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 groups in our study cohort, delayed and improper selection of antimicrobial agents occurred more frequently in the afebrile group, and were 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 elderly (9,19) and immunocompromised patients(20). These were not seen in our patients probably due to their cirrhotic condition, which already caused dysregulated immune response and absence of typical clinical manifestations compared with the general population(1). Cirrhotic patients presented bacteremia more easily than other comorbidities because of gut bacteria overgrowth and local immune defenses dysfunction(1), further precipitated by polymorphonuclear leukocyte dysfunction and complement deficiency, leading to substantially high mortality rate (range 26–59%) (4,21). Interestingly, cirrhosis itself had been recognized as a potential risk factor of afebrile bacteremia, further strengthening the distinct disease entity and treatment complexity(10).
Our cirrhotic patients were younger and predominantly male, and half of them had cirrhosis attributed to alcoholism, which was different from a recent epidemiological research on liver cirrhosis (22). Although the prognosis and survival of patients between alcoholic and non-alcoholic cirrhotic patients were similar in previous studies (23,24), alcoholic cirrhotic patients tended to have bacterial infections, less incidence of hepatocellular carcinoma formation, and more mortality events attributed to infectious disease(24,25). 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 majority of our cirrhotic patients(26). These could explained why our sicker patient cohort was more susceptible to acute illness, especially infection events, resulting in worse outcome compared with other comorbidities(21).
It is not surprising that the proportion 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 composed of SIRS criteria. Nevertheless, SIRS criteria exhibited poor accuracy in diagnosing cirrhotic patients with bacterial infection, including in-hospital mortality discrimination and septic shock development, ICU transfer or acute on chronic liver failure prediction(27). Cirrhotic patients may have hypersplenism, use beta-blockers, and present leukopenia and bradycardia, thus showing a lack of SIRS parameters (28,29). In concurrence with this hypothesis, more than half of our afebrile bacteremic patients presented absence of tachycardia or leukocytosis, which further lowered warning level for clinicians, thereby dismissing infectious diseases (9,10). 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 sepsis(27).
Unlike other diseases that were more likely to have bacteremia with respiratory or urinary tract origin, cirrhotic patients tended to have spontaneous bacterial peritonitis as their primary infection source, which was consistent with our results (4,12,13). 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 patients (4,11–13,30).
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 sepsis(31). Delayed antibiotics administration in bacteremic patients had been recognized as an independent risk factor of mortality(17,18). In cirrhotic patients, hypoalbuminemia leading to reduction of proteins binding to antimicrobial agents, and altered distribution and clearance of drugs also changed their pharmacokinetic activity, further influencing treatment effectiveness(1). Furthermore, cirrhotic bacteremic patients presented with non-specific symptoms because they had blunted inflammatory response, which hindered localization of the primary focus causing frequent delayed and improper antibiotics administration (4,21).
The 30-day mortality in our afebrile bacteremic group was substantially high (40%), and was similar to a previous afebrile bacteremia study(10). 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 severity(11,30,32). 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 assays(33).
Since more than half of our patients belonged to end-stage liver disease (ESLD), the mortality may attributed to their acute-on-chronic liver failure (ACLF), developing acute decompensation of liver cirrhosis, further associated with liver and other extra-hepatic organ failure(34). Nevertheless, bacterial infection was a common complication in cirrhotic patients and was the most common precipitating factor of ACLF(35), inducing excessive host immune system pro-inflammatory response and resulting in tissue damage even organ failure, including kidney, brain, gastrointestinal tract and coagulation system(34). In summary, the higher proportion of inappropriate treated infection in our afebrile bacteremic group could cause progression of sepsis and deterioration of liver function, both of which were related to mortality events.
It was unexpected that the rate of septic shock would not differ significantly between the two groups, probably because we only identified those needing vasoactive agents to maintain adequate hemodynamic stability during the ED course as shock condition, and not taking account of the following ICU or ordinary ward course. Therefore, we may have missed a portion of patients who developed shock later. Nevertheless, the analysis of cumulative survival probabilities and other organ failure parameters, including 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, which is also important in treating patients with sepsis or septic shock(31). 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 anti-pyretic agents before the ED visit, which may have influenced our stratification based on body temperature. Nonetheless, we defined the afebrile state as absence of fever during the entire ED course, thus minimizing the effect of anti-pyretic use before the ED treatment.