The incidence of infective endocarditis (IE), an infection of the heart endothelium, ranges between 5 to 7.9 cases per 100,000 individuals per year in the United States.1 If not diagnosed and treated promptly, organisms causing IE can damage or destroy heart valves leading to life-threatening complications and mortality. Diagnosis is challenging without a high index of suspicion based on patient history and presentation traditionally followed by blood cultures, imaging, serological, and molecular studies. A notable number of IE cases have been caused by fastidious, culture-negative organisms including Bartonella spp. Communication with laboratory staff regarding the physician’s suspected diagnosis along with the use of molecular testing can maximize the number of confirmed cases of Bartonella.
This case describes an immunocompetent, well-developed, and alert adult male with a history of progressive weakness, persistent fever at 39oC max, shortness of breath, abdominal pain, weight loss, fatigue, painless hematuria, and anemia — symptoms compatible with subacute native valve endocarditis.2 The patient had a history of hypertension and hypercholesterolemia but denies any preexisting heart or lung disease. Maternal family history was positive for heart disease. Physical examination of his abdomen was remarkable for left upper quadrant/flank area tenderness and splenomegaly with a wedge infarct confirmed by computed tomography (CT). An upper gastrointestinal endoscopy and colonoscopy were unremarkable and therefore an unlikely cause of anemia. Microscopic review of bone marrow showed no pathological findings.
Baseline studies included an elevated erythrocyte sedimentation rate of 61 mm/hour and complete blood count (hemoglobin 8.5 g/dL and hematocrit 25.1%) and differential blood count within normal limits. Blood cultures incubated for five days at 35o C and urine culture showed no growth. Urinalysis showed moderate blood and nineteen red blood cells per high power field. Serology tests were negative for syphilis, EBV, hepatitis B and C, leptospirosis, autoimmunity, and Lyme disease. Indirect immunofluorescent antibody (IFA) tests were positive for Bartonella henselae IgG >1:512 (reference negative < 1:64) and IgM negative (reference negative <1:20); Bartonella quintana was IgG negative (reference negative <1:64) and IgM negative 1:80 (reference negative <20) by.
A transesophageal echocardiogram (TEE) showed evidence of a highly mobile vegetation on the left cusp of the aortic valve associated with moderate-to-severe regurgitation consistent with infective endocarditis (IE). The patient was scheduled for an aortic value replacement with a mechanical valve prosthesis. At surgery, the patient’s valve showed evidence of granulation tissue and associated inflammation consistent with IE. The left coronary flap (cusp) was damaged and found to have a large vegetation that was excised and sent to the laboratory for histopathology and culture. The immunohistochemical analysis, modified Warthin-Starry silver-stained sample and conventional bacterial culture were negative. Remaining paraffin-embedded tissue was sent for a polymerase chain reaction (PCR) test designed to differentiate the most common species of Bartonella. Post-amplification melt curve analysis of the PCR product confirmed the presence of B. henselae.
Infective endocarditis occurs when organisms attach to one or more heart valves or endocardial tissue and cause infection. If not treated promptly, these organisms can damage or destroy heart valves leading to life-threatening complications. There are at least 45 Bartonella spp. with worldwide distribution, 13 proven or likely to be human pathogens.2 Although Staphylococcus aureus, coagulase-negative staphylococcus, viridans streptococci, and enterococci are common causes of IE, other fastidious organisms including Bartonella quintana and Bartonella henselae cause a small but notable number of IE cases.
Members of the genus Bartonella (formerly Rochalimaea) characteristically are small, fastidious, aerobic intracellular Gram-negative bacilli targeting RBCs and endothelial cells of blood and lymphatic vessels. B. quintana causes trench fever primarily in homeless persons and chronic alcoholics infested with human body lice that serve as a reservoir and vector for the pathogen. In contrast, B. henselae is well known as the causative agent of cat scratch disease (CSD) due to exposure through a cat lick, scratch, bite, or arthropod vector, the cat flea. However, the patient did not have a history of valvular disease, nor did he report a cat exposure. The major risk factors for B. henselae IE include preexisting valvular disease and contact with cats, an asymptomatic zoonotic reservoir with chronic bacteremia.
To establish a diagnosis of IE, the Modified Duke Criteria were used, based on pathological and clinical major and minor criteria.3,4 This patient had two major criteria (vegetation and regurgitation plus endocardial involvement confirmed by surgery) and one minor criteria (fever >=38o C) meeting the criteria for an active infection causing IE. The role of the laboratory is paramount in determining the offending agent since patients infected with other organisms known to cause IE can exhibit similar clinical manifestations.2 At least 2–3 blood culture sets from separate venipunctures with a maximum recommended blood volume per bottle and serology tests for IgG and IgM antibodies directed against the suspected agent should be included in the initial battery of tests. In addition, excised valvular tissue taken during surgery should be submitted for histopathology examination and culture.
Although Bartonella species can grow on cell-free media containing heme at 35–37oC with 5% supplemental CO2, e.g., chocolate agar, they may take at least 2–3 weeks to grow.2,3 By default, approximately 20% of cultures are positive due to the fastidious nature of Bartonella, lack of communication in alerting the laboratory of the suspected diagnosis, or empiric antibiotic therapy prior to culture.2,5,6
The IFA, considered a reference method for supporting a diagnosis of Bartonella, was positive for B. henselae IgG >1:512. Although B. quintana IgG was negative, the significance of a positive IgM 1:80 is unknown. That said, cross-reactive antibodies do occur between B. hensalae and B. quintana, as well as between Bartonella spp. and Chlamydia spp. and Coxiella burnetii that cause IE.3,5,6 Another serological test, Western blotting has been used to confirm a diagnosis of Bartonella for patients with a negative Bartonella IFA but positive PCR and clinical findings.7 B. henselae IE can also masquerade as small vessel vasculitis (SVV) with a similar presentation, e.g., fever, fatigue, renal and valvular involvement. If suspected, B. henselae IE may be differentiated from SVV by low complement 3 and antineutrophil cytoplasmic antibodies (ANCA).8 Echocardiography plays a key role in identifying patients who have negative blood cultures but present with signs and symptoms of IE and require surgery and valve replacement. When a valve is damaged, blood leaks back into the left ventricle, causes regurgitation, prevents the heart from efficiently pumping blood to the rest of the body, and results in fatigue and shortness of breath as seen in this patient. Although the use of platelet lymphocyte ratios have shown prognostic value in cardiovascular conditions, there is limited data regarding its predictive role in patients with IE.
Since laboratory diagnosis of Bartonella IE using traditional culture techniques remains challenging, post-amplification melt curve analysis of the PCR product from infected tissue was used to confirm the presence of B. henselae. Other methods that have been used include serum PCR since this sample is often readily available and a riboflavin synthase-encoding ribC gene along with a one-step procedure to prevent amplicon carryover and a thermal cycler to differentiate Bartonella species and shorten the delay in diagnosis before valvular surgery.9 Even though there are no in vitro antibiotic susceptibility test breakpoints because of the fastidious nature of Bartonella, knowing the etiology provided direction in selecting optimal therapy with IV vancomycin, ceftriaxone and gentamicin, metoprolol beta-blocker, and warfarin anticoagulant for this patient.2,3
A literature search of publications over the past 10 years suggests that there has been a significant increase in the number of cases of IE caused by B. henselae. This increase may reflect an improved recognition of Bartonella causing IE and the use of molecular tests with greater sensitivity and specificity in identifying Bartonella. Clinicians in turn may be more enthusiastic in ordering tests that provide more timely and reliable results for successful patient outcomes.6 Of note, improvements in diagnosis, management, and treatment of patients with IE have also been attributed to the use of early interventions with a multidisciplinary team including specialists in cardiology, infectious diseases, imaging, surgery, and improved communication with laboratory staff regarding their suspected diagnosis to maximize the number of confirmed cases of Bartonella.10
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7. Edouard S, Nabet C, Lepidi H, Fournier PE, Raoult D. Bartonella, a common cause of endocarditis: a report on 106 cases and review. J Clin Microbiol. 2015;53(3):824-9. doi:10.1128/JCM.02827-14.
8. Paudyal S, Kleven DT, Oliver AM. Bartonella Henselae endocarditis mimicking ANCA associated vasculitis. Case Rep Intern Med. 2016;3(2). doi:10.5430/crim.v3n2p29.
9. Zeaiter Z, Fournier PE, Greub G, Raoult D. Diagnosis of Bartonella endocarditis by a real-time nested PCR assay using serum. J Clin Microbiol. 2003;41(3):919-25. doi:10.1128/JCM.41.3.919-925.2003.
10. Davierwala PM, Marin-Cuartas M, Misfeld M, Borger MA. The value of an “Endocarditis Team.” Ann Cardiothor Surg. 2019;8(6):621-629. doi:10.21037/acs.2019.09.03.
Acknowledgement: The authors would like to thank Dr. Gary Procop, MD, MS, FCAP Chief Executive Officer of the American Board of Pathology and former Medical Director in Clinical Microbiology, Molecular Microbiology, Virology, Mycology, Parasitology, and Infectious Disease Pathologist at Cleveland Clinic, for kindly providing his help and expert advice in confirming the molecular diagnosis for this case.