Bartonella infections in immunocompromised individuals, including those with HIV, pose a diagnostic challenge. We present a young adult with HIV infection who developed neuroretinitis during immune reconstitution and was diagnosed with disseminated bartonellosis. His presentation illustrates the importance of maintaining a high index of suspicion for Bartonella infection in HIV patients with cat contact and the important role of tissue biopsy in confirming the diagnosis.
A 21-year-old man was admitted to Texas Children's Hospital with a 4-month long history of intermittent fever, 20-pound weight loss, nausea, and vomiting, and a 2-week history of blurred vision and headache. He had been diagnosed at 12 years of age with perinatally-acquired HIV infection and had been noncompliant with highly active antiretroviral therapy for the year before presentation. At evaluation 2 months before admission, his CD4 count was 34 cells/mm3 and the viral load was 1,165,026 copies/mL. A chest radiograph was normal and a blood culture for Mycobacterium avium-intracellulare complex (MAC) was sterile. Therapy was initiated 3 weeks before admission with efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla). One week later, he developed headaches and blurred vision. Ophthalmologic examination revealed bilateral papilledema.
The patient lived in Corpus Christi, Texas. He had no history of travel or known tuberculosis exposure. He smoked marijuana regularly but denied alcohol or other drug use. He was sexually active. He had 2 cats and a gerbil.
On admission, his temperature was 100.6°F and his weight was 57 kg. His general examination was notable for splenomegaly and ophthalmologic examination revealed bilateral papilledema with serous retinal detachment, cotton wool spots, subretinal fluid, and an infiltrative process involving the optic nerve. His visual acuity was 20/800 in the right and 20/400 in the left eye.
A white blood cell (WBC) count was 13,000/mm3 with 53% neutrophils, 17% band forms, and 19% lymphocytes. Screening tests for hepatic and renal function were normal. Cerebrospinal fluid (CSF) had 12 WBC/mm3 (90% monocytic), 5 red blood cells/mm3, protein of 86 mg/dL, and glucose of 50 mg/dL. The opening CSF pressure was normal (12 cm of H2O). Routine, acid-fast and fungal stains and cultures of CSF, cryptococcal antigen, and Venereal Disease Research Laboratory Test (VDRL) were negative or sterile. The CSF polymerase chain reaction (PCR) for enteroviruses, herpes simplex virus (HSV) 1 and 2, cytomegalovirus (CMV), Toxoplasma gondii, and Bartonella were negative. Serology and serum PCR for CMV and Epstein-Barr virus and serum cryptococcal antigen were negative. Fungal complement fixation testing and Toxocara titers were negative. Purified protein derivative testing and a QuantiFERON-TB gold test (Cellestis Ltd., Carnegie, Victoria, Australia) were negative.
Cranial magnetic resonance imaging (MRI) revealed bilateral papillitis and posterior choroidal surface enhancement and multiple parenchymal lesions most pronounced along the basal ganglia and hypothalamus. Abdominal ultrasound revealed splenomegaly with multiple microabscesses. A chest computed tomographic scan showed small peripheral pulmonary nodules with mediastinal lymphadenopathy.
Therapy was initiated with conventional amphotericin B and flucytosine for presumed cryptococcal meningitis and ganciclovir for treatment of possible CMV infection. Antiretroviral therapy was held. The patient's visual acuity progressively declined and when signs of increased intracranial pressure (vomiting and headache) had intensified by hospital day 8, doxycycline and rifampin were empirically initiated.
Open biopsy of a pulmonary nodule was performed on hospital day 10. Histopathologic examination revealed a discrete granuloma-like aggregate of epithelioid histiocytes, plasma cells, hemosiderin-laden macrophages, and a small central focus of necrosis with neutrophils. PCR for T. gondii, M. tuberculosis, HSV, and CMV as well as routine cultures, AFB stain and culture, fungal stain and culture were negative. The PCR for Bartonella species, performed on the lung tissue at the ARUP Laboratories (Salt Lake City, UT) was positive. Serum antibody titers to Bartonella henselae and Bartonella quintana were less than 1:64.
The patient became afebrile by hospital day 4. Amphotericin B, flucytosine, and ganciclovir were discontinued. Atripla was reinstituted on hospital day 14 when his vision had improved to 20/200. He was discharged home on hospital day 24 to continue doxycycline and rifampin. The CD4 cell count was 84 cells/mm3 and the viral load was 250 copies/mL at 1 week after hospital discharge. At a 4-month follow-up visit, the patient's visual acuity had improved to 20/40. The CD4 cell count was 143 cells/mm3 and the HIV viral load was <100 copies/mL. A 6-month course of doxycycline and rifampin is anticipated.
The seroprevalence of Bartonella in patients with HIV infection ranges from 16% to 40%, but seropositivity does not correlate directly with evidence of clinical infection.1,2 The disease spectrum can include lymphadenopathy, fever of unknown origin, bacteremia, neuroretinitis, bacillary angiomatosis, bacillary peliosis, splenitis, endocarditis, and osseous involvement. The 2 common human pathogens are B. henselae and B. quintana.
Our patient illustrates the limitations of serologic testing for bartonellosis in an immunocompromised patient in the setting of disseminated infection. Antigen-based testing by PCR of lung tissue was required to establish the diagnosis. Intact cell-mediated immunity also is crucial to controlling proliferation of intracellular bacteria.3 In HIV-infected individuals, a combination of weakened macrophage phagocytic function along with release of proinflammatory cytokines can facilitate progression of vascular proliferation resulting in angiogenesis and granuloma formation.3
Neuroretinitis in bartonellosis is well recognized as a manifestation of disseminated infection in immunocompetent hosts, but there is a paucity of data regarding this entity in patients with HIV infection. In the immunocompetent host, the hallmark of Bartonella neuroretinitis is a macular star lipid exudate.4,5 Other eye findings include optic neuritis, macular hole, retinal white dot syndrome, retinal and chorioretinal inflammatory foci, peripapillary subretinal fluid, peripapillary angiomatosis, iridocyclitis, serous retinal detachment, arterial or venous occlusion or vasculitis.4,5 Our patient did have serous retinal detachment with peripapillary subretinal fluid and optic neuritis but he lacked the distinctive macular star.
Some suggest that ocular bartonellosis is a hallmark of systemic disease. In HIV-positive patients, an abnormal vascular network with subretinal mass, unifocal choroiditis, and angiomatous lesions has been described.6 A diagnostic challenge in these patients is that the findings can mimic eye involvement with CMV, mycobacterial infections including tuberculosis and atypical mycobacteria, HSV, varicella zoster, Cryptococcus, toxoplasmosis, toxocariasis, Kaposi sarcoma, extrapulmonary Pneumocystis jirovecii, and other fungal diseases. Neuroretinitis can occur with HIV infection itself or immune reconstitution syndrome in the absence of a secondary infection. We suspect that our patient's parenchymal brain lesions were a consequence of HIV immune reconstitution. The improvement in his CD4 cell count and dramatic reduction in viral load several weeks into treatment for the Bartonella infection support this contention. Thus, the modest CSF pleocytosis with undetectable Bartonella antigen by PCR likely reflects a parameningeal process rather than invasion of the central nervous system.7
Hepatic or splenic microabscesses can occur in both immunocompetent and immunocompromised hosts but they are nonspecific and the finding of splenic microabscesses in our patient was not pathognomonic for Bartonella infection. In one report of 32 HIV-infected patients with unexplained fever, splenic microabscesses occurred in patients with tuberculosis (14), visceral leishmaniasis (7), MAC (5), Candida (1), Rhodococcus (1), Salmonella bacteremia (2), lymphoma (2), P. jerovecii (1 patient).8 Documented pulmonary involvement with Bartonella is rare even in disseminated infection, but pulmonary infiltrates have been reported in both immunocompetent and immunocompromised patients with bartonellosis suggesting underdiagnosis because of a lack of respiratory symptoms.9,10
Coinfections of Bartonella with other organisms also can occur. Among 33 HIV-positive patients with Bartonella infection, one was coinfected with MAC and 2 with Histoplasma capsulatum.11 Although disseminated MAC infections are common in these individuals, at least one-half of the patients infected with MAC have another identified infection.12 Coinfection with CMV and tuberculosis also has occurred.13,14
Approaches to diagnosis of Bartonella in HIV-infected patients include serologic testing, culture of cutaneous lesions and evaluation by histopathology and PCR of material from tissue specimens. Bartonella is difficult to cultivate from blood or tissues. Plating onto chocolate or heart infusion agar with 5% rabbit blood with incubation in 5% CO2 at 35 to 37°C for at least 21 days optimizes the yield. Indirect immunofluorescent antibody assay for antibodies to Bartonella and enzyme immunoassay for antibodies to B. henselae are available.15 Serologic results can be difficult to interpret in HIV-infected patients because they do not reliably mount a response in the setting of a low CD4 cell count. Thus, tissue biopsy and Bartonella PCR should be undertaken, if feasible, as exemplified by our patient. Hematoxylin-eosin stain demonstrates a necrotizing granuloma, whereas Warthin-Starry stain can reveal small dark-staining bacteria. The PCR for Bartonella is commercially available and can be used in both blood and tissue specimens.
There are no controlled trials of treatment for bartonellosis in HIV-infected individuals. Erythromycin and doxycycline are first-line agents. A minimum of 3-months treatment duration is recommended.15 If neuroretinitis or central nervous system disease is present, doxycycline and rifampin are indicated for treatment in children 8 years of age or older.15,16 In younger children, trimethoprim-sulfamethoxazole and rifampin can be employed.16 Since relapse can occur after a primary course, long-term suppressive therapy is recommended until the CD4 cell count exceeds 200 cells/mm3.15 Immune reconstitution syndrome has not been reported previously in HIV patients coinfected with Bartonella. We believe that this is a case of “unmasking” immune reconstitution disease provoked by Bartonella infection in an immunocompromised host because of the dramatic reduction of his viral load and increase in his CD4 cell counts within 3 weeks of initiating antiretroviral therapy.17 Some experts recommend deferring antiretroviral therapy initiation for 2 to 4 weeks after initiating treatment for Bartonella.15 Our patient's therapy was reinstituted after he had experienced initial improvement in visual acuity. Restoration of visual acuity in Bartonella neuroretinitis occurs in 1 to10 weeks after initiation of therapy in immunocompetent patients.5 Our patient's vision improved within 2 weeks and was restored by 4 months after initiation of appropriate therapy.
In summary, disseminated bartonellosis should be considered in the differential diagnosis for fever and neuroretinitis and a history of cat contact should be sought. Splenic or liver microabscesses, cutaneous lesions, and lymphadenopathy are additional diagnostic clues but may not be consistently present. Our patient's recovery illustrates the gratifying outcome possible when treatment of neuroretinitis can be pathogen-directed.
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