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      BCG vaccine protection from severe coronavirus disease 2019 (COVID-19)

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          Significance

          The COVID-19 pandemic is one of the most devastating in recent history. The bacillus Calmette−Guérin (BCG) vaccine against tuberculosis also confers broad protection against other infectious diseases, and it has been proposed that it could reduce the severity of COVID-19. This epidemiological study assessed the global linkage between BCG vaccination and COVID-19 mortality. Signals of BCG vaccination effect on COVID-19 mortality are influenced by social, economic, and demographic differences between countries. After mitigating multiple confounding factors, several significant associations between BCG vaccination and reduced COVID-19 deaths were observed. This study highlights the need for mechanistic studies behind the effect of BCG vaccination on COVID-19, and for clinical evaluation of the effectiveness of BCG vaccination to protect from severe COVID-19.

          Abstract

          A series of epidemiological explorations has suggested a negative association between national bacillus Calmette–Guérin (BCG) vaccination policy and the prevalence and mortality of coronavirus disease 2019 (COVID-19). However, these comparisons are difficult to validate due to broad differences between countries such as socioeconomic status, demographic structure, rural vs. urban settings, time of arrival of the pandemic, number of diagnostic tests and criteria for testing, and national control strategies to limit the spread of COVID-19. We review evidence for a potential biological basis of BCG cross-protection from severe COVID-19, and refine the epidemiological analysis to mitigate effects of potentially confounding factors (e.g., stage of the COVID-19 epidemic, development, rurality, population density, and age structure). A strong correlation between the BCG index, an estimation of the degree of universal BCG vaccination deployment in a country, and COVID-19 mortality in different socially similar European countries was observed ( r 2 = 0.88; P = 8 × 10 −7), indicating that every 10% increase in the BCG index was associated with a 10.4% reduction in COVID-19 mortality. Results fail to confirm the null hypothesis of no association between BCG vaccination and COVID-19 mortality, and suggest that BCG could have a protective effect. Nevertheless, the analyses are restricted to coarse-scale signals and should be considered with caution. BCG vaccination clinical trials are required to corroborate the patterns detected here, and to establish causality between BCG vaccination and protection from severe COVID-19. Public health implications of a plausible BCG cross-protection from severe COVID-19 are discussed.

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          An interactive web-based dashboard to track COVID-19 in real time

          In December, 2019, a local outbreak of pneumonia of initially unknown cause was detected in Wuhan (Hubei, China), and was quickly determined to be caused by a novel coronavirus, 1 namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The outbreak has since spread to every province of mainland China as well as 27 other countries and regions, with more than 70 000 confirmed cases as of Feb 17, 2020. 2 In response to this ongoing public health emergency, we developed an online interactive dashboard, hosted by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University, Baltimore, MD, USA, to visualise and track reported cases of coronavirus disease 2019 (COVID-19) in real time. The dashboard, first shared publicly on Jan 22, illustrates the location and number of confirmed COVID-19 cases, deaths, and recoveries for all affected countries. It was developed to provide researchers, public health authorities, and the general public with a user-friendly tool to track the outbreak as it unfolds. All data collected and displayed are made freely available, initially through Google Sheets and now through a GitHub repository, along with the feature layers of the dashboard, which are now included in the Esri Living Atlas. The dashboard reports cases at the province level in China; at the city level in the USA, Australia, and Canada; and at the country level otherwise. During Jan 22–31, all data collection and processing were done manually, and updates were typically done twice a day, morning and night (US Eastern Time). As the outbreak evolved, the manual reporting process became unsustainable; therefore, on Feb 1, we adopted a semi-automated living data stream strategy. Our primary data source is DXY, an online platform run by members of the Chinese medical community, which aggregates local media and government reports to provide cumulative totals of COVID-19 cases in near real time at the province level in China and at the country level otherwise. Every 15 min, the cumulative case counts are updated from DXY for all provinces in China and for other affected countries and regions. For countries and regions outside mainland China (including Hong Kong, Macau, and Taiwan), we found DXY cumulative case counts to frequently lag behind other sources; we therefore manually update these case numbers throughout the day when new cases are identified. To identify new cases, we monitor various Twitter feeds, online news services, and direct communication sent through the dashboard. Before manually updating the dashboard, we confirm the case numbers with regional and local health departments, including the respective centres for disease control and prevention (CDC) of China, Taiwan, and Europe, the Hong Kong Department of Health, the Macau Government, and WHO, as well as city-level and state-level health authorities. For city-level case reports in the USA, Australia, and Canada, which we began reporting on Feb 1, we rely on the US CDC, the government of Canada, the Australian Government Department of Health, and various state or territory health authorities. All manual updates (for countries and regions outside mainland China) are coordinated by a team at Johns Hopkins University. The case data reported on the dashboard aligns with the daily Chinese CDC 3 and WHO situation reports 2 for within and outside of mainland China, respectively (figure ). Furthermore, the dashboard is particularly effective at capturing the timing of the first reported case of COVID-19 in new countries or regions (appendix). With the exception of Australia, Hong Kong, and Italy, the CSSE at Johns Hopkins University has reported newly infected countries ahead of WHO, with Hong Kong and Italy reported within hours of the corresponding WHO situation report. Figure Comparison of COVID-19 case reporting from different sources Daily cumulative case numbers (starting Jan 22, 2020) reported by the Johns Hopkins University Center for Systems Science and Engineering (CSSE), WHO situation reports, and the Chinese Center for Disease Control and Prevention (Chinese CDC) for within (A) and outside (B) mainland China. Given the popularity and impact of the dashboard to date, we plan to continue hosting and managing the tool throughout the entirety of the COVID-19 outbreak and to build out its capabilities to establish a standing tool to monitor and report on future outbreaks. We believe our efforts are crucial to help inform modelling efforts and control measures during the earliest stages of the outbreak.
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            The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application

            Background: A novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in China in December 2019. There is limited support for many of its key epidemiologic features, including the incubation period for clinical disease (coronavirus disease 2019 [COVID-19]), which has important implications for surveillance and control activities. Objective: To estimate the length of the incubation period of COVID-19 and describe its public health implications. Design: Pooled analysis of confirmed COVID-19 cases reported between 4 January 2020 and 24 February 2020. Setting: News reports and press releases from 50 provinces, regions, and countries outside Wuhan, Hubei province, China. Participants: Persons with confirmed SARS-CoV-2 infection outside Hubei province, China. Measurements: Patient demographic characteristics and dates and times of possible exposure, symptom onset, fever onset, and hospitalization. Results: There were 181 confirmed cases with identifiable exposure and symptom onset windows to estimate the incubation period of COVID-19. The median incubation period was estimated to be 5.1 days (95% CI, 4.5 to 5.8 days), and 97.5% of those who develop symptoms will do so within 11.5 days (CI, 8.2 to 15.6 days) of infection. These estimates imply that, under conservative assumptions, 101 out of every 10 000 cases (99th percentile, 482) will develop symptoms after 14 days of active monitoring or quarantine. Limitation: Publicly reported cases may overrepresent severe cases, the incubation period for which may differ from that of mild cases. Conclusion: This work provides additional evidence for a median incubation period for COVID-19 of approximately 5 days, similar to SARS. Our results support current proposals for the length of quarantine or active monitoring of persons potentially exposed to SARS-CoV-2, although longer monitoring periods might be justified in extreme cases. Primary Funding Source: U.S. Centers for Disease Control and Prevention, National Institute of Allergy and Infectious Diseases, National Institute of General Medical Sciences, and Alexander von Humboldt Foundation.
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              Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR

              Summary In a series of 51 patients with chest CT and RT-PCR assay performed within 3 days, the sensitivity of CT for COVID-19 infection was 98% compared to RT-PCR sensitivity of 71% (p<.001). Introduction In December 2019, an outbreak of unexplained pneumonia in Wuhan [1] was caused by a new coronavirus infection named COVID-19 (Corona Virus Disease 2019). Noncontrast chest CT may be considered for early diagnosis of viral disease, although viral nucleic acid detection using real-time polymerase chain reaction (RT-PCR) remains the standard of reference. Chung et al. reported that chest CT may be negative for viral pneumonia of COVID-19 [2] at initial presentation (3/21 patients). Recently, Xie reported 5/167 (3%) patients who had negative RT-PCR for COVID-19 at initial presentation despite chest CT findings typical of viral pneumonia [3]. The purpose of this study was to compare the sensitivity of chest CT and viral nucleic acid assay at initial patient presentation. Materials and Methods The retrospective analysis was approved by institutional review board and patient consent was waived. Patients at Taizhou Enze Medical Center (Group) Enze Hospital were evaluated from January 19, 2020 to February 4, 2020. During this period, chest CT and RT-PCR (Shanghai ZJ Bio-Tech Co, Ltd, Shanghai, China) was performed for consecutive patients who presented with a history of 1) travel or residential history in Wuhan or local endemic areas or contact with individuals with individuals with fever or respiratory symptoms from these areas within 14 days and 2) had fever or acute respiratory symptoms of unknown cause. In the case of an initial negative RT-PCR test, repeat testing was performed at intervals of 1 day or more. Of these patients, we included all patients who had both noncontrast chest CT scan (slice thickness, 5mm) and RT-PCR testing within an interval of 3 days or less and who had an eventual confirmed diagnosis of COVID-19 infection by RT-PCR testing (Figure 1). Typical and atypical chest CT findings were recorded according to CT features previously described for COVD-19 (4,5). The detection rate of COVID-19 infection based on the initial chest CT and RT-PCR was compared. Statistical analysis was performed using McNemar Chi-squared test with significance at the p <.05 level. Figure 1: Flowchart for patient inclusion. Results 51 patients (29 men and 22 women) were included with median age of 45 (interquartile range, 39- 55) years. All patients had throat swab (45 patients) or sputum samples (6 patients) followed by one or more RT-PCR assays. The average time from initial disease onset to CT was 3 +/- 3 days; the average time from initial disease onset to RT-PCR testing was 3 +/- 3 days. 36/51 patients had initial positive RT-PCR for COVID-19. 12/51 patients had COVID-19 confirmed by two RT-PCR nucleic acid tests (1 to 2 days), 2 patients by three tests (2-5 days) and 1 patient by four tests (7 days) after initial onset. 50/51 (98%) patients had evidence of abnormal CT compatible with viral pneumonia at baseline while one patient had a normal CT. Of 50 patients with abnormal CT, 36 (72%) had typical CT manifestations (e.g. peripheral, subpleural ground glass opacities, often in the lower lobes (Figure 2) and 14 (28%) had atypical CT manifestations (Figure 3) [2]. In this patient sample, difference in detection rate for initial CT (50/51 [98%, 95% CI 90-100%]) patients was greater than first RT-PCR (36/51 [71%, 95%CI 56-83%]) patients (p<.001). Figure 2a: Examples of typical chest CT findings compatible with COVID-19 pneumonia in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 74 years old with fever and cough for 5 days. Axial chest CT shows bilateral subpleural ground glass opacities (GGO). B, female, 55 years old, with fever and cough for 7 days. Axial chest CT shows extensive bilateral ground glass opacities and consolidation; C, male, 43 years old, presenting with fever and cough for 1 week. Axial chest CT shows small bilateral areas of peripheral GGO with minimal consolidation; D, female, 43 years old presenting with fever with cough for 5 days. Axial chest CT shows a right lung region of peripheral consolidation. Figure 2b: Examples of typical chest CT findings compatible with COVID-19 pneumonia in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 74 years old with fever and cough for 5 days. Axial chest CT shows bilateral subpleural ground glass opacities (GGO). B, female, 55 years old, with fever and cough for 7 days. Axial chest CT shows extensive bilateral ground glass opacities and consolidation; C, male, 43 years old, presenting with fever and cough for 1 week. Axial chest CT shows small bilateral areas of peripheral GGO with minimal consolidation; D, female, 43 years old presenting with fever with cough for 5 days. Axial chest CT shows a right lung region of peripheral consolidation. Figure 2c: Examples of typical chest CT findings compatible with COVID-19 pneumonia in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 74 years old with fever and cough for 5 days. Axial chest CT shows bilateral subpleural ground glass opacities (GGO). B, female, 55 years old, with fever and cough for 7 days. Axial chest CT shows extensive bilateral ground glass opacities and consolidation; C, male, 43 years old, presenting with fever and cough for 1 week. Axial chest CT shows small bilateral areas of peripheral GGO with minimal consolidation; D, female, 43 years old presenting with fever with cough for 5 days. Axial chest CT shows a right lung region of peripheral consolidation. Figure 2d: Examples of typical chest CT findings compatible with COVID-19 pneumonia in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 74 years old with fever and cough for 5 days. Axial chest CT shows bilateral subpleural ground glass opacities (GGO). B, female, 55 years old, with fever and cough for 7 days. Axial chest CT shows extensive bilateral ground glass opacities and consolidation; C, male, 43 years old, presenting with fever and cough for 1 week. Axial chest CT shows small bilateral areas of peripheral GGO with minimal consolidation; D, female, 43 years old presenting with fever with cough for 5 days. Axial chest CT shows a right lung region of peripheral consolidation. Figure 3a: Examples of chest CT findings less commonly reported in COVID-19 infection (atypical) in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 36 years old with cough for 3 days. Axial chest CT shows a small focal and central ground glass opacity (GGO) in the right upper lobe; B, female, 40 years old. Axial chest CT shows small peripheral linear opacities bilaterally. C, male, 38 years old. Axial chest CT shows a GGO in the central left lower lobe; D, male, 31 years old with fever for 1 day. Axial chest CT shows a linear opacity in the left lower lateral mid lung. Figure 3b: Examples of chest CT findings less commonly reported in COVID-19 infection (atypical) in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 36 years old with cough for 3 days. Axial chest CT shows a small focal and central ground glass opacity (GGO) in the right upper lobe; B, female, 40 years old. Axial chest CT shows small peripheral linear opacities bilaterally. C, male, 38 years old. Axial chest CT shows a GGO in the central left lower lobe; D, male, 31 years old with fever for 1 day. Axial chest CT shows a linear opacity in the left lower lateral mid lung. Figure 3c: Examples of chest CT findings less commonly reported in COVID-19 infection (atypical) in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 36 years old with cough for 3 days. Axial chest CT shows a small focal and central ground glass opacity (GGO) in the right upper lobe; B, female, 40 years old. Axial chest CT shows small peripheral linear opacities bilaterally. C, male, 38 years old. Axial chest CT shows a GGO in the central left lower lobe; D, male, 31 years old with fever for 1 day. Axial chest CT shows a linear opacity in the left lower lateral mid lung. Figure 3d: Examples of chest CT findings less commonly reported in COVID-19 infection (atypical) in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 36 years old with cough for 3 days. Axial chest CT shows a small focal and central ground glass opacity (GGO) in the right upper lobe; B, female, 40 years old. Axial chest CT shows small peripheral linear opacities bilaterally. C, male, 38 years old. Axial chest CT shows a GGO in the central left lower lobe; D, male, 31 years old with fever for 1 day. Axial chest CT shows a linear opacity in the left lower lateral mid lung. Discussion In our series, the sensitivity of chest CT was greater than that of RT-PCR (98% vs 71%, respectively, p<.001). The reasons for the low efficiency of viral nucleic acid detection may include: 1) immature development of nucleic acid detection technology; 2) variation in detection rate from different manufacturers; 3) low patient viral load; or 4) improper clinical sampling. The reasons for the relatively lower RT-PCR detection rate in our sample compared to a prior report are unknown (3). Our results support the use of chest CT for screening for COVD-19 for patients with clinical and epidemiologic features compatible with COVID-19 infection particularly when RT-PCR testing is negative.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                28 July 2020
                9 July 2020
                9 July 2020
                : 117
                : 30
                : 17720-17726
                Affiliations
                [1] aDepartment of Fish and Wildlife Conservation, Virginia Polytechnic Institute and State University , Blacksburg, VA 24601;
                [2] bLaboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892
                Author notes
                1To whom correspondence may be addressed. Email: escobar1@ 123456vt.edu or cbarillas@ 123456niaid.nih.gov .

                Contributed by Carolina Barillas-Mury, June 9, 2020 (sent for review May 1, 2020; reviewed by Serap Aksoy and Rita R. Colwell)

                Author contributions: L.E.E., A.M.-C., and C.B.-M. designed research; L.E.E., A.M.-C., and C.B.-M. performed research; L.E.E. and A.M.-C. contributed new reagents/analytic tools; L.E.E., A.M.-C., and C.B.-M. analyzed data; L.E.E. and C.B.-M. wrote the paper; and A.M.-C. compiled epidemiological information from many different sources.

                Reviewers: S.A., Yale University; and R.R.C., University of Maryland, College Park.

                Author information
                https://orcid.org/0000-0001-5137-4836
                Article
                202008410
                10.1073/pnas.2008410117
                7395502
                32647056
                3378c915-8b33-409c-bf4b-140515353723
                Copyright © 2020 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

                History
                Page count
                Pages: 7
                Funding
                Funded by: HHS | National Institutes of Health (NIH) 100000002
                Award ID: Z01AI000947
                Award Recipient : Alvaro Molina-Cruz Award Recipient : Carolina Barillas-Mury
                Funded by: VT | Institute for Critical Technologies and Applied Science, Virginia Tech (ICTAS) 100011501
                Award ID: Start up funds
                Award Recipient : Luis E. Escobar
                Categories
                530
                Biological Sciences
                Applied Biological Sciences
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                bcg vaccination policy,covid-19 coronavirus,cross-protection,mortality,pandemic

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