Small Airways Dysfunction and Lung Hyperinflation in Long COVID-19 Patients as Potential Mechanisms of Persistent Dyspnoea
, Nikolaos Chynkiamis 1,2,*,†, Christina Anagnostopoulou 1,†, Christiana Lekka 1, Stavrina Zaneli 1, Nektarios Anagnostopoulos 1, Nikoleta Rovina 3, Christos F. Kampolis 4, Andriana I. Papaioannou 1, Georgios Kaltsakas 1,5,6, Ioannis Vogiatzis 1,7, Grigorios Stratakos 1, Petros Bakakos 1 and Nikolaos Koulouris 1
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsDear Editor,
The manuscript entitle “Small airways dysfunction and lung hyperinflation in long COVID-19 patients as potential mechanisms of persistent dyspnea “ (arm-3122293) was reviewed carefully. This study has focused to some symptoms of long COVID such as dysfunction and lung hyperinflation. The English level of the manuscript is acceptable, while there are some minor notes that is recommended to be fixed:
- Does pulmonary thromboembolism consider as a symptom of long COVID? Please clarify more in the introduction. (Ref: PMID: 36934279)
Author Response
Dear Editor,
The manuscript entitle “Small airways dysfunction and lung hyperinflation in long COVID-19 patients as potential mechanisms of persistent dyspnoea” (arm-3122293) was reviewed carefully. This study has focused to some symptoms of long COVID such as dysfunction and lung hyperinflation. The English level of the manuscript is acceptable, while there are some minor notes that is recommended to be fixed:
Comment 1
Does pulmonary thromboembolism consider as a symptom of long COVID? Please clarify more in the introduction. (Ref: PMID: 36934279)
Reply
We thank the reviewer for his/her important remark. Before diagnosing a patient with long COVID-19, it is important to exclude all the other possible causes of persistent dyspnoea. It is indeed observed that some patients recovering from SARS-CoV-2 infection present with prolonged breathlessness due to pulmonary thromboembolism. However, according to the NICE definition of long COVID-19, pulmonary thromboembolism is not considered a symptom of long COVID-19. We have clarified that in the second paragraph of the introduction on page 2, as follows:
“The most common symptoms of long COVID-19 include fatigue, dyspnoea, brain fog and post-exertional malaise. Although SARS-CoV-2 can cause thromboembolic episodes during the acute phase of the infection and the development of recurrent venous thromboembolism after hospital discharge has also been described, pulmonary thromboembolism is not included in the definition of long COVID-19.”
Reviewer 2 Report
Comments and Suggestions for AuthorsI am thankful to the journal for providing me the opportunity to review the article. Here are my few concerns regarding manuscript. Overall, the research article presents a valued contribution to the field of COVID-19 research. Addressing the suggested points for improvement would further strengthen the significance and impact of the study.
1. The study lacks a comprehensive explanation of the specific experimental techniques employed to evaluate small airways function and lung hyperinflation. For example, the authors fail to mention the specific criteria utilized to determine abnormal values for the various pulmonary function parameters measured. Additionally, providing more information regarding the standardization and reproducibility of the single-breath nitrogen washout technique showed clarity and usefulness.
2. The introduction section of the study lacks a comprehensive review of the existing literature on small airways dysfunction and lung hyperinflation in post-COVID-19 patients. The authors fail to adequately explain the importance of evaluating these parameters and their association with persistent dyspnea. To strength the rationale for the study, a more thorough discussion of the pathophysiological mechanisms underlying these respiratory complications is needed.
3. This study doesn’t discuss the possible effect of variables like the severity of the initial COVID-19 infection, the existence of comorbidities, and the use of corticosteroids or other drugs on the observed abnormalities in respiratory function. It is important to consider these factors in the analysis as they could significantly influence the study outcomes.
4. This study conducted a cross-sectional evaluation of respiratory function in patient with long COVID-19 patients, specifically focusing on a single assessment conducted several months after hospital discharge. However, in order to gain a deeper understanding of the natural progression of respiratory complications, it would be beneficial to have longitudinal data on the development of small airways dysfunction and lung hyperinflation over.
5. The finding of the study may have limited generalizability due to the relatively small sample size of 33 patients. To confirm the prevalence of this study, a larger, multi-center study would be necessary.
6. The clinical implication of the study finding on small airways dysfunction and lung hyperinflation in long COVID-19 patients are not clearly discussed.
7. The authors should provide more insight into how these findings may affect patient management and the need for targeted interventions.
Comments on the Quality of English Language
Minor editing of English language required
Author Response
Reviewer 2
I am thankful to the journal for providing me the opportunity to review the article. Here are my few concerns regarding manuscript. Overall, the research article presents a valued contribution to the field of COVID-19 research. Addressing the suggested points for improvement would further strengthen the significance and impact of the study.
Reply
We thank the reviewer for the positive feedback. We have read carefully and addressed all comments.
Comment 1
The study lacks a comprehensive explanation of the specific experimental techniques employed to evaluate small airways function and lung hyperinflation. For example, the authors fail to mention the specific criteria utilized to determine abnormal values for the various pulmonary function parameters measured. Additionally, providing more information regarding the standardization and reproducibility of the single-breath nitrogen washout technique showed clarity and usefulness.
Reply
We thank the reviewer for his/her comment. Thus, we included this information under sub-section 2.2 on page 3 as follows:
“Values <80% predicted for spirometric parameters and diffusion capacity are considered abnormal. In addition, values <80% and >120% predicted are considered abnormal for static lung volumes.”
Regarding the definition of lung hyperinflation, we stated in the original manuscript at the end of sub-section 2.2 on page 3 that RV/TLC ≥40% denotes static lung hyperinflation, as follows:
“Static lung hyperinflation was defined as RV/TLC ≥40%.”
Values >120% predicted for closing volume and closing capacity are considered abnormal. Regarding the importance of the single breath nitrogen washout technique in evaluating small airways function, we have underscored in the manuscript that it is the only reliable method to directly measure closing volume and closing capacity and assess ventilation heterogeneity via the slope of phase III. We have clarified that in the methods section under the 2.3 sub-section on page 3, as follows:
“2.3. Single-breath N2 washout technique
The single-breath N2 washout technique was used to assess small airways dysfunction. After expiration to residual volume, patients performed a slow maximal inspiration followed by a slow (~ 0.5 l/s) expiratory manoeuvre. Patients continued to expire until the inflection point on the simultaneous record of fractional expired N2 concentration (FEN2) vs expired volume was reached. By analysing the inflection point, values for closing volume (CV) and closing capacity (CC) were obtained. Open capacity was defined as the volume between total lung capacity (TLC) and the inflection point [21]. The best-fit line through phase III of the FEN2 (%) volume curve (ΔΝ2/ΔL) was used to figure the slope of phase III (SIII). The mean of minimum two acceptable tracings was described as the slope of the alveolar gas plateau during phase III. Values >120% predicted for closing capacity and closing volume were considered abnormal.”
Many studies have assessed the utilization of the single breath washout technique in COPD patients for the detection of small airways disease, confirming the feasibility and reproducibility of this diagnostic technique. We have included this in the introduction section, on pages 2 and 3 as follows:
“It is also a feasible and reproducible method for evaluating small airways disease as it is observed in COPD patients.”
Comment 2
The introduction section of the study lacks a comprehensive review of the existing literature on small airways dysfunction and lung hyperinflation in post-COVID-19 patients. The authors fail to adequately explain the importance of evaluating these parameters and their association with persistent dyspnoea. To strength the rationale for the study, a more thorough discussion of the pathophysiological mechanisms underlying these respiratory complications is needed.
Reply
We thank the reviewer for his/her comment. We have now included the following paragraph in the introduction section on page 2, as follows:
“SARS-CoV-2 viral particles were found by electron microscopy to be deposited in the distal airway mucosal epithelia. This could lead to inflammation of the bronchioles, reduction in their luminal diameter and bronchiolar hyper-responsiveness. The formation of mucosal plugs and bronchial damage in the distal parts of the small airways may result in small airways disease. The evaluation of small airways function is clinically important as it could explain the persistent dyspnoea which is related to decreased exercise capacity in COVID-19 survivors regardless of comorbidities, BMI, smoking status and time since the COVID-19 diagnosis.”
Comment 3
This study doesn’t discuss the possible effect of variables like the severity of the initial COVID-19 infection, the existence of comorbidities, and the use of corticosteroids or other drugs on the observed abnormalities in respiratory function. It is important to consider these factors in the analysis as they could significantly influence the study outcomes.
Reply
We thank the reviewer for his/her comment. All patients included in the analysis were hospitalized for moderate to severe COVID-19 with no major cardiac, respiratory or neuromuscular comorbidities. Moreover, during the acute phase of the disease, all patients received antiviral treatment (IV remdesivir for 5 days) and some of them low dose of corticosteroids (IV dexamethasone 6mg for 5 days), which we believe, is unlikely to affect the outcomes of our study. Accordingly, we have added the following statement in the results section on page 4.
“All patients included in the analysis were hospitalised for moderate to severe COVID-19 but without requiring ICU admission. During the acute phase of the disease, all patients received antiviral treatment, and few patients received low dose of corticosteroids. No cardiac, respiratory or neuromuscular comorbidities, which could affect respiratory function, were reported.”
Comment 4
This study conducted a cross-sectional evaluation of respiratory function in patient with long COVID-19 patients, specifically focusing on a single assessment conducted several months after hospital discharge. However, in order to gain a deeper understanding of the natural progression of respiratory complications, it would be beneficial to have longitudinal data on the development of small airways dysfunction and lung hyperinflation over.
Reply
We thank the reviewer for his/her comment. Unfortunately, we do not have longitudinal data on these patients. We have addressed this issue in the limitations section on page 7 as follows:
“Another limitation of the present study is that no follow-up visits were performed and thus, detecting any potential changes in small airways dysfunction, lung hyperinflation and post COVID-19 breathlessness over time was not possible.”
Comment 5
The finding of the study may have limited generalizability due to the relatively small sample size of 33 patients. To confirm the prevalence of this study, a larger, multi-centre study would be necessary.
Reply
We thank the reviewer for his/her comment. We have included in the limitations section on page 7 the following statement:
“Due to the small sample size, our study has limited generalizability and subgroup analyses were not possible. Furthermore, the effects of different treatments for COVID-19 on small airways were not evaluated in the present study and thus, still remain unknown.”
Comment 6
The clinical implication of the study finding on small airways dysfunction and lung hyperinflation in long COVID-19 patients are not clearly discussed.
Reply
We thank the reviewer for his/her comment. We have now included the following statement in the clinical implication section on page 7:
“It is well documented, that small airways disease is associated with worse spirometry results, poorer health status and quality of life in patients with COPD, making the small airways an important treatment target.”
Comment 7
The authors should provide more insight into how these findings may affect patient management and the need for targeted interventions.
Reply
We thank the reviewer for his/her comment. We have now added the following paragraph in the clinical implications section on page 7:
“Although long COVID-19 patients often present with small airways disease and lung hyperinflation, which are associated with persistent dyspnoea and decreased exercise capacity, little is known about the management of these patients. It is well documented, that small airways disease is associated with worse spirometry results, poorer health status and quality of life in patients with COPD, making the small airways an important treatment target. The use of inhaled long-acting bronchodilators or oral and/or inhaled corticosteroids three months after COVID-19 improves quality of life 15 months following the acute phase of the disease. Thus, it is possible that administering bronchodilation treatment for the management of patients with long COVID-19 and small airways dysfunction might be beneficial. Nevertheless, more studies are required to establish the beneficial effect of bronchodilation administration in these patients.”
