q fever is caused by the small gram - negative intracellular bacterium , coxiella burnetii .
it is rare and there are approximately 40 cases reported annually in the united states .
chronic q fever is also rare , occurring in < 5% of persons with acute infection and most commonly occurs as infective endocarditis ( ie ) or vascular infection .
we present a 52-year - old woman from michigan with chronic q fever presenting as prosthetic aortic valve infective endocarditis .
pcr testing for bacterial organisms performed on the explanted cardiac valve tissue confirmed the diagnosis of c. burnetii ie .
subsequent history identified consumption of raw milk from a shared cow in a local farm as the likely source of the pathogen .
a 52-year - old caucasian woman , who is an educator from kalamazoo , michigan , was referred to the cleveland clinic with a chief complaint of fever , chills , and progressive dyspnea on exertion of several months duration .
her fever , chills , and night sweats were more prominent in the last two weeks prior to evaluation .
she also complained of abdominal pain which had increased markedly in the last one month associated with nausea and non - bloody , non - bilious vomiting with reduced oral intake and involuntary weight loss of 25 pounds over this period .
she has rheumatoid arthritis ( ra ) and has been taking etanercept for the last 15 years .
she underwent an aortic valve replacement due to aortic regurgitation 12 years prior to presentation at our institution .
she denied exposure to sick contacts , invasive dental procedures , intravenous drug use , tick bites or recent travel .
she had a blood pressure of 104/57  mmhg and was tachycardic with a pulse rate of 135  bpm .
on cardiovascular exam , there was a 3/6 diastolic murmur appreciated in the left sternal area with the presence of normal s1 and s2 .
there was a well - healed median sternotomy scar from her prior open heart surgery . on abdominal examination ,
the spleen was palpable at 23  cm from the costal margin with tenderness to deep palpation in the left upper quadrant .
during the course of admission , laboratory tests showed a normocytic normochromic anemia with hemoglobin of 8.4  g / dl ( reference range 12.115.1  g / dl ) and a normal white blood cell count of 6.81  k/l ( reference range 4.511.0  k/l ) .
her splenomegaly was initially thought to be neoplastic or rheumatologic in etiology and thus she was referred for a bone marrow biopsy .
pathologic review of her bone marrow specimen revealed a hypercellular marrow but no clonal process or ring granulomas were identified .
a single blood culture ( one of the four ) was positive for growth of coagulase - negative staphylococcus .
this result prompted a transthoracic echocardiogram ( tte ) which was followed by a transesophageal echocardiogram ( tee ) given high clinical suspicion for ie .
these tests showed moderate ( 23 + ) prosthetic aortic regurgitation and an aortic root abscess .
she was started empirically on vancomycin and ceftriaxone and was scheduled for open heart surgery .
the patient underwent aortic valve and root replacement with a 22-mm aortic homograft on day 3 of admission .
pathologic examination of the surgical specimen showed abundant fibrinous exudate with mild inflammation , mostly macrophages .
a gomori 's methenamine silver stain demonstrated intracellular and extracellular small coccobacillary organisms ( fig .
1 ) , but no microorganisms were apparent on the gram and periodic acid - schiff stain .
16s rdna sequencing of the valves came back positive for c. burnetii on post - operative day 10 .
further retrospective history taking from the patient revealed that she had imbibed unpasteurized cow milk two years previously for a period of 2 months via cow sharing at a local farm in michigan . c. burnetii titers were consistent with chronic q fever ( high titers to igg phase 1 titers ) ( table 1 ) .
she was treated with oral doxycycline ( 100  mg orally twice daily ) and hydroxychloroquine ( 200  mg three times daily ) after checking for glucose-6-phosphate dehydrogenase deficiency . at six months
follow up , she has recovered with normal ophthalmologic evaluations ( to assess for retinal toxicity ) with plans to complete 18 months of treatment .
q fever is a zoonotic rickettsiosis caused by c. burnetii that is uncommon in the united states with approximately 40 cases reported annually .
it presents as an either acute or chronic infection and is manifested as a nonspecific flu - like illness in most patients .
the chronic form of infection presents as an endovascular infection causing endocarditis , mycotic aneurysm , or infected vascular graft .
15% of acute q fever and up to 6080% of chronic cases can develop endocarditis .
the largest documented outbreak of q fever occurred in the netherlands from 2007 to 2010 where more than 4000 cases were identified .
the etiology of this outbreak was felt to be increased contact between goat farms and high - population density areas .
aerosol transmission of bacteria from parturient animals and contact with bodily fluids of infected animals are the primary modes of transmission .
oral consumption of raw milk is considered a risk factor for transmission , but until recently was felt to play a minor role .
raw milk consumption has been associated with seroconversion but there was insufficient evidence of it causing clinical infection .
coxiella spores are extremely infectious and resistant to heat which emphasizes the need for pasteurization to effectively kill this species in milk products .
pasteurization for 30  min at 63  c ( 145  f ) or 15  s at 72  c ( 161  f ) can lead to eight decimal reductions in the number of coxiella spores .
a recent outbreak in michigan , where 5 cases were detected over a three month period in 2011 , has been reported where the only predisposing condition common to all infections was consumption of unpasteurized milk .
such consumption is common in farm workers , cow share owners , or those buying milk from bulk tanks . in a french study of 92 patients with chronic q fever between 1982 and 1990 ,
the risk factors for infection include immunosuppression ( 20.2% ) , preexisting heart or vascular conditions ( 88.4% ) and preexisting valvulopathy ( 88% ) .
prosthetic valves are associated with increased relative risk compared to the other factors for acquiring endocarditis amongst the chronic q fever patients .
tumor necrosis factor ( tnf ) plays an important role in the immune response against this pathogen .
experiments using an animal model consisting of knockout mice found that there was severe and fatal chronic q fever in severe combined immunodeficiency ( scid ) mice .
the artificial immunosuppression of mice in these studies have led to postulation that administration of tnf blockers may put patients at greater risk for chronic q fever .
one case has been reported of a ra patient on etanercept who did not have any acute phase of illness and was diagnosed after valve cultures obtained at the time of open heart surgery came back positive .
given its mechanism of tnf inhibition , cytokine production by the macrophages and lymphocytes is decreased .
since ra patients on immunotherapy are considered at increased risk of chronic infection , they need to be carefully monitored and counseled about decreasing risk of exposure .
the main symptoms of q fever endocarditis are fever , fatigue , weight loss , night sweats , and hepatosplenomegaly .
a study from france which included 92 patients with chronic q fever revealed anemia ( 60% of cases ) , increased erythrocyte sedimentation rate ( 100% of cases ) , and thrombocytopenia ( 50% of cases ) .
phase 1 is the virulent form with phase 2 being the avirulent form which is demonstrated by serial passage in cell culture or embryonated hen eggs .
only phase 1 organisms affect humans but antibodies are formed for both phases which are detected using serology .
development of antibodies only occurs to the phase 2 antigen in the acute form of infection .
chronic q fever is established if infection persists for more than 6 months and there is a presence of igg and iga to phase 1 and phase 2 antigens .
the presence of igg phase 1 titer > 1:800 along with iga phase 1 titer of > 1:25 is considered for the diagnosis of chronic disease .
hence the use of serologic titers in distinguishing the stage of disease or outcome is problematic .
shortcomings of serologic testing and culture as well as prolonged turn around times for these tests highlights the potential benefit of pcr on pathologic specimens , .
histologic examinations of infected cardiac valves show calcification , fibrosis , and typically pauci - inflammatory changes with very small or absent vegetations .
the usual medical treatment of chronic q fever is doxycycline and hydroxychloroquine for a period of 24 and 18 months in cases of prosthetic valve and native valve endocarditis , respectively .
hydroxychloroquine is lysosomotropic which increases the ph of the phagolysosomes , thus decreasing bacterial replication .
cotrimoxazole is an alternative used in pregnancy and for children below 8 years of age .
rifampicin , quinolones and macrolides are not as effective and there is limited evidence for their usage as alternative regimens .
treatment and serologic follow - up are controversial with most experts agreeing that monitoring for up to five years may be appropriate .
 chronic q fever caused by coxiella burnetii is uncommon in the united states and is most often associated with infective endocarditis . 
 we present a 52-year - old woman with a history of aortic valve replacement and rheumatoid arthritis treated with etanercept with chronic q fever manifesting as prosthetic valve infective endocarditis . 
 explanted valve tissue showed organisms confirmed to be c. burnetii by pcr ( polymerase chain reaction ) sequencing . 
 she subsequently reported consumption of unpasteurized cow milk which was the likely source of c. burnetii . 
 she continues to do well 6 months after valve replacement on oral doxycycline and hydroxychloroquine . 
Introduction
Clinical history
Discussion
Conflicts of interest