Host response signature trends in bacteraemia – authors’ response

Dear Editor,

We read with interest the letter from Brandon et al. [1] in response to our article ‘Host response signature trends in persistent bacteraemia and metastatic infection due to Staphylococcus aureus and Gram-negative bacilli: a prospective multicentre observational study’ [2]. We thank Brandon et al. for their contribution to the discussion about the role of SeptiCyte RAPID in patients with suspect of bloodstream infection and sepsis.

The authors of the letter are all shareholders and/or employees of Immunexpress Inc. and highlight that the assay is now approved in Australia by the Therapeutic Goods Administration (TGA), to be used in conjunction with clinical assessments in patients with suspicion of sepsis exhibiting ≥2 signs of Systemic Inflammatory Response Syndrome (SIRS). At the time when our paper was accepted for publication, TGA approval had not been granted to the assay yet (as this was obtained later in December 2023 [3]). Nonetheless, the Food and Drug Administration (FDA) had previously approved Septicyte RAPID for the same use – as we reported – although restricting its field of application to patients admitted to the Intensive Care Unit only [4].

In our paper we highlighted that the repeated use of SeptiCyte RAPID in the context of a proven episode of bacteraemia to detect the persistence of infection is out of the primary indication of the test [3,4]. Indeed, our aim was to explore the potential usefulness of the assay out of its primary indication in order to assess if the assay could determine how long it takes for the immunologic effects of severe infection to be ‘turned off’. Other biomarkers, such as the C-reactive protein, have been assessed for this purpose [5]. The time course of SIRS and time to clearance of bacteria from the blood is also an area under active study [6–8]. The management of patients with bloodstream infection is indeed complex and research efforts are warranted to bridge the knowledge gap in this field [9].

In our published manuscript, we highlighted that the performances of SeptiCyte RAPID we reported do not apply to the primary purpose of the test of differentiating sepsis from sterile inflammation, for which a promising performance of SeptiCyte has been suggested by previous studies [10]. Indeed, we agree with Brandon et al. that, when used as intended, SeptiCyte RAPID can have clinical utility by providing rapid results and guide management decisions in patients suspected of sepsis irrespective of the type of infection.

Brandon et al. report that a precise interpretation of the SeptiCyte RAPID test results in our study is made difficult by the lack of an index SeptiCyte RAPID result, the relatively long duration between the index blood culture and study Day 1 sample, a lack of information about antibiotic use, and potential differences in source control.

With respect to antibiotic use, all patients were receiving adequate treatment at the time of research blood samples collection, as at that stage antimicrobial sensitivities of bloodstream pathogens had been released to treating clinicians for therapy adjustment. Nonetheless, the presence of metastatic or persistent infection, including lack of source control, can sometimes affect patients’ clinical stability and recovery speed regardless of the administration of adequate antimicrobials. Given all patients were receiving effective therapy at the time of blood samples collection, adequate treatment was not included as a confounder in our mixed models when looking at the association between SeptiScore and the outcomes of interest (persistent BSI, metastatic and persistent infection).

With respect to differences in source control, this was part of the outcomes we evaluated in the context of persistent infection (defined as metastatic infection or lack of source control) and therefore the association between SeptiScores and source control has indeed been assessed in our study.

The lack of an index SeptiCyte RAPID result and the delay between the index blood culture and the research samples collection, have both been acknowledged as limitations in our discussion.

In their letter, Brandon et al. report that they have not observed any statistically significant difference in SeptiScores when comparing Gram positive versus Gram negative blood culture positive sepsis cases, when samples were taken at infection onset. To our knowledge these data are unpublished and likely of value for clinicians planning to embed SeptiCyte RAPID within their clinical practice as a diagnostic tool for the management of sepsis patients. As we did not have SeptiCyte samples collected at infection onset, we could not comment on the distribution of SeptiScores according to the different causative pathogens at this timepoint, as we acknowledged.

Despite all the limitations we acknowledged, we believe that our results are novel, as no published data are available about the trend of SeptiScores over time in patients with proven bloodstream infection in association with clinical data, including metastatic infection and effective source control. It is important to note that no difference in SeptiScores was observed at infection onset between Gram negative and Gram positive bacteraemia episodes according to the unpublished data from ImmunExpress, but the lower SeptiScores we observed over follow-up in the setting of S. aureus bacteraemia may prompt interesting speculations about the interactions of S. aureus with the host immune system. Indeed, as known, S. aureus has the capacity of evading the immune system in the context of a complex interplay with the host, being the most common cause of prolonged bacteraemia and deep-seated dissemination of infection [11,12]. In this context, we speculate whether the transcripts detected by SeptiCyte RAPID might be involved in the mechanisms of immune evasion of S. aureus [13]. Further studies are needed to clarify the trend of host response markers in patients with persistent S. aureus bacteraemia which may contribute to improve the management of affected patients.

With respect to study funding, we acknowledge that ImmunExpress provided a Biocartis Idylla instrument to Pathology Queensland. Nonetheless, the study was sponsored by the University of Queensland who paid for the SeptiCyte consumables and also a service fee to Pathology Queensland to be able to run the study samples on the Idylla instrument.

After the recent approval of SeptiCyte RAPID by the TGA we look forward to this test to be implemented in clinical practice in Australia, with the aim of improving the management of patients with sepsis.

Disclosure statement

DLP has research funding from Shionogi, Merck, bioMerieux, BioVersys and Pfizer and has received consulting fees from the AMR Action Fund, CARB-X, Aurobac, Pfizer, Merck, Cepheid, bioMerieux and Spero. PNAH reports research grants from Gilead, has served on advisory boards for OpGen, Merck and Sandoz, and has received honoraria from OpGen, Sandoz, Pfizer and bioMerieux. The other authors declare no conflict of interest.

Additional information

Funding

AMP is receiving a scholarship from the University of Queensland in support of her PhD candidature. No funding was received for the writing of this letter.