Gw. Waterer et al., Septic shock and respiratory failure in community-acquired pneumonia have different TNF polymorphism associations, AM J R CRIT, 163(7), 2001, pp. 1599-1604
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).