Chronic Q fever is a rare but increasingly recognized cause of culture-negative endocarditis in adults. The clinical manifestations of this infection are not well-known in children. In this paper we report Q fever endocarditis in a child. The diagnosis was established by isolation of Coxiella burnetii from aortic valve.
Case report. An 11-year-old boy from a rural region of Saudi Arabia was admitted in June, 1995, to King Faisal Specialist Hospital and Research Center because of intermittent fever, pallor and fatigue of 6 months duration. He was examined at a local hospital in his region and found to have a cardiac murmur. He had frequent contact with sheep and camels and drank raw milk. On admission his skin was pale and anicteric, his temperature was 38°C, the pulse and blood pressure were normal, weight was 25.4 kg and height was 120 cm. The precordium was active with a palpable thrill over the entire chest and in the right suprasternal area. A grade 4/6 ejection systolic murmur was heard maximally at the right upper sternal border. A soft early diastolic murmur was present. The liver and spleen were palpable 7 and 6 cm, respectively, below the coastal margins. Respiratory musculoskeletal and neurologic examinations were normal.
The hemoglobin was 9.5 g/dl, mean corpuscular volume 60.4 and leukocyte count 3.6 × 109/l with 25% neutrophils and 71% lymphocytes. The platelet count was 102 × 109/l. The erythrocyte sedimentation rate was 10 mm/h. Prothrombin time, partial thromboplastin time and fibrinogen were normal. The aspartate aminotransferase was 161 units/l and alanine aminotransferase was 103 units/l. The renal profile were normal. Malaria thin and thick smears were negative. Repeated blood culture was sterile. Electrocardiography showed left ventricular hypertrophy; echocardiogram confirmed the left ventricular hypertrophy with the presence of a a bicuspid aortic valve. Chest roentgenography showed slight cardiomegaly (cardiothoracic ratio, 1:1.7). Cardiac catheterization with an aortogram revealed bicuspid aortic valve with stenosis and second degree aortic regurgitation. Serologic evaluations for Brucella, Salmonella, Epstein-Barr virus, Toxoplasma gondii, Schistosoma, Leishmania, hepatitis C were negative. Using the microparticle enzyme immunoassay IgG but not IgM antibodies were found for cytomegalovirus and hepatitis A. The serum was positive against hepatitis B surface antibodies. The antibody titers to C. burnetii phase II as measured by complement-fixation (Bioscientia Institut für Labor untersuchungen Ingelheim GmbH, Germany) rose from 1:160 on June 19, 1995, to 1:320 on June 24, 1995, and 1:1280 on July 22, 1996.
The hospital course was characterized by repeated episodes of high fever of up to 39°C. He was treated with doxycycline 100 mg orally twice daily. He improved clinically and his fever subsided. He was discharged in August, 1995, and not examined again until June, 1996, when he arrived at a local hospital in his region with a 6-week history of fever and increased fatigability. He was treated with intravenous antibiotics (penicillin and gentamicin) without improvement. He was subsequently transferred to our hospital for further management. On arrival it was learned that he received a short course of doxycycline (6 weeks) after discharge from our hospital. Examination showed finger and toe clubbing but fever was absent. Blood pressure and pulse were normal. There was no change in heart auscultation and he continued to have hepatosplenomegaly. Respiratory, musculoskeletal and neurologic examination were normal. On admission investigations showed normal serum immunoglobulins, reduced serum complements (C3 was 3.2 g/l (normal, 6 to 17), C4 was 1.2 g/l (normal, 2 to 5)). Rheumatoid factor 54 IU/ml (normal, < 19), antinuclear antibodies 1/80, circulating immune complexes 7 μg/Eq/ml (normal, < 3). His urinalysis was significant for proteinuria of 0.8 to 2.9 g/day and 10 to 25 red blood cells/high power field. Echocardiogram revealed vegetations on the aortic leaflets. The patient was treated with tetracycline 250 mg orally every 8 h and rifampin 250 mg orally once daily. The persistence of renal insufficiency with microhematuria and proteinuria was the indication for renal biopsy which showed features consistent with membranoproliferative glomerulonephritis with mesangial interposition and prominent endothelial and mesangial electron-dense deposits (type I) and immunofluorescent study showing diffuse glomerular deposition of IgM, C3 and C1q. On July, 1996, the aortic valve was removed and a fresh antibiotic-preserved homograph valve was inserted. C. burnetii was detected in the valve tissue by capture-enzyme-linked immunosorbent assay and smear staining. Subsequently the organism grew in monkey renal cell culture (Fig. 1). After the operation the child remain afebrile and his course was favorable.
Discussion. Q fever was first recognized as a clinical entity in 1937.1 The disease is caused by C. burnetii, a strict intracellular pathogen that proliferates in the phagolysosome of the host cell and which humans acquire either by inhalation of infected dust or by ingestion of unpasteurized milk from farm animals.2, 3 Currently two forms of the disease have been described. The acute form is characterized by fever frequently associated with respiratory manifestation and hepatic involvement. The chronic form is rare but increasingly recognized as the cause of culture-negative endocarditis in adults.4 To our knowledge it has been described only in three children.5, 6 The first child, who had a congenital bicuspid aortic valve, as reported by Jones6 in 1980, presented with finger clubbing and hypertrophic osteoarthropathy. His echocardiography showed the presence of aortic valve vegetations and he had high antibody titers to the Phase I and II antigens of C. burnetii. The other two cases were known to have congenital heart disease.7 Diagnosis was made by serology and isolating the organism from blood in the first child and by serology and visualization of C. burnetii antigen by immunofluorescent staining of liver and spleen specimen in the other patient. The source of infection in our patient was from animal contact and raw milk ingestion.
Q fever endocarditis is one of the most indolent forms of infective endocarditis. It is not unusual for the infection to be mildly symptomatic for years before it is diagnosed. Valvular heart disease was almost invariably present. Vegetations are found in only 12% of cases by echocardiogram. In contrast to other forms of bacterial endocarditis where diagnosis relies primarily on positive blood cultures, C. burnetii does not grow in routine blood cultures and should be considered in the differential diagnosis of culture-negative endocarditis in children in addition to other fastidious microorganisms, especially those with unusual growth requirements. These organisms include nutritionally variant streptococci, HACEK group (Haemophilus aphrophilus, Actinobacillus actinomycetem comitans, Cardiobacterium hominis, Eikenella corrodens and Kingella kingae), Brucella, Nocardia, fungi, mycobacteria and Chlamydia. Serology (mostly complement-fixation test or indirect immunofluorescence tests) are the most commonly used diagnostic tool. To detect the chronic form of Q fever it is necessary to demonstrate a high IgG titer (1:200 or more) of antibody to Phase I antigen. In our patient the echocardiographic appearance of aortic valve vegetation and the isolation of C. burnetii from the resected aortic value confirmed the diagnosis.
The true incidence of glomerulonephritis in the course of chronic Q fever is unknown. Microhematuria has been often documented although its glomerular origin is usually unconfirmed.9 All previous series reported were in adults, few patient have presented either laboratory (heavy proteinuria, red blood cell casts) or histologic evidence of glomerular injury. Only Uff and Evans10 successfully attempted specific diagnostic techniques, confirming that the IgM eluted from this patient's blood showed specificity against C. burnetii.
Renal biopsy was made late in the course of infection in our patient. There were histologic signs suggestive of active glomerulonephritis on optical microscopy (proliferative changes) and immunofluorescent study (diffuse IgM, C3 and circulating immune complex deposits at the glomerular level). A renal specimen was negative for C. burnetii. The histologic lesions of glomerulonephritis associated with infective endocarditis are usually reversible with cure of the infection. However, sometimes renal injury continues and even progresses after apparent cure of infective endocarditis.9, 10
Q fever endocarditis requires prolonged therapy with antibiotics. Although various regimens have been proposed, tetracycline is the mainstay of treatment. Rifampin combined with either doxycycline or trimethoprim-sulfamethoxazole has been reported to be effective.11 The ideal duration of treatment is difficult to define given that no criteria for cure have been proposed at this time; suggestions range from 1 year to indefinite administration.12 Valve replacement is also frequently necessary for hemodynamic reasons. Our patient showed significant improvement after valve replacement and the combination of rifampin and tetracycline treatment. He was seen in the outpatient clinic 3, 6 and 9 months after discharge. His cardiac condition was stable with no recurrence of vegetation, renal and liver function improved and he was gaining weight.
The present case shows that chronic Q fever in children can present with most of the clinical manifestation described in adults, including endocarditis and glomerulonephritis. Q fever endocarditis should be considered in evaluating any case of culture-negative endocarditis in children, particularly in areas of high prevalence or when there is a previous history of raw milk ingestion.
Sami Al-Hajjar, M.D.
S. M. Hussain Qadri, Ph.D.
Essam Al-Sabban, M.D.
Cornelie Jäger, M.D.
Departments of Pediatrics (SAH, EAS) and Pathology (SAH, SMHQ)
King Faisal Specialist Hospital and Research Center
Riyadh, Saudi Arabia
Institut für Hygiene and Infektions Krankheiten de Tiere
Justus Liebig Universität
Giessen, Germany (CJ)
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