Pseudomembranous colitis in four patients with cystic fibrosis following lung transplantation

Abstract

In the present study, 4 patients with cystic fibrosis undergoing lung transplantation (from a total of 137) who developed fulminant pseudomembranous colitis are described. Initial presentation was variable and the mortality rate was 50% despite urgent colectomy. In one case the presenting abdominal distension was thought to be due to meconium ileus equivalent. It is concluded that Clostridium difficile colitis may be a difficult diagnosis in patients with cystic fibrosis and follows a fulminant course after lung transplantation.

BACKGROUND

Clostridium difficile colitis is an uncommon but important diagnosis in patients with cystic fibrosis (CF) following lung transplantation.

CASE PRESENTATION

Case 1: 2 months after lung transplantation, a 22-year-old man with CF was treated for acute allograft rejection and pulmonary infection with steroids and antibiotics. He initially received piperacillin–tazobactam, which was subsequently changed to flucloxacillin after 48 h following culture of Staphylococcus aureus from bronchoalveolar lavage fluid. His respiratory status improved over the following days but he developed abdominal pain, constipation and a palpable mass in the right iliac fossa. A clinical diagnosis of meconium ileus equivalent was made, a condition he had experienced previously. He was treated with gastrograffin and had a good bowel movement later that day. Although his symptoms initially settled, he developed further pain 3 days later with associated diarrhoea and a neutrophil leukocytosis. An abdominal radiograph showed thickened large bowel with very little luminal gas. A CT scan of the abdomen confirmed gross thickening of the entire colon consistent with severe pseudomembranous colitis (fig 1). Stool analysis confirmed C difficile toxin.

Figure 1.

CT scan of the abdomen showing gross thickening of the large bowel wall and obliteration of the lumen.

Case 2: 10 years after lung transplantation for CF, a 32-year-old woman developed neutropenic sepsis and renal failure. She was given intravenous piperacillin–tazobactam and continuous venovenous haemofiltration. Although she had diarrhoea, the stool was negative for C difficile toxin. A CT scan of the abdomen showed thickening of the colon. Flexible sigmoidoscopy with biopsies failed to show any evidence of infection or colitis. She improved over the next 3 days but then developed profuse diarrhoea and a neutrophil leukocytosis. A presumptive diagnosis of pseudomembranous colitis was made and metronidazole was given.

Case 3: a 28-year-old man with CF underwent lung transplantation and received aztreonam and clindamycin. His initial postoperative course was complicated by reperfusion injury requiring reintubation and renal failure. He developed abdominal distension and initially a clinical diagnosis of meconium ileus equivalent was made. Abdominal radiography showed a grossly dilated large bowel and a manual evacuation was performed. The following day he became septic and hypotensive and antimicrobial treatment was changed to piperacillin–tazobactam and fluconazole in the light of bronchoalveolar lavage culture. A laparotomy was performed on the suspicion of perforation. No perforation was found but a caecostomy was fashioned to decompress his bowel. At 37 days after transplantation he remained dependent on a ventilator and dialysis but without further bowel problems and off antibiotics. He developed right upper abdominal pain; ultrasonography revealed gall bladder sludge but also a thickened colon suggestive of colitis. A CT scan confirmed a grossly thickened large bowel at risk of perforation despite minimal diarrhoea rectally and only soft stool from his stoma. Piperacillin–tazobactam, metronidazole and caspofungin were given.

Case 4: a 38-year-old woman with CF underwent lung transplantation, complicated by early haemodynamic instability followed by renal failure and failed extubation. She then developed abdominal distension and diarrhoea, negative for C difficile toxin. Despite continuing episodes of diarrhoea and distension, stool toxin remained persistently negative. Bronchoalveolar lavage isolated Pseudomonas spp. and she was given ciprofloxacin and aztreonam. Diarrhoea, abdominal pain and distension remained problematic, and a CT scan showed thickened large bowel consistent with pseudomembranous colitis.

DIFFERENTIAL DIAGNOSIS

Meconium ileus equivalent.

OUTCOME AND FOLLOW-UP

Case 1: metronidazole was given, but because of the high risk of perforation a subtotal colectomy was performed. Severe pseudomembranous colitis was confirmed on histopathological examination.

Case 2: stool analysis subsequently confirmed C difficile and she gradually improved.

Case 3: colectomy was delayed as he initially refused consent but by this time he was deteriorating rapidly with sepsis. He died 1 week following colectomy from multiple organ failure. Histological examination of the resected colon showed severe pseudomembranous colitis.

Case 4: a further stool specimen tested positive for C difficile. Metronidazole was given with resolution of diarrhoea and negative stool toxin after 5 days. However, her clinical condition remained critical and she died 42 days after transplantation from multiorgan failure.

DISCUSSION

Clostridium difficile is a spore-forming Gram-positive bacillus. It is a well recognised cause of antibiotic-associated diarrhoea.¹ Asymptomatic carriage is rare in healthy adults but it is more frequent during hospitalisation, occurring in up to 25% of inpatients.^2,3 Clostridium difficile colitis results from a chain of events: first a disruption of bowel flora, followed by colonisation and finally toxin-mediated mucosal damage and inflammation.³ The clinical symptoms may vary from a mild diarrhoea to fulminant colitis with severe septic shock (seen in 1% to 3%).⁴ Diagnosis is made by the detection of toxins in the stool. Pseudomembranous colitis, the most severe manifestation of the disease, presents with diarrhoea, abdominal cramping and tenderness, with systemic symptoms that may lead to haemodynamic collapse. Treatment with metronidazole or vancomycin should be promptly initiated and improvement is generally seen within 48–72 h.³ Surgical intervention is mandatory in perforation and may be required in severe cases where medical treatment is not sufficient or where improvement is not seen.

Carriage rates of C difficile in patients with CF have been reported to be up to 50%, but despite this and the numerous courses of antibiotics and hospital admissions these patients undergo, pseudomembranous colitis remains rare.^2,5,6 The first case was described in 1992 with only a few subsequent reports.^2,6,7 A genotype link (N1303K mutation) has been described between CF and C difficile,⁷ although none of our patients possessed this genotype. To date, although various hypotheses have been suggested, there is no conclusive reason to explain the low rates of C difficile in CF.^7,8 Pseudomembranous colitis has been described with a high incidence in patients following lung transplantation by Dallal et al.¹ Their series of 2334 patients with C difficile over an 11-year period included 78 of 250 lung transplants causing significant morbidity and mortality.

Immunosuppression may have played a role in the variable presentation of the condition and is likely to be important in the pathogenesis of disease in our cases by increasing the risk of colonisation, as highlighted by the series of Dallal et al. Antibiotics had been administered in the preceding days to weeks in all patients.

Three of the four patients had been treated with piperacillin–tazobactam shortly before presentation. Piperacillin–tazobactam is not listed as a common cause of C difficile colonisation and, in fact, its use in the treatment of hospital-acquired infections is credited with lowering the incidence of C difficile.^1,9 However, the low overall rate of C difficile in our institution mitigates against this being the sole reason.

The persistent carriage of C difficile in the bowel of prospective transplant recipients with CF may represent a relative contraindication, particularly patients with a prior history of pseudomembranous colitis, and we recommend all lung transplant centres to be vigilant for this problem.

LEARNING POINTS

• Pseudomembranous colitis in patients with cystic fibrosis following lung transplant does not always present with diarrhoea, may initially be associated with toxin-negative stool and may have a similar presentation to meconium ileus equivalent.

• CT of the abdomen plays an important role in the management as it assists in the diagnosis of colitis, excludes meconium ileus equivalent and gives prognostic information regarding disease severity.