Clostridium difficile bacteria is most commonly associated with colonic infections. Fulminant pseudomembranous colitis has been reported to cause sepsis in children and adults.1-4 To our knowledge, severe C. difficile-associated pseudomembranous colitis has never been reported in a patient with sickle cell disease. We present a child with sickle cell disease who died of clinical sepsis and, on autopsy, was found to have diffuse pseudomembranous colitis. The stool was positive for C. difficile, toxin and all other cultures were negative.
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A 5-year-old girl with sickle cell disease was admitted to the pediatric intensive care unit with cardiogenic shock secondary to profound anemia and a suspected hemolytic crisis from a delayed transfusion reaction. The patient had been discharged home 3 days earlier after finishing a course of azithromycin for mycoplasma pneumonia. During that admission, ceftriaxone was also administered for 2 days, and a blood transfusion was given.
In the pediatric intensive care unit, the patient was intubated, fluid resuscitated, and transfused packed red blood cells. Ceftriaxone was also started for concerns of possible sepsis. Admission laboratory values were notable for hemoglobin 2.5 g/dL, lactate dehydrogenase 4105 U/L, and gross hematuria with no red blood cells on microscopic urinalysis. The chest radiograph showed pulmonary edema, but no pneumonia. The patient stabilized and was extubated approximately 36 hours after intubation. Fever and abdominal distension then developed, and 18 hours later, the patient was reintubated for progressive respiratory distress and severe abdominal distension. An abdominal radiographic series showed multiple dilated loops of bowel with no air in the rectum and no sign of perforation. A nasogastric tube was kept to suction, and a rectal tube was placed for drainage. Fever continued, and repeat blood, urine, and tracheal cultures were done, and ceftriaxone was continued. Pediatric surgery was consulted and felt that the patient had a severe ileus and recommended continuing nasogastric drainage and observation. Hypotension developed, and dopamine was started, followed by epinephrine for presumed septic shock. Antibiotics were changed from ceftriaxone to cefoxitin, vancomycin, meropenem, and tobramycin after infectious disease consultation, and repeat blood cultures were done. Severe metabolic acidosis developed with a lactate of 12.1 mg/dL (normal 0.3-2.4 mg/dL), as did refractory hypotension. There were no indications of a transfusion reaction at this time. Five days after admission, the patient had a cardiac arrest, and cardiopulmonary resuscitation was started. However, there was no return of spontaneous circulation, and the patient was pronounced dead. Stool was positive for C. difficile toxin A or B by enzyme-linked immunosorbent assay, but urine, blood, and tracheal cultures were negative. Nasopharyngeal direct fluorescent antibodies and viral cultures were also negative. An autopsy was performed and showed diffuse pseudomembranous colitis throughout the large bowel, but no sign of obstruction, infarction, or perforation.
C. difficile is an anaerobic gram-positive bacillus that causes antibiotic-associated diarrhea and pseudomembranous colitis. Intestinal colonization rates with C. difficile can be as high as 50% in healthy newborns and infants, but less than 5% in children older than 2 years. Severe and fatal disease has been reported in patients with immunodeficiency, Hirschsprung disease, and inflammatory bowel disease.5,6 A previous review of severe pseudomembranous colitis in pediatric patients reported 20% mortality in 43 patients. The deaths in that series were primarily attributed to shock caused by intravascular depletion from severe dehydration.4
Our patient developed fever, refractory hypotension, and severe metabolic acidosis and met clinical criteria for sepsis. However, all 4 sets of blood cultures were negative. It is possible that our patient had a bacterial infection that we were unable to culture in the laboratory. However, blood culture-negative sepsis in the setting of acute pseudomembranous colitis was previously described, and it was suggested that sepsis syndrome was stimulated by the cellular response of severe enterocolitis alone.1 We believe that this is the most likely explanation for the patient's demise on broad-spectrum antibiotics. We do not believe that the patient died of hypovolemia, as we were continually fluid resuscitating to keep a normal to high central venous pressure.
Unusual C. difficile infections in patients with sickle cell disease are not without merit, as chronic osteomyelitis has been described.7 Pseudomembranous colitis has also been reported in a pediatric patient with sickle cell disease, but that patient's stool was negative for C. difficile, and it was felt that ischemic colitis led to the pseudomembrane formation.8 That patient did not have any signs of sepsis. The autopsy on our patient, however, demonstrated the classic findings of pseudomembranous colitis, as seen in Figure 1. The relatively normal-appearing small bowel would argue against ischemia from the patient's initial cardiogenic shock as the sole cause of the diffuse colitis.
We believe that the use of antibiotics, the period of hypoperfusion to the bowel, and the patient's underlying hemoglobinopathy all contributed to a fulminant course of C. difficile colitis. It has been demonstrated that endotoxinemia occurs in sickle cell patients with evidence of poor reticuloendothelial function.9 Functional asplenia, an opsonophagocytic defect caused by an abnormality of the alternative complement pathway, and a deficiency of specific circulating antibodies are all felt to contribute to the immunodeficiency of sickle cell disease.10 What is not clear is whether C. difficile toxin-mediated illness is more likely in patients with sickle cell disease, similar to infections from encapsulated organisms. Clinical studies indicate that antitoxin responses in both serum and intestinal secretions may be protective against C. difficile and that both a toxoid vaccine and intravenous immunoglobulin may be helpful in refractory disease11-13 Furthermore, antibody response to toxin A has been related to severity of clinical course in C. difficile infection.14 Perhaps our host's inability to control the infection in the intestine because of low antibody response or poor opsonization capabilities led to further activation of the inflammatory cascade and sepsis syndrome. Intravenous immunoglobulin may then be a worthwhile therapy for sickle cell patients with C. difficile infections.
In conclusion, C. difficile can cause sepsis syndrome and should be considered in patients with fever, abdominal distension, and clinical signs of sepsis because treatment and surgical resection of the affected colon may be lifesaving. Patients with immunodeficiencies and other underlying conditions are at increased risk for C. difficile sepsis. Sickle cell disease may also be a predisposing condition to severe pseudomembranous colitis and sepsis.
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