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

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)

To evaluate whether administration of ganciclovir reduces serum IL-6 levels (i.e. reduction between baseline and 14 days post-randomization) in immunocompetent adults with severe sepsis or trauma associated respiratory failure.

Primary Hypotheses:

- In CMV seropositive adults with severe sepsis or trauma , pulmonary and systemic CMV reactivation amplifies and perpetuates both lung and systemic inflammation mediated through specific cytokines, and contributes to pulmonary injury and multiorgan system failure,

AND

- Prevention of CMV reactivation with ganciclovir decreases pulmonary and systemic inflammatory cytokines that are important in the pathogenesis of sepsis and trauma related complications.

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.