Bartonella henselae Infection: An Uncommon Mimicker of Autoimmune Disease

We present a case of a seven-year-old immunocompetent female patient who developed systemic symptoms mimicking an autoimmune rather than an infectious disease. The patient presented with rash, biquotidian fever, night sweats, and arthralgias. There was no antecedent history of cat contact. Investigations showed increased inflammatory markers, leukocytosis, thrombocytosis, hypercalcemia, and raised angiotensin-converting enzyme. Interferon-gamma releasing assay for tuberculosis infection was negative. Abdominal imaging demonstrated multifocal lesions of the liver and spleen (later proved to be granulomata), chest X-ray showed enlarged hilar lymph nodes, and ophthalmology review revealed uveitis. Clinical, laboratory, and imaging features pointed towards sarcoidosis. Subsequently, raised titers (IgM 1 : 32, IgG 1 : 256) against Bartonella confirmed the diagnosis of B. henselae infection. She was treated with gentamycin followed by ciprofloxacin; repeat investigations showed complete resolution of findings. The presence of hepatic and splenic lesions in children with bartonellosis is well documented. Our case, however, exhibited certain unusual findings such as the coexistence of acute ocular and systemic involvement in an immunocompetent host. Serological testing is an inexpensive and effective way to diagnose bartonellosis in immunocompetent patients; we suggest that bartonella serology is included in the baseline tests performed on children with prolonged fever even in the absence of contact with cats in countries where bartonellosis is prevalent.


Introduction
Cat scratch disease (CSD) is a common zoonosis in children caused by Bartonella henselae (B. henselae). Typical CSD, which occurs in 90% of cases, is characterized by low grade fever and subacute regional lymphadenitis following a recent history of cat contact. e disease has a self-limited course and usually resolves without the use of antibiotics. Apart from typical CSD, B. henselae has been recognized as a rare cause of fever of unknown origin (FUO) [1]. Nowadays, with the use of modern diagnostic tools the clinical spectrum of B. henselae disease has further expanded to include various additional clinical entities such as disseminated infection and septicemia, neurological, cardiovascular, ocular, and musculoskeletal manifestations [2]. We present a case of a sevenyear-old immunocompetent female patient who developed ocular and systemic symptoms mimicking an in�ammatory rather than an infectious disease.

Case Presentation
e patient, offspring of an unrelated Caucasian couple with uneventful past medical history, presented with a three-week history of malaise, poor appetite, weight loss, biquotidian fever, night sweats, arthralgias, and an erythematous papular rash. Prior to this presentation parents reported an episode of unilateral conjunctivitis which lasted for three days, successfully treated with topical antibiotics. ere was no antecedent history of cat contact; however the family lived in a rural area, and the child spent a lot of time playing outdoors. Investigations showed increased in�ammatory markers ESR 86 mm/h (reference range (rr): 0-20 mm/h), CRP 8 mg/dL (rr: 0-0.5 mg/dL), leukocytosis (18000/mm 3 (rr: 4000-12000/mm 3 )), thrombocytosis (650/mm 3 (rr: 150-450/mm 3 )), mild hypercalcemia (11.8 mg/dL (rr: 8.5-10.5 mg/dL)), and raised angiotensin converting enzyme (ACE) (120 mg/dL (rr: 25-68 mg/dL)). Liver functions tests were moderately raised (AST: 98 IU/mL (rr: 25-46 IU/mL), ALT: 78 (rr: 15-35 IU/mL)). Interferongamma releasing assay test for tuberculosis (Quantiferon Gold in Tube test) was negative. Testing for ANA, antids-DNA, ENA, anti-MPO, and anti-PR3 antibodies were negative. Abdominal imaging with ultrasound scan (USS) showed small hypoechoic lesions in the liver and spleen; subsequent magnetic resonance imaging (MRI) revealed multiple focal lesions in the aforementioned organs in keeping with granulomata ( Figure 1), with associated lymphadenopathy. e chest roentogram showed mildly enlarged hilar lymph nodes; electrocardiogram and echocardiography were normal. Renal function tests as well as renal and urinary tract imaging did not show any abnormal �ndings. Ophthalmology examination showed unilateral grade 1 anterior nongranulomatous uveitis; the posterior segment was clear, intraocular pressure was normal, and fundoscopy was unremarkable. Musculoskeletal examination was normal. Clinical, laboratory, and imaging features strongly suggested sarcoidosis, and a liver biopsy was planned in order to con�rm the diagnosis. �owever, raised titers ( Repeat MRI showed calci�cation of the liver and splenic lesions calci�ed, but there was no central necrosis ( Figure  2). Ophthalmology review held at monthly intervals for 12 months did not show any uveitis �ares following termination of topical and systemic treatment.

Discussion
e commonest manifestation of B. henselae infection is cat scratch disease. Typical CSD is characterized by low grade fever and tender unilateral regional lymphadenopathy.
In the majority of cases there is an antecedent history of direct cat contact. B. henselae has seasonal distribution from October to January. e disease course is oen mild and selflimiting, rendering monitoring of the true incidence difficult to estimate. B. henselae is a small, aerobic, intracellular gramnegative pleoomorphic bacillus, microscopically identi�ed by Warthin-Starry stain. e bacillus is very difficult to grow; hence culture is not routinely recommended. PCR in blood or tissue specimens is the most effective way to exclude bartonellosis; however this method lacks sensitivity (43-76%) [3]. On the other hand, serological testing is an inexpensive tool to diagnose B. henselae with 95% sensitivity and 98% speci�city [4]. An IgM IFA titer of 1 : 16 or above is usually considered evidence for early infection. An IgG IFA titer of greater than 1 : 256 is considered evidence of current or past B. henselae infection. In the presence of a positive history of cat contact and relevant clinical �ndings, titers are reliable and sensitive leading to prompt diagnosis and initiation of appropriate treatment, thus avoiding unnecessary invasive investigations. Nevertheless, in cases where results are equivocal or in cases of immune de�cient hosts, criteria have been proposed in order to reach diagnosis [5]. In few cases, however, symptoms and signs of the infection are constitutional and nonspeci�c. In a series of 146 children with PUO, B. henselae accounted for 5% of the  Figure 1 present signs of maturity. eir margin is more distinct (STIR image in (a)), as edema has resolved, and the peripheral enhancing rim is better de�ned (T1W image a�er IV contrast administration in (b)).
events [1]. In the context of PUO, a variety of rare systemic manifestations have been described including endocarditis, osteomyelitis, and hepatosplenic, pulmonary, and central nervous system involvement [2], although infrequent eye manifestations include Parinauds oculoglandular syndrome, characterized by fever, unilateral conjunctivitis, and preauricular lymphadenopathy, chorioretinitis, retinal vasculitis, optic neuritis, panuveitis, and iridocyclitis [6]. In the majority of cases ocular bartonellosis follows a chronic course [7]; acute uveitis has also been reported [8] in the absence, however, of concomitant systemic in�ammation. Other important infectious causes which could present with systemic and ocular involvement such as HSV 1 , leptospirosis, Toxocara, and tuberculosis, while histoplasmosis, toxoplasma, and CMV infections are not typically diagnosed in immunocompetent hosts. On the other hand, although rarely seen in children, the majority of small vessel granulomatous vasculitides could present acutely with systemic in�ammation, ocular and organ involvement. Sarcoidosis is an idiopathic multisystemic in�ammatory disease manifesting with noncaseating epithelioid cell granulomata in affected tissues. Classical sarcoidosis commonly presents with fever, malaise, lymphadenopathy, elevated in�ammatory markers, and raised ACE. �one of these �ndings, however, are speci�c for sarcoidosis, and tissue biopsy remains the gold standard for diagnosis. e mechanism by which ACE increases is the same either due to an infectious or an in�ammatory cause, while the reason why this phenomenon occurs remains unknown. Epithelioid cells and macrophages in the granuloma produce ACE, but this �nding is neither sensitive nor speci�c; nonetheless, it may assist in sarcoidosis disease monitoring. e differential diagnosis of multiple hepatic and splenic focal lesions with features of peripheral enhancing rim and perilesional edema in children includes the wide spectrum of systemic, usually nonbacterial, infections, systemic autoimmune diseases and malignancies, predominantly of lymphatic origin. In this particular child, serial imaging con�rmed the natural evolution of the lesions (from indistinct to better de�ned and eventually calci�ed on late imaging) which was unrelated to therapy and added additional value to the hypothesis that they represented granulomata.
e therapeutic approach for B. henselae infection is not standardized; it depends on disease severity and immune status. Typical CSD is a self-limited illness that resolves within 2 to 6 months and does not usually require treatment. Disease dissemination occurs in 14% of cases; therefore in patients with solid organ involvement and systemic in�ammation 3-4 weeks of antibiotics are required [9]. erapeutic agents which have shown satisfactory results include aminoglycosides, cefotaxime, and tetracyclines, while macrolides may be used in uncomplicated cases. Prevention is achieved by avoiding interactions with kittens, cats infested with �eas, and outdoor cats.

Conclusion
e presence of hepatosplenic lesions in children with bartonellosis is well documented. Acute uveitis caused by B. henselae, although exceedingly rare, has also been reported as an isolated �nding; the case described is rare as it presents the co-existence of acute ocular and hepatosplenic involvement in an immunocompetent host in the absence of cat contact history. Serological testing is an inexpensive and effective way to diagnose bartonellosis in immunocompetent patients. We suggest that B. henselae serology is included in the baseline tests performed in children with FUO even in the absence of direct contact with cats. We also suggest an ophthalmology examination on children with constitutional symptoms attributed to B. henselae. Ocular involvement harbors severe consequences and requires prolonged use of antibiotics and close monitoring.

Consent
Written informed consent was obtained from the patient for publication of this paper and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.