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Open AcceReviewViruses and thyroiditis an updateRachel Desailloud12 and Didier Hober1

Address 1Laboratoire de VirologieUPRES EA3610 Faculteacute de Meacutedecine Universiteacute Lille 2 CHRU Lille Centre de BiologiePathologie et Parc Eurasanteacute 59037 Lille France and 2Service dEndocrinologie-Diabeacutetologie-Nutrition CHU Amiens 80054 Amiens France

Email Rachel Desailloud - desailloudrachelchu-amiensfr Didier Hober - dhoberchru-lillefr

Corresponding author

AbstractViral infections are frequently cited as a major environmental factor involved in subacute thyroiditisand autoimmune thyroid diseases This review examines the data related to the role of viruses inthe development of thyroiditis

Our research has been focused on human data We have reviewed virological data for each typeof thyroiditis at different levels of evidence epidemiological data serological data or research oncirculating viruses direct evidence of thyroid tissue infection Interpretation of epidemiological andserological data must be cautious as they dont prove that this pathogen is responsible for thedisease However direct evidence of the presence of viruses or their components in the organ areavailable for retroviruses (HFV) and mumps in subacute thyroiditis for retroviruses (HTLV-1 HFVHIV and SV40) in Gravess disease and for HTLV-1 enterovirus rubella mumps virus HSV EBVand parvovirus in Hashimotos thyroiditis However it remains to determine whether they areresponsible for thyroid diseases or whether they are just innocent bystanders Further studies areneeded to clarify the relationship between viruses and thyroid diseases in order to develop newstrategies for prevention andor treatment

BackgroundViral infections are frequently cited as a major environ-mental factor implicated in subacute thyroiditis andautoimmune thyroid diseases [1] The term thyroiditisencompasses a heterogeneous group of disorders charac-terized by some form of thyroid inflammation To catego-rize the different forms of thyroiditis mostthyroidologists use the following terms iInfectious thy-roiditis (which includes all forms of infection other thanviral) iiSubacute thyroiditis (also called subacute granu-lomatous thyroiditis and which causes acute illness withsevere thyroid pain) iiiAutoimmune thyroid diseasewhich includes Hashimotos thyroiditis (and painless thy-roiditis also known as silent thyroiditis or subacute lym-

phocytic thyroiditis which is considered as a variant formof chronic Hashimotos thyroiditis) and Graves diseaseiiiiRiedels thyroiditis which is a very rare disease charac-terized by extensive fibrosis and mononuclear infiltration

This review examines the data related to the possible roleof viruses in the development of thyroiditis We haveadded thyroid lymphoma to the section on Riedels thy-roiditis as both diseases are known complications ofautoimmune thyroiditis Our research has been focusedon human data but we used some animal data in order toemphasize some mechanisms and to support such a pos-sibility in humans We have reviewed virological data atdifferent levels of evidence epidemiological data serolog-

Published 12 January 2009

Virology Journal 2009 65 doi1011861743-422X-6-5

Received 8 December 2008Accepted 12 January 2009

This article is available from httpwwwvirologyjcomcontent615

copy 2009 Desailloud and Hober licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (httpcreativecommonsorglicensesby20) which permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

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Virology Journal 2009 65 httpwwwvirologyjcomcontent615

ical data which have been associated with research intocirculating viruses and direct evidence of thyroid tissueinfection

ISubacute and autoimmune thyroiditis a viral infection of the thyroid glandFirst defined by De Quervain subacute thyroiditis is a self-limited inflammatory disorder of the thyroid gland Thedisease is most prevalent in females usually characterizedby a sudden onset of neck pain and thyrotoxicosis Clini-cally the disease has several characteristics typical of viralinfections including a typical viral prodrome with myal-gias malaise and fatigue Recurrent subacute thyroiditishas been reported [2] The follicles are often infiltratedresulting in disrupted basement membrane and rupture ofthe follicles The thyroid injury in subacute thyroiditis isthought to be the result of cytolytic T-cell recognition ofviral and cell antigens present in an appropriate complex[3]

I-AEpidemiological evidenceThe first descriptions showed a tendency for the disease tofollow upper respiratory tract infections or sore throatswhich explained why a viral infection has most often beenimplicated as the cause Clusters of the disease have beenreported during outbreaks of viral infection [4] Onset ofthe disease are observed between June and September andthis seasonal distribution is almost identical to that ofestablished infections due to some enteroviruses (Echovi-rus Coxsackievirus A and B) suggesting that enterovirusinfections might be responsible for a large proportion ofcases [56]

An association between subacute thyroiditis and HLA B35is noted in all ethnic groups tested [7] and two-thirds ofpatients manifest HLA-B35 Familial occurrence of suba-cute thyroiditis [8] and recurrence during the course oftime [9] are associated with HLA B35 Thus the onset ofsubacute thyroiditis is genetically influenced and itappears that subacute thyroiditis might occur through asusceptibility to viral infection in genetically predisposedindividuals HLA-B35 has been reported to be correlatedwith chronic active hepatitis with hepatitis B [10] withrapid progression of AIDS [11] and with the T lymphocyteresponses against human parvovirus B19 [12] Recentlythe medical records of 852 patients with subacute thy-roiditis have been studied The significant seasonal clus-ters of subacute thyroiditis during summer to earlyautumn was confirmed According to the authors thehistory of patients showed no obvious association withvirus infection Unfortunately no data on infections areavailable in the paper [2]

I-BVirological dataVirus-like particles were first demonstrated in the follicu-lar epithelium of a patient suffering from subacute thy-

roiditis Judging from the size it was thought to beinfluenza or mumps virus [13] which was concordantwith an increased frequency of antibodies to the influenzaB virus in patients with thyrotoxicosis [14] The same yearin five out of 28 patients with subacute thyroiditis a cyto-pathic virus was isolated by coculturing patient sampleswith susceptible cell lines[15] The agent was later studiedby electron microscopy and classified as a paramyxovirus[16] Subsequently the agent was reanalyzed by immun-ofluorescence and electron microscopy and was reclassi-fied as a foamy virus [17] However the implication offoamy virus has not been confirmed a more comprehen-sive study using different techniques demonstrated noassociation between foamy-virus infection and thyroiditisin 19 patients [18] Moreover the expression of HFV gagproteins had not been found by indirect immunofluores-cence [19] As part of a larger study investigating the prev-alence of foamy-virus infection in humans 59 patientswith thyroid disorders including 28 with Quervains thy-roiditis were analyzed by different techniques includingPCR Again there was no prevalence of foamy virus infec-tion [20] The origin of the foamy-virus-like agent in theoriginal publications remains unclear but because themore comprehensive study was unable to detect foamy-virus infection in de Quervain patients it is highlyunlikely that it is a causative agent of this condition [21]

Some cases could be due to the mumps virus Subacutethyroiditis has occurred in epidemic form patients withsubacute thyroiditis diagnosed during a mumps epidemicwere found to have circulating anti-mumps antibodieseven without clinical evidence of mumps [22] High titersof mumps antibodies have been found in some patientswith subacute thyroiditis and occasionally parotitis ororchitis usual in mumps were associated with thyroiditis[23] In favor of thyroid infection is the fact that in twopatients out of 11 with subacute thyroiditis diagnosedduring a mumps epidemic the mumps virus was culturedfrom thyroid tissue obtained at biopsy [22]

Enteroviruses have been suspected Patients with subacutethyroiditis who had no clinical evidence of viral diseasedemonstrated increases by at least four times in viral anti-bodies These viral antibodies included antibodies tomumps virus but also coxsackie adenovirus and influen-zae Coxsackie viral antibodies were the most commonlyfound and the changes in their titers most closely approx-imated the course of the disease [24] In a case report thy-roiditis was attributed to enterovirus IgM and IgG werefound at a quadruple titer against coxsackievirus B4whereas no other antibodies were found against othercoxsackies echoviruses or mumps [25] In 27 consecutivepatients with subacute thyroiditis antibody tests virusisolation and antigen detection were negative EnterovirusRNA was not detected by RT-PCR neither in blood sam-ples nor in the thyroid tissue in the fine-needle aspiration

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samples Common respiratory viruses were also screenedThere was no evidence of viral infections except onepatient who had acute CMV infection[26]

Case reports have implicated ndash CMV in an infant withacute infection and ndash EBV in an adult female because ofpositivity for Epstein-Barr virus-specific antibodies and ina 3-year-old girl suffering from infectious mononucleosisbecause of the presence of EBV DNA both in plasma andleukocytes [27-29] However when thyroid specimens ofnine patients obtained by fine-needle aspiration biopsywere examined no EBV or CMV DNA was detected [30]Serum virus-specific antibodies to measles rubellamumps type I herpes chicken pox human parvovirusB19 and CMV were found in 10 patients during the courseof illness In spite of the presence of IgG to each virus inmore than 70 of patients changes in the IgG titers wereobserved for those to measles rubella chicken pox orCMV in 4 patients [30] In an adult female subacute thy-roiditis was diagnosed one month after acute infectionsuggesting that rubella virus could also be implicated[31]

Viral antibody titers to common respiratory tract virusesare often elevated Since the titers fall promptly and arenot increased during recurrence [9] and since multipleviral antibodies may appear in the same patient the eleva-tion could be an anamnestic response due to the inflam-matory condition [32]

Although the search for a viral cause is usually unreward-ing it appears that the thyroid could respond with thy-roiditis after invasion by a variety of different viruses andthat no single agent is likely to be causative in the syn-drome of subacute thyroiditis

IIInvolment of viral infection in autoimmune thyroid diseases (AITD)The autoimmune thyroid diseases (AITD) are frequent[3334] and include Hashimotos thyroiditis and Gravesdisease Both disease are characterized by lymphocyticinfiltration and the presence of serum anti-thyroperoxy-dase antibody (TPOAb) andor anti-thyroglobulin anti-body (TgAb) for Hashimotos thyroiditis and TSHreceptor autoantibodies (TSHR-Ab) for Graves disease

The mechanisms by which infection may induce anautoimmune response are many and this makes infec-tions an attractive hypothesis for disease initiation[3536] Paradoxically infections may enhance AITD butmay also be protective Indeed the hygiene hypothesisimplies that the immune system is educated by multipleexposures to different infections allowing it to controlautoimmune responses better Thus improved livingstandards associated with decreased exposure to infec-

tions are associated with an increased risk of autoimmunedisease and the lower socio-economic groups have areduced prevalence of thyroid autoantibodies [3738]

However specific infections could be a triggering factor todisease initiation by liberating antigens (via cell destruc-tion or apoptosis) by forming altered antigens or causingmolecular mimicry by cytokine and chemokine secretionby inducing aberrant HLA-DR expression and Toll-LikeReceptor (TLR) activation TLRs are a family of cell surfacereceptors which protect mammals from pathogenicorganisms such as viruses and are present on non-immune cells including thyrocytes [39] Moreover TLR3recognizes double-stranded (ds) RNA assumed to bereleased by viral killing of cells The dsRNA binding toTLR3 mimicked in vitro by incubation with polyinosine-polycytidylic acid [Poly (IC)] leads not only to the induc-tion of inflammatory responses but also to the develop-ment of antigen-specific adaptive immunity [40] ThenHashimotos thyroiditis has been grouped with insulitisand type-1 diabetes colitis and atherosclerosis as anautoimmune and inflammatory disease associated withTLR34 overexpression which is in favor of environmen-tal pathogens [39]

In order to give a comprehensive review virological dataon Hashimotos thyroiditis and Graves disease areexposed together in the text but are summarized in inde-pendent tables (see tables 1 2 3) for each disease andclassified in terms of their levels of evidence of infectionof the thyroid tissue epidemiological serological (or cir-culating viral genome) and molecular

II-AEpidemiological dataII-A-1Temporal and geographical considerationsSeasonal trends possibly related to epidemic infectionshave been described in the diagnosis or relapse of Gravesdisease with higher rates in spring and summer [4142]Geographical differences have also been described in Eng-land in the incidence of Graves disease which could be anindirect sign of environmental factors [43]

More surprinsigly month of birth was studied in 664patients with Hashimotos hypothyroidism and in 359patients with Graves hyperthyroidism Patients had a dis-tinct pattern of distribution for month of birth comparedwith the general population These differences pointtowards a a seasonal viral infection as the initial trigger inthe perinatal period the clinical disease resulting fromfurther specific damage over time [44]

II-A-2Subacute thyroiditis a trigger of thyroid autoimmunityDamage to the thyroid in subacute thyroiditis which isthought to be a virus-associated syndrome might releasenormally sequestered antigens inducing an immune



response Unknown autoantibodies are found in patientswith subacute thyroiditis and a higher prevalence of thy-roid autoantibodies after a mean follow-up interval of 4years but at low titers has been observed [4546] How-ever thyroid autoantibodies appear at low titer onlyoften transiently and characterized autoimmune patholo-gies of the thyroid do not usually occur [32] Theseautoimmune phenomena could represent a nonspecificresponse to the inflammatory release of thyroid antigensrather than a specific autoimmune disease Rare cases ofHashimotos thyroiditis have been reported but severalcases of the occurrence of Graves disease after subacutethyroiditis have been published [47-49] To examine

whether subacute thyroiditis triggers TSH receptor anti-body 1697 patients with subacute thyroiditis were testedAntibodies were found positive in 2 of patients buthyperthyroidism was not always present and some of thepatients recovered from thyroid dysfunction withouttreatment Therefore subacute thyroiditis could triggerautoreactive B cells to produce TSH receptor antibodies[50]

II-A-3What about vaccinationPrevious natural infection or vaccination against measlesandor mumps seemed to have an inhibitory effect on thedevelopment of thyroid autoantibodies No evidence was

Table 1 Evidence for infection in subacute thyroiditis

in favour of infection references not in favour of infection references

Levels of data Epidemiologicaldistribution of disease during outbreaks of viral infection [422] no obvious association with virus infection [2932]seasonal distribution from June to September [256]

Serological andor circulating viral genomemumps virus [22-24] mumps virus [30]coxsackievirus [2425134] enterovirus [26]adenovirus [24] HSV-1 [30]EBV [2728] parvovirus B19 [30]measles chicken pox CMV [30]influenzae [1424]rubella [3031]CMV [2629]

Direct evidence of infectionhuman foamy virus [17] human foamy birus [18-20]mumps [22] enterovirus [26]

CMV and EBV [30]

Table 2 Evidence for infection in Hashimotos autoimmune thyroiditis


Levels of data Epidemiologicalantithyroid antibodies following subacute thyroiditis [3246] euthyroidism nonspecific autoimmune response [3246]unknown antithyroid antibodies following subacute thyroiditis

[45]

seasonality of month of birth [44]HTLV-1 [5253] SARS central hypothyroidism [115]HIV [65] HIV [6768]non-HIV retrovirus [69]congenital rubella [888991] congenital rubella [90]HCV HBV [107108110] HCV [111112]enterovirus infection during pregnancy [120] measles-mumps-rubella vaccination [51]

Serological andor circulating viral genomeHTLV-1 [54-5860137] HIAP-1 [78]congenital and acquired rubella [88-9092-94]EBV [99100]Parvovirus [104]

Direct evidence of infectionHTLV-1 [59] HFV [19]rubella [87] CMV [97]HSV [97] Enterovirus RNA detected in various thyroid disease [119]Parvoviru [103]EBV [132]



found that measles-mumps-rubella vaccination may trig-ger autoimmunity neither the prevalence nor the levels ofantibodies changed 3 months after vaccination [51]

II-BSpecific virus dataII-B-1RetrovirusII-B-1-aHuman T lymphotrophic virus-1 (HTLV-1)HTLV-1 is a human retrovirus highly endemic in the Car-ibbean islands Central Africa and south-west Japan

II-B-1-a1Hashimotos thyroiditisHuman T lymphotrophic virus-1 has been associated withvarious autoimmune disorders including Hashimotosthyroiditis in patients with HTLV1-associated myelopa-thytropical spastic paraparesis [5253] Two patients whodeveloped Hashimotos thyroiditis proven with biopsywere HTLV-I carriers but had no myelopathytropicalspastic paraparesis [54] A case-control study was thenconducted to determine the frequency of HTLV-I seropos-itivity among patients with Hashimotos thyroiditis andthe frequency of Hashimotos thyroiditis in patients withHTLV-I-associated myelopathytropical spastic parapare-sis The frequency is significantly higher in the two groupsthan in the general population [55] A high prevalence ofpositivity for thyroid autoantibodies (TPOAb andorTgAb) and hypothyroidism have also been described inthe adult T-cell leukaemia patients and the HTLV-I carriers[56] In prospective studies in blood donors the fre-quency of anti-thyroid antibodies tended to be higher indonors with anti-HTLV-I antibody HTLV-I and HTLV-IIproviral load are significantly higher in the peripheralblood of patients with Hashimotos thyroiditis than inasymptomatic HTLV carriers [5758] Thyroid tissues fromtwo patients with Hashimotos thyroiditis were examined

for the presence of HTLV-I The virus envelope protein andsignals for the mRNA were detected in many of the thyro-cytes from one of the patients by immunohistochemistryand in-situ hybridization respectively PCR-Southernblotting revealed the presence of HTLV-I DNA althoughno virus particles were found by electron microscopy Thepresent findings suggest that infection of thyroid tissuewith HTLV-I is possible [59] An association betweenHTLV-I infection and autoimmune thyroiditis may bethen strongly suspected

II-B-1-a2Graves disease (GD)Serum HTLV-I antibody is found in 6 of patients withGD 7 of patients with chronic thyroiditis and 2 ofpatients with nodular goiter[60] Beside the fact that anti-HLTV-I antibody and proviral DNA is detected in periph-eral lymphocytes of patients with GD [6061] proviralload in HTLV-I-infected patients with GD as observed inHashimotos thyroiditis is significantly higher than inasymptomatic HTLV-I carriers [57] GD and HTLV-I infec-tion seem to be interacting and resulting in onset of uvei-tis [6162] Indeed 5 of HTLV-I-positive patients withGD developed uveitis whereas none of the HTLV-I nega-tive patients with GD nor HTLV-I-positive patients withchronic thyroiditis or nodular goiter developed uveitis[60] The provirus load was significantly higher in theuveitis patients with GD than in those without GD [63]As in Hashimotos thyroididtis HTLV-I infectivity in thy-roid was proven HTLV-I DNA was detected by polymer-ase chain reaction in the thyroid tissue of an HTLV-I-infected male who was successively afflicted with GD fol-lowed by uveitis HTLV-I was isolated from thyroid tissueby coculture with peripheral blood lymphocytes [64]

Table 3 Evidence for infection in Graves disease


Levels of data Epidemiologicalseasonality of month of birth [44]higher diagnosis and relapse rate in spring and summer [4142]geographical distribution [43]antibodies or disease onset following subacute thyroiditis [47-50] nonspecific response to the inflammatory rection [32]HTLV1 [62]HIV [65] lack of anti-thyroid antibodies before the beginning of

HAART[75]

Serological andor circulating viral genomeHTLV1 [5760-62]HIAP-1 [78]HFV [8184] HFV [208283]parvovirus [106] Enterovirus [121]HHV6 HHV7 [101]

Direct evidence of infectionHTLV-1 [64]HIV-1 [70] SV40 [7273]

HIAP-1 [79]HFV [1980] HFV [83]SV40 [85] HSV CMV [97]



II-B-1-bHuman Immunodeficiency Virus (HIV)II-B-1-b1Hashimotos thyroiditisAutoimmune diseases in HIVAIDS have been reportedwith an array of autoantibodies including anti-thyroglob-ulin and anti-thyroid peroxidase [65]

A high prevalence of subclinical hypothyroidism with35 to 122 has been described in patients receivingHAART [66] A cross-sectional multicenter study was doneto determine the prevalence of and risk factors forhypothyroidism in HIV-infected patients Of the 350 HIV-infected patients studied 16 had hypothyroidism 26had overt hypothyroidism 66 had subclinical hypothy-roidism and 68 had a low level of free T4 The preva-lence of subclinical hypothyroidism was higher amongHIV-infected men A nested case-control study was con-ducted which compared hypothyroid and euthyroidpatients Only receipt of stavudine and low CD4 cellcount were associated with hypothyroidism [67] Thyroiddysfunction seemed therefore to be due to medicationand not to autoimmunity To confirm these data 22 HIV+hypothyroid patients and 22 HIV+ euthyroid controlsreceiving highly active anti-retroviral therapy wereincluded in an additional study No goiter or anti-thyroidantibodies were detected Thus in our experience HIV isnot a cause of autoimmune thyroiditis [68] Discordantdata have been published about these risk factors Mecha-nisms and screening of patients is discussed in a recentreview [66]

Some individuals possess antibodies that react to HIV-1Western blot proteins in patterns different from HIV infec-tion diagnostic Autoimmune thyroiditis is more frequentin patients exhibiting these indeterminate HIV-1 Westernblots in comparison with a control cohort of HIV-negativeblots These data suggested that patients infected withnon-HIV retrovirus could develop thyroid autoimmunity[69]

II-B-1-b2Graves disease (GD)Autoimmune diseases in HIVAIDS that have beenreported include GD [65] Several hypotheses have beenelaborated Using Southern blot analysis specific integra-tion of exogenous sequences homologous to HIV-1 gagregion was only found in genomic DNA of thyrocytesfrom patients with GD and not in normal thyrocytesThese findings suggested that retrovirus-like sequencescould be associated with thyroid autoimmunity [70]High reverse transcriptase activity which resembled thatdemonstrated in retroviruses has been observed in thyroidtissue extracts obtained by surgery from patients with GDThe reverse transcriptase existed in the thyroid tissue as acomplex with endogenous template RNA and the activitywas confirmed not to be due to other DNA polymerasesIn a permissive genetic and immunological environmentretroviral DNA integrated into genomic DNA could then

participate to the onset of GD [71] However in a studyusing sets of primer pairs designed to cover the wholespan of the HIV-1 gag region neither Southern blothybridization nor PCR gave positive signals in any of thesamples examined [72] as confirmed in another study[73] Homology between the HIV-I Nef protein and thehuman TSHR has been suggested [74] However a retro-spective analysis of serum samples of a patient with GDrevealed lack of anti-thyroid autoantibodies before thebeginning of antiretroviral treatment[75]

Despite many attempts results to date remain inconclu-sive concerning a direct role of HIV in the onset of GD buta special mechanism has been observed ndash the immunesystem recovery De novo diagnoses of thyroid diseasewere identified between 1996 and 2002 in seven HIVtreatment centers Patients were diagnosed as clinical caseentities and not discovered through thyroid function testscreening GD was diagnosed in 15 out of 17 patientsdiagnosed with AITD One patient developed hashithyro-toxicosis and another hypothyroidism AITD patientswere more likely than controls to be severely compro-mised at baseline and to experience greater CD4 incre-ments following HAART Regulatory T lymphocytes (Treg)appear to be important in suppressing autoimmune reac-tions It is possible that a relative deficiency of such cellsexplains the appearance of GD during immune systemrecovery [7576]

II-B-1-cHuman Intracisternal A-type particles type 1 (HIAP1)Intracisternal A-type particles (IAPs) are defective retrovi-ruses that assemble and bud at the membranes of theendoplasmic reticulum where they remain as immatureparticles consisting of uncleaved polyproteins antigeni-cally related to HIV [77] Serum antibodies against HIAP-I are detectable in 85 of GD patients compared to only19 of controls They are absent in patients with Hashi-motos thyroiditis as well as other forms of non-autoim-mune thyroid disease A genetically determinedimmunological susceptibility has been demonstrated theclass II HLA status allows interactions with HIAP-I expo-sure and this interaction could be a predisposing factor inthe pathogenesis of GD [78] Intracisternal A-type parti-cles have been reported in H9 cells co-cultured withhomogenates of salivary glands obtained from patientswith Sjoumlgren syndrome and with synovial fluid of patientswith rheumatoid arthritis However no HIAP-1 particlesare detected by electron microscopy in the H9 cells co-cul-tured with thyroid preparations of GD These data callinto question the involvement of HIAP-1 in the etio-pathogenesis of Graves disease [79]

II-B-1-dHuman Foamy Virus (HFV)Human foamy virus (HFV) is a member of the retroviralfamily of Spumaretroviridae Three retroviral structural



proteins of HFV ndash gag pol and env ndash can be identified byindirect immunofluorescence

II-B-1-d1Hashimotos thyroiditisFrom the thyroids of five patients with Hashimotos dis-ease four were negative for the structural protein and oneshowed a single small focus of anti-gag antibody reactivity[19]

II-B-1-d2Graves diseaseContrary to what has been found in Hashimotos thy-roiditis the expression of HFV gag proteins has been dem-onstrated by indirect immunofluorescence on theepithelial cells of seven out of seven thyroid glands ofpatients with GD whereas it was negative in 9 subacutethyroiditis and 2 normal glands The retrobulbar tissue of1 Graves disease patient with malignant exophthalmusrevealed also positive staining with anti-gag antibodies infibroblasts and fat cells [1980] In a search for spumaret-rovirus infection markers a group of 29 patients with GDand 23 controls were studied A positive signal with a spu-maretrovirus-specific genomic probe was found in DNAextracted from peripheral blood lymphocytes in 10patients and spumaretrovirus related sequences weredetected by PCR in the DNA of 19 patients All 23 controlsubjects were negative These results strongly suggest theexistence of an association between GD and the presenceof spumaretrovirus related infection markers[81] Otherstudies failed to detect the presence of antibodies by sev-eral immunodetection techniques and foamy virus DNAin peripheral blood lymphocytes [2082] and the presenceof the spumaretrovirus gag region sequence was not statis-tically significant in DNA extracted from the peripheralblood leukocytes and thyroid tissue of 81 patients withGD and of 66 controls [83] Nevertheless the nature ofthe HFV-related sequences identified in the genomes ofhealthy individuals and the GD patients appeared to bedifferent Three regions of HFV-related sequences wereamplified in 29 of the HFV-positive patients while nosamples in the control group amplified all three regionsThis suggests that these sequences may be used as a toolfor screening for HFV in GD patients [84]

These studies provide no evidence for a causative role forHFV in GD However the data do represent the possibilitythat HFV-like sequences may be implicated and this is apossibility especially in some geographically distinct pop-ulations [21]

II-B-1eSimian virus (SV40)Simian virus 40 (SV40) is a polyomavirus that is found inboth monkeys and humans Like other polyomavirusesSV40 is a DNA virus that has the potential to cause tumorsbut most often persists as a latent infection In a studydedicated to thyroid tumors SV40 sequences were alsoinvestigated in GD thyroid specimens normal thyroid tis-

sues and peripheral blood mononuclear cells of healthydonors Specific SV40 large T antigen sequences weredetected by PCR and filter hybridization in human thy-roid tissues from GD patients with a frequency of 20compared with a frequency of 10 of control normal thy-roid tissues from patients affected by multinodular goiter[85]

II-B-2Rubella virus (German measles)Thyroid disorders in patients with congenital rubella werefirst reported in 1975 [86] Infection of thyroid tissue byrubella was demonstrated in a case of congenital rubellawith Hashimotos thyroiditis immunofluorescent studiesof thyroid tissue demonstrated staining for rubella virusantigen [87] Thyroid autoantibodies anti-TPO or anti-Tgantibodies have been found more frequently in patientswith congenital rubella syndrome than in controls[8889] These studies are old and a recent study hasshown that humoral autoimmunity was not so frequentIn 37 subjects affected by or exposed to rubella duringfetal life one patient had diabetes four patients had clin-ical hypothyroidism and five patients were positive forTPOAb at the time of the examination [90] However inan Australian study the prevalence of thyroid disordersas well as diabetes and early menopause was higher insubjects with congenital rubella (studied 60 years aftertheir intrauterine infection) than the general populationIt is worthy of note that 41 of the subjects had undetec-table levels of rubella antibodies [91] Since most reportshave shown no evidence of active rubella infection at thetime of thyroid dysfunction the mechanisms proposedfor thyroid dysfunction are destruction of thyroid cells bylocal persistent rubella virus infection precipitation of anautoimmune reaction or both [92-96]

II-B-3HerpesviridaeThe Herpesviridae are a large family of DNA viruses thatshare a common structure and a common characteristicwhich is latent and re-occurring infections Herpesviridaecan cause lytic infections

II-B-3aHerpes Simplex Virus (HSV) and Cytomegalovirus (CMV)Thyroid tissue specimens were obtained postoperativelyfrom four patients with multinodular goiter and 18patients with AITD (GD and Hashimoto thyroiditis) Her-pesviridae DNA was detected using PCR-based assaysHerpesviridae DNA has been more frequently detected inAITD tissue specimens than in tissue specimens of multi-nodular goiters No statistically significant differenceswere observed concerning the specific strains HSV1HSV2 HSV 6 or HSV7 No CMV DNA was isolated fromany tissue specimen [97]

II-B-3bEpstein Barr Virus (EBV)EBV infection is known to be involved in tumoral diseasessuch as lymphoma but also in autoimmune diseases such



as multiple sclerosis rheumatoid arthritis and systemiclupus erythematosus [98] Antibodies against EBV viralcapsid antigen (IgG-VCA) and antibodies against earlyantigen (IgG-EA-DDR) have been more often found inthyroiditis than in controls [99] What is unusual is thatEBV may induce anti-T3 antibodies Acute EBV infectionwith severe primary hypothyroidism was described in a16-year old female patient She had high low FT4 and lowFT3 but discordant elevated total T3 Later 34 patientswith EBV infection were tested for thyroid hormone lev-els Five patients with acute EBV and one with previousinfection had total T3 values above the mean which wasdue to anti-T3 antibodies [100]

II-B-3cHuman Herpes Virus (HHV)HHV are ubiquitous tissue tropism widespread HHV6and HHV7 circulating DNA was searched in sixty Gravesdisease patients paired to 60 controls Both viruses infec-tion increased the risk for Graves disease especially HHV7that was significantly more frequent among patients(646) than in controls (387) Patients 72TP53 ProPro variants (inherited diminished TP53 apoptotic func-tion) had 5 times more chance to develop GD and almostthree times more chance to be infected by HHV7 which isconsistent with interaction between genetics and viralinfection in Graves disease physiopathology[101]

II-B-4ParvovirusThe B19 virus belongs to the Parvoviridae family of smallDNA viruses Parvovirus B19 is known for causing a child-hood exanthem but it has also been associated withautoimmune diseases autoimmune neutropenia throm-bocytopenia hemolytic anemia and rheumatoid arthritis[102] Recently a few studies have suggested the associa-tion of parvovirus infection with thyroiditis

II-B-4aHashimotos thyroiditisIntrathyroidal persistence of human parvovirus B19 DNAwith PCR has been detected for the first time in a patientwith Hashimotos thyroiditis The cell types responsiblefor the B19 DNA persistence are not determined andimmune cells infiltrating the thyroid may be the source ofB19 DNA However the possibility that thyroid epithelialcells harbor B19 DNA cannot be excluded [103]

Serum samples from 73 children and adolescents withHashimotos thyroiditis and from 73 age-matched con-trols have been analyzed for the presence of specific anti-bodies No differences are observed But Parvovirus B19DNA indicating recent B19-infection is detectable morefrequently in patients and a negative correlation existswith disease duration There is strong evidence that acuteparvovirus B19 infections are involved in the pathogene-sis of some cases of Hashimotos thyroiditis[104]

Parvovirus may also be present in the brain Some authorshypothesize that parvovirus B19 is a common humanpathogen which could explain the association betweenmental disorders and thyroid diseases because of its abil-ity to infect the brain and to induce autoimmunity Thishypothesis is based on the fact that they found in patientswith bipolar disorder both a thyroid disorder and brainB19 infection [105]

II-B-4bGraves diseaseA woman whose son had an episode of exanthem twoweeks previously was infected with parvovirus and suf-fered successively GD type-1 diabetes and rheumatic pol-yarthritis Serological tests showed IgM antibodies tohuman parvovirus B19 but no IgM antibodies to cytome-galovirus Epstein Barr virus rubella measles or Cox-sackie viruses Anti-TSH receptor antibody was positiveParvovirus viral protein 1 was detected in her bone mar-row samples but no analysis was done on thyroid tissue[106]

II-B-5Viral Hepatitis C and B (HCV and HBV)Discordant data are published about hepatitis Thyroidinvolvement may be regarded as the most frequent altera-tion in HCV positive patients and is more frequent than inHVB The prevalence of abnormally high levels of anti-thyroid antibodies varied markedly ranging from 2 to48 and subclinical hypothyroidism has been observedin 2 to 9 of patients with chronic hepatitis C [107108]In a retrospective cohort study which included 146394patients infected with HCV (individuals with humanimmunodeficiency virus were excluded) and 572293patients uninfected with HCV thyroiditis risk was slightlyincreased but there was no analysis of treatment [109]The prevalence of autoimmune thyroid disease in patientswith HCV differs from that in patients with the hepatitis Bvirus (HBV) before at the end of and 6 months after stop-ping treatment with IFN-alpha Positive levels of TPOAband TgAb were found in 20 and 11 of patients withHCV compared with 5 and 3 of patients with HBVrespectively At the end of IFN-alpha therapy thyroidgland dysfunction was more prevalent in patients withHCV (12) compared with those with HBV (3) withTSH levels significantly higher in the HCV group [110]Other authors dont find an association between hepatitisC virus and thyroid autoimmunity [111112] Thyroidautoimmunity may be a cytokine-induced disease in sus-ceptible patients Indeed the incidence is much greater infemales and positive anti-TPOAb patients prior to the ini-tiation of therapy According Marazuela thyroid dysfunc-tion secondary to interferon is reversible afterdiscontinuation of therapy [113] which is discordantwith Fernandez data [110] Variable geographic distribu-tion has also shown that genetic or environmental influ-ences could be implicated [114] On the whole the



distinctive role of the virus itself or antiviral treatmentremains to be clarified Abnormalities in thyroid functionshould be included among the complications of HCV syn-drome and patients should be periodically screened forthyroid involvement in order to identify patients in needof treatment as quoted in a recent review [107]

II-B-6SARS coronavirus (SARS-CoV)A substantial number of patients with SARS have shownabnormalities in thyroid function As SARS is a diseaseknown to cause multiple organ injury it has been sup-posed that SARS could have a harmful effect on the thy-roid gland However low serum triiodothyronine andthyroxine levels associated with decreased TSH concentra-tion are in favor of central hypothyroidism induced byhypophysitis or by hypothalamic dysfunction [115]

II-B-7EnterovirusII-B-7-aHashimotos thyroiditisEnteroviruses play a role in immune-mediated pathologi-cal processes such as chronic myositis and chronic dilatedcardiomyopathy [116] Epidemiologic and prospectivestudies have provided a body of arguments that stronglysuggest the role of enteroviruses in type-1 diabetes inwhich interestingly AITD is frequently observed[117118] Recently we have shown that EV-RNA can bedetected by real-time PCR in thyroid tissue from patientswith various thyroid diseases but no relationshipbetween the presence of EV-RNA and thyroiditis lym-phocytic infiltration or the presence of circulating TPOAbwas found Although the patients in our series are cer-tainly different from patients with classic Hashimotosthyroiditis which are rarely treated surgically our resultssuggest that the presence of EV-RNA in thyroid tissue isnot associated with autoimmune thyroiditis Its worthyto note that EV-RNA was detected in one patient with anormal thyroid [119] Maternal enterovirus infection dur-ing pregnancy has been linked to thyroiditis in childrenSera taken at delivery from mothers whose children sub-sequently developed AITD was analyzed for antibodiesagainst enterovirus and compared with a control groupOf the mothers whose children developed AITD 16were enterovirus IgM-positive compared with 7 in thecontrol group which was not statistically different How-ever the age at diagnosis of AITD was significantly lowerin the group of children with IgM-positive mothers com-pared with children with IgM-negative mothers Alsohypothyroidism was significantly more frequent in theIgM-positive group with no child in the IgM-negativegroup [120]

II-B-7-bGraves diseasePatients with recent onset of Graves hyperthyroidism(about two months before blood sample collection) have

been investigated in regard to enterovirus infection Anested PCR reaction with primers of the enterovirusgenome was employed on blood samples but all werenegative for RNA of the enterovirus group [121]

II-CViral involvement in the etiology of hypothyroidism animal models dataReovirus infection of a neonatal mouse can induce thy-roiditis and thyroid autoimmunity Mice infected withreovirus type 1 develop a thyroiditis characterized by focaldestruction of acinar tissue infiltration of the thyroid byinflammatory cells and production of autoantibodiesdirected against thyroglobulin and thyroid microsomes[122] The segment of the reovirus type 1 genome respon-sible for the induction of autoantibodies to thyroglobulinencodes a polypeptide that binds to surface receptors anddetermines the tissue tropism of the virus [123]

An endogenous retrovirus (ev 22) was found to beexpressed in obese-strain (OS) chickens but not in healthynormal strains Ev 22 is inherited autosomally in a domi-nant manner The OS chickens develop a hereditary spon-taneous autoimmune thyroiditis characterizedhistologically by lymphocytic infiltration of the thyroidgland Thyroiditis is associated with obesity and hyperlip-idemia A similar thyroiditis has also been induced in nor-mal chickens by retroviral infection [124]

Lymphocytic choriomeningitis virus (LCMV) can persistin the thyroid gland of three strains of mice neonatallyinfected with the virus Furthermore the virus that wasshown to persist mainly in the thyroid epithelial cells inwhich thyroglobulin is synthesized induced a reduction inthe level of thyroglobulin messenger RNA and circulatingthyroid hormones but there was no thyroid cell destruc-tion Then persistent apparently benign virus infectionwith LCMV can be induced in the thyroid of mice and thisinfection induces thyroid dysfunction This alteration inthyroid homeostasis is not caused to the thyroid byautoantibodies Moreover despite infection of the thyroidgland neither necrosis nor inflammation occurs [125]

Animals models show that a typical autoimmune thy-roiditis can be induced by a direct viral infection but alsoby an inherited retrovirus infection These models alsoshow that thyroid dysfunction can occur without inflam-mation or antithyroid autoantibodies Further studies arethen needed in humans to explore the role of viruses inthe pathogenesis of thyroid dysfunctions

IIILymphomas and Riedels thyroiditisLymphomas and Riedels thyroiditis are rare disorders butboth can occur in association with Hashimotos thyroidi-tis



III-ARiedels thyroiditisFibrous thyroiditis also known as Riedels thyroiditis ischaracterized by extensive fibrosis and mononuclear infil-tration that extends into adjacent tissues It may consist ina primary fibrosing disorder or in the local involvement ofa multifocal fibrosclerosis The etiology of Riedels thy-roiditis is not known It can occur in association withHashimotos thyroiditis [126] As this disease is rare theliterature is scarce

Two cases of Riedels thyroiditis onset have been reportedafter a subacute thyroiditis which is thought as alreadysaid to be a viral induced disaese Two women first diag-nosed with sub-acute thyroiditis developed an enlarge-ment of the thyroid gland and symptoms of compressioneight months and three years later respectively Post-oper-ative histopathologic evaluation showed Riedels thy-roiditis characteristics associated with sub-acutethyroiditis [127128]

Only one case report of infection has been reported ininternational literature A 36-year old woman had of long-term fever associated with a biologic inflammatory syn-drome which was reported as due to EBV infectionbecause of a positive EBV serology TSH concentrationlevels of TPOAb and thyrocalcitonin were normal Therewas a dramatic improvement after thyroidectomy withnormalization of inflammatory parameters The role ofEBV infection in the process of this unusual form ofRiedels thyroiditis was suspected [129]

III-BLymphomasThyroid lymphomas are nearly always of the non-Hodg-kins type Hodgkins lymphoma of the thyroid is exceed-ingly rare Preexisting chronic autoimmune thyroiditis isthe only known risk factor for primary thyroid lym-phoma and is present in about one-half of patients [130]

III-B-1Epstein Barr Virus (EBV)Epstein-Barr virus (EBV) is found in many lymphomasThe clinicopathological characteristics in the Hong KongChinese population and the presence of EBV in thyroidlymphomas were analyzed by reviewing data collectedover three decades EBV gene expression by in-situ hybrid-ization and immunohistochemistry were performed Pri-mary thyroid lymphomas were found in 23 patients andsecondary lymphomas were found in 9 patients EBV mes-senger RNAs were detected in one primary and one sec-ondary thyroid lymphoma [131]

One study explored the association of EBV with thyroidlymphoma (TL) and with chronic lymphocytic thyroiditis(CLTH) which is known to play an important role in thedevelopment of TL Thirty cases with TL and 28 withCLTH were studied for presence or absence of EBVgenome in the lesions using the polymerase chain reac-

tion (PCR) and the in-situ hybridization method EBVgenomes were detected by PCR in one CLTH and two TLIn-situ hybridization revealed positive signals in thenucleus of lymphoma cells which also expressed latentmembrane protein-1 [132]

EBV-related mRNA presence was investigated in 32 casesof malignant lymphoma of the thyroid by in-situ hybrid-ization and immunohistochemistry EBV-encoded smallRNA were detected in three cases [133] These findingsindicate that EBV implication in TL is possible but notcommon

III-B-2EnterovirusA patient with autoimmune thyroiditis had a transitoryrecurrence of her goiter during pregnancy with TPOAbbecoming strongly positive Six months post partum shehad a subacute thyroiditis Serology established the diag-nosis of viral thyroiditis due to a Coxsackie-B virus Twomonths later the goiter showed further growth in associ-ation with cervical lymphadenopathy and an enlarged leftparotid gland Histology revealed a primary thyroid lym-phoma

III-B-3Human T Lymphotropic Virus (HTLV1)Thyroid non-Hodgkins lymphoma in an area in whichadult T-cell leukemialymphoma (ATL) is not endemic isexclusively B-cell derived A study was carried out to exam-ine whether thyroid non-Hodgkins lymphoma in an areain which ATL is endemic is also exclusively of B-cell typeEight cases with thyroid non-Hodgkins lymphomaadmitted to the hospital situated in an ATL-endemic areawere studied Immunophenotypic study revealed all butone case to be of B-cell nature The T-cell type lymphomacase also had antibodies against HTLV-1 in the serum[134]

III-B-4Viral hepatitis C (HCV)Lymphomas are frequent in HCV-infected patients but nothyroid lymphoma has been reported in thesepatients[107]

III-B-5Human Immunodeficiency Virus (HIV)Two cases of thyroid lymphoma have been described inHIV-infected patients The first is a 31-year old womanwith acquired immunodeficiency syndrome (AIDS) whopresented a severe thyrotoxicosis and a markedlyenlarged diffuse tender goiter The patient died withindays of her presentation At autopsy near-completereplacement of the thyroid gland with anaplastic large celllymphoma was found without coexisting infectious orautoimmune processes in the gland [135] The secondcase was a child with vertical transmission-acquired HIVpresenting with lymphomatous infiltration of the thyroidgland at diagnosis [136]



ConclusionIdentifying etiological infections in human disease is dif-ficult Besides the fact that organ tissue is not always avail-able for direct study the interpretation of virological datamust be cautious The presence of antibodies directedtowards a virus does not prove that this pathogen isresponsible for the disease especially when the agent iscommon in the general population On the other handthe absence of viral markers at the onset of the diseasedoes not refute the viral hypothesis Indeed the triggeringinfection can take place many years previously A trigger-ing virus can be cleared from the body without any viro-logical trace except the presence of specific antibodies Itis relevant to look for viral agents in tissues in which theycan persist without systemic manifestation Direct evi-dence of the presence of viruses or their components inthe organ are available for retroviruses (HFV) and mumpsin subacute thyroiditis for retroviruses (HTLV-1 HFVHIV and SV40) in Gravess disease and for HTLV-1 enter-ovirus rubella mumps virus HSV EBV and parvovirus inHashimotos thyroiditis However it remains to deter-mine whether they are responsible for thyroid diseases orwhether they are just innocent bystanders

A viral disease is the result of an interaction between avirus and the host in which the genetic background playsa role Therefore it cannot be excluded that a virus plays arole in a disease even though most infected individuals donot show any sign of disease

Further studies are needed to clarify the relationshipbetween viruses and thyroid diseases in order to developnew strategies for their prevention andor the treatment

Competing interestsThe authors declare that they have no competing interests

Authors contributionsRD and DH conceived and wrote the review Authors readand approved the final manuscript

AcknowledgementsThe authors thank the teams of the Laboratory of VirologyUPRES EA3610 (Prof D Hober) and especially Anne Goffard and Delphine Caloone and of the Service dEndocrinologie-Diabeacutetologie-Nutrition CHU Amiens espe-cially Dr Saraval Marie and their collaborators This work was supported by a regional PHRC (PHRC Regional 2005) CHU Amiens CHRU Lille Min-istegravere de lEducation Nationale de la Recherche et de la Technologie Uni-versiteacute de Lille II France

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Abstract

Background

ISubacute and autoimmune thyroiditis a viral infection of the thyroid gland

I-AEpidemiological evidence

I-BVirological data

IIInvolment of viral infection in autoimmune thyroid diseases (AITD)

II-AEpidemiological data

II-A-1Temporal and geographical considerations

II-A-2Subacute thyroiditis a trigger of thyroid autoimmunity

II-A-3What about vaccination

II-BSpecific virus data

II-B-1Retrovirus

II-B-1-aHuman T lymphotrophic virus-1 (HTLV-1)

II-B-1-a1Hashimotos thyroiditis

II-B-1-a2Graves disease (GD)

II-B-1-bHuman Immunodeficiency Virus (HIV)

II-B-1-b1Hashimotos thyroiditis

II-B-1-b2Graves disease (GD)

II-B-1-cHuman Intracisternal A-type particles type 1 (HIAP1)

II-B-1-dHuman Foamy Virus (HFV)

II-B-1-d1Hashimotos thyroiditis

II-B-1-d2Graves disease

II-B-1eSimian virus (SV40)

II-B-2Rubella virus (German measles)

II-B-3Herpesviridae

II-B-3aHerpes Simplex Virus (HSV) and Cytomegalovirus (CMV)

II-B-3bEpstein Barr Virus (EBV)

II-B-3cHuman Herpes Virus (HHV)

II-B-4Parvovirus

II-B-4aHashimotos thyroiditis

II-B-4bGraves disease

II-B-5Viral Hepatitis C and B (HCV and HBV)

II-B-6SARS coronavirus (SARS-CoV)

II-B-7Enterovirus

II-B-7-aHashimotos thyroiditis

II-B-7-bGraves disease

II-CViral involvement in the etiology of hypothyroidism animal models data

IIILymphomas and Riedels thyroiditis

III-ARiedels thyroiditis

III-BLymphomas

III-B-1Epstein Barr Virus (EBV)

III-B-2Enterovirus

III-B-3Human T Lymphotropic Virus (HTLV1)

III-B-4Viral hepatitis C (HCV)

III-B-5Human Immunodeficiency Virus (HIV)

Conclusion

Competing interests

Authors contributions

Acknowledgements

References


ical data which have been associated with research intocirculating viruses and direct evidence of thyroid tissueinfection

ISubacute and autoimmune thyroiditis a viral infection of the thyroid glandFirst defined by De Quervain subacute thyroiditis is a self-limited inflammatory disorder of the thyroid gland Thedisease is most prevalent in females usually characterizedby a sudden onset of neck pain and thyrotoxicosis Clini-cally the disease has several characteristics typical of viralinfections including a typical viral prodrome with myal-gias malaise and fatigue Recurrent subacute thyroiditishas been reported [2] The follicles are often infiltratedresulting in disrupted basement membrane and rupture ofthe follicles The thyroid injury in subacute thyroiditis isthought to be the result of cytolytic T-cell recognition ofviral and cell antigens present in an appropriate complex[3]

I-AEpidemiological evidenceThe first descriptions showed a tendency for the disease tofollow upper respiratory tract infections or sore throatswhich explained why a viral infection has most often beenimplicated as the cause Clusters of the disease have beenreported during outbreaks of viral infection [4] Onset ofthe disease are observed between June and September andthis seasonal distribution is almost identical to that ofestablished infections due to some enteroviruses (Echovi-rus Coxsackievirus A and B) suggesting that enterovirusinfections might be responsible for a large proportion ofcases [56]

An association between subacute thyroiditis and HLA B35is noted in all ethnic groups tested [7] and two-thirds ofpatients manifest HLA-B35 Familial occurrence of suba-cute thyroiditis [8] and recurrence during the course oftime [9] are associated with HLA B35 Thus the onset ofsubacute thyroiditis is genetically influenced and itappears that subacute thyroiditis might occur through asusceptibility to viral infection in genetically predisposedindividuals HLA-B35 has been reported to be correlatedwith chronic active hepatitis with hepatitis B [10] withrapid progression of AIDS [11] and with the T lymphocyteresponses against human parvovirus B19 [12] Recentlythe medical records of 852 patients with subacute thy-roiditis have been studied The significant seasonal clus-ters of subacute thyroiditis during summer to earlyautumn was confirmed According to the authors thehistory of patients showed no obvious association withvirus infection Unfortunately no data on infections areavailable in the paper [2]

I-BVirological dataVirus-like particles were first demonstrated in the follicu-lar epithelium of a patient suffering from subacute thy-

roiditis Judging from the size it was thought to beinfluenza or mumps virus [13] which was concordantwith an increased frequency of antibodies to the influenzaB virus in patients with thyrotoxicosis [14] The same yearin five out of 28 patients with subacute thyroiditis a cyto-pathic virus was isolated by coculturing patient sampleswith susceptible cell lines[15] The agent was later studiedby electron microscopy and classified as a paramyxovirus[16] Subsequently the agent was reanalyzed by immun-ofluorescence and electron microscopy and was reclassi-fied as a foamy virus [17] However the implication offoamy virus has not been confirmed a more comprehen-sive study using different techniques demonstrated noassociation between foamy-virus infection and thyroiditisin 19 patients [18] Moreover the expression of HFV gagproteins had not been found by indirect immunofluores-cence [19] As part of a larger study investigating the prev-alence of foamy-virus infection in humans 59 patientswith thyroid disorders including 28 with Quervains thy-roiditis were analyzed by different techniques includingPCR Again there was no prevalence of foamy virus infec-tion [20] The origin of the foamy-virus-like agent in theoriginal publications remains unclear but because themore comprehensive study was unable to detect foamy-virus infection in de Quervain patients it is highlyunlikely that it is a causative agent of this condition [21]

Some cases could be due to the mumps virus Subacutethyroiditis has occurred in epidemic form patients withsubacute thyroiditis diagnosed during a mumps epidemicwere found to have circulating anti-mumps antibodieseven without clinical evidence of mumps [22] High titersof mumps antibodies have been found in some patientswith subacute thyroiditis and occasionally parotitis ororchitis usual in mumps were associated with thyroiditis[23] In favor of thyroid infection is the fact that in twopatients out of 11 with subacute thyroiditis diagnosedduring a mumps epidemic the mumps virus was culturedfrom thyroid tissue obtained at biopsy [22]

Enteroviruses have been suspected Patients with subacutethyroiditis who had no clinical evidence of viral diseasedemonstrated increases by at least four times in viral anti-bodies These viral antibodies included antibodies tomumps virus but also coxsackie adenovirus and influen-zae Coxsackie viral antibodies were the most commonlyfound and the changes in their titers most closely approx-imated the course of the disease [24] In a case report thy-roiditis was attributed to enterovirus IgM and IgG werefound at a quadruple titer against coxsackievirus B4whereas no other antibodies were found against othercoxsackies echoviruses or mumps [25] In 27 consecutivepatients with subacute thyroiditis antibody tests virusisolation and antigen detection were negative EnterovirusRNA was not detected by RT-PCR neither in blood sam-ples nor in the thyroid tissue in the fine-needle aspiration

























CMV and EBV [30]




[45]














HAART[75]



































































































































































































BioMedcentral































Abstract

Background



I-BVirological data







II-B-1Retrovirus













II-B-3Herpesviridae




II-B-4Parvovirus





II-B-7Enterovirus






III-BLymphomas


III-B-2Enterovirus




Conclusion

Competing interests


Acknowledgements

References
























CMV and EBV [30]




[45]














HAART[75]



































































































































































































BioMedcentral































Abstract

Background



I-BVirological data







II-B-1Retrovirus













II-B-3Herpesviridae




II-B-4Parvovirus





II-B-7Enterovirus






III-BLymphomas


III-B-2Enterovirus




Conclusion

Competing interests


Acknowledgements

References










HAART[75]



































































































































































































BioMedcentral































Abstract

Background



I-BVirological data







II-B-1Retrovirus













II-B-3Herpesviridae




II-B-4Parvovirus





II-B-7Enterovirus






III-BLymphomas


III-B-2Enterovirus




Conclusion

Competing interests


Acknowledgements

References































































































































































































BioMedcentral































Abstract

Background



I-BVirological data







II-B-1Retrovirus













II-B-3Herpesviridae




II-B-4Parvovirus





II-B-7Enterovirus






III-BLymphomas


III-B-2Enterovirus




Conclusion

Competing interests


Acknowledgements

References

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