The coronavirus disease 2019 (COVID-19) pandemic has already caused over 117.6 million confirmed cases the world over. Yet, researchers debate the exact incidence of reinfection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19’s causative pathogen. A preliminary answer is presented in an Israeli preprint that appears on the medRxiv* server.

Reinfection criteria

The question of reinfection is critical in helping to understand if herd immunity is achievable and desirable, as well as in shaping containment policies. As of now, it is widely assumed that patients who have recovered from the disease have a protective immune response against reinfection.

The earliest documented case of reinfection was reported in June 2020, but was followed by several others. The occurrence of reinfection is determined by sequencing the viral genome and finding it to be distinct from that of the strain that caused the initial infection.

Or else, the patient undergoes a real-time polymerase chain reaction (PCR) which turns out to be positive months after documented recovery from a COVID-19 episode.

In the first scenario, where two different strains of the virus causing two distinct infections in the same patient on two different occasions must be detected to fix the diagnosis, the chances of missing the diagnosis are high. This has led to the development of other criteria to identify true re-infections using data that is easier to obtain.

Reinfection is typically associated with milder symptoms, probably because the adaptive immune response is already primed by the earlier infection. The reverse has also been reported, however. True reinfections must be identified in order to pick up cases of prolonged viral shedding.

Earlier coronavirus infections have been known to be followed by reinfections, such as the human seasonal coronaviruses that cause the common cold. This was explained by research that showed that the immune response to such viruses not only developed rapidly but also waned quickly, thus providing the opportunity for reinfections to take place.

With other coronaviruses, most reinfections occur within 1-3 years of the original infection. With the ongoing pandemic, the potential for re-exposure to SARS-CoV-2 is far greater, allowing the immune response to be overridden or blunted, and reducing the delay before reinfection can occur.

Study details

The current preprint looked at the question of reinfection within an Israeli population, all of whom had one or more reinfections in August 2020. This study aimed to find the actual incidence of reinfection, by a large-scale measurement at the national level, using data from a large healthcare provider.

The study included almost 150,000 people enrolled in Maccabi Healthcare Services (MHS), between March 2020 and January 2021. This is the second-largest not-for-profit healthcare provider in Israel. It contains a quarter of the population, with data on the demographics, diagnoses, interventions and other information.

Of this population, 154 had documented SARS-CoV-2 infection at least twice, as shown by two positive PCR tests separated by a hundred or more days. This comes to 0.1% reinfection. Within a period of 200 days from the first positive test, 30 individuals were reinfected.

Of the reinfected group, 73, or a little less than half, had symptoms with both episodes. Most such individuals were between 10 and 19 years of age.

What are the implications?

This report strongly implies the occurrence of COVID-19 reinfections in MHS patients in Israel, at a frequency of one in a thousand when the two positive PCR tests are at least a hundred days apart. The researchers say these should be regarded as true reinfection incidence despite the fact that viral genomic sequencing was not carried out.

The factors in favor of such a diagnosis include the hundred days between two positive PCR tests and the absence of risk factors that could lead to prolonged shedding of the virus. These include mechanical ventilation, delay in hospital admission, and immunosuppression, none of which were present in this population.

In other words, viral shedding prolonged over more than three months could not be cited as a possible explanation for the positive PCR tests separated by such a long interval. Moreover, the presence of COVID-19 symptoms in ~47% of the patients reinforces the impression that these represent true reinfection events.

The highest number of reinfection events occurred in January 2021, though the reason is unknown. One explanation may be that different COVID-19 strains were circulating at this time, thus favoring reinfection with a different viral lineage.

The increased chances of reinfection among younger individuals also require explanation. Some hypotheses include the increased risk of exposure due to behavioral factors, such as the lack of social distancing and the use of masks.

It is possible that the minimum period of 100 days before a repeat positive PCR test was accepted as proof of reinfection may have excluded some genuine cases. Further study is necessary to evaluate other parameters of the reinfection group.

Reinfection proportion, albeit small, is not insignificant; as time passes the potential for reinfection increases. Health policymakers should acknowledge the possibility of reinfection and reconsider the differential message to recovered population.”

*Important Notice

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.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.