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To the Editor:

Bartonella henselae infection is well recognized as the responsible agent of cat-scratch disease (CSD), but also prolonged fever of unknown origin (FUO), endocarditis, hepatosplenic disease, encephalopathy, dermatological lesion, hemolytic anemia, and ocular diseases. Immunocompetent individuals infected by B. henselae start an interferon-γ-mediated T-helper 1 cell response, resulting in macrophage recruitment and stimulation, producing a decrease of bacterial load but also a subsequent granuloma formation.1, 2 In these patients, infection remains within lymphatics with a symptomatic immune response characterized by fever, generalized aches, anorexia, and nausea that lasts 2–4 months. Host immune status is determinant for clinical manifestations and response to infection. Immunodeficient patients are at higher risk of systemic bartonellosis characterized by neoangiogenic lesions or febrile bacteriemia.3 These have been described most commonly in HIV-infected,4 chemotherapy patients, and in transplant recipients. Currently, a newer group of high-risk patients should be taken into account: those undergoing tumor necrosis factor α (TNF-α) antagonists therapy for immune-related diseases.

We report the case of a 74-year-old woman, allergic to penicillin. Spondyloarthropathy was diagnosed in 1995 when she was taking prednisone 5 mg daily. In 2000, Crohn's disease (CD) was diagnosed and she had been in clinical remission for the last 8 years with azathioprine (2.5 mg/kg/day) and infliximab (5 mg/kg every 8 weeks). In March 2010 she was admitted to our hospital with abdominal pain, bloody diarrhea, and septic shock due to Campylobacter jejuni. A computed tomography (CT) scan showed no signs of CD activity and no lymphadenopathies. Empirical ciprofloxacin and metronidazole were started with a successful clinical outcome. Seven months later she was readmitted with fever (38.5°C) and headache. Blood tests showed C-reactive protein 18 mg/dL (0–0.8). Urine, stool, and blood cultures were negative and respiratory infection was discounted. A CT scan showed signs of mesenteric panniculitis, mediastinic and periceliac borderline lymphadenopathies, and homogenous splenomegaly without signs of CD activity or complications (Fig. 1). Symptomatic treatment was started and her fever disappeared. Two weeks later the fever reappeared with inflammatory signs in the blood test. We studied the FUO by means of mycobacteria cultures, Cytomegalovirus, Epstein Barr virus, and Treponema pallidum tests. Other serologic tests were added: Borrelia burgdorferi, Brucella, Rickettsia conorii, and Rickettsia typhi, Chlamydia psittaci, Coxiella burnetii, and Bordetella pertussis. An exhaustive anamnesis revealed that the patient had cats at home; therefore, B. henselae was tested. Because of the persistence of fever with important and concerning clinical upset, a wide-spectrum antibiotic suitable for penicillin allergics (tigecyclin 50 mg/12 hours) was started. Fever disappeared within 48 hours. Serology B. henselae immunoglobulin G was positive (1/1600). Treatment with tigecycline with subsequent rapid fever remission reinforced the diagnosis of systemic bartonellosis. Biological infection markers tended to normalization and the patient remained afebrile several months after the end of oral antibiotics.

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Figure 1. Notice the emergence of periceliac borderline lymphadenopathies and homogenous splenomegaly in the second CT scan (arrows).

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There is an increasing concern about opportunistic infections in patients with TNF-α antagonists, especially when these are combined with other immunomodulators. A systematic report showed a granulomatous infections rate (cases per 100,000 patients) of 239 with infliximab and 74 with etanercept. Tuberculosis was the most frequent. Other infections were histoplasmosis, candidiasis, listeriosis, coccidioidomycosis, and nocardiosis. There was one report of a case of Bartonella spp. infection in the infliximab group.5B. henselae infections have been described related to etanercept: a cervical lymphadenopathy6 and a CSD with mesenteric lymphadenopathy and splenic involvement.7 To our knowledge, this case is the first reported in the literature of systemic B. henselae infection during infliximab, azathioprine, adalimumab, or certoluzimab pegol.

Although the pathogenesis of B. henselae infection is not fully elucidated, experimental studies have shown that infected macrophages release high levels of human TNF-α.8 Thus, TNF-α blockade would interfere with the inflammatory response, allowing persistent B. henselae bacteriemia.

The initial approach to the patient treated with TNF-α antagonists presenting with FUO should include a comprehensive history (focused on fever pattern and epidemiological aspects such as recent travel, exposure to animals, the work environment, and recent contact with persons exhibiting similar symptoms), physical examination, and laboratory testing (e.g., culture for Mycobacteria, serologic tests for Toxoplasma, Brucella, C. burnetti, HIV, and EBV). Furthermore, in these patients even if a cat's contact is not demonstrated and typical signs are not observed (e.g., lymphadenopathies at physical exam), serologic tests for B. henselae should be considered. Our report also suggests that tigecycline, a new generation broad-spectrum tetracycline, could be considered as an alternative for systemic bartonellosis.

REFERENCES

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Alex Cañas-Ventura MD*, Erika Esteve MD*, Juan P. Horcajada MD, PhD*, Montserrat Andreu MD, PhD†, Hernando Knobel MD, PhD†, Lucía Márquez MD*, * Department of Gastroenterology, Hospital del Mar, Parc de Salut Mar, Pompeu Fabra University, Barcelona, Spain, † Department of Internal-Medicine-Infectious Diseases, Hospital del Mar, Parc de Salut Mar, Pompeu Fabra University, Barcelona, Spain.