Are Fatigue and Pain Overlooked in Subjects with Stable Chronic Obstructive Pulmonary Disease?

Round 1

Reviewer 1 Report

This is an interesting paper which adds a new angle to the existing literature.  However, the sample size is relatively small for correlational analysis.  In table 1 only the significant correlations are shown, and the insignificant ones are presented as a dash.  This must be corrected.  All correlations must be shown.  The reason is that the non-significant correlations may be approaching significance.  In addition, because so many correlations are being conducted with such a comparatively small sample, it is important to see the exact Spearman Rho value.  Statistical tests of correlations establish test only whether there is a correlation, not whether there is not.  So, it is highly plausible that there are in fact correlations where you report none but they are small - and possibly clinically insignificant.  By providing the Rho values themselves, the reader is able to make a more informed decision about your data.

  The most useful message I get from these data are that some COPD patients report fatigue and pain and some (the majority in your sample) do not.  It is certainly untrue to say that pain and fatigue are not experienced in COPD.  I think it reasonable from the overspill hypothesis to expect that pain - which often has an inflammatory etiology - is increased in COPD.  However, it is also likely that the degree of 'overspill' varies between patients as a function of general health.  My guess is that the patients who attend pulmonary rehab and have a generally healthier lifestyle experience less pain because there nonspecific inflammatory markers are lower.  After all, fatigue and depression are associated with higher levels of nonspecific inflammatory cytokines  You should consider the possibility that the reason for the low levels of pain and fatigue overall in your sample is that the general health of your patients is good due to overall care of the patients, including lifestyle advice and help.  You might like to note that there is an increase in pain in severe asthma - a couple of recent papers from different labs have shown the comorbidity of severe asthma and fibromyalgia. So, pain is not unusual in other respiratory conditions, though there is no simple causal relationship.  I liked the paper, but please focus on the individual differences between patients a little more.

Author Response

Author's Reply to the Review Report (Reviewer 1)

1. This is an interesting paper which adds a new angle to the existing literature. However, the sample size is relatively small for correlational analysis.

Response: We of course agree with you regarding the small sample size of the present study. As this is one of its limitations, we have written the following in the manuscript: “This single-center study was also limited by its small sample size and the fact that most of the subjects were male, even though it includes most of the stable COPD patients who attended our hospital during the study period.” (Lines 300-302).

 

2. In table 1 only the significant correlations are shown, and the insignificant ones are presented as a dash. This must be corrected. All correlations must be shown. The reason is that the non-significant correlations may be approaching significance. In addition, because so many correlations are being conducted with such a comparatively small sample, it is important to see the exact Spearman Rho value. Statistical tests of correlations establish test only whether there is a correlation, not whether there is not. So, it is highly plausible that there are in fact correlations where you report none but they are small - and possibly clinically insignificant. By providing the Rho values themselves, the reader is able to make a more informed decision about your data.

Response: According to your advice, the exact Spearman Rho value is provided in all cells, and all correlations are shown in Table 1 of the revision.

 

3. The most useful message I get from these data are that some COPD patients report fatigue and pain and some (the majority in your sample) do not. It is certainly untrue to say that pain and fatigue are not experienced in COPD. I think it reasonable from the overspill hypothesis to expect that pain - which often has an inflammatory etiology - is increased in COPD. However, it is also likely that the degree of 'overspill' varies between patients as a function of general health. My guess is that the patients who attend pulmonary rehab and have a generally healthier lifestyle experience less pain because their nonspecific inflammatory markers are lower. After all, fatigue and depression are associated with higher levels of nonspecific inflammatory cytokines You should consider the possibility that the reason for the low levels of pain and fatigue overall in your sample is that the general health of your patients is good due to overall care of the patients, including lifestyle advice and help. You might like to note that there is an increase in pain in severe asthma - a couple of recent papers from different labs have shown the comorbidity of severe asthma and fibromyalgia. So, pain is not unusual in other respiratory conditions, though there is no simple causal relationship. I liked the paper, but please focus on the individual differences between patients a little more.

Response: We are grateful to you for your helpful advice, indicating a high likelihood of an inflammatory etiology, or 'overspill' hypothesis. I agree and find this a fascinating hypothesis and have learned a lot from your comment. Unfortunately, data on nonspecific inflammatory cytokines were not collected in the present study so this additional information is not available for inclusion in the Results section. Therefore, we have inserted one paragraph into the discussion section that deals with the 'overspill' hypothesis. “Why do subjects with COPD experience fatigue or pain? Although an association between fatigue or pain and COPD has been frequently reported in the literature, only a few studies have explored the underlying mechanism of this association. It is considered that COPD is associated with systemic manifestations and comorbidities. One of the most important possible mechanisms is mediated by elevated levels of nonspecific inflammatory cytokines, which can derive from the lung and enter systemic circulation. This 'overspill' hypothesis may include not only comorbidities such as skeletal muscle dysfunction, cardiovascular disease, osteoporosis, and diabetes but also fatigue and pain. The relationship with inflammatory markers requires further study. In addition, from the point of view of the ‘overspill' hypothesis, comorbidities may have been one of the important outcomes. Since “no uncontrolled co-morbidities” was one of the inclusion criteria, most subjects with comorbidities were excluded from the present study. Data on comorbidities should have been collected in a quantitative way using the Charlson comorbidity index and this was a particular limitation of our study. Although it is reported that fibromyalgia should be distinguished from similar symptoms in subjects with severe asthma complaining of pain as well as extra-pulmonary asthma symptoms, it is believed that such patients were not included.” (Lines 271-287).

Author Response File: Author Response.docx

Reviewer 2 Report

This cohort study is well written and addresses some aspects of importance clinically to global assessment of COPD. The flow of the article is satisfactory and the quality of English good. The tables are informative and formatting is adequate. The key area for improvement for me is in the recording and considering of impact of co-morbidities, which are common and may well influence or explain the degree of fatigue and pain. Were co-morbidities collected? If so could they be added to the relevant tables and analysis of the relationship of some of them (or the overall burden via something like Charlson) to the overall levels seen of fatigue and pain. I would certainly favour looking at depression, anxiety, cardiac disease and cancer for instance, as specific concurrent conditions. Finally, there are some COPD questionnaires which include energy levels (eg CAT) and some discussion of the utility of the additional questionnaires studied v specific items in the CAT, or another COPD questionnaire would be helpful.

Author Response

Author's Reply to the Review Report (Reviewer 2)

1. The key area for improvement for me is in the recording and considering of impact of co-morbidities, which are common and may well influence or explain the degree of fatigue and pain. Were co-morbidities collected? If so could they be added to the relevant tables and analysis of the relationship of some of them (or the overall burden via something like Charlson) to the overall levels seen of fatigue and pain. I would certainly favour looking at depression, anxiety, cardiac disease and cancer for instance, as specific concurrent conditions.

Response: We thank you for your comments. We now appreciate that comorbidities should have been collected in a quantitative way using the Charlson comorbidity index and this was a particular limitation of our study. This was partly because, when the study started, we did not fully understand the importance of comorbidities. From the point of view of the 'overspill' hypothesis, comorbidities should have been one of the important outcomes. Since “no uncontrolled co-morbidities” was one of the inclusion criteria, most subjects with comorbidities were excluded from the present study. We have also inserted the following sentences: “In addition, from the point of view of the 'overspill' hypothesis, comorbidities may have been one of the important outcomes. Since “no uncontrolled co-morbidities” was one of the inclusion criteria, most subjects with comorbidities were excluded from the present study. Data on comorbidities should have been collected in a quantitative way using the Charlson comorbidity index and this was a particular limitation of our study. Although it is reported that fibromyalgia should be distinguished from similar symptoms in subjects with severe asthma complaining of pain as well as extra-pulmonary asthma symptoms, it is believed that such patients were not included.” (Lines 279-287).

 

2. Finally, there are some COPD questionnaires which include energy levels (eg CAT) and some discussion of the utility of the additional questionnaires studied v specific items in the CAT, or another COPD questionnaire would be helpful.

Response: We appreciate your interesting advice. However, as far as I know, this approach may be more difficult than first thought. First, since most developers and copyright holders dislike only partial use of their questionnaires, we are reluctant to break up these tools. In the case of the CAT, this was announced on the GSK website although the notification has now been removed. The Chronic Respiratory Disease Questionnaire (CRQ) has a domain of fatigue (not energy).

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

My comments have been adequately addressed in the discussion and response letter.