Study Reveals That Individuals That Only Had Mild COVID-19 Infections Still Exhibited Persistent Leukocyte Changes Even Three Months After ‘Recovery’!

Long COVID Research: A new study by researchers from McMaster University-Canada and University of Melbourne- Australia has found that individuals that only had mild COVID-19 infections still exhibited persistent leukocyte changes even three months after ‘recovery’!

 
It has been found that survivors of severe SARS-CoV-2 infections frequently suffer from a range of post-infection sequelae (PASC) or what is commonly known as long COVID.
 
However not much is known whether survivors of mild or asymptomatic infections can expect any long-term health consequences although a few studies certain medical conditions manifesting in them as well including heart issues, lung damage and prolonged inflammation.
 
 The study team investigated lasting changes to soluble inflammatory factors and cellular immune phenotype and function in individuals who had recovered from mild SARS-CoV-2 infections (n=22) compared to those that had recovered from other mild respiratory infections (n=11).
 
The study findings showed that individuals who had mild SARS-CoV-2 infections had elevated levels of C-reactive protein 1-3 months after symptom onset, and changes in phenotype and function of circulating T cells that were not apparent in individuals 6-9 months post-symptom onset. Markers of monocyte activation and expression of adherence and chemokine receptors indicative of altered migratory capacity were also higher at 1-3 months post-infection in individuals who had mild SARS-CoV-2, but these were no longer elevated by 6-9 months post-infection.
 
However shockingly polyclonal activation of T cells was higher in individuals who had recently experienced a mild SARS-CoV-2 infection compared to individuals with other recent respiratory infections. These data are indicative of prolonged immune activation and systemic inflammation that persists for up to three months after mild or asymptomatic SARS-CoV-2 infections.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2021.09.25.21264117v1              

The COVID-19 pandemic has baffled researchers with its apparently random pattern of severe disease. Caused by the SARS-CoV-2 coronavirus, COVID-19 has a mortality rate of 1% in most developed nations, thereby suggesting that most infections are asymptomatic or mild.
 
However the occurrence of persistent disability after SARS-CoV-2 infection has disturbed many scientists especially the medical and health conditions associated with what are collectively termed as long COVID.
 
The study discusses the rate of changes in peripheral blood white cells (WBCs) in individuals who have recovered from SARS-CoV-2 infection, and how these differed from alterations seen with other mild respiratory infections. The study team found short-lived changes in various cell subsets in circulation that differentiated mild COVID-19 from other conditions.  
 
The SARS-CoV-2 infection is known to cause atypical WBC changes. Rather than the expected acceleration of neutrophil-monocyte release from the bone marrow, without much impact on lym phocyte function or numbers, SARS-CoV-2 is associated with a frequent occurrence of early and severe lymphopenia. In fact, this finding is a mortality marker with COVID-19.
 
Importantly T-cell loss during COVID-19 is attributable to the death of these cells within the secondary lymphoid organs. Alternatively, this loss of T-cells could be attributed to their influx into the lungs or other organs following their recruitment. It is noteworthy that this recruitment is unnecessary and potentially harmful.
 
The other significant changes in severe COVID-19 include hypergranularity and nuclear changes in monocytes and neutrophils. These changes have been linked to the premature release of these cells from the bone marrow, thus affecting their maturation.
 
The ever-growing reports of long COVID-19, which refers to persistent health issues following recovery from the acute infection, indicate a broad spectrum of symptoms including easy and severe fatigability, pain, breathlessness, and increased risk of re-admission to the hospital for respiratory problems.
 
The study team focused the effect of the infection on immunity in mild or asymptomatic COVID-19 in this study.
 
The Long COVID Research study included individuals with mild respiratory symptoms who had a prior positive reverse-transcriptase polymerase chain reaction (RT-PCR) test for COVID-19, or were seropositive for SARS-CoV-2 antibodies, as well as those who were either seronegative or tested negative.
 
The study team found that activated CD4 and CD8 T-cells were increased after stimulation with one or more of the viral antigens; namely, the membrane glycoprotein (M), the nucleocapsid (N) or the spike (S), at 1-9 months after mild COVID-19.
 
These CD4 responses were comparable to all antigens and peaked at 1-3 months.
 
However, at this point, but not at 6-9 months, CD4 but not CD8 T-cells were markedly higher in COVID-19 recovered patients than in those who had recovered from other respiratory infections.
 
Typically immune activation can linger after recovery from severe infections. This is thought to cause prolonged weakness or tiredness in recovered patients.
 
Interestingly in the current study, evidence of prolonged inflammation was found, even though almost all participants had recovered clinically within a month of infection.
 
The observed biomarkers of continuing inflammation included C-reactive protein (CRP), tumor necrosis factor (TNF), and interleukin-6 (IL-6) in all seropositive individuals at 1-3 months.
 
However, at 6-9 months, there was no difference between these participants and those with other respiratory infections.
 
Surprisingly polyclonal activation of T-cells was stronger with COVID-19 patients than in the other group, and this trend continued to be observed in the later samples.
 
This study finding suggests the occurrence of slight but definite changes that may characterize the effect of COVID-19 in activating T-cells in contrast to other respiratory infections.
 
Although the total number of CD4 and CD8 T-cells remained similar in both groups up to 9 months, the T-cell phenotype showed differential markers. For instance, at 3 months from infection, natural killer (NK) cells were reduced, whereas regulatory T-cells increased at 1-3 months. These changes reverted to the profile found in other respiratory infections by 6-9 months.
 
It was also found that the central memory CD4 T-cells and terminally differentiated CD8 T-cells increased in COVID-19 patients at 1-3 months from symptom onset.
 
In comparison, the presence of these cells was indistinguishable from the response to other respiratory infections at 6-9 months. Other T-cell subsets showed no differences between the two groups.
 
However alarmingly monocytes showed an interesting pattern of change at 1-3 months. Classical monocytes are found at higher levels only during acute infection and, in this study, their number was not above normal.
 
However, at 1-3 months, CCR2 receptor expression was low on other monocyte populations, perhaps because the cells with the highest expression of this receptor had left the circulation for the tissues.
 
Also, the CX3CR2 chemokine receptor is typically found at higher levels on intermediate and non-classical monocytes, as it is a recruitment signal and associated with tissue repair. This marker was low at 1-3 months, thereby indicating that these cells had left the peripheral blood. The reduction in CX3CR2 expression is closely correlated with the proportion of S protein-specific CD4 T cells.
 
Worryingly M-specific CD8 T-cells were linked to HLA-DR expression on non-classical monocytes. Polyclonal T-cell activation markers were not found in association with the activation of myeloid series white cells, thus suggesting that these changes occurred as a result of the specific anti-SARS-CoV-2 immune response rather than as part of the generalized T-cell activation response to this virus.
 
Also the integrin marker CD11b was increased for a time on monocytes at 1-3 months from the onset of symptoms.
 
Collectively these changes indicate a systemic activation of the immune response, though transient, which may alter the pattern of migration in monocytes following mild infection with SARS-CoV-2. Either baseline inflammation levels are increased, or the immune response to the virus involves these monocytes as well.
 
The study findings indicate that even after mild COVID-19 and without long COVID, individuals may have high immune activation and systemic inflammation for 1-3 months after clinical resolution. The percentages of memory CD4 and CD8 T-cells that react to the S, M, and N antigens are similar to those previously reported for severe or moderate COVID-19.
In other words, memory cell responses do not correlate with clinical phenotype.
 
However, for the first time, non-specific T-cells were activated by Cytostim stimulation in patients recovering from COVID-19. The activation markers were higher in stimulated cells following mild COVID-19 than in the other respiratory infection group, with some remaining high at 6-9 months.
 
The study team said that perhaps the CD4-activated T-cells at 1-3 months after COVID-19 may be a response to high circulating IL-6 or other promoters of T-cell activation. Alternatively, these cells may be able to mount a faster and more robust response when activated.
 
The team said, “The Tregs may be involved in preventing tissue damage during acute respiratory infection; however, the elevation was observed in the convalescent phase.”
 
Dr Dawn M. E. Bowdish from McMaster Immunology Research Centre-McMaster University told Thailand Medical News, “Collectively, these data provide evidence that mild, and in some individuals even asymptomatic SARS-CoV-2 infections, can lead to sustained immune activation after resolution of symptoms, which is not observed in response to other mild respiratory infections. Whether this immune activation is more pronounced in patients with long-COVID, or more serious infections, remains to be seen.”
 
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