To clarify risk factors for cytomegalovirus (CMV) reactivation and disease in patients with systemic lupus erythematosus (SLE).
Methods
We reviewed patients with SLE who received remission induction therapy at our institution between May 2010 and October 2022 and enrolled those whose CMV pp65 antigen–positive cell counts were measured within 3 months of admission. Patients with CMV reactivation were divided into CMV disease (with any symptoms or end-organ disease due to CMV reactivation) and asymptomatic CMV reactivation. Risk factors for CMV reactivation and CMV disease were examined.
Results
We observed CMV reactivation in 64 of 130 patients. Age (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.09–3.78; p = 0.026), albumin (HR, 2.35; 95% CI, 1.09–5.07; p = 0.029), a high Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (HR, 1.73; 95% CI, 1.00–2.98; p = .048), and immunosuppressive drug use (HR, 1.94; 95% CI, 1.12–3.35; p = 0.018) were risk factors for CMV reactivation. CMV reactivation occurred more frequently when two or more risk factors were present. Among the 64 cases of CMV reactivation, 25 with disease had a higher number of CMV pp65 antigen–positive cells (6 vs 2; p = 0.02). The cut-off value for developing organ damage was 12 cells on two slides.
Conclusion
In SLE patients, age, albumin, a high SLEDAI, and immunosuppressive drug use were possible risk factors for CMV reactivation. Patients who develop organ damage have high numbers of CMV pp65 antigen–positive cells and are prone to be symptomatic with an antigenemia count >12 per two slides.
GriffithsPReevesM. Pathogenesis of human cytomegalovirus in the immunocompromised host. Nat Rev Microbiol2021; 19: 759–773.
2.
CannonMJSchmidDSHydeTB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol2010; 20: 202–213.
3.
KoJHPeckKRLeeWJ, et al.Clinical presentation and risk factors for cytomegalovirus colitis in immunocompetent adult patients. Clin Infect Dis2015; 60: e20–e26.
BekBBoeckhMLepeniesJ, et al.High-level sensitivity of quantitative pp65 cytomegalovirus (CMV) antigenemia assay for diagnosis of CMV disease in AIDS patients and follow-up. J Clin Microbiol1996; 34: 457–459.
6.
van den BergAPKlompmakerIJHaagsmaEB, et al.Antigenemia in the diagnosis and monitoring of active cytomegalovirus infection after liver transplantation. J Infect Dis1991; 164: 265–270.
7.
van den BergAPvan der BijWvan SonWJ, et al.Cytomegalovirus antigenemia as a useful marker of symptomatic cytomegalovirus infection after renal transplantation--a report of 130 consecutive patients. Transplantation1989; 48: 991–995.
8.
TakizawaYInokumaSTanakaY, et al.Clinical characteristics of cytomegalovirus infection in rheumatic diseases: multicentre survey in a large patient population. Rheumatology2008; 47: 1373–1378.
9.
KaneshitaSKidaTYokotaI, et al.Risk factors for cytomegalovirus disease with cytomegalovirus re-activation in patients with rheumatic disease. Mod Rheumatol2020; 30: 109–115.
10.
OtaYKanekoYTakeuchiT. Association between mortality and cytomegalovirus reactivation during remission induction therapy in patients with rheumatic diseases. Clin Exp Rheumatol2021; 39: 1324–1330.
11.
HochbergMC. Updating the American college of rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1997; 40: 1725.
12.
AringerMCostenbaderKDaikhD, et al.2019 european league against rheumatism/American college of rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol2019; 71: 1400–1412.
13.
BombardierCGladmanDDUrowitzMB, et al.Derivation of the SLEDAI. A disease activity index for lupus patients. The committee on prognosis studies in SLE. Arthritis Rheum1992; 35: 630–640.
14.
LjungmanPGriffithsPPayaC. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis2002; 34: 1094–1097.
15.
BoeckhMBowdenRAGooleyT, et al.Successful modification of a pp65 antigenemia-based early treatment strategy for prevention of cytomegalovirus disease in allogeneic marrow transplant recipients. Blood1999; 93: 1781–1782.
16.
GondoHMinematsuTHaradaM, et al.Cytomegalovirus (CMV) antigenaemia for rapid diagnosis and monitoring of CMV-Associated disease after bone marrow transplantation. Br J Haematol1994; 86: 130–137.
17.
EizuruYMinematsuTMinamishimaY, et al.Rapid diagnosis of cytomegalovirus infections by direct immunoperoxidase staining with human monoclonal antibody against an immediate-early antigen. Microbiol Immunol1991; 35: 1015–1022.
18.
RazonableRRHumarAAST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant2013; 13: 93–106.
19.
TsaiWPChenMHLeeMH, et al.Cytomegalovirus infection causes morbidity and mortality in patients with autoimmune diseases, particularly systemic lupus: in a Chinese population in Taiwan. Rheumatol Int2012; 32: 2901–2908.
20.
ZhangTYuZGaoS, et al.Clinical phenotypes and prognosis of cytomegalovirus infection in the pediatric systemic lupus erythematosus: a longitudinal analysis. Pediatr Rheumatol Online J2023; 21: 25.
21.
LeongAFongW. Factors associated with cytomegalovirus infection in antineutrophil cytoplasmic antibody-associated vasculitis: a narrative review. Int J Rheum Dis2022; 25: 1357–1367.
22.
ShimadaTHigashida-KonishiMIzumiK, et al.Risk factors associated with cytomegalovirus reactivation in patients receiving immunosuppressive therapy for rheumatic diseases: a retrospective study. Sci Rep2022; 12: 20926.
23.
SugaKNishiwakiANakamuraT, et al.Clinical significance of cytomegalovirus (CMV) pp65 antigenemia in the prediction of CMV infection during immunosuppressive therapy for rheumatic disease. Rheumatol Int2023; 43: 1093–1099.
24.
HanaokaRKurasawaKMaezawaR, et al.Reactivation of cytomegalovirus predicts poor prognosis in patients on intensive immunosuppressive treatment for collagen-vascular diseases. Mod Rheumatol2012; 22: 438–445.
25.
YamashitaMIshiiTIwamaN, et al.Incidence and clinical features of cytomegalovirus infection diagnosed by cytomegalovirus pp65 antigenemia assay during high dose corticosteroid therapy for collagen vascular diseases. Clin Exp Rheumatol2006; 24: 649–655.
26.
FuruiYSatakeMHoshiY, et al.Cytomegalovirus (CMV) seroprevalence in Japanese blood donors and high detection frequency of CMV DNA in elderly donors. Transfusion (Arlingt)2013; 53: 2190–2197.
27.
VincentJLDuboisMJNavickisRJ, et al.Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studies and controlled trials. Ann Surg2003; 237: 319–334.
28.
EmersonTEJr. Unique features of albumin: a brief review. Crit Care Med1989; 17: 690–694.
29.
ZoellnerHHouJYLoveryM, et al.Inhibition of microvascular endothelial apoptosis in tissue explants by serum albumin. Microvasc Res1999; 57: 162–173.
30.
MimozOSoredaSPadoinC, et al.Ceftriaxone pharmacokinetics during iatrogenic hydroxyethyl starch-induced hypoalbuminemia: a model to explore the effects of decreased protein binding capacity on highly bound drugs. Anesthesiology2000; 93: 735–743.
31.
Franch-ArcasG. The meaning of hypoalbuminaemia in clinical practice. Clin Nutr2001; 20: 265–269.
32.
HuangSTChenGYWuCH, et al.Effect of disease activity and position on autonomic nervous modulation in patients with systemic lupus erythematosus. Clin Rheumatol2008; 27: 295–300.
33.
SekiguchiAInoueYYamazakiS, et al.Demographic and clinical characteristics of cytomegalovirus reactivation in dermatomyositis. J Dermatol2020; 47: 876–881.
34.
SantosRPDos Reis-NetoETPinheiroMM. Incidence of cytomegalovirus antigenemia in patients with autoimmune rheumatic diseases: a 3-year retrospective study. Adv Rheumatol2019; 59: 18.
35.
DanzaARuiz-IrastorzaG. Infection risk in systemic lupus erythematosus patients: susceptibility factors and preventive strategies. Lupus2013; 22: 1286–1294.
36.
ChenHHChenYMChenTJ, et al.Risk of Herpes zoster in patients with systemic lupus erythematosus: a three-year follow-up study using a nationwide population-based cohort. Clinics2011; 66: 1177–1182.
37.
ForteEZhangZThorpEB, et al.Cytomegalovirus latency and reactivation: an intricate interplay with the host immune response. Front Cell Infect Microbiol2020; 10: 130.
38.
PostalMAppenzellerS. The role of tumor necrosis Factor-alpha (TNF-α) in the pathogenesis of systemic lupus erythematosus. Cytokine2011; 56: 537–543.
39.
DhitalRPandeyRKPoudelDR, et al.All-cause hospitalizations and mortality in systemic lupus erythematosus in the US: results from a national inpatient database. Rheumatol Int2020; 40: 393–397.
40.
BarberMRWDrenkardCFalasinnuT, et al.Global epidemiology of systemic lupus erythematosus. Nat Rev Rheumatol2021; 17: 515–532.
41.
FreemanRBJr. The ‘indirect’ effects of cytomegalovirus infection. Am J Transplant2009; 9: 2453–2458.
42.
YodaYHanaokaRIdeH, et al.Clinical evaluation of patients with inflammatory connective tissue diseases complicated by cytomegalovirus antigenemia. Mod Rheumatol2006; 16: 137–142.
43.
FujimotoDMatsushimaANagaoM, et al.Risk factors associated with elevated blood cytomegalovirus pp65 antigen levels in patients with autoimmune diseases. Mod Rheumatol2013; 23: 345–350.
44.
ChooHMCCherWQKwanYH, et al.Risk factors for cytomegalovirus disease in systemic lupus erythematosus (SLE): a systematic review. Adv Rheumatol2019; 59: 12.
45.
ChenYZhangLLiuY, et al.Clinical features and prognosis of systemic lupus erythematosus complicated by active cytomegalovirus infection: a retrospective cohort study. Front Immunol2024; 15: 1323923.
46.
KottonCNKumarDCaliendoAM, et al.and Transplantation Society International CMV Consensus Group. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation2013; 96: 333–360.
47.
JangEYParkSYLeeEJ, et al.Diagnostic performance of the cytomegalovirus (CMV) antigenemia assay in patients with CMV gastrointestinal disease. Clin Infect Dis2009; 48: e121–e124.
48.
OzakiTYamashitaHKanekoS, et al.Cytomegalovirus disease of the upper gastrointestinal tract in patients with rheumatic diseases: a case series and literature review. Clin Rheumatol2013; 32: 1683–1690.
