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Treatment of HIV-Related Inflammatory Cerebral Cryptococcoma with Adalimumab - brief report
  Clinical Infectious Diseases Jan 15 2010;50:e7-e10
Amy M. Sitapati,1 Cynthia L. Kao,1 Edward R. Cachay,1 Homeyra Masoumi,2 Robert S. Wallis,3 and W. Christopher Mathews1; for the Owen Clinic Study Group Departments of 1Medicine and 2Pathology, University of California, San Diego School of Medicine, San Diego; and 3Pfizer, New London, Connecticut Cryptococcomas have been described in AIDS patients in the setting of immune reconstitution inflammatory syndrome. We report the first case of human immunodeficiency virus-related inflammatory cerebral cryptococcoma to be treated with a recombinant human monoclonal tumor necrosis factor antagonist.
Up to 30% of patients with AIDS infected with Cryptococcus neoformans and treated with highly active antiretroviral therapy develop immune reconstitution inflammatory syndrome [1, 2]. Neurological worsening in cryptococcal disease can be attributed to subacute meningitis, meningoencophalitis, seizures, and uncommonly, ring-enhancing cryptococcomas [3-5]. Here, we present the first case of human immunodeficiency virus (HIV)-related inflammatory cerebral cryptococcoma to be treated with adalimumab (Humira), a recombinant human monoclonal immunoglobulin G1 tumor necrosis factor (TNF) antagonist.
Case report. The patient treated with adalimumab was a 28-year-old man who received a diagnosis of HIV infection in 2002. Secondary to concerns about stigma, he remained out of care until May 2006 when he presented with new onset of grand mal seizures. He received a diagnosis of cryptococcal meningitis on the basis of an initial serum cryptococcal antigen (CRAG) titer of 1:9375 and a cerebrospinal fluid (CSF) CRAG titer of 1:42. He was treated with liposomal amphotericin, 5-flucytosine, and levetiracetam. A ventriculoperitoneal shunt was placed to relieve persistent intracranial hypertension associated with optic nerve atrophy. Two months later, CSF cultures were sterile when a shunt malfunction necessitated revision. A few weeks later, combination antiretroviral therapy was initiated with efavirenz, lamivudine, and zidovudine. In August 2006, his HIV RNA level detected by polymerase chain reaction was <400 copies/mL, his CD4+ lymphocyte count was 20 cells/µL, and his serum CRAG titer was 1:4096. Treatment included fluconazole (200 mg daily), levetiracetam, and combination antiretroviral therapy simplification to coformulated efavirenz, emtricitabine, and tenofovir. Neurological status improved and surveillance computed tomography of brain without contrast in October 2006 showed the ventricular catheter and no evidence of a cerebral mass lesion.
In March 2008, nearly 22 months after the initial cryptococcal diagnosis, the patient developed increasing seizure frequency, new expressive aphasia, and right-sided weakness. Laboratory studies demonstrated an increase in CD4+ lymphocyte count from 80 to 149 cells/µL, a stable HIV RNA level <50 copies/mL, and a decrease in serum CRAG titer to 1:512. Tests of CSF demonstrated a white blood cell count of 0 cells/mm3, a red blood cell count of 3 cells/mm3, a glucose level of 59 mg/dL, a total protein level of 92 mg/dL, a negative India ink result, a CSF CRAG titer of 1:4, and a negative acid-fast bacilli smear result. Brain magnetic resonance imaging (MRI) before and after gadolinium revealed a new 5.3 x 2.5 x 3.6 cm complex lesion in the left temporal lobe that was causing mass effect with vasogenic edema, peripheral linear band enhancement, and mild medial uncal displacement. Stereotactic biopsy of the left temporal mass (Figure 1) confirmed meningitis with granulomatous encephalitis and cryptococcal elements. Fungal culture of the biopsy specimen was sterile. Divalproex was added to levetiracetam for improved seizure control.
In August 2008, brain MRI showed significant worsening of the left temporal lesion (6.0 x 3.4 x 3.3 cm) with significant increase in the surrounding vasogenic edema extending from the left temporal to the left frontal and parietal lobes with a new 7-mm midline shift, increased nodular leptomeningeal enhancement in the left temporal and frontoparietal regions, and worsening left uncal displacement. CSF tests maintained a noninflammatory profile (white blood cell count, 3 cells/mm3; red blood cell count, 0 cells/mm3; glucose level, 85 mg/dL; total protein level, 77 mg/dL; negative India ink result; CSF CRAG titer, 1:4). The symptoms and new cryptococcoma were attributed to immune reconstitution inflammatory syndrome. High-dose intravenous dexamethasone was administered with liposomal amphotericin and flucytosine. Repeat MRI imaging 1 week later showed improvement with reduction of midline shift from 7 mm to 2 mm. He was discharged on a 2-week taper regimen of dexamethasone, fluconazole 400 mg twice daily, and both levetiracetam and divalproex. From August through November 2008, the patient was hospitalized 7 more times for recurrent intractable seizure activity and worsening neurological deficits, including right-sided weakness, bradykinesia, and expressive aphasia. A brain MRI performed in November 2008 (Figure 2, left) showed marked vasogenic edema in those regions previously identified, the left frontal, temporal, and parietal lobes, decreased leptomeningeal enhancement, and no other significant changes, including the temporal lesion (5.2 x 2.3 x 3 cm). Despite adherence to therapy, the patient's clinical course worsened and neurosurgery had no intervention to offer. By December 2008, the patient was nonconversant and unable to perform activities of daily life.
On 4 December 2008, we obtained informed consent and initiated a TNF blockade with adalimumab (40 mg) subcutaneously every 2 weeks. Although the patient's purified protein derivative and QuantiFERON TB Gold test results were both negative, we prescribed isoniazid and pyridoxine because of concern about tuberculosis reactivation. Over the following 3 weeks, oral corticosteroids were tapered and stopped. One week after initiation of TNF blockade, the patient's gait and right hand function improved. Four weeks later, the patient experienced resolution of drooling, resumption of spontaneous conversation, and the ability to feed himself. Brain MRI imaging 4 weeks after starting adalimumb (Figure 2, right) showed marked decrease in left frontal, temporal, parietal lobes vasogenic edema, resolution of the left to right midline shift, persistent leptomeningeal enhancement, opening of the lateral ventricle, and no other change in the cryptococcoma. In February 2009, 10 weeks after the initiation of adalimumab, the patient continued to experience steady cognitive and motor improvement with independent activities of daily life. A substantial and sustained increase in CD4 count was observed 10 weeks after adalimumab initiation (CD4+ lymphocyte level, 696 cells/µL and 11%).
Central nervous system-related immune reconstitution inflammatory syndrome has been associated with neurological worsening in Mycobacterium tuberculosis infection, toxoplasmosis, progressive multifocal leukoencephalopathy, and C. neoformans-related meningitis and cryptococcoma formation [1, 6]. Although treatment options have included anti-inflammatories, suspension of antiretroviral therapy, and the addition of short courses of glucocorticoids for severe symptoms, the evidence supporting optimal therapeutics are limited [6, 7]. We have described a successful short-term alternative treatment with TNF-α blockade with adalimumab for the treatment of severely impairing neurological manifestations of a sterile inflammatory cerebral cryptococcoma. Although our patient initially responded to high doses of corticosteroids, neurological symptoms worsened each time the doses were tapered. Multiple CSF cultures and a brain biopsies remained sterile despite abundant evidence of residual antigen in brain tissue. In an attempt to find steroid-sparing treatment for this patient, we considered TNF-α blockade after noting the recent report of successful use of infliximab to treat severe paradoxical reaction to neurotuberculosis in a patient without HIV infection [8]. The adjunctive use of the TNF-antagonist etanercept has been described in HIV-associated pulmonary tuberculosis treatment [9]. These other clinical observations led us to postulate that high levels of TNF-α may characterize the inflammatory immune response to Cryptococcus. In considering the immunological mechanisms central to immune reconstitution cryptococcal disease, TNF-α recruitment of leukocytes is of major importance. Neutralization of TNF-α has been shown to reduce leukocyte recruitment by 80% [10]. Although TNF is considered a normal element of immune function, chronic inflammatory conditions can lead to excessive activation with significant tissue damage, such as that seen in rheumatoid arthritis [11]. TNF-α levels may be elevated in the CSF of patients cryptococcal meningitis [12, 13].
Adalimumab is a recombinant human immunoglobulin G1 monoclonal antibody specific for human TNF-α that binds to TNF-α and blocks interaction with the cell surface TNF receptors p55 and p75. Although the short-term response to TNF blockade in this patient has been favorable, many questions remain, including the optimal duration of treatment, the consequence of withdrawal of adalimumab, and potential adverse events and toxicities that have not yet manifested. The long-term effect of adalimumab on cryptococcal suppression for a patient receiving appropriate antifungal therapy remains unknown. Although new cryptococcal infections have been described in patients receiving TNF-blockade agents for rheumatoid arthritis (19 patients receiving infliximab or etanercept and 1 patient receiving adalimumab), it is not clear whether infection would have occurred if those patients had been receiving antifungal therapy [14]. On the basis of our experience with this case of cryptococcal immune reconstitution inflammatory syndrome and other reports of successful use of TNF-blockade in management of inflammatory manifestations of tuberculosis, we believe that systematic evaluation of the use of this class of immunomodulators for management of severe HIV-associated immune reconstitution disease is warranted.
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