The Effect of Heated, Humidified High‐Flow Air in COPD Patients With Chronic Bronchitis

TL;DR

A small study found that using heated, humidified high-flow air at night did not significantly improve outcomes for COPD patients with chronic bronchitis.

Contribution

This is the first pilot trial to assess the short-term effects of nocturnal HHHFA in COPD patients with chronic bronchitis.

Findings

No significant differences were observed between HHHFA and usual care in clinical or imaging outcomes.

The study was likely underpowered due to small sample size and recruitment challenges.

Baseline characteristics showed higher BMI and lower emphysema percentage in the intervention group.

Abstract

Heated, humidified high‐flow air (HHHFA) has been shown to reduce exacerbations in patients with COPD or bronchiectasis with significant sputum production. This pilot study evaluated the short‐term effects of nocturnal HHHFA in COPD patients with chronic bronchitis.

This was a prospective, single‐center, open‐label, randomized, placebo‐controlled trial. Participants with COPD, chronic bronchitis, and ≥ 2 exacerbations in the prior year were randomized to either nocturnal HHHFA or usual care. Assessments included sleep quality, dyspnea, quality of life, cough, lung function, imaging, and exercise capacity at baseline and 6 weeks.

Of 11 eligible participants, seven completed the study (four intervention, three control). Baseline characteristics were generally similar, though the intervention group had a higher BMI and a lower emphysema percentage. No statistically significant differences were observed between groups in primary or secondary outcomes.

Nocturnal HHHFA over 6 weeks did not improve clinical or imaging outcomes in this small cohort of COPD patients with chronic bronchitis. The study was likely underpowered due to recruitment challenges. Larger trials are needed to assess the potential of HHHFA in this population.

ClinicalTrials.gov identifier: NCT03959982

Tables

Table 1. Baseline characteristics.

	Control	HHHFA	p value
n	3	4
Age	61.00 [57.50, 70.00]	58.00 [56.50, 63.00]	0.72
Female	3 (100.0%)	2 (50.0%)	0.55
Race	3 (100.0%)	4 (100.0%)	NA
Body mass index, Kg/m2	24.18 [23.98, 25.57]	32.94 [29.61, 36.56]	0.034
Pack years	7.50 [4.75, 10.12]	12.25 [3.39, 27.88]	0.72
Current smoking	1 (33.3%)	3 (75.0)	0.74
Asthma	2 (66.7)	3 (75.0)	1
PSQI	11.00 [8.50, 11.00]	17.00 [15.25, 17.25]	0.15
MMRC	1.00 [0.50, 2.00]	2.50 [2.00, 3.25]	0.21
SGRQ	59.99 [48.17, 68.81]	70.81 [66.41, 72.67]	0.72
CAT	35.00 [32.00, 36.50]	32.00 [31.00, 33.00]	0.48
CASA‐Q cough	83.00 [66.50, 87.50]	66.50 [56.00, 81.25]	0.86
CASA‐Q impact	63.00 [47.00, 73.00]	62.50 [49.25, 77.25]	0.72
CASA‐Q sputum	75.00 [62.50, 83.50]	67.00 [67.00, 73.25]	0.86
6‐min walk distance, m	373.4 [365.0, 376.4]	245.9 [142.8, 340.2]	0.034
FEV1, L	1.14 [1.03, 1.77]	1.47 [1.38, 1.58]	0.72
FEV1% predicted	55.49 [46.02, 63.56]	54.64 [45.27, 61.56]	1
FVC, L	3.04 [2.87, 3.52]	3.12 [2.62, 3.79]	1
FVC % predicted	94.41 [94.05, 96.92]	91.18 [68.32, 113.59]	1
FEV1/FVC	42.00 [36.00, 51.00]	41.50 [39.50, 49.75]	0.72
RV, L	3.96 [3.02, 4.11]	3.41 [3.16, 3.50]	0.48
TLC, L	5.68 [5.25, 6.08]	5.38 [4.62, 6.32]	0.72
RV/TLC	65.55 [51.10, 73.80]	54.90 [52.49, 63.15]	1
% Emphysema	14.57 [10.29, 14.86]	2.80 [2.13, 3.37]	0.034
% Gas Trapping	56.81 [33.76, 59.22]	21.28 [17.45, 24.47]	0.48
% DPMFSAD	23.99 [14.92, 29.01]	6.33 [4.08, 7.59]	0.1657
Pi10, mm	3.96 [3.95, 3.98]	3.95 [3.94, 3.95]	0.48

Table 2. Association of heated, humidified high‐flow air with longitudinal outcome.

Change between baseline and 6-week follow-up visit	Coef (95% CI)	p value	Adjusted p value
PSQI∗	2.19 (−7.945, 12.3)	0.58	NA
MMRC	1.04 (0.03, 2.06)	0.05	0.32
CAT	5.15 (−3.01, 13.32)	0.16	0.54
SGRQ	14.83 (0.41, 29.25)	0.05	0.65
Casa‐Q cough domain	5.28 (−30.83, 41.39)	0.71	1.00
Casa‐Q impact	1.84 (−36.14, 39.82)	0.90	0.97
Casa‐Q sputum	−8.22 (−32.71, 16.28)	0.40	0.81
6‐min walk distance, m	−41.72 (−163.57, 80.13)	0.40	0.92
FEV1, mL	−54.49 (−681.4, 572.4)	0.82	0.96
RV, L	60.4 (−577.2, 698.1)	0.81	1.00
TLC, L	70.6 (−494.3, 635.5)	0.75	1.00
% Emphysema	−3.66 (−10.32, 2.99)	0.20	0.56
% Gas trapping	1.44 (−41.39, 44.27)	0.93	0.93
DPMFSAD	−3.75 (−21.11, 13.60)	0.58	1.00
Pi10, m	0.07 (−0.03, 0.17)	0.11	0.52

Full text

1. Introduction

Chronic obstructive pulmonary disease (COPD) is marked by exacerbations that increase in frequency with disease severity and often lead to hospitalizations—the primary driver of COPD‐related healthcare costs and a major burden for patients and families [1]. Chronic bronchitis, defined by persistent cough and sputum production for at least 3 months in 2 consecutive years, doubles the risk of exacerbations and hospitalizations [2]. It is also linked to worse dyspnea, reduced quality of life and sleep, and impaired exercise capacity due to air trapping and hyperinflation [2]. Despite its impact, treatment options beyond standard inhaled therapies remain limited.

Heated, humidified high‐flow air (HHHFA) has been shown to reduce exacerbations in patients with COPD or bronchiectasis with significant sputum production [3]. This pilot study evaluates the effect of nocturnal HHHFA in COPD patients with chronic bronchitis, focusing on short‐term outcomes including respiratory symptoms, quality of life, sleep, lung function, imaging features, and exercise capacity.

2. Methods

This was a prospective, single‐center, open‐label, randomized, placebo‐controlled trial. The study protocol was approved by the institutional review board (IRB #201905817;) Participants were eligible if they had COPD, defined as a post‐bronchodilator FEV₁/FVC ratio < 0.7 and a smoking history of ≥ 10 pack‐years, with a post‐bronchodilator FEV₁% predicted < 70%, chronic bronchitis, and ≥ 2 exacerbations in the previous year. Exclusion criteria included confirmed or suspected sleep apnea requiring positive airway pressure therapy, continuous oxygen supplementation, recent (< 2 weeks) respiratory infection, COPD exacerbation, acute bronchitis requiring antibiotics and systemic corticosteroids, upper airway or chest surgery within the past 6 months, pregnancy, and any condition that prevented the participant from wearing the HHHFA nasal cannula or completing study procedures. Participant recruitment began in February 2021 and was discontinued in January 2023 due to under recruitment. Eligible participants provided written informed consent and were then randomized to either the HHHFA intervention arm or the usual care arm using sealed envelopes. At baseline, participants completed the following assessments: Pittsburgh Sleep Quality Index (PSQI) [4], Medical Research Council (MRC) dyspnea scale [5], St. George′s Respiratory Questionnaire (SGRQ) [6–8], COPD assessment test (CAT) [9], and cough and sputum assessment questionnaire (CASA‐Q) [10]. They also underwent post‐bronchodilator spirometry, a 6‐minute walk test, and inspiratory and expiratory chest CT scans. These procedures were repeated at the 6‐week follow‐up visit.

2.1. Intervention

Participants assigned to the HHHFA arm trialed the device during the initial visit. Temperature and flow settings were adjusted for comfort within the allowable range of 32°C–37°C and 20–35 L/min, as previously described. Participants were instructed to use the device for ≥ 4 h during sleep. Compliance was verified using the device′s usage log.

2.2. Definitions

Functional small airway disease was quantified using the disease probability method (DPM^FSAD^) [11]. Changes in PSQI, mMRC, SGRQ, CAT, CASA‐Q scores, 6‐minute walk distance, FEV₁, RV, TLV, RV/TLC, % emphysema, % gas trapping, % DPM^FSAD^, and Pi10 (mm) were calculated as the difference between baseline and the 6‐week follow‐up visit. Positive values indicated higher measurements at follow‐up.

2.3. Statistical Analysis

Participants were grouped based on intervention status. Baseline characteristics were compared using the Wilcoxon rank‐sum test for continuous variables and Fisher′s exact test for categorical variables. Due to the small sample size and imbalance between groups despite randomization, we used linear regression models to assess associations between the intervention and primary/secondary outcomes, adjusting for baseline values (e.g., baseline PSQI). For secondary outcomes, we applied the Benjamini–Hochberg correction with a false discovery rate threshold of < 0.05.

3. Results

Of the 11 patients who met the eligibility criteria, two withdrew from the study. One withdrew prior to randomization due to a new diagnosis of lung cancer, and one participant randomized to the intervention arm dropped out before completing the study procedures. Among the remaining seven participants, four were assigned to the intervention group and three to the control group. Baseline characteristics were generally comparable (Table 1), except for two notable differences: participants in the intervention group had a significantly higher body mass index (BMI: 32.94 [interquartile interval (IQI): 29.61, 36.56]) compared with those in the control group (24.18 [IQI: 23.98, 25.57]; p = 0.034), and a lower percentage of emphysema (2.80% [IQI: 2.13, 3.37] vs. 14.57% [IQI: 10.29, 14.86]; p = <0.034). The primary outcome was not achieved, and none of the secondary outcomes showed statistically significant differences between groups (Table 2).

4. Discussion

In this single‐center study, we found that nocturnal use of HHHFA over a 6‐week period in patients with COPD and chronic bronchitis was not associated with improvements in sleep quality, dyspnea, cough, health‐related quality of life, exercise capacity, or CT‐based features of obstructive lung disease. These findings are likely attributable to the study being underpowered.

HHHFA is a well‐established treatment for acute hypoxemic respiratory failure [12]. More recently, it has demonstrated benefits in acute hypercapnic respiratory failure due to COPD exacerbations [13]. In patients with chronic hypercapnic respiratory failure secondary to COPD, HHHFA has been shown to reduce exacerbations and improve health‐related quality of life [14–16]. Additionally, in patients with COPD or bronchiectasis who experience a significant burden of chronic bronchitis (defined as ≥ 5 mL of daily sputum production), even short daily use of HHHFA (2 h) has been shown to reduce exacerbations and improve lung function [3].

In our study, however, no significant associations were observed—likely due to limited statistical power. Recruitment was particularly challenging, as the study was conducted during the COVID‐19 pandemic, which not only disrupted clinical research operations but also disproportionately affected patients with COPD [17–20]. These factors likely contributed to the difficulty in identifying and enrolling eligible participants and underscored the need for broader inclusion criteria in future trials. In addition, the strict inclusion and exclusion criteria—such as excluding patients on continuous oxygen therapy or those with sleep apnea—made enrollment particularly challenging. These limitations were compounded by the inherent difficulties of recruiting patients for home‐based respiratory device studies, where adherence to study protocols is often problematic. A recent study involving patients with hypercapnic respiratory failure due to COPD, recruited after hospital discharge, encountered similar recruitment barriers. Notably, patients assigned to HHHFA experienced reductions in nocturnal transcutaneous CO_2_ (PtcCO_2_) levels and improvements in health‐related quality of life [21]. A feasibility study similar to ours, which recruited patients upon discharge following a COPD exacerbation, showed trends toward improvement in clinical outcomes [22].

In summary, nocturnal HHHFA use over a 6‐week period in patients with COPD and chronic bronchitis did not improve sleep quality or other clinical outcomes in our study, which was likely underpowered. Future studies should target this population with larger sample sizes and broader inclusion criteria to better evaluate the potential of HHHFA in reducing the burden of COPD exacerbations.

Disclosure

VIDA, Astra Zeneca, GSK, and Fisher and Paykel Healthcare had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. They had no impact on the outcome of the clinical reports collection. Spyridon Fortis had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflicts of Interest

S.F. is supported by the Office of Rural Health and has served as a consultant for the Society of Hospital Medicine (SHM), and has stock options with ROMTech. E.A.H. is a founder and shareholder of VIDA Diagnostics. A.P.C. has served as a consultant for VIDA, Astra Zeneca, and GSK.

Author Contributions

Study concept: S.F., E.A.H., and A.P.C. Study design: S.F., E.A.H., and A.P.C. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: S.F. Critical revision of the manuscript for important intellectual content: all authors.

Funding

This study was supported by the ATS Foundation/Fisher and Paykel Healthcare Ltd. Research Award (ATS grant # RP‐2018‐05).

General Statement

Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States Government and of the National Institutes of Health′s National Center for Advancing Translational Sciences.