Interstitial lung diseases (ILDs) are commonly characterized by a progressive decline in pulmonary function leading to the development of hypoxemia, initially evident during exertion and, in advanced stages, also at rest, resulting in a significant limitation of physical activity.1 Structural damage to the pulmonary parenchyma in ILDs leads to a reduction in oxygen diffusion capacity, together with ventilation/perfusion mismatch and the presence of an intrapulmonary shunt component. These alterations promote persistent hypoxic pulmonary vasoconstriction, which may lead to vascular remodeling and, ultimately, the development of pulmonary hypertension. In this context, parameters such as PaO2, the alveolar-arterial oxygen gradient, and post-exercise SpO2 have been associated with the presence of pulmonary hypertension in patients with pulmonary fibrosis.2
In this regard, the 6-minute walk test is a validated tool for assessing exertional desaturation.3 Vibha et al. demonstrated that exertional desaturation to ≤88% during the 6-minute walk test was a strong predictor of mortality in individuals with usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP).4 In line with these findings, the clinical practice guidelines of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) on the prescription of home supplemental oxygen therapy establish sustained oxygen saturation ≤88% for at least 2min during exertion as a criterion for prescribing ambulatory oxygen therapy.5 For its part, the American Thoracic Society, based primarily on the results of the AmbOx clinical trial conducted by Dina Visca, recommends – although supported by low-quality evidence – the use of ambulatory oxygen therapy in patients with ILD and severe exertional desaturation. In the AmbOx study, conducted in patients with fibrotic ILD and exertional desaturation, the use of ambulatory oxygen therapy for two weeks was associated with an improvement in health-related quality of life.6,7 However, despite existing recommendations, an international Delphi survey published in 2019 had already revealed considerable variability in the thresholds used to prescribe supplemental oxygen therapy in patients with fibrotic ILD.8
Functional decline, reduced physical activity, and the development of pulmonary hypertension have been consistently associated with poorer survival in patients with fibrotic ILD.1 In this context, it could be hypothesized that correction of exertional hypoxemia through ambulatory oxygen therapy may translate into improvements in daily physical activity and exertional symptoms. However, the evidence available to date remains limited.
To address this question, the PFOX study was conducted, a multicenter, randomized, placebo-controlled trial performed in Australia and Sweden that evaluated the effect of ambulatory oxygen therapy on physical activity in patients with fibrotic ILD and exertional hypoxemia. The study included 116 participants (mean age 71±10 years; 68% male), predominantly diagnosed with idiopathic pulmonary fibrosis (48%), followed by connective tissue disease-associated ILD (13%), unclassifiable ILD (11%), and fibrotic hypersensitivity pneumonitis (10%). Participants had moderate physiological impairment, with a mean FVC of 70% predicted and a mean DLCO of 45% predicted, and had isolated exertional hypoxaemia, reaching a mean nadir SpO2 of 83% during the 6-minute walk test. Baseline daily physical activity was low, with a median of approximately 2900–3000 steps per day. None of the participants were enrolled in pulmonary rehabilitation at baseline, as current participation in a pulmonary rehabilitation programme was an exclusion criterion.9
Despite these clinical characteristics, the study failed to demonstrate significant benefits of ambulatory oxygen therapy on daily step count at 3 months, nor on other relevant outcomes related to symptoms, quality of life, or physical activity.9 Moreover, at both 3 and 6 months, mean daily use of the concentrator remained below 1h in both groups. In addition, by the 6-month follow-up, 30 participants had discontinued use of the portable concentrator, with no differences between groups. Among the main reasons reported were patient decision, lack of perceived benefit, initiation of long-term oxygen therapy, and factors related to device acceptability, including its weight, travel limitations, and safety concerns.9
The present study has several important strengths. To date, it is the largest randomized clinical trial conducted in patients with fibrotic ILD and isolated exertional hypoxaemia to evaluate the impact of ambulatory oxygen therapy, and it also incorporates a multicenter design involving seven participating centers.9 Nevertheless, its findings should be interpreted in light of several important limitations. First, the planned sample size was not achieved, and a substantial loss of participants occurred during follow-up, which may have compromised the statistical power of the study. Participants received either ambulatory oxygen or ambulatory air delivered through visually identical portable oxygen concentrators, with both the oxygen and sham devices used at the maximum pulse-dose setting of 5. However, the intervention was limited to pulse-dose portable oxygen concentrators, without evaluating other oxygen delivery modalities, thereby restricting the generalizability of the findings. In addition, oxygen delivery was not individually titrated according to each patient's requirements, which may have influenced therapeutic efficacy. The PFOX investigators also acknowledged differences in the oxygen dose delivered by the available systems. At an exercise-compatible respiratory rate, the estimated delivered FiO2 was approximately 0.30 with continuous-flow cylinder oxygen at 5L/min, compared with approximately 0.24 with the Inogen One portable oxygen concentrator. This lower delivered FiO2 raises the possibility that the oxygen dose provided by the portable concentrator was insufficient to adequately correct exertional hypoxaemia and influence clinical outcomes. Importantly, the PFOX trial did not directly assess the extent to which the portable concentrator corrected oxygen desaturation during exertion, limiting the interpretation of its negative findings. Finally, the heterogeneity of the study population makes it difficult to identify specific ILD subgroups that might benefit from the intervention, while the absence of race and ethnicity data limits the external validity of the results.
Particularly striking was the low adherence observed with treatment, with a mean daily use of less than 1h in both groups. At baseline, participants spent approximately 10–13% of their waking hours with an SpO2 ≤88%, suggesting that, despite meeting the inclusion criterion for isolated exertional hypoxaemia, the overall burden of hypoxaemia during daily life was relatively limited. At both 3 and 6 months, no significant between-group differences were observed in the proportion of waking time spent with an SpO2 ≤88%. Taken together, the relatively limited daily burden of hypoxaemia and the absence of a measurable improvement in daily oxygenation may, at least partially, explain the low device use and lack of clinical benefit.9 These findings call for a reconsideration of the role of ambulatory oxygen therapy in patients with fibrotic ILD and isolated exertional hypoxemia and highlight the need for further studies to better define its indications.
Nevertheless, beyond the indication itself, an arguably even more relevant issue emerges: the actual ability of current devices to meet physiological demands during exercise. Although appropriately titrated devices may correct resting hypoxemia, their ability to maintain adequate oxygenation during exertion may be limited, particularly in the absence of individualized titration during physical activity, which could explain the lack of impact on daily activity and symptoms. In this regard, the development of more efficient oxygen delivery systems that are lightweight and better adapted to daily life appears to be a priority.
The findings of the PFOX study not only challenge the routine prescription of ambulatory oxygen therapy in patients with fibrotic ILD and isolated exertional hypoxemia, but also question the ability of currently available devices to adequately meet the physiological demands of exercise. Consequently, the future of ambulatory oxygen therapy in ILD will likely depend both on improved patient selection and on the development of technologies capable of ensuring effective oxygen delivery during physical activity.
Artificial intelligence involvementThe authors acknowledge the use of ChatGPT (OpenAI) for English language review and translation optimization during the preparation of this manuscript.
FundingThere is not any specific funding for this work.
Authors’ contributionsDr. Antia Ferreiro-Posse: conceptualization, writing original draft, review, editing, approval last version. Dr Galo-Granados: conceptualization, review, editing, supervision, approval last version. Dr Mercedes Pallero-Castillo: conceptualization, review, editing, supervision, approval last version.
Conflict of interestThe authors have no conflicts of interest related to the present article.
