Informativeness of Immunological Predictors of Prolonged and Chronic Critical Illness Outcome is Limited by Patient’s Genotype

The aim of the study was to determine the contribution of cellular immune system parameters and the AQP4 (rs1058427) genetic polymorphism to the prognosis of course and outcome of patients with sequelae of severe brain injury (SBI), including patients who developed pneumonia.
Materials and Methods. The study included 464 intensive care unit (ICU) patients with prolonged or chronic critical illness (PCCI) admitted to the Federal Scientific and Clinical Center of Intensive Care Medicine and Rehabilitology (FSCCICMR) following SBI (strokes, traumatic brain and combined injuries, post-operative anoxic conditions, brain tumor surgery). Variants of the rs1058427 single-nucleotide polymorphism in the AQP4 gene were detected in DNA isolated from whole blood with organic solvents and using genotyping with tetraprimer PCR followed by electrophoretic identification of the products.
Results. The entire cohort was divided into three groups of patients: those admitted without signs of pneumonia in the first 48 hours of hospitalization but who developed nosocomial pneumonia after 48 hours (group 1); admitted without signs of pneumonia, in whom no signs of pneumonia were detected throughout the hospitalization (group 2); with pneumonia diagnosed upon admission, which developed in the previous medical institution prior to transferring to the FSCCICMR (group 3). For the cohort combining groups 1 and 2 (admitted without signs of pneumonia), increased values of the neutrophil-to-lymphocyte ratio (NLR) (OR = 1.8, 95% CI: 1.1–3.9, P = 0.0175, χ², N = 272) and neutrophil count (OR = 2.1, 95% CI: 1.3–3.5, P = 0.0038, χ², N = 272) on the first day of hospitalization were associated with an increased risk of pneumonia. In the same cohort, elevated neutrophil counts (over 6×10⁹/L) at admission significantly predicted adverse outcome, but only in the subgroup of patients with the AQP4 rs1058427 GG major genotype (95% CI: 1.0–4.5, HR = 2.1, P = 0.049, log-rank test). In group 3 (patients with pneumonia diagnosed upon admission), a significant association with adverse outcome was found for both neutrophils and NLR (HR = 3.1, 95% CI: 1.3–6.9, P = 0.019, log-rank test, N = 149, and HR = 2.9, 95% CI: 1.3–6.6, P = 0.026, log-rank test, N = 149, respectively) in patients with AQP4 GG genotype, not in alternative AQP4 allele T carriers. Thus, the prognostic value of elevated neutrophil counts in patients with PCCI («immunophenotype») depends significantly on the genetic polymorphism of AQP4, a gene that controls the initiation of immune cell migration and is pathogenically significant for the development of the infectious process.
Conclusion. For patients with consequences of SBI in PCCI, an increase in neutrophil counts above 6×10⁹/L upon hospitalization significantly predicts an adverse outcome only in patients homozygous for the AQP4 rs1058427 G allele (GG genotype). The unique genetically restricted clinical and laboratory phenotype («gene-immunophenotype») could be considered in personalized critical care medicine as an example of a candidate predicting paradigm.

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