As we have seen, although bacteria (through their PAMPs) initiate the septic response, it is the dysregulated host immune response that amplifies the process and causes the cellular injury that ultimately leads to the characteristic picture of multiorgan failure. There have been phenomenal advances in understanding the intricacies of the host response to sepsis which have been well reviewed elsewhere , and these have provided a rich source of potential targets  (Table 3). Broadly, two different approaches have been pursued: what might be called ‘immunosuppression’, aimed at several points in the inflammatory pathway, and ‘immunotherapy’, in which drugs are aimed at specific key elements.
Immunosuppression—steroids and intravenous immunoglobulin (IVIG) as examples
The first major clinical trials of steroids in the treatment of sepsis date back to the 1980s. A substantial body of preclinical data had suggested that many of the manifestations of sepsis were due to excess inflammation, and that anti-inflammatory doses of steroids would be beneficial. Indeed, in various animal models, including primates, steroids were very effective. On the basis of these findings, two large clinical trials of high-dose steroids were conducted and both concluded that these high-dose regimens were not effective in preventing death from sepsis, or, indeed, were perhaps even harmful, increasing the risk of superinfection [19,20].
More recently, Annane et al. suggested that some septic patients failed to respond adequately to the physiological ‘stress’ that occurs in sepsis. On the basis of pilot data showing that small doses of hydrocortisone reduced vasopressor dependency, they proceeded to carry out a prospective, randomized controlled trial in which patients with septic shock received replacement doses of hydrocortisone plus fludrocortisone or matching placebos, for 7 days . They enrolled 300 patients, and the main outcome measure was 28-day survival in patients who were shown to have adrenocortical insufficiency on the basis of a corticotropin test. There were fewer deaths in the active treatment group: 73 vs. 60, p 0.02.
It is still not clear whether this approach is genuinely based on ‘replacement therapy’ or is, in fact, simply a more modest dose of immunosuppression, and, indeed, the recent CORTICUS trial, which attempted to repeat the findings of the original study, failed to reproduce the beneficial outcome . A recently updated meta-analysis has tentatively concluded that low-dose steroids are beneficial for the subset of patients at high risk of death  but, in the absence of a trial that specifically addresses this question, the debate is likely to continue for some time.
The use of IVIG in sepsis also has a long history . It was initially thought that it might be useful because it contained anti-endotoxin antibodies  but, despite several clinical trials, this idea never really gained currency, and IVIG has largely disappeared from routine clinical use for sepsis with the exception of patients with streptococcal toxic shock syndrome (STSS). Group A streptococci produce exotoxins that have the property of superantigens, and it is this that is thought to underlie many of the manifestations of STSS (reviewed in ). Commercial preparations of IVIG contain antibodies to one of the major streptococcal exotoxins, streptococcal pyrogenic exotoxin A, , and it was thought that this might explain the somewhat anecdotal clinical evidence that large doses of IVIG seemed to be beneficial in this disease [27,28]. However, it has subsequently emerged that streptococcal pyrogenic exotoxin A is just one of many superantigenic toxins produced by streptococci, and it is not even the most potent.
If IVIG is indeed effective—and the clinical trial data are not of level 1 quality, either for STSS or, more generally, for sepsis —then it is more likely that it is acting as a non-specific immunosuppressant, in much the same way as it is effective in idiopathic thrombocytopenic purpura. In a very real sense, treating severe infection with immunosuppressives is counterintuitive, and the risk of making things worse and/or causing secondary infections is one of the main concerns with this approach. A more attractive strategy is targeted immunotherapy.