Skip to main content

Main menu

  • Online first
    • Online first
  • Current issue
    • Current issue
  • Archive
    • Archive
  • Submit a paper
    • Online submission site
    • Information for authors
  • About the journal
    • About the journal
    • Editorial board
    • Information for authors
    • FAQs
    • Thank you to our reviewers
      • Thank you to our reviewers
    • American Federation for Medical Research
  • Help
    • Contact us
    • Feedback form
    • Reprints
    • Permissions
    • Advertising
  • BMJ Journals

User menu

  • Login

Search

  • Advanced search
  • BMJ Journals
  • Login
  • Facebook
  • Twitter
JIM

Advanced Search

  • Online first
    • Online first
  • Current issue
    • Current issue
  • Archive
    • Archive
  • Submit a paper
    • Online submission site
    • Information for authors
  • About the journal
    • About the journal
    • Editorial board
    • Information for authors
    • FAQs
    • Thank you to our reviewers
    • American Federation for Medical Research
  • Help
    • Contact us
    • Feedback form
    • Reprints
    • Permissions
    • Advertising

Is blood lymphocyte count a prognostic biomarker in Staphylococcus aureus bacteremia?

Mathieu Blot, Abdeljalil Zeggay, Ludwig-Serge Aho-Glele, Caroline Laborde, Vincent Le Moing, Catherine Chirouze, Kevin Bouiller, Lionel Piroth
DOI: 10.1136/jim-2022-002356 Published 3 October 2022
Mathieu Blot
1 Department of Infectious Diseases, Dijon Bourgogne University Hospital, Dijon, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Mathieu Blot
Abdeljalil Zeggay
2 Department of Infectious Diseases, Besançon Bourgogne University Hospital, Besançon, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Abdeljalil Zeggay
Ludwig-Serge Aho-Glele
3 Epidemiology and Hospital Hygiene Department, Dijon Bourgogne University Hospital, Dijon, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Caroline Laborde
1 Department of Infectious Diseases, Dijon Bourgogne University Hospital, Dijon, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vincent Le Moing
4 Tropical and Infectious Diseases, University Hospital of Montpellier, Montpellier, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Catherine Chirouze
2 Department of Infectious Diseases, Besançon Bourgogne University Hospital, Besançon, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kevin Bouiller
2 Department of Infectious Diseases, Besançon Bourgogne University Hospital, Besançon, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lionel Piroth
1 Department of Infectious Diseases, Dijon Bourgogne University Hospital, Dijon, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • eLetters
  • Info & Metrics
  • PDF
Loading

Abstract

Lymphopenia is common in patients with sepsis and associated with mortality. Immune-stimulatory therapies likely to restore T-cells count and function are under investigation in sepsis. Our study aimed to assess whether lymphopenia is a reliable prognostic biomarker in Staphylococcus aureus bacteremia. We conducted an ancillary study of the prospective VIRSTA Study including 574 patients with S. aureus bacteremia in two tertiary care centers. Neither lymphocyte count at the onset nor lymphocyte change during the first 4 days was associated with 12-week mortality. These results highlight the importance of characterizing the immune profile of patients with sepsis according to the cause before investigating immunostimulatory therapies to restore lymphocyte proliferation and function.

What is already known on this topic

  • Lymphopenia is common in patients with sepsis and associated with mortality.

  • Immune-stimulatory therapies likely to restore T-cells count and function are under investigation in sepsis.

  • Staphylococcus aureus bacteremia is a leading cause of sepsis, but whether lymphopenia is associated with a worse outcome is unknown.

What this study adds

  • S. aureus bacteremia was associated with a 25% case fatality at 12 weeks in our study.

  • Neither lymphocyte count at the onset, nor lymphocyte change during the first 4 days, was associated with 12-week mortality in S. aureus bacteremia.

How this study might affect clinical research and practice

  • Lymphopenia is not a reliable prognostic biomarker in all causes of sepsis.

  • Heterogeneity of immune responses in patients with sepsis is thought to be one of the reasons behind the failure of immune-modulatory trials.

  • It is important to identify subgroups of patients with sepsis who are more likely to benefit from lymphocyte immune-stimulatory agents.

Introduction

Lymphopenia is common in patients with sepsis and associated with mortality.1 Immune-stimulatory therapies likely to restore T-cells count and function are under investigation in patients with sepsis.1 2 However, whether lymphopenia is a prognostic biomarker in all causes of sepsis, and whether it could be used to guide such immune-stimulatory therapies, must be investigated. Hence, we previously showed that cytopenia was associated with a poor outcome in pneumococcal bacteremic pneumonia.3 Considering that Staphylococcus aureus bacteremia (SAB) is a leading cause of sepsis and associated with high mortality,4 our study aimed to assess whether lymphopenia is a reliable prognostic biomarker in SAB.

Methods

This is an ancillary study of the observational prospective cohort VIRSTA Study4 including data from two French tertiary care centers (Dijon, Besançon). Consecutive patients were included if they had at least one positive blood culture specimen for S. aureus between April 2009 and October 2011. Exclusion criteria were age <18 years, pregnancy and adults under guardianship.4 The VIRSTA Study is registered in the European Clinical Trials Database under the number: 2008-A00680-55. Standardized electronic case report forms were prospectively filled locally. An immunodepression was considered if one of these criteria was present: HIV infection with CD4 <500/mm3, solid cancer, leukemia, lymphoma or immunosuppressive drug. Severe sepsis was defined by major organ dysfunction, or blood pressure <90 mm Hg or signs of hypoperfusion (confusion, oliguria, skin mottling, lactate elevation, metabolic acidosis), and septic shock by a severe sepsis requiring the use of vasopressive agents. White cell counts were retrospectively recorded the same day (or the day after if unavailable; D0–1) of the first positive blood culture for S. aureus, and 3 days later (or 4 if unavailable; D3–4). The main and secondary endpoints were, respectively, 12-week and 28-day mortality. For statistical analyses, continuous variables were compared with the Mann-Whitney test and categorical variables with the Χ2 or Fisher’s exact tests. Lymphocyte counts were presented using boxplots according to 12-week or 28-day mortality, in the whole cohort and after excluding immunocompromised patients. We used multivariable logistic regression to identify potential prognostic variables and including those with a p value of <0.20 in bivariate analysis, white cell count and immunodepression status. Multiple imputation by chained equations was used, with 30 imputations, for missing white cell counts. The distribution of imputed and observed data was compared and convergence of the imputation model was assessed. A p value lower than 0.05 was considered statistically significant. All analyses were performed using Stata V.13.1 or Prism V.8.0 software.

Results

Out of the 574 patients included, 119 died before 28 days and 145 died before 12 weeks (case fatality 21% and 25%, respectively). Patient characteristics are shown in table 1. The lymphocyte count at the time of the first positive blood culture was not significantly different between 12-week survivors and non-survivors (median (IQR) 750 (420–1180) vs 690 (300–1033)/mm3; p=0.132) and 28-day survivors and non-survivors (735 (400–1130) vs 700 (300–1125)/mm3; p=0.521) (figure 1A,B). In the sensitivity analysis considering the 365 immunocompetent patients, the lymphocyte count was significantly higher in 12-week survivors compared with non-survivors (935 (600–1293) vs 700 (300–1020)/mm3; p=0.007), but it was not significantly different for 28-day mortality (online supplemental figure 1A,B). In the multivariable analysis, age, chronic heart failure, center effect, temperature ≤38°C, severe sepsis, acute cardiac insufficiency and pneumonia were independently associated with 12-week mortality, but the lymphocyte count was not (figure 1C, online supplemental table 1). In addition, there was no significant difference in the overall change in the lymphocyte count over the 4-day period between 12-week survivors and non-survivors (figure 1D) and no significant difference in survival between the three groups according to the variation in lymphocyte count between D0–1 and D3–4 (increase >200/mm3, variation ≤200/mm3 and decrease >200/mm3) (figure 1E).

Supplementary data

[jim-2022-002356supp001.pdf]
Figure 1
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1

Lymphocyte count in patients with Staphylococcus aureus bacteremia. Lymphocyte count according to 28-day mortality (A) and 12-week mortality (B) in the whole cohort of patients with S. aureus bacteremia. Multivariable analysis of factors associated with 12-week mortality. For each variable included in the model, OR and 95% CIs are represented; multiple imputation was used for missing data in lymphocytes, neutrophils, monocytes and eosinophils count (n=241 patients with missing data, n=561 patients were considered in the analysis after imputation) (C). Lymphocyte count at D0–1 and D3–4 according to 12-week mortality, represented with the mean (SD) and connecting lines (D). Kaplan-Meier survival analysis comparing patients with S. aureus bacteremia and serial measurement of lymphocytes according to the variation in the lymphocyte count between D0–1 and D3–4 (increase >200/mm3, variation <200/mm3, decrease >200/mm3) (E); (D,E: n=133 patients with lymphocytes data available at the two time points).

View this table:
  • View inline
  • View popup
Table 1

Characteristics of 574 patients with Staphylococcus aureus bacteremia (SAB), according to 12-week mortality

Discussion

In patients with sepsis, it is crucial to obtain immune phenotype before investigating immune-modulatory agents such as adjunctive therapies with antibiotics. While the heterogeneity of immune responses in patients with sepsis is thought to be one of the biggest reasons behind the failure of immune-modulatory trials,5 the source of sepsis and microbiological etiology are two main factors that could be taken into account to capture this heterogeneity. Here, we focused on SAB, a leading cause of sepsis and associated with a 25% case fatality at 12 weeks in our study.

Several immunostimulatory agents likely to restore lymphocyte proliferation and function are currently being investigated in sepsis. For instance, interleukin 7 (CYT107) was found to be effective in reversing profound sepsis-induced lymphopenia in a randomized double-blind placebo-controlled phase IIb trial in patients with septic shock and severe lymphopenia,2 a well-known biomarker of sepsis-induced immune suppression. Lymphopenia at the onset of sepsis has been associated with poor outcomes in some studies6 but not in others.7 However, persistent lymphopenia on the fourth day following admission for sepsis was found to predict mortality.7 In patients with SAB, we showed that neither lymphocyte count at the onset of sepsis nor lymphocyte change between D0–1 and D3–4 was associated with 12-week or 28-day mortality.

Several hypotheses can be put forward to explain our findings. First, factors related to bacterial virulence may account for such differences. For example, while neutropenia is frequently observed in severe forms of invasive pneumococcal diseases,3 it is rarely observed in SAB, except in S. aureus-necrotizing pneumonia related to Panton-Valentin leukocidin expression.8 The source of sepsis could thus account for the varying outcomes, since lymphopenia was independently associated with mortality in community-acquired pneumonia.9 However, we observed no significant difference according to the origin of the infection (for instance, osteoarticular, lung, central nervous system, or endocarditis) (data not shown). Finally, immunosuppression-associated comorbidities could also explain the discrepancies. Accordingly, after we excluded immunocompromised patients, the lymphocyte count was associated with 12-week mortality. However, the lymphocyte count was not associated with 12-week mortality after adjusting on immunodepression status. Another remaining question is whether lymphocyte depletion is merely an epiphenomenon or whether it plays a central role in the lethality of sepsis.

Our study has several limitations. First, missing values of white cell count may have biased the results, even if multiple imputation was used. There was also a center effect, as shown in the multivariable analysis. Finally, even though we included 574 patients with SAB, our analysis may lack power.

In conclusion, unlike in patients with other types of sepsis, neither lymphocyte count at the onset nor lymphocyte change during the first 4 days was associated with a poor outcome in patients with SAB. These data underscore the importance of identifying subgroups of patients with sepsis who are more likely to benefit from lymphocyte immune-stimulatory agents.

Ethics statements

Patient consent for publication

Not required.

Ethics approval

This study involves human participants and was approved by the 'Comité de Protection des Personnes Sud-Méditerranée IV'. According to French legislation, and because no intervention was performed on patients, no written informed consent was given by the patients. Patients' records and information were anonymized and de-identified prior to analyses.

Acknowledgments

We would like to thank the VIRSTA-AEPEI Study Group (clinical centers: Besançon: Catherine Chirouze, Elodie Curlier, Cécile Descottes-Genon, Bruno Hoen, Isabelle Patry, Lucie Vettoretti; Dijon: Pascal Chavanet, Jean-Christophe Eicher, Marie-Christine Greusard, Catherine Neuwirth, Andre Péchinot, Lionel Piroth). We thank Suzanne Rankin for editing assistance.

Footnotes

  • Contributors MB, LP and VLM designed the study. CC, KB and LP included the patients. MB, AZ and CL collected the data. L-SA-G and MB analyzed the data. MB and KB wrote the manuscript. All the authors approved the final manuscript.

  • Funding The VIRSTA cohort study was funded by the French Ministry of Health (Programme Hospitalier de Recherche Clinique; PHRC 2008-A00680e55).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

References

  1. ↵
    1. Torres LK ,
    2. Pickkers P ,
    3. van der Poll T
    . Sepsis-Induced immunosuppression. Annu Rev Physiol 2021;27.
  2. ↵
    1. Francois B ,
    2. Jeannet R ,
    3. Daix T , et al
    . Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight 2018;3. doi:doi:10.1172/jci.insight.98960. [Epub ahead of print: 08 03 2018].pmid:http://www.ncbi.nlm.nih.gov/pubmed/29515037
  3. ↵
    1. Blot M ,
    2. Croisier D ,
    3. Péchinot A , et al
    . A leukocyte score to improve clinical outcome predictions in bacteremic pneumococcal pneumonia in adults. Open Forum Infect Dis 2014;1:ofu075.doi:10.1093/ofid/ofu075 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25734145
    OpenUrlCrossRefPubMed
  4. ↵
    1. Braquet P ,
    2. Alla F ,
    3. Cornu C , et al
    . Factors associated with 12 week case-fatality in Staphylococcus aureus bacteraemia: a prospective cohort study. Clin Microbiol Infect 2016;22:948.e1–948.e7.doi:10.1016/j.cmi.2016.07.034 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27515395
    OpenUrlPubMed
  5. ↵
    1. van der Poll T ,
    2. Shankar-Hari M ,
    3. Wiersinga WJ
    . The immunology of sepsis. Immunity 2021;54:2450–64.doi:10.1016/j.immuni.2021.10.012 pmid:http://www.ncbi.nlm.nih.gov/pubmed/34758337
    OpenUrlPubMed
  6. ↵
    1. Chung K-P ,
    2. Chang H-T ,
    3. Lo S-C , et al
    . Severe lymphopenia is associated with elevated plasma interleukin-15 levels and increased mortality during severe sepsis. Shock 2015;43:569–75.doi:10.1097/SHK.0000000000000347 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25692255
    OpenUrlCrossRefPubMed
  7. ↵
    1. Drewry AM ,
    2. Samra N ,
    3. Skrupky LP , et al
    . Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock 2014;42:383–91.doi:10.1097/SHK.0000000000000234 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25051284
    OpenUrlCrossRefPubMed
  8. ↵
    1. Khanafer N ,
    2. Sicot N ,
    3. Vanhems P , et al
    . Severe leukopenia in Staphylococcus aureus-necrotizing, community-acquired pneumonia: risk factors and impact on survival. BMC Infect Dis 2013;13:359.doi:10.1186/1471-2334-13-359 pmid:http://www.ncbi.nlm.nih.gov/pubmed/23915338
    OpenUrlCrossRefPubMed
  9. ↵
    1. Bermejo-Martin JF ,
    2. Cilloniz C ,
    3. Mendez R , et al
    . Lymphopenic community acquired pneumonia (L-CAP), an immunological phenotype associated with higher risk of mortality. EBioMedicine 2017;24:231–6.doi:10.1016/j.ebiom.2017.09.023 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28958655
    OpenUrlPubMed
PreviousNext
Back to top
Vol 70 Issue 7 Table of Contents
Journal of Investigative Medicine: 70 (7)
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Front Matter (PDF)
Email

Thank you for your interest in spreading the word on JIM.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Is blood lymphocyte count a prognostic biomarker in Staphylococcus aureus bacteremia?
(Your Name) has sent you a message from JIM
(Your Name) thought you would like to see the JIM web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Alerts
Sign In to Email Alerts with your Email Address
Citation Tools
Is blood lymphocyte count a prognostic biomarker in Staphylococcus aureus bacteremia?
Mathieu Blot, Abdeljalil Zeggay, Ludwig-Serge Aho-Glele, Caroline Laborde, Vincent Le Moing, Catherine Chirouze, Kevin Bouiller, Lionel Piroth
Journal of Investigative Medicine Oct 2022, 70 (7) 1549-1552; DOI: 10.1136/jim-2022-002356

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Cite This
  • APA
  • Chicago
  • Endnote
  • MLA
Loading
Is blood lymphocyte count a prognostic biomarker in Staphylococcus aureus bacteremia?
Mathieu Blot, Abdeljalil Zeggay, Ludwig-Serge Aho-Glele, Caroline Laborde, Vincent Le Moing, Catherine Chirouze, Kevin Bouiller, Lionel Piroth
Journal of Investigative Medicine Oct 2022, 70 (7) 1549-1552; DOI: 10.1136/jim-2022-002356
Download PDF

Share
Is blood lymphocyte count a prognostic biomarker in Staphylococcus aureus bacteremia?
Mathieu Blot, Abdeljalil Zeggay, Ludwig-Serge Aho-Glele, Caroline Laborde, Vincent Le Moing, Catherine Chirouze, Kevin Bouiller, Lionel Piroth
Journal of Investigative Medicine Oct 2022, 70 (7) 1549-1552; DOI: 10.1136/jim-2022-002356
Reddit logo Twitter logo Facebook logo Mendeley logo
Respond to this article
  • Tweet Widget
  • Facebook Like
  • Google Plus One
  • Article
    • Abstract
    • Introduction
    • Methods
    • Results
    • Discussion
    • Ethics statements
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • eLetters
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Trends and demographic patterns in biologic and corticosteroid prescriptions for inflammatory bowel disease: findings from electronic medical records, 2011–2020
  • Effect of intramuscular depot betamethasone injection in patients with fibromyalgia and elevated C-reactive protein levels
Show more Brief report

Similar Articles

 

CONTENT

  • Latest content
  • Current issue
  • Archive
  • Sign up for email alerts
  • RSS

JOURNAL

  • About the journal
  • Editorial board
  • Subscribe
  • Thank you to our reviewers
  • American Federation for Medical Research

AUTHORS

  • Information for authors
  • Submit a paper
  • Track your article
  • Open Access at BMJ

HELP

  • Contact us
  • Reprints
  • Permissions
  • Advertising
  • Feedback form

© 2023 American Federation for Medical Research