Blood CultureNegative Endocarditis

Reported blood culture-negative endocarditis (BCNE) rates have historically varied by study population, ranging from 2.5% to 31% [24]. These rates are still consistent among recent studies conducted in Spain (13.7%) [25], London (12.2%), and Sweden (20%) [26]. A recent review of 26 case series published between 1993 and 2003 showed BCNE rates of about 10% [3]. These rates are likely artificially high because of preceding antibiotic therapy. This effect was quantified in a retrospective review of 107 definite IE cases at a center in

Spain, in which 14/20 patients with negative blood cultures had received prior antibiotics, leaving 6/107 (5.6%) with BCNE [27]. Thus, excluding the cases confounded by antibiotic therapy prior to blood cultures, the frequency of "true" culture-negative endocarditis is much less, likely around 5%.

By definition, standard culture methods are inadequate to allow detection of the causative agents of BCNE. The largest study to address the etiology of BCNE, published by Houpikian and Raoult, involved 348 patients with suspected BCNE in France [28]. The authors attempted to determine the causative organism using a comprehensive serology panel, shell vial cultures and analysis of valve specimens by multiple methods, including PCR. These investigations showed that 167 cases (48%) were due to Coxiella burnetti, 99 (28%) due to Bartonella spp., 5 (1%) due to rare fastidious organisms, and 73 (21%) without an identified cause. Of the 73 undiagnosed cases, 58 had received antibiotics before the blood cultures, leaving only 15 (4.3%) unexplained cases.

Coxiella burnetti is reported to cause 3-5% of all endocarditis in France, Israel, and Great Britiain [16]. Underlying heart disease, immunocompromising conditions and animal contact are the major risk factors. Houpikian and Raoult's review of BCNE in France included 167 cases of Q fever IE [28]. Of these, 53 patients (35%) had underlying immunodeficiency and 139 (91%) had valvular disease, including 27 with prosthetic valves, and 70% had a history of contact with domestic animals. Reported outcomes of C. burnetti IE were previously poor with nearly two-thirds of patients developing congestive heart failure (CHF), but in this cohort only 38% developed CHF and mortality was only 3% (4/150). This improvement likely reflects better and more rapid diagnostics and more timely treatment.

Bartonella spp. are reported to cause 3% of all endocarditis [16]. In a recent review of Bartonella endocarditis, 75% of identified cases were caused by B. quintana and 25% by B. henselae [29]. Epidemiology was distinct for the two species, with B. quintana seen in patients who were homeless or alcoholic with exposure to body lice, and B. henselae in individuals with a history of exposure to cats.

Trophyrema whipplei, the Whipple disease bacterium, is an emerging cause of culture-negative endocarditis. In a review of 35 cases published in 2001, the disease was predominant in men, occurring on previously healthy valves in 88%, with a mortality rate of 57% (20 of 35 cases) [30].

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