Pneumatosis intestinalis in infants after orthotopic liver transplantation.

Abstract

Pneumatosis intestinalis is defined by radiologic findings of subserosal or submucosal gas within the wall of the small intestine or colon. Sampling intramural gas has shown it to be composed primarily of nitrogen, oxygen, and carbon dioxide, with lesser amounts of hydrogen, methane, propane, argon, ethane, butane, and nitrous oxide (1). Gas may also be detected in the portal venous system by abdominal radiograph or ultrasound. Other classic radiologic findings include gaseous collections between the liver and right diaphragm (Chilaiditi's sign) and pneumoperitoneum without clinical evidence of intestinal perforation. Pneumatosis intestinalis is a relatively uncommon and benign condition outside the setting of neonatology, where necrotizing enterocolitis is both common and consequential (2). In non-neonates, the peak incidence of pneumatosis intestinalis is the fourth decade of life, and it is rare in pediatric patients. Jamert (3) found in his review of 919 cases of pneumatosis intestinalis that only 8% occurred in patients younger than 20 years of age. It occurs 1.9 times more commonly in men than women. Pneumatosis intestinalis not due to necrotizing enterocolitis usually follows a self-limited course that requires little medical intervention, but can be a severe or fatal complication in patients with complex underlying diseases (4). Although some patients are asymptomatic and pneumatosis is discovered incidentally on abdominal roentgenogram, most exhibit mild symptoms including fever, diarrhea, colicky abdominal pain, excessive flatulence, rectal bleeding, and fecal incontinence. Most patients who develop pneumatosis have some gastrointestinal disease, but it has also been associated with obstructive pulmonary disease, such as asthma, emphysema, and cystic fibrosis. The conditions in which it has been observed in association with gastrointestinal mucosal injury include acid-peptic disease, vasculitis, inflammatory bowel disease, bowel obstruction, ischemic bowel disease, diverticulitis, leukemia, jejunoileal bypass, tuberculosis, infectious colitis, corticosteroid therapy, chemotherapy, radiotherapy, and colonoscopy. The mechanisms leading to the development of pneumatosis intestinalis have not been fully determined, but two elements seem to be required (3,5). A loss of mucosal integrity due to any necroinflammatory process permits the movement of luminal gas into the bowel wall. An increase in gaseous pressure within the lumen, which can result from excessive intrinsic gas production or the introduction of air during endoscopic procedures, can increase the flux of gas across injured mucosa to a rate that exceeds the capacity of the bowel's mechanisms to remove it. The result is the accumulation of submucosal and subserosal gas. It has been postulated that the pathogenesis of pneumatosis intestinalis in patients with obstructive pulmonary diseases differs from that in patients with gastrointestinal disease. The postulated mechanism involves alveolar rupture with dissection of the air retroperitoneally along periaortic adventitia, extending transdiaphragmatically to reach the mesenteric vascular tree (3). Pneumatosis intestinalis has been observed following hepatic, renal, and bone marrow transplantation, although rarely in children (6-11). We describe the clinical and radiologic findings of six infants who developed pneumatosis after orthotopic liver transplantation (OLT) and discuss its management in this setting. CASE REPORTS Case 1 A female infant with biliary atresia received OLT using a living related donor (12) at 6 months of age. Standard immunosuppression consisting of cyclosporine, azathioprine, and corticosteroids was administered (13). Acute cellular rejection 1 week postoperatively was treated with intravenous methylprednisolone, 10 mg/kg body weight per day for 3 days (pulse therapy). Thereafter, she developed bacterial pneumonia, rapidly progressed to respiratory failure, and required extracorporeal membrane oxygenation therapy (ECMO) for 16 days. After recovery from pulmonary disease, malnutrition, emesis, and poor feeding were her most significant problems. Upper gastrointestinal endoscopy was performed for diagnostic and therapeutic indications 2 months post-OLT. Duodenal biopsies revealed no evidence of cytomegalovirus (CMV) infection, and a nasojejunal feeding tube was placed to provide enteral nutrition. Enfamil infant formula was given as bolus feedings during the day and as a continuous drip at night. A bout of fever and diarrhea was briefly treated with ceftazidime and vancomycin until negative cultures were reported. CMV was detected in blood, and therapy with ganciclovir was initiated. One week later, 75 days post-OLT, she developed mucoid emesis. The abdominal examination was unchanged, but an abdominal radiograph demonstrated extensive pneumatosis involving most of the colon (Fig. 1). The stool was positive for occult blood. Her cyclosporine level was 166 ng/mL (whole blood concentration by high performance liquid chromatography; therapeutic range = 150-300 ng/mL). Feedings were discontinued, and no antibiotics were administered. A repeat abdominal radiograph 5 days later demonstrated marked reduction of pneumatosis, and the patient was given nothing orally for 7 days. The patient was discharged home 1 week later and is currently well 2 years post-OLT. Case 2 A female infant with biliary atresia underwent OLT at 14 months of age. Standard immunosuppression was administered. Acute cellular rejection in the second week post-OLT failed to respond to pulse methylpredisolone, and the patient was treated with monoclonal antibody (OKT3, Orthoclone) for 14 days with good response. At 5 weeks post-OLT, she developed fever, mucoid stools, rhinorrhea, and cough. The cyclosporine level was 92 ng/mL. The abdominal examination was benign and stools were negative for occult blood. Percutaneous liver biopsy revealed no evidence of rejection. Abdominal radiographs revealed pneumatosis and abdominal ultrasound demonstrated gas in multiple intrahepatic portal vein radicals (Fig. 2). Enteral feedings were discontinued, and antibiotics (mezlocillin, gentamicin and vancomycin) were administered because of the fever. After 4 days, there was no radiographic evidence of pneumatosis and all cultures remained negative. Antibiotics were discontinued and feedings were restarted. The patient was discharged home 2 days later and is well 2 years post-OLT. Case 3 A female infant with biliary atresia received an OLT using a living related donor at 6 months of age (12). Standard immunosuppression was administered. She developed acute cellular rejection 1 week post-OLT and was treated with pulse methylpred-nisolone. A repeat liver biopsy 1 week later demonstrated ongoing rejection, so a 14-day course of OKT3 was started. At 3 weeks post-OLT, she developed fever, abdominal distention, hematochezia, and foul-smelling drainage from her abdominal drain. Abdominal radiographs revealed pneumatosis in the right and left colon and pneumoperitoneum. Laparotomy revealed multiple intra-abdominal abscesses, but no identifiable site of intestinal perforation. Cultures of peritoneal fluid grew Staphylococcus aureus. Mezlocillin, gentamicin, vancomycin, and metronidazole were administered; OKT3 was discontinued, and cyclosporine was restarted. After 1 week, there was no radiographic evidence of pneumatosis. A week later feedings were restarted and antibiotics discontinued. The patient is alive and well 3 years post-OLT. Case 4 A female infant with biliary atresia underwent OLT using a living related donor at 15 months of age (12). Standard immunosuppression was administered. Laparotomy was performed on post-OLT day 7 for thrombectomy of the hepatic artery and repair of a bile leak. Widespread hepatic necrosis necessitated repeat OLT 14 days after the first OLT. Peritoneal cultures grew Enterococcus facium and Escherichia coli, which were treated with vancomycin, gentamicin, and timentin. Severe acute cellular rejection was treated sequentially with methylprednisolone pulses, OKT3, and tacrolimus (13). At 5 weeks after the second OLT, a chest radiograph performed for wheezing and tachypnea incidentally revealed pneumatosis intestinalis. The abdominal examination was normal, but the stools were positive for occult blood. Feedings were discontinued for 1 week until the process resolved. The patient is alive 6 months post-OLT, but has many medical problems including ductopenic allograft rejection, recurrent CMV hepatitis, and portal vein stenosis. Case 5 A male infant underwent OLT at 5 months of age. His neonatal history was notable for repair of tracheoesophageal fistula and placement of a gastrostomy tube. No cause was identified for his liver disease. Standard immunosuppression was administered, the course was uncomplicated, and he was discharged home on post-OLT day 27. He was readmitted 7 days later with diarrhea and 10% dehydration. Abdominal radiographs and ultrasound revealed pneumatosis (Fig. 3). The physical examination was normal after rehydration. Feedings were withheld and the patient was treated with ampicillin, gentamicin, and clindamycin. A urine culture was positive for E. facium. Repeat radiographs 2 days after admission revealed no pneumatosis, and gastrostomy tube feedings were restarted. Antibiotics were discontinued 2 days later, except for ampicillin, which was continued for the urinary tract infection. The patient died 5 months post-OLT during surgery for reconstruction of the esophagus. Case 6 A female infant with alpha-1-antitrypsin deficiency underwent split-liver OLT at 7 months of age (14). Standard immunosuppression was administered. Acute cellular rejection one week post-OLT was treated with pulse methylprednisolone. Three months later, the patient experienced 2 days of progressive anorexia, emesis, lethargy, fever, and distended abdomen. There was no radiographic evidence of pneumatosis intestinalis. Exploratory laparotomy identified small bowel obstruction and terminal ileal perforation secondary to adhesions. The Roux-en-Y was revised, and a limited terminal ileal resection was performed. Her postoperative course was uneventful, and she was discharged home 8 days after surgery, 4 months post-OLT. She returned 6 days later with diarrhea, dehydration, emesis, and fever. Her abdominal examination was normal, but abdominal radiographs revealed extensive pneumatosis (Fig. 4). Feedings were continued and antibiotics were not administered. Stool cultures were negative, including Clostridium difficile. The process resolved and the patient was discharged home after 8 days. She is well 6 years later. DISCUSSION Six cases of pneumatosis intestinalis have been identified among 350 children receiving OLT at the University of Chicago. Only six other cases of pneumatosis intestinalis in pediatric OLT recipients have previously been reported (15-18). Koep et al. described two cases with massive hematochezia occurring 2 months and 1.5 years after OLT, both of whom underwent colectomy with ileoproctostomy (15). Intraoperative findings consisted of pneumatosis intestinalis without mucosal ulcerations. King and Shuckett reported two instances of pneumatosis intestinalis identified in asymptomatic children by routine ultrasounds performed at 7 and 8 days post-OLT, both of whom recovered with no therapy. (16) Sachse et al. reported a single case in a child who had minimal symptoms. Therapy consisted of withholding feedings and no antibiotics were administered (17). Four days after resumption of enteral feedings, the patient developed fever, abdominal distention, vomiting, and subcutaneous emphysema of the abdominal wall. This disease recurrence resolved after 1 week of antibiotics and no enteral feeding. Janssen, Kalayoglu, and Sollinger (18) reported a case in a pediatric OLT recipient who was receiving lactulose therapy for hyperammonemia. This patient presented with intermittent abdominal distention, diarrhea, and a scrotal enlargement, thought to be a reducible hernia. Right inguinal exploration revealed no hernia, but intraoperative radiographs demonstrated pneumatosis. This patient was treated with hyperbaric O2, metronidazole, and a decreased steroid dose; after 3 days, radiographs demonstrated diminished pneumatosis. Our data and those previously reported suggest that pneumatosis intestinalis in pediatric OLT recipients usually has a good prognosis. It is not clear from the available data what therapy is needed in these cases. Our patients all recovered even though their treatment varied widely. Five patients had enteral feedings withheld, but in only two were they withheld specifically because of pneumatosis. Antibiotics were administered in five cases, two for fever and as a sepsis precaution, one for fever and a positive peritoneal culture, and two specifically for pneumatosis. Although most of our patients received antibiotics and were given nothing orally (NPO) for a brief time, we cannot estimate the effect that therapy had on the course of disease. Our experience, however, has led us to adopt a conservative approach to therapy. Asymptomatic patients are made NPO and given broad spectrum antibiotics for a brief time until it is clear that the process has not progressed to a more severe form and that cultures are negative. If pneumatosis is accompanied by more severe gastrointestinal problems such as hematochezia and paralytic ileus, patients should be treated as if they have necrotizing enterocolitis, with a week or more of intravenous hyperalimentation, antibiotics, and close observation for clinical or radiologic deterioration. Laparotomy and bowel resection are indicated only when there is evidence of bowel perforation and peritonitis. The pathogenesis of pneumatosis intestinalis in transplant recipients is not known, but several factors can be implicated. The immunocompromised state almost certainly plays a large role in children with leukemia and possibly in transplant recipients (19,20). High-dose corticosteroids, which are often administered to OLT recipients, can cause atrophy of lymphoid tissues. In theory, atrophy of intestinal lymphoid aggregates (Peyer's patches) can cause a breach of mucosal integrity, allowing the dissection of gas. The use of high-dose steroids to treat acute graft-versus-host disease has been associated with the onset of pneumatosis intestinalis in pediatric bone marrow transplant patients (9). However, pneumatosis developed in all but one of our patients at least 2 weeks after any high-dose corticosteroids had been administered. Other possible mechanisms commonly encountered in liver trasplant patients include surgical bowel obstruction and enteric infections, including those caused by CMV. Rarely encountered conditions in liver allograft recipients that could lead to pneumatosis include graft-versus-host disease and post-transplant malignancy requiring chemotherapy or radiotherapy. Each of these cause necroinflammatory changes in the bowel, which potentially increases the risk of developing pneumatosis intestinalis. Lactulose therapy has also been implicated (18,21). In addition, after OLT infants have a high risk of respiratory failure requiring mechanical ventilation, although that did not seem to play a role in the current series (22). Our patients ranged in age from 4 to 15 months at the time of diagnosis, which is younger than the previously reported patients, 26 months to 15 years. This likely is a reflection of our patient population, which tends to be younger than those at most pediatric liver transplant centers (23). The time period between transplantation and onset of pneumatosis ranged from 3 weeks to 3.5 months in our patients and 1 week and 1.5 years in the prior cases. Five of our patients manifested upper or lower gastrointestinal tract signs at the time of diagnosis. One was asymptomatic and identified by radiographs performed for other reasons, much like those reported by King and Shuckett who were identified by routine abdominal ultrasounds at 7 and 8 days post-OLT (16). That most of our patients had symptoms may reflect an institutional difference because our protocol calls for routine surveillance ultrasounds only on the first 3 days after OLT, which may be too early to routinely detect pneumatosis intestinalis. Although ultrasounds are performed liberally afterwards for various indications, an accurate estimate of the incidence of pneumatosis could only be obtained by adopting a surveillance protocol. We conclude that pneumatosis intestinalis in pediatric post-OLT patients in most instances has a good prognosis with conservative, nonoperative therapy.FIG. 1.: Eight-month-old female infant (Case 1), 75 days post-OLT. Supine plain radiograph of the abdomen demonstrates pneumatosis outlining most of the colon (arrows). The intestinal mucosa (arrowheads) appears as a thin line separating intraluminal from intramural gas.FIG. 2.: Transverse sonographic image of the transplanted liver segment at the level of the hepatic vein (HV) (Case 2). The liver parenchyma is studded with echogenic speckles representing air within small portal vein radicles.FIG. 3.: Six-month-old infant 1 month post-OLT (Case 5). Close-up sonographic image of the intestinal wall near the transplanted liver edge (L) demonstrates echogenic speckles (arrows) within the wall, the result of pneumatosis.FIG. 4.: Seven-month-old female (Case 6) 4 months post-OLT. Lateral view of the chest shows pneumatosis intestinalis involving the colon. Long sheaths of intramural gas (arrows) are separated from the intramural gas by the thin dense line of intestinal mucosa.