Predictors of Cytomegalovirus Infection in Patients with Connective Tissue Disease Treated by Pulsed Methylprednisolone Therapy: a Multicenter Retrospective Cohort Study

Overview

Journal BMC Infect Dis

Publisher Biomed Central

Date 2025 Jan 28

PMID 39875823

Authors

Haruka Ito

Takahiko Yoshimoto

Akatsuki Kokaze

Kuninobu Wakabayashi

Kazuteru Noguchi

Kiyoshi Matsui

Bunki Natsumoto

Keishi Fujio

Yutaro Hayashi

Yuko Kaneko

Takahisa Gono

Koh Okamoto

Shu Okugawa

Kyoji Moriya

Hirohiko Sueki

Affiliations

Soon will be listed here.

Abstract

Background: Cytomegalovirus (CMV) can cause life-threatening diseases in immunosuppressed patients. Some of the patients with connective tissue disease develop CMV infection, and approximately half of this group has been reported to have received pulsed-methylprednisolone (p-MPSL) therapy. This study aimed to identify predictors of the onset of CMV infection in patients receiving p-MPSL therapy for connective tissue disease.

Methods: This was a retrospective, multicenter cohort study. We included patients who received p-MPSL therapy for connective tissue disease and had CMV antigenemia measured between April 2011 and December 2020. Peripheral blood cell data before the start of p-MPSL therapy and at the start of steroid tapering were collected in addition to baseline characteristics, including age, sex, and body mass index. CMV infection was defined as detection of one or more CMV antigen-positive cells (CMV-positive). The study examined and compared the CMV-positive group with the CMV-negative group. Logistic regression analysis was used to explore the factors associated with CMV antigen positivity. Receiver operating characteristic curve analysis was used to identify the cut-off values for the factors associated with CMV antigen sensitivity.

Results: Of the 200 patients included, 87 had antigen positivity. Logistic regression analysis showed that age ≥ 65 years [adjusted odds ratio (aOR): 2.75, 95% confidence interval (CI): 1.54-4.92] and platelet count less than 30.20 × 10 /µL [aOR: 4.38, 95%CI: 2.21-8.68] at baseline were significantly associated with CMV antigen positivity. Lymphocyte count < 1440 /µL [aOR: 5.36, 95% CI: 1.96-14.65], neutrophil-to-lymphocyte ratio (NLR) ≥ 3.42 [aOR: 7.31, 95% CI: 2.52-21.22], and platelet-to-lymphocyte ratio (PLR) ≥ 145.28 [aOR:6.10, 95% CI: 2.24-16.64] at the start of steroid tapering also increased the OR for CMV infection. The areas under the receiver operating characteristic curves for lymphocytes, NLR, and PLR were 0.742, 0.693, and 0.673 respectively.

Conclusion: Platelet count, lymphocyte count, NLR, and PLR may be crucial predictors of the onset of CMV infection in patients with connective tissue disease. These easily obtainable factors may be clinically useful as predictors of CMV infection. A potential research area would be to validate the parameters in a prospective patient population.

References

Liu Y, Du X, Chen J, Jin Y, Peng L, Wang H . Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J Infect. 2020; 81(1):e6-e12. PMC: 7195072. DOI: 10.1016/j.jinf.2020.04.002. View

Braitch M, Harikrishnan S, Robins R, Nichols C, Fahey A, Showe L . Glucocorticoids increase CD4CD25 cell percentage and Foxp3 expression in patients with multiple sclerosis. Acta Neurol Scand. 2008; 119(4):239-45. PMC: 4467559. DOI: 10.1111/j.1600-0404.2008.01090.x. View

Koupenova M, Clancy L, Corkrey H, Freedman J . Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis. Circ Res. 2018; 122(2):337-351. PMC: 5777300. DOI: 10.1161/CIRCRESAHA.117.310795. View

Moosazadeh M, Maleki I, Alizadeh-Navaei R, Kheradmand M, Hedayatizadeh-Omran A, Shamshirian A . Normal values of neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio and platelet-to-lymphocyte ratio among Iranian population: Results of Tabari cohort. Caspian J Intern Med. 2019; 10(3):320-325. PMC: 6729162. DOI: 10.22088/cjim.10.3.320. View

Fang T, Wang Y, Yin X, Zhai Z, Zhang Y, Yang Y . Diagnostic Sensitivity of NLR and PLR in Early Diagnosis of Gastric Cancer. J Immunol Res. 2020; 2020:9146042. PMC: 7081040. DOI: 10.1155/2020/9146042. View

Damar Cakirca T, Torun A, Cakirca G, Portakal R . Role of NLR, PLR, ELR and CLR in differentiating COVID-19 patients with and without pneumonia. Int J Clin Pract. 2021; 75(11):e14781. PMC: 8646493. DOI: 10.1111/ijcp.14781. View

Milane A, Abou-Abbas L, Osmani L, Saber N, Mefleh N, Barbari A . Association Between Blood and Lymphocyte Levels of Cyclosporin A and Infectious Complications in Renal Transplant Patients. Dose Response. 2021; 19(4):15593258211042169. PMC: 8524715. DOI: 10.1177/15593258211042169. View

Harada M, Iwabuchi R, Yamaguchi A, Aomura D, Yamada Y, Sonoda K . Predictive Factors of Cytomegalovirus Viremia during the Clinical Course of Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis: A Single Center Observational Study. J Clin Med. 2023; 12(1). PMC: 9821060. DOI: 10.3390/jcm12010351. View

Batool N, Song D, Almas T, Alsubai A, Thakur T, Ismail H . Too much of a good thing: Immune reconstitution inflammatory syndrome in a patient with Still's disease. Ann Med Surg (Lond). 2022; 82:104590. PMC: 9577525. DOI: 10.1016/j.amsu.2022.104590. View

10.

Narayanan S, Banerjee C, Holt P . Cryptococcal immune reconstitution syndrome during steroid withdrawal treated with hydroxychloroquine. Int J Infect Dis. 2010; 15(1):e70-3. DOI: 10.1016/j.ijid.2010.09.006. View

11.

Mathian A, Jouenne R, Chader D, Cohen-Aubart F, Haroche J, Fadlallah J . Regulatory T Cell Responses to High-Dose Methylprednisolone in Active Systemic Lupus Erythematosus. PLoS One. 2015; 10(12):e0143689. PMC: 4667921. DOI: 10.1371/journal.pone.0143689. View

12.

Schroeder R, Michelon T, Fagundes I, Bortolotto A, Lammerhirt E, Oliveira J . Antigenemia for cytomegalovirus in renal transplantation: choosing a cutoff for the diagnosis criteria in cytomegalovirus disease. Transplant Proc. 2005; 37(6):2781-3. DOI: 10.1016/j.transproceed.2005.06.091. View

13.

Forget P, Khalifa C, Defour J, Latinne D, Van Pel M, De Kock M . What is the normal value of the neutrophil-to-lymphocyte ratio?. BMC Res Notes. 2017; 10(1):12. PMC: 5217256. DOI: 10.1186/s13104-016-2335-5. View

14.

Taylor G . Cytomegalovirus. Am Fam Physician. 2003; 67(3):519-24. View

15.

Janyst M, Kaleta B, Janyst K, Zagozdzon R, Kozlowska E, Lasek W . Comparative Study of Immunomodulatory Agents to Induce Human T Regulatory (Treg) Cells: Preferential Treg-Stimulatory Effect of Prednisolone and Rapamycin. Arch Immunol Ther Exp (Warsz). 2020; 68(4):20. PMC: 7292810. DOI: 10.1007/s00005-020-00582-6. View

16.

Ota Y, Kaneko Y, Takeuchi T . Association between mortality and cytomegalovirus reactivation during remission induction therapy in patients with rheumatic diseases. Clin Exp Rheumatol. 2020; 39(6):1324-1330. DOI: 10.55563/clinexprheumatol/pqa98i. View

17.

Kral J, Schrottmaier W, Salzmann M, Assinger A . Platelet Interaction with Innate Immune Cells. Transfus Med Hemother. 2016; 43(2):78-88. PMC: 4872052. DOI: 10.1159/000444807. View

18.

Liu Q, Chen H, Zeng Q . Clinical characteristics of COVID-19 patients with complication of cardiac arrhythmia. J Infect. 2020; 81(3):e6-e8. PMC: 7832264. DOI: 10.1016/j.jinf.2020.07.012. View

18.

Lin Y, Chen Y, Lee S, Lee T, Chen Y, Huang W . Long-Term Safety in HBsAg-Negative, HBcAb-Positive Patients with Rheumatic Diseases Receiving Maintained Steroid Therapy after Pulse Therapy. J Clin Med. 2021; 10(15). PMC: 8347429. DOI: 10.3390/jcm10153296. View

19.

Deng R, Yuan G, Ye Y, Luo W, Zhong J, Wang H . Qualitative evaluation of connective tissue disease with cytomegalovirus infection: A meta-analysis of case reports. Semin Arthritis Rheum. 2024; 65:152396. DOI: 10.1016/j.semarthrit.2024.152396. View