Convalescent plasma for outpatients with early COVID-19 (preprint)

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

A Cost-Benefit Analysis of COVID-19 Vaccination in Catalonia (preprint)

(1) Background: in epidemiological terms, it has been possible to calculate the savings in health resources and the reduction in health effects of COVID vaccines. From the point of view of economic evaluation, some studies have estimated its cost-effectiveness with the vaccination showing highly favorable results, which in some cases is cost-saving; (2) Methods: a cost-benefit analysis of the vaccination campaign in the North Metropolitan Health Region (Catalonia). An epidemiological model based on observational data and before and after comparison is used. The information on the doses used and the resources assigned (conventional hospital beds, ICU, number of tests) has been extracted from administrative data from the largest Primary Care provider in the region (Catalan Institute of Health). A distinction is made between the social perspective and the health system; (3) Results: the costs of vaccination are estimated at 137 million euros (€48.05/dose administered). This figure is significantly lower than the positive impacts of the vaccination campaign, which are estimated at 470 million euros (€164/dose administered). Of these, 18% corresponds to the reduction of ICU discharges, 16% to the reduction in conventional hospital discharges, 5% to the reduction in PCR tests and 1% to the reduction of RAT tests. Monetization of deaths and cases with sequelae avoided account for 53% and 5% of total savings, respectively. The benefit/cost ratio is estimated at 3.4 from a social perspective and 1.2 from a health system perspective. The social benefits of vaccination are estimated at €116.67 per dose of vaccine given (€19.93 from the point of view of the health system); (4) Conclusions: the mass vaccination campaign against COVID is cost-saving. From a social perspective, most of these savings come from the monetization of the reduction in mortality and cases with sequelae, although the intervention is equally widely cost-effective from the point of view of the health system thanks to the reduction in the use of resources. It is concluded that, from an economic perspective, the vaccination campaign has high social returns.

Limited immune responses after three months of BNT162b2 vaccine in SARS-CoV-2 uninfected elders living in long-term care facilities (preprint)

Background SARS-CoV-2 vaccination is the most effective strategy to protect elders living in long-term care facilities (LTCF) against severe COVID-19, but primary vaccine responses are less effective in older adults. Here, we characterized the humoral responses following 3 months after mRNA/BNT162b2 vaccine in institutionalized elders. Methods Plasma levels of specific SARS-CoV-2 total IgG, IgM and IgA antibodies were measured before and 3 months after vaccination in elders living in LTCF. Neutralization capacity was assessed in a pseudovirus neutralization assay against WH1 (original) and B.1.617.2/Delta variants. A group of younger adults was used as reference group. Results Three months after vaccination, uninfected-elders presented reduced specific SARS-CoV-2 IgG levels and significantly lower neutralization capacity against the WH1 and Delta virus compared to vaccinated uninfected younger individuals. In contrast, COVID-19 recovered elders showed significantly higher specific SARS-CoV-2 IgG levels after vaccination than younger counterparts, while showing similar neutralization activity against WH1 virus and increased neutralization capacity against Delta variant. Despite previously infected elders elicit potent cross-reactive immune responses similarly to younger individuals, higher quantities of specific SARS-CoV-2 IgG antibodies are required to reach the same neutralization levels. Conclusions While hybrid immunity seems to be active in previously infected elders after three months from mRNA/BNT162b2 vaccination, humoral immune responses are diminished in COVID-19 uninfected vaccinated residents living in LTCF. These results suggests that a vaccine booster dose should be prioritized for this particularly vulnerable population. Word summary While previously infected and vaccinated elders living in LTCF had comparable neutralizing antibody levels to younger individuals, vaccinated uninfected-residents showed limited neutralization capacity against both original and delta variants. Hybrid immunity seems to be active in elders and can be relevant to design vaccine boosting campaigns.

A Cost-Benefit Analysis of the COVID-19 Asymptomatic Mass Testing Strategy in the North Metropolitan Area of Barcelona (preprint)

The epidemiological situation generated by COVID-19 has highlighted the importance of applying non-pharmacological measures. Among these, mass screening of the asymptomatic general population has been established as a priority strategy by carrying out diagnostic tests to limit the spread of the virus. In this article, we aim to evaluate the economic impact of mass COVID-19 screenings of an asymptomatic population through a Cost-Benefit Analysis based on the estimated total costs of mass screening versus health gains and associated health costs avoided. Excluding the value of monetized health, the Benefit-Cost ratio was estimated at approximately 0.45. However, if monetized health is included in the calculation, the ratio is close to 1.20. The monetization of health is the critical element that tips the scales in favour of the desirability of screening. Screenings with the highest return are those that maximize the percentage of positives detected.

Economic Analysis of the Impact of Mass Workplace COVID-19 Testing on Health and Healthcare Resource Savings: A Case Study of SEAT in Catalonia (preprint)

Background: The epidemiological situation generated by COVID-19 has cast into sharp relief the delicate balance between public health priorities and the economy, with businesses obliged to toe a line between employee health and continued production. In an effort to detect as many cases as possible, isolate contacts, cut transmission chains and limit the spread of the virus in the workplace, mass testing strategies have been implemented in both public health and industrial contexts to minimize the risk of disruption in activity.Objective: To evaluate the economic impact of mass workplace testing strategy as carried out by a large automotive company in Catalonia in terms of health and healthcare resource savings.Methodology: Analysis of health costs and impacts based on the estimation of mortality and morbidity avoided because of screening and the resulting savings in healthcare costs.Results: The economic impact of the mass workplace testing strategies (using both PCR and RAT tests) was approximately €10.44 per test performed or €5,575.49 per positive detected. 38% of this figure corresponds to savings derived from better use of health resources (hospital beds, ICU beds and follow-up of infected cases), while the remaining 62% corresponds to improved health rates due to avoided morbidity and mortality. In scenarios with higher positivity rates and a greater impact of the infection on health and the use of health resources, these results could be up to ten times higher (€130.24 per test performed or €69,565.59 per positive detected).Conclusion: In the context of COVID-19, preventive actions carried out by the private sector to safeguard industrial production also have concomitant public benefits in the form of savings in healthcare costs. Thus, governmental bodies need to recognize the value of implementing such strategies in private settings and facilitate them through, for example, subsidies.Funding Statement: This research received no external funding.Declaration of Interests: None declared.

Impact of Mass Workplace COVID-19 Rapid Testing on Health and Healthcare Resource Savings (preprint)

Background: The epidemiological situation generated by COVID-19 has cast into sharp relief the delicate balance between public health priorities and the economy, with businesses obliged to toe a line between employee health and continued production. In an effort to detect as many cases as possible, isolate contacts, cut transmission chains and limit the spread of the virus in the workplace, mass testing strategies have been implemented in both public health and industrial contexts to minimize the risk of disruption in activity. Objective: To evaluate the economic impact of mass workplace testing strategy as carried out by a large automotive company in Catalonia in terms of health and healthcare resource savings. Methodology: Analysis of health costs and impacts based on the estimation of mortality and morbidity avoided because of screening and the resulting savings in healthcare costs. Results: The economic impact of the mass workplace testing strategies (using both PCR and RAT tests) was approximately €10.44 per test performed or €5,575.49 per positive detected. 38% of this figure corresponds to savings derived from better use of health resources (hospital beds, ICU beds and follow-up of infected cases), while the remaining 62% corresponds to improved health rates due to avoided morbidity and mortality. In scenarios with higher positivity rates and a greater impact of the infection on health and the use of health resources, these results could be up to ten times higher (€130.24 per test performed or €69,565.59 per positive detected). Conclusion: In the context of COVID-19, preventive actions carried out by the private sector to safeguard industrial production also have concomitant public benefits in the form of savings in healthcare costs. Thus, governmental bodies need to recognize the value of implementing such strategies in private settings and facilitate them through, for example, subsidies.

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

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.

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

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.

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

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 (preprint)

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