Immune-mediated inflammatory diseases as long-term sepsis complications: Long-term persistence of host dysregulation?

Sepsis results from the dysregulated host response to bacterial, viral, or fungal infections. Recent data suggest that the 28-day outcome of sepsis patients depends on the features of the immune reaction of the host. Four to 10% of patients with septic shock present an entirely pro-inflammatory course with a high risk for early death and features mimicking the macrophage activation syndrome (MALS)—that is, liver dysfunction, disseminated intravascular coagulation, and increases of blood ferritin and triglycerides. Almost 30% of patients with sepsis present with immunoparalysis, that is, failure of circulating mononuclear cells for production of cytokines upon ex vivo stimulation and defective antigen presentation, often leading to T cell exhaustion. However, the immune function of the majority lies at an intermediate state between MALS and immunoparalysis [1]. It may well be the case that this immune classification guides long-term outcomes of sepsis—a condition often called chronic critical illness (CCI) or persistent inflammation, immunosuppression, and catabolism syndrome (PICS). There are several host factors that impact the progression into CCI or PICS. The most important are age, the presence of cachexia, and the site of infection of the primary sepsis episode. These patients have profound disabilities associated with lymphopenia and increased expression of PD-1, expansion of myeloid-derived stem cells and T regulatory cells and dysfunctional erythropoiesis [2]. It is suggested that the 1-year mortality of sepsis survivors approaches 40%, and this may be associated with persisting immune dysregulations.

The article by Mageau et al. in this issue of the Journal of Internal Medicine breaks the boundaries and goes well beyond the traditional approach of long-term mortality and disabilities of sepsis survivors. Taking into consideration the complex immune dysregulation of sepsis, the authors ask themselves whether the original immune phenomena may lead to a predisposition for immune-mediated inflammatory diseases (IMIDs) among sepsis survivors. For their analysis, they used the French PMSI database, collecting information between January and November 2020 for 460,708 index cases of sepsis. They study as comparators 62,258 survivors from acute myocardial infarction (AMI). To avoid confounding bias, 62,257 sepsis survivors were selected to match with 62,257 survivors from AMI using the matching criteria of age, sex, active cancer, active malignant hematologic condition, HIV infection, and history of organ transplantation. Survivors of sepsis and AMI were followed up for 9 months, and all new diagnoses of IMIDs were recorded. Results were striking, as the incidence of IMIDs was 2.80 times higher in sepsis survivors than in AMI survivors. The time incidence for IMIDs started to increase after 16 days from the original sepsis episode. The hazard ratio was greater for immune thrombocytopenia, followed by Sjögren's syndrome, autoimmune hemolytic anemia, systemic lupus erythematosus, and ANCA-associated vasculitis. In a series of sensitivity analyses, the authors proved that the incidence of IMIDs among sepsis survivors remained high irrespective of whether the sepsis etiology was bacterial or viral and irrespective of the patient's comorbidities [3].

There are several recent publications on the long-term sequelae of sepsis survivors. The majority focus on cardiovascular events—mainly a composite of AMI, stroke, and cardiovascular death—and they report the 5-year follow-up period from the index sepsis case. In these publications, patients with preexisting cardiovascular diseases (CVDs) are excluded from the analysis. One analysis from Ontario between April 2007 and January 2017 followed-up 254,251 hospitalized patients for sepsis and matched them with a similar number of patients hospitalized for other reasons. Sepsis hospitalization was associated with a 1.30 hazard ratio for a greater incidence of CVDs. Interestingly, this was increased to 1.66 among patients aged 40 years or less [4]. This study confirms the results of one meta-analysis of 27 studies published between 2005 and 2017, of which 7 publications were population-based and the rest of the publications were based on hospitalized patients. In a retrospective analysis of almost 2.25 million adult hospital survivors from the OptumLabs Data Warehouse, the hazard ratio of new hospitalization for coronary heart disease, heart failure, stroke, and arrhythmia among sepsis survivors was 1.26, 1.51, 1.35, and 1.45, respectively [5].

At first glance, it is somehow difficult to find an association between the observed increase in the incidence of IMIDs and CVDs among sepsis survivors. As noted above, one of the recently described sepsis immunotypes is MALS. MALS is triggered by the excess production of interleukin (IL)-1β by the tissue macrophages [1]. Priming for the production of IL-1β makes patients prone to CVDs. This is supported by the results of the CANTOS trial and the results of the LoDoCo2 investigators. In the CANTOS trial, survivors from a first episode of AMI and blood high-sensitivity C-reactive protein above 2 mg/L were randomized to 5-year treatment with placebo or canakimumab once every 3 months. Canakinumab is one monoclonal antibody which targets IL-1β. Results showed a 15% decrease in the relative risk for major CVD events, including AMI, stroke, and cardiovascular death [6]. The LoDoCo2 investigator consortium randomized 5478 patients with evidence of coronary heart disease into 5-year treatment with placebo or 500 mg colchicine once daily. The primary endpoint was the incidence of an acute CVD event defined as a composite of cardiovascular death, AMI, ischemic stroke, or ischemia-driven coronary revascularization. The incidence of this endpoint was significantly decreased by 31% with colchicine treatment [7]. Both studies prove the importance of IL-1β to drive CVD complications because canakinumab directly blocks the activity of IL-1β and colchicine inhibits the formation of the NLRP3 inflammasome, which splits the proactive intracellular pro-IL-1β into the active IL-1β.

In a prospective study of our group, we monitored the over-time course of high-mobility group 1 (HMGB1) in patients with sepsis. We split patients into those with an early peak of HMGB1—notably before the first 7 days—and those with a late peak of HMGB1. HMGB1 is a danger-associated molecular pattern: It is released from dying cells, and it stimulates the production of IL-1β after binding to Toll-like receptor (TLR)-4. Indeed, patients with a late peak of HMGB1 had greater circulating levels of ferritin and of interferon-gamma, which is an indirect signature of TLR-4 activation. In patients with the late peak of HMGB1, the hazard for 28-day mortality was increased only if they had a medical history of cardiovascular comorbidities such as type 2 diabetes mellitus, congestive heart failure, or chronic renal disease [8]. The results suggest synergy between IL-1β primed by sepsis and cardiovascular comorbidities for unfavorable outcome. This synergy may also explain why the incident events of CVDs and of IMIDs arrive the first year after sepsis, when the inflammatory signature of sepsis on the organism of the host most likely persists.

Rehospitalization for infections is another major sequel of sepsis. An analysis of 159,864 sepsis patients from Germany revealed that 45.0% of survivors were rehospitalized for infection, whereas 56.6% received antibiotics as outpatients. The risk of infections post-sepsis was increased by 9.6% compared to the pre-sepsis period [9]. This predisposition to infections may well be explained by the immunoparalysis immunotype of the original sepsis episode, which often persists during the first year after sepsis [2].

The significance of the type of immune dysregulation for the future progression into CCI comes from the analysis of the SAVE-MORE randomized controlled trial. Patients with severe COVID-19 at risk for progression into severe respiratory failure due to early activation of the IL-1 cascade indicated by increased blood levels of the biomarker suPAR (soluble urokinase plasminogen activator receptor) were randomized to treatment with standard-of-care and placebo or anakinra. Anakinra is the recombinant antagonist of the IL-1 receptor and blocks the activity of both IL-1β and IL-1α. Early anakinra treatment prevented the progression into post-acute COVID syndrome [10].

The study by Mageau et al. [3] sheds light on another aspect of long-term sepsis consequences, namely, IMIDs. It is likely that IMIDs and CVDs have similar immune backgrounds greatly influenced by the type of immune dysregulation of the original sepsis episode. With this point of view, precision immunotherapy becomes a necessity because it may influence not only the 28-day outcome but also the incidence of long-term sepsis consequences. The study by Mageau et al. [3] is the first to elaborate on this necessity, and the authors are to be congratulated for this ground-breaking contribution.

Evangelos J. Giamarellos-Bourboulis has received honoraria from Abbott Products Operations AG, bioMérieux, Brahms, GSK, InflaRx, and Swedish Orphan BioVitrum AB; independent educational grants from Abbott Products Operations AG, bioMérieux, InflaRx, Johnson & Johnson, MSD, UCB, and Swedish Orphan Biovitrum AB; and funding from the Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grant EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis).