Temporal Relationship Between Elevation of Epstein-Barr Virus Antibody Titers and Initial Onset of Neurological Symptoms in Multiple Sclerosis
CONTEXT Infection with Epstein-Barr virus (EBV) has been associated with an increased risk of multiple sclerosis (MS), but the temporal relationship remains unclear. OBJECTIVE To determine whether antibodies to EBV are elevated before the onset of MS. DESIGN, SETTING, AND PARTICIPANTS Nested case-co...
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| creator | Levin, Lynn I Munger, Kassandra L Rubertone, Mark V Peck, Charles A Lennette, Evelyne T Spiegelman, Donna Ascherio, Alberto |
| description | CONTEXT Infection with Epstein-Barr virus (EBV) has been associated with an
increased risk of multiple sclerosis (MS), but the temporal relationship remains
unclear. OBJECTIVE To determine whether antibodies to EBV are elevated before the onset
of MS. DESIGN, SETTING, AND PARTICIPANTS Nested case-control study conducted among more than 3 million US military
personnel with blood samples collected between 1988 and 2000 and stored in
the Department of Defense Serum Repository. Cases were identified as individuals
granted temporary or permanent disability because of MS. For each case (n = 83),
2 controls matched by age, sex, race/ethnicity, and dates of blood sample
collection were selected. Serial samples collected before the onset of symptoms
were available for 69 matched case-control sets. MAIN OUTCOME MEASURES Antibodies including IgA against EBV viral capsid antigen (VCA), and
IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse
and restricted early antigens, and cytomegalovirus. RESULTS The average time between blood collection and MS onset was 4 years (range, |
| doi_str_mv | 10.1001/jama.293.20.2496 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_67866943</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><ama_id>200953</ama_id><sourcerecordid>850018041</sourcerecordid><originalsourceid>FETCH-LOGICAL-a428t-b97314d6bda7a5dc45d05fa09596b690d28495d920d341e3a14c09b118f5340f3</originalsourceid><addsrcrecordid>eNqF0k9vFCEUAHBiNHa7eteLISb1Niv_B45ts2qTahO7ep0wA6NsGBiB0eyX8DOLdtXEi1xIHj9eHu8BwBOMNhgh_HKvJ70him4I2hCmxD2wwpzKhnIl74MVQko2LZPsBJzmvEd1Ydo-BCeYK8xajlbg-85Oc0zaw_fW6-JiyJ_dDC9s-WZtgFtvv_6KwjjC7ZyLdaG50CnBjy4tGZ6H4vpoDnDnik0Z6mDgVXDF1YQ3Idvy8947u6To4yc31OjtYZpLnDJ0Ab5dfHGzt_B28DbF7PIj8GDUPtvHx30NPrza7i7fNNc3r68uz68bzYgsTa9aipkRvdGt5mZg3CA-aqS4Er1QyBDJFDeKIEMZtlRjNiDVYyxHThka6Rq8uMs7p_hlsbl0k8uD9V4HG5fciVYKoRj9L8Rt7TUSqMLn_8B9XFKoj-gIxgxhUmteg2dHtPSTNd2c3KTTofs9jwrOjkDn2q0x6TC4_Ne1mDPBZXVP71z9AH9OSZ03p_QHLhSjLQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>211401297</pqid></control><display><type>article</type><title>Temporal Relationship Between Elevation of Epstein-Barr Virus Antibody Titers and Initial Onset of Neurological Symptoms in Multiple Sclerosis</title><source>MEDLINE</source><source>American Medical Association Journals</source><creator>Levin, Lynn I ; Munger, Kassandra L ; Rubertone, Mark V ; Peck, Charles A ; Lennette, Evelyne T ; Spiegelman, Donna ; Ascherio, Alberto</creator><creatorcontrib>Levin, Lynn I ; Munger, Kassandra L ; Rubertone, Mark V ; Peck, Charles A ; Lennette, Evelyne T ; Spiegelman, Donna ; Ascherio, Alberto</creatorcontrib><description>CONTEXT Infection with Epstein-Barr virus (EBV) has been associated with an
increased risk of multiple sclerosis (MS), but the temporal relationship remains
unclear. OBJECTIVE To determine whether antibodies to EBV are elevated before the onset
of MS. DESIGN, SETTING, AND PARTICIPANTS Nested case-control study conducted among more than 3 million US military
personnel with blood samples collected between 1988 and 2000 and stored in
the Department of Defense Serum Repository. Cases were identified as individuals
granted temporary or permanent disability because of MS. For each case (n = 83),
2 controls matched by age, sex, race/ethnicity, and dates of blood sample
collection were selected. Serial samples collected before the onset of symptoms
were available for 69 matched case-control sets. MAIN OUTCOME MEASURES Antibodies including IgA against EBV viral capsid antigen (VCA), and
IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse
and restricted early antigens, and cytomegalovirus. RESULTS The average time between blood collection and MS onset was 4 years (range,
<1-11 years). The strongest predictors of MS were serum levels of IgG antibodies
to EBNA complex or EBNA-1. Among individuals who developed MS, serum antibody
titers to EBNA complex were similar to those of controls before the age of
20 years (geometric mean titers: cases = 245, controls = 265),
but 2- to 3-fold higher at age 25 years and older (cases = 684,
controls = 282; P<.001). The risk of
MS increased with these antibody titers; the relative risk (RR) in persons
with EBNA complex titers of at least 1280 compared with those with titers
less than 80 was 9.4 (95% confidence interval [CI], 2.5-35.4; P for trend <.001). In longitudinal analyses, a 4-fold increase
in anti-EBNA complex or anti–EBNA-1 titers during the follow-up was
associated with a 3-fold increase in MS risk (EBNA complex: RR , 3.0;
95% CI, 1.3-6.5; EBNA-1: RR, 3.0; 95% CI, 1.2-7.3). No association was
found between cytomegalovirus antibodies and MS. CONCLUSION These results suggest an age-dependent relationship between EBV infection
and development of MS.</description><identifier>ISSN: 0098-7484</identifier><identifier>ISSN: 1538-3598</identifier><identifier>EISSN: 1538-3598</identifier><identifier>DOI: 10.1001/jama.293.20.2496</identifier><identifier>PMID: 15914750</identifier><identifier>CODEN: JAMAAP</identifier><language>eng</language><publisher>Chicago, IL: American Medical Association</publisher><subject>Adult ; Antibodies, Viral - blood ; Biological and medical sciences ; Blood ; Case-Control Studies ; Clinical trials ; Epstein-Barr Virus Infections - immunology ; Epstein-Barr Virus Infections - physiopathology ; Epstein-Barr Virus Nuclear Antigens - immunology ; Female ; General aspects ; Herpesvirus 4, Human - immunology ; Humans ; Immunoglobulin A - blood ; Immunoglobulin G - blood ; Infections ; Longitudinal Studies ; Male ; Medical diagnosis ; Medical sciences ; Military Personnel ; Multiple sclerosis ; Multiple Sclerosis - blood ; Multiple Sclerosis - physiopathology ; Multiple Sclerosis - virology ; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis ; Neurology ; Risk Factors ; United States ; Viruses</subject><ispartof>JAMA : the journal of the American Medical Association, 2005-05, Vol.293 (20), p.2496-2500</ispartof><rights>2005 INIST-CNRS</rights><rights>Copyright American Medical Association May 25, 2005</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a428t-b97314d6bda7a5dc45d05fa09596b690d28495d920d341e3a14c09b118f5340f3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://jamanetwork.com/journals/jama/articlepdf/10.1001/jama.293.20.2496$$EPDF$$P50$$Gama$$H</linktopdf><linktohtml>$$Uhttps://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.293.20.2496$$EHTML$$P50$$Gama$$H</linktohtml><link.rule.ids>64,314,776,780,3327,27901,27902,76231,76234</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17154658$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15914750$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Levin, Lynn I</creatorcontrib><creatorcontrib>Munger, Kassandra L</creatorcontrib><creatorcontrib>Rubertone, Mark V</creatorcontrib><creatorcontrib>Peck, Charles A</creatorcontrib><creatorcontrib>Lennette, Evelyne T</creatorcontrib><creatorcontrib>Spiegelman, Donna</creatorcontrib><creatorcontrib>Ascherio, Alberto</creatorcontrib><title>Temporal Relationship Between Elevation of Epstein-Barr Virus Antibody Titers and Initial Onset of Neurological Symptoms in Multiple Sclerosis</title><title>JAMA : the journal of the American Medical Association</title><addtitle>JAMA</addtitle><description>CONTEXT Infection with Epstein-Barr virus (EBV) has been associated with an
increased risk of multiple sclerosis (MS), but the temporal relationship remains
unclear. OBJECTIVE To determine whether antibodies to EBV are elevated before the onset
of MS. DESIGN, SETTING, AND PARTICIPANTS Nested case-control study conducted among more than 3 million US military
personnel with blood samples collected between 1988 and 2000 and stored in
the Department of Defense Serum Repository. Cases were identified as individuals
granted temporary or permanent disability because of MS. For each case (n = 83),
2 controls matched by age, sex, race/ethnicity, and dates of blood sample
collection were selected. Serial samples collected before the onset of symptoms
were available for 69 matched case-control sets. MAIN OUTCOME MEASURES Antibodies including IgA against EBV viral capsid antigen (VCA), and
IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse
and restricted early antigens, and cytomegalovirus. RESULTS The average time between blood collection and MS onset was 4 years (range,
<1-11 years). The strongest predictors of MS were serum levels of IgG antibodies
to EBNA complex or EBNA-1. Among individuals who developed MS, serum antibody
titers to EBNA complex were similar to those of controls before the age of
20 years (geometric mean titers: cases = 245, controls = 265),
but 2- to 3-fold higher at age 25 years and older (cases = 684,
controls = 282; P<.001). The risk of
MS increased with these antibody titers; the relative risk (RR) in persons
with EBNA complex titers of at least 1280 compared with those with titers
less than 80 was 9.4 (95% confidence interval [CI], 2.5-35.4; P for trend <.001). In longitudinal analyses, a 4-fold increase
in anti-EBNA complex or anti–EBNA-1 titers during the follow-up was
associated with a 3-fold increase in MS risk (EBNA complex: RR , 3.0;
95% CI, 1.3-6.5; EBNA-1: RR, 3.0; 95% CI, 1.2-7.3). No association was
found between cytomegalovirus antibodies and MS. CONCLUSION These results suggest an age-dependent relationship between EBV infection
and development of MS.</description><subject>Adult</subject><subject>Antibodies, Viral - blood</subject><subject>Biological and medical sciences</subject><subject>Blood</subject><subject>Case-Control Studies</subject><subject>Clinical trials</subject><subject>Epstein-Barr Virus Infections - immunology</subject><subject>Epstein-Barr Virus Infections - physiopathology</subject><subject>Epstein-Barr Virus Nuclear Antigens - immunology</subject><subject>Female</subject><subject>General aspects</subject><subject>Herpesvirus 4, Human - immunology</subject><subject>Humans</subject><subject>Immunoglobulin A - blood</subject><subject>Immunoglobulin G - blood</subject><subject>Infections</subject><subject>Longitudinal Studies</subject><subject>Male</subject><subject>Medical diagnosis</subject><subject>Medical sciences</subject><subject>Military Personnel</subject><subject>Multiple sclerosis</subject><subject>Multiple Sclerosis - blood</subject><subject>Multiple Sclerosis - physiopathology</subject><subject>Multiple Sclerosis - virology</subject><subject>Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis</subject><subject>Neurology</subject><subject>Risk Factors</subject><subject>United States</subject><subject>Viruses</subject><issn>0098-7484</issn><issn>1538-3598</issn><issn>1538-3598</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0k9vFCEUAHBiNHa7eteLISb1Niv_B45ts2qTahO7ep0wA6NsGBiB0eyX8DOLdtXEi1xIHj9eHu8BwBOMNhgh_HKvJ70him4I2hCmxD2wwpzKhnIl74MVQko2LZPsBJzmvEd1Ydo-BCeYK8xajlbg-85Oc0zaw_fW6-JiyJ_dDC9s-WZtgFtvv_6KwjjC7ZyLdaG50CnBjy4tGZ6H4vpoDnDnik0Z6mDgVXDF1YQ3Idvy8947u6To4yc31OjtYZpLnDJ0Ab5dfHGzt_B28DbF7PIj8GDUPtvHx30NPrza7i7fNNc3r68uz68bzYgsTa9aipkRvdGt5mZg3CA-aqS4Er1QyBDJFDeKIEMZtlRjNiDVYyxHThka6Rq8uMs7p_hlsbl0k8uD9V4HG5fciVYKoRj9L8Rt7TUSqMLn_8B9XFKoj-gIxgxhUmteg2dHtPSTNd2c3KTTofs9jwrOjkDn2q0x6TC4_Ne1mDPBZXVP71z9AH9OSZ03p_QHLhSjLQ</recordid><startdate>20050525</startdate><enddate>20050525</enddate><creator>Levin, Lynn I</creator><creator>Munger, Kassandra L</creator><creator>Rubertone, Mark V</creator><creator>Peck, Charles A</creator><creator>Lennette, Evelyne T</creator><creator>Spiegelman, Donna</creator><creator>Ascherio, Alberto</creator><general>American Medical Association</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QL</scope><scope>7QP</scope><scope>7TK</scope><scope>7TS</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20050525</creationdate><title>Temporal Relationship Between Elevation of Epstein-Barr Virus Antibody Titers and Initial Onset of Neurological Symptoms in Multiple Sclerosis</title><author>Levin, Lynn I ; Munger, Kassandra L ; Rubertone, Mark V ; Peck, Charles A ; Lennette, Evelyne T ; Spiegelman, Donna ; Ascherio, Alberto</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a428t-b97314d6bda7a5dc45d05fa09596b690d28495d920d341e3a14c09b118f5340f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Adult</topic><topic>Antibodies, Viral - blood</topic><topic>Biological and medical sciences</topic><topic>Blood</topic><topic>Case-Control Studies</topic><topic>Clinical trials</topic><topic>Epstein-Barr Virus Infections - immunology</topic><topic>Epstein-Barr Virus Infections - physiopathology</topic><topic>Epstein-Barr Virus Nuclear Antigens - immunology</topic><topic>Female</topic><topic>General aspects</topic><topic>Herpesvirus 4, Human - immunology</topic><topic>Humans</topic><topic>Immunoglobulin A - blood</topic><topic>Immunoglobulin G - blood</topic><topic>Infections</topic><topic>Longitudinal Studies</topic><topic>Male</topic><topic>Medical diagnosis</topic><topic>Medical sciences</topic><topic>Military Personnel</topic><topic>Multiple sclerosis</topic><topic>Multiple Sclerosis - blood</topic><topic>Multiple Sclerosis - physiopathology</topic><topic>Multiple Sclerosis - virology</topic><topic>Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis</topic><topic>Neurology</topic><topic>Risk Factors</topic><topic>United States</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Levin, Lynn I</creatorcontrib><creatorcontrib>Munger, Kassandra L</creatorcontrib><creatorcontrib>Rubertone, Mark V</creatorcontrib><creatorcontrib>Peck, Charles A</creatorcontrib><creatorcontrib>Lennette, Evelyne T</creatorcontrib><creatorcontrib>Spiegelman, Donna</creatorcontrib><creatorcontrib>Ascherio, Alberto</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Physical Education Index</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>JAMA : the journal of the American Medical Association</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Levin, Lynn I</au><au>Munger, Kassandra L</au><au>Rubertone, Mark V</au><au>Peck, Charles A</au><au>Lennette, Evelyne T</au><au>Spiegelman, Donna</au><au>Ascherio, Alberto</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Temporal Relationship Between Elevation of Epstein-Barr Virus Antibody Titers and Initial Onset of Neurological Symptoms in Multiple Sclerosis</atitle><jtitle>JAMA : the journal of the American Medical Association</jtitle><addtitle>JAMA</addtitle><date>2005-05-25</date><risdate>2005</risdate><volume>293</volume><issue>20</issue><spage>2496</spage><epage>2500</epage><pages>2496-2500</pages><issn>0098-7484</issn><issn>1538-3598</issn><eissn>1538-3598</eissn><coden>JAMAAP</coden><abstract>CONTEXT Infection with Epstein-Barr virus (EBV) has been associated with an
increased risk of multiple sclerosis (MS), but the temporal relationship remains
unclear. OBJECTIVE To determine whether antibodies to EBV are elevated before the onset
of MS. DESIGN, SETTING, AND PARTICIPANTS Nested case-control study conducted among more than 3 million US military
personnel with blood samples collected between 1988 and 2000 and stored in
the Department of Defense Serum Repository. Cases were identified as individuals
granted temporary or permanent disability because of MS. For each case (n = 83),
2 controls matched by age, sex, race/ethnicity, and dates of blood sample
collection were selected. Serial samples collected before the onset of symptoms
were available for 69 matched case-control sets. MAIN OUTCOME MEASURES Antibodies including IgA against EBV viral capsid antigen (VCA), and
IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse
and restricted early antigens, and cytomegalovirus. RESULTS The average time between blood collection and MS onset was 4 years (range,
<1-11 years). The strongest predictors of MS were serum levels of IgG antibodies
to EBNA complex or EBNA-1. Among individuals who developed MS, serum antibody
titers to EBNA complex were similar to those of controls before the age of
20 years (geometric mean titers: cases = 245, controls = 265),
but 2- to 3-fold higher at age 25 years and older (cases = 684,
controls = 282; P<.001). The risk of
MS increased with these antibody titers; the relative risk (RR) in persons
with EBNA complex titers of at least 1280 compared with those with titers
less than 80 was 9.4 (95% confidence interval [CI], 2.5-35.4; P for trend <.001). In longitudinal analyses, a 4-fold increase
in anti-EBNA complex or anti–EBNA-1 titers during the follow-up was
associated with a 3-fold increase in MS risk (EBNA complex: RR , 3.0;
95% CI, 1.3-6.5; EBNA-1: RR, 3.0; 95% CI, 1.2-7.3). No association was
found between cytomegalovirus antibodies and MS. CONCLUSION These results suggest an age-dependent relationship between EBV infection
and development of MS.</abstract><cop>Chicago, IL</cop><pub>American Medical Association</pub><pmid>15914750</pmid><doi>10.1001/jama.293.20.2496</doi><tpages>5</tpages></addata></record> |
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| identifier | ISSN: 0098-7484 |
| ispartof | JAMA : the journal of the American Medical Association, 2005-05, Vol.293 (20), p.2496-2500 |
| issn | 0098-7484 1538-3598 1538-3598 |
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| source | MEDLINE; American Medical Association Journals |
| subjects | Adult Antibodies, Viral - blood Biological and medical sciences Blood Case-Control Studies Clinical trials Epstein-Barr Virus Infections - immunology Epstein-Barr Virus Infections - physiopathology Epstein-Barr Virus Nuclear Antigens - immunology Female General aspects Herpesvirus 4, Human - immunology Humans Immunoglobulin A - blood Immunoglobulin G - blood Infections Longitudinal Studies Male Medical diagnosis Medical sciences Military Personnel Multiple sclerosis Multiple Sclerosis - blood Multiple Sclerosis - physiopathology Multiple Sclerosis - virology Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis Neurology Risk Factors United States Viruses |
| title | Temporal Relationship Between Elevation of Epstein-Barr Virus Antibody Titers and Initial Onset of Neurological Symptoms in Multiple Sclerosis |
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