We report on a female infant with disseminated tuberculosis who presented with clinical sepsis and disseminated intravascular coagulation starting at 14 days of age. Parenteral ofloxacin combined with streptomycin were used because the enteral route was not possible and intravenous isoniazid and rifampicin were not available. Rare complications including infection-associated hemophagocytic syndrome, hypercalcemia, and adrenal insufficiency were detected and successfully managed.
Neonatal tuberculosis, an uncommon disease, is now a growing concern with the reemerging epidemic of tuberculosis in an era of acquired immunodeficiency syndrome.1 We are reporting a case of neonatal tuberculosis presenting with clinical sepsis and disseminated intravascular coagulation (DIC). The infant also developed rare complications of tuberculosis including infection-associated hemophagocytic syndrome (IAHS), adrenal insufficiency, and hypercalcemia.
A 3090-g female infant was born by vaginal delivery at term gestation to a 21-year-old woman who had an uncomplicated pregnancy. At 14 days of age, she developed fever and was prescribed an oral cloxacillin for diagnosis of omphalitis. Fever persisted and, 5 days later, she developed lethargy, marked abdominal distension, and vomiting. She was admitted to a hospital with a diagnosis of sepsis and was treated with cefotaxime and amikacin. The bacterial culture from blood was negative. Her clinical condition became progressively worse and she was transferred to Ramathibodi Hospital at age 23 days.
On admission (day 1), the infant was 3400 g, afebrile, lethargic, tachypneic, icteric, and had marked abdominal distension with moderate ascites and hepatosplenomegaly. The abdominal and chest radiographs demonstrated generalized intestinal dilatation and minimal bilateral peribronchial infiltrates. Complete blood cell (CBC) count showed hemoglobin of 11.3 g/dl, white blood cell (WBC) count of 3.9×103mm−3, platelet count of 58×103 mm−3, and 2+ Burr cells. Liver enzymes and bilirubin were slightly elevated, with a serum aspartate aminotransferase of 308 U/l, alanine aminotransferase of 77 U/l, total bilirubin of 3.4 mg/dl, and direct bilirubin of 2.1 mg/dl. Serum albumin was very low, being 21.7 g/l. The coagulation profile suggested DIC with a partial thromboplastin time of >200 seconds, prothrombin time of 24% (39.5 seconds), and thrombin time of 21.4 seconds. She received a broad-spectrum antibiotic (meropenem), fresh frozen plasma, and a platelet transfusion. Eight hours after admission, she developed hypotension, tachycardia, and dyspnea, and required mechanical ventilation and treatment for shock.
The infant's mother had a negative anti-HIV test. She was doing well until 12 days after delivery when she developed intermittent fever, but did not seek any medical advice. Her chest radiograph, obtained on day 11 of her illness when her infant was admitted to Ramathibodi Hospital, showed bilateral nodular infiltration compatible with miliary tuberculosis. Microscopic examination of a sputum specimen revealed rare acid-fast bacilli. Then, miliary tuberculosis was diagnosed and she was treated with isoniazid and rifampicin for 6 months with addition of pyrazinamide during the first 2 months.
Microscopic examination of tracheal and gastric aspirates from the infant on day 2 of the admission revealed a positive stain for acid-fast bacilli. Disseminated tuberculosis was then diagnosed. It was necessary to administer treatment parenterally because the infant was severely ill and had severe intestinal ileus. Parenteral isoniazid or rifampicin was not available in Thailand; therefore, parenteral streptomycin (20 mg/kg per day) and ofloxacin (10 mg/kg per day) were initiated together with intravenous hydrocortisone (4 mg/kg per day). A few days after initiation of antituberculosis therapy and intensive supporting care, the infant's condition improved. Lumbar puncture was performed to rule out tuberculous meningitis and revealed normal cerebrospinal fluid. On day 7, she was successfully extubated, and the enteral feedings were begun. Isoniazid (10 mg/kg per day) and ethambutol (20 mg/kg per day) were given by nasogastric tube feeding. Hydrocortisone was tapered off within 2 weeks. On day 16, antituberculosis treatment was changed to a combination of oral isoniazid, rifampicin, pyrazinamide, and ethambutol.
Five days later (day 21), the infant developed intermittent fever and progressive hepatosplenomegaly. At the same time, the WBC, platelet counts, and hemoglobin concentration began to drop. Bone marrow aspiration revealed hypercellularity and numerous macrophages ingesting mature red blood cells, WBC, and platelets. The findings were consistent with IAHS. She was treated with platelet and packed red blood cell transfusions together with daily administration of pooled intravenous immunoglobulin (Venoglobulin; Alpha Therapeutic, CA) at a dose of 400 mg/kg per day for 4 days. Despite intensive therapy and blood product replacement, hematologic abnormalities were not corrected. Pancytopenia persisted from days 28 to 37 with hemoglobin of 9 to 10 mg/dl, WBC of 0.7×103 to 1.7×103 mm−3, and platelets of 14×103 to 90×103 mm−3. On day 31, the infant developed pulmonary edema secondary to volume overload, and required mechanical ventilation. The serum cortisol was measured, with a level of 13 μg/dl during acute stress suggesting adrenal insufficiency. Therefore, a stress dose of hydrocortisone was initiated. From days 27 to 33, the infant also developed hypercalcemia with serum calcium of 12.3 to 14.2 mg/dl and serum albumin of 28.0 to 33.3 g/l. Serum calcium, however, returned to normal after hydration, administration of hydrocortisone, and furosemide. The IAHS was resolved and the CBC was normalized by day 41.
On day 42, the infant was readily extubated. Enteral feedings were resumed and slowly increased to full feeding with adequate weight gain. Hydrocortisone was gradually tapered off and was discontinued on day 56. The culture results of all specimens for Mycobacterium tuberculosis from the infant's blood, tracheal aspirates, and gastric aspirates were positive. As the organism was susceptible to isoniazid, rifampicin, streptomycin, ethambutol, and ofloxacin, the antituberculosis regimen was changed to oral isoniazid and rifampicin and was continued for a total course of 12 months. At 12 months of age, she was doing well with a body weight of 11.5 kg, normal physical and developmental findings, and a normal chest radiograph.
This neonate developed tuberculous bacillemia with multiple organ involvement beginning at 14 days of age. Clinical manifestations with fever, abdominal distension, and hepatosplenomegaly are common in congenital tuberculosis.1,3 Before delivery, the infant's mother did not have any symptoms of tuberculosis. This is consistent with a previous report that up to 75% mothers whose newborns had tuberculosis were asymptomatic before delivery.3 In our case, placental pathology was not performed due to lack of clinical signs and symptoms of tuberculosis at the time of delivery. The correct diagnosis in this neonate was made with the awareness of tuberculosis in the mother and the finding of acid-fast bacilli from the infant's tracheal and gastric aspirates. Positive cultures for M. tuberculosis were also detected from all specimens as well.
Streptomycin was the only available parenteral first-line antituberculous drug in Thailand. Streptomycin alone is not generally adequate for treatment of severe tuberculosis especially when a streptomycin-resistant organism is a possible causative agent. Ofloxacin, a 5-fluoroquinolone, is a recommended second-line antituberculous drug for adults.2 Enteral medication was not possible in this case because the infant was severely ill; therefore, parenteral ofloxacin was used in combination with streptomycin as an initial antituberculosis therapy, which resulted in clinical response without detectable adverse effect. Thus, parenteral ofloxacin may be useful as an alternative parenteral drug when parenteral isoniazid and rifampicin are not available, or when hepatotoxic drugs are contraindicated.
This infant is also one of a few reported cases of IAHS in neonatal tuberculosis.4,5 Abughali et al.3 reported a case of congenital tuberculosis with the onset of fever at 3 days of age. The disease was not diagnosed until 2 weeks of life. By that time, she had developed DIC and erythrophagocytosis. The condition was successfully treated with isoniazid, rifampicin, streptomycin, and hydrocortisone. Shaw et al.4 recently reported a 7-week-old girl who developed IAHS and rapidly died of undiagnosed pulmonary tuberculosis. Successful treatment of IAHS usually depends on a specific treatment for the known infectious agent and adequate supportive care. Treatment with intravenous immunoglobulin has been reported to improve the outcome of virus-associated hemophagocytic syndrome,5 but no information has been reported for the treatment of IAHS associated with tuberculosis. Our patient did not respond to treatment with intravenous immunoglobulin, and the resolution of IAHS seemed to be the result of an adequate treatment for tuberculosis.
Hypercalcemia is a well-recognized complication of tuberculosis in adults. However, the condition has rarely been reported in the pediatric age group6,7,8 and, to our knowledge, never in neonates. This is the first reported case of hypercalcemia in neonatal tuberculosis. This condition results from abnormal calcium metabolism due to endogenous overproduction of 1,25-dihydroxyvitamin D (calcitriol), an active metabolite of vitamin D, by activated macrophages.9 Nephrocalcinosis and liver calcification have occurred in a reported case of tuberculosis in a child.6
There has been no adequate evidence regarding the role of corticosteroid on acute disseminated tuberculosis.10 Data on corticosteroid use in congenital tuberculosis are very limited. A 2-week course of hydrocortisone (4 mg/kg per day) in disseminated neonatal tuberculosis with DIC was reported with a favorable outcome.3 In our case, hydrocortisone was given during the initial critical stage and adrenal insufficiency was detected during the later course of illness. This could be a result of tuberculosis of the adrenal gland or adrenal suppression from the previous use of corticosteroid. Physicians should be aware of this condition in order to improve the outcome of disseminated tuberculosis.
Adhikari M, Pillay T, Pillay DG . Tuberculosis in the newborn: an emerging disease. Pediatr Infect Dis J 1997; 16: 1108–12.
Drlica K, Malik M, Wang JY, Leviyz R, Burger RM . The fluoroquinolones as antituberculosis agents. In: Rom WN, Garay SM, editorsTuberculosis1st edBoston: Little, Brown and Company. 1996. p. 817–27.
Abughali N, Van der Kuyp F, Annable W, Kumar ML . Congenital tuberculosis. Pediatr Infect Dis J 1994; 13: 738–41.
Shaw PH, Brown D, Shulman ST . Tuberculosis-associated hemophagocytic syndrome in an infant. Pediatr Infect Dis J 2000; 19: 475–7.
Chen RL, Lin KH, Lin DT, et al. Immunomodulation treatment for childhood virus-associated hemophagocytic lymphohistocytosis. Br J Haematol 1995; 89: 182–90.
Wyllie JP, Chippindale AJ, Cant AJ . Miliary tuberculosis and symptomatic hypercalcemia. Pediatr Infect Dis J 1993; 12: 780–2.
Gaskin KJ, Vines RH . Hypercalcaemia: an unusual complication of tuberculosis. A case report. Aust Paediatr J 1978; 14: 44–7.
Gerritsen J, Knol K . Hypercalcemia in a child with miliary tuberculosis. Eur J Pediatr 1989; 148 7 650–1.
Dusso AS, Kamimura S, Galieni M, et al. γ-Interferon–induced resistance to 1,25-(OH)2 D3 in human monocytes and macrophages: a mechanism for the hypercalcemia of various granulomatoses. J Clin Endocrinol Metab 1997; 82: 2222–32.
Dooley DP, Carpenter JL, Rademacher S . Adjunctive corticosteroid therapy for tuberculosis: a critical appraisal of the literature. Clin Infect Dis 1997; 25: 872–87.
We thank the staff, fellows, and residents of the Department of Pediatrics involved in the care of this patient, especially Ampaiwan Chuansumrit (Division of Hematology), Pat Mahachokelertwattana (Division of Endocrinology), and Aroonwan Preutthipan (Division of Respiratory Disease).
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Okascharoen, C., Nuntnarumit, P. & Sirinavin, S. Neonatal Tuberculosis Associated With Shock, Disseminated Intravascular Coagulation, Hemophagocytic Syndrome, and Hypercalcemia: A Case Report. J Perinatol 23, 79–81 (2003). https://doi.org/10.1038/sj.jp.7210848
Journal of Perinatology (2016)
The Indian Journal of Pediatrics (2012)