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Risk factors for prolonged infection and secondary infection in pediatric severe sepsis

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Abstract

Purpose

Sepsis causes significant worldwide morbidity and mortality. Inability to clear an infection and secondary infections are known complications in severe sepsis and likely result in worsened outcomes. We sought to characterize risk factors of these complications.

Methods

We performed a secondary analysis of clinical data from 401 subjects enrolled in the PHENOtyping sepsis-induced Multiple organ failure Study. We examined factors associated with prolonged infection, defined as infection that continued to be identified 7 days or more from initial identification, and secondary infection, defined as new infections identified ≥ 3 days from presentation. Multivariable adjustment was performed to examine laboratory markers of immune depression, with immunocompromised and immunocompetent subjects analyzed separately.

Results

Illness severity, immunocompromised status, invasive procedures, and site of infection were associated with secondary infection and/or prolonged infection. Persistent lymphopenia, defined as an absolute lymphocyte count (ALC) < 1000 cells/µL twice in the first five days, and persistent neutropenia, defined as absolute neutrophil count (ANC) < 1000 cells/µL twice in the first five days, were associated with secondary and prolonged infections. When adjusted in multivariable analysis, persistent lymphopenia remained associated with secondary infection in both immunocompromised (aOR = 14.19, 95% CI [2.69, 262.22] and immunocompetent subjects (aOR = 2.09, 95% CI [1.03, 4.17]). Persistent neutropenia was independently associated with secondary infection in immunocompromised subjects (aOR = 5.34, 95% CI [1.92, 15.84]). Secondary and prolonged infections were associated with worse outcomes, including death.

Conclusions

Laboratory markers of immune suppression can be used to predict secondary infection. Lymphopenia is an independent risk factor in immunocompromised and immunocompetent patients for secondary infection.

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Data availability

The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at the University of Utah Data Coordinating Center.

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Acknowledgements

The authors would like to thank Dr. Gregory Storch for careful reading and feedback on the manuscript.

Funding

Supported, in part, by grant R01GM108618 (to Dr. Carcillo) from the National Institute of General Medical Sciences, and by 5U01HD049934-10S1 (to Dr Carcillo), from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services and the following cooperative agreements: U10HD049983, U10HD050096, U10HD049981, U10HD063108, U10HD063106, U10HD063114, U10HD050012, and U01HD049934.

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Authors and Affiliations

  1. Division of Pediatric Critical Care Medicine, Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, University of Pittsburgh, 4401 Penn Ave, FP Suite 2000, Pittsburgh, PA, 15224, USA

    Zachary Aldewereld & Joseph A. Carcillo

  2. Division of Pediatric Infectious Diseases, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

    Zachary Aldewereld

  3. University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Brendan Connolly

  4. Department of Pediatrics, University of Utah, Salt Lake City, UT, USA

    Russell K. Banks, Ron Reeder, Richard Holubkov & J. Michael Dean

  5. Department of Anesthesiology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Robert A. Berg & Athena F. Zuppa

  6. Division of Critical Care Medicine, Department of Pediatrics, Children’s National Hospital, Washington, DC, USA

    David Wessel & Murray M. Pollack

  7. Division of Critical Care Medicine, Department of Pediatrics, Children’s Hospital of Michigan, Detroit, MI, USA

    Kathleen Meert

  8. Division of Critical Care Medicine, Department of Pediatrics, The Research Institute at Nationwide Children’s Hospital Immune Surveillance Laboratory, and Nationwide Children’s Hospital, Columbus, OH, USA

    Mark Hall

  9. Division of Pediatric Critical Care Medicine, Department of Anesthesiology and Pediatrics, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    Christopher Newth

  10. Division of Critical Care Medicine, Department of Pediatrics, St. Louis Children’s Hospital, St. Louis, MO, USA

    John C. Lin & Allan Doctor

  11. Division of Critical Care Medicine, Department of Pediatrics, C. S. Mott Children’s Hospital, Ann Arbor, MI, USA

    Tim Cornell

  12. Division of Critical Care Medicine, Department of Pediatrics, Mattel Children’s Hospital at University of California Los Angeles, Los Angeles, CA, USA

    Rick E. Harrison

  13. College of Medicine, Central Michigan University, Mt Pleasant, MI, USA

    Kathleen Meert

Authors
  1. Zachary Aldewereld
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  2. Brendan Connolly
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  3. Russell K. Banks
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  4. Ron Reeder
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  5. Richard Holubkov
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  6. Robert A. Berg
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  7. David Wessel
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  9. Kathleen Meert
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  10. Mark Hall
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  11. Christopher Newth
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  12. John C. Lin
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  13. Allan Doctor
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  14. Tim Cornell
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  16. Athena F. Zuppa
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  17. J. Michael Dean
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  18. Joseph A. Carcillo
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Contributions

All authors contributed to the study conception and design. Data collection was performed by R.A.B., D.W., M.P., K.M., M.H., C.N., J.L., A.D., T.C., R.E.H., A.Z., J.M.D., and J.C. Analysis was performed by Z.A., B.C., R.K.B., R.R., R.H., and J.C.. The main manuscript text was written by Z.A. with contributions from R.B. and J.C. Figures and tables were prepared by R.B. and Z.A. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zachary Aldewereld or Joseph A. Carcillo.

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Conflict of interest

Zachary Aldewereld and Brendan Connolly have no conflicts of interest. Drs Carcillo, Berg, Wessel, Pollack, Meert, Hall, Newth, Doctor, Cornell, Harrison, Zuppa, Reeder, Banks, Holubkov, and Dean received support for article research from the NIH. Dr. Carcillo’s institution also received funding from the National Institute of General Medical Sciences. Dr. Pollack disclosed that his research is supported by philanthropy from Mallinckrodt Pharmaceuticals. Dr. Hall received funding from LaJolla Pharmaceuticals (service as a consultant), unrelated to the current submission. Dr. Newth received funding from Philips Research North America. Dr. Doctor’s institution received funding from the Department of Defense and Kalocyte. Dr. Cornell disclosed he is co-founder of Pre-Dixon Bio. Dr. Holubkov received funding from Pfizer (Data Safety Monitoring Board [DSMB] member), Medimmune (DSMB member), Physicians Committee for Responsible Medicine (biostatistical consulting), DURECT Corporation (biostatistical consulting), Armaron Bio (DSMB past member), and St Jude Medical (DSMB past member). The remaining authors have disclosed that they do not have any potential conflicts of interest.

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Aldewereld, Z., Connolly, B., Banks, R.K. et al. Risk factors for prolonged infection and secondary infection in pediatric severe sepsis. Infection (2024). https://doi.org/10.1007/s15010-024-02355-1

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