Long COVID-19 symptoms not associated with reduced cell-mediated immunity, finds study

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered the coronavirus disease 2019 (COVID-19) pandemic, which has caused over 104 million cases and well over 2.2 million deaths so far. While most infections are asymptomatic or very mild, there is a sizable minority of symptomatic infections which can become severe or life-threatening.

Some patients recover quickly and completely, while others develop persistent illness, requiring hospitalization or medical care for weeks or even months. While such features often reflect immune dysregulation, it is not clear if this is the case with persistent COVID-19.  A new preprint on the medRxiv* server deals with this condition, aiming to identify the underlying immunologic status in such patients.

Prolonged COVID-19 symptoms

Persistent COVID-19 is more common in older patients, especially those with coexisting illnesses, but has also been frequently reported in those with mild infection. About a fifth of young adult patients also report long-haul symptoms after confirmed SARS-CoV-2 infection, indisposing them to return to their daily activities even at three weeks from the onset of symptoms or a positive test.

Such symptoms are usually not compatible with the isolation of infectious virus, but SARS-CoV-2 RNA continues to be shed in the nose and stool for weeks after the diagnosis. The persistence of the viral antigen is also suggested by the presence of specific maturing memory B cells.

The immune dysregulation that is associated with such phenomena as antigen persistence or inflammation consequent upon infection – as in chronic hepatitis B or C infection, and in HIV – is most clearly seen in the cellular immunity compartment. The main features are a steady loss of T cell effector function and loss of specific cellular immunity.

Study details

The current study aimed to explore the associations between cell-mediated immunity and the period over which COVID-19 symptoms persisted. The researchers focused on patients who were convalescing after recovering from mild to moderate COVID-19.

Among 33 patients, 14 and 19 had a short and long period of symptoms, respectively, indicating a duration of 0-8 days and 18-61 days, respectively.

Magnitude of SARS-CoV-2 specific cellular immunity

The level of SARS-CoV-2 specific cell-mediated immunity was gauged using an IFN-γ ELISPOT (Interferon-gamma enzyme-linked immune absorbent spot) assay. The results showed that prolonged symptomatology in this condition was not linked to significant changes in specific cellular immunity, overall, relative to those who had rapid symptom resolution.

Pattern of reactivity

The overall cellular immune response as well as the level of reactivity against the SARS-CoV-2 Spike, nucleoprotein (N), and membrane (M) antigens showed no difference with duration of symptoms. However, short-duration patients typically showed reactivity against these three proteins, while long-duration patients also had reactivity to ORF3a.

Prolonged symptoms were associated with a small increase in cellular immunity against SARS-CoV-2 ORF3a and ORF7a. The magnitude of the response, in terms of specific CD4+ and CD8+ T cells directed against the spike antigen of the virus, was also similar in both ordinary and long-haul patients. The transcriptome of these CD4 T cells also appeared unchanged.

No correlation with seasonal coronavirus reactivity

Cellular immunity against seasonal coronaviruses also reached significant levels and correlated with each other but did not show any change in magnitude with duration of symptoms. Older patients had lower cross-reactive immune cells, however.

There was no correlation between SARS-CoV-2 Spike protein reactivity and reactivity to seasonal coronavirus spike protein. The level of anti-spike immunity to the seasonal coronaviruses did, however, show a correlation with reactivity to the SARS-CoV-2 N antigen.

What are the implications?

The findings of this study suggest that the presence of persistent COVID-19 symptoms in mild to moderate disease has no significant effect on cell-mediated immunity against SARS-CoV-2, nor is it associated with cellular immunity against seasonal human coronaviruses. The researchers suggest that this may indicate different immune processes underlying severe COVID-19 relative to prolonged mild disease.

On the other hand, previous infection with seasonal betacoronaviruses may affect the development of anti-SARS-CoV-2 N immunity. “In addition to providing insight into the mechanisms driving the development of SARS-CoV-2 specific cellular immunity, this observation may provide guidance as to which antigens may be most amenable in the development of a universal coronavirus vaccine.”

*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. Liji Thomas

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.


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