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Cluster phenotypes in a non-idiopathic pulmonary fibrosis fibrotic interstitial lung diseases cohort in Singapore

Background Non-idiopathic pulmonary fibrosis fibrosing interstitial lung diseases (F-ILDs) may demonstrate a progressive disease trajectory similar to idiopathic pulmonary fibrosis (IPF). We aimed to identify novel F-ILD phenotypes in a multi-ethnic South-East Asian population. Methods F-ILD subjects (n=201) were analysed using unsupervised hierarchical cluster analysis and their outcomes compared against IPF (n=86). Results Four clusters were identified. Cluster 1 (n=53, 26.4%) comprised older Chinese males with high body mass index (BMI) and comorbidity burden, higher baseline forced vital capacity (FVC) percentage predicted and lower diffusing capacity of the lung for carbon monoxide (DLCO) percentage predicted. They had similar mortality to IPF. Cluster 2 (n=67, 33.3%) had younger female non-smokers with low comorbidity burden, groundglass changes on high-resolution chest computed tomography (HRCT) and a positive anti-nuclear antibody (ANA) titre ≥1:160. They had lower baseline FVC and higher DLCO, low mortality and slower lung function decline. Cluster 3 (n=42, 20.9%) consisted male smokers with low comorbidity burden, emphysema on HRCT and high baseline lung function. They had low mortality and slow lung function decline. Cluster 4 (n=39, 19.4%) was the highest risk and comprised of mainly Indians with high BMI. They had the highest proportion of ischemic heart disease (IHD) and previous pulmonary tuberculosis. Subjects had the lowest baseline lung function, highest mortality, and fastest lung function decline. Survival differences across clusters remained significant following adjustment for treatment. Conclusions We identified four distinct F-ILD clinical phenotypes with varying disease trajectories. This demonstrates heterogeneity in F-ILD and the need for complementary approaches for classification and prognostication beyond ATS/ERS guideline diagnosis.

that the Methods section of the Supplementary Appendix is referred to. This now reads as, "Both numerical and categorical data were selected for cluster analysis based on clinical relevance and previous literature (Supplementary Material Appendix 1 Methods)." Changes in the text: Addition of "Methods" (Page 4, Line 62).

Reviewer B
A very creative way to classify the non-IPF fILD according to the local community. It would be interesting if you could include: Comment 1: HRCT pattern for each cluster which had been discussed in the MDD meeting (UIP pattern in non-IPF cohort is only found in 15 patients) Reviewer 2 Reply 1: We thank the reviewer for the comment and have included the radiological patterns in Table S1 of the Supplementary Appendix Tables section  (Supplementary Appendix Tables, page 13, Table S1).
Changes in the text: Addition of the radiology patterns observed in each of the clusters is in Table S1 (Supplementary Appendix Tables, page 13, Table S1).
Addition of "and radiological patterns" in the manuscript (Manuscript, page 6, line 109).
Comment 2: Perhaps comparing the characteristic of IPF and non-IPF in cluster 1 and 4 (cluster with lowest survival, similar in IPF patients) Reviewer 2 Reply 2: Thank you for the suggestion. We agree that it would be important to present the comparison of the characteristics of the IPF group against each of the respective clusters and have thus included a summary table of the p-values for the characteristics of each cluster compared against IPF. This is presented as Table S3 in the  Supplementary Appendix Tables section on page 15 and is referenced in the manuscript on page 7, lines 133-135.
Changes in the text: Addition of summary table of p-values for characteristics of each cluster compared against IPF (Supplementary Appendix Tables, page 15, Table S3). Addition of the line, "The p-values for each of the cluster's characteristics compared against IPF are summarized in Supplementary Appendix Table S3." (Manuscript, page 7, lines 133-135).
Comment 3: Are cluster 1,4 ILD patients fit in PF-ILD diagnosis? Reviewer 2 Reply 3: Although we did not examine for PF-ILD based on existing trial criteria, it is most likely that Clusters 1 and 4 subjects would fit in with a diagnosis of PF-ILD, as this is a retrospective diagnosis.
Change in the text: nil. Comment 4: Cluster 3 patients with more emphysema but FVC, DLco value almost similar (which I expect Dlco would be even lower in emphysema), the slowest lung function declination received more anti-fibrotic (AF) as compared to cluster 1,4. Any reason for that? Is AF initiation depending on patient's willingness, disease severity and affordability?
Reviewer 2 Reply 4: We thank the reviewer for his comment and agree with his observation that the DLco in Cluster 3 was higher than expected. We did consider that greater antifibrotic use may have been contributory to this, however as only 6/42 patients in this cluster (14.3%) were on antifibrotics, it is difficult to comment on whether this finding is due to antifibrotic use or other factors and hence further study would be required to explore this.
We agree with the reviewer that the cited factors are important considerations when starting antifibrotics. In Singapore, anti-fibrotics cost an average of SGD $3600 per month and financial subsidies are extremely limited. Hence, cost is a major consideration for patients who may decline treatment due to financial difficulties. We have added this important consideration into our discussion section (page, 13 lines 267-269) Change in text: Addition of the sentence, "In addition, due to cost limitations, such as for the use of antifibrotics, some subjects may have declined treatment and hence deteriorate more rapidly." (Manuscript, Page 13, lines 267-269).
Comment 5: comparing cluster 3 (slow decline) and 4 (fast decline), are the treatment initiated (more AF) in cluster 3 played a role in the progression of the lung function?
Reviewer 2 Reply 5: Thank you for the question. We recognize that this is an important consideration and have performed post-hoc analysis on the annual rate of FVC decline for Clusters 3 and 4 with and without antifibrotic therapy. The results are presented in the manuscript (lines 162-165 on pages 8-9) and in Table S6 (Supplementary Appendix  Tables, page 18). We found there was no significant difference in the annual rate of FVC decline between subjects who received antifibrotic therapy and those who did not, between both clusters. However, this is limited by the small number of subjects on antifibrotic therapy.
Changes in the text: Addition of the sentence, "Post-hoc analysis showed that there was no significant difference in the rate of FVC decline in subjects who received anti-fibrotic therapy and those who did not, for both Clusters 3 and 4. (Supplementary Appendix  Table S6)." (Manuscript, pages 8-9, lines 162-165). Table S6 (Supplementary Appendix, Tables, page 18).

Addition of
Comment 6: This is just a suggestion: An overview of the cluster phenotype in fILD Singapore cohort (characteristics and each of cluster survival compared to IPF) Followed by the cluster with similar disease progression like IPF, based on: a) lung function (FVC, Dlco) b) demographic c) the specific diagnosis of ILD (including the subset of CTD) d) HRCT pattern e) how many on AF, and actually requiring AF Reviewer 2 Reply 6: Thank you for the suggestions. The characteristics of IPF and the 4 clusters are summarised in Tables 1 and 2. We agree that it would be important to present the comparison of the characteristics of the IPF group against each of the respective clusters and have thus included a summary table of the p-values for the characteristics of each cluster compared against IPF. This is presented as Table S3 in the Supplementary  Appendix Tables section on page 15 and referenced in the manuscript on page 7, lines 133-135.
In Table S4, we compare the annual rate of FVC decline for each of the 4 clusters compared to IPF, which includes that of Cluster 1 (similar disease behaviour to IPF) and Cluster 4 (more aggressive behaviour than IPF). We have also included the radiological patterns and individual CTD diagnoses for each of the clusters in Table S1 of the Supplementary Appendix Tables section (Supplementary Appendix Tables, page 13,  Table S1).
We found that survival differences between the respective clusters and the IPF group remained significant after adjustment for treatment. We have also included post-hoc analysis on the annual rate of FVC decline for clusters with and without antifibrotic therapy, although this is limited by the small number of subjects on antifibrotic therapy. We do not have information available on the number of subjects for which antifibrotics were required, however this would be important to explore in further studies. Tables, page 15, Table S3). Addition of the line, "The p-values for each of the cluster's characteristics compared against IPF are summarized in Supplementary Appendix Table S3." (Manuscript, page 7, lines 133-135).

Changes in text: Addition of summary table of p-values for characteristics of each cluster compared against IPF (Supplementary Appendix
Addition of the CTD subtypes and radiology patterns observed in each of the clusters is in Table S1 (Supplementary Appendix Tables, page 13, Table S1). Addition of "and radiological patterns" in the manuscript (Manuscript, page 6, line 110-).
Addition of the sentence, "Post-hoc analysis showed that there was no significant difference in the rate of FVC decline in subjects who received anti-fibrotic therapy and those who did not, for both Clusters 3 and 4. (Supplementary Appendix Table S6)." (Manuscript,. Addition of Table S6 (Supplementary Appendix,  Tables, page 18).

Reviewer C
This study identified the four clusters of fibrotic ILD in South-East Asia and showed different prognosis and lung function trajectories for each cluster. These findings are important for the understanding of the heterogeneity of fibrotic ILD.

Major comments
Comment 1: Is there a difference in the prevalence of gastroesophageal reflux disease (GERD) among the four clusters? GERD may be associated with high body mass index, high exacerbation rate, disease progression of ILD.
Reviewer 3 Reply 1: We thank the reviewer for the comment and agree that GERD is an important consideration. This was initially omitted as the results were not statistically significant, however we recognize that this would still be of interest in the results and have hence included the results in the Tables section, in Table 2 (page 2, Table 2).
Comment 2: The statistic values should be listed in Table 1. Alternatively, the characteristics among IPF and each Cluster should be listed in one Table. As different clusters have different prognosis, Cluster 1 has similar survival to IPF, as shown in the legends of Figure 3A. Are there any similarities between the characteristics IPF and Cluster 1?
Reviewer 3 Reply 2: We thank the reviewer for the comment and have included a column of p-values in Specific to the reviewer's query, when Cluster 1 and IPF were compared, there was no significant difference in age, BMI, proportion of subjects with a high comorbidity burden, ischemic heart disease, GERD, pulmonary hypertension or an ANA titre >1:160 and mean FVC percentage predicted and DLCO percentage predicted. However, there were significant differences in sex, Chinese and Indian ethnicity, smoking status and number of pack years, proportion of subjects with a low comorbidity burden, hypertension, previous history of pulmonary tuberculosis and radiology.
Changes in the text: Addition of p-values column in Table 1 (Tables, Page 1, Table 1). Addition of summary table of p-values for characteristics of each cluster compared against IPF (Supplementary Appendix Tables, page 15, Table S3). Addition of the line, "The p-values for each of the cluster's characteristics compared against IPF are summarized in Supplementary Appendix Table S3." (Manuscript, page 7, lines 133-135).  Tables section, as Table S2 (page 14, Table S2). For greater clarity in presentation due to the different "Total n" values, we have separated the BAL cell count patterns and treatment received into two separate tables, which are Table  S2 in the Supplementary Appendix (page 14) and Table 3 in the Tables section (page 3), respectively.