Understanding the whole-system effects of COVID-19 and the immune system’s response to the virus is vital in vaccine and therapy development.
Research shows that both asymptomatic and symptomatic individuals with COVID-19 experience (single and multiple) organ impairment. In addition, some individuals experience symptoms long after initial infection. Understanding the T-cell response and how it is changing (i.e., clonally expanding, contracting, or changing repertoires) can provide a way to understand the short- and long-term effects of an infection, and how effective certain therapies may be. The immunoSEQ® T-MAP™ COVID tool provides a way to track these changes over time and across different patient populations and can help evaluate the effectiveness of different vaccines and therapies.
This article provides an overview of recent research on the effects of COVID-19 on different organ systems and highlights how a whole-systems approach can help in the development of vaccines and treatments in the long term.
Common symptoms of COVID-19
The most common symptoms of COVID-19 are fever, cough, and fatigue. (1) While SARS-CoV-2 infection is most commonly associated with respiratory effects, patients also experience myocardial involvement, neurological symptoms, eye inflammation, gastrointestinal symptoms, kidney failure, and liver damage (Figure 1).
Figure 1. Effects of COVID-19 on organs and systems. The virus, and the immune response to it, can affect a wide range of organs and systems, including the brain, eyes, nose, lungs, heart and blood vessels, liver, kidneys, and intestines. Patients with COVID-19 may also experience a broad range of long-term symptoms weeks to months after the acute infection has resolved. Adapted from Wadman et al. (2) and Nalbandian et al. (3)
SARS-CoV-2 can have a severe impact on airway and lung function, which can lead to loss of sense of smell, cough, acute respiratory distress, and death. (1) While the most prevalent symptoms are fever (78%), cough (57%), and fatigue (31%), severe cases may require ventilation. (4) Patients with pre-existing conditions, including age, obesity, hypertension, diabetes, heart disease, and chronic liver or kidney disease, are more likely to develop severe respiratory symptoms. (5)
Approximately 20–30% of hospitalized patients have evidence of myocardial involvement, and acute cardiac injury in hospitalized patients is also associated with mortality from COVID-19. It is thought that direct viral interaction of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2) receptors, which are abundant on myocardial and vascular tissue, is one of the mechanisms of cardiac injury associated with COVID-19. There are additional concerns for patients recovering from COVID-19, as myocarditis from other viral pathogens can evolve into myocardial disfunction, and assessing and preparing for possible long-term cardiac effects will be crucial. (6)
Gastro-intestinal and liver-related symptoms
Many patients also experience gastrointestinal and liver-related symptoms. One comprehensive study revealed that 16% of patients presented with gastrointestinal symptoms only. The most common digestive symptoms include anorexia, nausea, vomiting, and diarrhea. It is thought that the virus acts via the ACE2 receptor, which is present in multiple cell types including different lung cells, thereby accounting for the respiratory effects of infection, but also enterocytes in the ileum and colon. (7) With evidence of viral RNA in fecal matter, there is some evidence of fecal–oral transmission of the virus. (8) ACE2 receptors are also found in hepatocytes and cholangiocytes, and the host immune response can lead to liver damage and elevated liver enzyme levels. (7)
ACE2 receptors are also expressed in the kidney, and acute kidney injury has been reported in up to half of hospitalized patients with COVID-19. COVID-19-associated kidney injury was associated with decreased estimated glomerular filtration rate compared with patients who experienced kidney injury without COVID-19, which highlights the importance of monitoring kidney function after COVID-19 hospitalization. (9)
A broad range of acute neurological and psychiatric symptoms of COVID-19 have also been observed, including cerebrovascular events and altered mental status. (10) Of a global cohort study of patients hospitalized with COVID-19, approximately 80% showed neurological symptoms. (11) Self-reported symptoms included headache, anosmia, or ageusia, and common neurological syndromes included cephalopathy, coma, and stroke. (11)
An early tracking system in the UK showed an exponential growth in reported cases of neurological and psychiatric cases during the month of April 2020, similar to the overall COVID-19 data from the same region. Patients presented with cerebrovascular events, including ischemic stroke, intracerebral hemorrhage, and CNS vasculitis. Several patients also presented with altered mental status, such as unspecified encephalopathy, encephalitis, and new-onset neuropsychiatric disorders (new-onset psychosis, dementia-like syndrome, or affective disorder). In almost half the cases, altered mental status occurred in younger patients. (10)
Overall, these studies show that neurological manifestations are prevalent among hospitalized COVID-19 patients, with an increased risk for patients with pre-existing neurological disorders. Moreover, neurological signs in hospitalized patients were associated with higher mortality. (11)
Long-term effects of COVID-19
Some patients with COVID-19 also experience longer-term symptoms, lasting weeks or months. (12) In one study, 87.4% of patients reported experiencing at least one COVID-19 symptom 60 days after hospitalization. (12) Another study reported approximately 10% of people experiencing “chronic COVID-19,” defined as extending beyond 12 weeks from the onset of first symptoms. (13) Patients with longer-term infections have been reported to have increased inflammatory cytokines, monocytes, neutrophils, natural killer cells, and CD4+ T-cell counts. These patients also showed decreased CD8+ T-cell and total lymphocyte counts. (14)
Some common persistent symptoms include fatigue, headache, attention disorder, hair loss, and dyspnea. (3) Other symptoms include those relating to lung disease, cardiovascular disease, dermatological symptoms, neurological symptoms, and non-specific symptoms such as hair loss, tinnitus, and night sweats (Figure 2). (3,16)
Figure 2. The meta-analysis of the studies included an estimate for one symptom or more, and reported that 80% of the patients with COVID-19 have long-term symptoms. OCD, Obsessive–Compulsive Disorder; PTSD, post-traumatic stress disorder. Adapted from Lopez-Leon et al. (15)
It is not clear why some patients experience “long COVID.” One hypothesis suggests that long-term COVID-19 is an inflammatory response to newly budding virions. (16) Another possible explanation lies with autoimmune disease: COVID-19 has been associated with the development of post-infection autoimmune and rheumatological manifestations. (17)
Tracking and understanding the T-cell response in these patients could provide critical information on the nature of long-term COVID-19 symptoms.
The effect of COVID-19 in immunocompromised individuals
COVID-19 may affect individuals who are immunocompromised differently, either because of autoimmune disease or because they are receiving immunosuppressants (Table 1). In addition, people who are immunocompromised may not receive the same vaccination benefits as those who are immunocompetent. Understanding these differences in immune response to a SARS-CoV-2 infection or vaccination will help with the development of effective treatments and vaccinations for the immunocompromised population.
Table 1: Factors leading to immunocompromised status for different conditions
|Disease area||Factors that modify the immune response||Impact on the T-cell response||Benefit of tracking the T-cell response|
|Transplantation||Immunosuppressor treatment||Decreased T-cell and antibody response to SARS-CoV-2||Understand the risks of COVID-19 and response to vaccination for organ transplant recipients|
|Cancer||Immunocompromised status||T-cell exhaustion and decreased proliferation||Understand the risks of COVID-19 to individuals with cancer|
|Cancer||Chemotherapy||Decreased bone marrow production and white blood cell count||Understand the risks of COVID-19 for individuals undergoing treatment for cancer|
|Cancer||Immunotherapies||Increased tumor-infiltrating lymphocytes||Distinguish COVID-19 symptoms and side effects from immunotherapy|
|Autoimmune disease||Overactive aberrant immune response that can act like an autoimmune disease||Increased T-cell response||Track strength and repertoire of the T-cell response to SARS-CoV-2 and relationship to autoimmunity|
|Autoimmune disease||Autoreactive T cells||Increased T-cell response against self-antigens||Track autoimmune T-cell repertoire signatures|
It is possible that transplant patients, who often receive immunosuppressors as part of their treatment, do not elicit the same antibody response as immunocompetent patients. One study showed a lower efficacy of vaccines in solid organ transplant recipients after the first dose of an mRNA vaccine, and reduced antibody levels after the second dose compared with immunocompetent vaccinees. Low antibody levels were associated with the use of antimetabolite immunosuppressors. These data suggest that even after vaccination, a substantial proportion of transplant recipients will likely remain at risk for COVID-19. (18)
Many patients with cancer are also immunocompromised. On the one hand, patients with cancer are at higher risk of severe disease and adverse COVID-19-related events such as hospitalization, need for a ventilator, or death. (19) On the other hand, some researchers hypothesize that a reduced immune response in cancer patients, who are immunocompromised, may protect from the overactive immune stimulation that some patients with severe COVID-19 experience. (20) Understanding how the immune system in cancer patients reacts to SARS-CoV-2 may help understand the risks of COVID-19 for individuals with cancer.
In addition to understanding the effects of COVID-19 on cancer, monitoring the T-cell repertoire can have implications for understanding the impact of COVID-19 on cancer treatments. Chemotherapy decreases bone marrow production and white blood cell count, affecting the ability to elicit an immune response. (19) On the other hand, in patients undergoing immunotherapies, which function to increase the immune response against tumor cells, it may be difficult to distinguish between COVID-19 symptoms and side effects from immunotherapy. (19) Comparing the immune repertoire datasets of cancer patients and COVID-19 patients can help to determine if COVID-19 or immunotherapies may be the cause of some immune-related adverse events.
Finally, owing to the complex interplay of cancer, COVID-19, access to care, the immune system, and immunotherapies, it is crucial to understand whether oncology patients have had a past SARS-CoV-2 infection, especially patients enrolled in clinical trials. Patients in trials for immunotherapies have a higher likelihood of immune-related adverse events, so understanding their past T-cell immune response to SARS-CoV-2 can help rule out COVID-19 as a cause of adverse events.
In COVID-19, the overactive aberrant immune response can act like an autoimmune disease in that it can cause excessive tissue damage and inflammation. (21) This is not uncommon with viral infections, and may be caused by the dramatic T-cell response that the body elicits to fight off viral and other pathogens, damaging the bystander host cells in the process. Alternatively, it could be due to the autoreactive T cells that mistakenly react to the body’s own cells as if they were pathogenic invaders. (22)
Autoimmune signatures can often appear well after the causative infection and its symptoms have waned, and can appear in patients who were asymptomatic or had only mild symptoms, as was the case with children who developed multisystem inflammatory syndrome (MIS-C) and Kawasaki-like disease after being infected with SARS-CoV-2. (23)
It is vital to have a sensitive way to determine if people who present with autoimmune signatures have ever been exposed to SARS-CoV-2, or if their autoimmune problems stem from another issue. Comparing TCR sequences from patients with autoimmune disorders with those from patients with COVID-19 using the immunoSEQ® T-MAP™ COVID tool may help us to understand the mechanisms of COVID-19-related autoimmunity, and autoimmunity in general.
immunoSEQ T-MAP COVID: Understanding the T-cell response to COVID-19
Given the various effects of COVID-19 on different organs and organ systems, both in healthy and immunocompromised individuals, mapping the T-cell response over time is a helpful tool for vaccine and drug development and is important to better understand the long-term effects of COVID-19 and how the disease interacts with other conditions.
Research shows that asymptomatic and symptomatic individuals with COVID-19 experience organ impairment, and characterizing this population prior to trial enrollment will be important to help distinguish between drug/vaccine-related adverse events and COVID-19-related clinical implications. The immunoSEQ® Technology is a flexible, quantitative, accurate, reproducible, cost-effective, and scalable assay that can not only map T-cell immune responses to SARS-CoV-2, but also track these responses longitudinally over time in various sample types.
Moreover, it is important to understand the long-term symptoms of COVID-19 and have a sensitive way to determine if people who present with some of these symptoms or autoimmune signatures have ever been exposed to SARS-CoV-2, or if their symptoms stem from another issue. Sequencing their T-cell repertoires could do that. Comparing datasets from patients with autoimmune disorders with those from patients with COVID-19 using the immunoSEQ T-MAP COVID tool may help us to understand the mechanisms of COVID-19-related autoimmunity, and autoimmunity in general.
The immunoSEQ T-MAP COVID offering can be a powerful tool to help drive vaccine/drug development, understand whether patients presenting with certain acute or chronic symptoms have been exposed to SARS-CoV-2, and illuminate the interaction of COVID-19 with other conditions such as other infectious diseases, autoimmune disorders, and cancer. Read our previous blog post to learn more about immunoSEQ T-MAP COVID and its different research applications (Figure 3).
Figure 3. The immunoSEQ T-MAP COVID tool can be used to study and analyze the COVID-19 T-cell immune response map, allowing researchers to measure, analyze, and compare the T-cell response to COVID-19 in various applications.
If you think that the immunoSEQ Assay or immunoSEQ T-MAP COVID can help you in your research, contact us. A representative can advise you on anything from initial experimental design questions to data analysis queries.
Research Use Only. Not for use in diagnostic procedures.
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