Extracellular Water Ratio and Phase Angle as Predictors of Exacerbation in Chronic Obstructive Pulmonary Disease

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

.- General comments:

.- General comments:

 

Chronic obstructive pulmonary disease (COPD) is characterized by a high energy metabolism, often leads to malnutrition and is clearly linked to acute exacerbations. This interesting cases-control study investigates the association between malnutrition-related body composition and handgrip strength changes related to exacerbation frequencies in COPD patients.

Material and Methods. Doubts arise, was the sample size estimated? Why in the inclusion criteria you only considered men and those aged 45 or older and not e.g 40 years old as in other studies?

Perhaps it would be appropriate to briefly explain what the phase angle (PhA) is?

Why did you use the NRS-2002 scale and not another? NRS is an inpatient scale and the study sample includes outpatients (n=82). Please, briefly justify.

The subgroups of infrequent and frequent exacerbators are not matched (22 vs 55 y 69 vs 13). Couldn't this circumstance be a bias in itself?

Discussion. It’s a good job. Congrats!

References. This section includes 37 references. It is striking that 18 of them are limited in the introduction section, almost half. In the discussion there are only 16 limited quotes. note that 16 references (43%) without recent ones, this is five years or less from its publication. Consider including any additional ones.

 

Specific comments:

 

Page 1. Highlights:  What are the main findings?

“TBW”, it would be convenient explain this acronim.

 

“Body composition parameters like ECW/TBW and PhA can serve as predictive markers for assessing exacerbation risks”. Given the sample size, this statement seems somewhat pretentious.

Page 7. “Our findings revealed that patients who may benefit from cut-off value point reducing COPD exacerbation”.  Perhaps it would be more correct to express that this study demonstrates that patients who experience fewer exacerbations have a better phase angle (PhA) and ECW/TBW ratio.

Page 8. Line 247. “In this study, with a cut-off value of 4.85°. Why this and not another one?”. In this paragraph the acronym “PhA” is repeated up to seven times. Please, review. On the other hand, perhaps this paragraph would have more place in the introduction section.

Tables and figures. 3 tables and 2 figures are very interesting. Congrats!

Material and Methods. Doubts arise, was the sample size estimated? Why in the inclusion criteria you only considered men and those aged 45 or older and not e.g 40 years old as in other studies?

Perhaps it would be appropriate to briefly explain what the phase angle (PhA) is?

Why did you use the NRS-2002 scale and not another? NRS is an inpatient scale and the study sample includes outpatients (n=82). Please, briefly justify.

The subgroups of infrequent and frequent exacerbators are not matched (22 vs 55 y 69 vs 13). Couldn't this circumstance be a bias in itself?

Discussion. It’s a good job. Congrats!

References. This section includes 37 references. It is striking that 18 of them are limited in the introduction section, almost half. In the discussion there are only 16 limited quotes. note that 16 references (43%) without recent ones, this is five years or less from its publication. Consider including any additional ones.

 Specific comments:

 Page 1. Highlights:  What are the main findings?

“TBW”, it would be convenient explain this acronim.

“Body composition parameters like ECW/TBW and PhA can serve as predictive markers for assessing exacerbation risks”. Given the sample size, this statement seems somewhat pretentious.

Page 7. “Our findings revealed that patients who may benefit from cut-off value point reducing COPD exacerbation”.  Perhaps it would be more correct to express that this study demonstrates that patients who experience fewer exacerbations have a better phase angle (PhA) and ECW/TBW ratio.

Page 8. Line 247. “In this study, with a cut-off value of 4.85°. Why this and not another one?”. In this paragraph the acronym “PhA” is repeated up to seven times. Please, review. On the other hand, perhaps this paragraph would have more place in the introduction section.

Tables and figures. 3 tables and 2 figures are very interesting. Congrats!

Author Response

Response letter to Reviewer,                                   May 28, 2024

 

Dear Reviewer,

Appreciate so much the efforts you have done to help us to improve manuscript ID: arm-3009337 with the title “Extracellular water ratio and phase angle as predictors of exacerbation in chronic obstructive pulmonary disease”. We realize a lot of extraordinary efforts you have done to help us to improve the manuscript. As requested, we re-wrote the manuscript carefully based on the suggestions from the reviewers and the revised parts were red-labeled.

 

The following please see our replies to your comments point by point.

 

Best Regards,

Chih-Yuan Ko Ph. D.

 

Reviewer 1 Comments:

Chronic obstructive pulmonary disease (COPD) is characterized by a high energy metabolism, often leads to malnutrition and is clearly linked to acute exacerbations. This interesting cases-control study investigates the association between malnutrition-related body composition and handgrip strength changes related to exacerbation frequencies in COPD patients.

1. Material and Methods. Doubts arise, was the sample size estimated? Why in the inclusion criteria you only considered men and those aged 45 or older and not e.g 40 years old as in other studies?

Reply:

Thank you for your insightful comments and questions regarding our study. The sample size for our study was estimated based on preliminary data on extracellular water/total body water ratios. This calculation ensured that we had sufficient power to detect significant associations in our analysis.

Regarding the inclusion criteria, we focused on men aged 45 and older because symptomatic COPD is generally diagnosed around the age of 40 to 45 years and beyond. We adhered to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, which recommend considering individuals aged 45 and older for COPD studies. This approach aligns with the typical age of diagnosis and the demographic most affected by the disease.

 

2. Perhaps it would be appropriate to briefly explain what the phase angle (PhA) is?

Reply:

We appreciate your comments. The phase angle (PhA) relevant descriptions have been introduced in the Discussion section (lines 279-285) as “The phase angle (PhA) is derived from electrophysiological data and is not dependent on prediction equation from the BIA machine (Player et al., 2019). A healthy cell membrane acts as a good capacitor, with PhA reflecting the cell membrane's ability to store and delay current flow. Low PhA indicates cell death or compromised membrane permeability, which can negatively impact clinical outcomes. Thus, PhA serves as a marker of cellular health and nutritional status (Uemura et al., 2020). Conditions like sarcopenia and malnutrition are associated with reduced PhA, highlighting its role in indicating the prevalence of these conditions (Player et al., 2019; Di Vincenzo et al., 2021). PhA has been extensively studied in various clinical conditions, including chronic obstructive pulmonary disease (COPD). It provides valuable insights into the body's composition and can serve as a predictive marker for disease exacerbation and prognosis in COPD patients (Kyle et al., 2004; Norman et al., 2012).”

 

References:

Player EL, Morris P, Thomas T, Chan WY, Vyas R, Dutton J, Tang J, Alexandre L, Forbes A. Bioelectrical impedance analysis (BIA)-derived phase angle (PA) is a practical aid to nutritional assessment in hospital in-patients. Clin Nutr. 2019; 38(4):1700-1706.

Uemura K, Doi T, Tsutsumimoto K, Nakakubo S, Kim MJ, Kurita S, Ishii H, Shimada H. Predictivity of bioimpedance phase angle for incident disability in older adults. J Cachexia Sarcopenia Muscle. 2020; 11(1):46-54.

Di Vincenzo O, Marra M, Di Gregorio A, Pasanisi F, Scalfi L. Bioelectrical impedance analysis (BIA) -derived phase angle in sarcopenia: A systematic review. Clin Nutr. 2021; 40(5):3052-3061.

Kyle UG, Bosaeus I, De Lorenzo AD, Deurenberg P, Elia M, Gómez JM, Heitmann BL, Kent-Smith L, Melchior JC, Pirlich M, Scharfetter H, Schols AM, Pichard C; Composition of the ESPEN Working Group. Bioelectrical impedance analysis-part I: review of principles and methods. Clin Nutr. 2004; 23(5):1226-43.

Norman K, Stobäus N, Pirlich M, Bosy-Westphal A. Bioelectrical phase angle and impedance vector analysis--clinical relevance and applicability of impedance parameters. Clin Nutr. 2012; 31(6):854-61.

 

3. Why did you use the NRS-2002 scale and not another? NRS is an inpatient scale and the study sample includes outpatients (n=82). Please, briefly justify.

Reply:

Thank you for your question regarding our choice of the nutritional risk screening 2002 (NRS-2002) scale. We chose the NRS-2002 scale because it is the most commonly used and highly validated nutritional screening tool in China. The NRS-2002 has been shown to possess high reliability and validity across various patient populations, making it an ideal choice for our study (Kondrup et al., 2003).

While the NRS-2002 is indeed widely used in inpatient settings, it is also applicable for outpatient use (Bozzetti et al., 2012). The tool's comprehensive nature allows for effective nutritional risk assessment in both hospitalized patients and those in outpatient settings. This versatility makes it suitable for our study, which includes a significant number of outpatients (n=82).

 

References:

Kondrup J, Allison SP, Elia M, Vellas B, Plauth M; Educational and Clinical Practice Committee, European Society of Parenteral and Enteral Nutrition (ESPEN). ESPEN guidelines for nutrition screening 2002. Clin Nutr. 2003; 22(4):415-21.

Bozzetti F, Mariani L, Lo Vullo S; SCRINIO Working Group; Amerio ML, Biffi R, Caccialanza G, Capuano G, Correja I, Cozzaglio L, Di Leo A, Di Cosmo L, Finocchiaro C, Gavazzi C, Giannoni A, Magnanini P, Mantovani G, Pellegrini M, Rovera L, Sandri G, Tinivella M, Vigevani E. The nutritional risk in oncology: a study of 1,453 cancer outpatients. Support Care Cancer. 2012; 20(8):1919-28. doi: 10.1007/s00520-012-1387-x. Erratum in: Support Care Cancer. 2012; 20(8):1929. Capuano, Giovanni [corrected to Capuano, Giorgio].

 

4. The subgroups of infrequent and frequent exacerbators are not matched (22 vs 55 y 69 vs 13). Couldn't this circumstance be a bias in itself?

Reply:

Thank you for your insightful question regarding the matching of subgroups for infrequent and frequent exacerbators in our study. We acknowledge that the disparity in subgroup size could raise concerns about potential bias. However, it is important to note that such differences do not necessarily introduce bias, as long as appropriate statistical methods are used to adjust for confounding factors and ensure the robustness of the findings.

In our study, we employed multivariate regression analysis to adjust for potential confounders, thereby mitigating the risk of bias due to unequal subgroup sizes. Additionally, previous studies have demonstrated that subgroup size disparity does not inherently introduce bias if the data is appropriately handled and analyzed (Austin, 2008; Rothman et al, 2008).

To further support our approach, we reference literature that discusses the impact of sample size disparities and the effectiveness of statistical adjustments in maintaining the validity of the results (Austin, 2008; Imai et al, 2008). These studies highlight that, with careful statistical control, the reliability of the findings can be preserved despite subgroup size differences.

 

References:

Austin, P. C. A critical appraisal of propensity-score matching in the medical literature between 1996 and 2003. Statistics in Medicine 2008; 27(12): 2037-2049.

Rothman, K. J., Greenland, S., & Lash, T. L. Modern Epidemiology. Lippincott Williams & Wilkins 2008.

Imai, K., King, G., & Stuart, E. A. Misunderstandings between experimentalists and observationalists about causal inference. Journal of the Royal Statistical Society: Series A (Statistics in Society) 2008; 171(2): 481-502.

 

5. It’s a good job. Congrats!

Reply:

Thank you very much for your kind words and positive feedback on our discussion section.

 

6. This section includes 37 references. It is striking that 18 of them are limited in the introduction section, almost half. In the discussion there are only 16 limited quotes. note that 16 references (43%) without recent ones, this is five years or less from its publication. Consider including any additional ones.

Reply:

Thank you for your valuable feedback regarding the references in our manuscript. We acknowledge your concern about the distribution and recency of the references. To address this, we will revise the discussion section to include more citations from recent literature published within the last five years, in accordance with your suggestions. This will ensure that our manuscript reflects the most current research and strengthens the relevance of our findings.

 

7. Page 1. Highlights: What are the main findings?

Reply:

Thank you for your question regarding the main findings highlighted on page 1. Here are the main findings of our study and the relevant descriptions have been addressed in lines 16-20: (1) Significant differences in body composition parameters, including extracellular water ratio (ECW/TBW) and phase angle (PhA), were observed between frequent and infrequent exacerbators. (2) Increased exacerbation frequencies in COPD patients correlate with higher extracellular water ratios and lower phase angles.

 

8. “TBW”, it would be convenient explain this acronim.

Reply:

The total body water (TBW) relevant descriptions have been addressed in the Discussion section (lines 267-274) as “TBW refers to the overall volume of water contained within an individual's body, comprising approximately 60% of an adult's body weight. It is a fundamental parameter in body composition analysis, divided into intracellular water (ICW) and extracellular water (ECW) compartments. Accurate TBW measurements are essential for assessing hydration status, nutritional status, and overall health, particularly in clinical settings where precise fluid balance evaluation is critical (Kyle et al., 2004). Understanding and measuring TBW and its components (ICW and ECW) are crucial in both clinical and research contexts (Horino et al., 2023; Wang et al., 2023).”

 

References:

Kyle UG, Bosaeus I, De Lorenzo AD, Deurenberg P, Elia M, Gómez JM, Heitmann BL, Kent-Smith L, Melchior JC, Pirlich M, Scharfetter H, Schols AM, Pichard C; Composition of the ESPEN Working Group. Bioelectrical impedance analysis-part I: review of principles and methods. Clin Nutr. 2004; 23(5):1226-43.

Horino T, Tokunaga R, Miyamoto Y, Akiyama T, Daitoku N, Sakamoto Y, Ohuchi M, Ogawa K, Yoshida N, Baba H. Extracellular water to total body water ratio, a novel predictor of recurrence in patients with colorectal cancer. Ann Gastroenterol Surg. 2023; 8(1):98-106.

Wang X, Liang Q, Li Z, Li F. Body Composition and COPD: A New Perspective. Int J Chron Obstruct Pulmon Dis. 2023; 18:79-97.

 

9. “Body composition parameters like ECW/TBW and PhA can serve as predictive markers for assessing exacerbation risks”. Given the sample size, this statement seems somewhat pretentious.

Reply:

We understand the concern about the robustness of our findings given the sample size. Therefore, we would like to revise our statement to reflect a more cautious presentation as “Body composition parameters such as ECW/TBW and PhA might serve as predictive markers for exacerbation risks in COPD patients, aiding in targeted clinical interventions. However, larger studies are needed to confirm these findings and enhance their clinical relevance” in lines 22-24.

 

10. Page 7. “Our findings revealed that patients who may benefit from cut-off value point reducing COPD exacerbation”. Perhaps it would be more correct to express that this study demonstrates that patients who experience fewer exacerbations have a better phase angle (PhA) and ECW/TBW ratio.

Reply:

Thank you for your constructive feedback regarding the expression of our findings. The relevant descriptions have been addressed and revised in the Discussion section (lines 237-238).

 

11. Page 8. Line 247. “In this study, with a cut-off value of 4.85°. Why this and not another one?”. In this paragraph the acronym “PhA” is repeated up to seven times. Please, review. On the other hand, perhaps this paragraph would have more place in the introduction section.

Reply:

We appreciate your constructive suggestions. The cut-off value of 4.85° for the PhA was determined based on our experimental results. Our analysis indicated that this threshold effectively distinguished patients with different risks of COPD exacerbations. Patients with a PhA below 4.85° exhibited a higher frequency of exacerbations compared to those with a higher PhA, indicating that this cut-off value is significant in identifying at-risk patients.

For the sake of coherence and readability, we have retained the detailed explanation of PhA within the Discussion section. This ensures that the context and significance of PhA are thoroughly understood in relation to our findings. We have also rewritten the paragraph in English (lines 277-285).

 

12. Tables and figures. 3 tables and 2 figures are very interesting. Congrats!

Reply:

We greatly appreciate your recognition and support, which encourages us to continue our efforts in presenting clear and impactful data in our research.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

I have read with interest the study by Xie et al concerning the association of extracellular water ratio and phase angle with the risk of exacerbation in COPD patients. Accumulating data suggest that BIA may represent a useful tool for the investigation of body composition in COPD patients. Furthermore, it is acknowledged that muscle dysfunction is a significant component of the multi-systemic syndrome that accompanies COPD. Handgrip strength is a feasible measure of muscle function in these patients that can be used in various clinical settings. The present study is well-written and comprehensive. It provides interesting data concerning not only the body composition of COPD patients, but also their predictive ability for COPD exacerbations. I have no major comments

Author Response

Thank you for your positive feedback on our study.

Author Response File: Author Response.pdf