Procalcitonin as a Diagnostic and Monitoring Tool for Bacteraemia in Patients on Haemodialysis: A Systematic Review
Ryan C Maves
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
The authors performed a thorough systematic review and provided useful and practical diagnostic framework to approach bacterial infections in hemodialysis patients, well supported by the available literature in this topic
It is a systematic review and not an original paper. I think it is an accurate review, well conducted (I am not an expert as a reviewer), well balanced conclusions, interesting reading. No need to change to achieve its purposes
Author Response
Comment 1 :The authors performed a thorough systematic review and provided useful and practical diagnostic framework to approach bacterial infections in hemodialysis patients, well supported by the available literature in this topic
It is a systematic review and not an original paper. I think it is an accurate review, well conducted (I am not an expert as a reviewer), well balanced conclusions, interesting reading. No need to change to achieve its purposes
Response: Thank you for your encouraging feedback. Pleased to hear your thoughts about the review.
Reviewer 2 Report
Comments and Suggestions for Authors
Thank you for the opportunity to review this manuscript. In this paper, the authors conducted a systematic review of procalcitonin (PCT) as a biomarker in patients with bacteraemia and end-stage renal disease (ESRD) requiring haemodialysis. The paper is well-written in general and summarizes the existing data clearly. I have some comments that I hope will be of use to the authors and editors.
Abstract, line 19 – “Antibiotic use”, not “antibiotics use”.
Lines 34-35 – Increased mortality with hourly delays in appropriate antibiotics clearly occurs in patients with septic shock and probably in patients with acute organ dysfunction overall. Still, it is unclear that such increased mortality generally occurs in haemodynamically stable patients with bacteraemia. Additionally, I cannot find reference #16 online; I suspect that this is meant to refer to the Jensen procalcitonin trial (Jensen JU, Hein L, Lundgren B, et al. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med. 2011;39(9):2048-2058. doi:10.1097/CCM.0b013e31821e8791). Ironically, this study found evidence of harm in patients receiving PCT-guided therapy, which may undermine its use as a reference by the authors.
Line 48 – This is probably a minor issue of nomenclature, but are we still saying “renal failure” and not “chronic kidney disease” or “ESRD”? I defer to the authors and editors, but I wanted to verify that we are using contemporary terms.
Line 396 – CRP measurements require units here.
Line 434 – The figure referenced is labeled as “figure 3” on line 465, not as “figure 2”.
Figure 2 (inadvertently labeled as “Fig 3”) – I have some concerns about this proposed protocol. First, existing international guidelines recommend against the use of PCT as a basis for antibiotic initiation, given variability in the kinetics of PCT upregulation in early infection (see Evans LE et al, 2021 Surviving Sepsis Campaign). The data are stronger for PCT-guided discontinuation, however. Additionally, while this protocol is a reasonable construct based on the systematic review, it is just that: a systematic review. One could propose this protocol as a concept worth study, but it has neither been tested nor validated. I recommend removing this figure or else explicitly labeling it as a hypothesis that could be tested in a future trial.
Author Response
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Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files. |
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Comments 1: Abstract, line 19 – “Antibiotic use”, not “antibiotics use” |
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Response 1: Thanks for pointing this out. It’s an error on our part. We have made the correction- Abstract, line 19 “antibiotic use” |
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Comments 2: Lines 34-35 – Increased mortality with hourly delays in appropriate antibiotics clearly occurs in patients with septic shock and probably in patients with acute organ dysfunction overall. Still, it is unclear that such increased mortality generally occurs in haemodynamically stable patients with bacteraemia. Additionally, I cannot find reference #16 online; I suspect that this is meant to refer to the Jensen procalcitonin trial (Jensen JU, Hein L, Lundgren B, et al. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med. 2011;39(9):2048-2058. doi:10.1097/CCM.0b013e31821e8791). Ironically, this study found evidence of harm in patients receiving PCT-guided therapy, which may undermine its use as a reference by the authors. |
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Response 2: Thanks for pointing this out. Again, we agree that the occurrence of shock and multiorgan failure significantly increases the mortality risk. Accordingly, we have made changes to the manuscript to say, “Prompt initiation of appropriate antibiotics is critical as each hour of delay is associated with an increased mortality risk in patients with septic shock and organ dysfunction, which are well-recognised complications of bacteraemia and sepsis [21]. I need to apologise. I believe we included the wrong reference for #16. I have removed the citation and reference. Regarding this clinical trial “Jensen JU, Hein L, Lundgren B, et al. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med. 2011;39(9):2048-2058. doi:10.1097/CCM.0b013e31821e8791 “I have included a critical analysis of this study in the discussion section (from line 469 -479). I believe it is essential to consider both supporting and opposing evidence to provide a balanced perspective on the use of procalcitonin-guided antimicrobial stewardship. “An important clinical trial by Jensen et al. (2011) evaluated procalcitonin-guided antibiotic therapy in ICU patients, using procalcitonin levels as the primary determinant for adjusting the antibiotic regimen. The study found no clinical benefit and, in fact, reported increased mortality and greater antibiotic use in the procalcitonin group [16]. In contrast, our protocol uses procalcitonin as a supportive adjunct alongside clinical judgment and other lab tests. It incorporates a 60% reduction in procalcitonin after 72 hours as an indicator of treatment response and highlights the need for reassessment before escalation of antibiotics if there is no clinical improvement. Unlike the critically ill ICU population studied in the trial, where factors such as fungal infections may interfere with procalcitonin accuracy, our protocol is designed for non-ICU inpatients, offering a more targeted and context-appropriate application. Further rigorous evaluation is crucial to assess its effectiveness [16].” Comments 3: Line 48 – This is probably a minor issue of nomenclature, but are we still saying “renal failure” and not “chronic kidney disease” or “ESRD”? I defer to the authors and editors, but I wanted to verify that we are using contemporary terms Response 3: Thanks for pointing this out. Chronic kidney disease would be a better fit. I have changed “renal failure” to “chronic kidney disease” in line 48 Comments 4: Line 396 – CRP measurements require units here. Response 4: Thanks for pointing this out. The CRP unit has been included to line 396 “CRP >100mg/dl” Comments 5: Line 434 – The figure referenced is labeled as “figure 3” on line 465, not as“figure 2”. Response 5: Thanks for pointing out this error. I have changed the label to “Figure 2” Comments 6: Figure 2 (inadvertently labeled as “Fig 3”) – I have some concerns about this proposed protocol. First, existing international guidelines recommend against the use of PCT as a basis for antibiotic initiation, given variability in the kinetics of PCT upregulation in early infection (see Evans LE et al, 2021 Surviving Sepsis Campaign). The data are stronger for PCT-guided discontinuation, however. Additionally, while this protocol is a reasonable construct based on the systematic review, it is just that: a systematic review. One could propose this protocol as a concept worth study, but it has neither been tested nor validated. I recommend removing this figure or else explicitly labeling it as a hypothesis that could be tested in a future trial. Response 6: Thank you once again for this observation. We agree that the current evidence more strongly supports the use of procalcitonin to guide the discontinuation of antibiotics, rather than initiation. We also acknowledge that the proposed protocol, developed from the review findings, should be clearly presented as a hypothetical framework rather than a validated clinical tool. In response, we have revised the relevant section of the manuscript to clarify its hypothetical nature and ensure that it is not interpreted as an evidence-based or established protocol. Changes have been made to the discussion section , line 433-440 “Based on the synthesised recommendations from this review, a hypothetical procalcitonin-guided antibiotic framework was developed for haemodialysis patients presenting with symptoms suggestive of bacteraemia. This proposed approach is intended to support clinical decision-making around antibiotic use by incorporating procalcitonin levels. Presented as a flow chart in Figure 2, it outlines when to consider starting, stopping, re-evaluating, or escalating antibiotic therapy. It is important to note that this framework has not been clinically validated and should be viewed as a hypothesis generated from the current evidence base.” |
Reviewer 3 Report
Comments and Suggestions for Authors
A systematic review is devoted to a very interesting issue - determining the diagnostic significance of procalciotonin as a marker of bacteraemia in patients on haemodialysis.
The aim of the review was to try to develop recommendations for the use of procalciotonin in clinical practice in patients receiving haemodialysis.
The article contains new and important information sufficient to justify its publication. Although a systematic review with meta-analysis on a closely related topic was published in 2022: Diagnostic value of procalcitonin in bacterial infections in patients on haemodialysis. The authors therefore need to emphasise the differences and the usefulness of their systematic review.
The introduction lacks information regarding the influence of the cause of renal failure (acute kidney injury, chronic kidney disease), the duration of the patient's stay on haemodialysis on procalcitonin levels. The authors mention the potential removal of procalciotonin from the blood during haemodialysis and the difficulty of using it for diagnostic purposes. Therefore, strong arguments are required to justify its use for monitoring bacteraemia in patients on haemodialysis.
The literature was selected using the necessary guidelines: Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA 2020) and registered on the PROSPERO website.
The argumentation of the article was built on the relevant hypothesis. The methods used were appropriate. Heterogeneity was assessed and high heterogeneity was found, which limits the interpretation of the data.
The results have been analysed sufficiently, compared with the literature, and are consistent with the findings and conclusions in the article.
Despite the multiple limitations, which the authors stated in full, a consistent association between elevated blood procalcitonin levels and bacterial infection was established. This provides a benchmark for further research and possible proof of the feasibility of using procalcitonin in widespread clinical practice.
The article is not badly written and follows all norms of scientific writing.
The originality of the research was 85.67% when checked in the anti-plagiarism system.
Author Response
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Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files. |
Comments 1: A systematic review is devoted to a very interesting issue - determining the diagnostic significance of procalcitonin as a marker of bacteraemia in patients on haemodialysis.
The aim of the review was to try to develop recommendations for the use of procalciotonin in clinical practice in patients receiving haemodialysis.
The article contains new and important information sufficient to justify its publication.
Although a systematic review with meta-analysis on a closely related topic was published in 2022: Diagnostic value of procalcitonin in bacterial infections in patients on haemodialysis. The authors therefore need to emphasise the differences and the usefulness of their systematic review.
Response 1: We greatly appreciate your recognition of the clinical relevance and potential impact of this work. We agree that the systematic review published in 2022, which is included in our discussion section, highlights similar concepts with procalcitonin, particularly its diagnostic accuracy. Our review, however, focuses not only on the diagnostic value of procalcitonin but also on its practical application in guiding antimicrobial clinical decision making in the haemodialysis population, where the interpretation of biomarkers can be more complex. We have now included a paragraph in the discussion section highlighting this difference. It can be found in the discussion section 388 – 393: “A meta-analysis [41] highlighted that raising the PCT cutoff from 0.68–0.85 ng/ml to 1.5–15 ng/ml decreased sensitivity from 96% to 86% but increased specificity from 77% to 89%. Our review supports a PCT cutoff of 1.5 ng/ml. While this meta-analysis focused primarily on diagnostic accuracy, our review takes a more clinically applied perspective by exploring how procalcitonin can be used to guide antimicrobial decision-making in practice.”
Comments 2: The introduction lacks information regarding the influence of the cause of renal failure (acute kidney injury, chronic kidney disease), the duration of the patient's stay on haemodialysis on procalcitonin levels. The authors mention the potential removal of procalcitonin from the blood during haemodialysis and the difficulty of using it for diagnostic purposes. Therefore, strong arguments are required to justify its use for monitoring bacteraemia in patients on haemodialysis.
Response 2: Thanks for bringing this to our attention. We included the effects of chronic kidney disease and haemodialysis on procalcitonin levels. This is in the introduction, line 49 – 64. We also highlight the benefit of a pre-dialysis assay over an intradialytic or post dialysis PCT levels, found on line 259-262. To further express this, we have included this in the discussion, line 436-438: “Procalcitonin levels should be measured before a haemodialysis session to ensure optimal diagnostic and prognostic accuracy, as dialysis can reduce circulating PCT levels and compromise the reliability of result.”
Regarding these fluctuating values, most of the studies included in our review did not stratify patients based on this accordingly, we have included this to the limitations and highlighted that further studies are necessary. Discussion, Line 504 – 507 “Unmeasured confounding factors such as other treatments, fluctuations in procalcitonin levels due to timing of dialysis, chronic kidney disease, and other factors, for which no stratification was carried out, also increased bias risk. These limitations highlight the need for more rigorous research, including well-designed RCTs, to better investigate procalcitonin use in HD patients with bacteraemia.”
Comments 3: The literature was selected using the necessary guidelines: Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA 2020) and registered on the PROSPERO website.
The argumentation of the article was built on the relevant hypothesis. The methods used were appropriate. Heterogeneity was assessed and high heterogeneity was found, which limits the interpretation of the data.
The results have been analysed sufficiently, compared with the literature, and are consistent with the findings and conclusions in the article.
Despite the multiple limitations, which the authors stated in full, a consistent association between elevated blood procalcitonin levels and bacterial infection was established. This provides a benchmark for further research and possible proof of the feasibility of using procalcitonin in widespread clinical practice.
The article is not badly written and follows all norms of scientific writing.
The originality of the research was 85.67% when checked in the anti-plagiarism system.
Response 3: Thank you very much for your supportive comments on the methodology, analysis, and scientific writing.
Regarding heterogeneity, we acknowledge the difficulty in extrapolating our findings. we have revised the description of our proposed antibiotic protocol to emphasise that it is a hypothetical framework developed form the synthesised evidence and would require further rigorous testing. This can be found in the discussion section, line 439 – 445: “Based on the synthesised recommendations from this review, a hypothetical procalcitonin-guided antibiotic framework was developed for haemodialysis patients presenting with symptoms suggestive of bacteraemia. This proposed approach is intended to support clinical decision-making around antibiotic use by incorporating procalcitonin levels. Presented as a flow chart in Figure 2, it outlines when to consider starting, stopping, re-evaluating, or escalating antibiotic therapy. It is important to note that this framework has not been clinically validated and should be viewed as a hypothesis generated from the current evidence base.”
We hope these revisions address your concerns and strengthen the manuscript. Thank you again for your constructive feedback.
Round 2
Reviewer 3 Report
Comments and Suggestions for Authors
Dear editors and authors!
The authors carefully edited the article, took into account all comments and received an improved version of the manuscript.
This review is devoted to the actual problem - diagnostic significance of procalciotonin as a marker of bacteraemia in patients on haemodialysis to justify its use in clinical practice.
The article contains new and important information sufficient to justify its publication. Literature selection was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA 2020) guidelines and registered on the PROSPERO website.
The article's argumentation was built on appropriate evidence. The methods used were appropriate. Results were presented clearly and coherently, well illustrated with tables, appropriately analysed. The key points given reflect the main conclusions of the article.
The article is well written and conforms to all norms of scientific writing.
In this form it can be accepted for publication.
