Hepatosplenomegaly, pancytopenia, coagulopathy: Big words about a feverish infant
Oct 1, 2005
By: Fasika Woreta et al.
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You meet your new patient late one afternoon on the general pediatric service of your tertiary care hospital. He is a 2-month-old boy of Native American and Puerto Rican descent who has been undergoing evaluation of fever, hepatomegaly, and pancytopenia of uncertain cause.
You familiarize yourself with what has become a rocky infancy for this baby. He was in generally good health until two weeks ago when, you learn, he developed a rotavirus infection. The diarrhea was improving, but had not resolved, when, one week before admission, he developed a fever as high as 104° F and had a generalized tonic-clonic seizure. He was transported to a nearby community hospital and found to be anemic (hematocrit, 20%). There, he was given a transfusion of packed red blood cells. Multiple cultures (blood, urine, and CSF) were obtained and were ultimately negative. Empiric antibiotics were started for possible sepsis.
Over the next five days, the boy developed pancytopenia, ascites, hepatomegaly, direct hyperbilirubinemia, and coagulopathy, requiring transfusions of platelets, fresh frozen plasma, vitamin K, and additional packed RBCs. Bone marrow aspiration and biopsy showed normal cellularity, trilineage hematopoiesis, and no abnormal cells.
He was transferred to the pediatric intensive care unit (PICU) of your hospital for further evaluation and management of the coagulopathy and pancytopenia. There, these problems persisted and were managed with frequent blood product support (fresh frozen plasma, platelets, cryoprecipitate). Transjugular liver biopsy showed cholestasis with normal architecture and no evidence of intrahepatic disease. Biopsy specimens were sent for fungal, viral, and bacterial cultures and were ultimately negative.
Infectious disease, gastroenterology, and immunology specialists were consulted. Today, after three days in the PICU, the patient's transfusion-dependence had apparently resolved, he was no longer febrile and, after narrowing antibiotic coverage to cefotaxime, he was transferred to your care.
Arriving jaundiced and swollen
The brief history is significant for two infections. The infant was hospitalized at 11 days of age for respiratory syncytial virus bronchiolitis, which resolved without apparent complication. He then developed rotavirus infection. Neither is unusual, you consider, for a newborn in a late winter month.
The boy is the product of a full-term pregnancy; the mother is 29 years old, gravida 3, para 3. She confides that she is a recovering heroin addict who used heroin through the first trimester of this pregnancy. She received prenatal care, and routine prenatal testing was negative, including an HIV antibody test. The baby received hepatitis B vaccination at birth but has not yet received the 2-month-old vaccination. Medications include ranitidine (Zantac), which he has taken since he was 1 month old for gastroesophageal reflux disease.
The family history is significant for epilepsy in his mother and paternal grandfather. He has a 2-year-old brother and an 8-year-old half-sister, both in good health. He lives with his mother in a group home for previously incarcerated mothers who are recovering from heroin addiction.
On physical examination, you observe a baby who is alert and does not appear toxic but is diffusely jaundiced. He is now afebrile, with a pulse of 130/min and a respiratory rate of 48/min. Blood pressure is 102/57 mm Hg; O2 saturation, 98% on room air. Weight is 4.8 kg (at the 25th percentile, weight-for-age).
Physical examination is notable in several regards. Sclerae are icteric. The neck is supple without lymphadenopathy. Abdominal examination is remarkable for prominent distension, with a positive fluid wave and a liver palpable 4 cm below the right costal margin. There is splenomegaly, which had not been noted earlier; the spleen is palpable 3 cm below the costal margin. Extremities are well perfused, with a capillary refill of less than two seconds. There is a right femoral line in place, without erythema of surrounding skin. There is nonpitting trace edema of the lower extremities and marked scrotal edema. The rest of the examination is unremarkable.
Laboratory tests obtained in the PICU on the day of transfer show a white blood cell count of 2.2 X 103/μL, with 16% neutrophils, 71% lymphocytes, 12% monocytes, and 1% eosinophils. He is neutropenic, with an absolute neutrophil count of 0.34 X 103/μL. Hemoglobin (8.3 g/dL) and hematocrit (24.2%) are decreased; the platelet count is extremely low at 29 X 103/μL. Total bilirubin (8.9 mg/dL) and direct bilirubin (6.1 mg/dL) are significantly elevated. Aspartate aminotransferase (81 U/L [normal, 0-37 U/L]) and gamma glutamyl transferase (550 IU/L [normal, 12-55 IU/L]) are elevated, but alanine aminotransferase and alkaline phosphatase levels are within normal limits. Fibrinogen is low at 55 mg/dL (normal, 150-450 mg/dL); a d-dimer test is elevated at 6.62 mg/L (normal, 0.43-2.24 mg/L); prothrombin time is slightly elevated at 15.8 seconds; and the activated partial thromboplastin time is normal for age at 40 seconds. Albumin is 2.9 g/dL. Serum electrolytes and creatinine are normal.
The differential is broad
You consider how extensive the differential diagnosis is in an acutely ill 2-month-old with pancytopenia. Ingestion of a toxic substance (including prescription and over-the-counter medications), an infectious process, immune disorders, metabolic disorders, and hematologic processes such as leukemia, lymphoma, or a hemophagocytic syndrome—all could result in pancytopenia and prompt your patient's clinical picture. The boy is being given ranitidine, which can cause hepatotoxicity. Could the recent rotavirus infection explain the clinical picture? You've read case reports of viremia from rotavirus, with systemic manifestations. Notably, the extensive infectious disease workup has been unrevealing: serologic tests for enteroviruses, Histoplasma, Cryptococcus, HIV, hepatitis A and C antibody, cytomegalovirus and Epstein-Barr virus (EBV) antibody, Toxoplasma antibody, parainfluenza, influenza, adenovirus, respiratory syncytial virus, parvovirus, and Haemophilus influenzae type b antigen all return negative. Stool cultures for Salmonella, Shigella, Yersinia, and Campylobacter and a test for rotavirus antigen are also negative. So is a purified protein derivative skin test for Mycobacterium tuberculosis (none was placed on the mother or siblings).
More tests are needed
You decide to order abdominal computed tomography with intravenous contrast. The scan reveals hepatomegaly and an enlarged spleen with an irregular appearance, possibly indicating small implants, abscesses, or infarcts. A doppler ultrasound scan to further evaluate the splenic lesions shows splenomegaly but no areas of abnormal signal.
On the fourth day after transfer, the infant again begins spiking a fever, to a maximum axillary temperature of 104° F. The femoral line is removed and antibiotic coverage is broadened, although cultures of cerebrospinal fluid, blood, urine, and stool continue to show no growth. Persistent pancytopenia is managed with multiple blood and platelet transfusions. On the fifth day, blood cultures return positive for presumptive Enterococcus and the antibiotic coverage is appropriately broadened.
Given the boy's deterioration, you ask the hospital's pediatric hematologists to review the initial bone marrow biopsy and aspirate from the other hospital and to comment on the slightly increased number of histiocytes in the background. They also note one phagocytic histiocyte, which may be normal. Despite an unimpressive bone marrow, the team is concerned that your patient's clinical picture is highly suspicious for hemophagocytic lymphohistiocytosis; repeat bone marrow aspiration and biopsy, along with a lumbar puncture, are performed. Additional laboratory tests are ordered, and you take note of an elevated ferritin level (1,098 ng/mL [normal, 10-300 ng/mL]) and elevated serum triglycerides (237 mg/dL [normal, <150 mg/dL]).
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