Genes and Meningococcal Disease

Abstract

Source: Haralambous E, Hibberd ML, Hermans PWM, et al. Role of functional plasminogen-activator-inhibitor-1 4G/5G promotor polymorphism in susceptibility, severity, and outcome of meningococcal disease in Caucasian children. Crit Care Med. 2003;31:2788–2793.The authors from the Imperial College of London, United Kingdom, the Sophia Children’s Hospital in Rotterdam, The Netherlands, and St. Mary’s Hospital of London, UK, collaborated on a large case-controlled and family-based transmission study designed to investigate the relationship between the plasminogen-activator-inhibitor (PAI)-1 gene and mortality from meningococcal disease. The authors identified 510 patients with meningococcal disease from 2 cohorts. The Imperial College Cohort in the UK (348 patients treated from 1992–2002) included patients ages 2 months to 17.5 years and the Meningitis Research Foundation Cohort of the UK (162 subjects enrolled from 1996–1999) included patients ages 2 months to 67 years. Control subjects were 155 healthy Caucasian controls who lived in the UK and were ages 2 to 68 years. PAI-1 genotype was determined by analysis of DNA extracted from patients, controls and, when available, parents of the patients. The clinical diagnosis of meningococcal disease was classified as sepsis, meningitis, or “mixed” disease. Predicted mortality was evaluated using the Pediatric Risk of Mortality (PRISM) score. Actual mortality and vascular complications such as the need for skin grafting or amputation were also recorded.The 4G/4G genotype was found in 27% of patients and 31% of control subjects, the 4G/5G was found in 53% of patients and 48% of controls, and the 5G/5G was found in 20% of patients and 21% of controls. Patients with the 4G/4G genotype had significantly higher severity of illness, with a median PRISM score of 41% predicted mortality (compared to 23% for 4G/5G patients and 19% for 5G/5G patients). The percentage of patients who actually died with the 4G/4G genotype was also significantly higher (28% compared to 19% for the 4G/5G patients and 3% for 5G/5G patients.) The authors did not find a significant association between the PAI-1 genotypes and types of disease (meningitis, sepsis, or mixed disease). However, among survivors, patients with 4G/4G genotypes had a 2.7-fold greater risk of vascular complications.Meningococcal infection typically strikes young, otherwise healthy people. It is life-threatening and remains the leading cause of infectious death among children in the industrialized world.1 Meningococcal infections cause marked disturbances in coagulation and are a well-recognized cause of shock and purpura fulminans. Patients with shock and disseminated intravascular coagulation have a greater mortality than patients without shock.2Meningococcal infections cause low levels of protein C and elevated levels of PAI-1,3 which have been significantly associated with severity of illness and mortality.4 Inhibition of fibrinolysis by elevated PAI-1 levels leads to a procoagulant state and thrombosis. Carriers of the 4G allele produce higher levels of PAI-1. The authors now report a second study showing that the 4G/4G genotype is associated with an increased risk of severe illness, vascular insufficiency, and death. This paper describing allele frequencies is important because it confirms an association between disease severity and the functional polymorphism of the PAI-1 gene.5 While the risk of contracting meningococcal disease is not related to the polymorphism,2 severity of illness is associated with the 4G polymorphism.Protein C inhibits procoagulant pathways and neutralizes PAI-1.6,7 Activated protein C remains one of the few proven therapies that improve outcome for septic shock in adult patients. Currently, studies of activated protein C for children with severe sepsis are ongoing.8 To date, however, this therapy has not been proven to enhance outcomes among children with meningococcal septic shock.The role of genetics in how we handle infection is more than just a PAI-in-the-sky theory. It is now a reality that will determine new therapeutic approaches, which we look forward to reviewing and, subsequently, using on our sickest patients with life-threatening infections.