QJM Advance Access originally published online on March 10, 2005
QJM 2005 98(4):255-274; doi:10.1093/qjmed/hci039
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Borna disease virus and the evidence for human pathogenicity: a systematic review
From the NPHS Communciable Disease Surveillance Centre, Cardiff, UK
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Background: Borna disease is a neurological viral disease of veterinary importance in central Europe, although Borna Disease virus (BDV) has been reported to be present in animals in most continents. The hypothesis that BDV is associated with human illness is controversial. However, should even a small fraction of mental illness be attributable to infection with BDV, this would be an important finding, not least because illness in that sub-population would, theoretically, be preventable.
Methods: We systematically reviewed the evidence: that BDV infects humans; for the role of BDV in human neuropsychiatric illness; to assess the suitability of currently available laboratory methods for human epidemiological studies.
Results: We identified 75 documents published before the end of January 2000, describing 50 human studies for BDV. There were five case studies and 44 (sero)prevalence studies, in a variety of patient groups. Nineteen prevalence studies (43%) investigated seroprevalence, 11 (25%) investigated viral prevalence and 14 (32%) investigated both. Seroprevalence ranged from 0% to 48%, and prevalence of virus or viral footprints from 0% to 82%.
Discussion: Although agreed gold standard tests and evidence for test specificity are lacking, there is evidence that humans are exposed to the virus. Further epidemiological studies are required to establish whether there are associations with disease.
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Introduction |
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Borna disease was first described in the early 19th century as an ‘equine brain disease with signs of agitation’1 and obtained its name following an epidemic in military horses in Borna, Saxony, in 1885. Since then, this naturally occurring meningoencephalitic disease has been described mainly in horses, but also in sheep, cattle and other domesticated and wild animals and in a variety of experimentally infected host species.2 The aetiological agent, Borna disease virus (BDV), also causes clinically definable and reproducible behavioural abnormalities in rats and non-human primates, some of which resemble neuropsychiatric disorders in humans. Viral tropism for the limbic system, including excitatory fields in the hippocampus, has been reported.3,4 These areas of the brain govern emotions important to survival, visceral responses and olfactory sensations, and processes involved in memory. The detection of BDV antibodies and viral RNA in peripheral blood mononuclear cells (PBMCs) from psychiatric patients has furthered the suggestion that BDV is linked to human neuropsychiatric illness.5
Routes of transmission are unproven, but thought to be via excreta or nasal, saliva and conjunctival secretions, either directly or indirectly through contaminated food and water. BDV RNA has been detected in secretions from horses by reverse transcriptase polymerase chain reaction (RT-PCR), both in the presence and absence of clinical illness.6,7 The detection of viral markers in blood raises the possibility of blood-borne transmission. The virus itself is an enveloped, non-segmented negative-strand RNA virus, Order Mononegavirales, Family Bornaviridae (ICV Jerusalem). Several features of its molecular biology are remarkable, and some are relevant to questions regarding the detection and spread of the virus, and the epidemiology of disease. For example, the virus replicates at lower levels than many other viruses, producing low numbers of infectious particles, although cell to cell transmission of incomplete particles may occur.8 Sensitive methods are therefore required for virus detection and identification. Demonstration of BDV antigens in populations of PBMCs from hospitalised psychiatric patients was first reported by Bode et al., in 1994,9 and the detection of BDV RNA in PBMCs of neonatally infected rats10 stimulated investigation and detection in psychiatric patients.11 The detection of antibodies in humans was first reported in 1985, in patients with depression and psychiatric disorders.12 The s-antigen (p40 and p24 complex) initiates the major humoral response, and has been the main target for serological studies.13
The hypothesis that BDV is associated with human clinical illness is controversial. However, should even a small fraction of mental illness be attributable to infection with BDV, this would be an important finding, not least because illness in that sub-population would be potentially preventable. We performed a systematic review14 to: evaluate the evidence that BDV infects humans; evaluate the role of BDV in human neuropsychiatric illness; and assess the suitability of currently available laboratory methods for human epidemiological studies.
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Methods |
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On-line and library databases were used to identify any studies involving the detection of BDV or its markers in human subjects. The following sources were searched using the term ‘Borna’: Medline, 1966 to January 2000; Institute for Science Information (Current Contents and Science Citation Index); British Library Document Supply Centre (including System for Information on Grey Literature); BIDS, 1981 to January 2000; BIOSYS via Datastar on-line index system, 1970 to January 2000; and the Cochrane Collaboration on CD-Rom. The search was not limited by language or sources. Inclusion criteria were studies published prior to January 2000, where the study participants = human, investigation = antibody or antigen or viral markers, outcomes = prevalence data. This was followed by hand searching of the literature for further references, and by consultation with leading researchers, facilitated by the first UK workshop on Borna Disease Virus in March 2000.15
The primary studies were identified and assessed by the same researcher (RC). Due to the nature of the investigations and variation in methods and study groups found, meta-analysis was not undertaken. However, results were summarized to describe the studies undertaken, show the groups investigated, the tissue tested, laboratory methods used and results obtained. To facilitate cross-referencing, reports were allocated a study number, generated in chronological order. Seroprevalence (antibody) studies were allocated a number prefixed with ‘Ab’, studies for the prevalence of viral antigens or genetic markers were numbered with a ‘V’ prefix, and studies for both, were given an ‘AbV’ prefix. Individual case studies were described separately.
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Results |
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We identified 75 publications that contained details of 50 human case or prevalence studies of Borna disease. The study designs identified were: five case studies of individual patients, and 44 (sero)prevalence studies of 138 groups of patients, including five studies of monozygotic twins (Tables 1–3
). In 24/44 (55%) studies covering 64 groups of patients, a control or a comparison group was also tested to compare prevalence and to measure association between markers for infection and clinical illness. Epidemiological and exposure data was additionally gathered in just two studies. There were no studies in which the study design described the random or systematic recruitment of cases, selection of controls or systematic recruitment of a study cohort.
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Case studies
A case of encephalitis with neurological and psychiatric symptomology was attributed to BDV when an IgG titre of 1/10 was detected.84 Two family cases of psychiatric disorders were detected among 200 seropositive psychiatric cases. In both families, in addition to the primary patient, a second family member also had psychiatric or neurological illness as well as BDV antibodies.85 BDV antibodies were detected in a patient with motor neurone disease at a titre of 1/20.86 Six blood samples were taken from a patient with somatization disorder and schizophrenia, and whole blood tested for p24 and p40 gene sequences by reverse transcriptive polymerase chain reaction (RT-PCR).87 All samples contained both gene sequences.
Prevalence studies
Nineteen of 44 (43%) studies investigated seroprevalence, 11/44 (25%) investigated the prevalence of BDV, and 14/44 (32%) investigated both. Seroprevalence studies have been conducted in USA (5 studies), Germany (3 studies), Austria (2 studies), Japan (2 studies), Taiwan, Thailand and Israel (1 study each), and there were multicentre studies involving USA and Germany (2 studies), and USA, Europe and Africa (1 study). The location of one study was not specified. Prevalence studies have been conducted in Japan (4 studies), USA (3 studies), Germany (2 studies), Korea (1 study), and in USA and Europe as a muticentre study. Studies of both seroprevalence and prevalence have been conducted in Japan (8 studies), Germany (3 studies), UK (1 study), the Netherlands (1 study), and in one multicentre study in USA and Germany. Studies were predominantly of adults, but children were included in one study.
Prevalence in patient groups
A variety of patient groups have been studied (Tables 4 and 5): unspecified psychiatric patients, schizophrenia cases, major depressive disorder, other psychiatric disorders, neurology patients, dementia/Alzheimer's disease, multiple sclerosis, epilepsy and chronic fatigue syndrome, HIV/AIDS, EBV, parasitological infections and occupational groups. Five groups of monozygotic twins, concordant and discordant for schizophrenia and other disorders, have been studied. Patient groups were defined by internationally recognized criteria (Research Diagnostic Criteria, ICD codes, DSM codes or CDC guidelines) in 18/44 (41%) studies. Control or comparison groups were either from the local community or blood donors.
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Prevalence and seroprevalence varied widely (Table 6) from 0% (no evidence of infection), while the highest seroprevalence in a single study group was 48% in 50 HIV Clade E patients with STDs in Thailand. The highest prevalence of virus was 82% in 11 brains of schizophrenic patients. However this is an outlying result, and the median for this patient group was 0%. Median seroprevalence figures were highest (11%) in HIV/AIDS patients, and the highest median prevalence was 13% in astrocytic brain tumours, although this was a single study.
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Laboratory methods
Seroprevalence was mainly investigated by the detection of antibodies in serum or plasma (28 studies) but also in CSF and sera (2 studies), CSF only (1 study) and unspecified material (2 studies) (Table 4). Studies for genetic markers and viral antigens have been sought mainly in peripheral blood and PBMCs or leukocytes (PBLs) (15 studies), brain tissue (7 studies), CSF (1 study) and CSF, brain and blood (2 studies) (Table 5).
The laboratory methods used to test for BDV antibodies were: indirect immunofluorescence antibody/assay (IFA) (10 studies), double stain IFA (5 studies), Western blot using viral proteins (6 studies), Western blot using recombinant proteins (4 studies), enzyme-linked immunosorbent assay using recombinant proteins (recombinant ELISA) (4 studies), recombinant reverse type (RT) sandwich ELISA (1 study), electrochemiluminescence assay (1 study), and direct IFA (1 study); in one study, the method was not stated.
Test methods for antigens or genetic markers were immunohistochemistry with nested PCR (1 study), flow cytometry (1 study), enzyme immunoassay (EIA) (1 study), EIA with nested RT-PCR (1 study), and RT-PCR (3 studies). The most frequently used was nested RT-PCR for p24 and/or p40 gene sequences (17 studies).
Issues of sensitivity and specificity, reproducibility and reliability were rarely addressed. A second test was usually used for confirmation of antibody tests (Western blotting), and genetic markers were confirmed by Southern blotting, immunohistochemistry, competition experiments, in-situ hybridization and direct sequencing.
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Discussion |
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The neurological or psychiatric symptoms of human patients studied for Borna disease are clinically diverse, and given the frequently multi-factorial aetiology of mental illness, an alternative explanation would be possible for all of these cases. The presence of markers of BDV infection in a clinically ill patient cannot infer causation (see reference 88). Indeed, individuals may be predisposed to BDV infection because of altered immunocompetence during repeated affective episodes.12 Clinical case studies, however, are valuable for generating hypotheses that should be tested further in systematic epidemiological studies. These patients also provide the opportunity for molecular studies and characterisation of virus isolates.
Seroprevalence studies provide information and evidence of exposure to BDV, while prevalence studies measure the proportion of current infection. Many such studies have been carried out, in a variety of patient groups most usually selected by a clinical illness. However, while simple in their design, the validity of these studies is dependent on the sensitivity, specificity and reproducibility both of the diagnostic tests performed and of the diagnostic criteria used in the classification of patients. A wide range of seroprevalence even within specific clinical groups has been demonstrated, which may reflect geographical variation in prevalence, selection bias, or the different laboratory methods used. Median seroprevalence was highest for unspecified psychiatric in-patients (7%), neurotic, personality adjustment and mood disorder patients (6%), schizophrenics (5%) and patients with chronic fatigue syndrome (5%). These data might indicate a direction for future epidemiological studies. It is also of note that at least one person tested seropositive in every clinical group examined, except for those patients suffering from mental retardation and dementia. Other groups have been examined, probably opportunistically, such as children and adults with parasitological infections and HIV patients. Any other rationale for screening such patient groups is unclear.
Prevalence studies are usually of limited value in aetiological research, since prevalence reflects both the incidence and probability of surviving the disease.88 In these studies, incident mental illness is the outcome and previous exposure to BDV is the exposure of interest. To conclude that BDV has a role in any of these clinical syndromes requires that the prevalence in these groups (cases) be compared with the prevalence in another ‘healthy’ or ‘non-case’ group (controls). The outcome of such a study would be a measure of the strength of association between having a marker for BDV exposure and/or infection and being in a certain clinical group, conventionally expressed as an odds ratio. However, the odds ratio calculated in a case-control study will be a biased estimate unless the controls selected are representative of the population that are well, but could become cases. We have carried out a quantitative systematic review but have not attempted any meta-analysis methods (see reference 89). As it was unlikely that the same disease diagnostic criteria were applied across studies, and because of the variation in selection of controls, no attempt has been made to combine data from individual studies to calculate summary odds ratios. In many published BDV seroprevalence studies, there was not enough information provided on the selection of controls for the reader to assess whether they represented well individuals belonging to at-risk populations. In some studies the ‘control’ group should be considered a ‘comparison’ group, and was often small. In most studies, odds ratios were not calculated. Chen et al.45 reported a positive association between presence of BDV antibodies and schizophrenia in Chinese patients from Taiwan and presented their results as an odds ratio (odds ratio 4.63, 95%CI 2.25–9.52).
Few studies have attempted to investigate possible sources of human exposure to BDV. One published study33 found high seroprevalence in those exposed to ostriches (46%), but did not investigate possible confounding factors that may be associated both with handling ostriches and exposure to BDV, such as contact with other farm animals. Takahashi et al.83 found a high seropositive rate in people living near horse farms. For some individual cases, animal exposure histories have been reported together with the results of the sampling of animal contacts (e.g. reference 84). Histories of exposure to seropositive animals or animals with a history of Borna disease is important in assessing putative human cases. Further epidemiological studies could be carried out to identify possible exposures to BDV. Further animal studies would also prove useful to establish the host range and assess possible modes of transmission of the virus, including vectors or reservoirs of infection. Also of interest would be any links between reported human cases. Chen et al.45 also found higher BDV seroprevalence in first degree relatives of schizophrenic patients and mental health workers. This raises the possibility of person-to-person transmission, but could also be the result of bias in selection of controls and/or confounding factors. Family clusters of Borna disease have been reported from Germany84 and the identification and follow-up of such clusters could prove useful in providing further information on the zoonotic potential of BDV. Cases in the published literature attributed to infection with BDV have been from the geographical areas in central Europe where Borna disease is endemic in animals. Whilst this would appear consistent with the hypothesis that Borna disease is a zoonosis, it may simply be the result of ascertainment or publication bias.
There does appear to be evidence that people are exposed to BDV, or at least have antibodies that are reactive to BDV antigens. However, while a number of seroprevalence studies have been done, it is still difficult to conclude much about which population groups are most at risk and the natural history of human infection. Longitudinal studies are necessary to follow the serological response and clinical course in patients identified as antibody positive. Evidence that humans are infected with BDV, or a BDV-like virus, rather than exposed, is even more controversial. Conflicting results have arisen and evidence of infection or exposure by the detection of viral markers or antibodies, is not consistently linked to one currently defined disease in humans. Some results show that BDV RNA is detected in the absence of antibodies in serum, further complicating matters.
An agreed gold standard diagnostic test for BDV is lacking, and there is speculation concerning the specificity of the tests currently used. It has been suggested that PCR positives are the result of laboratory contamination.90,91 Further investigations have revealed novel isolates that may not amplify with previously described markers, and variation may be greater than previously thought.92 Multi-centre studies have tested the same samples in a number of different laboratories by a number of different methods but this has been performed in order to confirm a result rather than to validate tests in terms of their sensitivity and specificity, reproducibility and reliability. Of course, it is not possible to validate tests using populations of known cases and controls, because is not yet clear what criteria should be used to define a human case. A well-validated blood test would appear to be the most suitable test for epidemiological studies. Certainly there are practical difficulties in using brain tissue or CSF. In the absence of consensus as to the validity, it would appear that an antibody test would be the most suitable test by which to screen large population samples. A ‘gold-standard’ serological test for Borna disease virus should be developed that is suitable for testing animal and human samples in epidemiological studies. Clinical specimens should be swapped between experts, and data should be gathered on the sensitivity, specificity and reproducibility of any such ‘gold-standard’ developed. This might be most feasible using sera from clinical cases of Borna disease in animals.
The hypothesis that Borna disease is a zoonosis merits serious consideration and is worthy of further investigation.
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Acknowledgments |
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This research was funded by the Health and Safety Executive (Project number: 3490/R52.118).
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Footnotes |
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Address correspondence to Dr D.Rh. Thomas, NPHS Communicable Disease Surveillance Centre, Abton House, Wedal Road, Cardiff CF14 3QX. email: daniel.thomas{at}nphs.wales.nhs.uk
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References |
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