Disseminated cat-scratch disease: case report and review of the literature Chih-Chen Chang1, Chia-Jie Lee2, Liang-Shiou Ou3, Chao-Jan Wang1, Yhu-Chering Huang2,4 1

Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Linkou, Taiwan, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan, 3Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan, 4 Chang Gung University College of Medicine, Kweishan, Taoyuan, Taiwan 2

Cat scratch disease (CSD) can present as a systemic disease in 5–10% of cases and lead to various disease entities. A previously healthy 16-month-old boy presented with fever for 7 days without other obvious symptoms. Abdominal computed tomography scan demonstrated enlarged right inguinal lymph nodes and multiple small round hypodensities in the spleen. Despite antibiotic treatment for 1 week, the fever persisted and the intrasplenic lesions progressed. Inguinal lymph node biopsy confirmed CSD by immunohistochemistry staining. The diagnosis of CSD was also supported by a history of contact, imaging and serological findings. The patient recovered after treatment with azithromycin for a total of 5 weeks and, in serial follow-up, the hepatosplenic micro-abscesses resolved after 4th months. Keywords: Bartonella henselae, Cat scratch disease, Immunohistochemistry stain, Splenic abscess

Introduction Cat scratch disease (CSD) is a human infectious disease caused by Bartonella henselae, a fastidious, Gram-negative bacillus, and is associated with a history of cat scratch or bite. It manifests mainly as acute regional lymphadenopathy and fever, but rarely it can also present as a systemic disease which includes visceral organs, neurological and ocular involvement. The first human case of CSD in Taiwan was diagnosed by a serological test in 1998.1 Since then, there have been only a few case reports, and there are no reports of diagnosis with monoclonal anti-Bartonella henselae antibody.2 A boy with disseminated CSD is presented.

Case Report A 16-month-old boy was admitted to the Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan with a temperature rising to 40.1uuC and chills for 7 days. The patient was previously healthy without a past medical, travel or hereditary disorder history. His family had two pet cats in the home, but denied that the patient had been scratched or bitten by them. Results of physical examination were, Correspondence to: Y-C Huang, Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Children’s Hospital, No. 5, Fu-Shin Street, Kweishan 333, Taoyuan, Taiwan. Fax: þ886 3 328 8957; email [email protected]

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DOI 10.1179/2046905515Y.0000000005

unremarkable apart from palpable lymph nodules in the right inguinal region. Investigations. The white cell count was 15.1|109/ L (neutrophils 48%, lymphocytes 40%, monocytes 11%, atypical lymphocytes 1% and bands 0%). Serum C-reactive protein levels 137 mg/L (v5) and there was mild elevation of alanine aminotransferase (65 U/L). Blood and urine cultures were normal. A screen for auto-immune disease, Widal test and virus serology including cytomegalovirus, Epstein– Barr virus and parvovirus were negative. Abdominal sonography demonstrated hepatosplenomegaly, multiple small hypo-echogenic splenic nodules, and enlarged lymph nodes (LNs) in the splenic hilum (Fig. 1A). Empirical vancomycin and ceftriaxone were administered in view of possible intra-abdominal infection. Abdominal computed tomography (CT) scan demonstrated enlarged right inguinal LNs and multiple small round hypodensities in the spleen (Fig. 1B). Despite 1 week of antibiotic treatment, the fever persisted and repeat sonography demonstrated intrasplenic hypoechoic lesions. Lymph node biopsy was considered to rule out lymphoma, metastatic disease, mycobacterial or other bacterial infection. However, his parents were reluctant about the invasive procedure, so the biopsy was not performed until 2 weeks after admission. Histology showed necrotising granulomatous inflammation (Fig. 1C) which suggested CSD. Immunohistochemical (IHC)

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Systemic Bartonella henselae infection

Figure 1 (A) Abdominal sonography demonstrating multiple round hypo-echoic nodules and enlarged lymph nodes in the splenic hilum; (B) CT demonstrating hepatomegaly and multiple oval hypodensities (arrow); (C) Lymph node showing granulomatous inflammation (haematoxylin and eosin staining, original magnification 3 200) (arrow); (D) Immunohistochemical stain using monoclonal antibody for B. henselae detected the presence of the bacterium (red staining in the granuloma) (arrow)

staining with monoclonal anti-Bartonella henselae antibody (clone H2A10, Biocare Medical, Concord, CA) detected bacilli within the necrotising granuloma (Fig. 1D). Additionally, paired serum samples were sent to the Taiwan Centers for Disease Control for serological analysis by indirect fluorescence assay (IFA), immunoglobulin G and immunoglobulin M to B. henselae were both positive, confirming the diagnosis of CSD complicated by splenic microabscesses. Oral administration of azithromycin was initiated with 10 mg/kg/day from the 3rd day of admission and was continued for 2 weeks until defervescence. However, follow-up abdominal sonography found residual abscesses in the spleen. Azithromycin was therefore, administered for an additional 3 weeks and the patient was discharged on the 25th days after admission. Follow-up abdominal sonography 4 months later showed no hepatosplenomegaly or splenic micro-abscesses.

B. henselae can cause systemic disease in 5–10% of CSD and lead to various complications such as prolonged fever of unknown origin, hepatosplenic disease, encephalopathy, osteomyelitis and ocular disease.4 In addition to prolonged fever, hepatosplenic CSD infection typically presents with dull abdominal pain and 53% present with hepatomegaly and/or splenomegaly. Abdominal imaging may detect micro-abscesses in the liver or spleen in more than 50% of patients with hepatosplenic CSD.5 Owing to the variable clinical symptoms, the difficulty of culturing B. henselae and the lack of a diagnostic gold standard, the diagnosis of CSD is a challenge. Diagnosis relies on a combination of contact history and serological, clinical, histological and imaging criteria. In this case, the patient met all of the four diagnostic criteria for CSD adapted by Margileth,6 which include cat contact history, splenic micro-abscesses on CT scan, positive IFA assay for B. henselae and granulomatous inflammation of a lymph node. Several diagnostic techniques assist clinicians in diagnosing CSD, but none of them are without pitfalls. Histopathological examination, such as Warthin–Starry stain, can demonstrate the organisms but the stain is difficult to perform and interpret7 and histopathological diagnosis is invasive. Serology for B. henselae antibodies is the most frequently used test for laboratory diagnosis. However, this method has variable sensitivity (14–100% for IgG, 2–50% for IgM) and specificity (34–100% for

Discussion CSD caused by B. henselae usually begins with erythematous papules at the site of inoculation and regional lymphadenopathy appears 1–3 weeks later. In the majority of cases, lymphadenopathy typically involves a single lymph node, frequently in the axillary and epitrochlear nodes (46%), head and neck (26%) and groin (17.5%).3 In this case, there was right inguinal lymphadenopathy, which suggests that the cat contact occurred in the lower extremity.

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IgG, 86–100% for IgM). Inability to distinguish active from prior infection is also a disadvantage.3,8 Advanced diagnostic techniques such as polymerase chain reaction (PCR) have been used to detect B. henselae, but its usefulness is limited by the variable sensitivity (43–76%), the need for specialised equipment and the cost.3,9 Recently, an additional IHC stain using a commercial monoclonal antibody (clone H2A10, Biocare Medical, Concord, CA) to diagnose CSD has become available and will enhance the ability to diagnose CSD. However, the diagnostic sensitivity of IHC is lower than that of PCR. In view of the lower cost and greater availability of IHC, it has been recommended that IHC analysis be performed before PCR in patients with suspicious CSD.10 The value of antibiotic therapy in CSD remains debatable because of the benign outcome in most manifestations. Azithromycin is used primarily for lymph node disease. In systemic CSD, a combination of gentamicin and an oral agent such as trimethoprim/sulfamethoxazole, rifampicin, ciprofloxacin or azithromycin has demonstrated a favourable response. However, there are no control trials of antibiotic therapy for hepatosplenic CSD. It is difficult to determine whether any single antibiotic regimen is superior in the treatment. Arisoy et al. recommended rifampin at 20 mg/kg/day 12-hourly for 14 days, or in combination.5 We used azithromycin (10 mg/kg) for 5 weeks and resolution of the hepatosplenic micro-abscesses was noted after 4 months of follow-up. Another case of systemic CSD had been reported recently in Taiwan.2 A 9-year-old girl presented with prolonged fever and abdominal pain. Multiple hypodense nodular lesions were detected in the spleen and both kidneys, and she underwent exploratory laparotomy and partial splenectomy to establish the diagnosis. She recovered after 4 weeks of tetracycline and rifampicin. Similar to our patient, she also presented with prolonged fever without obvious focus and required invasive procedures for diagnosis. Antibiotic treatment with tetracycline combined with rifampicin or azithromcyin alone can both lead to total recovery and resolution of images.

Systemic Bartonella henselae infection

Hepatosplenic CSD may present only as prolonged fever in an immunocompetent host and may be confused with lymphoma, carcinoma or mycobacterial or fungal infection. Currently, several diagnostic modalities are available but confirmation of disseminated CSD remains challenging. IHC staining can contribute to aetiological confirmation. Most importantly, clinicians should always consider B. henselae infection as a possibility in patients with fever of unknown origin.

Disclaimer Statements Contributors Funding Conflicts of interest Ethics approval References 1 Lee SC, Fung CP, Lee N, Shieh WB. Cat-scratch disease caused by Bartonella henselae: the first case report in Taiwan. J Formos Med Assoc. 1998;97:569–72. 2 Liao HM, Huang FY, Chi H, Wang NL, Chen BF. Systemic cat scratch disease. J Formos Med Assoc. 2006;105:674–9. 3 Florin TA, Zaoutis TE, Zaoutis LB. Beyond cat scratch disease: widening spectrum of Bartonella henselae infection. Pediatrics. 2008;121:e1413–25. 4 Hopkins KL, Simoneaux SF, Patrick LE, Wyly JB, Dalton MJ, Snitzer JA. Imaging manifestations of cat-scratch disease. AJR. 1996;166:435–8. 5 Arisoy ES, Correa AG, Wagner ML, Kaplan SL. Hepatosplenic cat-scratch disease in children: selected clinical features and treatment. Clin Infect Dis. 1999;28:778–84. 6 Margileth AM. Recent advances in diagnosis and treatment of cat scratch disease. Curr Infect Dis Rep. 2000;2:141–6. 7 Cheuk W, Chan AK, Wong MC, Chan JK. Confirmation of diagnosis of cat scratch disease by immunohistochemistry. Am J Surg Pathol. 2006;30:274–5. 8 Sander A, Berner R, Ruess M. Serodiagnosis of cat scratch disease: response to Bartonella henselae in children and a review of diagnostic methods. Eur J Clin Microbiol Infect Dis. 2001;20:392–401. 9 Sander A, Posselt M, Bohm N, Ruess M, Altwegg M. Detection of Bartonella henselae DNA by two different PCR assays and determination of the genotypes of strains involved in histologically defined cat scratch disease. J Clin Microbiol. 1999;37:993–7. 10 Caponetti GC, Pantanowitz L, Marconi S, Havens JM, Lamps LW, Otis CN. Evaluation of immunohistochemistry in identifying Bartonella henselae in cat-scratch disease. Am J Clin Pathol. 2009;131:250–6.

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Disseminated cat-scratch disease: case report and review of the literature.

Cat scratch disease (CSD) can present as a systemic disease in 5-10% of cases and lead to various disease entities. A previously healthy 16-month-old ...
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