Crossing the Barrier: Eikenella corrodens Bacteremia Following CNS Infection in a Patient Treated with Nivolumab—A Case Report and Literature Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The review case report written by Cosio etal. showed that the patient initially received anticancer therapy; however, treatment was discontinued due to an ischemic reaction in the left hand. Subsequently, the patient’s condition deteriorated, with clinical suspicion of an ongoing systemic infection. Brain CT imaging revealed left hemispheric swelling, a midline shift, and evidence of sinus-originating infection. Blood cultures identified Eikenella corrodens as the causative agent of the bloodstream infection. The results and tests conducted for the patient were thorough, including a detailed analysis of their culture test results and an MRI scan of the brain. It is necessary to the need for rapid biomarkers of immune perturbation and predictive tools for infectious complications caused by bacterial infection. References were accurate and relevant. 

Author Response

Dear Reviewer,
Thank you very much for giving us the opportunity to revise our manuscript (Submission ID: microorganisms-3830930). Great thanks for your valuable comments that undoubtedly have improved the quality of our paper.
Please, you will find below a point-to-point letter in order to respond to your comments and suggestions. All the changes were highlighted in red in the revised manuscript (marked copy).
Please let me know if you require any additional information on our paper.
Looking forward to hearing from you soon.
Best regards,
Terenzio Cosio and Maurizio Sanguinetti

The review case report written by Cosio et al. showed that the patient initially received anticancer therapy; however, treatment was discontinued due to an ischemic reaction in the left hand. Subsequently, the patient’s condition deteriorated, with clinical suspicion of an ongoing systemic infection. Brain CT imaging revealed left hemispheric swelling, a midline shift, and evidence of sinus-originating infection. Blood cultures identified Eikenella corrodens as the causative agent of the bloodstream infection. The results and tests conducted for the patient were thorough, including a detailed analysis of their culture test results and an MRI scan of the brain. It is necessary to the need for rapid biomarkers of immune perturbation and predictive tools for infectious complications caused by bacterial infection. References were accurate and relevant.

Thank you very much for your interest and we have appreciated all your feedback.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Although the article only covers a single case, it is of great interest to the reader. The case presented is well researched and discussed.
1) In my opinion, the discussion needs to be structured
2) The refusal of neurosurgical intervention is explained by the poor prognosis, but no alternatives or discussion of possible risks/benefits of the intervention are presented.
3) Only 5 cases out of 54 found are included. I would recommend expanding the discussion.

Author Response

Dear Reviewer,

Thank you very much for giving us the opportunity to revise our manuscript (Submission ID: microorganisms-3830930). Great thanks for your valuable comments that undoubtedly have improved the quality of our paper.

Please, you will find below a point-to-point letter in order to respond to your comments and suggestions. All the changes were highlighted in red in the revised manuscript (marked copy).

Please let me know if you require any additional information on our paper.

Looking forward to hearing from you soon.

Best regards,

Terenzio Cosio and Maurizio Sanguinetti

 

Although the article only covers a single case, it is of great interest to the reader. The case presented is well researched and discussed.

Thank you very much for your interest and for your valuable comments and suggestions aimed to improve our manuscript.

1) In my opinion, the discussion needs to be structured

1) Thank you for the suggestion. Discussion has been improved as suggested.

2) The refusal of neurosurgical intervention is explained by the poor prognosis, but no alternatives or discussion of possible risks/benefits of the intervention are presented.

2) Thank you for the suggestion. We have improved the clinical information and reviewed alternative approach in the discussion section.

3) Only 5 cases out of 54 found are included. I would recommend expanding the discussion.

3) The discussion section has been modified according to your suggestions.

 

Finally, we have appreciated all of your feedback and have carefully considered your suggestions for improving our manuscript.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

In the present article, the authors describe a case report of a patient with advanced nasopharyngeal carcinoma under nivolumab treatment that showed signs of bacteria infection. Using a combination of DNA sequencing (rRNA gene), culturing, and MALD-TOF mass spectrometry the microorganism was identified as Eikenella corrodens, a bacterium that is a part of the normal oropharyngeal flora. Neuroimaging was also applied to demonstrate the intracranial infection foci. Then, the authors performed a literature review to highlight the potential for secondary bacterial infections by Eikenella corrodens and bacteremia in oncologic patients with CNS infection.

Nivolumab, an antibody that acts as an immune checkpoint inhibitor enhances anti-tumor immunity but at the same time it induces a dysregulation in the immune system that may increase susceptibility to infections. The mechanisms that account for this are analyzed by the authors. Thus, the development of bacterial infections due to administration of immune checkpoint inhibitors should be taken into consideration in the clinic.

The literature review supports the conclusions.

Further, the authors describe the clinical challenges that need to be addressed and the problems that could arise in the diagnosis of bacterial infections such as Eikenella corrodens that needs special conditions and is a slow grown Gram(-)bacterium.

Overall, the study is well designed and interesting mainly to clinicians. Therefore I recommend its publication with only one minor comment.

 

Minor comment

Nivolumab treatment was initiated on 2023 and is continued up to now? Initiation time and termination should be clearly stated.

Author Response

Dear Reviewer,

Thank you very much for giving us the opportunity to revise our manuscript (Submission ID: microorganisms-3830930). Great thanks for your valuable comments that undoubtedly have improved the quality of our paper.

Please, you will find below a point-to-point letter in order to respond to your comments and suggestions. All the changes were highlighted in red in the revised manuscript (marked copy).

Please let me know if you require any additional information on our paper.

Looking forward to hearing from you soon.

Best regards,

Terenzio Cosio and Maurizio Sanguinetti

 

In the present article, the authors describe a case report of a patient with advanced nasopharyngeal carcinoma under nivolumab treatment that showed signs of bacteria infection. Using a combination of DNA sequencing (rRNA gene), culturing, and MALD-TOF mass spectrometry the microorganism was identified as Eikenella corrodens, a bacterium that is a part of the normal oropharyngeal flora. Neuroimaging was also applied to demonstrate the intracranial infection foci. Then, the authors performed a literature review to highlight the potential for secondary bacterial infections by Eikenella corrodens and bacteremia in oncologic patients with CNS infection. Nivolumab, an antibody that acts as an immune checkpoint inhibitor enhances anti-tumor immunity but at the same time it induces a dysregulation in the immune system that may increase susceptibility to infections. The mechanisms that account for this are analyzed by the authors. Thus, the development of bacterial infections due to administration of immune checkpoint inhibitors should be taken into consideration in the clinic. The literature review supports the conclusions. Further, the authors describe the clinical challenges that need to be addressed and the problems that could arise in the diagnosis of bacterial infections such as Eikenella corrodens that needs special conditions and is a slow grown Gram(-) bacterium. Overall, the study is well designed and interesting mainly to clinicians. Therefore I recommend its publication with only one minor comment.

Thank you very much for your interest and for your valuable comments and suggestions aimed to improve our manuscript.

 

Minor comment

Nivolumab treatment was initiated on 2023 and is continued up to now? Initiation time and termination should be clearly stated.

Dear reviewer, thank you for the suggestion. We have added clinical management and explicit details about treatment in the case report section.

 

Finally, we have appreciated all of your feedback and have carefully considered your suggestions for improving our manuscript.

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

The authors present a well-documented case of Eikenella corrodens bacteremia following CNS infection in a patient with advanced nasopharyngeal carcinoma treated with nivolumab. The case is clinically relevant, and the discussion provides an interesting perspective on the potential role of immune checkpoint inhibitors in modulating susceptibility to infections.

I have the following minor concerns: 

• The section on immune checkpoint inhibitors and infection risk is important but remains partly speculative. Including more recent data (systematic reviews or registries of infectious complications in ICI-treated patients) would strengthen the argument.

• Only 5 cases were finally included; please clarify whether additional reports of E. corrodens bacteremia (not strictly CNS-related) were identified and excluded, and justify the strict criteria.

• While MIC values are provided, interpretation remains challenging due to lack of CLSI/EUCAST breakpoints. Please clarify whether surrogate criteria (e.g., Haemophilus spp.) were applied and discuss implications for clinical management.

• The manuscript reports transition to palliative care, but it would be useful to clarify whether bacteremia clearance was documented before end-of-life transfer.

• In a few places the text is repetitive (e.g., description of ICI-related dysregulation). Consider light editing to improve conciseness.

Author Response

Dear Reviewer,

Thank you very much for giving us the opportunity to revise our manuscript (Submission ID: microorganisms-3830930). Great thanks for your valuable comments that undoubtedly have improved the quality of our paper.

Please, you will find below a point-to-point letter in order to respond to your comments and suggestions. All the changes were highlighted in red in the revised manuscript (marked copy).

Please let me know if you require any additional information on our paper.

Looking forward to hearing from you soon.

Best regards,

Terenzio Cosio and Maurizio Sanguinetti

 

The authors present a well-documented case of Eikenella corrodens bacteremia following CNS infection in a patient with advanced nasopharyngeal carcinoma treated with nivolumab. The case is clinically relevant, and the discussion provides an interesting perspective on the potential role of immune checkpoint inhibitors in modulating susceptibility to infections.

Thank you very much for your interest and for your valuable comments and suggestions aimed to improve our manuscript.

 

I have the following minor concerns: 

• The section on immune checkpoint inhibitors and infection risk is important but remains partly speculative. Including more recent data (systematic reviews or registries of infectious complications in ICI-treated patients) would strengthen the argument.
• Thank you for the suggestion. We have added recent published data from clinical trials to strengthen the argument.

 

• Only 5 cases were finally included; please clarify whether additional reports of E. corrodens bacteremia (not strictly CNS-related) were identified and excluded, and justify the strict criteria.
• We have clarified this point and improved the discussion section accordingly to your suggestion.

 

• While MIC values are provided, interpretation remains challenging due to lack of CLSI/EUCAST breakpoints. Please clarify whether surrogate criteria (e.g., Haemophilus spp.) were applied and discuss implications for clinical management.
• Thank you for the suggestion. We have highlighted this point in the discussion section.

 

• The manuscript reports transition to palliative care, but it would be useful to clarify whether bacteremia clearance was documented before end-of-life transfer.
• Thank you for the suggestion. We have reported the management of the bacteriemia and clarify this point in the case report section.

 

• In a few places the text is repetitive (e.g., description of ICI-related dysregulation). Consider light editing to improve conciseness.
• We have edited the main file according to your suggestion.

 

Finally, we have appreciated all of your feedback and have carefully considered your suggestions for improving our manuscript.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors took into account all my comments. The article can be accepted in its current form.