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Revista médica de Chile

versión impresa ISSN 0034-9887

Rev. méd. Chile vol.147 no.10 Santiago oct. 2019

http://dx.doi.org/10.4067/s0034-98872019001001340 

Caso Clínico

Infectious endocarditis by Bartonella species. Report of two cases

Endocarditis infecciosa por Bartonella. Descripción de dos casos en Chile

Ignacio Delama1  2 

Roberto Mondaca3 

Ignacia Aguayo4 

Andrés Roldán2  5 

Marcela Ferrés6 

Alberto Fica1  2 

1Subdepartamento de Medicina, Hospital Base de Valdivia. Valdivia, Chile

2Escuela de Medicina. Facultad de Medicina. Campus Isla Teja, Universidad Austral de Chile. Valdivia, Chile

3Programa de Especialización en Medicina Interna, Escuela de Graduados, Facultad de Medicina. Universidad Austral de Chile. Valdivia, Chile

4Interna de la Carrera de Medicina, Escuela de Medicina, Campus Isla Teja. Universidad Austral de Chile. Valdivia, Chile

5Subdepartamento de Neurología, Hospital Base de Valdivia. Valdivia, Chile

6Laboratorio de Infectología y Virología, Departamento de Enfermedades Infecciosas e Inmunología Pediátricas, Facultad de Medicina, Pontificia Universidad Católica de Chile. Santiago, Chile

ABSTRACT

Infectious endocarditis (IE) by Bartonella species is an emerging problem worldwide. We report two cases of native valve Bartonella-associated IE events, both affecting adult male patients with a history of alcohol abuse and a low socioeconomic status. Admissions were due to pancytopenia and bleeding in one case and embolic stroke in the other. Blood cultures were negative and IgG indirect immunofluorescence assays (IFA) were positive for B. henselae/B. quintana in high titers (1/16,384-1/16,384, and 1/32,768 -1/16,384, respectively). Cases were classified as definitive IE events according to modified Duke criteria due to the presence of valve vegetations with at least three minor criteria. One patient required aortic mechanical valve replacement and survived, and the other died after a massive hemorrhagic transformation of his stroke. PCR amplification and sequencing of the 16S ribosomal bacterial DNA from a valve tissue sample obtained at surgery in the patient who survived, confirmed B. quintana as the etiological agent. Bartonella-associated IE is an emerging problem in Chile, present in disadvantaged populations. It should be suspected in patients with culture-negative IE. IFA does not discriminate between B. henselae and B. quintana infection, but high titers suggest IE. Complementary PCR techniques may help to elucidate the final causative agent.

Key words: Bartonella; Endocarditis, Bacterial; Fluorescent Antibody Technique, Indirect; Sequence Analysis, DNA; Stroke

RESUMEN

La endocarditis infecciosa(EI) asociada a Bartonella es un problema emergente a nivel mundial. Publicamos los 2 primeros casos de EI en válvula nativa asociados a Bartonella en Chile, los que afectaron a pacientes masculinos con historia de consumo de alcohol y bajos ingresos. La hospitalización fue provocada por pancitopenia y hemorragias en un caso y por un evento cerebrovascular en el otro. Se solicitó serología para Bartonella por inmunofluorescencia indirecta (IFI) para ampliar el estudio ante hemocultivos negativos y en ambos casos se reportaron resultados intensamente positivos para B. henselae y B. quintana1/16.384-1/16.384 y 1/32.768 -1/16.384, respectivamente). Los casos se clasificaron como eventos definitivos de EI según los criterios modificados de Duke debido a la presencia de vegetaciones valvulares con al menos 3 criterios menores. Un paciente requirió reemplazo valvular aórtico y sobrevivió, y el otro falleció tras una transformación hemorrágica masiva del infarto cerebral. La amplificación del ADN ribosomal 16S por RCP y posterior secuenciación de una muestra de tejido valvular confirmó la presencia de B. quintana. La EI por Bartonella sp. es un problema emergente en Chile, probablemente asociada a poblaciones desfavorecidas, la que debe ser sospechada en pacientes con cultivos negativos. La IFI no permite discriminar infecciones por B. henselae o B. quintana pero los títulos altos sugieren EI. Técnicas complementarias por RCP pueden ayudar a dilucidar el diagnóstico.

Palabras clave: Bartonella; Endocarditis Bacteriana; Accidente Cerebrovascular

Blood-culture-negative infective endocarditis (IE) can be explained by sterilized cultures in previously treated patients, fastidious or slow growing agents (HACEK group, deficient Streptococci, Candida sp.), or true blood culture-negative microorganisms1,2. Several agents like Coxiella burnetti, Bartonella sp., Brucella sp. Tropheryma whipplei, Chlamydiophila, and Mycobacterium chimaera belong to the latter group2. Bartonella species are considered emergent pathogens in culture-negative IE with increasing reports in recent years310.

Bacteria of the genus Bartonella includes facultative Gram-negative intracellular pathogens, able to form biofilms, and its diagnosis has been made possible by serology or molecular methods such as detection of Bartonella 16S rRNA gene sequences or other PCR gene targets in tissue or blood samples3,8.

Serology methods involve indirect fluorescent antibody assay (IFA) or ELISA tests. Both have problems of cross-reactivity betweenB. quintana and B. henselae3. Of note, IFA titers ≥ 1/3,200 have a high positive predictive value for IE by these agents (100%)4. Western blotting with cross-adsorption circumvents problems of cross-reactivity and increases both sensitivity and specificity4. In large clinical series dedicated to IE secondary to Bartonella sp, B. quintana lightly surpasses B. henselae in frequency4.

B. quintana, the agent of trench fever, has a human reservoir with worldwide distribution and nowadays is mostly associated to alcoholic and homeless populations in urban settings3. Infection between humans is transmitted by body lice and possible by fleas11,12. B. henselae is endemic in Chile, and transmission to humans has been linked to cats3,13. Infections have mainly involved children with cat scratch disease and other Bartonella infections have been rarely described in our country1416.

In recent years, we have observed two patients with IE by Bartonella species, a condition not reported in Chile before. Patients gave their informed consent for this report.

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.

Table 1 Features observed in two cases of infectious endocarditis associated to Bartonella species 

Parameter Case 1 Case 2
Age in years, gender 57, male 67, male
Habits Cannabis, cocaine pasta base and alcohol abuse Alcohol abuse
Contact with cats Positive Positive
Socioeconomic status Low, no income Low income group, below percentile 25th
Symptoms initiation before admission 4 months (weigth loss) 3 months (effort dyspnea)
Main clinical picture Pancytopenia with multiple site bleeding. Congestive heart failure thereafter Cerebrovascular accident
Findings associated to infectious endocarditis during physical exam Mild systolic murmur Janeway lesions Holosystolic murmur of recent appearance.
ESR 66 mm/h 61 mm/h
Hematuria Present, 100% dysmorfic cells Present, 90% dysmorfic cells
C3-C4/ Rheumatoid factor (RF) Not done Hypocomplementemia and elevated RF
Blood cultures Negative Negative
Main echocardiogram findings Aortic valve vegetations, global contractile dysfunction Mitral valve tendineous cord rupture with vegetations
Bartonella serology by IFA B. henselae IgG 1/16,384 B. quintana IgG 1/16,384 B. henselae IgG 1/32,768
B. quintana IgG 1/16,384
16S Ribosomal DNA amplification and sequencing Positive for B. quintana Not done
Antibiotic treatment after Bartonella infection diagnosis Ceftriaxone + doxycycline + azithromycin.
Gentamycin was not used by CRF Stage 3
Doxycycline + rifampin + gentamycin
Outcome Aortic valve replacement. Discharged alive Brain infarct with massive hemorrhagic transformation, Deceased
Case classification according to modified Duke criteria Definitive case
1 major criterion (valve vegetations, abscess) + 3 minor criteria (vascular: Janeway lesions; immunological: glomerulonephritis; microbiological: Positive B. quintana detection in valve tissue)
Definitive case
1 major criterion (valve vegetations) + 3 minor criteria (vascular: embolic brain infarct; immunological: hycomplementemic glomerulonephritis; microbiological: serological evidence of Bartonella sp. infection)

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 country1719. 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 series3,4. 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 disease4,20.

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 yield4,8,9. 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.

Trabajo no recibió financiamiento.

Aknowledgments:

To Eugenio Montaner, MD, Servicio de Cardiología, Hospital Base de Valdivia, for his kindly technical helps with echocardiograms.

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Received: August 02, 2019; Accepted: October 30, 2019

Correspondencia a: Dr. Alberto Fica Médico Infectólogo, Subdepartamento de Medicina, Hospital Base de Valdivia. Bueras 1003, Valdivia, Región de Los Ríos, Chile. albertoficacubillos@gmail.com

Conflicto de Interés: ninguno.

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