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Clear and unambiguous. References are sufficient. Global structure looks professional. Results look relevant.
Original and rigorous.
Good impact; adequate novelty; conclusions well stated.
None
Please response to the reviewers point by point
The manuscript has already been accepted by me in the second round; however, the other reviewer's considerations need to be addressed to further improve the manuscript.
The manuscript has already been accepted by me in the second round; however, the other reviewer's considerations need to be addressed to further improve the manuscript.
The manuscript has already been accepted by me in the second round; however, the other reviewer's considerations need to be addressed to further improve the manuscript.
None
Clear and unambigous.
Novelty and research questions and methods well described and defined
Impact and novelty are evident. Conlusions well stated.
1. A jam in the reference list is still pending, becuase Authors, while correcting reference n. 28 (Cataudella et al.), pasted the subsequent reference Liu Y, Du X, Chen J, Jin Y, Peng L, Wang HH, Luo M, Chen L, Zhao Y.. Neutrophil-to- lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J. Infect. 81, e1e6 (2020), that acctually results unnumbered. Therefore, the number sequence higher that 28 should be modified because should be increased of 1 unity both in the list and n the text.
2. In the reference list, the addition of the refernce [43]. Regolo, Matteo, et al. Assessing humoral immuno-inflammatory pathways associated with respiratory failure in COVID-19 patients. J Clin Med, 12(12), 4057.(2023) should run according to journal's guidelines.
Please respond to the reviewers point by point.
**PeerJ Staff Note:** It is PeerJ policy that additional references suggested during the peer-review process should only be included if the authors agree that they are relevant and useful.
The authors have addressed all queries.
The authors have addressed all queries.
The authors have addressed all queries.
The authors have addressed all queries.
The rational for the background of the study is more clearer in the revised manuscript. However, the narrative for sepsis and COVID-19 seems need more detailed; Sepsis is also having cytokines-storm (see https://pmc.ncbi.nlm.nih.gov/articles/PMC4378830/; https://www.nejm.org/doi/full/10.1056/NEJMra202613; https://www.mdpi.com/1422-0067/23/19/11740). Please clarify properly the sentences in line 146-152.
The explanation of linezolid is not suitable in the method section, it will be better to put in the discussion section. Method section should be concise and straight forward, leaving any doubtful argumentation. Otherwise, the method section become unclear and difficult to follow. Please read back and revise the accordingly.
The box plot is still need to be added more informative information. As example, Figure 1, what is the Y-axis of each of parameter described?
Please revise the statement in line 570-571, as example the use of hydroxychloroquine. Perhaps previously mentioned as treatment during COVID-19, however since the manuscript are made present day, updating the information is need up to present day (see https://www.who.int/news-room/questions-and-answers/item/coronavirus-disease-(covid-19)-hydroxychloroquine). And this might be applicable with other drugs observed in the manuscript. Therefore, previous comment given was about updating the reference or literature that used and cited in this study.
Still changes are pending.
Linezolid’s issue: this antibiotic was previously used in a unknown, presumably low, number of COVID-19 patients with bacterial pneumonia and these data were published in a “letter to the Editor”, as claimed by Authors (Moghadam VD, Momenimovahed Z, Ghorbani M, Khodadadi J. Linezolid a potential treatment for COVID-19 coinfections. Braz J Anesthesiol. 2021 Mar-Apr;71(2):198). So, Linezolid use in Covid-19 patients still remains off-label as anti-Covid-19 drug, since its efficacy should be mainly related to its anti-bacterial activity, addressed to treat bacterial co-infection, likely developed as complication of Covid-19 infection. Therefore, to avoid misunderstanding, the message on linezolid’s efficacy should be better explained, and perhaps smoothened, underscoring what said above.
Some changes are still needed.
1. Table 2: Significance of NLR in different treatments. I would expect to see baseline compared to data on treatment. How did you test significance given in Table 2? What is the meaning of the significance shown in this Table?
2. The meaning of Table 3 is very difficult to understand.
3. It remains unknown how many patients had Covid-19 Pneumonia and/or other complications (thromboembolism, respiratory failure, septic shock and so on). NLR behaviour should be related to these complications, rather than, or however more than, to drugs used. In fact, as I said in my previous review report, the degree of inflammatory state could change accordingly, on the basis of different degree of inflammatory state.
1. Legends within Figg.4 to 6 are almost unreadable.
2.As said in Brief reporting, Linezolid’s issue: this antibiotic was previously used in a unknown, presumably low, number of COVID-19 patients with bacterial pneumonia and these data were published in a “letter to the Editor”, as claimed by Authors (Moghadam VD, Momenimovahed Z, Ghorbani M, Khodadadi J. Linezolid a potential treatment for COVID-19 coinfections. Braz J Anesthesiol. 2021 Mar-Apr;71(2):198). So, Linezolid use in Covid-19 patients still remains off-label as anti-Covid-19 drug, since its efficacy should be mainly related to its anti-bacterial activity, addressed to treat bacterial co-infection, likely developed as complication of Covid-19 infection. Therefore, to avoid misunderstanding, the message on linezolid’s efficacy should be better explained, and perhaps smoothened, underscoring what said above.
3. Table 2: Significance of NLR in different treatments. I would expect to see baseline compared to data on treatment. How did you test significance given in Table 2? What is the meaning of the significance shown in this Table?
4. The meaning of Table 3 is very difficult to understand.
5. Limitations paragrapgh: although data on CRP and PaO2/FiO2 for some reasons were not available, both references by Regolo et al. (J Clin Med 2022; and 2023) should be acknowledged and discussed, to underscore their relationships and the complementary prognostic role of CRP and NLR, as well as the complementary impact of CRP, meutrophils, limphocytes and their ratio on PaO2/FiO2.
6. As said in Experimental design, it remains unknown how many patients had Covid-19 Pneumonia and/or other complications (thromboembolism, respiratory failure, septic shock and so on). NLR behaviour should be related to these complications, rather than, or however more than, to drugs used. In fact, as I said in my previous review report, the degree of inflammatory state could change accordingly, on the basis of different degree of inflammatory state.
Ovderall structure of this paper still show many flaws.
The reference of Cataudella et al., (n.28) should actually run as follows: J Am Geriatr Soc. 2017 Aug;65(8):1796-1801. The one you cited (J Am Geriatr Soc 2018) is a Letter to the Editor in response to Karakonstantis and colleagues, who asked for further details on results published in 2017.
Please respond to the reviewers point by point.
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What are the inclusion and exclusion patient criteria? Is a high Neutrophil to Lymphocyte Ratio solely from patients with COVID-19? If it only occurs in patients with COVID, this point had to be added in the title.
The author should add information to explain the background for choosing NLR, N, and L values as a treatment outcome. How can these N and L values improve the immune system?
What parameter (or variable) in modulating Immune Response and Inflammation (as stated in the Title) refers to?
The conclusion (These findings propose that NLR can serve as a valuable biomarker for predicting treatment efficacy) is overstated. What are NLR sensitivity and specificity? How can the NLR predict the treatment efficacy? What is its (NLR) association with (patient) death?
Methods
Does ‘acute respiratory illness admitted to the intensive care units’ mean ‘severe COVID-19 patients on mechanical ventilation’?
Results
This cohort study observed patients over time. What is the exact specific time of start observation, and when is the time collected outcome data is collected? How many days of treatment for each drug in Table 2? What variables are compared (analyzed) that produce the p-value in Table 2? Table 2 and Figure 2 are a duplication.
Do patients receive a single drug (in Table 3)? How do the authors anticipate confounding factors because of the combination therapy?
There is a risk of patient attrition because of more than 20% missing data (Table 1, undocumented)
Study limitation.
Discussions
There are 3 Tables and 6 Figures. The author should discuss all results subsequently.
Conclusions
The conclusion did not answer the study’s objective. Efficacy implies the positive association between NLR and the patient outcome (survival or death). Which therapy can reduce NLR and death?
Study’s objective: This study will evaluate the relationship between immune response markers, specifically NLR, NC, and LR, and the efficacy across several different treatments in patients with severe respiratory illnesses.
Conclusion: While many treatments were evaluated, Tocilizumab, Oseltamivir, and Linezolid demonstrated the most notable effects, reinforcing the predictive role of NLR. However, the weak correlations between NLR and specific treatments suggest that a single biomarker may not be sufficient for guiding clinical decisions.
1. This is an interesting topic of evaluation for immune response during COVID-19, which was not described properly in another study. Therefore, the concept and idea for the topic are good and well-understood.
2. The paper is well-written, and the structure of the manuscript is well-structured.
3. The graph needs more legend/information, e.g., x-axis, y-axis. There is a lack of information in the graph; no information for the value of the graph.
4. The references are quite numerous, within the same year of publication. Moreover, the pre-print is used as a reference, which needs to be updated (since 2025, there may be more published data on COVID-19, from previous pre-prints).
1. The title does not reflect the NLR; the author uses the terms modulating Immune Response and Inflammation, which imply many parameters. This should be considered as the major revision of the manuscript.
2. The background needs improvement, many lack of information as the rationale for the objective of the study, e.g., why is choosing the NLR? The NLR is a dynamic marker that may change over time. Moreover, what is the issue with the treatment, particularly in COVID-19? This needs to be addressed properly.
3. What is the reason for using the COVID-19 population as the study population? A similar treatment, e.g. antibacterial agent or an antiviral, is also given to a Sepsis patient, for example. Please explain more clearly in the introduction.
4. The method section is an important part to revise for this manuscript, as the major revision:
a. Which of the NLR data is used in this study? As mentioned earlier, the NLR is a dynamic variable and can be changed over time. This is not clear for the data observation in this study, moreover, the study also wants to evaluate the treatment effect.
b. There is no information about the population included for the severity of COVID-19. This may lead to bias of the NLR and treatment effect.
c. Is there any of the study population having co-infection or secondary infection? This is not clear to the population.
d. The variable section is too confusing; the author needs to describe properly for the study variable clearly.
e. Line 157: The author described about comparison group for statistical analysis. What is the group of this study?
The result section needs to be revised since there is inconsistent information with the factual knowledge:
Line 206-209: "The most promising results were observed with Ostilomavir (7.54±5.33, p = 0.004) and Linezolid (9.44 ± 8.91, p = 0.029), both of which demonstrated significant effects on NLR, suggesting their potential role in reducing inflammation or enhancing immune function in COVID-19 patients". This is a generalization and potential for misleading, particularly for linezolid. This study did not show the population with different severities, e.g., the presence of secondary infection or co-infection.
Later in the discussion, this information becomes truly misleading, as mentioned in lines 272-277: "Linezolid, an antibiotic typically used to treat bacterial infections, also demonstrated a significant effect on NLR (p = 0.029). This finding suggested that Linezolid may have immunomodulatory properties beyond its antimicrobial effects, potentially reducing inflammation in COVID-19 patients. Previous research has confirmed better clinical and microbiological efficacy of linezolid compared to vancomycin, which is a common and popular antibiotic prescribed by doctors [42, 43]." References 42 and 43 did not support this information. The author needs to evaluate the consistency of information within the manuscript.
All the results are too generalized, there is no stratification analysis based on comorbidities, severity of the diseases. The author needs to have a separate analysis that stratifies by a certain variable to see the homogeneity of the population.
Too much unclear information and unsupported references within the author analysis.
This paper by Al Mutair et al., entitled “Evaluating the role of antibiotics, Antiviral drugs, and Biologic agents in modulating Immune Response and Inflammation: A Multicenter Cohort Study,” tried to retrospectively correlate therapeutic effects of a number of drugs with NLR, which mirrors the derangement between innate and adaptive immunity. Unfortunately, some flaws in basic reporting have influenced both experimental design and validity of the findings.
1. Basic reporting: NLR can mirror the derangement between innate and adaptive immunity in several pathophysiological states, including neoplastic diseases, and not only in inflammatory diseases (lines 100-106) (see and cite for reference Buonacera et al. Int J Mol Sci 2022). It does not make any sense to pool together several inflammatory diseases, because this strategy misses differences, if any, in the patterns of their biomarkers. Bearing this concept in mind, evaluation of NLR and its relationships must be assessed for a single disease and not for pathophysiological states, because, for example, characteristics of COVID-19 patients' pneumonia are different from those of other kinds of pneumonia, despite sharing the same inflammatory pathogenetic mechanism. Moreover, it should be specified that data of de Jager et al. (ref. N. 25) on NLR were obtained in Community Acquired Pneumonia (CAP), and confirmed in older patients (Cataudella et al., J Am Geriatr Soc 2017), so suggesting that the prognostic role of NLR in patients with CAP is independent of aging.
2. Unfortunately, some flaws in basic reporting have influenced both experimental design and validity of the findings. It does not make any sense to pool together several inflammatory diseases, because this strategy misses differences, if any, in the patterns of their biomarkers.
The validity of the findings does not appear to be based on an adequate experimental design.
For example, previous reports in Covid-19 patients showed that, while neutrophils, lymphocytes, NLR, and C Reactive Protein (CRP) differently predicted prognosis in Covid-19 patients (Regolo et al., J Clin Med 2022; Regolo et al., J Clin Med 2023), only NLR resulted inversely related to PaO2/FiO2, a recognized marker of respiratory failure occurring as a consequence of inflammation (Regolo et al., J Clin Med 2023). In the present paper, data on CRP are missing, as well as other characteristics of COVID-19 patients.
3. As to Linezolid, that is an antibiotic used in bacterial infections; there is no previous report, to the best of my knowledge, suggesting its use in COVID-19 disease, because this is a viral disease. Therefore, the sentence (lines 273-275) suggesting its potential use in COVID-19 patients, because this antibiotic possesses anti-inflammatory properties, is really unreasonable.
**PeerJ Staff Note:** It is PeerJ policy that additional references suggested during the peer-review process should only be included if the authors are in agreement that they are relevant and useful.
On the whole, this paper needs to be restructured in its literature background and its experimental design, to adequately warrant its findings.
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