A study published in the journal Frontiers in Immunology suggests that sepsis can cause changes in the functioning of defense cells that persist even after hospital discharge.
According to the authors, this cellular reprogramming may be associated with the so-called post-sepsis syndrome, whose symptoms include frequent reinfections, cardiovascular changes, cognitive deficiencies, decline in physical functioning and poor quality of life.
The phenomenon would explain why most individuals who survive the disease die a few years later or develop long-term disabilities, leaving their immune function impaired and a state of chronic inflammation.
Considered one of the main causes of death in Intensive Care Units (ICUs) in the world, sepsis is a systemic organic dysfunction that occurs in response to an infectious agent. It is mainly caused by bacteria and fungi. The defense system starts to fight not only this agent, but also the organism itself, generating organ dysfunction.
When not recognized and treated early, it can lead to septic shock and multiple organ failure. People severely affected by Covid-19 and other infectious diseases are at increased risk of developing and dying from the widespread infection.
It is estimated that around 49 million new cases of sepsis are registered worldwide each year. The hospital mortality of these patients is above 40%, reaching 55% in Brazil, according to the Spread study (acronym for Sepsis Prevalence Assessment Database), carried out with the support of Fapesp.
In the article published in Frontiers, the researchers present a list of studies carried out and the numbers of deaths recorded within five years after hospital discharge.
“The massive infection and the intense immune response that accompanies it with large increases in cytokine concentration [proteínas inflamatórias] in the blood during sepsis can promote irreversible cellular metabolic reprogramming. Cell reprogramming is unlikely to occur only in leukocytes or bone marrow, and may be recorded in many tissues and cells. And this leads to systemic organ dysfunction,” the researchers write in the paper.
Biomedical researcher Raquel Bragante Gritte, who shares the first authorship of the article with Talita Souza-Siqueira, says that one of the hypotheses studied by the group is that metabolic reprogramming begins in the bone marrow, causing cells to have a pro-inflammatory profile. “When we collected blood from patients, even three years after discharge from the ICU, we found that monocytes [um tipo de célula de defesa] they were activated, ready for battle, and they should be neutral, with activation only when they were ‘recruited’ for the fabric”, says Gritte, in an interview with Agência Fapesp.
Historic
The Frontiers article is one of the first of the group on the subject. It describes the results of the line of research by physicians and professors at the University of São Paulo (USP) Marcel Cerqueira César Machado, who has the support of Fapesp, and Francisco Garcia Soriano. It summarizes recent findings from studies available on PubMed (recognized database of scientific abstracts) on the outcome of septic patients after hospital discharge.
According to Gritte, the study group followed 62 patients at the University Hospital of USP for three years after discharge from the ICU. During this period, changes in monocytes, neutrophils and lymphocytes (types of leukocytes) were analyzed, as well as microRNAs, in an attempt to identify prognostic markers or factors associated with the post-sepsis syndrome.
“Our hypothesis is that leukocytes retain a memory of sepsis, helping to explain why the patient remains ill even after hospital discharge”, says Professor Rui Curi, from the Cruzeiro do Sul University and the Butantan Institute, one of the supervisors of the work together with Machado and Soriano.
In the paper, the researchers speculate that sepsis may generate a specific monocyte phenotype that would remain active after hospital discharge. “Reprogramming of cellular metabolism is involved in the specific functions of different subtypes of lymphocytes. Various stimuli and conditions alter leukocyte metabolism [linfócitos, monócitos e neutrófilos]including the very availability of nutrients in the microenvironment.”
According to Gritte, a next step would be to carry out research with the bone marrow, looking for what generates the cellular reprogramming caused by sepsis. “We believe that the key to this change lies in the marrow. Another way, however, would be for the activation to occur in the blood. We have to carry out a deeper evaluation to find answers.”
The knowledge acquired in this study may be the basis for developing strategies to minimize or block post-sepsis changes in the future.
In 2020, the World Health Organization (WHO) published the 1st Global Report on sepsis in which it points out gaps in knowledge about the infection, especially in poorer countries, hampering efforts to combat deaths and disabilities resulting from it.
WHO recommends expanding funding and capacity to research epidemiological evidence on sepsis, as well as developing rapid, affordable and appropriate diagnostic tools to improve the identification, prevention and treatment of widespread infection.
The article “Why Septic Patients Remain Sick After Hospital Discharge?” can be read here.
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