Skip to main content
Download PDF

Immortal time bias: a possible explanation for “Impact of acyclovir use on survival of patients with ventilator-associated pneumonia and high load herpes simplex virus replication”

Critical Care volume 24, Article number: 355 (2020) Cite this article

Dear editor,

We have with great interest read the paper “Impact of acyclovir use on survival of patients with ventilator-associated pneumonia and high load herpes simplex virus replication” published recently in Critical Care [1]. The study describes impact of acyclovir treatment on mortality in patients with ventilator-associated pneumonia who tested positive for herpes simplex virus in respiratory secretions. The authors conclude that treatment with acyclovir in patients with high HSV viral load decreases mortality in this population dramatically.

The authors address an important scientific question. However, we have concerns regarding the statistical analyses of survival. The authors seem to separate patients in acyclovir treated and not treated patients. This statistical strategy may lead to immortal time bias, which is a bias that results in substantial overestimation of the effect of medical treatment [2, 3]. Even for medical treatment without effect, that bias may lead to large estimates that are “statistically significant”. We identified potential scenarios in the current study in which immortal time bias could occur: (1) acyclovir treatment precedes HSV-positive test leading to immortal time included in the acyclovir treated group (Fig. 1a) and (2) HSV-positive test precedes acyclovir treatment leading to immortal time excluded from the untreated group (Fig. 1b), both of which would lead to an “artificial” survival advantage for the treated group.

Fig. 1
figure 1

Potential immortal time bias in the current study. a Acyclovir treatment preceding HSV test, time is started at acyclovir treatment leading to an immortal time from start of treatment to HSV test. b HSV test preceding acyclovir treatment leading to excluded immortal time from the untreated group

Full size image

We therefore suggest that the authors reanalyze their data, in which they start observation at the date of test for herpes simplex virus and include acyclovir treatment as a time updated exposure.

Availability of data and materials

Not applicable.

References

  1. Schuierer L, et al. Impact of acyclovir use on survival of patients with ventilator-associated pneumonia and high load herpes simplex virus replication. Crit Care Lond Engl. 2020;24:12.

    Article  Google Scholar 

  2. Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol. 2008;167:492–9.

    Article  Google Scholar 

  3. Rothman KJ, Greenland S, Lash TL. Modern epidemiology - 3rd Ed. Wolters Kluwer Health, Lippincott Williams & Wilkins;2008.

Download references

Acknowledgements

None.

Funding

None.

Author information

Authors and Affiliations

  1. Department of Clinical Microbiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Magnus Glindvad Ahlström

  2. Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Lars Haukali Omland & Niels Obel

  3. Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre Hospital, Hvidovre, Denmark

    Andreas Ronit

Authors
  1. Magnus Glindvad Ahlström
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lars Haukali Omland
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andreas Ronit
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Niels Obel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MGA identified the potential problem. All authors contributed to the discussion of the problem, wrote initial drafts, and approved the final manuscript.

Corresponding author

Correspondence to Magnus Glindvad Ahlström.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

All authors report no competing interests.

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 http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) 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

Ahlström, M.G., Omland, L.H., Ronit, A. et al. Immortal time bias: a possible explanation for “Impact of acyclovir use on survival of patients with ventilator-associated pneumonia and high load herpes simplex virus replication”. Crit Care 24, 355 (2020). https://doi.org/10.1186/s13054-020-03073-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13054-020-03073-4

Critical Care

ISSN: 1364-8535