Answer to Question2

The likely organisms are similar to those seen in children with other risk factors. E. coli is the commonest Gram-negative bacterium isolated (25-50%), followed by Klebsiella (15-20%) and Enterobacter species (5-10%). The most common Gram-positive bacteria are Enterococcus species (10-20%). Anaerobes, such as Bacteroides and Clostridia, are usually present as part of a mixed infection.

Answer to Question 4

Many children with biliary atresia who experience an episode of cholangitis have recurrent episodes. In her case she had suspected cholangitic abscesses at the initial episode. Eradication of organisms from the bile is dependent upon adequate biliary antibiotic concentrations. Not all antibiotics penetrate the bile equally well and although the initial infection responded well clinically, it is possible that she either developed a second ascending infection or that the organism was not cleared from the residual hepatic abscesses as it was not possible to drain all the abscesses percutaneously. Recurrent cholangitis may result in deteriorating liver function and can be an indication for liver transplantation. Although she had clinical evidence of biliary cirrhosis and portal hypertension, her liver synthetic function was well preserved.

Repeat abdominal sonar revealed innumerable irregular cholangitic abscesses of varying sizes throughout both lobes of the liver, the largest 18 x 20 x 38mm, with thick echogenic debris and fluid-fluid levels suggestive of purulent material. Multiple intrahepatic collections were again aspirated percutaneously. She was treated with intravenous cefotaxime for six weeks and was discharged on oral cefuroxime as cholangitis prophylaxis, an antibiotic to which the organism was sensitive.

Two months later she was readmitted again with a diagnosis of cholangitic abscesses. Again Klebsiella pneumoniae was cultured from blood with the same sensitivity profile as the previous culture.

Question 5. Given the sensitivity and resistance profile of the organism, what agents have better excretion into the bile and would also be appropriate to treat recurrent cholangitis? What prophylactic antibiotics should she receive, as she was developing recurrent episodes of cholangitis on antibiotic prophylaxis?

Answer to Question 6

She has antibody to hepatitis B and measles but none to hepatitis A, mumps or rubella and equivocal VZV IgG. She should ideally receive MMR, hepatitis A and VZV vaccines prior to transplantation. Transplantation should be delayed by at least four weeks after the administration after any live vaccines.(6)

She subsequently received both MMR and hepatitis A vaccines, but not varicella zoster as it was out of stock countrywide. At follow up she was well and experienced no further episodes of cholangitis on cotrimoxazole prophylaxis. She subsequently underwent successful orthotopic liver transplantation at the age of two and a half years.

Discussion:

Biliary atresia is a progressive obliterative cholangiopathy resulting in complete obstruction to bile flow in early infancy. It is the single most common condition resulting in need for liver transplantation in children. The aetiology is unknown and various theories include abnormal bile duct development antenatally, viral infection, toxin exposure and possible immune-mediated biliary damage. Infants with biliary atresia present in the first weeks of life with pale stools, dark urine and jaundice, typically being otherwise healthy and thriving.

Kasai procedure was developed in 1959 and aims to restore bile flow by resecting the atretic bile duct remnants and anastomosing a loop of bile either directly onto the CBD or the porta hepatis after all atretic bile ducts have been resected, this procedure remains before the age of 8 weeks remains the first intervention of children with biliary atresia.

If successful the portoenterostomy allows bile to drain into the small intestine and results in the bilirubin dropping to less than 34umol/L (2mg/dL). Even with a successful Kasai, biliary cirrhosis progresses at a variable rate and most patients will ultimately need a liver transplant.(4) Without a Kasai, if the diagnosis of biliary atresia is missed or delayed, biliary cirrhosis develops in infancy and survival beyond two years of age is unlikely without a liver transplant.(4) The Kasai portoenterostomy places a child at risk of ascending cholangitis because of the abnormal anatomy and bacterial stasis in the region of the roux limb, the reported incidence is 40-50% of children with biliary atresia who have a Kasai.(2,4,7,8) Cholangitis is more likely to occur where there is bile flow present, so a child with a well-functioning Kasai is at risk for cholangitis.(7) Most children who develop cholangitis do so within the two years after the Kasai procedure. (1,4) Cholangitis is one of the most important determinants of long-term survival of biliary atresia patients with their native liver. Cholangitis post-Kasai has been associated with reduced rates of 1-, 3- and 5-year native liver survival compared to children not experiencing cholangitis (92%, 76%, 76% vs 80%, 51%, 23%).(4,7)

In cases where an organism is identified, these are typically Gram-negative intestinal flora(7). It is important that antibiotics are commenced as soon as the diagnosis of cholangitis is suspected - based on the clinical presentation of signs of systemic infection with features of biliary disease - and not to delay awaiting confirmation of the diagnosis as cultures are positive in fewer than 30% of cases.(1,4) The duration of treatment for acute cholangitis is at least fourteen days, but a longer duration of three to four months may be needed with liver abscess or recurrent cholangitis, in particular in children with biliary atresia who have a portoenterostomy.(3,7,9) Eradication of organisms depends upon biliary excretion and effective antibiotic concentrations in the bile.(9)

Although there is little evidence, it is common practice to use prophylactic antibiotics to prevent cholangitis either as a primary intervention or after an initial episode. This lack of data pertains to the requirement for prevention, the best drugs to use and the duration.(4) The only randomised controlled trial compared trimethoprim/sulfamethoxazole(TMP/SMX) (n=9) with neomycin (n=10) as secondary prophylaxis of cholangitis in Taiwanese children with biliary atresia, finding no statistical difference between regimens, but a lower recurrence rate compared to a historical control group treated with ceftriaxone.(10) In a retrospective cohort study, children who received primary antibiotic prophylaxis, mostly TMP/SMX, had a reduced rate of cholangitis (5/34, 15%) compared to those who did not receive prophylaxis (4/7, 57%), however a large number of the children in this study had a portocholecystostomy or portoduodenostomy and not a traditional Kasai, which might have a confounding effect.(11) In another retrospective cohort study from the Netherlands, patients received a variety of different antibiotics as prophylaxis including neomycin, colistin, nystatin, ciprofloxacin and TMP/SMX, finding that antibiotic prophylaxis did not reduce the incidence of cholangitis.(12) It should be noted that when prevention is provided there is a risk of developing disease with drug resistant organisms as occurred in this case. Probiotics may also play a role in the prevention of ascending cholangitis.

Children with biliary atresia should receive all routine EPI vaccines and also be vaccinated against hepatitis A. Hepatitis B antibody titres should be monitored annually and additional vaccination doses given if titres drop below 10IU/ml. Many of these children will require liver transplantation and vaccine preventable diseases have been reported to increase morbidity and mortality post-transplantation.(13–15) Patients who are liver transplant candidates should receive all vaccines, including live vaccines (measles, mumps, rubella and varicella) before transplantation and ideally before end-stage liver disease has developed.(13,14,16) Live vaccines are contraindicated lifelong post-transplant due to immunosuppression and the possibility of vaccine-induced disease. Vaccines are more immunogenic if given before end-stage liver disease develops.(13,15,16)