The main finding of our study is that in septic shock the duration of hypotension, measured by SOFA, is independently associated with monocyte HLA-DR expression, an important measure of cellular immune suppression. Immune suppression is increasingly recognized as a pathogenic mechanism for late mortality from sepsis 8,9
. Multiple immune derangements have been reported in patients with sepsis including decreased monocytic surface expression of HLA-DR 9
, decreased in vitro cytokine release in response to LPS or TNF simulation 27
, attenuated neutrophil oxidative burst 28
, cytomegalovirus viremia 24
and apoptosis with massive loss of lymphocytes, monocytes and dendritic cells 29
. The resulting functional immune suppression is readily observed by the clinician as an increased incidence of nosocomial infection with organisms that are normally easily cleared by the healthy host. Our study, conducted in a large multicenter cohort of patients presenting to the ED with CAP, explored one possible contributor to the severity of immune suppression following infection--the magnitude and duration of systemic arterial hypotension – and to our knowledge is the first report to evaluate this relationship in human sepsis.
In a secondary analysis plasma levels of markers of anti-inflammation (IL-10) and pro-inflammation (IL-6) were related to CV SOFA (Table E2
), and also independently to mHLA-DR expression (Table E3
). This does not suggest that the association between CV SOFA and mHLA-DR is mediated by these particular cytokines. However, since pro- and anti-inflammatory mediators are almost universally elevated in patients with sepsis, and covary with each other and illness severity, we include this subset as covariates to estimate the magnitude and duration of the systemic inflammatory response3,16,30
. Notably, IL-6 and IL-10 are not known to themselves induce hypotension or capillary leak 31
. The mechanism of monocyte deactivation from hypotension is unclear, though tissue hypoxia has pleiotropic effects on monocytes through both hyoxia-inducible factor-1α dependent and independent pathways.32,33
. Immune suppression following hemorrhagic shock is attenuated by chloroquine and prolactin administration34,35
Perhaps the most serious threat to the validity of our study is whether we may just be capturing illness severity despite covariate adjustment, as nonsurvivors are known to have lower levels of mHLA-DR4,6,9
. To explore this possibility, we tested the association of our covariate panel with 90-day mortality outcome (), and found that noncardiovascular SOFA score and other severity indicators were independently associated with risk for death, whereas CV SOFATOT
did not remain predictive in multivariate analysis. This suggests that our models adequately account for the effect of illness severity on immunosuppression, in effect isolating hypotension as a physiologic quantity rather than a severity marker, and persistent association with hypotension can be taken to be independent of illness severity. However in this observational trial we cannot state causality for the association noted between hypotension and cellular immune suppression.
An additional limitation is that for ethical reasons we cannot extricate the effect of hypotension on immune function from the impact of vasopressor use, a class of drugs which have complex immunomodulatory effects 25
. However, a sensitivity analysis using our multivariate model of CV SOFATOT
vs. day 3 mHLA-DR but excluding patients given vasopressors (n=19/525, ) showed minimal effect on significance testing (p=0.005 in the most parsimonious model). Other therapies delivered to critically ill patients are also potentially immunomodulatory, including mechanical ventilation and transfusion. Our multivariate models included these interventions, but it is possible there are important unobserved predictors not related to those in the model.
In conclusion, these data support the hypothesis that immunosuppression resulting from community-acquired pneumonia is, at least in part, related to the duration of systemic arterial hypotension. Further research is needed to explore the mechanisms of this relationship, and whether immunosuppression from septic shock may be attenuated by therapy to reduce the duration of hypotension.