How can physicians distinguish between COVID-19 persistence and SARS-CoV-2 reinfection?

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The presence of antibodies against SARS-CoV-2 in individuals who contracted COVID-19 has been well documented.

Research suggests that in the majority of cases, anti-SARS-CoV-2 antibodies can persist for six months or more in those who recover from COVID-19. However, reinfection has also be observed in many individuals across all age groups. Further, the severity of the infection was also found to vary across cases.

With regard to SARS-CoV-2 reinfection cases, not many studies are available on viral characteristics, degree of sequence heterogeneity, and the point of mutation. The location of the mutation point can be determined by comparing the reference sequence with the reinfecting variants. Physicians are encountering an increase in the number of cases associated with disease persistence, especially in immunocompromised individuals. Researchers have found that persistent COVID-19 can affect an individual with a wide range of severity – from asymptomatic to severe disease – and that recurrent symptoms can persist for several months.

One of the most challenging tasks of physicians has been differentiating between persistent COVID-19 and SARS-CoV-2 reinfection. Recently, a team of researchers analyzed SARS-CoV-2 sequences from the publicly available reports on reinfection and persistence. They further characterized the markers of reinfecting sequences and studied the mutation rate in newly evolved persistent variants. Their research was released on the medRxiv* preprint server.

The team conducted a systematic literature review, published in Pubmed form initial reports through February 2021. They included both peer-reviewed and preprint reports. To review the literature and report search results, they have used Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). They also included nasopharyngeal or anterior nasal sequences in their study. Platforms such as NextClade and snp-sites were utilized to obtain and analyze sequences required for studying mutations.

The severity of the disease after reinfection was classified based on symptoms. Nucleotide sequence alignment was performed using MAFFT (Multiple Alignment using Fast Fourier Transform). The team also constructed a maximum likelihood (ML) phylogenetic tree for the best-fit nucleotide sequence, using IQ-Tree with 1000-bootstrap replicates.

The mutation analysis strategy for reinfection cases was determined in the following ways:

(a) Identification of the change in amino acids sequence for the reinfection compared to the first infection sequence. The frequency of amino acid changes within each gene was related to the frequency of changes in the remainder of the genome by X2 test with Yates correction. The relationship between disease severity and the number of amino acid changes in the genome was also assessed using a Mann-Whitney test.

(b) Identification of unique characteristics of reinfecting viruses. In this regard, sequences discussed in (a) and reinfection sequences were compared to passing sequences in the community using NextStrain clade.

The researchers determined that rare mutations or polymorphisms were present in the reinfecting sequence and not the initial variant. Previously, scientists suggested that the reinfection occurs due to a decline in SARS-CoV-2 antibodies or due to the development of new variants. This research has revealed that reinfection does not rely on variants. However, in most cases, reinfection occurs due to infection by a different variant such as SARS-CoV-2 B.1.1.7 as their infectivity is higher than the other virus.

Researchers have identified viral mutations throughout the genome of SARS-CoV-2. The frequency of mutation in the S gene was marginally higher when compared to the rate of mutation across the entire genome. The study on immunocompromised individuals infected with SARS-CoV-2 showed a higher rate of viral evolution than in healthy individuals. However, the limited amount of data on immunosuppressed individuals prevents researchers from absolute interpretation. Therefore, scientists have recommended greater monitoring of the immunocompromised patients infected with SARS-CoV-2. The possibility of the rate of evolution of the virus is more in such individuals, leading to the development of more variants.

A second limitation of the current research is that it does not include immunity profiling. The team overlooked a report related to persistent COVID-19 and B-cell dysfunction, owing to the unavailability of a full-length sequence. Previous studies have revealed that T cells play an important role in protecting the host against SARS-CoV-2.

The current study has revealed that, in general, two factors can be used to differentiate reinfection from persistence. These are,  

  1. Reinfections have been mostly associated with immunocompetent individuals. However, the majority of persistent SARS-CoV-2 infection cases have been reported in immunosuppressed patients.
  2. Phylogenetic analysis can generally differentiate between reinfection and persistence. However, slow evolution rate, limited viral diversity, limited sampling, and varying durations between samples prevent differentiating between reinfection and persistent infection using phylogenetic study.

Researchers have also emphasized the need for more work to explore the factors that increase the risk of reinfections and persistent COVID-19.

*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.

Journal reference:
Dr. Priyom Bose

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.


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