Cytomegalovirus Reactivation in Acute Necrotizing Pancreatitis

Background and Rationale for the Study Acute pancreatitis is one of the frequently encountered systemic diseases presenting with a wide spectrum of presentation ranging from mild disease which has a better outcome compared to severe disease which usually leads to admission to the intensive care unit (ICU), and is associated with high mortality. According to the revised Atlanta classification (2012), acute pancreatitis is now divided into two distinct subtypes, necrotizing pancreatitis and interstitial edematous pancreatitis (IEP), based on the presence or absence of necrosis. In severe acute pancreatitis, inflammation leads to peri-pancreatic fluid collections of which four distinct subtypes are identified. Acute necrotic collections (ANC) and walled-off necrosis (WON) which occur in patients with necrotizing pancreatitis, contain variable amounts of fluid and necrotic debris which can either be sterile or infective. The mortality rates for sterile necrosis remain comparatively low (5%-10%), but superinfection of the necrotic pancreas and peri-pancreatic tissue/ fluid collections increases the mortality rate considerably (20%-30%).

The infected pancreatic necrosum when cultured, usually demonstrates mono-microbial flora in 60-87% of patients and poly-microbial flora in 13-40% of patients. The most common organisms isolated are gram-negative bacteria, mainly Escherichia coli and Klebsiella pneumonia followed by gram-positive bacteria. With the increased use of antibiotic therapies in the ICU the incidence of pancreatic fungal infections is also on the rise. Fungal pancreatic infections, predominantly caused by Candida species, have been identified in up to one-half with a longer hospital stay and a lower one-year survival than patients with bacterial pancreatic infections only.

Traditionally, critically ill patients have been considered immunocompetent but the presence of sepsis and its immunomodulatory effects may lead to reactivation of dormant viral infections. In recent years, Cytomegalovirus (CMV) reactivation in critically ill patients has been recognized with as high as 71% incidence. Sepsis due to its immunomodulatory effects may lead to the reactivation of CMV due to the release of pro-inflammatory cytokines such as TNF-alpha and IL-1beta which has the ability to activate several transcription factors contributing to CMV reactivation. Studies showed that CMV infection in critically ill patients was consistently associated with undetectable IFN-γ T cell responses within the first 2 days of admission to the ICU and that viral load was inversely related to IFN-γ T cell responses. Similar results were found in septic patients who display immune system paralysis, reduced Th1 cell function, increased IL-10 production (anti-inflammatory), and global lymphopenia affecting natural killer cells (NK) quantitatively and qualitatively related to their interferon production.

Studies have documented significantly higher organ failure rates and mortality in critically ill patients with CMV reactivation. In a systematic review to investigate the association between CMV reactivation and clinical outcomes in immunocompetent critically ill patients, including Itwenty-two studies, CMV reactivation was associated with increased ICU mortality, overall mortality, duration of mechanical ventilation, nosocomial infections, and ICU length of stay. CMV reactivation has also been studied in specific critically ill cohorts, exhibiting their impact on mortality. The effect of CMV reactivation on mortality in immunocompetent acute respiratory distress syndrome (ARDS) patients has also been studied. Of 399 ARDS patients, 68 % were CMV seropositive and reactivation occurred in 27 % of them which was associated with overall increased ICU mortality. In another study among the septic shock cohort (329 patients), herpesvirus reactivations were documented in 68% of patients without prior immunodeficiency, and concluded that reactivations could be independently associated with mortality.

However, no studies are currently available investigating CMV reactivation in patients with acute necrotizing pancreatitis (ANP). The investigators aimed to study the prevalence of CMV reactivation and its viral load kinetics in critically ill patients with ANP