CAMPYLOBACTER SEPSIS IN HUMAN IMMUNODEFICIENCY VIRUS-INFECTED CHILDREN (1997)

Campylobacter jejuni is a common cause of acute gastroenteritis in humans.1,2 However, systemic infections caused by C. jejuni have rarely been reported. It has been estimated that only 0.4% of C. jejuni isolates are from blood.1 In this paper we describe the clinical manifestations and the outcome of four children with advanced HIV disease and C. jejuni bacteremia. Methods. We reviewed the medical records of 297 children with human immunodeficiency virus infection treated at 4 tertiary hospitals in Madrid between January, 1984, and December, 1995. These hospitals are referring centers in which more than 95% of the children with HIV infection living in the Madrid area, the area with the highest prevalence of HIV infection in Spain, are managed. Patients with stool and/or blood cultures positive for Campylobacter sp. were selected. Campylobacter sepsis was defined as a clinical illness associated with isolation of Campylobacter sp. from blood. Standard microbiologic procedures were used to isolate and identify C. jejuni. We collected the following data from each patient with Campylobacter septicemia: age; sex; status of HIV infection according to the new Centers for Disease Control classification of HIV infection in children3; CD4 and CD8 T lymphocyte subsets; clinical presentation; antibiotics administered; duration of therapy; outcome of the sepsis; period of time during which C. jejuni continued to be isolated from stools; and long term outcome. Results. We identified 45 patients in whom C. jejuni was isolated from stools. Blood cultures were obtained from 27 patients and C. jejuni grew in 4 (15%) of them. All the children with C. jejuni sepsis were in an advanced stage of HIV infection (Category C) and severe immunosuppression (N3) according to the new Centers for Disease Control classification of HIV infection in children.3 The stage of HIV infection in those children in whom blood culture was sterile or not done was: C3, 22 children; C2, 2 children; B3, 11 children; B2, 4 children; A2 and A1, 1 child each. Clinical presentation of C. jejuni sepsis consisted of fever and diarrhea in three children and fever without diarrhea in one child. Laboratory values are showed in Table 1. Two patients had clinical findings and biochemistry values consistent with cholangitis. Clinical response to antibiotic therapy was good (in every patient the strain of C. jejuni isolated from blood was susceptible to the antibiotic used before the results of blood cultures). Patients improved and blood cultures became sterile within 4 days of treatment but Campylobacter infection tended to be persistent in stools. Three children with septicemia died shortly after (2, 6 and 6.5 months) the beginning of Campylobacter sepsis.TABLE 1: Immunologic status and laboratory data in four patients with HIV infection and Campylobacter jejuni bacteremia Case reports.Case 1. A 5-month-old vertically HIV-infected class C3 infant was admitted to hospital because of a 5-day history of bloody diarrhea and low grade fever. He had hepatosplenomegaly and thrombocytopenia at birth. Azidothymidine therapy and trimethoprim-sulfamethoxazole prophylaxis were started at the first month of age. At admission the infant's temperature was 37.7°C and he appeared pale and mildly ill. The weight was 3.1 kg and the body length was 54 cm (both values below the third percentile). He had hepatosplenomegaly and a whitish ulcer, 1 cm in diameter, was present on the soft palate. Laboratory values, CD4 and CD8 lymphocyte counts are presented in Table 1. Blood and stool cultures grew C. jejuni. The infant was given oral erythromycin and intravenous cefotaxime. Blood cultures became sterile within 4 days after the beginning of treatment and the diarrhea improved. However, C. jejuni has been intermittently isolated from feces for 9 months. Liver enzymes became normal in ∼2 months. Now the patient is 15 months old and has AIDS with wasting syndrome and HIV-related encephalopathy. Case 2. This infant was a 28-month-old, class C3 HIV-infected female born to an HIV-infected mother. She had a history of recurrent bacterial otitis, subacute encephalopathy, wasting syndrome, oral and esophageal candidiasis and HIV-related myocardiopathy. She had fluctuating levels of liver enzymes and hepatitis C antibodies (PCR for hepatitis C was not done). She was receiving azidothymidine treatment and trimethoprim-sulfamethoxazole prophylaxis. The baby was admitted to the hospital because of a 7-day history of low grade fever and jaundice. No diarrhea was noticed. On admission physical examination showed a severely malnourished infant weighing 7.6 kg, with a height of 76 cm (both measurements below the third percentile) and fever of 38.3°C. She had scleral and skin icterus. The liver edge was felt 2 cm below the right costal margin. She had oral candidiasis. Laboratory data are shown in Table 1. Laboratory studies were consistent with active cytomegalovirus infection. Abdominal ultrasound revealed hepatomegaly and no dilatation of the biliary tract. Blood and stool cultures grew C. jejuni. The infant was treated with intravenous gentamicin. Blood cultures became sterile but C. jejuni was again isolated from stools on several occasions. The patient continued with low grade intermittent fever but jaundice became less prominent and there was a progressive decrease of liver enzymes. Forty days after the jaundice began, the patient suddenly developed a right hemiparesis and tremors. During the following days she developed focal and generalized seizures. Brain computed tomography scan showed cerebral atrophy and no focal lesions. She died from multisystem failure 2 months after the onset of the jaundice. Case 3. The child was a 3-year-old class C3 HIV-infected female, with a previous history of HIV-related encephalopathy, wasting syndrome, recurrent oral candidiasis and recurrent otitis media. She was born to an HIV-infected mother. She was receiving zidovudine, trimethoprim-sulfamethoxazole prophylaxis and monthly intravenous immunoglobulins. She was admitted to the hospital because of a 4-day history of high fever and diarrhea with 8 to 10 loose non-bloody stools per day. Physical examination revealed a severely malnourished 6-kg febrile infant. Laboratory values are shown in Table 1. Immunoglobulins were: IgG 410 mg/dl; IgA 46 mg/dl; IgM 94 mg/dl. Blood and stool cultures grew C. jejuni. The patient was treated with intravenous erythromycin for 15 days. Blood cultures became sterile but stool cultures remained positive for C. jejuni for 1 month. The patient died from wasting syndrome and other AIDS-related conditions 6 months after the episode of C. jejuni bacteremia. Case 4. A 15-month-old class C3 HIV-infected female infant was hospitalized because a 5-day history of high fever and bloody diarrhea. She had a previous history of gastroenteritis, malnutrition, persistent hepatosplenomegaly, oral candidiasis, recurrent respiratory infections and a disseminated bronchopneumonia suspected to be P. carinii pneumonia. She had been receiving zidovudine therapy and continuous prophylaxis with fluconazole and trimethoprim-sulfamethoxazole for the previous 7 months. On physical examination the patient appeared mildly ill with a weight of 9.4 kg (between the 10th and 25th percentiles) and a height of 74 cm (10th percentile). There was hepatosplenomegaly. Blood chemistries and lymphocyte subsets are shown in Table 1. Blood and stool cultures grew C. jejuni. Once the results of stool cultures were known, treatment with oral erythromycin was started. Two days later when the results of blood cultures were available, intravenous erythromycin was substituted for oral erythromycin. Fever abated after 2 days of intravenous treatment and diarrhea improved. However C. jejuni continued to be isolated intermittently from stools for 1 month. During the following months the patient developed severe HIV encephalopathy. She died suddenly from shock and respiratory failure 6 months later. Discussion. Although C. jejuni is a well-known cause of acute self-limited gastroenteritis in humans, bacteremia is an infrequent clinical manifestation of this infection. It has been estimated that only 0.4% of C. jejuni isolates are from blood.1 By contrast Campylobacter fetus frequently causes extraintestinal disease.4-6 Although C. jejuni bacteremia may occasionally occur in previously healthy people, the great majority of cases of extraintestinal infections caused by Campylobacter spp. are associated with predisposing factors such as liver cirrhosis,4-7 biliary tract disease,7 hypogammaglobulinemia,5,7,8-10 immunosuppression,5,6,11 malnutrition12 and other chronic debilitating diseases.4-6, 7 Age also seems to be an important risk factor for C. jejuni extraintestinal disease, and with >50% of cases occurring in patients at the extreme age brackets of life.7 In the last few years patients with HIV infection have emerged as a high risk group for both C. jejuni infection and bacteremia.13-15 Among people with AIDS the incidence of C. jejuni infections is almost 40 times higher than among the general population.14 Although invasive bacterial diseases are a hallmark of pediatric HIV infection, no cases of Campylobacter bacteremia in HIV-infected children have been previously published to our knowledge. The retrospective nature of this study does not permit an exact estimate of the risk of bacteremia in HIV-infected children with Campylobacter enteritis. Considering the number of blood cultures obtained, the rate of bacteremia among our HIV-infected children was 15%. However, this figure may be overestimated because of some bias. It is thus very likely that blood cultures were taken preferentially from those patients with more severe clinical picture. Nevertheless it is clear that the rate of C. jejuni bacteremia in our children with HIV infection exceeds by many times the rate in the general population.1 The reason for this increased risk of C. jejuni extraintestinal disease in HIV-infected people is not completely understood. The majority of C. jejuni and Campylobacter coli isolates are usually susceptible to the bactericidal activity in normal human serum whereas C. fetus is highly resistant.16 This bactericidal activity results from antibody and is complement-dependent.16, 17 In HIV-infected patients Campylobacter infections tend to persist or relapse despite treatment13, 18 and it has been shown that Campylobacter-specific antibody production may be defective in AIDS patients who cannot clear the microorganism.13 Perhaps the humoral immunodeficiency that characterizes the HIV-infected children causes a loss of the capacity to produce specific antibodies for Campylobacter species, which in turn might bring about defective killing of the microorganism in a similar way to that which occurs in people with hypogammaglobulinemia and other immunocompromising conditions.8-11 Therefore endogenous relapses rather than exogenous reinfections are responsible for recurrences in these people.9 It has been postulated that Campylobacter infection may be a marker for the severity of HIV infection and predispose to a shorter survival.14 Most cases of Campylobacter sp. bacteremia in HIV-infected people occur in the setting of advanced HIV infection.13, 15, 18 Our patients had very low CD4 lymphocyte counts and percentages and several AIDS-defining conditions; three died shortly after having Campylobacter bacteremia. Campylobacter sp. may be associated with biliary tract disease in AIDS13 and non-AIDS patients.4, 5, 7 Two of our children (Cases 1 and 2) had clinical and laboratory findings suggesting cholangitis. However, a causal relation between Campylobacter infection and biliary tract disease cannot be established because other causes of cholangitis in AIDS patients were not ruled out. In summary HIV-infected people have a high risk for both Campylobacter infection and bacteremia. This infection is difficult to eradicate and may have a deleterious effect on the progression of HIV disease. Thus its prevention, through suitable cooking practices and strict hygienic measures, is important in this population. For the above reasons blood cultures should be obtained from every HIV-infected child with C. jejuni enteritis. Jesús Ruiz-Contreras, M.D. José T. Ramos, Ph.D. Teresa Hernández-Sampelayo, Ph.D. Maribel de José, Ph.D. Julián Clemente, Ph.D. María D. Gurbindo, M.D. The Madrid HIV Pediatric Infection; Collaborative Study Group Unidad de Inmunodeficiencias; Department of Pediatrics; Hospital Doce de Octubre; Universidad Complutense (JRC, JTR, JC, JB, JS) Department of Pediatrics; Hospital Gregorio Marañón; Universidad Autónoma; Madrid (THS, MDG) Department of Pediatrics; Hospital La Paz; Universidad Autónoma (MDJ, MJGM); Centro de Investigación Carlos III (MJC, PMF, MJM, JV) Madrid, Spain