Comparison between mid-nasal swabs and buccal swabs for SARS-CoV-2 detection in mild COVID-19 patients

BackgroundThe use of rapid antigen diagnostics tests (Ag-RDT) has gained widespread acceptance as an alternative method for diagnosis of COVID-19 outside of health care settings. Various authors have reported that saliva is a reliable specimen, alternative to nasopharyngeal and mid-nasal swabs, to detect SARS-CoV-2 infections by RT-PCR. We assessed the performance of buccal swabs containing saliva for SARS-CoV-2 detection by Ag-RDT, using mid-nasal specimens as a reference in the northern area of Barcelona (Catalonia, Spain) MethodsIn the context of routine clinical diagnosis of mild COVID-19 patients, we enrolled 300 adults in a study to directly compare mid-nasal swabs and saliva specimens for SARS-CoV-2 detection by Ag-RDT.. When mid-nasal and buccal Ag-RDTs showed discordant results, a third mid-nasal swab was collected and analysed by RT-PCR. ResultsPaired samples were successfully obtained in 300 suspected cases of SARS-CoV-2 infection. Of the 300 paired samples, Ag-RDT with the mid-nasal swab detected 139 (46.3%) positive COVID-19 cases. In comparison, buccal swabs showed a sensitivity and specificity of 31.7% (44/139) and 98.8% (159/161), respectively. 65 discordant results with positive mid-nasal swabs and negative buccal swabs were tested by RT-qPCR. All samples tested by Rt-PCR resulted positive, with a mean cycle threshold (Ct) of 28.3 (SD 7.3). ConclusionOur findings show that mid-nasal swabs have better performance than buccal swabs for detecting SARS-CoV-2 with Ag-RDT tests. Of note, the sensitivity of buccal samples was affected in samples with high viral loads (Ct<33), suggesting that buccal swabs might not be sensitive enough to detect individuals at risk of transmission. Taken together, the existing literature and the results provided in our analysis we advise against the use of buccal specimens for SARS-CoV-2 diagnostics with Ag-RDT.

Cross-sectional study to assess the efficacy of SARS-CoV-2 vaccination in patients with monoclonal gammopathies

SARS-CoV-2 vaccination is the most effective strategy to protect patients with haematologic malignancies against severe COVID-19, but primary vaccine responses are less effective in this population. Here, we characterized the humoral responses following 3 months after mRNA-based vaccines in patients at different stages of the same plasma cell diseases, including monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and multiple myeloma on first line therapy (MM), compared to a healthy control population matched by sex and age. We observed that plasmas from uninfected MM patients after 3 months post-vaccine have lower SARS-CoV-2 specific IgG and IgA antibodies and decreased neutralization capacity compared with MGUS and SMM individuals, and a group of healthy controls. Importantly, we detected significantly higher plasma neutralization capacity in MM individuals who recovered from COVID-19 compared to their uninfected counterparts, highlighting that hybrid immunity elicit stronger immune responses even in this immunocompromised population. In contrast to MM group, no differences in the vaccine-induced humoral response were observed between uninfected MGUS, SMM and healthy individuals. In conclusion, a booster vaccine dose is recommended in uninfected MM patients to develop an adequate and effective humoral response to SARS-CoV-2 vaccine.

Evaluation of a support system for health professionals confined by COVID-19.

OBJECTIVE: To evaluate the implementation of a telephone system in a department of Primary Care in Barcelona, Spain, supporting health professionals confined by COVID-19. METHODS: We conducted an observational, descriptive, cross-sectional study with confined professionals, between March 11 and May 31, 2020. We emailed a questionnaire with 18 closed-ended questions and one open-ended question and performed a descriptive analysis of the closed-ended answers and an analysis of the thematic content of the open-ended question. RESULTS: Thirty-nine hundred and ninety-eight professionals evaluated the system overall with a score of 6.54 on a scale of 1 to 10. The evaluation of the format of calls made in the support system had higher scores, while the psychological support unit and the coordination of the different groups had lower scores. The content analysis of the open-ended question provides explanatory arguments for the quantitative results. CONCLUSIONS: The study allowed a valid and reliable evaluation of the implementation of a support system for confined professionals, in addition to recognizing areas for improvement.

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

BackgroundSARS-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. MethodsPlasma 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. ResultsThree 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. ConclusionsWhile 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 summaryWhile 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.

Antibody kinetics to SARS-CoV-2 at 13.5 months, by disease severity

BackgroundUnderstanding humoral responses and seroprevalence in SARS-CoV-2 infection is essential for guiding vaccination strategies in both infected and uninfected individuals. MethodsWe determine the kinetics of IgM against the nucleocapsid (N) and IgG against the spike (S) and N proteins of SARS-CoV-2 in a cohort of 860 health professionals (healthy and infected) in northern Barcelona. We model the kinetics of IgG and IgM at nine time points over 13.5 months from infection, using non-linear mixed models by sex and clinical disease severity. ResultsOf the 781 participants who were followed up, 478 (61.2%) became infected with SARS-CoV-2. Significant differences were found for the three antibodies by disease severity and sex. At day 270 after diagnosis, median IgM(N) levels were already below the positivity threshold in patients with asymptomatic and mild-moderate disease, while IgG(N, S) levels remained positive to days 360 and 270, respectively. Kinetic modelling showed a general rise in both IgM(N) and IgG(N) levels up to day 30, followed by a decay whose rate depended on disease severity. IgG(S) levels increased at day 15 and remained relatively constant over time. ConclusionsWe describe kinetic models of IgM(N) and IgG(N, S) SARS-CoV-2 antibodies at 13.5 months from infection and disease spectrum. Our analyses delineate differences in the kinetics of IgM and IgG over a year and differences in the levels of IgM and IgG as early as 15 days from symptoms onset in severe cases. These results can inform public health policies around vaccination criteria. Funded by the regional Ministry of Health of the Generalitat de Catalunya (Call COVID19-PoC SLT16_04; NCT04885478)

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.

Evaluation of a support system for health professionals confined by COVID-19 / Evaluación de un circuito de apoyo a profesionales sanitarios confinados por COVID-19

ABSTRACT OBJECTIVE To evaluate the implementation of a telephone system in a department of Primary Care in Barcelona, Spain, supporting health professionals confined by COVID-19. METHODS We conducted an observational, descriptive, cross-sectional study with confined professionals, between March 11 and May 31, 2020. We emailed a questionnaire with 18 closed-ended questions and one open-ended question and performed a descriptive analysis of the closed-ended answers and an analysis of the thematic content of the open-ended question. RESULTS Thirty-nine hundred and ninety-eight professionals evaluated the system overall with a score of 6.54 on a scale of 1 to 10. The evaluation of the format of calls made in the support system had higher scores, while the psychological support unit and the coordination of the different groups had lower scores. The content analysis of the open-ended question provides explanatory arguments for the quantitative results. CONCLUSIONS The study allowed a valid and reliable evaluation of the implementation of a support system for confined professionals, in addition to recognizing areas for improvement.

RESUMEN OBJETIVOS Evaluar la implementación de un circuito telefónico de apoyo a profesionales sanitarios confinados por COVID-19 en una dirección de Atención Primaria de Barcelona, en España. MÉTODOS Estudio observacional, descriptivo y transversal, realizado con profesionales confinados en domicilio entre el 11 de marzo y el 31 de mayo de 2020. Se envió por correo electrónico un cuestionario con 18 preguntas cerradas y una abierta. Se realizó un análisis descriptivo de las respuestas cerradas y un análisis del contenido temático de la pregunta abierta. RESULTADOS 398 profesionales puntuaron globalmente el circuito con 6,54 en una escala de 1 a 10. El formato de las llamadas realizadas en el circuito de apoyo se estimó con las puntuaciones máximas, la unidad de apoyo psicológico y la coordinación por diferentes colectivos se evaluaron con las puntuaciones más bajas. El análisis del contenido de la pregunta abierta ofrece argumentos explicativos de los resultados cuantitativos. CONCLUSIONES El estudio permitió evaluar de manera válida y fiable la implementación de un circuito de apoyo a profesionales confinados, además de reconocer áreas de mejora.

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.

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