Invasive Pulmonary Aspergillosis in Coronavirus Disease 2019 Patients Lights and Shadows in the Current Landscape
Round 1
Reviewer 1 Report
Estimated Editorial Office of Advances in Respiratory Medicine ,
I've read the present narrative review with great interest and pleasure, benefiting of a text well written, up to date, and characterized by an appropriate and plain text.
In this text, Tsotsolis Kotoulas , and Lavrentieva provide a detailed outline about the invasive pulmonary aspergillosis, including the new and somehow worrisome details on the increasing occurrence and similarly raising resistance rates, and some glimpses about novel antifungine drugs.
From my point of view, the only shortcoming of the present paper is represented by quite high number of acronyms the Authors are relying on across the main text. Authors could easily fix this potential issue by implementing a summary Table with all of the used acronyms as a novel Table 1.
Author Response
Reply to reviewer 1
First of all, we would like to thank the reviewer for the much-appreciated time and effort dedicated to our submission as well as for the valuable recommendation that was suggested.
Reviewer
Estimated Editorial Office of Advances in Respiratory Medicine,
I've read the present narrative review with great interest and pleasure, benefiting of a text well written, up to date, and characterized by an appropriate and plain text.
In this text, Tsotsolis, Kotoulas, and Lavrentieva provide a detailed outline about the invasive pulmonary aspergillosis, including the new and somehow worrisome details on the increasing occurrence and similarly raising resistance rates, and some glimpses about novel antifungine drugs.
From my point of view, the only shortcoming of the present paper is represented by quite high number of acronyms the Authors are relying on across the main text. Authors could easily fix this potential issue by implementing a summary Table with all of the used acronyms as a novel Table 1.
Response: Thank you for your valuable comment. The list of abbreviations has been created and added to the text as Table 2 in the Appendix A.
Reviewer 2 Report
I thank you for this interesting article which provides a good summary of the current situation regarding CAPA.
I have noticed a few errors and clumsy phrases in English I think you will have to attend to, ideally through a thorough reading by a native speaker (eg. line 14 : "even" is ill-placed and leads to the opposite of what you mean, line 17 : benefit by/from, line 73 you mistook caused by for causing (or the virus for the disease), line 196, a subject is missing, line 299 you mistook bare for bear, line 319 a preposition is missing, line 354 is very clumsy...). Probably an English native speaker would get your text rid of many comas too.
As well, I noticed some italic use that is unaccounted for (line 458, line 487, etc).
More importantly, I was interested by your table 1, which seems at first very didactic and useful. Unfortunately there are some lacks and mistakes in it when it comes to the Diagnostic value, and this is an important issue. On one hand, the table would benefit from a more systematic presentation (eg. sensitivity high, specificity low, NPV high, PPV low): for example you don't describe PPV for BDG assay. On the other hand, some information is utterly wrong in the table and casts doubt in the reader's mind : for GM in BAL, you associate moderate sensitivity with low PPV and high specificity with high NPV. In fact it is the other way around : high specificity is associated with a risk for false negatives and therefore a low NPV but a good PPV, while high sensitivity leads to a high risk of false positives and therefore a good NPV but low PPV. I won't detail further but you should definitely make a deep revision of this table.
In the treatment section, I was most suprised by line 397, in which you suggest the use of a combination of isavuconazole and voriconazole. I read two of the articles you cite to account for this, but did not find any mention of such a combination. I was unfortunately not able to reach for the text of reference 98, but I don't think this combination therapy should be mentionned, or else with more data about it as it is most unusual.
Further in this section, I noticed you introduce rezafungin twice (line 446 and 450), but that you still consider caspofungin as a "novel" echinocandin (line 471).
Paragraph 474 to 477 needs reformulation and probably belongs to the diagnostic challenges more than the therapeutic challenges.
I thank you for your work and wish you a successful process to the publishing.
Author Response
Reply to reviewer 2
First of all, we would like to thank the reviewer for the much-appreciated time and effort dedicated to our submission as well as for the valuable recommendations and corrections that were suggested. We very much appreciate the comments on the manuscript which certainly helped improve the quality of the paper. We followed all the suggested revision points. All changes made are marked in red.
Reviewer
I thank you for this interesting article which provides a good summary of the current situation regarding CAPA.
I have noticed a few errors and clumsy phrases in English I think you will have to attend to, ideally through a thorough reading by a native speaker (e.g. line 14: "even" is ill-placed and leads to the opposite of what you mean, line 17 : benefit by/from, line 73 you mistook caused by for causing (or the virus for the disease), line 196, a subject is missing, line 299 you mistook bare for bear, line 319 a preposition is missing, line 354 is very clumsy...). Probably an English native speaker would get your text rid of many comas too.
As well, I noticed some italic use that is unaccounted for (line 458, line 487, etc.).
Response: Thank you for the comment. We rechecked grammatical errors and punctuation throughout the manuscript.
Reviewer
More importantly, I was interested by your table 1, which seems at first very didactic and useful. Unfortunately, there are some lacks and mistakes in it when it comes to the Diagnostic value, and this is an important issue. On one hand, the table would benefit from a more systematic presentation (e.g., sensitivity high, specificity low, NPV high, PPV low): for example, you don't describe PPV for BDG assay. On the other hand, some information is utterly wrong in the table and casts doubt in the reader's mind : for GM in BAL, you associate moderate sensitivity with low PPV and high specificity with high NPV. In fact, it is the other way around: high specificity is associated with a risk for false negatives and therefore a low NPV but a good PPV, while high sensitivity leads to a high risk of false positives and therefore a good NPV but low PPV. I won't detail further but you should definitely make a deep revision of this table.
Response: Thank you for this valuable comment. The references have been carefully reevaluated, and the Table has been revised as suggested. Explanation of abbreviations have been added in the footnote.
Reviewer
In the treatment section, I was most surprised by line 397, in which you suggest the use of a combination of isavuconazole and voriconazole. I read two of the articles you cite to account for this, but did not find any mention of such a combination. I was unfortunately not able to reach for the text of reference 98, but I don't think this combination therapy should be mentioned, or else with more data about it as it is most unusual.
Response: Thank you for bringing this to our attention. You are right. References 95 and 99 did not mention the combination of these two antifungals so they have been omitted from this part of the manuscript; we only kept reference 98 which includes a brief report on the use of combination of isavuconazole and voriconazole in Belgian ICU case series.
Reviewer
Further in this section, I noticed you introduce rezafungin twice (line 446 and 450), but that you still consider caspofungin as a "novel" echinocandin (line 471).
Response: Thank you for identifying this error. The phrase ‘’a novel, once weekly echinocandin, which is under development and presents increased activity against Aspergillus,’’ has been omitted from this sentence. Caspofungin was also removed from the text.
Reviewer 3 Report
To the authors,
Tsotsolis et al. prepared a interesting review titled “Invasive pulmonary aspergillosis in Coronavirus disease 2019 patients. Lights and shadows in the current landscape”. The manuscript is well written.
However, I have some suggestions:
1. List in Lien 86ff: I would consider adding limited access to CT imaging in overwhelming Covid-19 surges. Or restricted use of imaging due to safety precautions. This might of course be locval differences.
2. Paragraph starting at Line 110: It should be disscusse that the retrospective assessment of the impact of CAPA on mortality may be subject to bias and confounding. Rigorous adjustment methods are necessary to rule out associations (eg sicker patients, who have a higher riks of death, also have a higher risk of developing CAPA)
3. It would be great to read something about the risk of prescribing antifungals in patients who are misclassified as positive cases. Does the literature suggest that “too many or too less” patients empirically treated?
Author Response
Reply to reviewer 3
First of all, we would like to thank the reviewer for the much-appreciated time and effort dedicated to our submission as well as for the valuable recommendations and corrections that were suggested. We very much appreciate the comments on the manuscript which certainly helped improve the quality of the paper. We followed all the suggested revision points. All changes made are marked in red.
Reviewer
List in Lien 86ff: I would consider adding limited access to CT imaging in overwhelming Covid-19 surges. Or restricted use of imaging due to safety precautions. This might of course be local differences.
Response: Thank you for your valuable comment. The following changes have been made to the last paragraph of the section 2.5. The role of diagnostic radiology.
Due to severe life-threatening hypoxia and challenges in mechanical ventilation, CT scanning is not considered possible for many patients with SARS-CoV-2. When performed, the differentiation between COVID-19 and Aspergillus associated lesions could additionally be proved extremely complex [35]. Moreover, patient transfer to CT in these cases is often resource intensive. Clinical justification of CT procedures should be made on a local level, CT should be reserved for cases where healthcare team discussion highlights a clear clinical indication.
Reviewer
Paragraph starting at Line 110: It should be discussed that the retrospective assessment of the impact of CAPA on mortality may be subject to bias and confounding. Rigorous adjustment methods are necessary to rule out associations (eg sicker patients, who have a higher risk of death, also have a higher risk of developing CAPA)
Response: Thank you for your remarks. We have added the following sentences according to your suggestions.
It remains unclear whether COVID-19-associated pulmonary aspergillosis directly contributes to increased mortality rates or unequally affects the most severely ill patients who are burdened from comorbidities. The high heterogeneity in mortality among studies could be explained by the limited number of patients with CAPA and the differences in treatment strategies.
Reviewer
It would be great to read something about the risk of prescribing antifungals in patients who are misclassified as positive cases. Does the literature suggest that “too many or too less” patients empirically treated?
Response: Thank you very much for your valuable comment. Additional paragraph and two additional references (ref. 115 and ref.116) have been added to the section 2.7. Challenges in the treatment of IPA in patients with SARS-CoV-2 infection.
The appropriate use of antimicrobial agents improves clinical outcomes and reduces antimicrobial resistance. Nevertheless, data on inappropriate prescription of antifungal treatment and negative outcomes are inconsistent. Aldrees et al. performed a retrospective chart review for patients who received antifungal treatment. The appropriateness of the dosage, initiation time, agent selection, and duration of therapy was evaluated based on international recommendations. Overall, 270 (76.1%) patients received empirical treatment, 56.3% of which had received antifungal treatment for more than five days despite the absence of proven fungal infection. Only 39% of patients who were subjected to antifungal therapy met all study criteria for appropriate prescription. A recently published study by Estella et al. investigated the impact of early anticipatory antifungal treatment on the incidence of CAPA and outcomes of critically ill patients with pneumonia. There was a comparison between two analysis periods based on whether antifungal therapy had been initiated early or late. The results of the study demonstrated that early initiation of antifungal therapy was associated with a decrease in the incidence and mortality of pulmonary aspergillosis. Conflicting data in the literature regarding the appropriate prescription of antifungals mandate the use of antimicrobial stewardship programs which can improve the prompt utilization of antifungal therapies.
Aldrees, A., Ghonem, L., Almajid, F., Barry, M., Mayet, A., & Almohaya, A. M. (2021). Evaluating the Inappropriate Prescribing and Utilization of Caspofungin, a Four-Year Analysis at a Teaching Hospital in Saudi Arabia. Antibiotics (Basel, Switzerland), 10(12), 1498. https://doi.org/10.3390/antibiotics10121498
Estella Á, Recuerda Núñez M, Lagares C, Gracia Romero M, Torres E, Alados Arboledas JC, Antón Escors Á, González García C, Sandar Núñez D, López Prieto D, Sánchez Calvo JM. Anticipatory Antifungal Treatment in Critically Ill Patients with SARS-CoV-2 Pneumonia. Journal of Fungi. 2023; 9(3):288. https://doi.org/10.3390/jof9030288
Author Response File: 
Author Response.pdf
Round 2
Reviewer 1 Report
The present paper has been improved according to my previous recommendations.
I'm therefore endorsing the eventual acceptance of this study.
Well done.
Author Response
Thank you very much
Reviewer 2 Report
I thank you for your revised manuscript. Most of my concerns were thouroughly addressed. I still have hesitations on the PPV/NPV table, because some data are not fully congruent. But as you now cite metrics, this can be attributed to heterogenous results and seems sound.
I have therefore no further inquiry and wish you the best for your further work in the field.
Author Response
Thank you very much
Reviewer 3 Report
No further comments form my side.
Author Response
Thank you very much
