|Ahead of print publication
Return to work strategy with antibody-based tests in COVID19: An observational study from a metropolitan area, India
Sougat Ray1, Naveen Chawla2, Ayon Gupta3, Kiran Kumar Maramaraj4, Sanjeev Kumar5, Kavita B Anand6
1 Professor, Community Medicine & SSO (H), HQWNC, Mumbai, India
2 Professor, Pathology & CMO, HQWNC, Mumbai, India
3 PhD Scholar, Centre for Community Medicine, AIIMS, New Delhi, India
4 Associate Professor, Community Medicine, ACMS, New Delhi, India
5 PMO, HQWNC, Mumbai, India
6 Associate Professor, Microbiology, AFMC, Pune, India
|Date of Submission||13-Jul-2020|
|Date of Decision||31-Jul-2020|
|Date of Acceptance||04-Aug-2020|
|Date of Web Publication||09-Sep-2020|
Professor Pathology & CMO, HQWNC, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: The utility of antibody tests in policy making is limited to seroprevalence surveys. World Health Organisation has stated that recovered people have antibodies to SARS-CoV-2. Convalescent serum contains antibodies that can neutralize the virus in cell cultures and IgG is both a marker for viral exposure and an indicator of recovery. We undertook this study to report immune response as a return to work strategy in a containment zone of 757 adults from a working mens' hostel. Methodology: The individuals were divided into three cohorts. Cohort-A comprised of RTPCR confirmed cases, Cohort-B comprised of those who were admitted as suspects but were negative in Rt-PCR test and Cohort-C were those, who remained asymptomatic. We studied the clinical features and undertook a qualitative antibody test of all adult males from the hostel after transmission of the disease was assumed to be over in the containment zone. Result: Dry cough, sore throat and fever were the most common presenting symptoms. (Fig 1). On serology testing, 47/87 (54.04%) tested IgG positive from Cohort A and 25/74 (32.05%) individuals were IgG positive from Cohort B with a significant statistical difference (p<0.05). There were 176 (29.72%) individuals who were IgG positive from Cohort C (Table 1), who remained asymptomatic. We found the seroconversion rate to IgG to be 67.85% (19/28) in symptomatic confirmed cases [OR 2.50 (0.97-6.43)]. None of the subjects tested positive for IgM. Conclusion: We found around half of the confirmed cases to seroconvert to IgG and antibodies were not detected in the rest. The utility of the test in return to work decision is therefore, debatable. The study found almost 30% of the unconfirmed individuals to have seroconverted, indicating presence of asymptomatic transmission. Preventive measures of social distancing, wearing of masks alongwith well ventilated offices with adequate air exchange mechanisms would be the future strategy for work place functioning.
Keywords: Antibody testing, asymptomatic transmission, COVID, return to work, seroconversion
|How to cite this URL:|
Ray S, Chawla N, Gupta A, Maramaraj KK, Kumar S, Anand KB. Return to work strategy with antibody-based tests in COVID19: An observational study from a metropolitan area, India. J Mar Med Soc [Epub ahead of print] [cited 2020 Sep 19]. Available from: http://www.marinemedicalsociety.in/preprintarticle.asp?id=294579
| Background|| |
Human history is no stranger to the devastating effects of pandemics through the ages. From the Antonine plague of the 2nd century, the Black Death of the Middle Ages, the Spanish Flu of 1918 to the relatively recent pandemic flu outbreak in 2009, humans have found a way to deal with the direct and indirect consequences of widespread contagion and move on with their lives. Despite this lived experience, the ferocity of the COVID-19 onslaught caught the world unprepared. Epidemiologists have long feared the emergence of a highly contagious, virulent pathogen spread by the respiratory route. The characteristics of high infectivity via the respiratory route of the virus and presymptomatic or asymptomatic transmission to contacts in a highly globalized and interconnected world constituted the perfect storm, one which is still ravaging the world and looks set to do so in the short-to-medium term till the deployment of a safe and effective vaccine.
The lack of innate immunity to a novel coronavirus and unavailability of definitive treatment for COVID-19 meant that the nonpharmacological interventions of social distancing, mask wearing, and frequent handwashing coupled with widespread testing, contact tracing, and case isolation were the primary strategies available to decision-makers worldwide to contain the spread of COVID-19. “Lockdowns” were imposed by governments worldwide to ensure social distancing norms. India was quick to close its international borders and enforce an immediate lockdown, which the World Health Organization (WHO) praised as “tough and timely.” However, despite strictly enforcing a 10-week national lockdown, the spread of COVID-19 could not be completely contained, and since June 1, 2020, when the country started “unlocking” in phases, the virus has come roaring back. The economic consequences of further prolonging the lockdown were recognized as being unsustainable, and therefore, the country has entered a “new normal,” one in which we have to learn to live with the virus.
Restarting the economy in the post-COVID-19 world makes it incumbent on employers to devise “return to work” strategies which build confidence in a relatively risk-free return to work in the workforce. A common thread in many such strategies is the documentation of immunity based on past exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among workers and prioritizing their return to workplaces on the basis of these, “immunity passports” assuming that they are protected against reinfection.
Testing strategies to document recovery
The current gold standard for documenting presence or absence of SARS-COV-2 antigen is reverse transcription–polymerase chain reaction (RT-PCR)-based tests. However, concerns over false-negative results and positivity on RT-PCR during the convalescent period due to the mere presence of noninfective viral RNA have been raised. Moreover, the procedure is laborious, invasive, and the results are valid only at the time when the test is conducted, i.e., a negative test does not give any information about the immune status of the individual.
Antibody-based serological tests can play an important role in determining whether individuals were ever infected, even if the person remained asymptomatic. They detect past viral infection indirectly by measuring the host immune response to the virus. Immunoglobulin M (IgM) antibodies are indicators of recent or active infection, while IgG antibodies which develop later and persist longer indicate past infection and potential immunity from reinfection. However, immunity to reinfection based on the presence of circulating antibodies is yet to be established in the case of SARS-CoV-2. The added advantage of serological tests is that they are less invasive (fingerprick test) and the results are available rapidly. These characteristics make them the method of choice for screening large populations rapidly. The science behind antibody testing in SARS-CoV-2 is still developing., The WHO recommends the validation of available serological tests for SARS-CoV-2 in different situations so that public health policy decisions may be undertaken for effective disease control while restarting economic activities safely. This observational study carried out in all 757 adult male residents of a men's hostel in a building complex in a metropolitan area of Western India attempts to examine the utility of blood serology testing for antibodies to SARS-CoV-2 as a basis for a return to work strategies.
| Methods|| |
The study setting was a working men's hostel inside a building complex in a metropolitan area of Western India which reported COVID19 outbreak. Pursuant to local administrative orders, the building and the surrounding campus were declared a “containment zone” and ingress and egress were restricted. After confirmation of the first case, case finding by RT-PCR testing and contact tracing and case isolation were carried out by trained health workers as per the following case definitions: a suspect case was defined as a patient with acute respiratory illness (fever and at least one sign/symptom of respiratory disease [e.g., cough, shortness of breath]) and a history of residence in/travel from a country/area or territory reporting local transmission of COVID-19 disease or history of contact with confirmed case during the 14 days prior to symptom onset. High-risk contacts were defined as persons staying in the same close environment of a COVID-19 patient (including workplace, classroom, household or gatherings, and anyone in close proximity [within 3 ft]) of the confirmed case for >15 min without personal protective equipment. A confirmed case was defined as a person with laboratory confirmation of COVID-19 infection based on RT-PCR test results, irrespective of clinical signs and symptoms.
All confirmed cases were admitted in a dedicated COVID hospital, and suspect cases and contacts who tested negative on RT-PCR testing were asked to self-quarantine for 14 days. The confirmed cases were discharged from the hospital after two negative RT-PCR test results as per the extant policy. The clinical symptoms of the confirmed cases were recorded.
Subsequently, voluntary serological testing was carried out for 757 adult male residents after obtaining informed consent at the end of May 2020 and as per the ICMR guideline in vogue. The individuals were divided into three cohorts. The first cohort comprised confirmed cases and the second cohort comprised suspect cases or high-risk contacts who were found to be negative on RT-PCR testing. Asymptomatic cases who were never subjected to RT-PCR testing made up the third cohort. The serological tests were carried out on an average 40 days after the declaration of the building complex to be containment zone. This meant that the first cohort completed an average of 22 days after discharge from the hospital and the second cohort completed an average of 32 days after testing negative in RT-PCR. Venous blood samples were obtained at the laboratory and tests were carried out using StandardM Q COVID-19 IgM/IgG Duo Test, a rapid immunochromatography, qualitative assay, as per instructions of the manufacturer. The manufacturer SD BioSensor claimed combined sensitivity and specificity of 81.8% and 96.6%, respectively. Color change in the control line was regarded as a valid test. If a line was observed for IgM and/or IgG, the test was considered positive. Statistical analyses were performed using OpenEpi.
| Results|| |
We had 87 of the 757 (11.49%) male adults enrolled in this study to have tested positive for COVID-19 on RT-PCR. There were 28/87 (32.18%) symptomatic cases and 59 were asymptomatic in the first cohort of confirmed cases. The second cohort of high-risk contacts and suspects who tested negative on RT-PCR comprised 78/757 (10.30%) individuals [Figure 1]. The remaining study participants (592/757) were asymptomatic and remained untested. The distribution of symptoms among confirmed cases is depicted in [Figure 1]. Dry cough was the most common presenting symptom.
|Figure 1: Frequency of symptoms in COVID19 cases (confirmed by reverse transcription–polymerase chain reaction)|
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On serology testing, 47/87 (54.04%) tested IgG positive from the first cohort. In the second cohort, 25/78 (32.05%) individuals were IgG positive and 176 (29.72%) individuals from the third cohort were also found to be IgG positive [Table 1] and [Figure 2]. The odds of IgG positivity in the first cohort were statistically significant (odds ratio [OR] – 2.49, 95% confidence interval [C.I.]: 1.31–4.72, P = 0.002) as compared to the second cohort. The odds of positivity of IgG were also higher (OR – 2.50, 95% C.I: 0.97–6.43) in symptomatic individuals (19/28) among confirmed cases in the first cohort rather than asymptomatic ones (27/59), though this finding was not statistically significant. None of the subjects tested positive for IgM, possibly due to a lag of 3–4 weeks in antibody testing.
|Table 1: Distribution of antibody test serology in individuals as per the reverse transcriptase-polymerase chain reaction test result|
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|Figure 2: Laboratory results of a voluntary immunoglobulin G antibody estimation study in a containment zone|
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| Discussion|| |
Immunity to a viral pathogen via natural infection typically develops over 1–2 weeks and involves an initial nonspecific response consisting of recruitment of macrophages, neutrophils, and dendritic cells to arrest and clear the viral load, followed by an adaptive response in which specific antibodies bind to viral sites and inhibit replication. T-cell-mediated cellular immunity which recognizes and eliminates cells containing viral RNA copies is another facet of the adaptive response. The combined adaptive response may clear the viral load and, if sufficiently strong, may prevent progression to severe disease and reinfection. Measuring the presence of specific antibodies in the blood of individuals with viral exposure serves as an indicator of adequacy of this adaptive response. Demonstrable robust immunity postexposure to SARS-CoV-2 may help to undertake informed decisions on how and when to ease social distancing restrictions and to decide on a return to work strategies.,
The N and S proteins are the most immunogenic antigens found in SARS-CoV-2. Antibodies against the N protein are earlier to appear and antibodies against the S protein develop later. Although the extent of protective immunity afforded by SARS-CoV-2 antibodies is yet unknown, their presence in serum usually correlates well with antiviral immunity. IgG antibodies were found to have lasted for at least 1 year against SARS-CoV, the virus having high homogeneity with SARS-CoV 2. In our study, however, we found that only 47/87 (54.04%) of the individuals who tested positive for SARS-CoV-2 on RT-PCR had detectable levels of circulating IgG antibodies, after an average of 22 days of discharge from the hospital. The finding that nearly half of the study subjects who were confirmed as infected with SARS-CoV-2 on RT-PCR did not show the presence of IgG antibodies differs from that reported by Long et al. who found that 81.1% of asymptomatic confirmed cases and 83.8% of symptomatic cases had demonstrable levels of IgG approximately 3–4 weeks post infection. However, our results are comparable with a study carried out onboard the US Navy aircraft carrier USS Roosevelt, which reported an outbreak of COVID19, only 228/382 (59.7%) initially RT-PCR-positive individuals had a positive IgG ELISA result, 4–6 weeks post the duration of the outbreak onboard. The higher prevalence of IgG antibodies in 19 out of 28 symptomatic individuals (67.85%) in our study is in line with reported literature and can be explained by relatively higher level of immune system activation in symptomatic rather than asymptomatic cases.
Long et al. in a different study also reported their serological findings in a cluster of 164 close contacts of patients with known COVID-19, 30 days after exposure. There were 16 RT-PCR-confirmed cases and they were all positive for virus-specific IgG and/or IgM. Moreover, 7 of the 148 individuals who were negative for RT-PCR had positive virus-specific IgG and/or IgM, indicating that 4.3% (7/164) of the close contacts were missed by the nucleic acid test. We found a higher proportion (25/78, 32.05%) of individuals who had circulating IgG antibodies but tested negative on RT-PCR. This finding reiterates the importance of a high level of training competency for laboratory workers and health staff collecting nasopharyngeal samples for RT-PCR testing. Further, there were 176 (29.72%) asymptomatic individuals in the third cohort with detectable IgG antibodies, indicating high asymptomatic transmission in our cluster. This finding is similar to that onboard USS Roosevelt where a fifth of the infected personnel were found to be asymptomatic.
Studies in Wanzhou, China, have reported a rapid waning of anti-SARS-CoV-2 antibodies in the early convalescent period. This decay of antibodies is faster than that reported for SARS-CoV by Cao et al. and Javier Ibarrondo et al., who reported a half-life of 73 days for IgG antibodies to SARS-CoV-2 based on serial testing of antibodies from sera of 34 convalescent patients who had mild illness and concluded that humoral immunity against SARS-CoV-2 is not long lasting, especially in mild-to-moderate cases which constitute the majority of the caseload.
The relatively low levels of neutralizing antibodies in recovered individuals could indicate a potentially critical role for cell-mediated immunity in recovery. Higher prevalence of IgG antibodies in symptomatic cases correlates well with the T-cell response against the SARS-CoV-2 spike protein which can be explained by the inflammatory cytokine milieu observed only in symptomatic patients., Cell-mediated immunity mediated by T-cells and reactive memory B-cells may be critical in medium to long-term protection from reinfection. Further research is required to quantify the level of protection afforded by cell-mediated immunity given that humoral immunity is inconclusive both in terms of level as well as the duration of protection from reinfection. Apart from “immunity passports,” our findings also indicate caution in terms of interpretation of herd immunity and vaccine trial results. It was a cross-sectional one-time study, and therefore, the subjects were likely to be in different phases of seroconversion.
The antibody test carried out in our study was qualitative in nature and denoted the presence of circulating antibodies against SARS-CoV-2 nucleocapsid antigen. These antibodies must be capable of neutralizing the virusin vivo and establish a certain level of protective titer to be classified as protective antibodies, which can be estimated by COVID-19 IgG ELISA antibody test.
| Conclusion|| |
Of 757 residents, we found 54% of confirmed cases with demonstrable IgG antibodies. Antibodies were not detected in the rest, adding to the dilemma of understanding the utility of the test in return to work decisions. The study found almost 30% of asymptomatic individuals to have seroconverted, indicating presence of a high level of asymptomatic transmission in a containment zone. In this current pandemic, to counter the challenge of bringing back the new normal life activities, more research will be required for understanding seroconversion in COVID 19. Kits should undergo stringent quality control and evaluations of their performance to detect true seroconversion. The potential of antibody cross-reactivity with other human coronaviruses is also a possibility which needs to be evaluated to prevent false positives.
Reinfections with seasonal coronaviruses are known to occur in nature. However, the elapsed time between infections does not mean that the protective immunity lasted for the same period because the reinfection was also dependent on re-exposure. As of July 1, 2020, there is no evidence to suggest that recovered individuals with demonstrable antibodies are immune to subsequent reinfection. Covid-19 is essentially a new disease, and the study of viral dynamics and host immune response is still underway. The duration for which antibodies are present after seroconversion and whether these are protective also needs to be established before policy decisions can be made based on antibody testing. Basic administrative measures such as stratifying the workforce, reducing overcrowding, and mandating self-declaration for those who feel ill and work from home tools and environmental controls such as the use of physical and social distancing, use of masks and management of air exchange, and filtration in indoor air-conditioning systems will be the future strategy for workplace operationalization.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]