








key: cord-311633-i9ret7bw
authors: Péré, Hélène; Védie, Benoit; Vernet, Raphaël; Demory, Nathalie; Kassis, Najiby; Mirault, Tristan; Lazareth, Hélène; Volle, Geoffroy; Denoix, Elsa; Lebeaux, David; Podglajen, Isabelle; Bélec, Laurent; Veyer, David
title: Unexpected diagnosis of COVID-19-associated disorders by SARS-CoV-2-specific serology
date: 2020-08-04
journal: J Clin Virol
DOI: 10.1016/j.jcv.2020.104568
sha: 
doc_id: 311633
cord_uid: i9ret7bw

Facing the ongoing pandemic caused by SARS-CoV-2, there is an urgent need for serological assays identifying individuals with on-going infection as well as past coronavirus infectious disease 2019 (COVID-19). We herein evaluated the analytical performances of the CE IVD-labeled Abbott SARS-CoV-2 IgG assay (Des Plaines, IL, USA) carried out with the automated Abbott Architect™ i2000 platform at Hôpital Européen Georges Pompidou, Paris, France, using serum sample panels obtained from health-workers with COVID-19 history confirmed by positive nucleic acid amplification-based diagnosis and from patients randomly selected for whom serum samples were collected before the COVID-19 epidemic. The Abbott SARS-CoV-2 IgG assay showed sensitivity of 94% and specificity of 100%, demonstrating high analytical performances allowing convenient management of suspected on-going and past-infections. In addition, the SARS-CoV-2 IgG positivity rates were compared in COVID-19 positive and COVID-19 free areas from our hospital. Thus, the frequency of SARS-CoV-2-specific IgG was around 10-fold higher in COVID-19 areas than COVID-19 free areas (75% versus 8%; P < 0.001). Interestingly, several inpatients hospitalized in COVID-19 free areas suffering from a wide range of unexplained clinical features including cardiac, vascular, renal, metabolic and infectious disorders, were unexpectedly found seropositive for SARS-CoV-2 IgG by systematic routine serology, suggesting possible causal involvement of SARS-CoV-2 infection. Taken together, these observations highlight the potential interest of SARS-CoV-2-specific serology in the context of COVID-19 epidemic, especially to assess past SARS-CoV-2 infection as well as possible unexpected COVID-19-associated disorders.

Coronavirus disease 2019 caused by SARS-CoV-2 was declared by the World Health Organization (WHO) as global pandemic on March 11, 2020 [1] [2] [3] .

Controlling the outbreak in the community and in hospitals mainly relied on the availability and the sensitivity and specificity of RT-PCR testing [4, 5] . Rapidly, it was demonstrated that serological testing looking for specific SARS-CoV-2 IgG and/or IgM could increase the sensitivity of the diagnosis [6] [7] [8] [9] [10] . On March 2, 2020, the WHO recommended serological testing in addition to molecular diagnosis for the diagnosis of strongly suspected patients of SARS-CoV-2 infection with negative RT-PCR [11] .

At April, the Abbott SARS-CoV-2 IgG assay (Abbott GmbH, Rungis, France) received CE-IVD label and was installed on our automated i2000 platform (Abbott Architect™ i2000) at Hôpital Européen Georges Pompidou (HEGP). Our hospital, belonging to the Assistance Publique-Hôpitaux de Paris, which represents the largest group of university hospitals in Europe, has been organized since mid-March to attend to patients with COVID-19 related conditions (COVID-positive area) in distinct areas from the patients without COVID-19 related conditions (COVID-free area). To analytically and clinically validate the Abbott SARS-CoV-2 IgG assay, we tested pre-epidemic sera, sera from pauci-symptomatic health-worker with SARS-CoV-2 positive RT-PCR and sera from hospitalized patients from both the COVID-positive area and the COVID-free area. To date, few data are available on serology testing, focusing mainly on the time of seroconversion after the onset of symptoms and the neutralizing capability of the produced antibodies [9, 12, 13, 14] .

We herein report on lessons learned from our analytical and clinical validation of the Abbott SARS-CoV-2 IgG assay, including unexpected diagnosis of COVID-19 associated disorders by SARS-CoV-2-specific serology assay. Sensitivity was assessed using sera from hospital staff who had a history of positive SARS-CoV-2 RT-PCR at least one month before serology testing. Specimens were collected by occupational medicine.

Finally, sera were also obtained from patients attending the hospital during the pandemic period, in April 2020, either for COVID-19 related conditions in COVID-positive area of the hospital or for non-COVID-19 related conditions in COVID-free area, for further SARS-CoV-2 IgG serological testing. Abbott SARS-CoV-2 IgG assay sensitivity. Hundred sera collected from hospital healthworkers previously positive for SARS-CoV-2 RT-PCR were tested for SARS-CoV-2 IgG. In this group of health-workers, 69% were female and the median age was 34 (IQR=19.5 years) (Table 1) . Median delay between RT-PCR and serology was 39.5 days (IQR=9.25 days).

Ninety-four serum tested positive for SARS-CoV-2 IgG. The sensitivity of the Abbott SARS-

CoV-2 IgG assay was 94% (95% IC: 87%-98%) ( Table 1) The median age of the hospitalized patients was 60 years (IQR=25) and 31% of them were female. The difference between the demographic data (age and sex) within the health workers and the hospitalized patients were statistically significant (P=2.85x10 -17 and P=1.94x10 -8 , respectively) ( Table 1 ).

Out of the 63 patients hospitalized for COVID-19 related conditions that were tested for SARS-CoV2 IgG, 47 (74.6%) tested positive ( Table 1) Chest CT-scan findings were only suggestive of acute bronchitis. SARS-CoV-2 RT-PCR was negative again, while index value of SARS-CoV-2 IgG was 2.1.

To our knowledge, this is the second study assessing the analytical performances of the Abbott SARS-CoV-2 IgG assay, the first one with samples collected in Europe. In the first study, both specificity (99.9%) and sensitivity (100% after 17 days since the onset of symptoms) were excellent [14] . Our results confirmed the excellent specificity of the assay (100%) but our sensitivity results were not as good as expected, especially in the healthworker group (sensitivity=94%). Our results from the patients hospitalized for COVID-19

were more comparable to the ones observed in the study of Bryan et al. [14] . Indeed, the median delay before the detectability of SARS-CoV-2 IgG since the onset of symptoms was 17 days, as it has previously been described, and every tested patient after 20 days were positive. Various hypotheses could be given to explain this discrepancy between hospitalized patients and health-workers. Firstly, among health workers, only 2 were hospitalized and 98 J o u r n a l P r e -p r o o f were not hospitalized and had only little symptoms. Furthermore, the median ages as well as the sex ratio between these 2 groups were statistically different. Whether any of these factors (age, sex and symptoms) could be responsible for the relatively low sensitivity (94%) in our health workers group would need further investigations. One could also hypothesize that the sensitivity of the test might depend on the SARS-CoV-2 strain and that some specific antibodies might be not detected by the assay. Furthermore, out of the 6 health workers that tested negative with positive RT-PCR, only one had a very low index value at 0.1, all the others had at least an index value of 0.4, which could indicate that some antibodies are produced but are weakly detected. Among these 6 health-workers, one was tested for seroneutralizing antibodies in a research protocol context. He was positive with a low titer according to the technique (data not shown), which is in agreement with the fact that some antibodies are produced.

In our study, we took advantage of our hospital organization, which was structured in COVID-positive area and COVID-free area to test some patients from the COVID-free area.

IgG positivity in this area was 8.3% which is much higher when compared to the 1.79% described by Bryan et al [14] . This could be explained by the fact that our samples were collected by mid-April, at the time of the epidemic peak in France and that a greater percentage of the population had been exposed to the virus at this time. Nevertheless, these results confirmed that the organization in COVID-positive and COVID-free area was efficient as the IgG positivity was highly different between both sectors.

Finally, our work demonstrated that SARS-CoV-2 serology could be a useful tool to retrospectively diagnose COVID-19 infections with 8 cases of unexpected COVID-19 diagnosis in the COVID-19 free area. Clinical features of these 8 patients were in agreement with the wide variety of organs that could be affected by SARS-CoV-2 [15] [16] [17] [18] [19] . Indeed, 2 patients presented with nephropathy, 2 patients with cardiac symptoms, 2 patients with J o u r n a l P r e -p r o o f vascular symptoms, one patient with hyperglycemia and the last one with bacterial pneumonia. To our knowledge, this is the first study that underlines the retrospective clinical value of SARS-CoV-2 specific serology, especially when recent history of SARS-CoV-2 infection was not obvious. There is no doubt that generalizing the serology diagnosis would reveal unexpected SARS-CoV-2 infections associated with various organ disorders.

J o u r n a l P r e -p r o o f 

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