A Chronic Illness Characterized by Fatigue, Neurologic and Immunologic Disorders, and Active Human Herpesvirus Type 6 Infection
Arch Intern Med.1992; 152: 1611-1616.
Dedra Buchwald, MD; Paul R. Cheney, MD, PhD; Daniel L. Peterson, MD; Berch Henry, PhD; Susan B. Wormsley, BS; Ann Geiger, BA; Dharam V. Ablashi, DVM; S. Zaki Salahuddin, MS; Carl Saxinger, PhD; Royce Biddle, MD; Ron Kikinis, MD; Ferenc A. Jolesz, MD; Thomas Folks, PhD; N. Balachandran, PhD; James B. Peter, MD, PhD; Robert C. Gallo, MD; and Anthony L. Komaroff, MD
Abstract
▪ Objective:To conduct neurologic, immunologic, and virologie studies in patients with a chronic debilitating illness of acute onset.
▪ Design: Cohort study with comparison to matched, healthy control subjects.
▪ Patients: We studied 259 patients who sought care in one medical practice; 29% of the patients were regularly bedridden or shut-in.
▪ Main Outcome Measures: Detailed medical history, physical examination, conventional hematologic and chemistry testing, magnetic resonance imaging (MRI) studies, lymphocyte phenotyping studies, and assays for active infection of patients' lymphocytes with human herpesvirus type 6 (HHV-6).
▪ Main Results: Patients had a higher mean ( SD) CD4/CD8 T-cell ratio than matched healthy controls (3.16 1.5 compared with 2.3 1.0, respectively; P < 0.003). Magnetic resonance scans of the brain showed punctate, subcortical areas of high signal intensity consistent with edema or demyelination in 78% of patients (95% CI, 72% to 86%) and in 21% of controls (CI, 11% to 36%) (P < 10-9). Primary cell culture of lymphocytes showed active replication of HHV-6 in 79 of 113 patients (70%; CI, 61% to 78%) and in 8 of 40 controls (20%; CI, 9% to 36%) (P < 10-8), a finding confirmed by assays using monoclonal antibodies specific for HHV-6 proteins and by polymerase chain reaction assays specific for HHV-6 DNA.
▪ Conclusions: Neurologic symptoms, MRI findings, and lymphocyte phenotyping studies suggest that the patients may have been experiencing a chronic, immunologically mediated inflammatory process of the central nervous system. The active replication of HHV-6 most likely represents reactivation of latent infection, perhaps due to immunologic dysfunction. Our study did not directly address whether HHV-6, a lymphotropic and gliotropic virus, plays a role in producing the symptoms or the immunologic and neurologic dysfunction seen in this illness. Whether the findings in our patients, who came from a relatively small geographic area, will be generalizable to other patients with a similar syndrome remains to be seen.
Article and Author Information
For current author affiliations and addresses, see end of text.
Grant Support: By the National Institutes of Health (grants R01AI 26788, R01AI27314, U01AI32246, 2P01CA41167 and SK04NS01083); and by funds from M. Palevsky, S. Harris, the S. Sydney DeYoung Foundation, the Minann Foundation, the Pioneer Foundation, the Rowland Foundation, and Sierra Research Institute. Dr. Buchwald was supported by a fellowship from the Henry J. Kaiser Family Foundation and by a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression.
Requests for Reprints: Anthony L. Komaroff, Division of General Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston MA 02115.
Current Author Addresses: Dr. Buchwald: Harborview Medical Center, General Internal Medicine, 325 Ninth Avenue, ZA-60, Seattle, WA 98104-2402.
Dr. Cheney: 10620 Park Avenue, Suite 234, Charlotte, NC 28210.
Dr. Peterson: 865 Tahoe Boulevard, Suite 306, Incline Village, NV 98450.
Dr. Henry: Washoe County Sheriffs Division, Forensic Science Division, 911 Parr Boulevard, Reno NV 89512-1000.
Ms. Wormsley: Cytometry Associates, 11575 Sorrento Valley Road, #204, San Diego, CA 92121.
Ms. Geiger: 1737 Broadview Lane, #416, Ann Arbor, MI 48105.
Dr. Ablashi: Laboratory of Cellular and Molecular Biology, Building 37, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Prof. Salahuddin: Huntington Memorial Hospital, University of Southern California, AIDS Research Laboratory, 744 Fairmont Avenue, Pasadena, CA 91105.
Drs. Saxinger and Gallo: Laboratory of Tumor Cell Biology, Building 37, Room 6B10, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Dr. Biddle: Stockton Radiology Medical Group, 1617 North California Street, California Medical Center, Suite 1A, Stockton, CA 95204.
Drs. Kikinis, Jolesz, and Komaroff: Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.
Dr. Folks: Division of Virology, Centers for Disease Control, 1600 Clifton Road, Atlanta GA 30333.
Dr. Balachandran: Department of Microbiology, University of Kansas Medical Center, Kansas City, KS 66103.
Dr. Peter: Specialty Laboratories, Inc., P.O. Box 92722, Santa Monica, CA 90009.
Arch Intern Med.1992; 152: 1611-1616.
Dedra Buchwald, MD; Paul R. Cheney, MD, PhD; Daniel L. Peterson, MD; Berch Henry, PhD; Susan B. Wormsley, BS; Ann Geiger, BA; Dharam V. Ablashi, DVM; S. Zaki Salahuddin, MS; Carl Saxinger, PhD; Royce Biddle, MD; Ron Kikinis, MD; Ferenc A. Jolesz, MD; Thomas Folks, PhD; N. Balachandran, PhD; James B. Peter, MD, PhD; Robert C. Gallo, MD; and Anthony L. Komaroff, MD
Abstract
▪ Objective:To conduct neurologic, immunologic, and virologie studies in patients with a chronic debilitating illness of acute onset.
▪ Design: Cohort study with comparison to matched, healthy control subjects.
▪ Patients: We studied 259 patients who sought care in one medical practice; 29% of the patients were regularly bedridden or shut-in.
▪ Main Outcome Measures: Detailed medical history, physical examination, conventional hematologic and chemistry testing, magnetic resonance imaging (MRI) studies, lymphocyte phenotyping studies, and assays for active infection of patients' lymphocytes with human herpesvirus type 6 (HHV-6).
▪ Main Results: Patients had a higher mean ( SD) CD4/CD8 T-cell ratio than matched healthy controls (3.16 1.5 compared with 2.3 1.0, respectively; P < 0.003). Magnetic resonance scans of the brain showed punctate, subcortical areas of high signal intensity consistent with edema or demyelination in 78% of patients (95% CI, 72% to 86%) and in 21% of controls (CI, 11% to 36%) (P < 10-9). Primary cell culture of lymphocytes showed active replication of HHV-6 in 79 of 113 patients (70%; CI, 61% to 78%) and in 8 of 40 controls (20%; CI, 9% to 36%) (P < 10-8), a finding confirmed by assays using monoclonal antibodies specific for HHV-6 proteins and by polymerase chain reaction assays specific for HHV-6 DNA.
▪ Conclusions: Neurologic symptoms, MRI findings, and lymphocyte phenotyping studies suggest that the patients may have been experiencing a chronic, immunologically mediated inflammatory process of the central nervous system. The active replication of HHV-6 most likely represents reactivation of latent infection, perhaps due to immunologic dysfunction. Our study did not directly address whether HHV-6, a lymphotropic and gliotropic virus, plays a role in producing the symptoms or the immunologic and neurologic dysfunction seen in this illness. Whether the findings in our patients, who came from a relatively small geographic area, will be generalizable to other patients with a similar syndrome remains to be seen.
Article and Author Information
For current author affiliations and addresses, see end of text.
Grant Support: By the National Institutes of Health (grants R01AI 26788, R01AI27314, U01AI32246, 2P01CA41167 and SK04NS01083); and by funds from M. Palevsky, S. Harris, the S. Sydney DeYoung Foundation, the Minann Foundation, the Pioneer Foundation, the Rowland Foundation, and Sierra Research Institute. Dr. Buchwald was supported by a fellowship from the Henry J. Kaiser Family Foundation and by a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression.
Requests for Reprints: Anthony L. Komaroff, Division of General Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston MA 02115.
Current Author Addresses: Dr. Buchwald: Harborview Medical Center, General Internal Medicine, 325 Ninth Avenue, ZA-60, Seattle, WA 98104-2402.
Dr. Cheney: 10620 Park Avenue, Suite 234, Charlotte, NC 28210.
Dr. Peterson: 865 Tahoe Boulevard, Suite 306, Incline Village, NV 98450.
Dr. Henry: Washoe County Sheriffs Division, Forensic Science Division, 911 Parr Boulevard, Reno NV 89512-1000.
Ms. Wormsley: Cytometry Associates, 11575 Sorrento Valley Road, #204, San Diego, CA 92121.
Ms. Geiger: 1737 Broadview Lane, #416, Ann Arbor, MI 48105.
Dr. Ablashi: Laboratory of Cellular and Molecular Biology, Building 37, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Prof. Salahuddin: Huntington Memorial Hospital, University of Southern California, AIDS Research Laboratory, 744 Fairmont Avenue, Pasadena, CA 91105.
Drs. Saxinger and Gallo: Laboratory of Tumor Cell Biology, Building 37, Room 6B10, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Dr. Biddle: Stockton Radiology Medical Group, 1617 North California Street, California Medical Center, Suite 1A, Stockton, CA 95204.
Drs. Kikinis, Jolesz, and Komaroff: Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.
Dr. Folks: Division of Virology, Centers for Disease Control, 1600 Clifton Road, Atlanta GA 30333.
Dr. Balachandran: Department of Microbiology, University of Kansas Medical Center, Kansas City, KS 66103.
Dr. Peter: Specialty Laboratories, Inc., P.O. Box 92722, Santa Monica, CA 90009.
