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Should we be moving from suppression to stimulation to deal with immunoparalysis in sepsis patients? “Failure of clinical development of agents that attenuate proinflammatory phenomena has shed light on strategies of immuno­stimulation.” KEYWORDS: clarithromycin n IFN-g n IgM n immunosuppression n sepsis

The failure of most clinical trials has led to considerable consideration regarding the future of immunotherapy in sepsis. Most of these trials studied the efficacy of agents that block proinflammatory cytokines such as TNF‑a and IL‑1b. These cytokines are secreted during the initial stages of sepsis by circulating monocytes and tissue macrophages. When circulating monocytes are isolated for at least 24 h after clinical development of sepsis, they fail to produce similar amounts of TNF‑a, IL‑1b and IL‑6 compared with the monocytes of healthy volunteers [1]. In parallel, their transcriptional activity for these mediators is severely downregulated. It appears that a similar situation takes place in tissues. In a recent study, leukocytes were isolated from the spleen of cadavers of 29 patients dying from trauma and of 40 patients dying from sepsis. The results confirmed the severe suppression of both the innate and adaptive immune responses of splenocytes comprising impaired cytokine production, defective antigen presentation and increased lymphocyte apoptosis [2]. This phenomenon of the exhaustion of the immune response after the initial septic insult is known as sepsis-related immunoparalysis or immunosuppression. In most conducted trials, agents that block proinf lammatory mediators are administered later than the peak of proinflammatory responses; at the time of their administration, circulating monocytes are exhausted for cytokine production. As a consequence, treatment increases further exhaustion and hampers the restoration of their function. This is probably, in part, due to the failure of the strategies to overwhelm the proinflammatory response of the host. Despite the disappointment for the outcome of these trials, knowledge for the phenomenon of immunoparalysis has boosted enthusiasm for future trials with agents that stimulate immune responses.

In a clinical trial of our group, patients with ventilator-associated pneumonia (VAP) were randomized into blind intravenous treatment with placebo or with clarithromycin for 3 consecutive days. Blind treatment was given as adjunctive therapy on top of antimicrobials. Clarithromycin treatment was accompanied by earlier resolution of VAP within 10 days instead of 15.5 days of the placebo arm (p = 0.011). However, no survival benefit from treatment with clarithromycin was seen in the overall study population, but was only seen within the subgroup of patients with septic shock and multiple organ dysfunctions (MODs); odds ratio for death in this subgroup decreased from 19.00 in the placebo arm to 3.78 in the clarithromycin arm (p = 0.048) [3]. Monocytes were isolated from the bloodstream of the patients for seven consecutive days; serum TNF‑a and IL‑10 were measured on the same days. The most striking differences between groups were found among patients with septic shock and MODs who experienced survival benefit from clarithromycin treatment; the ratio of serum IL‑10/TNF‑a, that is an index of immunoparalysis, decreased, the expression of CD86 on monocytes, that is an index of effective antigen presentation, increased; and the ex vivo production of IL‑6 by monocytes was increased [4]. Although these results do not necessarily imply the mode of action of clarithromycin, they underscore that survival benefit from septic shock and MODs is linked with reversal of immunoparalysis. Until now, no well-powered randomized clinical trial (RCT) of immunostimulation has even been conducted in patients with severe sepsis. The major question is which agent may be considered as a promising candidate for that RCT. Immunoglobulins enriched with IgM (IgM preparations), GM‑CSF, G‑CSF, recombinant IFN‑g (rIFN‑g) and recombinant IL‑7 (rIL‑7) tend to be the most promising candidates.

10.2217/IMT.13.161 © 2014 Future Medicine Ltd

Immunotherapy (2014) 6(2), 113–115

Evangelos J Giamarellos-Bourboulis 4th Department of Internal Medicine, University of Athens, Medical School, ATTIKON University Hospital, 1 Rimini Street, 12462 Athens, Greece and Integrated Research & Treatment Center, Center for Sepsis Control & Care, Jena University Hospital, Jena, Germany Tel.: +30 210 58 31 994 Fax: +30 210 53 26 446 [email protected]

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Among them, IgM preparations are more close to the bedside. Part of the phenomenon of immunoparalysis involves exhaustion of B lymphocytes for IgM production. IgM is a polyvalent immunoglobulin that is very effective for the opsonization of microrganisms and for the blockade of bacterial endotoxins and cytokines [5]. Two observational studies have shown that circulating levels are decreased in septic shock [6,7]. Data from the ana­ lysis of 332 patients enrolled from 27 study sites of the Hellenic Sepsis Study Group revealed that circulating IgM was at normal levels in severe sepsis and then abruptly decreased when septic shock developed. In these cases, the total body distribution of IgM in survivors was greater than nonsurvivors [8]. Conducted RCTs have failed to demonstrate any survival benefit from adjunctive treatment with intravenous immunoglobulins in severe sepsis. In one meta-ana­lysis, patients treated with IgM preparations were analyzed separately; the relative risk of death decreased by 34% among adults and by 50% among neonates [9]. However, the need to conduct large-scale RCTs remains.

“The efficacy of recombinant IFN‑g was

tested in a setting of experimental endotoxemia of healthy human volunteers. Enrolled volunteers became tolerant to bacterial endotoxin … by the first injection of lipopolysaccharide.” IFN‑g stimulates the gene expression of most proinflammatory cytokines and primes phagocytosis by neutrophils. NK cells are the main reservoir during early immune responses. Production of IFN‑g by NK cells is downregulated in sepsis and this provides a rationale for its use as immunostimulation treatment [10]. The efficacy of rIFN‑g was tested in a setting of experimental endotoxemia of healthy human volunteers. Enrolled volunteers became tolerant to bacterial endotoxin (lipopolysaccharide; LPS) by the first injection of LPS. Subcutaneous doses of blind treatment with placebo or rIFN‑g were then given every 48 h; after the third dose, a second dose of LPS was given. Serum TNF‑a and expression of HLA‑DR on circulating monocytes decreased after the second dose of LPS in the placebo group; in the IFN‑g arm, serum TNF‑a increased, as well as expression of HLA‑DR on monocytes [11]. Although results provided a clear-cut rationale for partial restoration of immunoparalysis by IFN‑g, the function of monocytes for cytokine production was not studied. 114

Immunotherapy (2014) 6(2)

Sparse evidence is available for the clinical efficacy of rIFN‑g in sepsis patients. In a nonrandomized study, IFN‑g was administered intravenously for 7 days in nine patients with sepsis and low expression of HLA‑DR on monocytes (

Should we be moving from suppression to stimulation to deal with immunoparalysis in sepsis patients?

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