How to stop the strictest lockdown conditions in Spain and put an end to the pandemic with a Spanish national testing strategy

Shortly after the WHO declared the COVID-19 outbreak a Pandemic, the Spanish government put the country under the highest level of alert and imposed a series of nationwide lockdown periods starting on March 14th with a recent easing of conditions.

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Authors:

Antonio Martínez-Lara1, M.Sc., Michelle L. Seth-Smith2, M.Sc., Santiago Munné2,3, Ph.D., Martín Varsavsky2, M.Sc., José A. Horcajadas2, Ph.D.

1 Pronacera Therapeutics, c/ Miró, 11. Olivares, 41804, Seville, Spain          
2 Overture Life, Avda. Europa, 4. Alcobendas, 28108, Madrid, Spain
3 Dept. Ob/Gyn, Yale University, New Haven, 06511, CT, USA


Shortly after the WHO declared the COVID-19 outbreak a Pandemic, the Spanish government put the country under the highest level of alert and imposed a series of nationwide lockdown periods starting on March 14th with a recent easing of conditions. The lockdown conditions have been widely publicized as the strictest in Europe and have severely limited utilization   of roads and public spaces with imposition of heavy fines.

The Spanish government has however been ranked in a Global Response and Leadership Index as the country that has managed the health crisis the worst (1). To date, Spain has 228,030 PCR confirmed cases* and total of 26,920 deaths* becoming one of the countries with the highest death rate per 100,000 inhabitants (2) and highest Case Fatality Rate of around 10%.

It is estimated that around 60% of the population would have to be immune to SARS-CoV-2 for the pandemic to be stopped. Extrapolating these data to Spain, with a population of 47 million, more than 28 million immunized individuals would be needed in order to break the current trend. Assuming that all the PCRs performed were utilized to only diagnose new patients, and with the current capacity of 47,000 PCRs per day, testing of 28 million would take 595 days to screen 60% of the population and more than 1,000 days to screen the whole country, which in view of the social and political considerations, is unrealistic.   

RT-PCR assays are recommended for diagnosis of SARS-CoV-2 infection to detect the presence of viral nucleic acids as this technique is able to detect 90% of cases after 8-14 days after onset of symptoms and 70% after 15-29 days (3). Although major viral dynamics in infected patients are still yet to be fully determined, a combination of PCR and direct viral antigen detection would be useful in order to fully understand the course of the infection. A recent study showed this dual detection strategy to have comparable results to PCR alone, resulting in a sensitivity of 98% and specificity of 100% (4). Furthermore, the strategy to detect individual serum antibodies, IgM and IgG rather than total antibodies, would further improve the understanding of the course of the infection.  Sensitivity of individual antibody detection has been shown to be greater than 90% at the 2nd week after the onset of symptoms (5). Although these three approaches would be complementary, they are not cost-effective for nationwide or rapid screening.

In the present communication, we wish to present, a cost-effective strategy for rapid and small scale screening using high quality commercially available rapid serology tests that will be of tremendous benefit to and other countries suffering from the onslaught of the pandemic.

We have evaluated all commercially available SARS-CoV-2 rapid serology tests using publications pooled from two platforms (FINDDx and COVID testing project) (6,7) to determine proven rapid test quality. We have based ours analysis on publications that contained test specificity and sensitivity data and disregarded the rest due to paucity of data. We provide our conclusions in Table 1, which ranks SARS-CoV-2 rapid serology test by a score, based on the number of tests performed and performance data. Tests have been classified into three groups in respect to “score”, built by calculating the arithmetic mean of sensitivity and specificity: providing a first score of over 90% (n=4), tests with scores a score ranging between 80-90% (n=12) and tests under 80% (n=8). It is surprising to see some tests receiving CE-IVD marketing authorization with a score lower than 65% and validation performed on only 32 patients (see Table 1).



Table 1: Test performance evaluation of SARS-CoV-2 serological assays. Data of 23 selected test containing specificity and sensitivity data, ranked by score. To screen the data on April 30th, 2,020, the registry consisted of 154 studies, with 37 tests described. Only sensitivity and specificity data are shown for 27 tests, of which 23 are for antibodies comprising a total 42 studies of validation. Sensitivity was calculated as the mean of the sum percent positivity by time interval (1-5 days, 6-10 days, 11-15 days, 16-20 days and > 20 days). Specificity was calculated as the mean of the sum percent positivity by kind of assay (IgM, IgG and IgM +/or IgG).

Because Fertility and Reproductive Medicine professional bodies have not published rapid SARS-CoV-2 test guidelines specific to Fertility Clinics, we present a simple guide comparing the performance of SARS-CoV-2 rapid serology tests to facilitate selecting the best quality tests in the market, for the benefit of OBGYN fertility centers.

This strategy would avoid redundant testing using low quality tests that will necessarily imply extra expenses deriving from repeated testing and further allowing Clinics to return to normal activities in the shortest possible time frame.

Gynecological and in vitro fertilization clinics and gamete banks should follow the recommendations of the local (ASEBIR and SEF in Spain) and international (ASRM, ESHRE and Red LARA) organizations in and out (WHO) of our field of reproduction. The guidelines of what to do (PCR, rapid tests or ELISA) and when to do (first visit, before oocyte retrieval, before transfer,…) should come from these organizations without allowing this disease make us entering in paranoia. Our objective with this analysis is simply to provide the possibility of comparing the performance of SARS-CoV-2 rapid serology tests in order to advise accordingly the scientific and medical community (specially IVF centers), but also to provide useful information to policy makers, public and private companies in support of their national deconfinement efforts.

*The number of cases and deaths have been updated to the date of May, 13th.


References:

1.     GRID Index: Tracking the Global Leadership Response in the COVID-19 Crisis. Institute of Certified Management Accounts (ICMA), April 14, 2020. https://www.cmawebline.org/ontarget/grid-index-tracking-the-global-leadership-response-in-the-covid-19-crisis/#_ftn10 

2.     Coronavirus Resource Center – John Hopkins University, 2020. https://coronavirus.jhu.edu/map.html

3.     Laboratory testing for 2019 novel coronavirus (2019-nCoV) in suspected human cases. Interim guidance. https://www.who.int/publications-detail/laboratory-testing-for-2019-novel-coronavirus-in-suspected-human-cases-20200117

4.     Diao B., Wen K. et al.Chen J., Liu Y., Yuan A., Han C., Chen J., Pan Y., Chen L., Dan Y., Wang J., Chen Y., Deng G., Zhou H., Wu Y.  Diagnosis of Acute Respiratory Syndrome Coronavirus 2 Infection by Detection of Nucleocapsid Protein. News in Proteomics Research, 12 Mar 2020.

https://www.medrxiv.org/content/10.1101/2020.03.07.20032524v2.full.pdf

5.     To W, Tsang T-Y, Leung W-S, Tam AR, Wu T-C, Lung DC, Yip C-Y, Cai J-P, Chan M-C, Chik S-H, Lau P-L, Choi Y-C, Chen L-L, Chan W-M, Chan K-H, Ip JD, Ng C-K, Poon W-S, Luo C-T, Cheng C-C, Chan F-W, Hung F-N, Chen Z, Chen H, Yuen K-W. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. News in Proteomics Research, 12 Mar 2020. https://www.thelancet.com/action/showPdf?pii=S1473-3099%2820%2930196-1

6.     Foundation for Innovative New Diagnostics (FINDDx). www.finddx.org

7.     The COVID testing project. https://covidtestingproject.org

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Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.

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