Healthcare workers are at increased risk of acquiring infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but also of passing it on to their patients. An especially high-risk patient population for COVID-19 consists of people with weakened immunity, such as those on immunosuppressive drugs or those with chronic kidney disease (CKD). Patients with kidney disease in need of dialysis or following a kidney transplant are very much at risk of death following COVID-19, with some studies showing a mortality rate of 27% to 31%.
The Study: Serologic Testing for Past COVID-19
A new study published in the preprint server medRxiv* in July 2020 reports that nephrology workers caring for patients with CKD are not consistently positive for the virus on antibody testing, unlike the results obtained with COVID-19 patients. The researchers turned to antibody testing to obtain evidence of past infection with the virus, rather than reverse transcriptase-polymerase chain reaction (RT PCR) which picks up acute infection.
The study aimed to detect the prevalence of the infection in this group. Prior research shows that all patients who are positive for the SARS-CoV-2 virus by RT PCR seroconvert to IgM and IgG antibodies within 3 weeks of symptom onset, either in sequence or simultaneously. However, the pattern of antibody development in asymptomatic workers is less clear. Thus, the researchers in the current study used different techniques to comprehensively examine the antibody response among healthcare workers in a tertiary hospital set up in Austria.
The study made use of ten commercially available tests to detect anti-SARS-CoV-2 IgG and IgM antibodies directed against the nucleocapsid (N) and spike (S) proteins of the virus, including enzyme-linked immunosorbent assays (ELISA), chemiluminescence immunoassay (CLIA), and electrochemiluminescence immunoassay (ECLIA).
The research had 235 participants, 11 of whom had contact with confirmed COVID-19 cases and 36 with potential cases (~5% and 15% respectively). About 40% had traveled either within or outside Austria. Over a quarter of them had a history of symptoms which might have been related to mild COVID-19, but the 19 who had been tested by PCR had a negative result. Overall, the study included 313 nasopharyngeal swabs from 179 individuals, accounting for over three-quarters of the group, all of which were negative.
The researchers considered that 60/235 participants had a borderline positive or positive antibody test, either IgM or IgG, by ELISA, with at least one of two tests being positive. Of these, 18 and 3 were positive for IgM and IgG respectively, while the rest were borderline positives.
At follow up, these 60 individuals were negative for PCR in nasopharyngeal swabs at 18 days from baseline, except for five who were not tested. Antibody testing resulted in 18 positives on follow up, of which 10 had anti-N IgG, and two had anti-S IgG, in one or both of two tests. Six individuals developed IgA antibodies to the virus in this period. Neutralizing antibodies were absent in all these cases. Overall, five of the 18 tested positive for IgG on both antibody tests, which comes to 2% of the whole cohort. Only one had a history of potentially related symptoms, however.
On comparing with a set of 5 samples from confirmed COVID-19 cases, all five were positive for antibodies in most of the tests, with four of five having neutralizing antibodies to the virus, while the fifth had the mildest symptoms.
Reasons for Low Seroprevalence
The successful use of containment strategies and high-quality medical care facilities would prevent exposure of healthcare workers at the institution where the study was carried out. Secondly, the baseline seroprevalence of anti-SARS-CoV-2 IgG among the study population was low, at about 2%. Finally, commercial ELISA and other serologic tests may be too insensitive for the detection of low levels of antibodies in individuals with an asymptomatic or mild infection or may pick up cross-reactive antibodies and yield false-positive results.
Prior research confirms that the use of anti-spike protein antibodies is more sensitive than those that detect the nucleocapsid protein, and IgG tests are more reliable than the IgM tests, especially when testing is carried out at a later time from symptom onset. Using both IgG and IgM proved to be more sensitive than either test alone. All tests were specific to up to 99% but had low positive predictive value.
The low antibody prevalence shows the success of the lockdown and other measures taken to prevent exposure risk for healthcare workers in hospital settings. However, only one of five patients with IgG positivity had symptoms possibly related to viral exposure, indicating an 80% asymptomatic infection rate among the total number of infections. This is in contrast to the 40% asymptomatic prevalence estimated so far. Even in China and the US, healthcare workers exposed to positive cases have a seroprevalence of 17% to 44%, though this figure is lower in other places.
However, the current study used multiple testing systems and an orthogonal workup to confirm positives and borderline positives in a follow-up serum sample tested by other methods. This could have increased the sensitivity and specificity of the results.
The lack of neutralizing antibodies in any study participant is another telling finding. In contrast, all of the confirmed COVID-19 cases had both IgM and IgG antibodies in two or more tests, and four had neutralizing antibodies.
Another factor to consider is the presence of cross-reactive antibodies and T cells against multiple SARS-CoV-2 antigens in healthy unexposed individuals. The different pattern of antibody response to N and S antigens in study participants and COVID-19 patients also points to the possibility that the inconsistent and weak antibody responses in the health workers in the study is due to cross-reaction rather than true seroconversion following SARS-CoV-2 infection.
The researchers comment, “Single antibody tests do not allow for correct detection of true seroconversion and have no acceptable sensitivity and/or specificity in largely asymptomatic and SARS-CoV-2 RT-PCR negative individuals.” This is an important suggestion in the face of the increasing tendency to rely on single antibody testing to estimate the seroprevalence of large populations of asymptomatic people.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.