Skip to main content

Comment to "Human cytomegalovirus seropositivity is associated with reduced patient survival during sepsis"

The Original Article was published on 31 October 2023

We have read with great interest the clinical study and subsequent commentary by M Unterberg et al. published in Critical Care [1,2,3]. The study showed a robust correlation between human cytomegalovirus (HCMV) seropositivity and increased mortality. In addition, the study identified several biomarkers that could predict clinical outcomes in sepsis patients. This work marks a notable advancement in the field, shifting the focus from simply monitoring for HCMV reactivation to a more nuanced evaluation of HCMV serology as an indicator of latent infection. However, further refinement of certain details could have increased the study's depth.

First, a quantitative assessment of the prognostic impact of varying HCMV IgG levels on sepsis patient outcomes is warranted, rather than relying solely on qualitative serology. Active HCMV infection should be considered when IgG levels significantly exceed the reference value by more than fourfold [4, 5]. It is also important to recognize that the absence of HCMV IgG does not definitively rule out infection, particularly in critically ill patients with compromised immune function, such as those with septic shock, who may not be able to produce the necessary antibodies [6]. Thus, it is possible that the current study underestimated the incidence of HCMV seropositivity and reactivation. Furthermore, a comprehensive analysis of multiple biomarkers of HCMV infection, including IgG, IgM, DNAemia, and PP65 antigen, may provide a more detailed understanding of the status of infection.

Second, it is imperative to delineate the etiology and phase of sepsis. Differential analysis is necessary due to the differences in incidence and mortality rates between pulmonary and non-pulmonary sepsis. Our previous study found that patients with severe pneumonia made up nearly 70% of the immunocompetent patients with critical illness [7]. Furthermore, mortality risk associated with HCMV IgG detection may vary between the early stages (characterized by overwhelming inflammation) and the later stages(characterized by refractory inflammation, immunosuppression, and risk of secondary infections) [6]. Third, the study did not detail the antiviral prophylaxis or preemptive therapy regimens of the study population, which is a significant omission. The specific treatment protocols and medications used could significantly influence clinical outcomes [8,9,10]. Finally, proteomic sequencing methods might miss numerous biomarkers, however, their integration with transcriptomic or metabolomic sequencing may reveal the pathogenic mechanisms of HCMV in sepsis patients and provide novel therapeutic targets.

In conclusion, the study by Unterberg et al. attempts to predict the clinical prognosis of sepsis patients based on their HCMV serologic status, thus contributing positively to the advancement of the field. Nevertheless, more in-depth and meticulous research is essential to fully understand the interplay between HCMV serologic status and the clinical outcome of sepsis patients.

Availability of data and materials

Not applicable.


  1. Unterberg M, Ehrentraut SF, Bracht T, et al. Human cytomegalovirus seropositivity is associated with reduced patient survival during sepsis. Crit Care. 2023;27(1):417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wang H, Zhong L. Comment on human cytomegalovirus seropositivity is associated with reduced patient survival during sepsis. Crit Care. 2023;27(1):445.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Koos B, Unterberg M, Rahmel T, et al. Response to comment on human cytomegalovirus seropositivity is associated with reduced patient survival during sepsis. Crit Care. 2023;27(1):464.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Grangeot-Keros L, Cointe D. Diagnosis and prognostic markers of HCMV infection. J Clin Virol. 2001;21(3):213–21.

    Article  CAS  PubMed  Google Scholar 

  5. Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis. 2017;64(1):87–91.

    Article  PubMed  Google Scholar 

  6. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13(12):862–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhang Z, Liu X, Sang L, et al. Cytomegalovirus reactivation in immunocompetent mechanical ventilation patients: a prospective observational study. BMC Infect Dis. 2021;21(1):1026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Limaye AP, Stapleton RD, Peng L, et al. Effect of ganciclovir on IL-6 levels among cytomegalovirus-seropositive adults with critical illness: a randomized clinical trial. JAMA. 2017;318(8):731–40.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Papazian L, Jaber S, Hraiech S, et al. Preemptive ganciclovir for mechanically ventilated patients with cytomegalovirus reactivation. Ann Intensive Care. 2021;11(1):33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cowley NJ, Owen A, Shiels SC, et al. Safety and efficacy of antiviral therapy for prevention of cytomegalovirus reactivation in immunocompetent critically ill patients: a randomized clinical trial. JAMA Intern Med. 2017;177(6):774–83.

    Article  PubMed  PubMed Central  Google Scholar 

Download references


Not applicable.


The study was funded by the National Natural Science Foundation of China (No. 82070084), Science and Technology Program of Guangzhou (Nos. SL2023A04J00179, 2024A04J3312), and Guangzhou Medical University Students Extracurricular Academic Technology Project (Nos. 2022A006, 2022B004).

Author information

Authors and Affiliations



ZHZ, XCL, and RZ wrote the manuscript; YML and XQL reviewed and revised the manuscript. YML and XQL contributed equally to this work. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yimin Li or Xiaoqing Liu.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Accordance statement

Not applicable.

Competing interests

None of the authors has any conflict of interest to report.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Z., Liu, X., Zhang, R. et al. Comment to "Human cytomegalovirus seropositivity is associated with reduced patient survival during sepsis". Crit Care 28, 182 (2024).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: