Septic shock and respiratory failure in community-acquired pneumonia have different TNF polymorphism associations

Genetic factors are likely to contribute to the variable presentation of co mmunity-acquired pneumonia (CAP). The purpose of this prospective cohort st udy was to determine whether the LT alpha +250 (TNF beta +250) and TNF alph a -308 gene polymorphisms are associated with different presentations of CA P. Septic shock (SS) was defined using American College of Chest Physicians /Society of Critical Care Medicine (ACCP-SCCM) criteria. Type I respiratory failure (T1RF) was defined as an O-2 saturation on room air of < 90% with a normal Pco(2). A total of 280 patients were genotyped; 31 had SS, 80 had T1RF. Genotype proportions are given in the order of AA/GA/ GG. The proport ion of patients in each genotype developing SS was as follows: LT<alpha>+25 0 0.19/0.07/0.09 (p = 0.01 AA versus non-AA); TNF alpha -308 0.16/0.06/0.12 (p = NS). Carrying at least one AA (tumor necrosis factor [TNF] high secre tor) genotype had an 18.0% risk of SS versus 6.8% (p = 0.006). GG homozygot es (TNF low secretors) at both loci had only a 2.9% risk of SS. Septic shoc k was associated with the LT alpha +250:TNF alpha -308 A:G haplotype but no t the A:A haplotype, suggesting that LT alpha +250 is a marker, rather than a causative polymorphism. Carriage of the G:G haplotype had a significant protective effect against the development of septic shock (p = 0.011). T1RF was not associated with LT alpha +250 AA genotype. In the absence of septi c shock, there was a significant trend to greater T1RF in patients with LT alpha +250 GG (TNF alpha hyposecretor) genotype (p = 0.03). Our finding of different genotype associations for SS and T1RF has important implications for immunotherapy in both CAP and sepsis, as well as for the definition of the systemic inflammatory response syndrome (SIRS).