How does Covid-19 affect the immune system over weeks and months?

Anna Wedderburn spoke with Irish researchers of a recent study that examined the links between long Covid and the immune system

A study by Dr Liam Townsend, Specialist Registrar in Infectious Diseases, and Dr Clíona Ní Cheallaigh, Consultant
in Infectious Diseases, both at St James’s Hospital in Dublin, was recently published in the journal Frontiers
in Immunology.

Their research investigated links between long Covid and the immune system. The study found that although some people’s immune systems remained altered up to 14 weeks post-SARS-CoV-2 infection, these changes did not correspond with symptoms of long Covid. Instead, persistent immune system changes were associated with age and severity of initial disease.

Dr Ní Cheallaigh told the Medical Independent there were many symptoms associated with long Covid, including fatigue, brain fog, and inability to exercise or work to the level prior to infection. She explained that they considered this “might be due to persistent changes in the immune system”. The research team therefore wanted to investigate whether this was the case.

Research

Blood samples were taken from a group of 40 individuals when they first acquired Covid-19 and again 10 weeks later. Blood samples were also taken from 71 individuals 14 weeks after having been infected with SARS-CoV-2. Stored blood samples from 40 individuals taken before the emergence of SARS-CoV-2 were used as healthy controls, as they were guaranteed to have not been exposed to the virus.

Flow cytometry and enzyme-linked immunosorbent assays (ELISAs) were carried out on all the blood samples cited above. Flow cytometry enabled the research team to identify the different types and levels of immune cells in each blood sample, while ELISAs allowed for the levels of immune molecules IL-6, IL-8, IL-1β, TNFα, and soluble CD25, to be measured. Dr Townsend also carried out a physical health assessment of study participants to assess the lasting impact of Covid-19 on these individuals.

Dr Townsend explained that acute Covid-19 is characterised by a large expansion of myeloid cells, particularly immature neutrophils and immature monocytes, and lymphopenia. This study showed that at convalescence, the myeloid cells had all recovered to the levels of the healthy controls. However, there were “persistent changes in lymphocyte populations at convalescence, with increased activated lymphocytes, and decreased naive lymphocytes” at 10 weeks and 14 weeks post-SARS-CoV-2 infection in certain individuals. Interestingly, these persisting changes in the immune system did not correlate with long Covid symptoms. Instead, individuals were more likely to have persisting changes in the immune system if they had initially suffered a severe SARS-CoV-2 infection, or if they were over the age of 60.

Asked if Covid-19 was the only infection that made a lasting impact on the immune system, Dr Townsend replied: “It’s described a little bit in influenza, but the main problem is that it’s really not studied in other infections.”
According to Dr Ní Cheallaigh, age has a significant effect on recovery from most illnesses and “a hallmark of aging is that you lose your reserve”. For example, “if you get sepsis, you don’t have enough reserves to maintain your blood pressure, and if you get kidney disease, you don’t have enough reserves to maintain your kidney function.” She said this was particularly true of the immune system, as the thymus becomes involuted, and there were unlikely to be the same quantities of immune cells being produced by the bone marrow when fresh immune cells were required.

Although this may sound as though
the immune system is not necessarily related to long Covid, both Dr Townsend and Dr Ní Cheallaigh said that this cannot be stated at present. Dr Townsend noted “this isn’t a comprehensive review of the immune system, so we can’t say it’s not the immune system”.
“We can just say it’s not related to the inflammatory markers we measured, or to the immune cell populations we measured.”

Cytokines

Dr Townsend noted they did not look at the function of the various immune cells and they only examined the circulating immune system: The immune cells and immune molecules, or cytokines, found within the blood. They did not study the immune system in other parts of the body, such as cerebrospinal fluid.

Dr Ní Cheallaigh explained that although there may be normal levels of circulating cytokines in the blood, it was possible that the blood-brain barrier of those with long Covid – which is normally very tight and keeps the brain isolated from elements circulating in the blood – may become leaky and more permeable to cytokines. There is already some evidence that the blood-brain barrier “may get leaky in Covid”, Dr Ní Cheallaigh said.

“So what may happen is that even normal levels of circulation cytokines, for example, may be able to go into the brain and produce these sickness phenomena.” Dr Ní Cheallaigh is currently involved in developing an application to investigate this hypothesis.

One of the reasons why long Covid is difficult to study is there are “probably several syndromes and pathologies in long Covid, and at the moment they’re all lumped into one”, Dr Ní Cheallaigh said.

She said it is not currently known or understood what causes chronic fatigue in other post-viral infections, nor is there a comprehensive understanding in regard to brain fog, concentration, and memory, all of which are affected in long Covid.

Many people also report a prolonged abnormal heart rate after contracting Covid-19. Dr Ní Cheallaigh cited the example of an active 14-year-old boy who, after having Covid-19 last year, had not been able to return to football as any time his heart rate goes above 120bpm he gets “an horrendous migraine”.

Dr Ní Cheallaigh said another common symptom of long Covid was that the heart rate quickens considerably while eating. From these symptoms, Dr Ní Cheallaigh believed there “may be something in the autonomic nervous system” or in the nerves that regulate blood flow that might be contributing to long Covid.

ICU

Dr Ní Cheallaigh also highlighted the impact of severe Covid-19 on physical and mental health, particularly where intensive care treatment was required. “It’s well recognised that just the effect of being sedated and ventilated and not moving for a number of weeks is actually really bad for you,” Dr Ní Cheallaigh said.
Patients get “post-ICU neuropathy, post-ICU myopathy, post-ICU depression and anxiety” and all of these are “in the mix” for long Covid.

In terms of the relevance of this research in a clinical setting, Dr Townsend said it has shown that testing for cytokines and immune cell populations “do not add to the diagnostic tests for patients with long Covid”.

Dr Ní Cheallaigh added there are a number of immune modulators that can be considered for treating long Covid. Many treatment approaches they believed might have been useful in long Covid were not likely to be beneficial.
In conclusion, Dr Ní Cheallaigh said that working with Dr Townsend on this project was “brilliant”. “We were so lucky to have him on the ground, he’s super dynamic.
He just sees the situation and runs with it.”

The paper ‘Longitudinal analysis of
Covid-19 patients shows age-associated
T- cell changes independent of ongoing illhealth’ can be found at the following link:
www.frontiersin.org/articles/10.3389/
fimmu.2021.676932/full