A recent article reports the INSPIRE trial, a study evaluating whether a precision immunotherapy strategy using the interleukin-1 (IL-1) receptor antagonist anakinra can prevent progression to organ dysfunction and death in adults hospitalised with community-acquired or hospital-acquired pneumonia who are identified as high risk by elevated presepsin levels. The study addresses an important clinical problem: despite appropriate antimicrobial therapy, pneumonia frequently progresses to sepsis and organ failure, and mortality remains high. Early identification of patients at risk and targeted immunomodulation are therefore unmet needs.
The investigators hypothesise that presepsin, the soluble CD14 subtype released following activation of innate immune pathways, could serve both as an early prognostic biomarker and as an indicator of IL-1 pathway activation. Levels above 350 pg/ml had previously been associated with sepsis and poor outcomes. The authors propose that patients with elevated presepsin but without established organ dysfunction might benefit from early IL-1 blockade using anakinra to prevent deterioration.
INSPIRE was conducted in four internal medicine departments in Greece between March 2023 and June 2024. Adults with radiologically confirmed community- or hospital-acquired pneumonia, a qSOFA score of 1, and plasma presepsin >350 pg/ml were eligible. Patients were randomised 1:1 to standard-of-care therapy plus either subcutaneous anakinra 100 mg daily for ten days or matched placebo.
The primary endpoint was progression to organ dysfunction, defined as either a ≥2-point increase in SOFA score by day 7 or death by day 90. Secondary endpoints included changes in SOFA score, incidence of new organ dysfunction, time to hospital discharge, 28- and 90-day mortality, biomarker kinetics, and cytokine production by peripheral blood mononuclear cells (PBMCs).
Of 371 screened patients, 60 were randomised. Baseline characteristics, severity scores, microbiology, and treatments were similar between groups. Most cases were community-acquired pneumonia. All patients were followed for 90 days.
The primary outcome showed a clear benefit of anakinra. Progression to organ dysfunction occurred in 50% of placebo-treated patients compared with 20% of anakinra-treated patients, an absolute difference of 30%, which was statistically significant.
Mortality outcomes also favoured treatment. Twenty-eight-day mortality was 33.3% in the placebo group versus 13.3% with anakinra. Ninety-day mortality was 43.3% versus 20.0%, respectively. Patients receiving anakinra experienced greater reductions in SOFA scores and were discharged earlier from hospital.
Biomarker analyses supported the mechanistic rationale. A ≥50% decrease in presepsin occurred sooner and more frequently with anakinra. Calprotectin, another marker of innate immune activation, also declined more rapidly in treated patients. In contrast, procalcitonin kinetics did not differ between groups. Functional assays showed reduced production of pro-inflammatory cytokines, particularly TNF-α and IFN-γ, by PBMCs in the anakinra arm. Decreases in IL-1–related pathways were observed without broad immunosuppression.
Presepsin itself demonstrated prognostic value. Patients with levels ≤350 pg/ml had very low rates of progression and death compared with those above the threshold, supporting its role as a risk-enrichment biomarker. Post-hoc analyses suggest that alternative tools such as SCORE2 or calprotectin might help identify high-risk patients where presepsin testing is unavailable.
Serious treatment-emergent adverse events occurred in 50% of placebo patients and 33.3% of those receiving anakinra, with none attributed to study treatment. The most common events were infections and cardiac disorders. No unexpected safety signals or suspected unexpected serious adverse reactions were reported.
The authors conclude that presepsin-guided administration of anakinra prevents progression to organ dysfunction, reduces mortality, and shortens hospital stay in patients with pneumonia at early risk of sepsis. This represents one of the first demonstrations of a precision immunotherapy approach in bacterial pneumonia, targeting the IL-1 pathway before overt organ failure develops.
Larger trials are needed to confirm efficacy and define optimal implementation. Nonetheless, INSPIRE provides proof-of-concept that biomarker-guided immunomodulation can improve outcomes in pneumonia and supports further investigation of personalised treatment strategies.
Source: The Lancet
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