Ganciclovir/Valganciclovir for Prevention of CMV Reactivation in Acute Injury of the Lung and Respiratory Failure

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.

Inclusion Criteria:

1. Subject/next of kin informed consent

2. Age >= 18 years

3. CMV IgG seropositive. The following tests are acceptable:

- FDA licensed test in a local lab approved by the coordinating center (FHCRC,
Seattle, WA).

- Test in central study lab (ARUP, Salt Lake City, UT)

- A report that patient has previously been tested and found to be CMV seropositive
at any time (a credible next of kin report is acceptable; confirmatory test will
be done but results are not required for randomization)

4. Intubated and requiring mechanical positive pressure ventilation (including Acute Lung
Injury/ARDS (EA Consensus Definition))

5. Meets criteria for either:

1. Severe sepsis criteria (as defined in appendix G) within a 24-hour time period
within the 120 hour window

OR

2. Trauma with respiratory failure and an ISS score > 15 within a 24 hour time
period, and within the 120 hour window (where mechanical ventilation is not due
solely to a head injury)

6. On the day of randomization (by local criteria):

- Not eligible for SBT (use of sedation and/or vasopressor does not specifically
contraindicate SBT),or

- Failed SBT

Exclusion Criteria:

1. BMI > 60 (1st weight during hospital admission)

2. Known or suspected immunosuppression, including:

- HIV+ (i.e. prior positive test or clinical signs of suspicion of HIV/AIDS; a
negative HIV test is not required for enrollment)

- stem cell transplantation:

- within 6 months after autologous transplantation or

- within 1 years after allogeneic transplantation (regardless of
immunosuppression)

- greater than 1 year of allogeneic transplantation if still taking systemic
immunosuppression or prophylactic antibiotics (e.g. for chronic graft versus
host disease)

Note: if details of stem cell transplantation are unknown, patients who do not take
systemic immunosuppression and do not take anti-infective prophylaxis are acceptable
for enrollment and randomization.

- solid organ transplantation with receipt of systemic immunosuppression (any
time).

- cytotoxic anti-cancer chemotherapy within the past three months (Note:
next-of-kin estimate is acceptable).

- congenital immunodeficiency requiring antimicrobial prophylaxis (e.g. TMP-SMX,
dapsone, antifungal drugs, intravenous immunoglobulin).

- receipt of one or more of the following in the indicated time period:

- within 6 months: alemtuzumab, antithymocyte/antilymphocyte antibodies

- within 3 months: immunomodulator therapy (TNF-alpha antagonist, rituximab,
tocilizumab, IL1 receptor antagonist and other biologics)

- within 30 days:

- corticosteroids > 10 mg/day (chronic administration, daily average over
the time period)

- topical steroids are permissible

- use of hydrocortisone in "stress doses" up to 100 mg four times a
day (400mg/daily) for up to 4 days prior to randomization is
permissible

- use of temporary short-term (up to 2 weeks) increased doses of
systemic steroids (up tp 1 mg/kg) for exacerbation of chronic
conditions are permissible.

- methotrexate (> 10.0 mg/week)

- azathioprine (> 75 mg/day)

Note: if no information on these agents is available in the history and no direct or
indirect evidence exists from the history that any condition exists that requires
treatment with these agents (based on the investigator's assessment), the subject may
be enrolled. For all drug information, next-of-kin estimates are acceptable. See
Appendix D for commonly prescribed immunosuppressive agents.

3. Expected to survive < 72 hours (in the opinion of the investigator)

4. Has been hospitalized for > 120 hours (subjects who are transferred from a chronic
care ward, such as a rehabilitation unit, with an acute event are acceptable).

5. Pregnant or breastfeeding (either currently or expected within one month).

Note: for women of childbearing age (18-60 years, unless documentation of surgical
sterilization [hysterectomy, tubal ligation, oophorectomy]), if a pregnancy test has
not been done as part of initial ICU admission work-up, it will be ordered stat and
documented to be negative before randomization. Both urine and blood tests are
acceptable.

6. Absolute neutrophil count < 1,000/mm3 (if no ANC value is available, the WBC must be >
2500/mm3)

7. Use of cidofovir within seven (7) days of patient randomization. The use of the
following antivirals is permitted under the following conditions:

- Ganciclovir, foscarnet, high-dose acyclovir, or valacyclovir until the day of
randomization

- Acyclovir as empiric therapy for central nervous system HSV or VZV infection
until the diagnosis can be excluded

- For enrolled patients during the active study drug phase, acyclovir, famciclovir,
valacyclovir for treatment of HSV or VZV infection as clinically indicated.

8. Currently enrolled in an interventional trial of an investigational therapeutic agent
known or suspected to have anti-CMV activity, or to be associated with significant
known hematologic toxicity (Note: confirm eligibility with one of the study medical
directors at the coordinating site).

9. At baseline patients who have both a tracheostomy, and have been on continuous 24-hour
chronic mechanical ventilation.

10. Patients with Child Class C Cirrhosis.

11. Patients with pre-existing interstitial lung disease.