Molecular Epidemiology of ARDS

BACKGROUND:

The acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and
mortality around the world. In the United States alone there are 150,000 cases per year.
Although there have been significant scientific advances in understanding the clinical and
pathophysical aspects of the syndrome, there is as yet no specific therapy for ARDS.
Moreover, although major risk factors for the development of ARDS include sepsis, aspiration,
and multiple trauma, only a minority of patients with these risk factors develop ARDS.
Individual differences in susceptibility to chronic disease have been a subject of active
molecular epidemiologic investigations for the past decade. In particular, risk factors for
cancer conferred by heritable polymorphisms and various metabolic functions have been
reported. More recently, a polymorphism of endothelial nitrate oxide synthase has been
associated with an increased susceptibility to coronary-artery disease, and polymorphisms in
GSTM1 have been associated with an increased risk of developing asbestosis. A recent study of
tumor necrosis factor (TNF) polymorphisms has been associated with poor outcome in ARDS.

DESIGN NARRATIVE:

The case-control study examined the association between specific polymorphisms in several
genes coding for specific inflammatory responses and for surfactant protein and their
potential association with increased susceptibility to ARDS. The first objective was to
assess the role of candidate-gene polymorphisms as risk factors for ARDS in a case-control
study. The second objective was to assess the relationship between genotype and phenotype for
candidate markers in cases and controls. The third objective was to assess the role of these
polymorphisms in clinical outcome (survival, recovery) using patients from both the proposed
case-control study and the multicenter case series and clinical trial sponsored by the NHLBI
ARDS network. By combining both a large case-control study and case series from the network,
the study had the advantages of sufficient case ascertainment, statistical power, diagnostic
standardization, uniform outcome criteria and study efficiency. Overall, the results of this
study should provide new insights into the epidemiology of ARDS and allow for possible
preventive strategies as well as possible modifications of therapeutic interventions for the
Network Phase III trials.

The investigators test the hypothesis that there is an increased risk of ARDS in patients
with heritable traits relating to inflammatory cytokines and surfactant. They are examining
risk and prognosis, and examining case and control genetics in relation to cytokine levels.
They also plan to do a case-series analysis from a separate study of the ARDS network. They
will examine TNF alpha and beta, interleukin-1 receptor antagonist, surfactant protein B and
interleukin-10 (IL-10).

Eligibility Criteria:

All those with risk factors for ARDS - eg, pneumonia, trauma, sepsis.

Vulnerable populations (incarcerated, pregnant, etc.) will be excluded from enrollment. The
following medical conditions will also exclude from study:

1. immunocompromised patients

2. patients with chronic lung disease that may appear like ARDS

3. pulmonary vasculitis patients

4. patients with diffuse alveolar hemorrhage

5. patients treated with immune-modulating agents within 3 weeks of admission

6. patients unable to intubate because of DNI order or patient is placed on comfort
measures only