New research provides important insights into the role played by the immune system in preventing—and in some cases increasing the severity of – COVID-19 symptoms in patients. It also finds clues to why some people experience “long COVID.”
Among the key findings, which have not yet been peer-reviewed, are:
- Individuals who have asymptomatic or mild disease show a robust immune response early on during infection.
- Patients requiring admission to hospital have impaired immune responses and systemic inflammation (that is, chronic inflammation that may affect several organs) from the time of symptom onset.
- Persistent abnormalities in immune cells and a change in the body’s inflammatory response may contribute to ‘long COVID.”
The immune response associated with COVID-19 is complex. Most people who get infected by SARS-CoV-2 mount a successful antiviral response, resulting in few if any symptoms.
In a minority of patients, however, there is evidence that the immune system over-reacts, leading to a flood of immune cells (a ‘cytokine storm’) and to chronic inflammation and damage to multiple organs, often resulting in death.
To better understand the relationship between the immune response and COVID-19 symptoms, scientists at the University of Cambridge and Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, have been recruiting individuals who test positive for SARS-CoV-2 to the COVID-19 cohort of the NIHR BioResource.
These individuals range from asymptomatic healthcare workers in whom the virus was detected on routine screening, through to patients requiring assisted ventilation. The team take blood samples from patients over several months, as well as continuing to measure their symptoms.
In research published today, the team analyzed samples from 207 COVID-19 patients with a range of disease severities taken at regular interviews over three months following the onset of symptoms. They compared the samples against those taken from 45 healthy controls.
Because of the urgent need to share information relating to the pandemic, the researchers have published their report on MedRXiv. It has not yet been peer-reviewed.
Professor Ken Smith, senior co-author and Director of the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), said: “The NIHR BioResource has allowed us to address two important questions regarding SARS-CoV-2. Firstly, how does the very early immune response in patients who recovered from disease with few or no symptoms, compare with those who experienced severe disease?
And secondly, for those patients who experience severe disease, how rapidly does their immune system recover and how might this relate to ‘long COVID’?”
The team found evidence of an early, robust adaptive immune response in those infected individuals whose disease was asymptomatic or mildly symptomatic. An adaptive immune response is where the immune system identifies an infection and then produces T cells, B cells and antibodies specific to the virus to fight back.
These individuals produced the immune components in larger numbers than patients with more severe COVID-19 managed, and within the first week of infection – after which these numbers rapidly returned to normal. There was no evidence in these individuals of systemic inflammation that can lead to damage in multiple organs.
In patients requiring admission to hospital, the early adaptive immune response was delayed, and profound abnormalities in a number of white cell subsets were present. Also present in the first blood sample taken from these patients was evidence of increased inflammation, something not seen in those with asymptomatic or mild disease.
This suggests that an abnormal inflammatory component to the immune response is present even around the time of diagnosis in individuals who progress to severe disease.
The team found that key molecular signatures produced in response to inflammation were present in patients admitted to hospital. They say that these signatures could potentially be used to predict the severity of a patient’s disease, as well as correlating with their risk of COVID-19 associated death.
Dr. Paul Lyons, senior co-author, also from CITIID, said: “Our evidence suggests that the journey to severe COVID-19 may be established immediately after infection, or at the latest around the time that they begin to show symptoms.
This finding could have major implications as to how the disease needs to be managed, as it suggests we need to begin treatment to stop the immune system causing damage very early on, and perhaps even pre-emptively in high risk groups screened and diagnosed before symptoms develop.”
The researchers found no evidence of a relationship between viral load and progression to inflammatory disease. However, once inflammatory disease was established, viral load was associated with subsequent outcome.
The study also provides clues to the biology underlying cases of ‘long COVID’ – where patients report experiencing symptoms of the disease, including fatigue, for several months after infection, even when they no longer test positive for SARS-CoV-2.
The team found that profound alterations in many immune cell types often persisted for weeks or even months after SARS-CoV-2 infection, and these problems resolved themselves very differently depending on the type of immune cell.
Some recover as systemic inflammation itself resolves, while others recover even in the face of persistent systemic inflammation. However, some cell populations remain markedly abnormal, or show only limited recovery, even after systemic inflammation has resolved and patients have been discharged from hospital.
Dr. Laura Bergamaschi, the study’s first author, said: “It’s these populations of immune cells that still show abnormalities even when everything else seems to have resolved itself that might be of importance in long COVID. For some cell types, it may be that they are just slow to regenerate, but for others, including some types of T and B cells, it appears something is continuing to drive their activity.
The more we understand about this, the more likely we will be able to better treat patients whose lives continue to be blighted by the after-effects of COVID-19.”
Professor John Bradley, Chief Investigator of the NIHR BioResource, said: “The NIHR BioResource is a unique resource made possible by the strong links that exist in the UK between doctors and scientists in the NHS and at our universities. It’s because of collaborations such as this that we have learnt so much in such a short time about SARS-CoV-2.”
A great proportion of COVID-19 studies concluded risk factors contributing to severe disease and adverse outcomes include advanced age (>60 years) and male sex, with comorbidities, such as hypertension, diabetes mellitus, and cardiovascular disease.
The most common initial clinical symptoms were fever, cough, dyspnea, and fatigue.4–8 However, it is unclear whether the symptoms will become more insidious as the pandemic progresses and will gradually evolve into a virus similar to influenza or remain latent in humans for a long period of time, as suggested by Chen et al.48
Wide ranges of laboratory abnormalities were reported with different disease severity, but marked changes were more commonly seen in samples from severe and critically ill patients.24
Hematologic parameters, including lymphopenia, leukocytosis with increased neutrophil count, increased NLR, and thrombocytopenia, were the most common findings observed and positively correlated with disease severity.22,30,47 A strikingly decreased lymphocyte count was associated with severe disease and higher complication rate.
The decreases in both CD4 and CD8 T lymphocytes are best explained by the roles these T-lymphocyte subsets play in eliminating virus-infected cells, and this is consistent with low lymphocyte counts being associated with poor case outcomes.32,64
An upward trend of CRP, ferritin, SAA, procalcitonin, and the most prominent cytokine, IL-6, and a downward trend of albumin and/or prealbumin were frequently observed during progression from mild to severe/critical condition, and in nonsurvivors. Serial measurements of these markers can be used to predict disease course, severity, and mortality.22,37,47
It has been postulated that SARS-CoV-2 may target alveolar macrophages via the angiotensin converting enzyme 2 (ACE2) receptor, leading to an increase in cytokine secretion, including IL-6 and TNF-α, which subsequently induces the elevation of various APPs, such as CRP, SAA, and complement factor, which are significantly upregulated in the severely ill group.
Changes in coagulation parameters, including prolonged PT, elevated D-dimer, and elevated fibrinogen or FDP, were common findings in severe disease and nonsurvivors.4,30 Prolonged PT and higher serum D-dimer levels were postulated to demonstrate a hypercoagulable state rather than consumptive coagulopathy.
It was proposed that hyperfibrinogenemia leads to fibrin polymerization, thrombus formation, and eventually complications or adverse outcome.40 Other biomarkers, such as LDH, CK, BNP, AST, and ALT, have been associated in several studies with severe and critically ill disease, and their levels likely indicate adverse outcome.24,55,56 AST-dominant elevations were common in COVID-19 patients and appeared to reflect true hepatic injury.55 Additionally, AST level correlated with markers for muscle injury, including LDH and CK.55
To date, molecular testing identifying viral particles on nasopharyngeal specimens by RT-PCR remains the gold standard in the diagnosis of SARS-CoV-2 infection. Concurrent antibody testing can aid in increasing detection sensitivity.75 Other specimen sources, such as self-collected saliva, which is less painful and does not require trained personnel for collection, should be considered as preferable alternatives for SARS-CoV-2 screening of health care workers and asymptomatic cases.11,76
The sensitivity of SARS-CoV-2 detection from saliva samples was demonstrated to be comparable to that of nasopharyngeal swabs in early hospitalization.76 The results were more consistent during extended hospitalization and recovery, most likely because of less temporal SARS-CoV-2 variability.76 Routine blood tests may also be used as early predictors of the molecular testing result.
They can serve as an alternative for identifying SARS-CoV-2 infection in countries with heavy outbreaks and a shortage of RT-PCR reagents or specialized labs, because they have been shown to have detection rates comparable with those of molecular tests.25 Moreover, early recognition of severe disease or disease that is likely to progress is absolutely essential for timely triage of patients.
Measurement of soluble PSP or sCD14-ST in peripheral blood may be used for early diagnosis of sepsis and for risk stratification.53 The use of proteomic approaches and nontraditional samples, like cerebrospinal fluid, may identify additional biomarkers that may be helpful in the pathophysiology and prognosis of COVID-19 disease.20,46
Interpretation of the results of several studies presented in this review is limited because of the predominantly retrospective study designs, small sample sizes, multiple sampling biases (ie, most were single-center studies with cohorts from east Asian ethnic groups), lack of uniformity of disease severity definition based on variable RT-PCR methods, and lack of exact timeline of laboratory sample collection, as well as lack of serial sample measurements.
This information is important because a defined timeline of collection and serial sampling performance may aid in clinical decision-making during the acute phase of disease. In addition, a great proportion of studies were cut short and failed to report final outcomes because of the need for prompt data publishing during the current pandemic. Overall, the reader should be cautioned when viewing medRxiv papers presented prior to peer review. It is recommended that updated peer-reviewed published versions of these original studies be evaluated when/if available.
The dynamic changes in biomarker levels may assist in predicting disease course, prognosis, and outcome. Indicators of systemic inflammation, such as NLR and systemic immune-inflammation index or coagulopathy screening using a DIC scoring system, could be appropriately used to predict disease severity, possible complications, and outcome.
Finally, COVID-19 Severity Score and clinical decision support tools can additionally be used employing combined measurements of multiple biomarkers to predict mortality. In summary, WBC, lymphocyte, and platelet counts, CRP, ferritin, and IL-6 may be potential prognosticators of progression to critical illness.
Therefore, prospective studies with larger cohorts, clearly defined disease severity, and serial measurements with defined sampling collection timelines are imperative to further confirming the correlation and significance of the current findings.
reference link: https://meridian.allenpress.com/aplm/article/144/12/1465/442581/Predicting-Disease-Severity-and-Outcome-in-COVID
More information: Laura Bergamaschi et al. Early immune pathology and persistent dysregulation characterize severe COVID-19, MedRxiv (2021). DOI: 10.1101/2021.01.11.20248765