Persistent Hepatitis and Repeated Wheezing in an Infant

A 1-year-old Japanese boy was admitted to our hospital because of increased aspartate aminotransferase and alanine aminotransferase values; 784 and 857 IU/L, respectively. He had been followed-up in our outpatient clinic for recurrent wheezing during the past 5 months, and his hepatic enzyme elevation was found incidentally on routine blood examination. His medical history was significant for asthma and for an allergy to dogs. On admission, he was afebrile, and his only clinical symptom was recurrent wheezing for which he had been taking theophylline. He had no jaundice and no hepatomegaly. He had been exposed to multiple dogs and cats in his home and that of his grandparents. Peripheral blood examination showed a white blood cell count of 7 × 103 mm−3, with 27% neutrophils, 57% lymphocytes, 14% monocytes, and 2% atypical lymphocytes. Erythrocyte sedimentation rate was 58 mm/h, and the C-reactive protein level was 1.24 mg/dL. Coagulation studies were normal. Lactate dehydrogenase was 786 IU/L and γ-glutamyl transpeptidase was 92 IU/L. Chest radiograph and imaging studies of the liver (including ultrasonography and computed tomography) were normal. Infection, hematologic and neoplastic diseases, metabolic disorders, drug toxicity, and immune and allergic diseases were considered as possible causes of the liver dysfunction. Ophthalmologic and otolaryngologic examinations were normal. Ferritin and ceruloplasmin were 37 ng/mL and 47 mg/dL, respectively. Antibody tests for hepatitis A, B, C, E, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, human herpes virus-6, parvovirus, and Toxoplasma gondii were either negative or consistent with past infection. Autoantibody testing (including antinuclear antibody, antimitochondrial antibody, and antismooth muscle antibody) and amino acid analysis were negative. Serum markers of liver fibrosis (collagen Type IV, hyaluronic acid, and N-terminal peptide of type X procollagen) and tumor marker assays (alpha-fetoprotein, carcinoembryonic antigen, and neuron-specific enolase) were all normal. Because of the possibility of drug-induced hepatotoxicity, theophylline therapy was discontinued, and the patient was observed without specific treatment. Drug lymphocyte stimulation test for theophylline proved negative, arguing against drug-induced allergic hepatitis. During the patient's 4-week hospitalization, aspartate aminotransferase and alanine aminotransferase values fluctuated between 200 and 900 IU/L, and his C-reactive protein and erythrocyte sedimentation rate continued to be elevated, peaking at 1.33 mg/dL and 63 mm/h, respectively. Nevertheless, the patient remained afebrile and was well-appearing except for recurrent wheezing. A serologic test result ultimately revealed the diagnosis. For denouement see p. 768. Denouement Continued from p. 763. The patient's serum was tested for Coxiella burnetii by indirect immunofluorescent antibody assay. Although his stored sera obtained 2 and 4 months previously had neither detectable phase 2 IgG (<1:16) nor IgM (<1:16) antibodies, serum obtained on admission was positive for phase 2 IgM antibody (1:16). Another sample obtained 17 days after admission was positive for both phase 2 IgG (1:16) and IgM antibodies (1:64) against C. burnetii. Q fever was diagnosed, and the patient was treated with clarithromycin (15 mg/kg/d) for 2 weeks. The patient's serum inflammatory markers and liver transaminase concentrations returned to normal within 2 weeks. Although his wheezing also resolved while on treatment for Q fever, this was thought to be coincidental. Q fever is a worldwide zoonosis caused by C. burnetii. Infected farm animals and domestic pets such as dogs and cats are the main reservoirs of infection. In humans, the disease occurs in acute and chronic forms, which are distinguishable on the basis of clinical features, temporal course, and serologic profile. Acute Q fever is more common than chronic infection and has a variety of clinical manifestations. In 50% of cases, the infection occurs as an asymptomatic seroconversion.1 Other manifestations of acute Q fever include acute self-limited febrile illness, atypical pneumonia, hepatitis, meningitis, or some combination of these features. Chronic Q fever is defined by a clinical evolution of greater than 6 months, and the predominant form is endocarditis, which primarily affects patients with underlying valvulopathy.2 The diagnosis of Q fever is usually based on serologic testing, and the most commonly used method has been immunofluorescent antibody. The presence of phase 2 IgG titers of ≥1:200 and/or IgM titers of ≥1:50 on a single serum specimen or a 4-fold rise in antibody titer between acute and convalescent sera is generally considered diagnostic of acute Q fever. However, specific antibodies are often absent in first 2–3 weeks of illness, making early diagnosis by serology difficult. Newer polymerase chain reaction-based techniques may decrease the diagnostic delay by offering increased sensitivity over serologic testing alone.3 Chronic Q fever is characterized by the presence of phase 1 IgG titers of ≥1:800. The overwhelming majority of reports on the various manifestations of acute Q fever are found in the adult literature. Q fever is believed to be rare in children, but this might be because the diagnosis is often unrecognized. Seroepidemiologic studies demonstrate that children in Japan are frequently exposed to C. burnetii; however, following infection, they are less frequently symptomatic than adults and may have milder disease.4 Hepatitis has been reported in 11–65% of patients with acute Q fever.5 Elevation of aspartate aminotransferase and/or alanine aminotransferase values is present in up to 85% of patients,6 although jaundice occurs in less than 5%.7 Usually, transaminase abnormalities are mild, in the range of 2–3-fold above normal,6 but are often accompanied by fever and, less frequently, abdominal pain, anorexia, nausea, emesis, and diarrhea. Our patient's transaminase levels increased more than 5–20-fold above normal and the elevations persisted for 4 weeks without associated fever, hepatomegaly, or jaundice. In addition, his general condition was good and his only symptom was recurrent wheezing. Other cases of Q fever-associated hepatitis in young children have been reported previously. A 2-year-old girl was diagnosed with chronic Q fever after presenting with acute pericarditis and cardiac tamponade.8 One month after recovery and hospital discharge, she developed evidence of hepatic injury (aspartate aminotransferase and alanine aminotransferase increased to 250 IU and 300 IU, respectively), which was associated with a rising phase 1 IgG titer to C. burnetii. Her liver enzyme abnormalities normalized with antimicrobial therapy. In another report, a 2-year-old boy presented with jaundice and prolonged fevers and was diagnosed with Q fever by serology. Despite treatment with tetracyclines and chloramphenicol, his hepatic involvement progressed, and he died of hepatic failure.9 When treatment is indicated for acute Q fever, doxycycline is considered the drug of choice. However, because few cases of this infection have been documented in children, there are no controlled studies to determine the optimal therapy in this age group. C. burnetii is susceptible in vitro to tetracyclines, rifampin, fluoroquinolones, trimethoprim-sulfamethoxazole, and clarithromycin.2,10 Because tetracyclines and fluoroquinolones are generally avoided in younger children, we treated our patient with clarithromycin for 2 weeks with resolution of her laboratory abnormalities and no side effects. Current epidemiologic studies suggest that C. burnetii infection is an important public health problem in Japan.11 Because Q fever is often unrecognized, particularly in children, awareness of the disease, its varied manifestations, its diagnosis, and its treatment is important for clinicians. As our case illustrates, Q fever should be added to the differential diagnosis of unexplained hepatitis in children. Prospective studies are required to better define the incidence, clinical spectrum, treatment, and morbidity associated with Q fever in children. ACKNOWLEDGMENTS The authors thank Dr. Peter M. Olley (Emeritus Professor, University of Alberta) for assistance in preparing this manuscript.

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