Case of the Month

October 2017

Penelope Rose1,2, Ronalda de Lacy1, Elizabeth Goddard1

1 Paediatric Gastroenterology, Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, University of Cape Town

2 Tygerberg Children’s Hospital, Department of Paediatrics and Child Health, Stellenbosch University

Case history

A one year old girl known with biliary atresia and a well-functioning Kasai portoenterostomy (bile ducts removed and a loop of intestine brought up to replace them) presented with fever and worsening jaundice of a day’s duration. She had been diagnosed with biliary atresia and had a Kasai portoenterostomy performed at the age of 8 weeks. She was also HIV-exposed and on the PMTCT program, but was confirmed PCR negative on three separate occasions. On examination she was found to be pyrexial and jaundiced with firm hepatosplenomegaly but no ascites or peritonism. She was haemodynamically stable, alert and had no evidence of bleeding.

Question 1 - What is the most likely diagnosis and why? What would the appropriate initial investigations and further management be?

Answer to Q1.

The most likely diagnosis is cholangitis. The Kasai portoenterostomy places a child at risk of ascending cholangitis. Children with biliary atresia and cholangitis typically present with fever and increased jaundice.(1) They may also develop abdominal pain, pale stools, have clinical evidence of sepsis and their liver enzymes may worsen from baseline.(2–4)

The child should be admitted to hospital, blood cultures as well as full blood count and differential count, bilirubin and liver enzymes, electrolytes, creatinine, septic markers and coagulation studies should be considered.

The results of her investigations are detailed in the following Table

Question 2 Which organisms would you suspect? What antibiotics should be used?

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.

She must be commenced on intravenous broad-spectrum antibiotics that will cover Gram-negative enteric bacteria and Enterococcus. In this case we chose a combination of cefotaxime and ampicillin. Ceftriaxone should be avoided as it has may cause biliary sludge and raised liver enzymes.(5)

After 48 hours she had deteriorated, remaining pyrexial and developing respiratory distress requiring nasal CPAP. Her septic markers remained elevated but blood cultures had not grown any organism.

Question 3. If the patient does not improve, what further investigation is indicated?

Answer to Question 3

An abdominal ultrasound should be performed. If the child has not responded clinically within 48 hours, consider reinvestigating with repeat blood cultures and consider escalating antibiotic therapy. For nosocomial infections, local hospital acquired gram negative organisms should be covered.

An abdominal ultrasound found multiple intrahepatic biliary collections measuring between 20 x 30mm to 34 x 30mm in size. On previous ultrasounds the liver and spleen had been enlarged, but there were no intrahepatic cysts or bile lakes noted.

The four largest cholangeal abscesses were drained percutaneously under ultrasound guidance. All blood cultures and cultures of pus aspirated from the abscesses were negative. The child’s clinical condition improved post-drainage of the abscesses, her fever resolved and she no longer required any respiratory support. In consultation with surgical colleagues it was agreed to complete a prolonged course of intravenous antibiotics. 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) Her liver enzymes returned to baseline levels prior to discharge. She was discharged after a three week course of intravenous antibiotics on oral ciprofloxacin prophylaxis.

She was followed up as an outpatient and was well until she returned unwell four months later with fever and deepening jaundice. She was readmitted with a presumed diagnosis of cholangitis, reinvestigated and started empirically on intravenous ampicillin and cefotaxime. Blood cultures grew Klebsiella pneumoniae:

Question 4. Why did she re-present with cholangitis?

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 5

Although the organism is sensitive to second and third generation cephalosporins, these antibiotics are poorly secreted into bile. Piperacillin has good bile penetration with a bile/serum ratio >4. Both ampicillin and trimethoprim have moderate bile excretion (bile/serum ratio 1-4). In this case the organism is resistant to amoxicillin/ampicillin and amoxicillin-clavulanic acid.

The child was treated with piperacillin-tazobactam due to its superior bile excretion despite the organism being sensitive to cefuroxime and cefotaxime/ceftriaxone. She responded well and fever settled within 48 hours. Liver enzymes returned to baseline over the next ten days. She completed a course of two and a half weeks’ duration and was subsequently discharged on cotrimoxazole prophylaxis. Because the trimethoprim penetration of the bile is only moderate, she was treated with high dose cotrimoxazole.

She was also evaluated and found to be a suitable liver transplant candidate and listed on the active liver transplant list. As part of her evaluation prior to transplantation, her vaccine antibody titre levels were checked. Her results were as follows:

Hepatitis A AntibodyNegative
Hepatitis B s AntibodyTitre >1000
Varicella zoster virus IgGEquivocal
Measles IgGPositive
Mumps IgGNegative
Rubella IgGNegative

Question 6. How can these results be interpreted and what action should be taken?
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.


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)

Lessons from this case

  • Have a high index of suspicion for ascending cholangitis in children with biliary atresia who have a Kasai portoenterostomy. Children should be started on empiric broad-spectrum antibiotic cover until the diagnosis is excluded.
  • Antibiotics for the treatment or prophylaxis of cholangitis should have adequate excretion into the bile to eradicate infection.
  • Children with chronic liver disease should receive all routine EPI vaccines as well as vaccines not routinely provided such as hepatitis A, MMR and varicella zoster vaccines. Vaccine-preventable diseases are a major source of morbidity and mortality among transplant recipients. It is important to assess and document seroconversion prior to transplantation and to evaluate hepatitis B antibody titres.
  • References
  • Makin E, Davenport M. Diseases of the Liver and Biliary System in Children. 4th ed. Kelly D, editor. Chichester, UK: Wiley Blackwell; 2017. 415-429 p.
  • Luo Y, Zheng S. Current concept about postoperative cholangitis in biliary atresia. World J Pediatr. 2008;4(1):14–9.
  • Verma A. Bacterial, Fungal and Parasitic Infections of the Liver. In: Guandalini S, Dhawan A, Branski D, editors. Textbook of Pediatric Gastroenterology, Hepatology and Nutrition: a Comprehensive Guide to Practice. Switzerland: Springer; 2016. p. 693–9.
  • Sundaram S, Mack C, Feldman A, Sokol R. Biliary Atresia: Indications and Timing of Liver Transplantation and Optimization of Pretransplant Care. Liver Transpl. 2016;23:96–109.
  • Division of Pharmacology Faculty of Health Sciences University of Cape Town D of PF of HSU of CT. South African Medicines Formulary. 8th ed. Cape Town, South Africa: FA Print; 2008. 275-6 p.
  • Rubin L, Levin M, Ljungman P, Davies E. 2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host. Clin Infect Dis. 2013;58(3):e44–100.
  • Feldman AG, Mack CL. Biliary Atresia. J Pediatr Gastroenterol Nutr. 2015;61(2):167–75.
  • Dooley K, Flexner C, Hackman J, Peloquin CA, Nuermberger E, Chaisson RE, et al. Repeated administration of high-dose intermittent rifapentine reduces rifapentine and moxifloxacin plasma concentrations. Antimicrob Agents Chemother [Internet]. 2008/09/04. 2008;52(11):4037–42. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18765687
  • Dooley JS, Hamilton-Miller JM, Brumfitt W, Sherlock S. Antibiotics in the treatment of biliary infection. Gut. 1984;25(9):988–98.
  • . Bu L, Huey L, Chang C. Prophylactic oral antibiotics in prevention of recurrent cholangitis after the Kasai portoenterostomy. J Pediatr Surg. 2003;38:590–3.
  • Lally K, Kanegaye J, Matsumura M. Perioperative factors affecting the outcome following repair of biliary atresia. Pediatrics. 1989;83:723–6.
  • de Vries W, Zacharias J, Henk G. Biliary atresia in the Netherlands: outcome of patients diagnosed between 1987 and 2008. J Pediatr. 2012;160:638–44.
  • . Avery RK, Michaels M. Update on immunizations in solid organ transplant recipients: What clinicians need to know. Am J Transplant. 2008;8(1):9–14.
  • Miyairi I, Funaki T, Saitoh A. Immunization practices in solid organ transplant recipients. Vaccine. 2016;34(16):1958–64.
  • Squires R, Ng V, Romero R, Ekong U, Hardikar W, Emre S, et al. Evaluation of the Pediatric Patient for Liver Transplantation: 2014 Practice Guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatolo. Hepatology. 2014;60(1):362–98.
  • Munksgaard B. Guidelines for vaccination of solid organ transplant. Am J Transplant. 2004;4:160–3.

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