Recovery from severe COVID-19 is characterized by the gradual decline of certain white blood cells and changes in the molecular control of the immune system. This is the conclusion reached by an international research team coordinated by the DZNE, which reports on it in the journal Cell Reports Medicine . The scientists examined the blood of 139 patients receiving intensive care treatment. Using a novel method of data analysis, they identified mechanisms of overarching importance that characterize the recovery process from an immunological perspective, despite individual differences in the course of the disease over time. These findings demonstrate a novel approach to assessing disease status that could contribute to more targeted and therefore effective treatment.
The current study is the result of an international project in which the DZNE cooperated with the Helmholtz Zentrum München , the Technion Institute in Israel and Radboud University in the Netherlands. The challenge for the scientists was to identify commonalities in the data from different patients. With COVID-19, as with many other diseases, the recovery process can vary greatly from person to person, which is reflected, for example, in how symptoms develop and how long hospitalization takes.
“This makes it difficult to identify generalizable cellular and molecular mechanisms underlying the disease. However, such findings are important in order to understand the nature of the disease and the body's reaction - and thus also in order to decide on the optimal treatment," says bioinformatician and genomic researcher Dr. Amit Frishberg , first author of the current specialist publication. “That’s why we used a novel method that we recently developed to analyze the data. Our computational approach is designed to identify common patterns that may not be obvious in the diversity of findings from different patients.”
Blood tests
COVID-19 can affect many organs. However, the disease is known to be largely influenced by the immune reaction. “This reaction is reflected in the blood, because that’s where the white blood cells ,” says Frishberg. “These cells are essential components of the immune system. That’s why our study focused on the blood of patients.”
In total, the researchers examined blood samples from 139 adults whose ages ranged from 21 to 86 years, most of whom were male. The data came from three different cohorts. All patients were treated in an intensive care unit and ventilated: 105 recovered sufficiently to be discharged from the intensive care unit, while 34 died. Most of the people examined here had several blood samples taken, usually within a period of around three weeks after admission to the intensive care unit. Some patients also provided self-reports about their state of health three months after admission to the intensive care unit (and later discharge).
A common thread
The analysis showed that the recovery process is accompanied by a gradual reduction in the number of so-called neutrophils. They are the most common white blood cells and act as one of the first lines of defense against pathogens in the immune system's arsenal. “We have found that patients with severe COVID-19 have high numbers of mature, i.e. fully developed, neutrophils in their blood, the amount of which decreases during the recovery process. The levels of other white blood cells also change as the blood returns to normal, with some of them decreasing while others increasing. However, these changes are less pronounced than in neutrophils,” says Frishberg.
“We also see that in intensive care patients, an increase in mature neutrophils over a long period of time is very likely to lead to a fatal outcome. This is possibly because the constant increase is accompanied by an excessive and therefore harmful immune reaction. The number of these cells in the blood could therefore serve as a biomarker and be more meaningful for predicting disease development than other biomarkers that are currently being discussed.”
The researchers discovered further changes in the course of recovery that affect molecular signaling pathways and regulatory mechanisms of the immune system. “The remarkable thing about our results is that recovery followed the same biological pattern in all patients, despite individual differences in the time course of the disease. So there is a common thread, so to speak. In our data, we found no evidence that the recovery process after a severe COVID-19 illness can follow different trajectories,” says Frishberg.
Alignment of transcriptomes
For their analysis, the scientists relied primarily on blood transcriptomes. These data sets reflect the gene activity of all blood cells at a specific point in time. As a rule, more than 10,000 different genes are recorded. “Blood transcriptomes provide a very detailed picture of the immunological process,” says Prof. Joachim Schultze, director of systems medicine at the DZNE and professor at the University of Bonn , who was also involved in the current study. “The analysis of this very complex data requires computer-aided procedures. This is where our new approach came into play.”
The method used by the researchers is based on a calculation algorithm that puts all transcriptomes from different patients in a common order. “This is based on similarities and the assumption that all recovered patients ultimately have the same recovery process. One way to think of this is that each transcriptome represents a snapshot of the disease state that evolves into the next snapshot. Similar to how many individual images ultimately make a film,” says Schultze. From this series of individual, experimentally obtained transcriptomes, a model calculated that reflects the continuous course of the recovery process.
The biological dynamics over time are characterized by parameters calculated by the algorithm . “Since the recovery process can vary from person to person, the same immunological situation can arise in different patients at different times. “Chronological time is therefore not a suitable measurement for recording the development of the recovery process on a biological level ,” explains Schultze. “Our method is therefore based on the calculation of a parameter called pseudotime, which is assigned to each patient sample. A low pseudotime represents a severe state of illness or an initial state of recovery, while a high pseudotime represents an advanced state of recovery.”
Approach for better treatment
From this model, the researchers were able to derive their findings about the decline in neutrophils and the changes in the regulatory mechanisms, none of which were apparent from the raw data. In addition, access to data from different cohorts allowed them to validate their results and check whether the assumptions on which their model was based were actually consistent with the experimental findings.
“Our study shows how algorithms and modeling can be used to extract insights from complex data. We believe this is a powerful approach with broad application potential. Many diseases are characterized by heterogeneous and patient-specific recovery courses. “In view of this, our analysis method could also be useful for researching diseases other than COVID-19,” said Schultze. “The bottom line is that our study presents a novel approach to assess the recovery status of intensive care patients based on blood transcriptomes. This could contribute to a more targeted and therefore more effective treatment of COVID-19. In view of this, it might be worthwhile to examine the extent to which such examinations can be implemented in clinical routine.”
About the DZNE: The DZNE is a federally and state-funded research institute that has ten locations nationwide. It is dedicated to diseases of the brain and nervous system such as Alzheimer's, Parkinson's and ALS, which are associated with dementia, movement disorders and other serious health impairments. To date, there is no cure for these diseases, which place an enormous burden on countless sufferers, their families and the healthcare system. The aim of the DZNE is to develop novel strategies for prevention, diagnosis, care and treatment and to put them into practice. To this end, the DZNE cooperates with universities, university hospitals and other institutions at home and abroad. The institute is a member of the Helmholtz Association and is one of the German centers for health research.
Original publication
Mature neutrophils and a NFkB-to- IFN transition determine the unifying disease recovery dynamics in COVID-19.
Amit Frishberg et al.
Cell Reports Medicine (2022).
DOI: 10.1016/j.xcrm.2022.100652
Source: German health portal
Further articles on the topic of Covid-19 can be found HERE
Notes:
1) This content reflects the current state of affairs at the time of publication. The reproduction of individual images, screenshots, embeds or video sequences serves to discuss the topic. 2) Individual contributions were created through the use of machine assistance and were carefully checked by the Mimikama editorial team before publication. ( Reason )