Nine months into the COVID-19 pandemic, scientists are still seeking to understand the protective immunity that develops against the causative agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite the increasing need for serological tests in epidemiology, their clinical value has not been fully established. A new paper published in the Journal of Medical Virology in September 2020 describes the relationship of COVID-19 disease symptoms with the serological status over time.
Assessing Seroconversion Status
The researchers from the University of Tokyo and Osaka City University performed a retrospective analysis of all patients who had a positive COVID-19 test, that is, by transcription-polymerase chain reaction (RT-PCR) using nasopharyngeal swabs. The study period was between March 1 and May 15, 2020.
They then picked out the patients who were hospitalized and who had a fever, and who had been serologically tested two or more times. The researchers excluded patients with immunodeficiency diseases since this could weaken the antibody response and thus dilute the test results. There were 18 patients in the final cohort.
All patients had mild to moderate disease, none required intubation, and all were discharged home within four weeks. The median patient age was 52 years, and 77% were males. The most common comorbidities were hypertension, dyslipidemia, and asthma, with the first having the greatest frequency.
The serum samples were assessed for IgM and IgG antibodies against the spike protein, using semi-quantitative immunofluorescence kits. The median test interval between successive tests was nine days.
Seroconversion in Defervescence
They found that seroconversion, which was defined as the first day on which a serological test returned a positive result, occurred only after the phase in which fever was present. All patients showed Immunoglobulin G (IgG) antibodies, except for one. All of the IgG-positive patients seroconverted after the fever resolved, except for one. Thus, 17/18 patients had IgG antibodies against the S protein at a median duration of 15 days from the onset of symptoms.
Almost the same number, that is, 16/18, developed Immunoglobulin M (IgM) antibodies at about the same median interval, and all except one experienced seroconversion only after they became afebrile. The sole case in which fever persisted after antibody development was attributed to the presence of pulmonary embolism, especially since the RT PCR had reverted to negative at the time. For all other cases, the RT PCR became negative, indicating viral clearance, only after or along with seroconversion.
In two patients who also had impairment in lung oxygenation, and anosmia or ageusia, seroconversion occurred after the fever went down. This shows that in all cases, seroconversion is associated with convalescence in patients who have uncomplicated non-critical COVID-19. This agrees with the findings of earlier studies on viruses like the dengue virus.
Implications
The importance of the current study lies firstly in its implications that serological tests are often negative in the early phase or symptomatic stage of COVID-19, and thus probably lack diagnostic value. This does not support the findings of the Infectious Disease Society of America (2020), which notes that antibody testing may be useful to pick up patients with COVID-19 symptoms but return a negative RT PCR.
Secondly, the occurrence of seroconversion is probably linked to a non-infectious stage of the infection. An earlier observational study showed that COVID-19 could be transmitted on or before the onset of symptoms, while later on, a week afterward, the patient was likely to be less contagious. In the current study, IgG antibodies formed after ten or more days from the earliest symptom, and after the resolution of fever. This affirms the validity of the guidelines put forward by the US Centers for Disease Control and Prevention (CDC), that anti-infective precautions can be relaxed by this time. This strategy does not need any testing before allowing a patient to be moved out of isolation. However, based on these findings, the researchers suggest that a positive IgG could be used to discriminate patients who can safely be released from isolation, rather than a negative RT PCR. The latter may remain positive even if viral RNA fragments linger in the body, rendering it unsuitable for this purpose. Of course, medical factors and the time since symptoms began will also factor in this decision. Thus, more research would be necessary to validate the use of antibody markers as indicating the non-infectious status of COVID-19 cases.
The study was performed with some limitations, having a small sample size, using one particular method for antibody detection, and without a standard time interval of antibody assessment. Nonetheless, it raises questions that must be answered by further research.
The researchers say, “We highlighted here that in non-critical symptomatic COVID-19 patients, most seroconversion of IgG antibody against SARS-CoV-2 occurred only after symptoms were resolved.” In most cases, therefore, seroconversion is a marker of clinical recovery in COVID-19.
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