Laboratory diagnosis of human cytomegalovirus (HCMV) central nervous system disease in AIDS patients

Abstract

Human cytomegaloviruses (HCMV) are a subgroup of herpesviruses that can spread efficiently in normal immunocompetent individuals, causing little overt disease [1]. Latency or a low level persistent shedding of virus generally follows primary infection. Under certain conditions re-infection can also occur. This large reservoir of latently infected individuals can serve as a source of infection after viral re-activation for persons with immunosuppression, including bone marrow and solid organ transplant recipients [2,3] and persons with acquired immunodeficiency syndrome (AIDS) [4–6]. Cytomegalovirus is a primary cause of life threatening illness and contributes significantly to morbidity and morality in HIV infected persons [4–8]. HCMV invasive disease may be due to primary infection but generally is related to HCMV reactivation in association with progression to AIDS and CD4 T cell counts B100 cells per mm [9–11]. Clinical manifestations of HCMV infection in AIDS patients include gastrointestinal disease, retinitis, pneumonia and central nervous system (CNS) disease [5]. Pathological studies of autopsy specimens have demonstrated that 15–25% of AIDS patients have HCMV-CNS disease at the time of death [7]. The distinct HCMV neurological syndromes associated with AIDS include peripheral neuropathy, ventriculoencephalitis, myelitis/polyradiculopathy, and diffuse micronodular encephalitis with dementia [12]. Although these distinct syndromes are well described, the clinical presentations of HCMV-CNS disease can often be nonspecific and difficult to differentiate from other AIDS related neurologic diseases, including AIDS Dementia Complex (ADC) and other opportunistic infections [13]. The presumptive diagnosis of HCMV-CNS disease is primarily based upon clinical presentation, serologic testing, neuroradiologic studies including computerized tomography (CT) and magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) chemistries and the magnitude and types of CSF pleocytosis [5,12,14]. CSF from AIDS patients with HCMV-CNS disease often demonstrate an elevated white blood cell count with either a predominance of lymphocytic or polymorphonuclear leukocytes, as demonstrated in cases of HCMV polyradiculopathy [14–16]. In addition, CSF protein may be elevated and CSF glucose normal or low [15,16]. Viral culture of CSF may yield HCMV, however, several studies have clearly demonstrated that CSF culture is positive in only approximately 50% of patients with HCMV-CNS disease [14,17–19]. Lack of culture sensitivity may be attributed to the loss of viability during specimen transport and the small number of viral particles present or incomplete virions. In addition, HCMV culture is relatively slow, requiring between 1 and 4 weeks for positivity. Various technologies, including antigen detection assays and molecular methods have been developed to more accurately and rapidly detect HCMV in patients with active HCMV disease (review in [20]). The application of these technologies for the detection of clinically relevant HCMV in the CNS could rapidly and accurately diagnose HCMV-CNS disease and decrease the number of patients placed unnecessarily on empiric therapy [21]. In addition, monitoring HCMV levels in the CNS after the initiation of therapy could provide a measure for * Tel.: +1-516-7191079; fax: +1-516-7191254. E-mail address: cginocch@nshs.edu (C.C. Ginocchio).