CONGENITAL BRUCELLOSIS IN A PREMATURE INFANT

Abstract

Brucellosis is a febrile illness caused by brucellae. Nucleic acid hybridization studies indicate that only one species of Brucella exists; however, the genus has historically been divided into species based on the natural animal hosts.1 Brucellosis is primarily a disease of animals. Human infection is usually acquired by contact with infected animals.2, 3 The acquisition of brucellosis by food contamination has been growing in incidence.4 The major reservoirs include goats and sheep (Brucella melitensis), swine (Brucella suis) and cattle (Brucella abortus). These Gram-negative coccobacilli remain viable in fomites or water for many days before transmission by ingestion of infected milk, cheese products or meat.4, 5 Although brucellosis is an important human infection in many parts of the world, human to human transmission, especially perinatal transmission, is uncommon.2, 6 We report one case of perinatal transmission of B. melitensis from an infected mother to her preterm infant. Case report. A 17-year-old primigravida with a history of one prenatal visit, presented to our hospital with malaise, abdominal cramps and vaginal bleeding. "Flu"-like symptoms had recently occurred in her family members. She was febrile (38.6°C) and had ruptured fetal membranes. A complete blood count (CBC) revealed an elevated fraction of segmented and immature neutrophils. Blood cultures were drawn and she was treated with intravenous ampicillin and gentamicin. Three days later she went into preterm labor and delivered vaginally a viable 24-week 650-g female infant. Apgar scores were 7 at 1 and 5 min. Histopathologic examination of the placenta by a pediatric pathologist showed acute and chronic chorioamnionitis and funisitis. A placental Gram-stained smear was negative, but a culture was positive for coagulase-negative Staphylococcus. Because of the infant's extreme prematurity, she was intubated soon after birth, given prophylactic surfactant and placed on synchronous intermittent mandatory ventilation. Pertinent findings on physical examination were significant hypotension requiring vasopressors, a systolic grade II heart murmur, a 4- by 2-cm midline abdominal mass (later found to be a hematoma) and small infarctions of the distal phalanx of the left finger and the right thumb suspected to be septic emboli. Blood cultures were drawn and the infant was given 200 mg/kg/day of ampicillin and 2.5 mg/kg/day of gentamicin. The first CBC revealed neutropenia (absolute neutrophil count, 1728/mm3 which then dropped to 1080/mm3) and thrombocytopenia (60 000/mm3 platelets). Clotting studies were normal. Because of hemodynamic instability and persistent neutropenia and thrombocytopenia, antibiotics were changed to vancomycin and cefotaxime on the third day of life. Although initial blood cultures remained negative, antibiotics were continued for 10 days. The infant's hospital course was complicated by mild hyaline membrane disease and immature lungs requiring synchronous intermittent mandatory ventilation support for the first 52 days of life. On Day 14 the patient was given a 42-day course of dexamethasone to treat developing bronchopulmonary dysplasia. On the 36th day several episodes of desaturation, abdominal distension and bloody stools occurred. Enteral feedings were stopped, a full evaluation for sepsis was done and vancomycin and cefotaxime were started. A CBC showed an elevated fraction of segmented and immature neutrophils; 7 days later blood cultures grew B. melitensis. Vancomycin was discontinued and cefotaxime was continued for a total of 21 days. When gentamicin was added for 5 days feeding was resumed; trimethoprim-sulfamethoxazole was also added for a total of 4 weeks. Liver function tests and CBC were periodically monitored and remained normal. No vegetations on the cardiac valves or liver abscess were found on ultrasound examination. It was discovered at this time that a blood culture performed on the mother 3 days before the delivery was positive for B. melitensis. She was subsequently contacted and treated with rifampin 600 mg twice daily and trimethoprim-sulfamethoxazole double strength twice daily for 3 weeks. Further history revealed that the mother had lived on a family farm in Mexico until 1 month before the delivery of her preterm infant. Although she could not recall eating unpasteurized goat cheese, she was involved in the care of goats and cows at the farm. Blood cultures from the infant several days after completing her treatment were negative. She was discharged home at a chronologic age of 3.5 months. She was last seen at our developmental follow-up clinic at the age of 7 months (adjusted age of 4 months) and was doing well. Her neurodevelopment and physical growth were normal for her adjusted age. Discussion. Brucellae are facultative intracellular, small, noncapsulated, aerobic, non-spore-forming, nonmotile Gram-negative coccobacilli.1-3 They are difficult to cultivate because of their slow growing nature and their requirement for special media and high CO2 tension.1-3 The isolation of small Gram-negative coccobacilli that are oxidase- and urease-positive should alert the laboratory that the organism could be Brucella. Human to human transmission is rare2 but has been reported in association with blood transfusions, bone marrow transplantation, transplacental or perinatal exposure2, 3, 6-8 and possibly postnatally, through human milk.9, 10 Although infected pregnant animals transfer brucellae to their off-spring transplacentally with resultant massive wastage of conception, this mode of transmission and resultant interference with the normal course of pregnancy has been disputed in humans.2 The discrepancy between the abortive effect of brucellosis in animals and that in humans has been ascribed to erythritol, a carbohydrate nutrient essential for growth of Brucella in the fetal and placental tissues of domestic animals but not of humans.11-13 However, a few reports have documented isolation of Brucella spp. from aborted human fetuses or premature still births and from their respective placental or maternal blood and lochia,14-16 but there are very few cases of proven congenital brucellosis in live born infants.7, 17 In our case the mother with documented bacteriologic evidence of brucellosis went into preterm labor. Although placental cultures for brucellosis were negative, there was pathologic evidence of an acute and chronic infectious process, i.e. neutrophils, lymphocytes and monocytes infiltrating the chorion and amnion. However, the characteristic lesions of Brucella, consisting of multiple, minute noncaseating granulomas, were not seen. In addition the lack of clinical suspicion, the fastidious nature of the organism and the absence of erythritol in human placentas may have contributed to the failure to identify the organism in the placental culture. Vagueness of the symptoms of brucellosis in this mother is similar to that reported in the literature.15, 17 This makes diagnosis difficult during pregnancy. Because blood cultures from neonates in our hospital are routinely plated on blood tryptic soy agar and MacConkey agar, the maternal course of antibiotics together with a less than optimal method of culture could have delayed bacteriologic diagnosis in the infant. Both ampicillin and gentamicin have good tissue penetrance and cross the placenta well. In addition gentamicin has been considered a good alternative treatment for Brucella,18 and ampicillin alone has been shown, in one report, to be effective in a premature infant with brucellosis.7 Differentiation between brucellosis and other bacterial infections in the newborn can be very difficult as noted in this and other cases.17 Our infant's initial presentation of leukopenia and thrombocytopenia are signs associated with complications of prematurity and a wide variety of neonatal problems.19 In addition the initial clinical findings of digital infarctions, although not reported specifically with Brucella, are well-recognized complications of septicemia. Furthermore the neonatal immune system is immature, the response to well-characterized infective processes varies from that described in older children and hence clinical manifestations may differ. For example brucellosis was reported to cause enterocolitis in an infant with suspected perinatal transmission.20 A similar presentation in our patient led to a second sepsis workup which yielded the offending organism. Because Brucella organisms are facultative intracellular parasites, they evade humoral immune defenses.1, 21 Intracellular survival is prolonged unless specific cellular immunity develops. Cellular immunity depends on macrophages processing the brucellar antigen and presenting it to T cells that then produce cytokines. These agents, of which interferon-γ is the most efficient in this context, activate macrophages to greater bactericidal potency.21 This inflammatory response is also enhanced by the autocrine production of other cytokines such as tumor necrosis factor α and interleukin 1.21 However, those host defense mechanisms in new born infants, particularly preterm infants, are deficient.22, 23 It is likely that the use of corticosteroids may have further reduced the resistance of this infant to the infection. Standard antibiotic regimens in the intensive care nursery are insufficient for the treatment of brucellosis. Tetracycline, in combination with streptomycin,24 or gentamicin with either doxycycline or tetracycline are recommended therapy in older children or adults25. Because of the untoward side effects of tetracycline in children younger than 10 years of age,26 alternate regimens have been considered and a variety of drugs can be used safely.27, 28 We used a combination of gentamicin and trimethoprim-sulfamethoxazole, as recommended by Lubani et al.29 Sadhana Chheda, M.B., B.S. Suzanne M. Lopez, M.D. Ellen P. Sanderson, B.S., C.L.S. Division of Neonatology; Department of Pediatrics (SC, SML); Department of Healthcare Epidemiology (EPS); University Of Texas Medical Branch at; Galveston; Galveston, TX