Case 1

A 57-year-old male patient, with a past medical history of chronic renal failure (CRF) stage 3, tobacco smoking, and alcohol and drug abuse (cannabis and cocaine pasta base),was initially hospitalized during April 2017 by weight loss, gastrointestinal bleeding, epistaxis, gross hematuria, pancytopenia (hemoglobin 7.8 g/dL, WBC count 3,980/µL; platelets count 14,000 µL), and hypoalbuminemia. A mild midsystolic murmur was registered. He received a short course of ceftriaxone and clindamycin, did not require transfusions and was discharged after being stabilized. No blood cultures were taken, and murmur was attributed to anemia. He was readmitted one month later with effort dyspnea, cough with hemoptoic sputum but without fever.

Exams revealed the persistence of macrocytic anemia, thrombocytopenia, and appearance of microscopic hematuria with dysmorphic red blood cells (100%). CT imaging detected bilateral pleural effusion and fluid analysis showed a transudate. Erythrocyte sedimentation rate (ESR) was 66 mm/h. Microbiological analysis from a bronchoalveolar lavage discarded tuberculosis and fungal infections. A bone marrow examination discarded a lymphoproliferative disorder. Not a definitive diagnosis was reached and was discharged with vitamin B12-folic acid therapy and follow-up controls. After three weeks, he was readmitted, with constipation, lower limb edema, hemoptysis, abdominal pain due to hepatomegaly and Janeway lesions. Pancytopenia persisted, and a direct Coombs test was positive. Bilateral pleural effusion and cardiomegaly was detected by chest-x-ray. A transthoracic echocardiogram (TTE) indicated global contractile dysfunction (ejection fraction 35%) and a degenerative aortic valve disease with two vegetations.

After blood cultures, empirical treatment with ceftriaxone and ampicillin was initiated as part of the global management of his heart failure. He evolved with hypotension, fever, tachypnea, and persistent heart failure being transferred to the ICU where he received vasoactive drugs and non-invasive mechanical ventilation. As blood cultures were negative, serological studies forBartonella spwere requested and resulted positive at high titers forB. henselaeandB. quintana(IFA IgG 1/16,384 - 1/16,384). History of contact with a domestic cat was obtained (Table 1). Doxycycline (100 mg oral route BID) was added to therapy. A follow-up echocardiography revealed a phlegmonous aortic valve with an abscess on the aortic valve, and azithromycin was added as salvage therapy. He was referred to another hospital where he underwent a mechanical aortic valve replacement. A tissue sample was obtained during surgery for PCR amplification of the 16s ribosomal DNA followed by sequencing. Results indicated the presence ofB. quintanain the valve tissue sample. He evolved satisfactorily but remained with severe myocardial dysfunction (left ventricle ejection fraction 22%). This case was defined as a definitive endocarditis (Table 1). The patient had a low socioeconomic status according to health insurance information. HIV test was negative.

Case 2

A 67-year-old male patient with heavy alcohol consumption was admitted on June 2019 by a cerebrovascular accident with left hemiparesis and effort dyspnea in the preceding three months. He was conscious, had fever (37.5°C) and no arrhythmia. There was not past history of smoking or obesity. Laboratory evaluation showed mild anemia (hemoglobin 13.1 g/dL) without leukocytosis and an elevated ESR (61 mm/h). Total cholesterol and triglycerides were normal. Brain tomography indicated a right frontoparietal hypodensity suggesting a right posterior frontal infarction. (Figure 1A). Due to a mild increase in hemiparesis, a new brain CT obtained at 72 h showed a hemorrhagic zone in the infarcted area (Figure 1B). A new holosystolic mitral murmur was detected, and IE was suspected.

Figure 1 A: CT brain image without contrast media taken at admission. A front-parietal infarction is signaled by a white arrow. B: Image taken 3 days later showing a hyperdense zone inside the infarction zone, indicating a hemorrhagic transformation (white arrow). 1C. A late intracerebral hemorrhage occurring after near 1 month. Hemorrhage is associated with midline displacement. 

No dental procedures, urinary, intestinal or skin disorders were detected. Blood cultures remained negative, and empirical treatment with cloxacillin, ampicillin and gentamicin was started. Additional exams showed microhematuria (5-10 per high power field) of dysmorphic predominance (90%), hypocomplementemia (C3 81.2 mg/dL [Normal Value 90-180 mg/dL]; C4 4.2 mg/dL [Normal value 10-40 mg/dL]), and an elevated rheumatoid factor (102 UI/mL; [Normal value 0-14 UI/mL]). After antibiotic treatment started, fever disappeared, ESR decreased to 38 mm/h, and the patient remained stable. A TTE indicated a mitral degenerative valve disease with no vegetations or abscesses, but a transesophageal echocardiogram (TEE) showed a mitral valve tendinous cord rupture with moderate insufficiency and vegetations. Serologic studies for B. henselae revealed a high positive IgG IFA positive result (1/32,768) that was cross-reactive with B. quintana at one lower dilution (1/16,384). Treatment was changed to doxycycline 100 mg BID, rifampin 300 mg BID both by the oral route, maintaining iv gentamicin. An attempt to amplify gene targets of B. henselae from a blood sample a week after gentamicin started was unsuccessful. The patient admitted contact with cats from his neighbor that he fed every night but without touching them. He remained in stable conditions, but unfortunately, he suddenly presented a massive intracerebral hemorrhage on the 29th day of admission, out of surgical scope (Figure 1C), and died. He was not receiving anticoagulants nor antiaggregant drugs. The event was classified as a definitive IE case (Table 1). HIV test was not studied, and serological tests for C. burnetii serology were negative. His monthly income was low (Table 1).

Discussion

Cases presented here illustrate the emergence of IE by Bartonella species in Chile, enlarging the list of possible etiological agents involved in this condition in our country^17–19. To the best of our knowledge, Bartonella-associated IE has not been described in Chile before. Patients shared similar features: both were males, had a history of alcohol consumption, and a low socioeconomic status, a profile that has been described in large series^3,4. For B. quintana, a pathogen of human reservoir, these conditions may be a proxy of debilitated patients living in urban trench conditions³. IFA does not discriminate between B. henselae and B. quintana infection, but high titers, as in our patients, are only associated with IE, and rarely to disseminated disease^4,20.

Our small series also illustrates the relevance of including studies beyond classical blood cultures in pursuing the etiological agent involved in IE cases, especially when they are negative. Serological studies, together with PCR amplification and sequencing of different gene targets of blood or valve samples, may enhance the diagnostic yield^4,8,9. This strategy may recognize not only Bartonella infections but also those provoked by Brucella and Coxiella burnetii². All of these techniques are currently available in Chile. Specific living conditions, habits, and zoonotic exposures may improve the clinical suspicion.

Clinical manifestations and prognosis of IE by Bartonella species are somewhat similar to other causes. Diagnostic limitations already commented, together with special therapeutic requirement, are the most relevant differences. Only observational studies are available that have compared different compounds and outcomes forBartonella IE, so a definitive therapeutic regimen is not yet defined²¹. Gentamycin has been associated with higher recovery rates when compared to other antibiotics and less mortality if at least 14 days are completed²¹. Doxycycline has a lower performance if not accompanied by aminoglycosides. One of our patients died despite receiving this compound but after neurological complications.

In conclusion, Bartonella species provoke IE in Chile, and serological and PCR techniques are available for diagnosis. These agents must be searched when blood cultures remain negative or when specific behaviors or zoonotic exposures are detected. Prognosis is similar to other causes of IE, but therapy appears to rely on aminoglycosides compounds.