The most prevalent pathogen among these uncommon causes of culture-negative IE in this group has varied glob- ally according to published data.236 Incidence data from population-based surveys for IE caused by these organisms are lacking in the United States. In PVE cases, the timing of infection onset can also be important in defining pathogens.235 Limitations such as referral bias and sampling bias may have affected the findings.235 237 Results of a large prospective analysis of referred samples from culture-negative IE performed by a well-recognized reference laboratory deserve additional comment.236 First, there was identification of a pathogen in 62.7% of 759 cases; in 2.5%, a noninfectious origin (see below) was confirmed. Second, serological results were positive in 47.7% of cases, primarily for Coxiella and Bartonella species infection. Third, PCR identified a pathogen in two thirds of the valves studied. Fourth, no cause was defined in 35% of cases. Treatment of the wide variety of microorganisms that cause culture-negative IE without prior antibiotic exposure has been described anecdotally, and regimens of choice are based on limited data and can be found in other publications. Noninfectious causes of valvular vegetations can produce a syndrome similar to culture-negative IE. Perhaps the one that has received the most attention is anti-phospholipid anti- body (APA) syndrome,238 which has been described as both a primary and a secondary syndrome and is associated with the presence of APA. In its secondary form, the APA syndrome has been linked to autoimmune disorders, particularly sys- temic lupus erythematosus, and malignancies. Sterile valvular vegetations form and embolize, clinically mimicking in many respects culture-negative IE. The mitral valve is most often affected, and valvular regurgitation is the predominant func- tional abnormality seen in APA syndrome with complicating valvular involvement. 