Point by Point Response to Reviewers’ Comments

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Author response: Yes.

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Author response: Our article does not contain any code.

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Author response: The data contain potentially identifying or sensitive patient information, and the Research Ethics Committee has imposed restrictions on them. Requests for additional study-related data should be directed to the Ethics Committee of West China Hospital, Sichuan University, via email at hxlcyjglb@163.com.

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Author response: The data contain potentially identifying or sensitive patient information, and the Research Ethics Committee has imposed restrictions on them. Requests for additional study-related data should be directed to the Ethics Committee of West China Hospital, Sichuan University, via email at hxlcyjglb@163.com. The datasets are available from the Ethics Committee upon reasonable request.

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Author response: Yes.

6. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Author response: We have reviewed our reference list to ensure that it is complete and correct.

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Author response: The reviewer's comments do not cover the above-mentioned matters.

Additional Editor Comments:

Reviewer #1: The idea of the manuscript is good, although the COVID-19 as the main topic has switched into common disease.

Please see the upload files for detailed of comment specific related the manuscript, and author need to clarify each of the question clearly.

1. The title is clear and well-described the purpose of the study outcome among the population.

Author response 1#: Thank you very much for your recognition.

2. In the Introduction: the rationale observing the clinical characteristics is clear enough, however since the COVID-19 has moved to endemic state, similar with seasonal influenza, it needs more elaborate argumentation with present situation. Please elaborate with other situation which mimic with COVID-19 with bacteria infection, that common occur in healthcare facilities.

Author response 1#: Thank you very much for your suggestion. According to your advice, we added that “The transition of COVID-19 has moved from a pandemic to an endemic state in recent years, akin to seasonal influenza which projects asynchronous surges of SARS-CoV-2 in different regions”in the introduction section. Besides, we added the elaborate with other situation which mimic with COVID-19 with bacteria infection, that common occur in healthcare facilities. The phenomenon of bacterial coinfections is not unique to COVID-19 and has been observed in other viral respiratory infections. Viral infections, such as those caused by influenza and respiratory syncytial virus, are well-documented to predispose individuals to bacterial infections, which can exacerbate disease severity and increase mortality rates. The revision located on Page 4, line 52-55 and line 58-62, marked red.

3. May the predictive model of the study applied with other viral bacterial infection, e.g. bacterial + viral sepsis? If yes, please add information into the manuscript, especially into the introduction.

Author response 1#: Thank you very much for your suggestion. We recognize that the predictive model of the study applied with other viral bacterial infection could provide more robust support for our conclusions. Consequently, we plan to incorporate a validation cohort regarding bacterial + viral sepsis in our future research.

4. In the method section:

- The immune response may be altered due to comorbidities in the population of COVID-19, however, there is no information about the screening of comorbidities among the population, as the enrollment criteria.

Author response 1#: Thank you very much for your suggestion. According to your advice, we added the comorbidities in the Data Retrieval section. The following data were collected: comorbidities (including hypertension, diabetes, cardiovascular disease, chronic lung/renal diseases, immune system disease, and malignancy). The revision located on Page 8, line 146-147, marked red. Table 1 shows the comorbidities. The revision located on Page 10.

- The population was taken between Dec 2022 — Feb 2023, How does the impact of the virus variant to co-infection/secondary bacterial infection? As we know that the shifting of variant play role during the pandemic, which implies to the clinical characteristics and disease outcome.

Author response 1#: Thank you very much for your suggestion. Our hospital tested the SARS-CoV-2 by RT-PCR test, but no subtype analysis was conducted. However, according to the Chinese Center for Disease Control and Prevention (CDC), the BA.5 subvariants was the dominant circulating variant (reached to 43%) at the time (around December 2022 to March 2023) when conducting this study in Chengdu, China. We added above information in the Enrollment criteria. The revision located on Page 6, line 108-111, marked red.

5. Result section 3.2: The paragraph written is difficult to follow, author need simplify and highlight the important finding of the study.

Author response 1#: Thank you very much for your suggestion. We modified it, and simplify and highlight the important finding of the study. Out of 1060 positive culture samples (Fig. 1a), the predominant isolates were Acinetobacter baumanii (244 cases, 23.02%), Klebsiella pneumoniae (204 cases, 19.25%), and Pseudomonas aeruginosa (90 cases, 8.49%). Among these, 833 sputum samples were positive for bacteria (Fig. 1b), with Acinetobacter baumanii (210 cases, 25.21%), Klebsiella pneumoniae (165 cases, 19.81%), and Pseudomonas aeruginosa (83 cases, 9.96%) as the main isolates. Additionally, 168 blood cultures were positive, primarily for Acinetobacter baumanii (32 cases, 19.05%), Klebsiella pneumoniae (27 cases, 16.07%), and Enterococcus faecium (20 cases, 11.9%) (Fig. 1c). There were only 13 cases in which the results of blood culture and respiratory tract culture were consistent. The revision located on Page 12-13, line 192-211, marked red.

6. The Figure 2 describes the stratification of patient recovery and death, based on antibiotic. What is the purposes to stratified using this approach?

Author response 1#: Thank you very much for your suggestion. The stratification of patient recovery and death based on antibiotic use is a critical approach in managing pneumonia. The primary purpose of stratifying patients in this manner is to optimize antibiotic therapy, ensuring that patients receive the most appropriate treatment based on their specific clinical conditions and the characteristics of the pathogens involved.

7. PREDICTIVE MODEL abbreviation seems confusing to read, may be need other abbreviation or synonym, e.g. predictive model, etc.

Author response 1#: Thank you very much for your suggestion. We modified “PREDICTIVE MODEL abbreviation” to “predictive model”. The revision located on Page 17, line 259-260, line 263, line 265, line 267 and Table 4, marked red.

8. In the discussion, there is no information about the further implication of this study to the recent situation since the COVID-19 has been turned into endemic phase. As mentioned earlier, does all the predictive model applies to other URTI or severe immune response disease, e.e.g sepsis?

Author response 1#: Thank you very much for your suggestion. Despite the transition of the COVID-19 pandemic to an endemic phase, the virus is expected to persist for an extended period. The occurrence of COVID-19 complicated by bacterial pneumonia will continue to be a prevalent clinical scenario. The findings of this study hold significant clinical relevance for the early diagnosis of COVID-19 complicated by pneumonia and for reducing mortality in these patients. The revision located on Page 24, line 391-395, marked red.

However, this study did not include research on patients with upper respiratory tract infections (URTI), sepsis, or similar conditions. Future research will focus on these populations to further validate the predictive model and assess its applicability to infections in other parts. We have added the above limitations in the Discussion section. The revision located on Page 24-25, line 402-405, marked red.

Reviewer #2: The study is devoted to an essential problem – finding a way to predict the likelihood of bacterial pneumonia in patients with COVID-19. It is known that there are no reliable diagnostic criteria, which leads to hypo- and hyperdiagnosis and, accordingly, unjustified prescription of antibiotics.

However, despite the relevance of the problem raised by the paper, there are significant questions on methodology and the results that I would ask to clarify.

Materials and Methods

1. Selection of the population to be analysed

Why did the authors choose to combine bacterial pneumonia as coinfections and secondary infection (namely nosocomial pneumonia) into one group? These are different cohorts of patients, with different risk factors on the development of pneumonia, different aetiology, prognosis, and decisions to be made. It is well known that if we select good studies, bacterial coinfections in COVID-19 remain rare, but secondary superinfections, including nosocomial pneumonia, are frequent and indeed significantly worsen the prognosis.

Author response 2#: Thank you very much for your suggestion. We carefully re-examined the data and found no co-infections. A total of 1,386 cases involved combined bacterial pneumonia, all of which were classified as secondary bacterial pneumonia. The revision located on Page 9, line 174-175, marked red.

2. Inclusion/exclusion criteria

- One of the exclusion criteria requires clarification:

3) positive sputum culture results considered to reflect colonisation or contamination on the basis of clinical judgement. What does clinical judgement mean in this case to assess the results as insignificant? What specific criteria were used?

- Selection of the control group: why the absence of sputum (it is also quite common in bacterial pneumonia, especially at the onset of the disease) as well as recovery without AB therapy allowed to exclude bacterial co-/superinfection?

Author response 2#: Thank you very much for your suggestion. Two researchers, each holding the title of Associate Chief Physician or higher, independently assessed whether cases constituted contamination, colonization, or infection, adhering to the National Health Commission of the People's Republic of China (2001) Diagnostic Criteria for Nosocomial Infection (Trial). In instances of disagreement, a face-to-face discussion was conducted to reach a consensus. If a case was identified as contamination or colonization, the treatment plan remained unchanged, although relevant indicators and clinical symptoms were closely monitored. The revision located on Page 7, line 129-135, marked red. References: The National Health Commission of the People's Republic of China (2001) Diagnostic Criteria

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