The enigma of sepsis (original) (raw)
The idea that sepsis was caused by an overwhelming reaction of the patient to invading microorganisms was probably at least partially based on the observation that, on many occasions, no clinical evidence for infection (e.g., positive bacterial blood cultures) was found in patients with septic symptoms. In 1972, Lewis Thomas noted in The New England Journal of Medicine that “it is our response that makes the disease” and that the patient was, therefore, more endangered by this response than by the invading microorganisms (10). According to this view, interventions designed to attenuate immune and inflammatory responses might be clinically useful. In the 1960s, the first clinical trials featuring suppression of the immune and inflammatory responses were conducted, in which septic patients were treated with supraphysiological doses of glucocorticoids (11) (Table 3). However, these studies were unsuccessful, despite the fact that more recent studies have suggested benefits from low-dose glucocorticoid treatment (see “Failure of clinical trials in sepsis”).
Targets in clinical trials for the treatment of sepsis
As mentioned above, the predominant source of infection in septic patients before the late 1980s was Gram-negative bacteria. LPS, the main component of the Gram-negative bacterial cell wall, was known to stimulate release of inflammatory mediators from various cell types and induce acute infectious symptoms when injected into animals. In 1969, Davis and colleagues found that infusion of IgGs improved survival in an experimental setting after endotoxin infusion (12). Based on these and other findings, LPS blockade became a target for clinical intervention (13).
Given the frequency of Gram-negative infections in septic patients, it was assumed that large amounts of circulating LPS must be present. Based on this assumption, animal models of sepsis were established mainly in rodents, in which large doses of LPS had been administered. In contrast to the responses observed following bacterial infection (e.g., bacteria delivered by intraperitoneal or i.v. injection, or released into the peritoneal cavity in the cecal ligation and puncture [CLP] model), LPS infusion models often did not mimic the changes observed during sepsis (Figure 1). This fact became apparent in the case of TNF-α, a potent proinflammatory mediator. In addition, infusion of TNF-α into animals induced the symptoms characteristic of sepsis (14), while passive immunization with anti–TNF-α was protective (15, 16). High levels of TNF-α have been found in the serum of humans following i.v. injection of LPS (15). In 1985, Beutler and colleagues found that passive immunization against TNF-α protected mice from lethal endotoxic shock (16). These results were confirmed when Tracey et al. found that TNF-α blockade was beneficial in animal models of shock following infusion of endotoxin or Escherichia coli (17, 18). But subsequent clinical trials failed to demonstrate the utility of this therapy in septic humans (19) and in CLP mice (20). Why?
Possible reasons for failure in sepsis trials. The flow diagram reflects various stages in the development of sepsis therapies that precede clinical trials in sepsis patients. At each stage, possible reasons for failure of the strategy are listed. The murine LPS infusion model illustrates that anti–TNF-α antibody treatment can successfully increase survival rates of septic animals; however, this same therapy proved unsuccessful in clinical trials in humans with sepsis.
One possible explanation is that the results obtained from studies performed in LPS infusion animal models did not accurately reflect clinical developments in human sepsis. Serum TNF-α levels after infusion of LPS into mice were later described to be more than 200-fold higher than in CLP animals (20). In a similar study, CLP mice treated with anti–TNF-α antibodies showed not improved survival but, rather, a tendency toward worsened outcomes (21). Interestingly, the circulating LPS levels in the CLP sepsis model (which more accurately reflects the dynamics of sepsis occurring in humans) were found to be very low, and extreme elevations of TNF-α levels were not observed in rodent LPS infusion models (21). As indicated above, TNF-α levels observed in CLP models are generally very low and not comparable to TNF-α levels found after LPS infusion. In addition, LPS levels in septic patients are also reported to be low, and while in some cases of sepsis in humans (e.g., meningococcal sepsis in infants) elevated serum levels of TNF-α have been found in up to 90% of patients (22), several other clinical studies in septic patients reported only minimally elevated or undetectable levels of TNF-α (23). The failure of anti–TNF-α and anti-LPS interventions in septic patients can be seen as an example of how conclusions based on animal models may not hold true in humans, or may not be applicable to human sepsis because of incorrect assumptions underlying the animal models (e.g., that LPS is a major initiator of sepsis and is present in the serum at high levels during sepsis) (Figure 1). Currently, there is general agreement among researchers in the field that LPS injection may serve as a model for endotoxic shock but not for sepsis.