Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis

Abstract

Background: A subanalysis of a randomized clinical trial indicated sepsis survival benefit from interleukin (IL)-1 blockade in patients with features of the macrophage activation-like syndrome (MALS). This study aimed to investigate the frequency of MALS and to develop a biomarker of diagnosis and prognosis.

Methods: Patients with infections and systemic inflammatory response syndrome were assigned to one test cohort (n = 3417) and a validation cohort (n = 1704). MALS was diagnosed for patients scoring positive either for the hemophagocytic syndrome score and/or having both hepatobiliary dysfunction and disseminated intravascular coagulation. Logistic regression analysis was used to estimate the predictive value of MALS for 10-day mortality in both cohorts. Ferritin, sCD163, IL-6, IL-10, IL-18, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) were measured in the blood the first 24 h; ferritin measurements were repeated in 747 patients on day 3.

Results: The frequency of MALS was 3.7% and 4.3% in the test and the validation cohort, respectively. In both cohorts, MALS was an independent risk factor for 10-day mortality. A ferritin level above 4420 ng/ml was accompanied by 66.7% and 66% mortality after 28 days, respectively. Ferritin levels above 4420 ng/ml were associated with an increase of IL-6, IL-18, INF-γ, and sCD163 and a decreased IL-10/TNF-α ratio, indicating predominance of pro-inflammatory phenomena. Any less than 15% decrease of ferritin on day 3 was associated with more than 90% sensitivity for unfavorable outcome after 10 days. This high mortality risk was also validated in an independent Swedish cohort (n = 109).

Conclusions: MALS is an independent life-threatening entity in sepsis. Ferritin measurements can provide early diagnosis of MALS and may allow for specific treatment.

Keywords: Ferritin; Interleukin-18; Macrophages; Outcome; Sepsis.

Conflict of interest statement

Ethics approval and consent to participate

The protocol was approved by the following ethics committees:

• Ethics Committee of “Alexandra” General Hospital of Athens

• Ethics Committee of 251 Air Force General Hospital of Athens

• Ethics Committee of Attikon University General Hospital of Athens

• Ethics Committee of Asklipieion General Hospital of Voula, Territory of Athens

• Ethics Committee of “Center for Trauma Resuscitation- KAT” General Hospital of Athens

• Ethics Committee of “Evangelismos” General Hospital of Athens

• Ethics Committee of “Evgenideio” Hospital of Athens

• Ethics Committee of “Hippokrateio” General Hospital of Athens

• Ethics Committee of “Hygeia” General Hospital of Athens

• Ethics Committee of “G. Gennimatas” General Hospital of Athens

• Ethics Committee of “Laikon” General Hospital of Athens

• Ethics Committee of “Konstantopouleio-Aghia Olga” General Hospital of Athens

• Ethics Committee of “Korgialeneion-Benakion” General Hospital of Athens

• Ethics Committee of “Sismanogleion” General Hospital of Athens

• Ethics Committee of “Sotiria” Athens General Hospital

• Ethics Committee of “Thriasio” Elefsis General Hospital Territory of Athens

• Ethics Committee of “Aghios Dimitrios” General Hospital of Thessaloniki

• Ethics Committee of “G. Gennimatas” General Hospital of Thessaloniki

• Ethics Committee of “Aghios Pavlos” General Hospital of Thessaloniki

• Ethics Committee of “Theagenio” Hospital of Thessaloniki

• Ethics Committee of “Metaxa” Hospital of Piraeus

• Ethics Committee of “Tzaneio” General Hospital of Piraeus

• Ethics Committee of University General Hospital of Alexandroupolis

• Ethics Committee of General Hospital of Argos

• Ethics Committee of General Hospital of Arta

• Ethics Committee of General Hospital of Chios

• Ethics Committee of University General Hospital of Ioannina

• Ethics Committee of General Hospital of Karditsa

• Ethics Committee of General Hospital of Korinthos

• Ethics Committee of General Hospital of Lamia

• Ethics Committee of University General Hospital of Larissa

• Ethics Committee of General Hospital of Nicosia

• Ethics Committee of General Hospital of Nafplion

• Ethics Committee of University General Hospital of Patras

• Ethics Committee of General Hospital of Ptolemaida

• Ethics Committee of General Hospital of Sparti

• Ethics Committee of General Hospital of Trikala

• Ethics Committee of General Hospital of Zakynthos

The patients were enrolled after they provided written consent or their legal representative provided it in the case of patients unable to consent.

Competing interests

EJGB has received honoraria (paid to the University of Athens) from AbbVie, Biotest, Brahms GmbH, and The Medicines Company; has received compensation as a consultant for Astellas Greece and for XBiotech (paid to the University of Athens); and has received independent educational grants (paid to the University of Athens) from AbbVie and Sanofi. He is funded by the FrameWork 7 program HemoSpec and by the Horizon 2020 Marie Curie project European Sepsis Academy (granted to the University of Athens). The other authors do not report any competing interests.

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Figures

Fig. 1

Study flow chart. APACHE Acute Physiology and Chronic Health Evaluation, IFN-γ interferon gamma, IL interleukin, MALS macrophage activation-like syndrome, SD standard deviation, SIRS systemic inflammatory response syndrome, SOFA Sequential Organ Failure Assessment, TNF-α tumor necrosis factor alpha. *p non-significant between the two cohorts, CCI: Charlson's Comorbidity Index

Fig. 2

Aspects of macrophage activation-like syndrome (MALS) in both cohorts. a Score of hemophagocytotic syndrome (HS), b co-presence of hepatobiliary dysfunction (HBD) and disseminated intravascular coagulation (DIC), c serum triglyceride levels, and d logistic regression analysis of factors associated with mortality within 10 days; p values are provided. ARDS acute respiratory distress syndrome, AKI acute kidney injury, CI confidence interval, OR odds ratio

Fig. 3

Development of ferritin as biomarker for the detection of macrophage activation-like syndrome (MALS) in the test cohort. a ROC curve of ferritin for the detection of MALS, AUC area under the curve. b Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of serum ferritin level 4420 ng/ml for the detection of MALS

Fig. 4

Serum ferritin as biomarker for final outcome in sepsis. a Comparison of early mortality between the Greek test cohort and the Greek validation cohort for patients with ferritin > 4420 ng/ml. b–d Kaplan-Meier curves of survival in the test Greek cohort (b), in the Greek validation cohort (c), and in the Swedish validation cohort (d) for 28 days in relation to ferritin levels. Log-rank tests and p values are provided. Ferr ferritin

Fig. 5

Signs of hyper-inflammation in relation to serum ferritin. Comparison of serum levels of interleukin (IL)-6 (a), IL-10/TNF-α ratio (b), IL-18 (c), interferon gamma (IFN-γ) (d), and sCD163 (e) in relation to the level of serum ferritin. The ratio IL-10/TNF-α is an expression of the balance between anti-inflammation and hyper-inflammation; p values are provided

Fig. 6

Serum ferritin as a surrogate marker of final outcome among patients with macrophage activation-like syndrome (MALS). a Serum levels on days 1 and 3 among 10-day survivors and non-survivors of MALS. b Serum levels on days 1 and 3 among 10-day survivors and non-survivors without MALS. c ROC curve of the % change of serum ferritin between days 1 and 3 as prognostic of death after 10 days among patients with MALS. AUC area under the curve. d 10-day mortality of patients with MALS with more than or less than 15% ferritin decrease between days 1 and 3. p values are provided. CI confidence interval, OR odds ratio