Mechanisms of a syndrome

By combining experimental studies and clinical investigation, researchers contribute to international efforts to understand the physiopathological mechanisms of sepsis

By  Fábio de Castro

Agência FAPESP – By combining clinical and experimental studies over the last four years, a group of São Paulo researchers has contributed to international scientific efforts that have resulted in major advances in understanding the physiopathological mechanism of sepsis – a syndrome characterized by a set of grave manifestations throughout an entire organism, produced from systemic infections.

In addition to experimental studies, the scientists linked to the FAPESP-funded Thematic Project, Sepsis: Integrating Basic Research and Clinical Investigation, conducted clinical research on sepsis in a network of Intensive Care Units (ICUs) throughout São Paulo City.

According to project coordinator Reinaldo Salomão, professor at the Medical Department of Universidade Federal de São Paulo (Unifesp), a more precise understanding of the mechanisms of sepsis will be useful for planning treatment policies for the syndrome and for the development of new therapeutic approaches.

“Better comprehension of physiopathological mechanisms is a fundamental step so that we can identify new therapeutic targets in the future. To make this possible, some interaction between experimental and clinical research is fundamental,” he told Agência FAPESP.

According to Salomão, sepsis is a problem that has still not been given its due attention in the public health realm. The syndrome, he underscores, is more common than thought.

“In general, when dealing with problems like hemorrhagic strokes or acute myocardial heart attacks, for example, the population knows how to recognize the symptoms and to seek help. But with sepsis, which is an extremely common problem, there is not much awareness,” he explained.

On the other hand, observing a patient with sepsis is something impressive. “In general, the patient has fever, tachycardia, difficulty breathing, low blood pressure and reduced oxygenation in tissues. It is dramatic,” he says.

According to Salomão, clinical research shows that the incidence of sepsis is high and its epidemiology is dynamic, impacting different populations.. A study conducted in São Paulo by members of the project showed that 30% of ICU patients are hospitalized due to sepsis, or develop the syndrome during their hospitalization.

“A nationwide multicentric study also corroborated this percentage. If we project this incidence for all the intensive therapy beds available in the country, we will have something like 400,000 cases of sepsis per year,” he stated.

The cost associated with septic patients in medical literature is widely varied. Some studies show values as high as US$ 20,000 per patient. “A study published in the magazine Pharmacoeconomics indicated that in Brazil the average daily cost of treatment reaches US$ 1,000. As the treatments last an average of 10 days, we can estimate roughly US$ 10,000 per patient,” he said.

The syndrome, according to Salomão, has different “stages.” Sepsis corresponds to the initial stage involving clinical complications that lead to organic dysfunctions. When there is organic dysfunction, grave sepsis occurs. When a patient can no longer withstand the pressure and s/he becomes hypertensive, the septic shock sets in.

“In general, for everyone in two cases of grave sepsis, one results in death. In better scenarios, one in three cases ends in the death of a patient. Because it is as common as it is grave, we have a critical situation from an epidemiological and social point of view,” he explains.   
  
It is within this epidemiological context that the group led by Salomão has been studying sepsis for over 20 years. According to him, during this period the research has been supported by FAPESP through different Regular Research Awards. “In the Thematic research area, we brought together scientists involved in clinical studies and other experimental models concerned with the experimental design of sepsis,” he said.

The group formed a network of researchers with activities in different ICUs throughout São Paulo city in order to conduct the clinical studies. The network involves major hospitals like Albert Einstein, Sírio Libanês and Unifesp’s Hospital São Paulo. “Recently, Hospital Santa Marcelina and Hospital das Clínicas joined the network. But the data obtained by the project to date were extracted from three other institutions,” he said.

Multiprofessional teams in the ICUs within the network identified and monitored patients with sepsis with a view to answering epidemiological questions. The central concern was prognostic factors related to more precocious or later patient deaths. The interventions associated with better patient survival rates were also monitored in the study.

“Patient data were collected in electronic records so that we could study both the epidemiological aspects like etiology – or rather, identifying which bacteria cause infections and determining the most appropriate treatment,” he explained.

At the same time, the blood samples collected during the study were sent to Unifesp’s Immunology Laboratory for Infectious and Parasitic Disease, under the coordination of Salomão. There, the samples were processed and stored, especially with the objective of making future studies possible on aspects related to the response of hosts of the syndrome as means of clarifying its mechanisms.

“Sepsis is a syndrome characterized by systemic inflammatory response triggered by infection. But it is interesting to note that the greater part of sepsis is the result of the response that the host generates to control infection. There is, however, certain ambivalence: this clinical profile occurs in part due to the response of the host’s organism, but if this response did not occur, the patient could die much quicker. The inflammatory response is associated with an injury, but is fundamental for the survival of the patient,” he says.

Reprogramming of functions

The host’s response has been the focus of the laboratory studies, according to Salomão. “Our priority is understanding the regulation of cellular functions in patients with sepsis, considering, for example, that the cell maintains its activity, if it manages to phagocytize bacteria, if it produces inflammatory cytokines, if there is expression of bacteria recognition receptors, if there is cell signaling or how gene expression occurs for regulation of immunological response,” he explains.

Studies conducted by the group helped show that, although sepsis is described as a syndrome of systemic inflammatory response, it is not necessarily an exacerbated response. One study published by Salomão and colleagues in a 2006 edition of Shock magazine showed that throughout several stages of sepsis, the response could be exacerbated or diminished.

“In the first place, the inflammatory response is harmful, but, on the other hand it is protective and necessary. In second place, it is not static: as soon as the host produces a response, the organism attempts to control it, in order not to die from the inflammation,” he says.

Approximately 15 years ago, according to Salomão, doctors attempted to block inflammatory responses in treating sepsis. But with the new discoveries, they realized that depending on the stage of the illness, the response is already greatly diminished and needs to be activated.

“The literature does mention that the second stage of sepsis corresponds to immunoparalysis. We began to understand that this posterior phase does not consist solely of paralysis. The diminished response is possibly a reprogramming of functions,” he adds

Another article published in 2008 in Critical Care magazine indicates that this biphasic characteristic of inflammatory response linked to sepsis is not the same for all cells.

“When monocytes can no longer produce inflammatory cytokines, we studied the neutrophyles of peripheral blood and saw that they remained active. This suggests that the response could be distinct for different types of cells.  The monocyte could have a depressed response in the production inflammatory cytokines, but have all other activities in intact. We studied phagocytosis and we saw that these functions had been preserved. This makes it very evident that we are talking about reprogramming functions,” he said.

Another article published in Critical Care magazine in 2009, described studies in patients with sepsis, showing that there could be more genes regulated positively or negatively depending on the stage of the illness. Eventually, the dynamic was distinct according to the cell that had been evaluated. The article was the subject of an editorial in the magazine. 

“The premise was probably correct: there was regulation of gene expression according to the stage of sepsis. And it was different in mononuclear cells and in polymorphonuclear cells,” said Salomão.

The researchers also conducted tolerance studies. An article published in the March edition of Immunobiology showed that the tolerance of lipopolysaccharide, a mechanism involved in the diminishing of cellular response, had regulation similar to that found in septic patients. “In utilizing rigorously controlled models and variables, this study revealed important aspects of the mechanism of sepsis,” he explained.

The Thematic Project generated several other articles published in international magazines. According to Salomão, the group will continue studies on the topic after the project is concluded in August.

“Some studies showed that macrophages are different from other subpopulations that vary according to the stage of the disease. Some of these macrophages are activated in the traditional manner and others have alternative activation mechanisms. We saw that some alternatively activated macrophages have a function profile similar to those seen in patients with sepsis. This will be the new focus of research,” he affirmed.