Phenotype-based appropriateness of IGM-enriched polyclonal immunoglobulin use in critical illness: report of an expert consensus

Abstract

Sepsis and septic shock result from a dysregulated host response to infection, encompassing both hyperinflammatory and immunosuppressed phenotypes. Although immunomodulatory adjunctive therapies have been extensively investigated over the past decades, none have demonstrated consistent clinical efficacy. In contrast, low circulating immunoglobulin levels are common in septic patients and are associated with greater disease severity and poorer outcomes, providing a biological rationale for the use of polyclonal intravenous immunoglobulins (IVIg) as phenotype-targeted adjunctive therapies. This expert consensus sought to systematically evaluate the appropriateness of IVIg therapy across predefined and clinically relevant scenarios in critically ill patients and deliver pragmatic, phenotype-oriented guidance. A multidisciplinary Italian panel comprising experts in intensive care, infectious diseases, transplant medicine, and oncology applied a modified RAND/UCLA Appropriateness Method. The process integrated a structured literature review (PubMed, EMBASE, and the Cochrane Library) with anonymous 9-point Likert scale ratings. Indications were classified according to the median score as appropriate (7–9), uncertain (4–6), or inappropriate (1–3), and interpanel disagreement was assessed using the Interpercentile Range Adjusted for Symmetry. The expert panel evaluated seven phenotypes that were identified as the most clinically relevant and extensively addressed in the available literature. IVIg use was judged appropriate without formal disagreement in severe community-acquired pneumonia with hyperinflammation plus shock (median 8), low IgM < 60 mg/dL (median 8), or prior immunosuppression (median 8), whereas hyperinflammation without shock was uncertain (median 6). Appropriateness was also supported for abdominal infection with endotoxaemic shock, immune suppression/paralysis, or low IgM (all median 8); sepsis in solid-organ transplant recipients (median 7), particularly with low IgM (median 8), while prophylaxis in high-risk transplant recipients was uncertain (median 5). IVIg was rated appropriate for overwhelming septic shock with severe hyperinflammation (median 8), especially with low IgM (median 8) and toxin-mediated syndromes (median 9); for post–cardiac surgery sepsis with immune suppression (median 7) but not clearly for hyperinflammation (uncertain, median 6); for multidrug-resistant pathogen sepsis with immune suppression (median 7–8); and in haematologic malignancies, as prophylaxis or treatment primarily when immunoglobulins are low (medians 7–8), with prophylaxis otherwise uncertain. Across all phenotypes, IgM-enriched preparations were consistently preferred (median 8–9). Available evidence suggests no major safety signals, although adverse events are likely to be underreported. Overall, the consensus supports personalised, phenotype-oriented consideration of IgM-enriched IVIg as an adjunctive strategy to optimise standard care, while underscoring persistent evidence gaps and the need for adequately powered trials to define timing, dosing, and responsive subgroups.