Trial Information

A Randomized Double-Blind Placebo-Controlled Trial of Ganciclovir/Valganciclovir for Prevention of Cytomegalovirus Reactivation in Acute Injury of the Lung and Respiratory Failure (The GRAIL Study)

Critical illness due to severe sepsis and trauma are major causes of morbidity and
mortality, and a substantial economic burden in the United States and worldwide. Despite
advances in clinical care, patients with sepsis and trauma-associated respiratory failure
represent specific populations with high rates of adverse outcomes. The etiology of
respiratory failure in patients with severe sepsis and trauma is multifactorial, but acute
lung injury (ALI) is one of the leading causes, and is associated with prolonged ICU and
hospital stays, mortality, and long-term sequelae. Other than general supportive care, few
specific interventions other than lung protective ventilation have been shown to improve
outcomes in such patients. New approaches for understanding the pathogenesis and developing
better therapies are urgently needed.

Acute Lung Injury (ALI) is a syndrome consisting of acute hypoxemic respiratory failure with
bilateral pulmonary infiltrates that is associated with both pulmonary and nonpulmonary risk
factors (eg. sepsis, trauma) and that is not due primarily to left atrial hypertension.
Although a distinction between ALI and a more severe subtype (termed acute respiratory
distress syndrome (ARDS) has been made, the pathogenesis, risk factors, and outcomes appear
to be similar and for the purposes of this protocol, the term acute lung injury [ALI] will
be used to encompass both entities. Accepted consensus definitions of ALI have been
introduced and are now widely used for laboratory and clinical investigations of ALI. Acute
Lung Injury (ALI) is defined as:

- PaO2/FiO2 <300

- Bilateral pulmonary infiltrates on chest x-ray

- Pulmonary Capillary Wedge Pressure <18mmHg or no clinical evidence of increased left
atrial pressure Although a broad range of risk factors for ALI have been described,
those that account for the majority of cases include: sepsis, pneumonia, trauma, and
aspiration. It is well established that severe trauma is recognized as a precipitating
cause of ALI. Recent studies have demonstrated that the incidence of acute lung injury
(ALI) is much higher than previously thought, with an estimated age-adjusted incidence
of 86 per 100,000 persons per year, resulting in an estimated ~190,000 cases annually
in the US. The clinical and health care system impact of ALI is substantial, with an
estimated 2,154,000 intensive care unit (ICU) days, 3,622,000 hospital days, and 75,000
deaths in 2000, and is expected to grow significantly given the marked age-related
incidence and the aging population. Although general improvements in ICU care over the
last 2 decades have led to a trend towards lower mortality due to certain
ALI-associated risk factors (trauma, aspiration), the most common causes of ALI, sepsis
and pneumonia, remain associated with high mortality rates of ~25-35%. Mortality in ALI
is most commonly due to secondary infections/sepsis and multiorgan system failure
rather than primary respiratory failure due to hypoxemia, highlighting the systemic
nature of ALI. Even among initial survivors of ALI, substantial pulmonary and
nonpulmonary functional impairment remains for months to years. Specifically, a
proportion of those who survive the initial insult are at risk for prolonged mechanical
ventilation and ICU/hospital stay, and the risk factors remain poorly defined. It has
been hypothesized that a "2nd hit" may predispose certain patients to greater morbidity
in this setting. Despite intensive basic and clinical investigation, only a single
intervention (low-tidal volume ["lung protective"] ventilation) is generally accepted
to decrease mortality in ALI, while multiple other strategies have failed to improve
survival either in early clinical studies or definitive efficacy trials. Thus, given
the high incidence and continued substantial clinical impact of ALI despite
improvements in general medical/ICU care, and limited proven options other than
lung-protective ventilation, new approaches to understanding the pathophysiology and
identifying novel targets for intervention in ALI are a high priority.

Overly intense, persistent and dysregulated pulmonary and systemic inflammation has emerged
as the leading hypothesis for the pathogenesis of ALI and its complications, but the
contributory factors and mechanisms are incompletely defined. Several carefully-conducted
prospective human studies have shown an association between specific inflammatory biomarkers
in blood and BALF (both the initial levels at onset and changes over time) and important
clinical outcomes in ALI. [Animal models have also demonstrated an association between
inflammatory cytokines and non-pulmonary organ injury and dysfunction] In addition, one of
the most important interventions (low-tidal volume ["lung protective"] ventilation) shown to
decrease mortality in ALI is associated with reductions in inflammatory cytokines (IL-6,
IL-8) in blood and bronchoalveolar lavage fluid [BALF].

Cytomegalovirus (CMV) is a ubiquitous virus in humans worldwide, and has been linked to
adverse clinical outcomes including prolongation of mechanical ventilation, increased length
of stay, and mortality in multiple studies of critically-ill, apparently immunocompetent,
seropositive adults.

Cytomegalovirus (CMV) is a human herpes virus known to infect more than 50-90% of US adults
and is known to be a major cause of morbidity and mortality in immunocompromised patients.
CMV infection can be acquired through multiple means, including: mother-to-child (in utero,
breast milk), infected body fluids (saliva, genital secretions), blood transfusion or organ
transplant. The prevalence of CMV infection increases with age throughout life such that by
age 90, ~90% of persons will have acquired CMV infection. In immunocompetent persons,
following primary infection by any of the routes noted above, CMV is controlled by the
immune system and establishes latency ("dormancy") in multiple organs/cell-types for the
life of the host. In particular, the lung represents one of the largest reservoirs of latent
CMV in seropositive hosts, and may explain the propensity for CMV-associated pulmonary
disease in predisposed hosts. During periods of immunosuppression (or as a result of
specific stimuli such as TNF-α, LPS, or catecholamines that are commonly associated with
critical illness & sepsis [CMV can reactivate from latency (preferentially in the lung) to
produce active infection (viral replication). In persons with impaired cellular immunity,
reactivation can progress to high-grade CMV replication and commonly leads to tissue injury
and clinically-evident disease such as CMV pneumonia. Lower-grade CMV reactivation that is
otherwise clinically silent ("subclinical") can also be detected in apparently
immunocompetent persons with critical illness using sensitive techniques such as PCR. In
addition, even low-level, otherwise asymptomatic subclinical CMV reactivation can produce
significant biologic effects both in vitro and in vivo, such as inflammation, fibrosis and
immunosuppression. Each of these biologic effects of subclinical CMV infection has either
previously been demonstrated (inflammation, fibrosis) or could theoretically be important
(immunosuppression) in sepsis-associated ALI and its complications. These biological effects
of CMV have been shown to occur through various mediators and other indirect means
[Importantly, several important CMV-associated adverse clinical outcomes in transplant
populations [allograft rejection, secondary infections] are not necessarily accompanied by
overt CMV disease and can only be detected by relatively sensitive means of virus detection
such as PCR.

Reactivation of CMV in apparently immunocompetent patients with critical illness due to a
broad range of causes has been documented in multiple prior studies using a variety of
virologic techniques. The specific triggers for CMV reactivation from latency have been
identified and are known to be elevated in patients with sepsis and acute lung injury [A
prospective study in intubated patients with sepsis from Germany reported more than 60% rate
of CMV DNA detection in tracheal aspirates.

In addition to CMV reactivation in sepsis, CMV reactivation has also been demonstrated
specifically in lung and blood of patients with acute lung injury.

Retrospectively testing samples collected in a prospective observational cohort study of
patients at risk of developing ARDS, CMV reactivation (ie. CMV DNA by PCR) was detected in
BALF and/or plasma of 2/5 [40%] of subjects who developed ARDS, in sequential samples from
7/20 [35%] patients with ARDS, but not in patients at risk but who did not develop ARDS
(0/5) [Limaye 2009 unpublished data]. In a separate study, CMV reactivation was
retrospectively assessed by PCR in BALF of 88 subjects enrolled in a randomized trial of
fish oil for treatment of ALI. Seropositivity at baseline (ie. evidence of latent CMV
infection) in the cohort was 65% (similar to prior age-related estimates), and CMV
reactivation (ie. CMV DNA by PCR) was detected in BALF of 12/57 [21%] patients [Limaye
unpublished data 2009].

Several lines of evidence have linked CMV reactivation with adverse clinical outcomes in
non-immunosuppressed adults with critical illness. In a recent meta-analysis, CMV
reactivation (compared to no reactivation) was associated with a 2-fold increased odds of
mortality in ICU patients.

In addition to mortality, recent studies have demonstrated a strong and independent
association between CMV reactivation and increased hospital and ICU length of stay and
duration of mechanical ventilation.