Absence of evidence for bornavirus infection in schizophrenia, bipolar disorder and major depressive disorder.

In 1983, reports of antibodies in subjects with major depressive disorder (MDD) to an as-yet uncharacterized infectious agent associated with meningoencephalitis in horses and sheep led to molecular cloning of the genome of a novel, negative-stranded neurotropic virus, Borna disease virus (BDV). This advance has enabled the development of new diagnostic assays, including in situ hybridization, PCR and serology based on recombinant proteins. Since these assays were first implemented in 1990, more than 80 studies have reported an association between BDV and a wide range of human illnesses that include MDD, bipolar disorder (BD), schizophrenia (SZ), anxiety disorder, chronic fatigue syndrome, multiple sclerosis, amyotrophic lateral sclerosis, dementia and glioblastoma multiforme. However, to date there has been no blinded case-control study of the epidemiology of BDV infection. Here, in a United States-based, multi-center, yoked case-control study with standardized methods for clinical assessment and blinded serological and molecular analysis, we report the absence of association of psychiatric illness with antibodies to BDV or with BDV nucleic acids in serially collected serum and white blood cell samples from 396 subjects, a study population comprised of 198 matched pairs of patients and healthy controls (52 SZ/control pairs, 66 BD/control pairs and 80 MDD/control pairs). Our results argue strongly against a role for BDV in the pathogenesis of these psychiatric disorders.

Oversight and monitoring of blood safety in the United States.

The US blood safety vigilance system is composed of a network of interwoven programs, now organized under a formal structure, with the Assistant Secretary of Health and DHHS Blood Safety Committee bearing overall responsibility. It takes advantage of the breadth of expertise and close collaborative relationship of transfusion medicine and infectious disease scientists within and outside of the government. Core elements include an array of ongoing surveillance programs for monitoring established as well as new and emerging infectious agents that may pose a risk to blood safety, and the existence of historical and contemporary repositories of donor and recipient specimens that enable rapid investigation of putative new risks. This report summarizes the historical events that shaped the US blood safety oversight system, reviews the current organization and decision-making processes related to blood safety issues, and highlights key surveillance systems and research programs which monitor the US and global blood supplies for known and potential emerging risks.

Blood safety.

Since blood is a biologic product, it is unlikely that the risk for transfusion-transmitted infection will ever be reduced to zero. The approach to emerging infections associated with transfusion of blood and blood products includes assessing the transmissibility of the agent by this route; developing effective prevention strategies, including screening tests and donor deferral policies; improving viral and bacterial inactivation procedures; and surveillance for known, as well as emerging and poorly characterized, transfusion-transmitted agents. Vigilance is needed to help ensure proper balance between safety and the availability of blood. Finally, vigilance needs to extend to the developing world, where the basic elements to reduce transfusion-transmitted infections and systems of disease surveillance are often not available.

Emerging issues in blood safety.

Improvements in donor selection, testing of donors for markers of infection, and viral inactivation of plasma-derived products have helped reduce the risk of transfusion-associated infections, including hepatitis B (HBV), hepatitis C (HCV), and human immunodeficiency viruses (HIV). The potential for transmission of emerging infections is illustrated by current concerns about group O strains of HIV, nonenveloped viruses, newly discovered microbial agents, prions, Chagas' disease, tick-borne infections, and the need to assess the frequency of transfusion reactions associated with bacterial contamination.

Assessment of occupational risk for hantavirus infection in Arizona and New Mexico.

Differentiating occupational exposure from other potential domestic or recreational exposure(s) for Sin Nombre virus (SNV) infection is an epidemiologic challenge. Interviews on work-related activities were conducted, and serum specimens were obtained from 494 workers in Arizona and New Mexico. These workers may have been exposed to rodents and rodent excreta at work, but their primary occupation did not require rodent contact (National Park Service [n = 193]; Navajo Agricultural Product Industry [n = 65], utility companies [n = 169] and plumbing and heating contractors [n = 67]. Within each occupational group (farm workers [n = 57], laborers [n = 20], professionals [n = 70], repairers [n = 211], service industry workers [n = 83], and technicians [n = 53], the majority of workers reported working in areas that had rodent droppings (range, 75 to 95%); 70% of laborers and 64% of service industry workers reported handling rodents. More than 60% of workers in each group, except technicians, reported reopening and cleaning or working in closed spaces. Approximately 90% of laborers, repairers, and farm workers reported hand-plowing. Although the risk for occupationally related SNV infection appears to be low, workers frequently performed risk activities associated with hantavirus pulmonary syndrome (HPS). All workers were seronegative for SNV by enzyme-linked immunoassay or Western blot testing. These findings, the known occupational exposure of some HPS cases, and the high HPS case-fatality rate (52%) support the need for recommendations to reduce human contact with rodents in the workplace. Increased understanding of hantavirus transmission to humans will help focus future recommendations to minimize human exposures effectively.

HTLV-associated myelopathy in a cohort of HTLV-I and HTLV-II-infected blood donors. The REDS investigators.

OBJECTIVE: HTLV-I-associated myelopathy (HAM) is a slowly progressive spastic paraparesis caused by infection with human T-lymphotropic virus type I (HTLV-I). The prevalence of HAM among those infected with HTLV-I is poorly defined, and the association of a similar myelopathy with HTLV-II infection has not been confirmed. DESIGN: Cross-sectional examination of HTLV-I, HTLV-II, and control subjects from the baseline visit of a cohort study. SETTING/ SUBJECTS: Persons testing HTLV seropositive at the time of blood donation at five U.S. blood centers, their seropositive sex partners, and a matched control group of HTLV seronegative blood donors. MEASUREMENTS: HTLV-I and HTLV-II were differentiated by serology and/or polymerase chain reaction. All subjects received systematic neurologic screening examinations. RESULTS: A diagnosis of myelopathy was confirmed in four of 166 HTLV-I subjects (2.4%, 95% confidence interval 0.7%, 6.1%) and in one of 404 HTLV-II subjects (0.25%, 95% confidence interval 0.0%, 0.6%). None of the 798 controls had a similar myelopathy, although one had longstanding typical multiple sclerosis. CONCLUSIONS: Our data also suggest that HAM occurs more frequently among HTLV-I-infected subjects than reported by previous studies. The HTLV-II infected myelopathy patient identified in this cohort, together with three other case reports in the literature, implies a pathogenic role for this human retrovirus. The diagnosis of HTLV-associated myelopathy should be considered in cases of spastic paraparesis or neurogenic bladder when risk factors for HTLV-I or HTLV-II infection are present.

Risk of occupational exposure to potentially infectious nonhuman primate materials and to simian immunodeficiency virus.

Five hundred fifty persons who worked with nonhuman primates (NHP) or with NHP material in 13 North American research institutions were surveyed for potential occupational exposures and tested for antibodies to simian immunodeficiency virus (SIV). Needlesticks and mucocutaneous exposures were reported more frequently among persons who handled SIV-negative or SIV-status-unknown (SIV-N/U) animals (36% and 35%) or who worked with SIV-N/U material in the laboratory (18% and 17%) than among persons who handled SIV-positive NHP (SIV-P) (9% and 4%) or worked with SIV-P material (6% and 8%). The risk for needlesticks when working with both SIV-N/U and SIV-P animals and the risk for mucocutaneous exposures from SIV-N/U animals increased with the number of years working with NHP. Persons who performed invasive tasks (e.g., obtaining blood samples, performing surgery/autopsies) were more likely than others to sustain needlesticks (adjusted OR = 3.55, 95%CI = 1.40-9.02). Two (0.4%) of 550 persons had antibodies to SIV. One appears to be infected with SIV, as previously reported. These data suggest that persons who work with NHP or with NHP material are at risk for occupational exposure to potentially infectious materials including SIV. Prevention strategies are needed to reduce the risk for needlesticks and mucocutaneous exposures around all NHP, and safety guidelines should emphasize prevention options for invasive tasks performed with animals.

An international collaborative study of the effects of coinfection with human T-lymphotropic virus type II on human immunodeficiency virus type 1 disease progression in injection drug users.

To determine whether human T-lymphotropic virus (HTLV) type II coinfection affects progression of human immunodeficiency virus type 1 (HIV) infection, longitudinal data on 370 HIV-infected injection drug users (IDUs) with known HIV seroconversion dates from four cohort studies were pooled. HTLV infection was determined by EIA and confirmed and typed by Western blot. Proportional hazards models were used to determine whether HTLV-II infection was associated with AIDS or AIDS-related mortality. Regression analyses were used to compare declines in CD4 cell percents in singly and dually infected persons. Of 370 IDUs, 61 (16%) were HTLV-II-coinfected. During follow-up, 43 (12%) developed and 24 (6%) died of AIDS. HTLV-II coinfection was not associated with progression to AIDS (relative hazard [RH], .82; 95% confidence interval [CI], 0.34-1.94]) or AIDS mortality (RH, 1.69; 95% CI, 0.62-4.60). Rates of decline in CD4 cell percent were similar in singly and dually infected IDUs. These results suggest that HTLV-II does not affect the progression of HIV infection.

Male-to-female transmission of human T-cell lymphotropic virus types I and II: association with viral load. The Retrovirus Epidemiology Donor Study Group.

SUMMARY: Risk factors for male-to-female sexual transmission of human T-lymphotropic virus types I and II (HTLV-I/II) were investigated among HTLV-seropositive volunteer blood donors and their long-term (> or = 6 month) sex partners. Direction of transmission in concordantly seropositive pairs was assessed by analyzing risk factors for HTLV infection. Donors and their partners were also questioned regarding sexual behaviors during their relationships; HTLV antibody titers and viral load were determined for specimens from male partners. Among 31 couples in whom HTLV-infected men likely transmitted infection to their partners (11 HTLV-I and 20 HTLV-II) and 25 male-positive, female-negative couples (8 HTLV-I and 17 HTLV-II), HTLV transmitter men had been in their relationships longer (mean 225 months vs. 122 months) and had higher viral loads (geometric mean 257,549 vs. 2,945 copies/300,000 cells for HTLV-I; 5,541 vs. 118 copies/300,000 cells for HTLV-II) than non-transmitters (P = 0.018 and P = 0.001 for duration of relationship and viral load, respectively, logistic regression analysis). Transmitter men also tended to have higher antibody titers against various env and whole virus proteins than non-transmitters. The identification of high viral load and duration of relationship as risk factors provides a biologically plausible framework in which to assess risk of sexual transmission of the HTLVs.

Hantavirus pulmonary syndrome: the first 100 US cases.

In the spring of 1993, hantavirus pulmonary syndrome (HPS) "emerged" in the southwestern United States, where a multiagency investigation led to the rapid description of this new clinical entity and its etiology. Analysis of the first 100 US cases identified showed that the disease was distributed in 21 states, had gone unrecognized since at least 1959, and had a distinct spring-early summer seasonality. Of the infected persons, 54% were male; 63% were Caucasian, 35% were Native American, and 2% were African American. The average age of case-patients was 34.9 years, and 8 were children or adolescents aged < or = 16 years. The overall case-fatality rate was 52%. There was a 91% concordance among serologic, immunohistochemical, and molecular results. HPS in the United States is caused by at least three newly described pathogenic hantaviruses, each of which has a distinct rodent host, and cases of HPS have been recently recognized in Canada and South America. National surveillance of this sporadic disease remains essential for further defining the epidemiology and clinical spectrum.

Retroviral risk factors in patients with autoimmune disease.

OBJECTIVE: Retroviruses can cause immunoregulatory disturbances and may play a role in the pathogenesis of autoimmune disorders. Little is known about the frequency of behavioral risk factors for exogenous retroviral infections in patients with autoimmune diseases. We compare the frequency of recognized risk factors for retroviral infections among patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and controls. METHODS: Patients with SLE and RA from a university rheumatology clinic and control patients were enrolled in this study. The presence of retroviral risk factors (intravenous drug use, prostitution, increased number of sex partners, sexually transmitted diseases, high risk sex partners, blood transfusion) was determined by a self-administered questionnaire. RESULTS: We surveyed 81 patients with SLE and 117 with RA and 100 healthy controls. Patients in all groups reported similar exposure to all risk factors surveyed for retroviral infection except sexually transmitted disease, which was reported more often in patients with SLE (25% of SLE versus 11% of RA and 11% of controls, p = 0.013). CONCLUSION: Self-reported retroviral risk factors were generally not increased in patients with autoimmune disease compared to healthy controls; the role of exogenous retroviruses in the pathogenesis of SLE and RA remains unclear.

Utility of emergency, telephone-based national surveillance for Hantavirus pulmonary syndrome. Hantavirus Task Force.

On May 27, 1993, in response to the outbreak investigation of newly recognized Hantavirus pulmonary syndrome (HPS) in the Four Corners states (New Mexico, Arizona, Utah, and Colorado), the Centers for Disease Control and Prevention established a national surveillance case definition for severe, unexplained respiratory disease to determine the extent of HPS throughout the United States. A toll-free telephone hotline number was instituted to provide updated information about unexplained respiratory illness and to serve as a passive mechanism for reporting suspected cases. Clinical information was obtained from callers reporting suspected cases, and diagnostic specimens and medical record reviews were requested from health care providers. From June 3 through December 31, 1993, the hotline received 21,443 telephone inquiries; callers identified 280 suspected cases living outside the Four Corners states with at least one specimen available for diagnostic testing. By December 31, 1993, 21 confirmed cases (age range, 14 to 58 years) residing in 11 states outside the Four Corners region had been identified. This passive surveillance system was successful in rapidly identifying the widespread sporadic geographic distribution for HPS cases throughout the United States and could serve as a model for similar emergencies. Expanding and coordinating surveillance systems for the early detection, tracking, and evaluation of emerging infections is a critical component of disease prevention.

Retrospective diagnosis of hantavirus pulmonary syndrome, 1978-1993: implications for emerging infectious diseases.

OBJECTIVE: To investigate the occurrence of unrecognized cases of hantavirus pulmonary syndrome preceding the detection of the 1993 outbreak in the southwestern United States and the initial description of the syndrome. DESIGN: Retrospective clinicopathologic and immunohistologic study. PATIENTS: Eighty-two patients who died prior to April 1993 with histologically unexplained noncardiogenic pulmonary edema. METHODS: Clinicopathologic review and immunohistochemical evaluation of autopsy tissues for evidence of hantaviral infection. RESULTS: Twelve retrospective fatal cases of hantavirus pulmonary syndrome were identified through clinicopathologic review and immunohistochemical testing of tissues. Patients' ages ranged from 16 to 49 years. The earliest identified case occurred in 1978, 15 years prior to the outbreak of hantavirus pulmonary syndrome in the southwestern United States. Immunohistochemical testing showed widespread deposition of hantaviral antigens, primarily within endothelial cells, similar to the pattern observed with current hantavirus pulmonary syndrome cases. CONCLUSIONS: Although hantavirus pulmonary syndrome was first recognized in 1993, the findings from this study document the earlier existence of this disease. These findings underscore the need for systematic archiving and analysis of clinical information and specimens from patients with diseases of unknown etiology to facilitate the study of new clinical entities and their associated etiologic agents.

Hantavirus pulmonary syndrome in Florida: association with the newly identified Black Creek Canal virus.

Hantavirus pulmonary syndrome (HPS) is a recently recognized viral zoonosis. The first recognized cases were caused by a newly described hantavirus. Sin Nombre virus (previously known as Muerto Canyon virus), isolated from Peromyscus maniculatus (deer mouse). We describe a 33-year-old Floridian man who resided outside the ecologic range of P maniculatus but was found to have serologic evidence of a hantavirus infection during evaluation of azotemia associated with adult respiratory distress syndrome. Small mammal trapping conducted around this patient's residence demonstrated the presence of antihantaviral antibodies in 13% of Sigmodon hispidus [cotton rat). Serologic testing using antigen derived from the Black Creek Canal hantavirus subsequently isolated from this rodent established that this patient was acutely infected with this new pathogenic American hantavirus. HPS is not confined to the geographical distribution of P maniculatus and should be suspected in individuals with febrile respiratory syndromes, perhaps associated with azotemia, throughout the continental United States.

Molecular subtyping of human T-cell lymphotropic virus type 2 by single-strand conformation polymorphism analysis. Retrovirus Epidemiology Donor Study Group.

Molecular subtyping of human T-cell lymphotropic virus type 2 (HTLV-2) by the currently used method of restriction fragment length polymorphism analysis may not be sufficiently discriminatory for transmission studies because of the predominance of single restriction types in various HTLV-2-infected populations. The utility of single-strand conformations polymorphism (SSCP) analysis was evaluated as a tool to improve the sensitivity of the subtyping of HTLV-2. The assay was designed to target a highly variable region in the long terminal repeat and was shown to be able to detect single nucleotide changes in cloned HTLV-2 sequences. Analysis of 52 HTLV-2 samples, of which 32 were from 16 sex partner pairs (16 males, 16 females), showed nine different SSCP patterns. Identical SSCP results were obtained for each of the 16 couples, suggesting the presence of similar viral genotypes and, therefore, supporting the likelihood of sexual transmission of HTLV-2 in each of these couples. Furthermore, SSCP analysis of seven HTLV-2 samples of the same restriction type (b5) showed five different SSCP patterns. Nucleotide sequencing of two samples with distinct SSCP patterns confirmed the sequence differences. SSCP provides a facile and discriminatory tool for the differentiation of HTLV-2 strains, including those previously indistinguishable by restriction fragment length polymorphism.

Investigation of proviral load in individuals infected with human T-lymphotropic virus type II.

Human T-lymphotrophic virus type II (HTLV-II) has not yet been associated with any disease. Little is known about the proviral loads of HTLV-II in vivo and its relationship, if any, to lack of pathogenicity. We determined the HTLV-II proviral copy number in peripheral blood lymphocyte (PBL) samples from 49 HTLV-II-infected individuals, of whom 25 were coinfected with human immunodeficiency virus type 1 (HIV-1). The HTLV-II copy numbers were determined by polymerase chain reaction (PCR) amplification of end-point dilutions of PBL lysates, followed by hybridization to a 32P-labeled HTLV-II-specific probe. The proviral copy number for the 49 samples ranged from < 0.02 to 200 per 1000 PBLs; 6% had < 0.02, 16% had 0.02, 20% had 0.2, 18% had 2, 31% had 20, and 8% had 200 copies per 1000 PBLs. The distributions of HTLV-II copy numbers in the coinfected and singly infected subgroups were not significantly different (Wilcoxon rank sum, p = 0.24). In the coinfected subgroup, there was no significant correlation between the HTLV-II proviral load and the counts of CD4-positive lymphocytes or CD8-positive lymphocytes (Spearman Coefficient = 0.26, p = 0.20; = 0.091, p = 0.67, respectively). Our data demonstrate the presence of a wide range of viral loads in HTLV-II-infected individuals. The high viral loads (> or = 20 copies/1000 lymphocytes) detected in 39% of our samples suggest that the low pathogenicity of HTLV-II is not related to the presence of low viral loads in the infected subjects. Our data from the HIV-1 coinfected individuals show no apparent effect of HIV-1 on HTLV-II proviral loads.