Fever, Hepatosplenomegaly and Rash in a Newborn

A 4-day-old Hispanic girl was transferred to the University of California Davis Medical Center for evaluation of fever. The baby was born at 38 weeks of gestation, weighing 3100 g, to a 24-year-old gravida 3, para 1 to 2 Hispanic mother. The baby was born vaginally through thick meconium, with Apgar scores of 9 at 1 min and 9 at 5 min. At 2 days of age the baby, still hospitalized, developed a fever of 38.6°C but was relatively well appearing without dyspnea or hemodynamic compromise. At 3 days of age the white blood count was 13 400/mm3 with 48% neutrophils, 29% band forms and 17% lymphocytes; the platelet count was 96 000/mm3. The cerebrospinal fluid examination revealed 4 white blood cells/mm3 (all mononuclear cells), protein 91 mg/dl and glucose 49 mg/dl. Alanine aminotransferase was 20 U/l. Viral surveillance cultures were submitted because of several papulovesicular lesions observed on the back. Ampicillin and gentamicin therapy was begun at 2 days of age and acyclovir was added at 4 days of age. All cultures including viral cultures were negative. Physical examination upon transfer to our hospital at 4 days revealed a temperature of 38.6°C, heart rate of 130 beats/min and respiratory rate of 40/min. She was fussy but consolable, pale and mildly ill appearing. Pertinent findings included three 0.3- to 0.5-cm scabbing lesions scattered on the scalp, a normal lung examination without tachypnea, retractions or adventitial sounds, a liver edge palpable 4 cm below the right costal margin in the midclavicular line, a spleen tip 3 cm below the left costal margin and bilateral inguinal lymph nodes 0.5 cm in diameter. Roentgenographic evaluation showed an enlarged liver and spleen and a diffuse reticular pattern in the lung fields. The complete blood count was essentially unchanged; the aspartate aminotransferase was 66 U/l, alanine aminotransferase 54 U/l and gammaglutamyl transpeptidase 555 U/l at 6 days of life. The mother had developed fever at the time of delivery. She was briefly treated with antimicrobials and discharged from the hospital. By telephone interview the mother stated that she was still febrile 1 week after delivery. Her main symptoms were malaise, abdominal pain and headache. She denied respiratory symptoms, vomiting, diarrhea and rash. Her husband believed that she was jaundiced. Maternal HIV, cytomegalovirus, Epstein-Barr virus, viral hepatitis and toxoplasmosis titers were submitted. The father worked at a dairy farm in the Sacramento area and he brought home raw milk. The mother served her family the milk but reported that she always boiled it first The baby continued to appear pale, ill and febrile. On the baby's tenth day of life, the mother visited the nursery; she had head and neck pain and was ill appearing. Her husband reported that in addition to the headache, he felt that she was having personality changes that began the week before delivery. The mother was admitted to the hospital and evaluations revealed the diagnosis. Ann M. Loeffler, M.D. Department of Infectious Diseases Children's Hospital Oakland, CA Jay M. Milstein, M.D.; David L. Kosh, M.D. Department of Pediatrics, (JMM) and Family Practice Department (DLK) University of California, Davis Sacramento, CA For denouement see p. 724 DENOUEMENT-Continued from p. 722. A purified protein derivative (PPD) skin test had not been placed during the pregnancy, but the mother had had a negative PPD 2 years earlier. There was no known exposure to tuberculosis, but the family traveled yearly to Mexico. The mother's cerebrospinal fluid contained 212 white blood cells/mm3, protein of 177 mg/dl and glucose of 30 mg/dl. At 48 h her PPD skin test showed 18 mm of induration. The baby's PPD skin test had no induration, but three gastric aspirates and an endotracheal aspirate showed many acidfast bacilli on staining. The mother's cerebrospinal fluid and the baby's gastric aspirate, blood and endotracheal aspirate all grew Mycobacterium tuberculosis complex. The organism was susceptible to isoniazid, rifampin, streptomycin and ethambutol and resistant to pyrazinamide. The isolate was identified as Mycobacterium bovis by the California Department of Health Services Microbial Diseases Laboratory. The father and 2-year-old brother had 15 and 12 mm of induration, respectively, in response to PPD skin tests. More than 1000 cows in the herd where the father of the infant worked were tested and none was skin test-positive. Infant and mother were treated with four-drug antituberculous therapy. Both have had slow but steady improvement. The baby was last evaluated at 5 months of age with some growth and developmental delay, but otherwise normal physical examination. The family subsequently relocated and was lost to follow-up evaluation. Congenital tuberculosis is rare; fewer than 300 cases have been reported in the medical literature.1 In 3 reviews of active tuberculosis in pregnancy only 3 of more than 1700 infants developed congenital tuberculosis.1 To distinguish between congenital tuberculosis and postnatally acquired tuberculosis, standardized criteria were proposed by Beitzke in 1935.2 To be classified as having congenital tuberculosis, the child must have proved tuberculosis with lesions in the first few days of life or a primary hepatic complex and proof of exclusion of postnatal infection. Infection is transmitted hematogenously or by aspiration of infected amniotic fluid. With fever and skin lesions beginning at 2 days of age, our patient can be classified as having been congenitally infected, and hematogenous acquisition seems most likely. Unfortunately the mother's placenta was not evaluated. The symptoms of congenital tuberculosis are similar to those of other congenital infections. Symptoms usually begin in the first few days to months of life (mean, 2 to 4 weeks).3-5 Fever, respiratory distress and hepatosplenomegaly are common. Other findings include irritability, lethargy and failure to thrive. Less common findings include skin lesions, such as those seen in our patient, described as small erythematous papules with central crusting.3 Many infants with congenital tuberculosis are tuberculin skin test-negative.3 M. bovis is now an unusual cause of tuberculosis. It causes the same spectrum of disease as M. tuberculosis although infection with M. bovis usually follows consumption of contaminated milk. Special testing is required to distinguish M. bovis from M. tuberculosis, but the antimicrobial susceptibility pattern of isolated pyrazinamide resistance should prompt consideration of an infection with M. bovis. In our case all of the cows tested were skin test-negative. Although it is possible that the infected cow was missed or left the herd, M. bovis is very contagious within a herd; therefore it is quite possible that the family was infected in Mexico. Postnatally acquired tuberculosis is more common than congenital tuberculosis. Women who are tuberculin skin test-positive during pregnancy should be evaluated for active disease. If the mother has active disease or is recently infected, therapy for tuberculosis should be initiated immediately. If the mother is asymptomatic specific therapy can be deferred until after pregnancy if follow-up can be assured. Because 42% of infants infected with tuberculosis develop active disease, it is very important to prevent postnatal infection by separating the baby from any inadequately treated contacts with active tuberculosis including the mother. Prompt skin testing of all household and close contacts should allow for therapy when appropriate, before the baby's delivery. Babies born to tuberculin skin test-positive mothers should be examined for signs and symptoms of tuberculosis and tuberculin skin testing of the infants should be performed at 1 and 3 months of age. If avoidance of persons with active tuberculosis cannot be assured or if the mother has hematogenously spread tuberculosis, prophylaxis with isoniazid is sometimes indicated.6 Without treatment babies with congenital tuberculosis frequently die. Treatment should include four drugs, at least until susceptibility patterns are known. Isoniazid, rifampin, pyrazinamide and streptomycin are frequently chosen; ethambutol is not recommended because of the optic neuritis which cannot be easily monitored at this age. Dosages and duration of therapy are recommended by the Committee on Infectious Diseases of the American Academy of Pediatrics.6