In this retrospective study, we analyzed the therapeutic efficacy of intravenous multiple antibiotics for cholangitis, based on a before-and-after comparison of 153 cholangitis patients after PKE procedure. To investigate the severity of cholangitis and the related antibiotics treatments, we further compared the difference of infection markers and liver function among the 3groups based on the treatment of intravenous antibiotics.
Cholangitis is the most common complication after PKE procedure. In recent years, the mechanism of cholangitis has been studied, but not unified. It is generally believed that bile duct injury, bile duct dysplasia, intestinal microbial migration and retrograde infection caused by intestinal contents reflux are the main causes of cholangitis (8). When the occurrence of biliary insufficiency obstruction, bile drainage is not sufficient, intestinal dysfunction and other reasons, can cause intestinal bacteria migration and intrahepatic reproduction, eventually lead to cholangitis. Evidence supports the hypothesis that bacterial translocation from the enteric conduit is the main pathogenic mechanism (9). Reduced lymph drainage at the porta hepatis and an insufficient volume of bile flow from a partially obstructed biliary tree were recognized as possible causative factors for the bacterial translocation. It has been reported that gram-positive bacteria, especially Enterococci species, occupied a significant portion of the etiologic pathogens of cholangitis after KPE. In previous studies, the most frequently isolated bacteria were E. coli, K. pneumoniae, and P. aeruginosa, E. cloacae. Enterococcus faecium is a well-known intestinal bacterium that is known to cause acute cholangitis in adults, Baek SH et al. reported that Enterococci faecium had a high prevalence rate in culture-proven cholangitis, but easily development to antimicrobial resistance, which demonstrates that they may be considered as a pathogen of recurrent cholangitis and intractable cholangitis after KPE (8).
In present, many researches divided cholangitis into early cholangitis and late cholangitis. Early cholangitis is associated with edema, necrosis and granulation tissue proliferation at the anastomotic stoma, which will lead to the small bile duct obstruction. The late cholangitis is more concerned with the progressive damage of small bile ducts due to the abnormal development of the bile duct in the patients (9). Several previous studies have demonstrated that early cholangitis is associated with a poor prognosis (4,5). In our study, the patients’ age in ICSTS group is elder than IMP and IVIG groups, we further discover that age at the first episode cholangitis is eldest in ICSTS group, indicates that the elder age of the patients, the milder of cholangitis, tend to have a better outcome, though it’s just a rough trend. It was common acknowledged that an elder age at KPE usually indicates a potential for more severe liver damage and poor outcomes (10), though no study has demonstrated the relation between surgical age and cholangitis, in our study, we find out that IVIG group trend to have elder surgical age than the other two groups. Recurrent episodes of cholangitis result in inflammatory reaction, bile duct injury and stenosis, lead to poor bile drainage can finally cause intrahepatic bile duct cystic dilation to form bile lake, which is also a risk factor for another episode cholangitis and a sign of poor prognosis (4). In our study, we assessed the frequency and recurrent episodes of cholangitis in 3 groups, the IVIG group shows a highest cholangitis frequency (3.57 ± 0.43times) and the recurrent rate is 85.7%, significantly higher than the other two groups, which is consistent with previous studies that recurrent cholangitis resulting in poor prognosis.
Cholangitis is the most common complication in BA patients after KPE, the incidence is about 50%~90%. It has reported that varies regimes for prevention of cholangitis in patients with BA after KPE, prophylactic antibiotics after KPE to reduce the incidence of cholangitis is universal, but few published studies provide satisfactory evidence for its benefit [11]. furthermore, the latest research, Wen Bo Pang et al. reported that prophylactic imipenem-cilastatin and human immunoglobulin is effectively on the prevention of early-onset cholangitis (12). Although the use of steroids plays active role in bile flow after Kasai procedures, there was no evidence that it plays any role on prevention of cholangitis. There is no debate that cholangitis is the most common risk factor influence the quality of life in KPE patients. Each episode of cholangitis would damage the liver function, accelerate liver fibrosis, and lead to poor prognosis, therefore, an early diagnosis and timely antimicrobial management are important to prevent liver persistent damage caused by cholangitis (3,4).
Up to now, no studies had a standard protocol for the evaluation of suspected ascending cholangitis, most reported that the diagnosis was based on clinical presentation and liver biochemistries: unexplainable fever, recurrent jaundice or acholic stools, increased bilirubin levels, elevated WBC and CRP (6). Blood culture can confirm detect the pathogenic bacteria causing cholangitis, but the positive rate is very low, ranging from 8.9–35.1% (8,13,14). It was reported that liver biopsy could be considered to obtain liver tissue sample for bacterial culturing, however, it is not easy to perform in children owing to its invasiveness. Some rare diagnostic methods include: bile culture is invasive, and liver puncture is not guaranteed to take bile unless there is a definite bile lake (15).
When a patient after PKE procedure is suffering from an episode of cholangitis, which antibiotics are the best choice? During the last three decades, the type of antibiotics used for cholangitis after PKE has changed over time. In the early 1980s, second-generation cephalosporins (cefuroxime and cefamandole) with or without aminoglycoside (gentamicin and amikacin) were commonly used. Since 1989, third-generation cephalosporins (usually cefoperazone) were widely used. In 2004, meropenem was introduced as a suitable candidate, suggested became an effective first-line antibiotic. Unfortunately, the efficacy of antibiotics in the treatment of cholangitis PKE decreased as time goes on (3). The probably reasons are following, Unreasonably and irregularly applied antibiotics contribute to pharmaceutical resistance,the pathogenic bacteria was variable and easily development to antimicrobial resistance. Furthermore, recurrent cholangitis lead to serious hepatic hilum fibrosis and the drug concentration is not enough.
Each episode of cholangitis would damage the liver function, accelerate liver fibrosis, and lead to various complications, at the same time, in order to treatment cholangitis, a variety of drugs will increase the burden of the liver, affect the prognosis of children. Previous studies have suggested that recurrent episode and inadequately treated cholangitis could lead to progressive liver failure (16). Therefore, judicious empiric antimicrobial management are, therefore, important to prevent liver damage caused by cholangitis and the emergence of multi-drug-resistant organisms. In this study, IVIG group had a significant high level of T (39.45 ± 0.23℃) and WBC (21.01 ± 1.16 × 109/L), as well as CRP (122.39 ± 18.65 mg/L), the liver function including ALT, AST, γ-GGT and DBL were significant elevated and higher than the other two groups. We indicate that intravenous antibiotics were more likely to consider the infection markers and liver function, a patient with serious infection and worse liver function was prefer given higher level intravenous, such as IMP, even more combined with IVIG.
Third-generation cephalosporins (usually cefoperazone) and meropenem are dominant in treating cholangitis, however, recent study showed that more than half of cholangitis patient treatment with meropenem are invalid and eventually required a switch of antibiotics, indicated that meropenem alone may no longer be the most appropriate antibiotics. An early switch or addition of antibiotics should be considered in intractable cholangitis to minimize the damage to the biliary drainage (3). It has been reported that infants with BA always experience immune dysregulation and deficiency in addition to inflammatory conditions. IVIG is known to reduce inflammatory cytokines and to increase anti-inflammatory regulatory T cells. Numerous mechanisms for the anti-inflammatory action of IVIG have been proposed, including interference with the cytokine network, neutralization of autoantibodies, modulation of effector functions of T and B cells, and enhancement of regulatory T cells. In addition, human immunoglobulin reduces progressive intra-hepatic bile duct injury. The previous studies have shown that supplementation of IVIG with severe infection rapidly improved the immune function and anti-infection ability of the children, and reduced the development of the systemic inflammatory response syndrome, previous study considered of IVIG use in infants with BA to diminish the progressive intrahepatic bile duct injury (17–19). Our previous study showed that IVIG as add-on treatment may be an effective treatment for the cholangitis acute episode (7). In this study, after three days treatment, the three groups all attained relatively high antifebrile rate of 82.2%, 80% and 92.9%, and hospital stay length had no significant difference, indicate that the three groups patients all obtained satisfactory therapeutic efficiency, though IVIG group displayed more serious infection and worse liver function before treatment. With three months followed up, unfortunately, IVIG group had a significant higher recurrent rate of 82% compared with ICSTS group (23%) and IMP group (37%), the cholangitis frequency is 1.36 ± 0.28 times in IVIG group, which is the most frequent group. Furthermore, IVIG group also had a worse adverse outcomes rate (21.4%, 2 death and 1 LT), significantly higher than the others. The reason may be that supplementation of IVIG with severe infection rapidly improved the immune function, but the duration seems to be limited, serious and intractable cholangitis PKE tend to has a poor prognosis.
However, our study had limitations and shortages. It was a retrospective study with small sample, which may have a slight deviation, Prospective study is needed to verify it. In this study, we didn’t analyze the blood culture, for not all patients received blood culture and the positive rate is low. We just analyze the outcome of the following 3months, long-term follow-up should be further recorded. IVIG is not a routine treatment for cholangitis, we would obtain parental consent before application of IVIG and all the patients had equal rights to given the best treatment.
There is no unified guideline treatment of intravenous antibiotics for cholangitis PKE, IVIG as supplementary treatment may improve short-outcome of serious and intractable cholangitis. Personalized intravenous antibiotics to treat cholangitis considering recurrent episode, the severity of infection and liver function, may be a more appropriate treatment strategy. A multi-center prospective study should be studied to provide a standard intravenous antibiotics treatment of cholangitis.