Cirrhosis is one of the long-term sequelae of biliary atresia (BA) in pediatric patients [1]. Children with BA with delayed diagnosis or could not have adequate bile flow after hepatic portoenterostomy (also known as Kasai operation) generally experience several cirrhosis-related complications such as portal hypertension and variceal bleeding, delayed growth, and malnutrition [2]. Furthermore, a number of children with cirrhosis can also develop potential infection-related life-threatening conditions such as acute cholangitis, spontaneous bacterial peritonitis (SBP), and sepsis/bacteremia [2]. Multifactorial pathogenic mechanisms can exert an excessive inflammatory response and thus induce circulatory dysfunction and acute decompensation that leads to morbidity and death [3].

While there have been numerous studies exploring the characteristics of infections in adult patients with cirrhosis, there is a lack of research in children. The characterization of impact of infections such as septicemia [4,5], SBP [6], acute cholangitis [7], infected biloma in children with BA [8,9], and urinary tract infection have been reported [10]. However, these children can also suffer from other common viral infections such as upper and lower respiratory tract infections, otitis media, and acute gastroenteritis. The incidence of various infections in the tropical countries may be even higher when compared to a report from westernized countries [11]. The evaluation for potential etiologies can therefore be challenging, time-consuming and labor-intensive which can also make the management more difficult or further delayed when compared to the children without cirrhosis. A recent study by Shiau et al. [12] also found that age at Kasai operation and platelet count are risk factors for serious infections.

Moreover, as signs and symptoms can be nonspecific, several biomarkers including C-reactive protein (CRP) [13], procalcitonin [14], or interleukin (IL)-6 [15], have been used to aid and differentiate serious bacterial infection with other less severe infections in patients with cirrhosis; but the yield of the aforementioned markers remain inconclusive [12]. In adults, septic patients with pneumonia or >1 site of infection had a higher mortality [16]. A recent study by Singh et al. found that ascites fluid infection (AFI) was found in 31% children with chronic liver disease and almost half of them were nosocomial infection resulting in high mortality. It was also concluded that children with AFI and worsening cirrhosis should be evaluated for liver transplantation (LT) [17]. Children with cirrhosis who develop several episodes of cholangitis and septicemia are also at risk for LT18) and death [11,12].

With the limited data on this regard in children with BA with cirrhosis, therefore we aimed to study on the characteristics of infection, evaluation and management, potential risk factors for developing infection, clinical outcomes, which remain a gap in the current knowledge. Such studies would likely provide benefits for patient care in effectively managing BA children presenting with suspected infection and possibly leading to an improved prognosis.

In a single-center cohort of BA children with cirrhosis, bacterial infections were common, with cholangitis being the most common bacterial infection, accounting for nearly 40% of total bacterial infection. Other liver disease-related infections such as infected biloma and AFI were also relatively common in our population. While comparing between the 3 groups (bacterial infection, viral infection, and no infection), no statistically significant differences of demographics, performed Kasai operation, or baseline clinical condition were observed. This finding is consistent with a study from Taiwan [12] that reported cholangitis in 46.2% of post-Kasai patients, reinforcing its role as a leading infectious complication in this population.

Bacterial infections were associated with significantly higher PELD scores both at the first visit and the fever episode as well as bilirubin levels as a person-related data (Table 3). These parameters reflect the severity of liver dysfunction in these children with chronic liver disease. Similarly, Bolia et al. [25] demonstrated that a higher Child-Pugh score, along with lower serum albumin and elevated international normalized ratio, was associated with an increased risk of infection in children with acute liver failure and decompensated chronic liver disease. This finding was parallel between Child-Pugh and PELD scores across different studies emphasizing the relevance of liver disease severity in predisposing to various types of infections. Cirrhosis is an immunomodulatory deficiency state [26], predisposing such patients to other various infections through multiple mechanisms [19,27], such as bacterial overgrowth and small intestinal barrier dysfunction resulting in further bacterial translocation [4,6,27,28]. Genetic variants in those with cirrhosis have also been noted to be associated with an increased risk and severity of infection [29].

From Table 4 as described the infection episode-related data, CRP and PELD score were 2 significant independent associated factors of proven/suspected bacterial infection (vs. presumed viral infection). Other clinical and laboratory parameters such as high-grade fever, abnormal blood cell indices, procalcitonin or hypoalbuminemia were not statistically significant. A recent study by Shiau et al. [12] also found that platelet count is one of the risk factors for future serious infections. From our study, CRP levels showed good discriminatory power with an area under the ROC curve of 0.80 at a cutoff of 31 mg/L, yielding an accuracy of 73%. This finding may support the clinical utility of CRP as a biomarker for an identification of bacterial infection in this population. However, this cutoff value is notably higher than those reported in previous pediatric studies. For instance, Bolia et al. [30] and Kalvandi et al. [31] reported an optimal threshold of 6 mg/L in children with acute liver failure, decompensated chronic liver disease, or ascites, with good diagnostic performance for bacterial infections and mainly for SBP. Similarly, Deutsch et al. [13] demonstrated that a CRP cutoff of 10 mg/L was appropriate for detecting bacterial infections in adult patients with cirrhosis. This relatively high CRP threshold and limited number of documented test maybe due to that CRP was being performed selectively in cases with more severe clinical presentations and/or when followup of treatment response was deemed necessary by the treating physician.

We found that native liver survival was significantly reduced in patients with bacterial infection (adjusted HR, 1.88), reinforcing the role of infection in liver function deterioration and loss of transplant-free survival. Although a higher PELD score was associated with an increased risk of death and transplantation in the univariate analysis, it did not retain statistical significance in the multivariable analysis (Table 5). These findings highlight the detrimental effect of bacterial infection on the preservation of native liver function and suggest that the management of bacterial infection may likely be crucial in improving long-term liver outcomes [27]. Based on our results and existing evidence, cholangitis is the most common cause of proven/suspected bacterial infection in children with BA, likely related to previous Kasai portoenterostomy. Moreover, our study demonstrated that, after adjusting for disease severity scores and prior history of infection before referral, proven/suspected bacterial infection was associated with a lower probability of native liver survival (i.e., higher rates of LT or death). However, there is currently dearth of studies evaluating the clinical outcomes in patients with BA and cirrhosis after bacterial infections. Therefore, this aspect reported in the present study addresses the existing knowledge gap.

This study examined infections in a relatively large cohort of children with BA, encompassing not only bacterial infections but also viral infectious etiologies. We evaluated the utility of clinical and laboratory parameters in differentiating bacterial infections from other infections, and to explore the clinical outcomes associated with bacterial infections. However, several limitations should be acknowledged. First, the retrospective design inherently limits data completeness, and missing data were unavoidable. In addition, data collection was limited to the ‘documented’ infection episodes, resulting in inconsistent timing across patients and preventing longitudinal assessment of changes in clinical status or risk factors over time. Accordingly, this may have contributed to the relatively high proportion of patients classified into the “no documented infection” group. The CRP was measured in just 40% of the total infection episodes as it may be due to that CRP was performed based on clinical indication and selectively checked in cases with more severe clinical presentations or those mostly diagnosed with proven/suspected bacterial infections. Patients with milder clinical presentations, such as low-grade fever, viral illness, or upper respiratory tract infections, were less likely to undergo CRP testing. Therefore, we acknowledge this as a limitation in this retrospective study. The median follow-up duration was approximately 10 months, which may be considered relatively short. This is largely attributable to the fact that most patients in this cohort were referred for LT, and the evaluation and treatment process was typically completed within a relatively short timeframe.

In conclusion, infections mainly cholangitis and bacteremia are common in children with cirrhosis due to BA. A higher PELD score at the first visit and during febrile episodes, as well as elevated bilirubin levels, were significantly associated with proven or suspected bacterial infection. Specific clinical and laboratory parameters, such as CRP, are useful in differentiating bacterial infections from other causes of fever. Bacterial infection was also associated with a decreased early survival rate. Developing appropriate strategies to manage and prevent such bacterial infections could improve clinical outcomes.