Scratching Beneath the Surface

The mitral valve aneurysm, abscesses, and heart failure warranted valve replacement. Surgery should be considered for all patients with Bartonella IE, primarily because delayed diagnosis often leads to irreversible valve damage. Ideally, surgically explanted tissue should be divided into 2 portions: half should be sent to pathology and stained with H&E, Warthin-Starry, and Steiner staining procedures, while the other half should be sent for culture, and then PCR if stains are negative.

His symptoms are compatible with subacute IE, which is typically more difficult to diagnose than acute IE due to its insidious onset. He meets criteria for blood culture negative IE based on 3 sets of negative blood cultures for greater than 5 days and major criteria for IE. The pathologic changes are consistent with B. henselae infection.

The incidence of IE in the United States is 40,000 cases per year¹ with an in-hospital mortality of 15%-20% and a 1-year mortality of up to 40%.^2,3 Five to 20% of patients with IE never develop positive blood cultures⁴ due to receipt of antibiotics prior to culture, inadequate microbiologic testing, or infection caused by noncultivable bacteria (eg, Tropheryma whipplei), fastidious extracellular bacteria (eg, HACEK group and nutritionally variant streptococci), or by intracellular pathogens with complex nutrient requirements (eg, Bartonella, Chlamydia, Brucella, or Coxiella). Previous administration of antibiotics reduces the likelihood of isolating an organism by 35%-40%.⁵ Patients meeting criteria for BCNE should prompt consideration of serologic testing. The most prevalent pathogens vary globally, and incidence data in the US is scarce. Worldwide, the majority of BCNE cases are caused by Coxiella, Bartonella, and Brucella species.^6,7

When clinical suspicion for IE remains high despite negative cultures, detailed history can uncover clues and guide additional testing. For example, contact with contaminated milk products or farm animals are associated with Brucella, Coxiella, and Erysipelothrix species IE.^7,8 Bartonella species are zoonotic gram-negative bacilli with a tropism for endothelial cells and are transmitted by arthropod vectors (ie, fleas, lice, ticks, and sandflies), cat scratches, or cat bites. Bartonella may account for 3%-4% of all cases of IE, most of which are due to B. henselae and B. quintana.^{7, 9} Underlying heart valve disease, alcoholism, cirrhosis, and homelessness are associated with B. henselae endocarditis.¹⁰

Diagnostic criteria are lacking for B. henselae IE, and the modified Duke criteria is of limited utility for diagnosing Bartonella IE because blood cultures are often negative and echocardiographic evidence of vegetation is not always apparent. Serology plays a critical role in the diagnosis of Bartonella infections. The addition of positive serology, Western blot or PCR for B. henselae and B. quintana as a major criterion in the modified Duke criteria for IE has been proposed but has not yet been formally accepted.⁹ For B. henselae IE, an IgG titer of ≥1:800 has been recommended as a cutoff for subacute IE because it combines a high specificity and positive predictive value along with reasonable sensitivity and negative predictive value in this situation.⁹ The humoral immune response rises over time, and thus acute IE due to Bartonella may not generate a substantial IgG titer. Interestingly, because of the indolent nature of this pathogen, most cases of IE present once IgG titers have begun to rise. Serum PCR testing has shown a sensitivity and specificity of 58% and 100%, respectively.¹¹ Isolation by blood culture requires specific growth media and prolonged incubation, with a sensitivity as low as 20% and 30% for blood and tissue, respectively.¹⁰ The microbiology laboratory should be notified of suspected Bartonella to intensify efforts to cultivate this organism. If infection with Coxiella or Brucella is suspected, the lab should also be informed, both to increase diagnostic yield and to trigger enhanced biosafety precautions when handling the specimens. Despite attempts to optimize the yield, up to 75% of Bartonella IE may remain culture negative,^12,13 making it difficult to meet the current major modified Duke criterion of positive blood cultures. H&E staining of valve tissue infected with Bartonella commonly reveals increased inflammation, fibrosis, and calcified granulomas relative to endocarditis from other causes.¹⁴ The Warthin-Starry silver stain can identify small, darkly staining bacteria in more than 75% of Bartonella endocarditis; however, this stain is not specific for Bartonella species.⁹

This case highlights the challenge of diagnosing subacute IE because this patient received antibiotics and steroids prior to presentation, clouding the clinical picture. Although he did not exhibit textbook signs of endocarditis, his symptoms (new onset heart failure and new regurgitant murmurs) prioritized the diagnosis. The combination of elevated serum titers, positive PCR, valve granulomas and abscesses on TEE, and pathology findings led the discussant to the correct diagnosis. Scratching beneath the surface revealed his penchant for cats, but this was only considered a key epidemiological feature later in his clinical course.