A 60 year old woman was admitted in the Department of Internal Medicine because of a 15 day history of intermittent fever of 38  C, aching pain over the forehead and fatigue. She reported no rigors, arthralgias, nausea, vomiting rash, postnasal drip, cough, diarrhea, urinary symptoms and any other pain or weight loss.
At the onset of fever, she had been referred to another clinic where she was thought to suffer from some infection. White blood cell count was 11,500/mul, ESR 50 mm/h and CRP 7 mg/dl (normal value <0.5 mg/dl). However, blood and urine cultures were sterile, CT imaging of the brain, sinus, chest and abdomen-pelvis showed no sites of infection and transthoracic echocardiography was normal. Her fever resolved without antibiotics, and after her discharge on the fifth hospital day she stayed afebrile for a further 5 days before her symptoms recurred.
The patient had no other medical history. She mentioned trekking as a hobby and had been on vacation to Cyprus 2 months earlier. She had no known allergies, had never smoked and had no recent exposure to ill persons.
When she presented to our Department, clinical examination confirmed temperature of 38.2  C while all other vital signs were normal. There was no neck stiffness and the remainder of the neurologic examination was normal. Chest was clear on auscultation but she had a 2/6 systolic murmur at the mitral area which was not present at her previous hospitalization. There were no hepatosplenomegaly, lymphadenopathy, abdominal tenderness or masses. She had no skin lesions and temporal arteries were clinically normal bilaterally.
Laboratory analysis revealed raised ESR (100 mm/h) and CRP (17 mg/dl - normal value <0.5). White cell count was 10,000 mm3 with 72% neutrophils and 21% lymphocytes. Hemoglobin was 12 g/dl and platelet count 200,000/mm3. Electrolytes, total protein, albumin, globulin, uric acid and LDH were normal, as were tests of coagulation, renal and liver function.
Six sets of blood cultures were obtained from different sites at the peak of fever and when she was afebrile, and trans-esophageal echocardiography (TEE) was performed on suspicion of infective endocarditis. Blood cultures were all sterile, however TEE showed a small mitral lesion which resembled vegetation. No abnormality or serious regurgitation of the valve was noticed.
These findings were considered indicative of blood culture negative infective endocarditis. Treatment with intravenous ceftriaxone 2 g was administered focusing on the HACEK group of bacteria. Further diagnostic tests were pursued for fastidious organisms including brucella agglutinin tests (Wright, Wright Coombs), serologic tests for C. burnetii, Bartonella, Chlamydia, Mycoplasma, as well PCR for Tropheryma whippelii. Prolonged incubation of the blood cultures was requested to address the possibilities of HACEK pathogens, and nutritionally deficient streptococci (Abiotrophia defective, Granulicatella). The LightCycler SeptiFast test was also performed to detect, as a multiplex real-time PCR assay, possible bacteria or fungi causing bloodstream infection.
All tests were negative except for the screening test for C. burnetii. An IgG anti-phase II antibody titer of 1/1024 and an IgM anti-phase II antibody titer of 1/64 were detected. Anti-phase I antibodies were IgG 1/256 whereas IgM as well as PCR were found negative (National Reference Center of Parasitology Zoonoses and Geographical Medicine in Heraklion-Crete). These results were strongly indicative of acute Q fever. It is established in the literature that endocarditis is the major clinical manifestation of chronic Q fever. As a result, our first estimation of endocarditis based on the TEE findings and the diagnosis of acute Q fever were contradictory. Considering the febrile course and positive serology, treatment was changed from ceftriaxone to doxycycline 100 mg bid plus hydroxychloroquine 600 mg daily, in case of evolution to chronic Q fever. After 7 days of treatment, the fever persisted. Even more, the patient presented with more frequent and higher peaks of fever up to 38.5  C which did not respond to regular non-steroidal anti-inflammatory drugs. The patient appeared unwell and laboratory analysis revealed a further rise of inflammatory markers (ESR: 120 mm/h and CRP: 22 mg/ml) and worsening anemia of chronic disease. Renal and liver function remained normal. A second TEE showed the same mitral valve lesion. Therefore, further work-up was performed.
Serum ferritin level was 400 ng/ml (normal range 10-291 ng/ml), not markedly raised to suggest adult-onset Still's disease. PCR assay for CMV was negative as was the serologic test for HIV and the quantiferon test as evidence of latent tuberculosis. The AgK39 for leishmaniasis was also negative. Temporal artery biopsy was normal and bone marrow analysis revealed a reactive marrow with no signs of infiltration or granuloma. Endoscopy of the gastrointestinal tract and biopsies did not suggest inflammatory bowel disease. Investigations for the possibility of a systemic autoimmune disease were requested: serum complement levels were normal; antinuclear antibodies were borderline weak positive at 1/80, anti-dsDNA, ANCA, RF Factor and all other autoantibodies were negative, with the exception of IgM anticardiolipin antibodies and the anti beta2 GPI IgM antibodies, which were twice the normal values.
The patient's constitutional symptoms, valvular involvement, raised inflammatory markers and some positive autoantibodies suggested the possibility of a non infectious systemic inflammatory process. FDG-PET/CT scan was requested, which revealed increased uptake of FDG (indicating any kind of inflammation) in the ascending aorta, aortic arch and thoracic descending aorta, strongly suggestive of the presence of a large vessel vasculitis/aortitis (Fig. 1). We concluded that our patient was suffering from acute Q fever, complicated by aortitis. Treatment with intravenous methylprednisolone, 1 g daily for 3 days was initiated. The patient became afebrile within 24 h, inflammatory markers returned to normal and her general status improved markedly and rapidly. Serological follow up, 21 days after the first screening, confirmed the diagnosis of acute Q fever. An IgG anti-phase II antibody titer of 1/512 and an IgM anti-phase II antibody titer of 1/128 were detected, whereas an IgG anti-phase I antibody was only 1/256 (Table 1). The patient recovered and she was discharged from hospital on 15 mg of methotrexate once a week, 32 mg of methylprednisolone per day to be tapered, 200 mg of doxycycline and 600 mg of hydroxychloroquine daily, for at least 1 year.