Rheumatology International

, Volume 39, Issue 7, pp 1229–1240 | Cite as

Reactivation of latent cytomegalovirus infection in patients with rheumatologic disease: a case–control study

  • Bradley J. GardinerEmail author
  • Erica M. Haas
  • Rosemary C. Bailey
  • Jennifer K. Chow
  • David R. Snydman
Observational Research


The disease burden, risk factors and clinical sequelae of CMV reactivation in patients with rheumatologic conditions is poorly understood. We have described a cohort with underlying rheumatic disease and CMV, and compared a subgroup with systemic lupus erythematosus (SLE) to controls to identify potential risk factors for CMV reactivation. Adults with rheumatic disease and CMV infection from 2000–2015 were identified. SLE cases were matched 3:1 with controls based on age, sex and year of admission, and compared. Fourteen patients were included (6 SLE, 4 rheumatoid arthritis, 2 sarcoidosis, 1 psoriatic arthritis, 1 microscopic polyangiitis). Seven had viremia alone, the remainder tissue-invasive disease. Thirteen received glucocorticoids prior to CMV reactivation. Fever was the most common symptom, and coinfections were seen in eight including four with bacteremia. Thirteen received antiviral therapy (median 33 days), four died during hospitalization. Six patients with underlying SLE and CMV reactivation were compared to 18 SLE controls. Cases received more glucocorticoids prior to admission (median 36.5 vs. 2.5 mg/day, p = 0.006), had longer hospitalizations (median 47 vs. 7 days, p = 0.006) and more coinfections (67% vs. 17%, p = 0.04). There were no significant differences in symptoms at presentation. CMV reactivation occurs in patients with rheumatologic disease, can result in severe clinical sequelae, and is difficult to distinguish from a flare of the underlying disease. Patients with CMV received higher doses of glucocorticoids and developed more co-infections. CMV should be considered during the evaluation of a febrile illness in this complex patient population.


Cytomegalovirus Rheumatic disease Systemic lupus erythematosus 



The authors would like to acknowledge the assistance of Jacob Garrell and Shelley Bame-Aldred for help with data collection, and Robin Ruthazer for statistical support.

Author contributions

BG was involved in all aspects of this project including study design, data collection, analysis, interpretation and manuscript preparation. EH and RB contributed to data collection and manuscript preparation. JC and DS provided oversight and assisted with study design, analysis and manuscript editing. All authors read, contributed to and approved the final version of the manuscript and agree to be accountable for all aspects of the work.


This work was supported by the Tufts Medical Center Division of Geographic Medicine and Infectious Disease Francis P. Tally MD Fellowship, and the National Institutes of Health Clinical and Translational Science Award (grant number UL1TR001064).

Compliance with ethical standards

Conflict of interest

DRS reports being on advisory boards for Merck, Shire, Chimerix, Takeda and Moderna and being a grant recipient from Merck, Summit, Actelion, Tetraphase and Seres Therapeutics. All other authors report no potential conflicts of interest.

Ethical standards

This study was approved by the Tufts Medical Center institutional review board (July 12, 2017, Approval Number 12618) and performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent

Informed consent was not required given its retrospective nature and minimal risk.

Supplementary material

296_2019_4324_MOESM1_ESM.docx (173 kb)
Supplementary material 1 (DOCX 174 kb)


  1. 1.
    Gandhi MK, Khanna R (2004) Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments. Lancet Infect Dis 4(12):725–738. CrossRefGoogle Scholar
  2. 2.
    Griffiths P, Baraniak I, Reeves M (2015) The pathogenesis of human cytomegalovirus. J Pathol 235(2):288–297. CrossRefGoogle Scholar
  3. 3.
    Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Danziger-Isakov L, Humar A, Transplantation Society International CMVCG (2013) Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 96(4):333–360. CrossRefGoogle Scholar
  4. 4.
    Nogalski MT, Collins-McMillen D, Yurochko AD (2014) Overview of human cytomegalovirus pathogenesis. Methods Mol Biol 1119:15–28. CrossRefGoogle Scholar
  5. 5.
    Ozaki T, Yamashita H, Kaneko S, Yorifuji H, Takahashi H, Ueda Y, Takahashi Y, Kaneko H, Kano T, Mimori A (2013) Cytomegalovirus disease of the upper gastrointestinal tract in patients with rheumatic diseases: a case series and literature review. Clin Rheumatol 32(11):1683–1690. CrossRefGoogle Scholar
  6. 6.
    Takizawa Y, Inokuma S, Tanaka Y, Saito K, Atsumi T, Hirakata M, Kameda H, Hirohata S, Kondo H, Kumagai S, Tanaka Y (2008) Clinical characteristics of cytomegalovirus infection in rheumatic diseases: multicentre survey in a large patient population. Rheumatology (Oxford) 47(9):1373–1378. CrossRefGoogle Scholar
  7. 7.
    Zhang L, Tao J, Wen Y, Li L, Wu X, Li X, Li X (2017) Cytomegalovirus infection in patients with lupus nephritis: clinical and laboratory features and therapeutic considerations. Clin Exp Med. Google Scholar
  8. 8.
    Mori T, Kameda H, Ogawa H, Iizuka A, Sekiguchi N, Takei H, Nagasawa H, Tokuhira M, Tanaka T, Saito Y, Amano K, Abe T, Takeuchi T (2004) Incidence of cytomegalovirus reactivation in patients with inflammatory connective tissue diseases who are under immunosuppressive therapy. J Rheumatol 31(7):1349–1351Google Scholar
  9. 9.
    Galloway JB, Hyrich KL, Mercer LK, Dixon WG, Fu B, Ustianowski AP, Watson KD, Lunt M, Symmons DP, Consortium BCC, British Society for Rheumatology Biologics R (2011) Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology (Oxford) 50(1):124–131. CrossRefGoogle Scholar
  10. 10.
    Tsai WP, Chen MH, Lee MH, Yu KH, Wu MW, Liou LB (2012) Cytomegalovirus infection causes morbidity and mortality in patients with autoimmune diseases, particularly systemic lupus: in a Chinese population in Taiwan. Rheumatol Int 32(9):2901–2908. CrossRefGoogle Scholar
  11. 11.
    Berman N, Belmont HM (2017) Disseminated cytomegalovirus infection complicating active treatment of systemic lupus erythematosus: an emerging problem. Lupus 26(4):431–434. CrossRefGoogle Scholar
  12. 12.
    Lee KY, Yoo BW, Ahn SS, Bae WH, Lee H, Jung SM, Lee SW, Park YB, Song JJ (2017) Predictors of mortality in autoimmune disease patients with concurrent cytomegalovirus infections detected by quantitative real-time PCR. PLoS ONE 12(7):e0181590. CrossRefGoogle Scholar
  13. 13.
    Choo HMC, Cher WQ, Kwan YH, Fong WWS (2019) Risk factors for cytomegalovirus disease in systemic lupus erythematosus (SLE): a systematic review. Adv Rheumatol 59(1):12. CrossRefGoogle Scholar
  14. 14.
    Ramos-Casals M, Cuadrado MJ, Alba P, Sanna G, Brito-Zeron P, Bertolaccini L, Babini A, Moreno A, D'Cruz D, Khamashta MA (2008) Acute viral infections in patients with systemic lupus erythematosus: description of 23 cases and review of the literature. Medicine (Baltimore) 87(6):311–318. CrossRefGoogle Scholar
  15. 15.
    Yoon KH, Fong KY, Tambyah PA (2002) Fatal cytomegalovirus infection in two patients with systemic lupus erythematosus undergoing intensive immunosuppressive therapy: role for cytomegalovirus vigilance and prophylaxis? J Clin Rheumatol 8(4):217–222CrossRefGoogle Scholar
  16. 16.
    Sekigawa I, Nawata M, Seta N, Yamada M, Iida N, Hashimoto H (2002) Cytomegalovirus infection in patients with systemic lupus erythematosus. Clin Exp Rheumatol 20(4):559–564Google Scholar
  17. 17.
    Perez-Mercado AE, Vila-Perez S (2010) Cytomegalovirus as a trigger for systemic lupus erythematosus. J Clin Rheumatol 16(7):335–337. CrossRefGoogle Scholar
  18. 18.
    Lim CC, Tung YT, Tan BH, Lee PH, Mok IY, Oon L, Chan KP, Choo JC (2017) Epidemiology and risk factors for cytomegalovirus infection in glomerular diseases treated with immunosuppressive therapy. Nephrology (Carlton) 23(7):676–681. CrossRefGoogle Scholar
  19. 19.
    Mencarini J, Spinicci M, Bartalesi F (2016) Risk of cytomegalovirus reactivation in patients with immune-mediated inflammatory diseases undergoing biologic treatment: a real matter? Reumatismo 68(3):144–147. CrossRefGoogle Scholar
  20. 20.
    Xue Y, Jiang L, Wan WG, Chen YM, Zhang J, Zhang ZC (2016) Cytomegalovirus pneumonia in patients with rheumatic diseases after immunosuppressive therapy: a single center study in China. Chin Med J (Engl) 129(3):267–273. CrossRefGoogle Scholar
  21. 21.
    Buttgereit F, da Silva JA, Boers M, Burmester GR, Cutolo M, Jacobs J, Kirwan J, Kohler L, Van Riel P, Vischer T, Bijlsma JW (2002) Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology. Ann Rheum Dis 61(8):718–722CrossRefGoogle Scholar
  22. 22.
    Medicode Ingenix (1998) ICD-9-CM : International classification of diseases, 9th revision, clinical modification. Physician ICD-9-CM, 5th edn. Medicode, Salt Lake CityGoogle Scholar
  23. 23.
    Genentech (2015) Valcyte (valganciclovir), package insert. Genentech, San Francisco, California, USAGoogle Scholar
  24. 24.
    Genentech (2016) Cytovene (ganciclovir), package insert. Genentech, San Francisco, California, USAGoogle Scholar
  25. 25.
    Ikeda K, Nakajima S, Tanji K, Hirai T, Uomori K, Morimoto S, Tomita S, Fukunaga M, Tamura N, Sekigawa I (2017) Intestinal perforation due to hemorrhagic cytomegalovirus enteritis in a patient with severe uncontrolled lupus nephritis: a case and review of the literature. Rheumatol Int 37(8):1395–1399. CrossRefGoogle Scholar
  26. 26.
    Hanley PJ, Bollard CM (2014) Controlling cytomegalovirus: helping the immune system take the lead. Viruses 6(6):2242–2258. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of MedicineTufts UniversityBostonUSA
  2. 2.Division of Geographic Medicine and Infectious DiseaseTufts Medical CenterBostonUSA
  3. 3.Tufts Clinical and Translational Science InstituteTufts UniversityBostonUSA

Personalised recommendations