The objective of this paper is to conduct a systematic review and meta-analysis on the risk of developing elevated antiphospholipid (aPL) antibodies and related thromboembolic and/or pregnancy events following a viral infection.
Method
We searched Medline, EMBASE, Web of Science, PubMed ePubs, and Cochrane Central Register of Controlled Trials through June 2016. Independent observational studies of elevated aPL antibodies in patients with a viral infection compared with controls or patients with lupus were included.
Results
We analyzed 73 publications for 60 studies. Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) were most commonly reported. Compared with healthy controls, patients with HIV were more likely to develop elevated anticardiolipin (aCL) antibodies (risk ratio (RR) 10.5, 95% confidence interval (CI) 5.6–19.4), as were those with HCV (RR 6.3, 95% CI 3.9–10.1), hepatitis B virus (HBV) (RR 4.2, 95% CI 1.8–9.5), and Epstein-Barr virus (EBV) (RR 10.9 95% CI 5.4–22.2). The only statistically significant increased risk for anti-β2-glycoprotein I (anti-β2-GPI) antibodies was observed in patients with HCV (RR 4.8 95% CI 1.0–22.3). Compared with patients with lupus, patients with HIV were more likely to develop elevated aCL antibodies (RR 1.8, 95% CI 1.3–2.6), and those with EBV, elevated anti-β2-GPI antibodies (RR 2.2, 95% CI 1.3–3.9). Thromboembolic events were most prevalent in patients with elevated aPL antibodies who had HCV (9.1%, 95% CI 3.0–18.1), and HBV (5.9%, 95% CI 2.0–11.9) infections, and pregnancy events were most prevalent in those with parvovirus B19 (16.3%, 95% CI 0.78–45.7). However, compared to virus-infected patients with negative aPL antibodies, the only statistically significant increased risk was observed in those with HCV and positive aPL.
Conclusions
Viral infection can increase the risk of developing elevated aPL antibodies and associated thromboembolic events. Results are contingent on the reported information.
JubyAGDavisP. Prevalence and disease associations of certain autoantibodies in elderly patients. Clin Invest Med1998; 21: 4–11.
2.
LevineJSBranchDWRauchJ. The antiphospholipid syndrome. N Engl J Med2002; 346: 752–763.
3.
MchraniTPetriMEpidemiology of the antiphospholipid syndrome. In: AshersonRA (ed). Handbook of systemic autoimmune diseases, Amsterdam: Elsevier, 2009, pp. 13–34.
4.
PetriM. Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun2000; 15: 145–151.
5.
ShiWKrilisSAChongBHGordonSChestermanCN. Prevalence of lupus anticoagulant and anticardiolipin antibodies in a healthy population. Aust N Z J Med1990; 20: 231–236.
6.
MiyakisSLockshinMDAtsumiTet al.International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost2006; 4: 295–306.
7.
CerveraRPietteJCFontJet al.Antiphospholipid syndrome: Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum2002; 46: 1019–1027.
8.
KoikeT. Antiphospholipid syndrome: 30 years and our contribution. Int J Rheum Dis2015; 18: 233–241.
9.
ShoenfeldYBlankMCerveraRFontJRaschiEMeroniPL. Infectious origin of the antiphospholipid syndrome. Ann Rheum Dis2006; 65: 2–6.
10.
Abdel-WahabNLopez-OlivoMAPinto-PatarroyoGPSuarez-AlmazorME. Systematic review of case reports of antiphospholipid syndrome following infection. Lupus2016; 25: 1520–1531.
StataCorp. Stata Statistical Software: Release 11. StataCorp LP; College Station, TX.
14.
EggerMDavey SmithGSchneiderMMinderC. Bias in meta-analysis detected by a simple, graphical test. BMJ1997; 315: 629–634.
15.
SterneJASuttonAJIoannidisJPet al.Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ2011; 343: d4002–d4002.
16.
BlankAYamaguchiKNishimuraYet al.Anticardiolipin antibodies in diverse conditions associated with HTLV-I infection. J Acquir Immune Defic Syndr Hum Retrovirol1995; 10: 80–80.
17.
FaghiriZWilsonWATaheriFBartonENMorganOSGharaviAE. Antibodies to cardiolipin and beta2-glycoprotein-1 in HTLV-1-associated myelopathy/tropical spastic paraparesis. Lupus1999; 8: 210–214.
18.
Medina-RodriguezFGuzmanCJaraLJet al.Rheumatic manifestations in human immunodeficiency virus positive and negative individuals: A study of 2 populations with similar risk factors. J Rheumatol1993; 20: 1880–1884.
19.
ZanonEPittoniMVaselliGet al.Anticardiolipin antibodies in hemophiliac and nonhemophiliac patients with chronic hepatitis C. Clin Appl Thromb Hemost1998; 4: 205–208.
20.
GratacósETorresPJVidalJet al.Prevalence and clinical significance of anticardiolipin antibodies in pregnancies complicated by parvovirus B19 infection. Prenat Diagn1995; 15: 1109–1113.
21.
Martínez-RojanoHJuárez HernandezELadrón De-GuevaraGdel Carmen Gorbea-RoblesM. Rheumatologic manifestations of pediatric HIV infection. AIDS Patient Care STDs2001; 15: 519–526.
22.
AbuafNLapercheSRajoelyBet al.Autoantibodies to phospholipids and to the coagulation proteins in AIDS. Thromb Haemost1997; 77: 856–861.
23.
BironCAndréaniHBlancPet al.Prevalence of antiphospholipid antibodies in patients with chronic liver disease related to alcohol or hepatitis C virus: Correlation with liver injury. J Lab Clin Med1998; 131: 243–250.
24.
HuhJYYiDYHwangSGChoiJJKangMS. Characterization of antiphospholipid antibodies in chronic hepatitis B infection. Korean J Hematol2011; 46: 36–40.
25.
PalomoIAlarcónMSepulvedaCPereiraJEspinolaRPierangeliS. Prevalence of antiphospholipid and antiplatelet antibodies in human immunodeficiency virus (HIV)-infected Chilean patients. J Clin Lab Anal2003; 17: 209–215.
26.
JohnstoneFDKilpatrickDCBurnsSM. Anticardiolipin antibodies and pregnancy outcome in women with human immunodeficiency virus infection. Obstet Gynecol1992; 80: 92–96.
27.
DalekosGNKistisKGBoumbaDSet al.Increased incidence of anti-cardiolipin antibodies in patients with hepatitis C is not associated with aetiopathogenetic link to anti-phospholipid syndrome. Eur J Gastroenterol Hepatol2000; 12: 67–74.
28.
Di PrimaMASoriceMAmendoleaMAet al.Autoimmunity and AIDS. I. Correlation between anti-cardiolipin antibodies and Pneumocystis carinii pneumonia [article in Italian]. Medicina (Firenze)1988; 8: 423–425.
29.
LeroyVArvieuxJJacobMCMaynard-MuetMBaudMZarskiJP. Prevalence and significance of anticardiolipin, anti-beta2 glycoprotein I and anti-prothrombin antibodies in chronic hepatitis C. Br J Haematol1998; 101: 468–474.
30.
MangiaAMargaglioneMCascavillaIet al.Anticardiolipin antibodies in patients with liver disease. Am J Gastroenterol1999; 94: 2983–2987.
31.
MasalaCSoriceMDi PrimaMAet al.Anticardiolipin antibodies in opportunistic infections in AIDS. EOS1991; 11: 109–114.
32.
MatsudaJSaitohNGotohMet al.High prevalence of anti-phospholipid antibodies and anti-thyroglobulin antibody in patients with hepatitis C virus infection treated with interferon-alpha. Am J Gastroenterol1995; 90: 1138–1141.
33.
PeredaIBartolomé-PachecoMJMartínMLópez-EscribanoHEchevarriaSLópez-HoyosM. Antitissue transglutaminase antibodies in HIV infection and effect of highly active antiretroviral therapy. J Acquir Immune Defic Syndr2001; 27: 507–508.
34.
PrietoJYusteJRBeloquiOet al.Anticardiolipin antibodies in chronic hepatitis C: Implication of hepatitis C virus as the cause of the antiphospholipid syndrome. Hepatology1996; 23: 199–204.
35.
SedlacekDUlcová-GallováZMilichovskáLNovákováPRokytaZ. Seven antiphospholipid antibodies in HIV-positive patients: Correlation with clinical course and laboratory findings. Am J Reprod Immunol2003; 50: 439–443.
36.
HaradaMFujisawaYSakisakaSet al.High prevalence of anticardiolipin antibodies in hepatitis C virus infection: Lack of effects on thrombocytopenia and thrombotic complications. J Gastroenterol2000; 35: 272–277.
37.
ToyoshimaMOkunoTMaegakiYYoneeCMaruyamaSKawanoY. Primary human herpesvirus-6 infections induce anticardiolipin antibodies. Dev Med Child Neurol2012; 54: 176–177.
38.
AlessandriCBombardieriMDi ProsperoLet al.Anti-lysobisphosphatidic acid antibodies in patients with antiphospholipid syndrome and systemic lupus erythematosus. Clin Exp Immunol2005; 140: 173–180.
39.
ZachouKLiaskosCChristodoulouDKet al.Anti-cardiolipin antibodies in patients with chronic viral hepatitis are independent of beta2-glycoprotein I cofactor or features of antiphospholipid syndrome. Eur J Clin Invest2003; 33: 161–168.
40.
AttaAMEstevamPParanáRPereiraCMLeiteBCSousa-AttaML. Antiphospholipid antibodies in Brazilian hepatitis C virus carriers. Braz J Med Biol Res2008; 41: 489–492.
41.
ConstansJGuérinVCouchouronAet al.Autoantibodies directed against phospholipids or human beta 2-glycoprotein I in HIV-seropositive patients: Relationship with endothelial activation and antimalonic dialdehyde antibodies. Eur J Clin Invest1998; 28: 115–122.
42.
Soto-VegaERuiz-ArgüellesAMendoza-PintoCet al.Antiphospholipid antibodies in Mexican HIV-positive patients. Inmunología2013; 32: 12–16.
GuerinJFeigheryCSimRBJacksonJ. Antibodies to beta2-glycoprotein I—A specific marker for the antiphospholipid syndrome. Clin Exp Immunol1997; 109: 304–309.
AmbrosinoPLupoliRTarantinoPDi MinnoATarantinoLDi MinnoMN. Viral hepatitis and anti-phospholipid antibodies positivity: A systematic review and meta-analysis. Dig Liv Dis2015; 47: 478–487.
49.
PangbornMC. A new serologically active phospholipid from beef heart. Proc Soc Exp Biol Med1941; 48: 484–486.
50.
MichaelisL. Precipitin reaction bei syphilis. Berl Klin Wochenschr1907; 44: 1635–1645.
51.
WassermanANeisserABruckC. Eine serodiagnostiche Reaction bei Syphilis. Dtsch Med Wochenschr1906; 32: 745–745.
52.
LandsteinerKMüllerRPötzlO. Zur Frage der Komplementbindungsreaktion bei Syphilis. Wien Klin Wochenschr1907; 20: 1565–1565.
53.
LynchFWBoyntonREKimballAC. False positive serologic reactions for syphilis due to smallpox vaccination (vaccinia). JAMA1941; 115: 591–591.
54.
PutkonenT. Biologic false-positive seroreactions for syphilis: Type, incidence, and cause. JAMA1952; 150: 467–473.
55.
HarveyAMShulmanLESystemic lupus erythematosus and chronic biological false positive test for syphilis. In: DuboisE (ed). Lupus erythematosus. 4th ed, Los Angeles: University of California Press, 1974, pp. 196–209.
56.
KoikeTSueishiMFunakiHTomiokaHYoshidaS. Anti-phospholipid antibodies and biological false positive serological test for syphilis in patients with systemic lupus erythematosus. Clin Exp Immunol1984; 56: 193–199.
57.
MooreJELutzW. Natural history of SLE: Approach to its study through chronic biologic false positive reactions. J Chron Dis1949; 1: 297–297.
58.
HughesGRHarrisNNGharaviAE. The anticardiolipin syndrome. J Rheumatol1986; 13: 486–489.
59.
GalliMComfuriusPMaassenCet al.Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet1990; 335: 1544–1547.
60.
MatsuuraEIgarashiYFujimotoMIchikawaKKoikeT. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet1990; 336: 177–178.
61.
MatsuuraEIgarashiYYasudaTTriplettDAKoikeT. Anticardiolipin antibodies recognize beta 2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med1994; 179: 457–462.
62.
McNeilHPSimpsonRJChestermanCNKrilisSA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: Beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A1990; 87: 4120–4124.
63.
GharaviAESammaritanoLRWenJet al.Characteristics of human immunodeficiency virus and chlorpromazine induced antiphospholipid antibodies: Effect of beta 2 glycoprotein I on binding to phospholipid. J Rheumatol1994; 21: 94–99.
64.
HuntJEMcNeilHPMorganGJCrameriRMKrilisSA. A phospholipid-beta 2-glycoprotein I complex is an antigen for anticardiolipin antibodies occurring in autoimmune disease but not with infection. Lupus1992; 1: 75–81.
65.
RoubeyRAPrattCWBuyonJPWinfieldJB. Lupus anticoagulant activity of autoimmune antiphospholipid antibodies is dependent upon beta 2-glycoprotein I. J Clin Invest1992; 90: 1100–1104.
66.
LoizouSCazabonJKWalportMJTaitDSoAK. Similarities of specificity and cofactor dependence in serum antiphospholipid antibodies from patients with human parvovirus B19 infection and from those with systemic lupus erythematosus. Arthritis Rheum1997; 40: 103–108.
67.
LacknerKJMüller-CallejaN. Pathogenesis of the antiphospholipid syndrome revisited: Time to challenge the dogma. J Thromb Haemost2016; 14: 1117–1129.
68.
BarrileAQuattrocchiPBonannoDet al.Presence and significance of anticardiolipin antibodies in infectious diseases [article in Italian]. Recenti Prog Med1992; 83: 350–353.
69.
CarreñoLMonteagudoILópez-LongoFJet al.Anticardiolipin antibodies in pediatric patients with human immunodeficiency virus. J Rheumatol1994; 21: 1344–1346.
70.
ChretienPMonierJCOksmanFet al.Autoantibodies and human immunodeficiency viruses infection: A case-control study. Clin Exp Rheumatol2003; 21: 210–212.
71.
Coll DarocaJGutiérrez-CebolladaJYazbeckHBergésARubiés-PratJ. Anticardiolipin antibodies and acquired immunodeficiency syndrome: prognostic marker or association with HIV infection?Infection1992; 20: 140–142.
72.
DerilGMTrottiRBrustiaRBonoGMinoliL. Anticardiolipin antibodies in HIV infection. Clin Chem1995; 41: S100–S100.
73.
González DomínguezJOrtegaCJuradoRet al.Anticardiolipin antibodies in parenteral drug addicts: Relationship with HIV [article in Spanish]. Rev Clin Esp (Barc)1995; 195: 8–11.
74.
MacleanCFleggPJKilpatrickDC. Anti-cardiolipin antibodies and HIV infection. Clin Exp Immunol1990; 81: 263–266.
75.
MassabkiPSAccetturiCNishieIAda SilvaNPSatoEIAndradeLE. Clinical implications of autoantibodies in HIV infection. AIDS1997; 11: 1845–1850.
76.
MulhallBPNaselliGWhittinghamS. Anticardiolipin antibodies in homosexual men: Prevalence and lack of association with human immunodeficiency virus (HIV) infection. J Clin Immunol1989; 9: 208–213.
77.
PetrovasCVlachoyiannopoulosPGKordossisTMoutsopoulosHM. Antiphospholipid antibodies in HIV infection and SLE with or without anti-phospholipid syndrome: Comparisons of phospholipid specificity, avidity and reactivity with beta2-GPI. J Autoimmun1999; 13: 347–355.
78.
WeissLYouJFGiralPAlhenc-GelasMSengerDKazatchkineMD. Anticardiolipin antibodies are associated with anti-endothelial cell antibodies but not with antibeta 2 glycoprotein I antibodies in HIV infection. Clin Immunol Immunopathol1995; 77: 69–74.
79.
SoriceMGriggiTArcieriPet al.Protein S and HIV infection. The role of anticardiolipin and anti-protein S antibodies. Thromb Res1994; 73: 165–175.
80.
AgarwalNHandaRAcharyaSKWaliJPDindaAKAggarwalP. A study of autoimmune markers in hepatitis C infection. Indian J Med Res2001; 113: 170–174.
81.
CacoubPMussetLAmouraZet al.Anticardiolipin, anti-beta2-glycoprotein I, and antinucleosome antibodies in hepatitis C virus infection and mixed cryoglobulinemia. Multivirc Group. J Rheumatol1997; 24: 2139–2144.
82.
GuerreroFJLepeJAGarridoAPalomoS. The association between hepatitis C virus infection and anticardiolipin antibodies [article in Spanish]. Med Clin (Barc)1998; 110: 319–319.
83.
HimotoTYoneyamaHKurokohchiKet al.Clinical relevance of antibodies to cardiolipin in patients with chronic hepatitis C. J Clin Lab Anal2012; 26: 342–348.
84.
NagaoYTsuboneKKimuraRet al.High prevalence of anticardiolipin antibodies in patients with HCV-associated oral lichen planus. Int J Mol Med2002; 9: 293–297.
85.
Ordi-RosJVillarrealJMonegalFSauledaSEstebanIVilardellM. Anticardiolipin antibodies in patients with chronic hepatitis C virus infection: characterization in relation to antiphospholipid syndrome. Clin Diagn Lab Immunol2000; 7: 241–244.
86.
Romero GómezMLópez LacombaDGarcía-DíazEet al.Prevalence and clinical significance of antiphospholipid antibodies in chronic hepatitis C [article in Spanish]. Med Clin (Barc)2000; 114: 367–370.
87.
SalazarLAGarcia-SamperXSuarez-CarpioRet al.Hypothyroidism in noninterferon treated-HCV infected individuals is associated with abnormalities in the regulation of Th17 cells. Hepat Res Treat2010; 2010: 971095–971095.
88.
SthoegerZMFogelMSmirovAet al.Anticardiolipin autoantibodies in serum samples and cryoglobulins of patients with chronic hepatitis C infection. Ann Rheum Dis2000; 59: 483–486.
89.
ZachouKLiaskosCRigopoulouEet al.Presence of high avidity anticardiolipin antibodies in patients with autoimmune cholestatic liver diseases. Clin Immunol2006; 119: 203–212.
90.
AdebajoAOCharlesPMainiRNHazlemanBL. Autoantibodies in malaria,tuberculosis and hepatitis B in a west African population. Clin Exp Immunol1993; 92: 73–76.
91.
ElefsiniotisISDiamantisIDDourakisSPKafiriGPantazisKMavrogiannisC. Anticardiolipin antibodies in chronic hepatitis B and chronic hepatitis D infection, and hepatitis B-related hepatocellular carcinoma. Relationship with portal vein thrombosis. Eur J Gastroenterol Hepatol2003; 15: 721–726.
92.
DostálCPaleckováATrnavskýKet al.Anticardiolipin antibodies in infectious mononucleosis. J Rheumatol1990; 17: 1573–1574.
93.
SoriceMPittoniVGriggiTet al.Specificity of anti-phospholipid antibodies in infectious mononucleosis: A role for anti-cofactor protein antibodies. Clin Exp Immunol2000; 120: 301–306.
94.
Elías CalvoCJPérez SurribasDOteo RevueltaJADorronsoro IberoI. Lupus anticoagulant in patients infected by the HIV virus in its various stages [article in Spanish]. Med Clin (Barc)1993; 100: 797–798.
95.
NdakotsuMASalawuLDurosinmiMA. Lupus anticoagulant in Nigerian patients living with human immunodeficiency virus/acquired immunodeficiency syndrome. J Microbiol Immunol Infect2009; 42: 69–73.
96.
CaporaliRLonghiMDe GennaroFDi LauroMCarnevaleRMontecuccoC. Antiphospholipid antibody-associated thrombocytopenia in autoimmune diseases. Med Sci Res1988; 16: 537–537.
97.
GuerinJCaseyEFeigheryCJacksonJ. Anti-beta 2-glycoprotein I antibody isotype and IgG subclass in antiphospholipid syndrome patients. Autoimmunity1999; 31: 109–116.
98.
LapercheSRajoelyBRouquetteAMDeschampsARobertAAbuafN. Patients with antiphospholipid antibodies different from anti-beta2 glycoprotein I activity according to an autoimmune disease or HIV infection. 655 case reports [article in French]. Rev Med Interne1993; 14: 520–520.
99.
AdebajoAOCharlesPMainiRNHazlemanBL. Anticardiolipin antibodies in association with chronic infections. Br J Rheumatol1992; 31: 45–45.
100.
BironCAndreaniHBlancPet al.Antiphospholipid antibodies in patients with chronic hepatitis C virus infection or alcoholic liver disease. Preliminary results. Ann Med Interne (Paris)1996; 147(Suppl 1): 48–49.
101.
CollJYazbeckHGutiérrezJ. Anticardiolipin antibodies in patients with the human immunodeficiency virus type 1 [article in Spanish]. Med Clin (Barc)1993; 100: 357–358.
102.
DostálCPaleckováANovákMJahnMDostálCJr. Why are there anticardiolipin antibodies in patients with infectious mononucleosis and in patients with systemic lupus erythematosus? [article in Czech]. Vnitr Lek1990; 36: 1050–1056.
103.
HaradaMFujisawaYSakisakaSet al.High prevalence of anticardiolipin antibodies and platelet-associated immunoglobulin G in hepatitis C virus infection. Gastroenterology2000; 118: A944–A944.
104.
HuntJEMcNeilHPKrilisSA. Anticardiolipin antibodies from autoimmune-disease and infection have different binding specificities. FASEB J1991; 5: A1088–A1088.
105.
Romero-GómezMGuilAGarcía-DíazEet al.Prevalence and clinical significance of antiphospholipid antibodies (APA) in viral chronic liver disease. J Hepatol2000; 32: 102–102.
106.
GabetaSNormanGLGatselisNet al.IgA anti-b2GPI antibodies in patients with autoimmune liver diseases. J Clin Immunol2008; 28: 501–511.
107.
LiaskosCRigopoulouEZachouKet al.Prevalence and clinical significance of anticardiolipin antibodies in patients with type 1 autoimmune hepatitis. J Autoimmun2005; 24: 251–260.
108.
ZachouKLiaskosCChristodoulouDet al.Anti-cardiolipin antibodies (anti-CL) in patients with hepatitis C virus (HCV) infection are independent of beta2-glycoprotein I (b2GPI) co-factor or features of antiphospholipid syndrome (APS). J Hepatol2002; 36: 139–139.
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