The Role of High-Resolution Lung Computed Tomography to Distinguish Between Fibrosing Hypersensitivity Pneumonitis and Usual Interstitial Pneumonia

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Abstract: Adequate

Introduction:

Minor changes needed:

I do not know what you mean by are necessary in the following sentence (69 and 70). It may just be a grammar issue: HRCT abnormalities indicative of small airway disease are necessary such as ill-defined centrilobular nodules, or GGOs with mosaic attenuation, or three-density pattern [4].  Also the word ill is capitalized.

 

GGO is an atypical feature for UIP. For line 74, I would remove superimposed with mild GGO from this sentence as I would not want people to consider this a normal feature.

 

Methods and Materials:

For the HRCT analysis, evidence of air trapping (mosaic attenuation) is a key feature of HP and can really assist in the diagnosis of this condition. End expiratory imaging is key for that evaluation; were end-expiratory images available for review in these cases?-If not this may explain why the mosaic attenuation was not a key feature in diagnosis of fHP.

 

Results:

Adequate

Discussion:

I think the discussion is very good and covers a range of topics appropriately. No major changes needed.

Author Response

Comment 1: I do not know what you mean by are necessary in the following sentence (69 and 70). It may just be a grammar issue: HRCT abnormalities indicative of small airway disease are necessary such as ill-defined centrilobular nodules, or GGOs with mosaic attenuation, or three-density pattern [4].  Also the word ill is capitalized.

Response 1: Thanks a lot for this comment. In lines 69 and 70, we discussed HRCT features of fibrotic hypersensitivity pneumonitis: “HRCT abnormalities indicative of small airway disease are necessary such as Ill-defined centrilobular nodules, or GGOs with mosaic attenuation, or three-density pattern”. We changed this phrase in the manuscript.

Comment 2: GGO is an atypical feature for UIP. For line 74, I would remove superimposed with mild GGO from this sentence as I would not want people to consider this a normal feature.

 Response 2: Thank you so much for this notification. The phrase you have mentioned above is a citation from recent clinical guidelines [Raghu G., Remy-Jardin M., Myers J.L., Richeldi L., et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am. J. Respir. Crit. Care Med. 2018;198(5):e44-e68. doi: 10.1164/rccm.201807-1255ST.], [Raghu G., Remy-Jardin M., Richeldi L., Thomson C.C., et al. Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am. J. Respir. Crit. Care Med. 2022;205(9):e18-e47. doi: 10.1164/rccm.202202-0399ST.].

In this context, mild GGO superimposed on fibrotic lesions should be considered also as a fibrotic sign and not as an inflammatory feature.

Comment 3: Methods and Materials:

For the HRCT analysis, evidence of air trapping (mosaic attenuation) is a key feature of HP and can really assist in the diagnosis of this condition. End expiratory imaging is key for that evaluation; were end-expiratory images available for review in these cases?-If not this may explain why the mosaic attenuation was not a key feature in diagnosis of fHP.

Response 3: Thank you very much for a relevant point. End-expiratory HRCT scans have not been performed for these patients. As our study was retrospective, we were not able change this situation. We added this limitation in the Discussion.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The results presented in the manuscript are not genuinely new. These are well-established findings, so the study does not contribute any new knowledge. In such cases, it is important to critically discuss the results and evaluate their clinical significance. Such analysis is lacking.

For example:

1. The authors found that emphysema is more common in IPF patients. Emphysema itself is not characteristic of either IPF or fHP. It directly depends on the amount and duration of smoking and the level of alpha-1 antitrypsin in the blood.
2. Honeycombing, as a finding, must also be assessed within a specific context—considering the duration of the disease (both IPF and fHP). Honeycombing alone cannot serve as a sign for differential diagnosis without knowing the disease duration.

The second and fourth tables contain repetitive information.

Author Response

Comment 1: The authors found that emphysema is more common in IPF patients. Emphysema itself is not characteristic of either IPF or fHP. It directly depends on the amount and duration of smoking and the level of alpha-1 antitrypsin in the blood.

Response 1: Thanks a lot for this comment. We completely agree with you, but combination of IPF and emphysema is well-described in published literature as combined pulmonary fibrosis and emphysema (CPFE)s syndrome. Therefore, frequent finding of emphysema in patients with IPF does not conflict with this diagnosis. Moreover, frequency of emphysema differed significantly in patient with fHP and UIP/IPF in our study, but in further analysis, emphysema was not of diagnostic value in differentiating these diseases.

Comment 2: Honeycombing, as a finding, must also be assessed within a specific context—considering the duration of the disease (both IPF and fHP). Honeycombing alone cannot serve as a sign for differential diagnosis without knowing the disease duration.

Response 2: Thank you very much for a relevant point. Unfortunately, we did not have precise information about the duration of the disease. However, we used honeycombing not as a single differentiating feature, but in combination with centrilobilar nodules, and diffuse axial and craniocaudal distribution of abnormal findings.

Comment 3: The second and fourth tables contain repetitive information.

Response 3: Thanks a lot for this comment. Tables 2 and 4 are different, the Table 2 demonstrates frequency of different HRCT findings including centrilobular nodules, mosaic attenuation, emphysema, GGO, consolidation, reticulation, honeycombing, and traction bronchiectasis in fHP and IPF/UIP patients, and the Table 4 shows diagnostic values of main HRCT signs of fHP vs UIP patterns.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The aim of this study was to develop HRCT criteria to diagnose fHP in patients with UIP-like pattern.

I suggest to:

1.clarify the aim in the introduction. The final sentence states the aim is to "diagnose fHP in patients with UIP-like pattern." The methodology, however, compares fHP/UIP-like to IPF/UIP. Clarify that the goal is to differentiate fHP with a UIP-like pattern from true IPF/UIP.

2.Justify the use of different diagnostic standards (biopsy for fHP, clinical/HRCT for IPF). A brief rationale is needed.

3.Specify the number of radiologists and their interobserver agreement. Their consensus process for discrepant reads should be described.

4.The excellent AUC (0.953) should be contextualized in the discussion 

5.The small sample size, particularly of the IPF/UIP group (n=24), should be noted as a factor that can make logistic regression models unstable.

6.Consider to cite Floridi C et al "A Radiological diagnosis of Coronavirus Disease 2019 (COVID-19): a Practical Guide" when you discuss the main radiological findings of COVID19.

Author Response

Comment 1: Clarify the aim in the introduction. The final sentence states the aim is to "diagnose fHP in patients with UIP-like pattern." The methodology, however, compares fHP/UIP-like to IPF/UIP. Clarify that the goal is to differentiate fHP with a UIP-like pattern from true IPF/UIP.

Response 1: Thanks a lot for this comment.  According to the Reviewer’s advice we clarified that the goal of our study was to differentiate fHR with UIP-like pattern from IPF/UIP.

Comment 2: Justify the use of different diagnostic standards (biopsy for fHP, clinical/HRCT for IPF). A brief rationale is needed.

Response 2: Thank you very much for this question. According to the current guidelines, typical or probable UIP pattern on ling HRCT scans in a patient with clinical probability of IPF and no clinical concern for an alternative diagnosis does not need histopathological confirmation, so IPF patients with HRCT-patterns of typical or probable UIP did not undergo lung biopsy. fHP patients with a history of any environmental exposure and a clinical course compatible with HP underwent video-assisted thoracoscopic (VATS) lung tissue biopsy because clinical findings were suggestive for HP, but HRCT findings were in line with UIP-like pattern.

Comment 3: Specify the number of radiologists and their interobserver agreement. Their consensus process for discrepant reads should be described.

Response 3: Thank you very much for this question. HRCT scans were analyzed by two independent radiologists. Interobserver discrepancies were resolved by consensus. We added this phrase to Materials and Methods.

Comment 4: The excellent AUC (0.953) should be contextualized in the discussion 

Response 4: Thank you very much for this comment. We have added this information into Discussion.

Comment 5:  The small sample size, particularly of the IPF/UIP group (n=24), should be noted as a factor that can make logistic regression models unstable.

Response 5: Thank you very much for this comment. We have added this information into Discussion.

Comment 6: Consider to cite Floridi C et al "A Radiological diagnosis of Coronavirus Disease 2019 (COVID-19): a Practical Guide" when you discuss the main radiological findings of COVID19.

Response 6: Thanks a lot for your prpposal. We have added [Floridi C, Fogante M, Agostini A, Borgheresi A, Cellina M, Natella R, Bruno F, Cozzi D, Maggialetti N, Palumbo P, Miele V, Carotti M, Giovagnoni A. Radiological diagnosis of Coronavirus Disease 2019 (COVID-19): A Practical Guide. Acta Biomed. 2020 Jul 13;91(8-S):51-59. doi: 10.23750/abm.v91i8-S.9973.] in the Discussion part.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Unfortunately, my comments were essentially ignored. Previous comments remain valid.
Moreover, repeated information within tables has not been corrected.

Unfortunately, the authors did not take the review seriously.

Author Response

Comment 1: The authors found that emphysema is more common in IPF patients. Emphysema itself is not characteristic of either IPF or fHP. It directly depends on the amount and duration of smoking and the level of alpha-1 antitrypsin in the blood.

Response 1: Thanks a lot for this comment. We completely agree with you, but combination of IPF and emphysema is well-described in published literature as combined pulmonary fibrosis and emphysema (CPFE)s syndrome. Therefore, frequent finding of emphysema in patients with IPF does not conflict with this diagnosis. Moreover, frequency of emphysema differed significantly in patient with fHP and UIP/IPF in our study, but in further analysis, emphysema was not of diagnostic value in differentiating these diseases. Unfortunately, we could not assess the duration of the disease in our study due to the lack of clinical information in the database used.

Comment 2: Honeycombing, as a finding, must also be assessed within a specific context—considering the duration of the disease (both IPF and fHP). Honeycombing alone cannot serve as a sign for differential diagnosis without knowing the disease duration.

Response 2: Thank you very much for a relevant point. Unfortunately, we did not have precise information about the duration of the disease. However, we used honeycombing not as a single differentiating feature, but in combination with centrilobular nodules, and diffuse axial and craniocaudal distribution of abnormal findings.

Comment 3: The second and fourth tables contain repetitive information.

Response 3: Thanks a lot for this comment. We improved Tables 2 and 4 by eliminating the repeated lines.

Author Response File: Author Response.docx