (OR 0.658, 95% CI 0.394-1.085). CP did not decrease the time to full symptom resolution (p=0.62). ConclusionTreatment with CP of outpatients in the first 7 days of symptoms did not improve the outcome of COVID-19. The possible beneficial effect in patients with [≤]5 days of symptoms requires further study. RegistrationNCT04621123 and NCT04589949 on https://www.clinicaltrials.gov Funding sourceZONMW, the Netherlands, grant number 10430062010001. SUPPORT-E, grant number 101015756 YoMeCorono, www.tomecorono.com The Fight AIDS and Infectious Diseases Foundation with funding from the pharmaceutical company Grifols S.A

Estimating the relationship between mobility, non-pharmaceutical interventions, and COVID-19 transmission in Ghana

BackgroundGovernments around the world have implemented non-pharmaceutical interventions to limit the transmission of COVID-19. While lockdowns and physical distancing have proven effective for reducing COVID-19 transmission, there is still limited understanding of how NPI measures are reflected in indicators of human mobility. Further, there is a lack of understanding about how findings from high-income settings correspond to low and middle-income contexts. MethodsIn this study, we assess the relationship between indicators of human mobility, NPIs, and estimates of Rt, a real-time measure of the intensity of COVID-19 transmission. We construct a multilevel generalised linear mixed model, combining local disease surveillance data from subnational districts of Ghana with the timing of NPIs and indicators of human mobility from Google and Vodafone Ghana. FindingsWe observe a relationship between reductions in human mobility and decreases in Rt during the early stages of the COVID-19 epidemic in Ghana. We find that the strength of this relationship varies through time, decreasing after the most stringent period of interventions in the early epidemic. InterpretationOur findings demonstrate how the association of NPI and mobility indicators with COVID-19 transmission may vary through time. Further, we demonstrate the utility of combining local disease surveillance data with large scale human mobility data to augment existing surveillance capacity and monitor the impact of NPI policies. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and preprint archives for articles published in English that contained information about the COVID-19 pandemic published up to Nov 1, 2021, using the search terms "coronavirus", "CoV", "COVID-19", "mobility", "movement", and "flow". The data thus far suggests that NPI measures including physical distancing, reduction of travel, and use of personal protective equipment have been demonstrated to reduce COVID-19 transmission. Much of the existing research focuses on comparisons of NPI stringency with COVID-19 transmission among different high-income countries, or on high-income countries, leaving critical questions about the applicability of these findings to low- and middle-income settings. Added value of this studyWe used a detailed COVID-19 surveillance dataset from Ghana, and unique high resolution spatial data on human mobility from Vodafone Ghana as well as Google smartphone GPS location data. We show how human mobility and NPI stringency were associated with changes in the effective reproduction number (Rt). We further demonstrate how this association was strongest in the early COVID-19 outbreak in Ghana, decreasing after the relaxation of national restrictions. Implications of all the available evidenceThe change in association between human mobility, NPI stringency, and Rt may reflect a "decoupling" of NPI stringency and human mobility from disease transmission in Ghana as the COVID-19 epidemic progressed. This finding provides public health decision makers with important insights for the understanding of the utility of mobility data for predicting the spread of COVID-19.

Quantifying the relationship between SARS-CoV-2 viral load and infectiousness.

The relationship between SARS-CoV-2 viral load and infectiousness is not known. Using data from a prospective cohort of index cases and high-risk contact, we reconstructed by modelling the viral load at the time of contact and the probability of infection. The effect of viral load was particularly large in household contacts, with a transmission probability that increased to as much as 37% when the viral load was greater than 10 log10 copies per mL. The transmission probability peaked at symptom onset in most individuals, with a median probability of transmission of 15%, that hindered large individual variations (IQR: [8, 37]). The model also projects the effects of variants on disease transmission. Based on the current knowledge that viral load is increased by 2 to 4-fold on average, we estimate that infection with B1.1.7 virus could lead to an increase in the probability of transmission by 8 to 17%.

Performance characteristics of five antigen-detecting rapid diagnostic test (Ag-RDT) for SARS-CoV-2 asymptomatic infection: a head-to-head benchmark comparison

Background Mass testing for early identification and isolation of infectious COVID-19 individuals, irrespective of concurrent symptoms, is an efficacious strategy to reduce disease transmission. Antigen-detecting rapid diagnostic tests (Ag-RDT) appear as a potentially suitable tool for mass testing on account of their ease-of-use, fast turnaround time, and low cost. However, benchmark comparisons are scarce, particularly in the context of unexposed asymptomatic individuals. Methods We used nasopharyngeal specimens from unexposed asymptomatic individuals to assess five Ag-RDTs: PanBio™ COVID-19 Ag Rapid test (Abbott), CLINITEST® Rapid COVID-19 Antigen Test (Siemens), SARS-CoV-2 Rapid Antigen Test (Roche Diagnostics), SARS-CoV-2 Antigen Rapid Test Kit (Lepu Medical), and COVID-19 Coronavirus Rapid Antigen Test Cassette (Surescreen). Samples were collected between December 2020-January 2021 during the third wave of the epidemic in Spain. Findings The analysis included 101 specimens with confirmed positive PCR results and 185 with negative PCR. For the overall sample, the performance parameters of Ag-RDTs were as follows: Abbott assay, sensitivity 38·6% (95% CI 29·1–48·8) and specificity 99·5% (97–100%); Siemens, sensitivity 51·5% (41·3–61·6) and specificity 98·4% (95·3–99·6); Roche, sensitivity 43·6% (33·7–53·8) and specificity 96·2% (92·4–98·5); Lepu, sensitivity 45·5% (35·6–55·8) and specificity 89·2% (83·8–93·3%); Surescreen, sensitivity 28·8% (20·2–38·6) and specificity 97·8% (94·5–99·4%). For specimens with cycle threshold (Ct) <30 in RT-qPCR, all Ag-RDT achieved a sensitivity of at least 70%, with Siemens, Roche, and Lepu assays showing sensitivities higher than 80%. In models according to population prevalence, all Ag-RDTs will have a NPV >99% and a PPV<50% at 1% prevalence. Interpretation Two commercial, widely available assays can be used for SARS-CoV-2 antigen testing to achieve sensitivity in specimens with a Ct<30 and specificity of at least 80% and 96%, respectively. Estimated negative and positive predictive values suggests the suitability of Ag-RDTs for mass screenings of SARS-CoV-2 infection in the general population. Funding Blueberry diagnostics, Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, and #YoMeCorono.org crowdfunding campaign. Evidence before this study In December 2020, we searched on PubMed for articles containing the terms “antigen”, “test” (or Ag-RDT), and “SARS-CoV-2” or “COVID-19” either in the title or the abstract. Our search yielded 79 entries corresponding to articles written in English. Of them, 33 were articles presenting the diagnostic performance of qualitative lateral-flow antigen-detecting rapid diagnostic tests (Ag-RDT). Four of these articles reported the results of head-to-head comparisons of various Ag-RDTs; in all cases, the number of tests was lower than the recommended for retrospective assessments of diagnostic performance (i.e., minimum of 100 PCR positive and 100 PCR negative). Furthermore, all head-to-head comparisons found in the literature included specimens obtained among individuals with varying disease status (none of which asymptomatic), thus limiting the adequacy of the estimates for an asymptomatic screening strategy. Added value of this study We compared for the first time head-to-head five Ag-RDT using a powered set of fresh respiratory specimens PCR-confirmed positive or negative, collected from unexposed asymptomatic individuals during screening campaigns for early detection of SARS-CoV-2 infection. The sample size was large enough to draw robust conclusions. Our analysis identified four Ag-RDTs (i.e., assays marketed by Abbott, Siemens, Roche, and Surescreen) with specificity higher than 96%. Despite the low sensitivity for the overall sample (range 29% to 51%), the corresponding values for the subset of samples with Ct <30 were higher than 80% for Siemens, Roche, and Lepu assays. The estimated NPV for a screening performed in an area with 1% prevalence would be >99% for all tests, while the PPV would be <50%. Implications of all the available evidence Current data on the diagnostic performance of Ag-RDTs is heterogeneous and precludes benchmark assessments. Furthermore, the screening of asymptomatic populations is currently not considered among the intended uses of Ag-RDT, mostly because of lack of evidence on test performance in samples from unexposed asymptomatic individuals. Our findings add to the current evidence in two ways: first, we provide benchmarking data on Ag-RDTs, assessed head-to-head in a single set of respiratory specimens; second, we provide data on the diagnostic performance of Ag-RDTs in unexposed asymptomatic individuals. Our findings support the idea that Ag-RDTs can be used for mass screening in low prevalence settings and accurately rule out a highly infectious case in such setting.

SARS-CoV-2 infection suppresses ACE2 function and antiviral immune response in the upper respiratory tract of infected patients

There is an urgent need to elucidate the molecular mechanisms underlying the transmissibility and pathogenesis of SARS-CoV-2. ACE2 is a host ectopeptidase with well-described anti-inflammatory and tissue protective functions and the receptor for the virus. Understanding SARS-CoV-2-ACE2 interaction and the expression of antiviral host genes in early infection phase is crucial for fighting the pandemic. We tested the significance of soluble ACE2 enzymatic activity longitudinally in positive nasopharyngeal swabs at two time points after symptom consultation, along with gene expression profiles of ACE2, its proteases, ADAM17 and TMPRRS2, and interferon-stimulated genes (ISGs), DDX58, CXCL10 and IL-6. Soluble ACE2 activity decreased during infection course, in parallel to ACE2 gene expression. On the contrary, SARS-CoV-2 infection induced expression of the ISG genes in positive SARS-CoV-2 samples at baseline compared to negative control subjects, although this increase wanes with time. These changes positively correlated with viral load. Our results demonstrate the existence of mechanisms by which SARS-CoV-2 suppress ACE2 expression and function casting doubt on the IFN-induced upregulation of the receptor. Moreover, we show that initial intracellular viral sensing and subsequent ISG induction is also rapidly downregulated. Overall, our results offer new insights into ACE2 dynamics and inflammatory response in the human upper respiratory tract that may contribute to understand the early antiviral host response to SARS-CoV-2 infection.

Risk factors for mortality of residents in nursing homes with Covid-19: a retrospective cohort study

BackgroundNursing homes have shown remarkably high Covid-19 incidence and mortality. We aimed to explore the contribution of structural factors of nursing home facilities and the surrounding district to all-cause and Covid-19-related deaths during a SARS-CoV-2 outbreak. MethodsIn this retrospective cohort study, we investigated the risk factors of Covid-19 mortality at the facility level in nursing homes in Catalonia (North-East Spain). The investigated factors included characteristics of the residents (age, gender, comorbidities, and complexity and/or advanced disease), structural features of the nursing home (total number of residents, residents who return home during the pandemic, and capacity for pandemic response, based on an ad hoc score of availability of twelve essential items for implementing preventive measures), and sociodemographic profile of the catchment district (household income, population density, and population incidence of Covid-19). Study endpoints included all-cause death and Covid-19-related death (either PCR-confirmed or clinical suspicion). FindingsThe analysis included 167 nursing homes that provide long-term care to 8,716 residents. Between March 1 and June 1, 2020, 1,629 deaths were reported in these nursing homes; 1,089 (66{square}9%) of them were Covid-19-confirmed. The multivariable regression showed a higher risk of death associated with a higher percentage of complex patients (HR 1{square}09; 95%CI 1{square}05-1{square}12 per 10% increase) or those with advanced diseases (1{square}13; 1{square}07-1{square}19), lower capacity for implementing preventive measures (1{square}08; 1{square}05-1{square}10 per 1-point increase), and districts with a higher incidence of Covid-19 (2{square}98; 2{square}53-3{square}50 per 1000 cases/100,000 population increase). A higher population density of the catchment area was a protective factor (0{square}60; 0{square}50-0{square}72 per log10 people/Km2 increase). InterpretationPresence of residents with complex/advance disease, low capacity for pandemic response and location in areas with high incidence of Covid-19 are risk factors for Covid-19 mortality in nursing homes and may help policymakers to prioritize preventative interventions for pandemic containment. FundingCrowdfunding campaign YoMeCorono (https://www.yomecorono.com/), and Generalitat de Catalunya. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for studies exploring the management of Covid-19 in long-term care settings. The search was performed on May 1, 2020, and included the keywords "Covid-19", "nursing home", "long term care", and "skilled nursing facility" with no language restriction. In addition to descriptive reports of Covid-19 mortality in the long-term care setting, we found studies providing evidence on the influence of age and comorbidities to mortality at the individual level. Some authors reported comparisons in the incidence and mortality of Covid-19 between facilities and country areas, and suggested the characteristics of each area/facility that may explain differences in mortality. However, we found no published works specifically investigating the contribution of structural features of the facility and sociodemographic characteristics of the area to explaining differences in Covid-19 mortality among long-term care facilities. Added value of this studyThis is the first analysis of risk of mortality at a facility level of residents with Covid-19 in nursing homes. We enrolled up to 167 nursing homes providing long-term care to 8,716 residents and we actively identified risk factors for Covid-19 mortality at the facility level. We found that nursing homes with lower capacity for pandemic response, and located in districts with a higher incidence of Covid-19 had significantly higher risks of Covid-19 mortality. The percentage of complex and/or advanced disease patients was also a risk factor. Implications of all the available evidenceOur findings provide policymakers with critical information to prioritize long-term care facilities at higher risk when deploying preventative interventions to minimize mortality in this setting. The association between mortality within the nursing home and Covid-19 incidence in the catchment area reinforces the importance of preventing the entry of SARS-CoV-2 into facilities. Nursing homes with limited capacity to implement containment measures should be prioritized when deploying preventative interventions for minimizing Covid-19 mortality in long-term care facilities.

Analytical and Clinical Performance of the Panbio COVID-19 Antigen-Detecting Rapid Diagnostic Test

BackgroundThe current standard for COVID-19 diagnosis, RT-qPCR, has important drawbacks for its use as a tool for epidemiological control, including the need of laboratory-processing, high cost, and long turnaround from sampling to results release. Antigen-based rapid diagnostic tests (Ag-RDT) provide a promising alternative for this purpose. MethodsWe assessed the analytical and clinical performance of the Ag-RDT Panbio COVID-19 Ag Test (Abbott), using RT-qPCR as a reference test. The clinical performance was assessed using nasopharyngeal swabs, collected in routine practice for case confirmation and contact tracing, and nasal mid-turbinate swabs, collected in preventive screenings of asymptomatic individuals. Fresh samples were analysed by RT-q-PCR, stored at -80 {degrees}C, and analysed using the Ag-RDT according to the manufacturer instructions. FindingsThe Ag-RDT had a limit of detection of 6{middle dot}5x105 copies/reaction. The clinical performance was assessed on 1,406 frozen swabs with a PCR result available: 951 (67{middle dot}7%) positive and 455 (32{middle dot}4%) negative. The Ag-RDT identified the presence of SARS-CoV-2 in 872 of 951 PCR-positive samples (91{middle dot}7%; 95% CI 89{middle dot}8-93{middle dot}4 and ruled out its presence in 450 of 455 PCR-negative samples (specificity 98{middle dot}9%; 95% CI 97{middle dot}5- 99{middle dot}6). Sensitivity increased in samples with lower Ct values (Ct <25, 98{middle dot}2%; Ct<30, 94{middle dot}9%) and was higher among symptomatic cases (92{middle dot}6%) and their contacts (94{middle dot}2%) than among asymptomatic individuals (79{middle dot}5%). In the setting of asymptomatic screening, sensitivity also increased with lower Ct values (Ct <25, 100%; Ct<30, 98{middle dot}6%). Assuming a pre-test probability of 5%, the negative and positive predictive values were 99{middle dot}6% (99{middle dot}5 - 99{middle dot}6) and 81{middle dot}5% (65{middle dot}0 - 93{middle dot}2), respectively. InterpretationThe Panbio COVID-19 Ag-RDT has high sensitivity for detecting the presence of SARS-CoV-2 in nasal or nasopharyngeal swabs of both, symptomatic and asymptomatic individuals. The diagnostic performance of the test is particularly good in samples with viral loads associated with high risk of viral transmission (Ct <25), which show high positive and negative predictive values even when assuming a prevalence as low as 5%. FundingBlueberry diagnostics, Fundacio Institut dInvestigacio en Ciencies de la Salut Germans Trias i Pujol, and #YoMeCorono.org crowfunding campaing. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSOn October 6, 2020, we searched PubMed for articles containing "Antigen", "test", "SARS-CoV-2", "COVID-19" and "performance" in either the title or the abstract. We found five studies that showed the accuracy of point-of-care tests in identifying SARS-CoV-2 antigens for confirmation of clinically suspected COVID-19. We found high variability in the diagnostic accuracy of Ag-RDT. Most tests showed high specificity (i.e., 99% or higher), whereas sensitivity ranged from 11% to 92%; only one test reported sensitivity higher than 60%. We found no studies investigating the diagnostic accuracy of the Panbio COVID-19 Ag Test. We found no studies that assessed the performance of Ag-RDT for population-level screening of asymptomatic individuals. Added value of this studyOur analysis provides information regarding the diagnostic accuracy of the Panbio COVID-19 Ag Test when tested on 1,406 frozen samples of nasopharyngeal and nasal swabs collected in routine practice for diagnostic confirmation of symptomatic individuals with suspected COVID-19 or contacts exposed to a positive case, and preventive screenings of unexposed asymptomatic individuals. Compared with RT-qPCR as reference test, the Ag-RDT showed a sensitivity and specificity of 91{middle dot}7% and 98{middle dot}9%. Test sensitivity increased in samples with viral load associated with high risk of transmission (Ct <25), reaching more than 98%, regardless of the presence of symptoms. Implications of all the available evidenceAvailable evidence show variability in the diagnostic performance of marketed Ag-RDT. Our results provide substantial evidence that the point-of-care Panbio COVID-19 Ag Test can accurately identify SARS-CoV-2 antigens in people with suspected clinical COVID-19 as well as in asymptomatic people with high viral load and therefore, associated with higher risk of transmission. This finding represents a potentially useful advance for mass screening of asymptomatic people at the point-of-care.

Transmission of COVID-19 in 282 clusters in Catalonia, Spain: a cohort study

BackgroundThere remains limited data on what variables affect risk of transmission of SARS-CoV-2 and developing symptomatic Covid-19 and in particular the relationship to viral load (VL). We analysed data from linked index cases and their contacts to explore factors associated with transmission of SARS-CoV-2. MethodsPatients were recruited as part of a randomized control trial, conducted between March to April 2020, that aimed to assess if hydroxychloroquine reduced transmission of SARS-CoV-2. Non-hospitalised Covid-19 cases and their contacts were identified through the local surveillance system. VL, measured by quantitative PCR from a nasopharyngeal swab, was assessed at enrollment, at day 14, and whenever the participant reported Covid-19-like symptoms. Risk of transmission, developing symptomatic disease and incubation dynamics were evaluated using regression analysis. FindingsWe identified 314 cases, 282 of which had at least one contact (753 contacts in total). Ninety (33%) of 282 clusters had at least one transmission event. The secondary attack rate was 16% (125/753), with a variation from 12% to 24% for VL of the index case of <106, and >109 copies/mL, respectively (OR per log10 increase in VL 1.3 95%CI 1.1-1.6). Increased risk of transmission was also associated with household contact (OR 2.7; 1.4-5.06) and age of the contact (OR 1.02 per year; 1.01-1.04). The proportion of PCR positive contacts who developed symptomatic Covid-19 was 40.3% (181/449), with a variation from 25% to 60% for VL of the contact <107, and >109 copies/mL (HR log10 increase in VL 1.12; 95% CI 1.05 - 1.2). Time to onset of symptomatic disease decreased from a median of 7 days (IQR 5-10) for individuals with an initial viral load <107 to 6 days (4-8) and 5 days (3-8) for individuals with an initial viral load of 107-109 and >109, respectively. InterpretationViral load of index cases is a leading driver of SARS-CoV-2 transmission. The risk of symptomatic Covid-19 is strongly associated with viral load of contacts at baseline and shortens the incubation time in a dose-dependent manner. FundingCrowdfunding campaign YoMeCorono (http://www.yomecorono.com/), and Generalitat de Catalunya. Support for laboratory equipment from Foundation Dormeur. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSIn September 2020, we searched PubMed database for articles reporting on factors influencing transmission and the risk of developing symptomatic disease. Search terms included "Covid-19", "SARS-CoV-2", "transmission", "incubation time", and "risk", with no language restrictions. By 20th September, various authors had reported on retrospective analyses of clusters of index cases and their corresponding contacts, as well as series of patients who developed symptomatic Covid-19 disease after PCR positive result. Besides describing the secondary attack rate, various authors identified risk factors for transmission associated with the place and duration of exposure and the lack of use of personal protective equipment. A single study suggested that symptomatic individuals might be more likely to transmit than asymptomatic cases but we found no clear evidence regarding the influence of viral load of the index case on transmission risk. Similarly, although various retrospective series of patients with positive PCR results had reported incubation times elsewhere, the characteristics of index case and contacts that may influence the risk of developing symptomatic Covid-19 and the time to this event had been barely addressed. Added value of this studyWe analyzed data from a large cluster-randomized clinical trial on post-exposure therapy for Covid-19 that provide new information on SARS-CoV-2 transmission dynamics. Several design components add value to this dataset. Notably, quantitative PCR was available for the index cases to estimate risk of transmission. Furthermore, quantitative PCR was also performed on asymptomatic contacts at the time of enrollment allowing to investigate the dynamics of symptomatic disease onset among them. We found that the viral load of the index case was the leading determinant of the risk of SARS-CoV-2 PCR positivity among contacts. Among contacts who were SARS-CoV-2 PCR positive at baseline, viral load significantly influenced the risk of developing the symptomatic disease in a dose-dependent manner. This influence also became apparent in the incubation time, which shortened with increasing baseline viral loads. Implication of all the available evidenceOur results provide important insights into the knowledge regarding the risk of SARS-CoV-2 transmission and Covid-19 development. The fact that the transmission risk is primarily driven by the viral load of index cases, more than other factors such as their symptoms or age, suggests that all cases should be considered potential transmitters irrespective of their presentation and encourages assessing viral load in cases with a larger number of close contacts. Similarly, our results regarding the risk and expected time to developing symptomatic Covid-19 encourage risk stratification of newly diagnosed SARS-CoV-2 infections based on the initial viral load.

A Cluster-Randomized Trial of Hydroxychloroquine as Prevention of Covid-19 Transmission and Disease

BackgroundCurrent strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are limited to non-pharmacological interventions. Hydroxychloroquine (HCQ) has been proposed as a postexposure therapy to prevent Coronavirus disease 2019 (Covid-19) but definitive evidence is lacking. MethodsWe conducted an open-label, cluster-randomized trial including asymptomatic contacts exposed to a PCR-positive Covid-19 case in Catalonia, Spain. Clusters were randomized to receive no specific therapy (control arm) or HCQ 800mg once, followed by 400mg daily for 6 days (intervention arm). The primary outcome was PCR-confirmed symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, either symptomatically compatible or a PCR-positive result regardless of symptoms. Adverse events (AEs) were assessed up to 28 days. ResultsThe analysis included 2,314 healthy contacts of 672 Covid-19 index cases identified between Mar 17 and Apr 28, 2020. A total of 1,198 were randomly allocated to usual care and 1,116 to HCQ therapy. There was no significant difference in the primary outcome of PCR-confirmed, symptomatic Covid-19 disease (6.2% usual care vs. 5.7% HCQ; risk ratio 0.89 [95% confidence interval 0.54-1.46]), nor evidence of beneficial effects on prevention of SARS-CoV-2 transmission (17.8% usual care vs. 18.7% HCQ). The incidence of AEs was higher in the intervention arm than in the control arm (5.9% usual care vs 51.6% HCQ), but no treatment-related serious AEs were reported. ConclusionsPostexposure therapy with HCQ did not prevent SARS-CoV-2 disease and infection in healthy individuals exposed to a PCR-positive case. Our findings do not support HCQ as postexposure prophylaxis for Covid-19. ClinicalTrials.gov registration numberNCT04304053

A SYSTEMATIC ANALYSIS OF THE TIME COURSE TO DEVELOP TREATMENTS FOR COVID-19

BACKGROUNDThe spread of COVID-19 from Wuhan China, has been alarmingly rapid. Epidemiologic techniques succeeded in containing the disease in China, but efforts have not been as successful in the rest of the World, with a total of 29,155,581 confirmed cases of COVID-19, including 926,544 deaths worldwide as of September 15, 2020. Projections are for continued new infections and deaths if no effective therapeutic interventions can be initiated over the next several months. We performed a systematic review to determine the potential time course for development of treatments and vaccines, focusing on availability now and continuing in the last half of 2020. METHODS Clinical TrialsWe reviewed up-to-date information from several sources to identify potential treatments for COVID-19: The Reagan-Udall Expanded Access Navigator COVID-19 Treatment Hub was used to track the efforts of companies to develop agents. We focused on trials completed as of September 1, 2020 on identified agents We used several different sources: (A) covid-trials.org, then validated results on (B) clinicaltrials.gov and the (C) World Health Organizations International Clinical Trials Registry Platform (WHO ICTRP). We excluded studies which were clearly observational, with no randomization, control, or comparison group. We further set a cutoff of 100 for numbers of subjects, since smaller trial size could lack statistical power to establish superiority of the intervention over the control. PublicationsWe searched for published trial results on pubmed.gov and on medRxiv, the preprint server, and used a targeted Google search to find announcements of unpublished trial results RESULTS Clinical Trials in RecruitmentAs of our cutoff date of April 1, 2020, we found 409 trials meeting our minimum requirement of 100 subjects. The WHO Solidarity megatrial for hospitalized patients was launched in over 100 countries, actively comparing hydroxychloroquine (HCQ), lopanovir/ritonavir (LPV/r) alone and in combination with interferon beta-1, and remdesivir. The LPV/r alone and HCQ arms have already been discontinued. Of these, only 9 were conducted on outpatients. A few vaccine trials are hoping to complete Phase 3 enrollment by the end of the third quarter 2020, but a prolonged follow-up of patients will likely be required. Clinical trials CompletedAs of September 1, 2020, there were 231 trials reporting completion, Of these, only 59 studies enrolled 100 or more subjects. There were 34 trials in hospitalized patients, 9 directed at outpatients, and 8 prevention studies, Published DataAs of September 1, 2020 we found 70 publications reporting findings in human studies on 13 classes of drugs and on 6 vaccines. There were 33 randomized placebo or active control studies; the rest were retrospective observational. Only seven publications dealt with outpatient care, the rest all in hospitalized patients. Available TreatmentsAt this time, remdesivir and convalescent plasma have been granted emergency use authorization in the U.S.A., solely for hospitalized patients. There is also support for glucocorticoid treatment of the COVID-19 respiratory distress syndrome. No treatments or prophylaxis are offered for outpatients. CONCLUSIONCOVID-19 is propagated primarily by infected ambulatory individuals. There have been no options brought forward for prevention and non-hospital treatment with only a few randomized, controlled outpatient studies expected to yield results in time to impact on the continuing pandemic by the end of 2020. It will be necessary for public health authorities to make hard decisions, with limited data, to prevent the continued spread of the disease. The choices will be hardest when dealing with possible early release of safe and effective vaccines which would, of course, be of greatest benefit to the Worlds population.

Towards elimination of yaws in Papua New Guinea

@#Yaws is a chronic infectious disease caused by Treponema pallidum subsp. pertenue, which causes disease of the skin, bones and joints and is spread by skin-to-skin contact. Most cases are seen in young children living in rural remote communities in coastal areas. A major campaign to eradicate yaws between 1953 and 1958, by mass treatment of affected communities with long-acting, injectable penicillin, reduced the number of cases by 95% in Papua New Guinea (PNG), but yaws has reappeared in recent years. In the period 2008- 2015 PNG reported >25,000 cases per year, and the country is currently home to about 40% of all the cases of yaws in the world. In 2012, one oral dose of azithromycin was shown to be as effective as intramuscular penicillin in the treatment of the disease, and the World Health Organization launched a new initiative to eradicate yaws by 2020. The new treatment policy recommends mass azithromycin treatment of the entire population in endemic areas. Continued vigilance for the development of macrolide resistance in T. pallidum ssp. pertenue will be important as the drug is introduced into public health practice.