ABSTRACT
Background: Convalescent 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. Methods: Two 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. Results: Of 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). Conclusion: Treatment 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. Registration: NCT04621123 and NCT04589949 on https://www.clinicaltrials.gov
Subject(s)
COVID-19 , Death , ConvalescenceABSTRACT
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 log 10 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%.
ABSTRACT
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. Research in context 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.
Subject(s)
COVID-19 , Mental Retardation, X-LinkedABSTRACT
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.