Adult Emergency Department Patients with Liver Cirrhosis: Clinical Characteristics and Outcomes.
In this ED-based single-center retrospective study, we investigated the prevalence, clinical characteristics and outcomes in afebrile bacteremic patients with liver cirrhosis. We demonstrated that although baseline characteristics were similar between the afebrile and febrile patients in our study cohort, delayed and improper selection of antimicrobial agents occurred more frequently in the afebrile group, which was at an increased risk of organ failure, including higher rate of ICU transfer and endotracheal intubation, further associated with higher mortality rate.
Previous studies considered afebrile bacteremia as a unique phenomenon in the elderly9,22 and immunocompromised patients23. These were not seen among our patients, probably due to their cirrhotic condition, which already caused dysregulated immune response and the absence of typical clinical manifestations compared with the general population1. Cirrhotic patients presented bacteremia more frequently than other comorbidities because of gut bacteria overgrowth and local immune defenses dysfunction1, further precipitated by polymorphonuclear leukocyte dysfunction and complement deficiency, leading to substantially high mortality rate (range 26–59%)4,24. Interestingly, cirrhosis itself has been recognized as a potential risk factor of afebrile bacteremia, further strengthening the distinct disease entity and treatment complexity10.
Our patients with cirrhosis were younger and predominantly male, and half of them had cirrhosis attributed to alcoholism, which was different from a recent epidemiological research on liver cirrhosis25. Although the prognosis and survival of patients between alcoholic and non-alcoholic cirrhosis were similar in previous studies26,27, alcoholic cirrhotic patients tended to have bacterial infections, less incidence of hepatocellular carcinoma formation, and more mortality events attributed to infectious disease27. Previous systemic reviews demonstrated that in hospitalized patients with decompensated cirrhosis related acute illness, median survival is <6 months with Child-Pugh score ≥10 or MELD score ≥18, which was seen in the majority of our cirrhotic patients28. These reports could explain why our sicker patient cohort was more susceptible to acute illness, especially infection events, resulting in worse outcome compared with other comorbidities24.
It is not surprising that the proportion of patients fulfilled the SIRS criteria in the afebrile group was far less than that of the febrile group because they were divided by body temperature, a determinant included in SIRS criteria. Nevertheless, SIRS criteria exhibited poor accuracy in diagnosing cirrhotic patients with a bacterial infection, including in-hospital mortality discrimination and septic shock development, ICU transfer or acute on chronic liver failure prediction13. Cirrhotic patients may have hypersplenism, use beta-blockers, and present leukopenia and bradycardia, thus showing a lack of the SIRS parameters11,29. Furthermore, reduced production of acute- phase proteins, such as C-reactive protein (CRP), in patients with decompensated liver cirrhosis, made them had a weaker severity prediction and stratification ability in response to infection1,30. In concurrence with these issues, more than half of our afebrile bacteremic patients presented absence of tachycardia or leukocytosis, neither with marked CRP elevation, which further lowered the warning level for clinicians, thereby dismissing infectious diseases9,10. Also, other scoring systems (such as Pitt bacteremia score) which rely on inflammatory parameters including the presentation of fever, revealed limited ability in bacteremia severity stratification in patients with cirrhosis1.
It had been proposed that markers of organ dysfunction rather than inflammatory variables have better prognosis impact and mortality prediction performance in cirrhotic patients with sepsis13,19. The CLIF-SOFA score, which incorporated six variables of organ dysfunction (kidney, liver, cerebral, lung, coagulation, circulatory), has been validated as a useful tool for short-term mortality prediction in cirrhotic patients with acute decompensation19. Acute-on-chronic liver failure (ACLF), which is characterized by acute deterioration of liver function with or without extra-hepatic organ failure, carries a significantly higher risk of mortality especially when accompanied by organ failure12. The bacterial infection is the common identifiable factor triggering ACLF, and both of them could result in liver function deterioration with multiple organ failure, and mortality in patients with cirrhosis12,31. In concert with this concept, the bacteremia events precipitated our fragile cirrhotic patients to both sepsis and ACLF progression, leading to mortality and other adverse outcomes. The independent 30-day mortality prediction ability of the CLIF-SOFA score in our regression model also strengthens the idea that the extent of organ dysfunction correlated better with the prognostic significance in patients with cirrhosis19.
Unlike other diseases that were more likely to have bacteremia with respiratory or urinary tract origin, cirrhotic patients tend to have spontaneous bacterial peritonitis as their primary infection source, which is consistent with our results4,15,16. The distribution of bacteremic isolates in our study cohort was similar to previous studies, predominantly presenting gram-negative pathogens including Escherichia coli and Klebsiella pneumoniae predominantly, suggesting that the gastrointestinal tract is the most common source of bacterial infection in cirrhotic patients4,14,15,16,32.
The timing and selection of antibiotics treatment differed significantly between our afebrile and febrile groups, with much higher rate of inappropriate use noted in the afebrile one. Prompt and appropriate antibiotics management is a crucial element in treating patients with sepsis33 as delayed antibiotics administration in patients with bacteremia has been recognized as an independent risk factor of mortality1,12,32. Interestingly, in contrast with the newest Surviving Sepsis Campaign guidelines that recommended the broad-spectrum antibiotics to be administrated within 1 hour for patients with sepsis and septic shock33, there were no unambiguous definitions regarding the “appropriate timing” of antibiotics administration in previous bacteremia studies, although most of them used 24 hours as the cut point4,14,20,21. The significantly higher rate of ineffective antibiotic administration in our patients (31/104, 29.8%) was unexpected, although the agents were prescribed in accordance with the international recommendations regarding the treatment of bacterial infection in patients with cirrhosis12. This was possibly because some of (13/31) the cases were classified as primary bacteremia that lack the typical signs of infection. Meanwhile, the high yield of multi-drug-resistant pathogens in our study is also consistent with the finding that the prevalence of multi-drug-resistant bacteria in cirrhotic patients has increased worldwide12. It was more prominent in the afebrile group who had blunted inflammatory response and showed absence of conventional inflammatory parameters, further complicating the identification of the infection source and choice of antimicrobial regimen4,24.
The 30-day mortality in our afebrile bacteremic group was substantially higher (40%), and was similar to a previous afebrile bacteremia study10. This could be attributed to their higher proportion of inappropriate antibiotics treatment, since timely and adequate antimicrobial therapy was still considered as an important prognostic factor in cirrhotic bacteremic patients, regardless of their comorbidities or infection severity14,32,34. In this study we demonstrated that body temperature is not a reliable marker for clinicians to differentiate infectious events in patients with cirrhosis, and could overlook the disease severity of the afebrile patients, thus delaying initiation of sepsis bundle, including antibiotics treatment, resulting in higher mortality risk. Another explanation for grave prognosis in the afebrile group is the consequence of their highly impaired systemic immune response to infection, predisposing serious complications and mortality, although this had not been validated by immunological assays35.
The lack of significant differences in the rate of septic shock between the two groups was unexpected, and probably because we only identified those patients needing vasoactive agents to maintain hemodynamic stability during the ED course as the shock condition, not taking account of the following ICU or ordinary ward course. Therefore, we may have missed a portion of patients who developed shock later. Also, we found no significant differences in the proportion of renal replacement therapy between the two groups, which could be because the majority of the patients (81/104, 77.9%) had no kidney failure defined in CLIF-SOFA scoring system (i.e., serum creatinine <2.0 mg/dl), hence only 6 of them received renal replacement therapy making the comparison less meaningful. Nevertheless, the analysis of cumulative survival probabilities and other organ failure parameters, including the rate of ICU transfer and respiratory failure, all indicated a far worse prognosis in afebrile patients.
There were several limitations in our study, including its monocentric and retrospective design. First, we did not calculate the detailed amount of fluid administration in bacteremic patients; although the source control was recorded and compared between the two groups, we didn’t take account of the actual timing of these interventions which could also influence the prognosis of patients with sepsis and septic shock33. Second, the different epidemiological data of our study cohort may limit the extrapolation ability of these results. Third, all data obtained from the manual chart reviews and electronic medical records made recall and selection bias inevitable. Fourth, our study failed to recognize patients who did not undergo blood culture tests in the ED, but developed bacteremia subsequently. Finally, some patients may have taken antipyretic agents before the ED visit, which may have influenced our stratification based on body temperature. Nonetheless, we defined the afebrile state as the absence of fever during the entire ED course, thus minimizing the effect of anti-pyretic use before the ED treatment.
In summary, afebrile bacteremic patients with liver cirrhosis conform a unique, but not a minority group. They have multifactorial immune system impairment and, lack of typical manifestations of infectious disease, which results in delayed diagnosis and inappropriate antimicrobial agent use. They carry an overwhelmingly higher rate of respiratory failure and, ICU transfer, further associated with a worse prognosis. Clinicians should pay more attention while treating cirrhotic patients, and rely not only on their body temperature or laboratory results; while the parameters of organ dysfunction such as the CLIF-SOFA score, have been validated as a more reliable prognostic factor in cirrhotic patients with bacteremia. They should always keep in mind the possibility of occult severe infection when unusual clinical manifestations are presented, such as lethargy, confusion, unexplained hypotension, or other symptoms of organ dysfunction. Only early recognition and prompt treatment can avoid deterioration of the patients and improve their outcomes.
