The major findings of our study
Diverse clinical manifestations had been reported in HFRS patients, ranging from mild and acute influenza-like illness to more severe shock syndrome. Apart from acute renal insufficiency, up to one-third of HFRS patients exhibited extrarenal organ involvement, with pancreatobiliary diseases as the most common manifestation, including acalculous cholecystitis, pancreatitis, and cholangitis . In 1950s, Hullinghorst and Steer reported pathological evidence of pancreatitis in one-third of HFRS autopsies during the Korean conflict . The reported prevalence of AP among HFRS patients was highly variable in observational studies, with a pooled prevalence of 6.8% (36/529) . We found that 8.4% of HFRS patients in our cohort developed AP. The observed difference in prevalence of AP among HFRS patients might be related, at least in part, to the causative viruses , geographic region , male-to-female ratio , prevalence of risk factors (such as alcohol misuse and history of gallstones), and time course during disease progression. For example, the highest prevalence of AP was reported by Bui-Mansfield and colleagues in a group of 13 male patients with HFRS , whereas the lowest prevalence of AP was reported by Zhu and coworkers in 218 HFRS patients (150 males and 68 females) .
Another major finding of our study was that AP was an independent risk factor for 90-day mortality in HFRS patients, which had never been studied in the above-mentioned observational studies, possibly due to the limited number of AP cases (3 to 12) in the individual study. However, pooled results from these studies suggested similar mortality rates [8.3% (3/36) in HFRS patients with AP vs 4.9% (24/493) in HFRS patients without AP, p = 0.3618]. In comparison, the 29 cases in our cohort represented the largest number of AP cases among HFRS patients ever reported, which allowed us to investigate the impact of AP on mortality in univariate and multivariate analyses. The significantly higher mortality rate in HFRS patients with AP (24.1% vs. 2.2%) could be explained by the severity of acute illness, as demonstrated by more pronounced inflammation (higher white cell count and CRP levels), liver dysfunction, more life-sustaining therapies (including mechanical ventilation and RRT), and more ICU admissions (44.8% vs. 3.8%).
It is a common belief that early recognition of patients with AP might be very important to improve clinical outcome of this potentially life-threatening condition. However, early diagnosis of AP among HFRS patients might be difficult, as both diseases shared some common clinical signs/symptoms, such as nausea/vomiting and abdominal pain. For example, abdominal pain was a presenting symptom in 30–90% of HFRS patients, which might explain the observed high misdiagnosis rate (up to 90%) . As a result, HFRS patients with abdominal pain should be subject to further laboratory (i.e. pancreatic and/or liver enzymes) and imaging (i.e. abdominal CT scan or ultrasonography) investigations, in order to determine the presence and severity of pancreatobiliary complications.
The major strength of our study was the robustness of the study result (i.e. AP as an independent risk factor for mortality), which was supported by univariate analysis, multivariate regression analysis adjusted for PS, and PS-matched case-control analysis. Our study was also subject to limitations. First, this was a retrospective single-center study, the result of which might not be generalized to other settings and required further validation by prospective multicenter studies. Nonetheless, the number of AP cases as well as HFRS patients in our cohort was significantly higher than that in previous studies. Second, the prevalence of AP might be underestimated, because laboratory (serum amylase or lipase) and abdominal imaging investigations were only performed in selected but not all HFRS patients.
In conclusion, our study indicated that AP was independently associated with higher mortality in HFRS patients. While considering the difficulty of early recognition of AP among HFRS patients with similar signs and/or symptoms, further laboratory and imaging studies might help identify these patients at risk of poor clinical prognosis.