To the Editor:
We have read with great interest the article by Nagata and colleagues (1) published in this issue of the Journal, “Home High-Flow Nasal Cannula Oxygen Therapy for Stable Hypercapnic COPD: A Randomized Trial,” which provided positive results for long-term high-flow nasal cannula oxygen therapy (HFNC) in reducing the risk of moderate/severe exacerbations in patients with stable hypercapnia and chronic obstructive pulmonary disease (COPD). We congratulate Nagata and colleagues for this excellent work that provides more choices for this population. Compared with previously published studies, several advancements, such as controlling the adherence to HFNC and recruiting only patients with hypercapnia, have been made in their work. Nevertheless, the study has some flaws that deserve more discussion.
First, we address the inclusion criteria. This study recruited patients with COPD with PaCO2 > 45 mm Hg; the final mean value was 50 mm Hg, which is relatively lower (around 10 mm Hg) than many past studies (2, 3) assessing the efficacy of noninvasive ventilation for this population, indicating that the included patients presented a lower severity of disease. In addition, HFNC presented a weak performance in lowering the PaCO2. Thus, the conclusion should be extrapolated with caution to those patients with higher PaCO2 to avoid delaying the initiation of noninvasive ventilation for this population.
Moreover, long-acting beta agonist (LABA) and long-acting muscarinic agent (LAMA) were prescribed more frequently in the HFNC/LTOT group and may play a role in reducing the risk of exacerbations. In addition, the long-term oxygen therapy (LTOT) group showed a higher rate of inhaled corticosteroids (ICS) use, suggesting the presence of eosinophilic inflammation in this group, which indicated a higher risk of future exacerbations (4).
Second, patients in the HFNC/LTOT group showed a lower PaO2 at baseline but a higher PaO2 at the 12-month visit, indicating that HFNC exerted more impact on the improvement of PaO2 than PaCO2. It is reasonable to attribute the benefit of HFNC to providing more adequate oxygen therapy. Moreover, the published data did not display the adherence to conventional oxygen therapy, and we are concerned that inadequate oxygen therapy in the LTOT group may increase the difference between these two groups.
Third, the main outcome of exacerbations relied highly on patient dairies, and the sham device was not blinded for patients. A lower level of self-assessment may exist for patients in the control group, which may result in misdiagnosis of exacerbations for daily fluctuation of symptoms. The limitations of the original data may not be compensated for by inviting a third blind team to complete the final diagnosis.
Moreover, we noticed that a few subjects reported more than 10 counts, and even 18 counts, of exacerbation in the LTOT group. In the situation of a relatively small sample size and exacerbation counts, these patients provided close to one-third of the total number of exacerbations in the control group. Although the investigators included patients with at least one moderate/severe exacerbation in the past year before enrollment to assure a high risk of future exacerbation, hospitalizations due to severe exacerbation may predict worse outcomes than a moderate exacerbation, and frequent exacerbations in the past year may contribute to more exacerbations in the future than those who reported only one or two exacerbations in the past year (5). Therefore, the number and the severity of exacerbations in the past year should also be listed as a potential confounding factor, and it is necessary to confirm the presence of other potential lung diseases, such as bronchiectasis, because the latter may contribute to a great number of exacerbations (6).
In conclusion, we believe that future studies are important to evaluate the efficacy of HFNC in patients with a higher degree of hypercapnia, with better control of enrollment criteria.
Acknowledgments
Acknowledgment
We thank Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the English text of a draft of this manuscript.
Footnotes
Supported by Basic research program of Guangzhou grant/award number 202102010224; Clinical Transformation program of the First Affiliated Hospital of Guangzhou Medical University grant/award numbers ZH201802 and ZH201914; High‐level university program of Guangzhou Medical University grant/award number 2017(160); and Opening Project of State Key Laboratory of Respiratory Disease grant/award numbers SKLRD‐0P‐202115 and SKLRD-Z-202203.
Originally Published in Press as DOI: 10.1164/rccm.202210-1877LE on November 8, 2022
Author disclosures are available with the text of this letter at www.atsjournals.org.
References
- 1. Nagata K, Horie T, Chohnabayashi N, Jinta T, Tsugitomi R, Shiraki A, et al. FLOCOP study investigators Home high-flow nasal cannula oxygen therapy for stable hypercapnic COPD: a randomized trial. Am J Respir Crit Care Med . 2022;206:1326–1335. doi: 10.1164/rccm.202201-0199OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Murphy PB, Rehal S, Arbane G, Bourke S, Calverley PMA, Crook AM, et al. Effect of home noninvasive ventilation with oxygen therapy vs oxygen therapy alone on hospital readmission or death after an acute COPD exacerbation: a randomized clinical trial. JAMA . 2017;317:2177–2186. doi: 10.1001/jama.2017.4451. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Köhnlein T, Windisch W, Köhler D, Drabik A, Geiseler J, Hartl S, et al. Non-invasive positive pressure ventilation for the treatment of severe stable chronic obstructive pulmonary disease: a prospective, multicentre, randomised, controlled clinical trial. Lancet Respir Med . 2014;2:698–705. doi: 10.1016/S2213-2600(14)70153-5. [DOI] [PubMed] [Google Scholar]
- 4. Vedel-Krogh S, Nielsen S-F, Lange P, Vestbo J, Nordestgaard BG. Blood eosinophils and exacerbations in chronic obstructive pulmonary disease: the Copenhagen General Population Study. Am J Respir Crit Care Med . 2016;193:965–974. doi: 10.1164/rccm.201509-1869OC. [DOI] [PubMed] [Google Scholar]
- 5. Husebø G-R, Bakke P-S, Aanerud M, Hardie JA, Ueland T, Grønseth R, et al. Predictors of exacerbations in chronic obstructive pulmonary disease--results from the Bergen COPD cohort study. PLoS One . 2014;9:e109721. doi: 10.1371/journal.pone.0109721. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Martínez-García M-A, de la Rosa Carrillo D, Soler-Cataluña JJ, Donat-Sanz Y, Serra PC, Lerma MA, et al. Prognostic value of bronchiectasis in patients with moderate-to-severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med . 2013;187:823–831. doi: 10.1164/rccm.201208-1518OC. [DOI] [PubMed] [Google Scholar]