SARS-CoV-2: Asymptomatic infected individuals show long-term elevated levels of inflammatory proteins

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A new study by researchers from the University of Tartu-Estonia has alarmingly revealed that majority of SARS-CoV-2 infected individuals who were asymptomatic exhibited long term elevated inflammatory protein levels.


The study findings showed that the four inflammatory biomarkers S100A12, TGF-alpha, IL18, and OSM remain elevated up to 7 to eight months and in some cases even longer and still ongoing in the asymptomatic individuals. These biomarkers are all associated with activated macrophage-monocytic cells.

https://www.frontiersin.org/articles/10.3389/fimmu.2021.709759/full

So that readers understand the alarming implications of the study findings, when one is living with long term inflammation, the body’s inflammatory response can eventually start damaging healthy cells, tissues, and organs. Over time, this can lead to DNA damage, tissue death, and internal scarring.

When left untreated, prolonged chronic inflammation can increase one’s risk for diseases like diabetes, heart disease, cancer, rheumatoid arthritis and various autoimmune diseases.

Comprehending the persistence of immune responses in asymptomatic individuals merit special attention because of their importance in controlling the spread of the infections and also understanding possible arising long term health conditions.

The research team studied the antibody and T cell responses, and a wide range of inflammation markers, in 56 SARS-CoV-2 antibody-positive individuals, identified by a population screen after the first wave of SARS-CoV-2 infection.

These, mostly asymptomatic individuals, were reanalyzed 7-8 months after their infection together with 115 age-matched seronegative controls.

The study team found that 7-8 months after the infection their antibodies to SARS-CoV-2 Nucleocapsid (N) protein declined whereas the team found no decrease in the antibodies to Spike receptor-binding domain (S-RBD) when compared to the findings at seropositivity identification.

In contrast to antibodies to N protein, the antibodies to S-RBD correlated with the viral neutralization capacity and with CD4+ T cell responses as measured by antigen-specific upregulation of CD137 and CD69 markers.

Unexpectedly the study found the asymptomatic antibody-positive individuals to have increased serum levels of S100A12, TGF-alpha, IL18, and OSM, the markers of activated macrophages-monocytes, suggesting long-term persistent inflammatory effect associated with the viral infection in asymptomatic individuals.

S100A12 is known as a lymphocyte-activating alarmin, expressed by activated monocyte-macrophages and neutrophils.

The upregulated serum levels of S100A12 and OSM are characteristic for patients with severe COVID-19, but as they are overexpressed at sites of inflammation, their serum levels correlate with the disease activity of many inflammatory diseases, including sepsis and other pulmonary infections.

Hence the study findings strongly suggest a persistent pulmonary inflammation process even in patients with asymptomatic or mild SARS-CoV-2 infection.

The inflammation process may be associated with prevalent radiological findings of lung opacities and airway abnormalities in a third of the asymptomatic cases but its long-term persistence months after the infection is unexpected.

The study findings support the evidence for the long-term persistence of the inflammation process and the need for post-infection clinical monitoring of SARS-CoV-2 infected asymptomatic individuals.


Discussion

We here studied antibody and T cell responses to the SARS-CoV-2 virus and analyzed inflammation markers in asymptomatic individuals 7-8 months after the infection. We found a decrease in antibodies to N protein but relatively stable levels of S-RBD antibodies. Asymptomatic individuals developed memory T cell responses, which correlated with S-RBD antibodies, and a small subset of them had persistently elevated levels of monocyte-macrophage-associated inflammatory protein levels in their blood.

We here found decreased antibodies to SARS-CoV-2 N protein over time, which we detected by commercial CLIA and in-house LIPS assay, however, the S-RBD antibody levels were not changed.

Importantly, the S-RBD antibodies correlated with the virus neutralization and with T cell responses to SARS-CoV-2 N, S, and M proteins. Earlier studies in SARS-CoV-2 infected asymptomatic individuals and in patients with mild disease have mostly reported the virus-specific antibodies to decline over time, or stable in some studies.

In a study with more than 200 individuals, S-RBD IgG titers were found relatively stable, though the moderate decline in antibodies was seen in over 8 months (7). In another longitudinal study including 1965 healthcare workers with no or mild symptoms, Havervall and colleagues reported stable antibodies to the SARS-CoV-2 S protein in 96% and N protein in 80% of individuals at four months post-infection (24).

Other studies have reported prominent decline in antibodies to S protein. Long et al. found 93% of asymptomatic individuals to have a reduction in anti-SARS-CoV-2 antibody levels during the early convalescent phase (5). Chen et al. found a significant decline in anti-S-RBD antibodies 7 months after the infection in hospitalized cases (25).

The decline in antibody levels to N and S-RBD after 5 months was also reported by Gaebler et al. (26). We note that in the asymptomatic group of our study, the S-RBD antibody levels showed more individual pattern as they increased in some and decreased in others. Our results also suggest that testing for both S-RBD and N protein antibodies should be considered to evaluate the long-term antibody responses in infected individuals.

We here report an unexpected finding of higher levels of inflammation markers associated with monocyte-macrophage lineage. S100A12, TGF-alpha, IL18, and OSM were higher in antibody-positive individuals after 7-8 months suggesting their involvement in SARS-CoV-2 pathogenesis. S100A12 is known as a lymphocyte-activating alarmin, expressed by activated monocyte-macrophages and neutrophils (27).

The upregulated serum levels of S100A12 and OSM are characteristic for patients with severe COVID-19 (23, 28), but as they are overexpressed at sites of inflammation, their serum levels correlate with the disease activity of many inflammatory diseases, including sepsis and other pulmonary infections (29, 30).

Thus, our results strongly suggest a persistent pulmonary inflammation process even in patients with asymptomatic or mild SARS-CoV-2 infection. The inflammation process may be associated with prevalent radiological findings of lung opacities and airway abnormalities in a third of the asymptomatic cases (3) but its long-term persistence months after the infection is unexpected.

Our study has limitations. First, although our cohort included sex- and age-matched individuals from the same geographical regions, we cannot exclude the possibility that other comorbidities or infections may influence the inflammatory protein levels in studied individuals. Second, we have not studied the role of seasonal coronaviruses, which may affect our results on T cell responses or antibody levels.

Third, we did not study the antigen-specific memory B cells to confirm the persistence of B cell responses to SARS-CoV-2. Further studies are needed to identify whether the elevated levels of inflammation markers are related to the long-term effect of the viral pulmonary inflammation or pose a risk factor for the increased infectivity for the SARS-CoV-2 virus.

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