Oxygen in interstitial lung diseases

When and why should patients with ILD be started on LTOT?

Chronic resting hypoxaemia usually develops in advanced ILD, and is associated with disabling breathlessness, and a median survival of less than a year [3]. The use of LTOT is largely based on two large randomised controlled trials (RCTs) in COPD, which showed improved survival in patients with severe resting hypoxaemia treated with supplemental oxygen for at least 15 h a day [4, 5]. There are no published RCTs of LTOT in ILD, with only one small (N=62) unpublished study with high risk of bias, reporting no difference in the survival of patients with ILD treated with LTOT compared with room air [6]. However, despite a limited evidence base, all major ILD international guidelines strongly recommend LTOT (for at least 15 h a day) in ILD patients with stable severe daytime hypoxaemia (arterial oxygen tension (P_aO2) <56 mmHg (<7.4 kPa)) or less severe resting hypoxaemia (P_aO2 56–59 mmHg (7.4–8 kPa)) with evidence of hypoxic organ damage, including pulmonary hypertension (PH)/right heart failure [7–9]. The guidelines have extrapolated the evidence from COPD trials, in consideration of the markedly reduced survival of hypoxaemic ILD patients [3], the beneficial palliative effects of supplemental oxygen in relieving breathlessness [10], and the potential prevention of hypoxic-induced organ damage. However, it is uncertain whether LTOT prevents adverse clinical outcomes in patients with ILD, such as hospitalisation or acute exacerbation, or affects overall survival [11].

As the disease progresses, patients with ILD often suffer from debilitating symptoms, particularly dyspnoea. Palliative care support can be a valuable intervention but is not always available and is often offered late [12, 13]. In recommending supplemental oxygen in hypoxaemic patients at rest, it is recognised that oxygen has a role in symptom palliation in the hypoxaemic ILD patient, particularly for the relief of dyspnoea in advanced ILD [12, 14]. In the severely hypoxaemic patient, high-flow nasal oxygen has been shown to be associated with a similar survival to noninvasive ventilation in ILD patients with do-not-intubate orders, but to be better tolerated, allowing oral intake and for patients to be able to converse right up to death [15].

It is not clear whether earlier initiation of LTOT would benefit ILD patients with less severe resting hypoxaemia. In COPD patients with moderate resting hypoxaemia, LTOT was not associated with improved survival or quality of life [16–18]. However, a recent study found that patients with ILD and moderate resting hypoxaemia (P_aO2 56–59 mmHg (7.4–8 kPa) without hypoxic organ damage) untreated with LTOT, had a comparably poor prognosis to those with severe resting hypoxaemia treated with LTOT, and significantly worse than that of patients with COPD with hypoxaemia (whether moderate or severe) [19]. The authors hypothesised that LTOT may be indicated earlier in ILD than in COPD. In response to these findings, the population-based retrospective DISCOVERY study [20] collected data from the Swedish registry on 2408 ILD patients with moderate (56–65 mmHg (7.4–8.7 kPa)) or severe (<55 mmHg (<7.4 kPa); 56–60 mmHg (7.4–8 kPa) with hypoxic damage) hypoxaemia treated with LTOT. After controlling for confounders, no difference was observed in transplant-free survival in ILD patients with moderate compared with severe hypoxaemia despite LTOT. However, as acknowledged by the authors, patients with moderate resting hypoxaemia treated with LTOT may have been more likely than untreated patients to have other comorbidities including PH or heart failure. Although suggestive of a lack of benefit of LTOT initiation in patients with less severe hypoxaemia, the findings of this study would need to be confirmed prospectively.

Is ambulatory oxygen therapy helpful in ILD patients and when should it be considered?

Severe exertional hypoxaemia is frequent in ILD patients, often occurring in the absence of resting hypoxaemia, and contributing to exercise intolerance, poor quality of life and reduced survival [21, 22]. In patients with exertional hypoxaemia, ambulatory oxygen therapy (AOT) can be used during exercise and/or activities of daily life [7, 23, 24]. AOT can be delivered via liquid oxygen, oxygen gas cylinders or portable oxygen concentrators (POCs). As POCs concentrate oxygen from the air, most only provide oxygen with pulsed rather than continuous delivery, reaching lower maximum flows than oxygen cylinders or liquid oxygen. Pulsed delivery with lower oxygen flows may be insufficient to correct hypoxaemia in patients with advanced ILD experiencing severe exertional desaturation.

The more severe exertional hypoxaemia seen in patients with ILD, compared with COPD, highlights the need for ILD-specific studies [25]. The 2-week crossover Ambulatory Oxygen in Fibrotic Lung Disease (AmbOx) trial showed that AOT was associated with improvement in breathlessness and quality of life in patients with ILD and isolated exertional hypoxaemia (peripheral capillary oxygen saturation (S_pO2) ≤88% on 6-min walk test (6MWT)) [26].

Current practice guidelines provide contradictory indications for initiating AOT in ILD patients. The British Thoracic Society guidelines state that AOT should not routinely be offered to patients who are not eligible for LTOT, although recognising that some breathless patients may benefit from AOT [7]. By contrast, the more recent American Thoracic Society guidelines, published after the AmbOx trial, reached a conditional recommendation for AOT prescription for patients with ILD with severe exertional desaturation (S_pO2 ≤88% on 6MWT), despite low certainty due to the paucity of evidence [8]. The Australian guidelines also recommend AOT for these patients [9]. An international Delphi survey supports AOT in ILD patients with exertional desaturation, although a consensus on desaturation thresholds for initiation of AOT was not reached [11].

The currently recruiting PFOX trial is a double-blind placebo-controlled trial comparing quality of life and physical activity between ambulatory oxygen and placebo air delivered via POC for 6 months in ILD patients with exertional desaturation [27, 28]. The benefits of AOT are likely to depend on whether optimal correction of exertional hypoxia is achieved, particularly with more strenuous exertion. Many currently available modes of oxygen delivery may not provide enough oxygen to fully relieve hypoxaemia in ILD patients. The ongoing High Oxygen Delivery to Preserve Exercise Capacity in Patients with IPF treated with Nintedanib (HOPE-IPF) trial will evaluate the impact of exercise training using high oxygen delivery (60% oxygen) on cycle endurance time and symptoms, compared with exercise training where oxygen supplementation is targeted at S_pO2 ≥88% [29]. It is hypothesised that the higher oxygen flows will allow greater exercise intensity and thereby improved exercise tolerance and quality of life [29, 30]. Interestingly, a pilot crossover study of domiciliary high-flow nasal cannula oxygen (HFNC) in 10 ILD patients already on either AOT or LTOT, where patients were asked to use the HFNC for 8 h a day, was associated with improvements in 6MWT distance and breathlessness, suggesting this modality should be further studied in ILD patients [30, 31].

How can exertional desaturation be assessed?

Ensuring adequate ambulatory oxygen prescription in ILD relies upon regular testing for exertional desaturation [22, 32]. The 6MWT is a widely used field exercise test [33], enabling monitoring of disease progression and supplemental oxygen need [34, 35]. Desaturation to ≤88% on 6MWT is the most used threshold for AOT prescription [8], although ILD patients with less severe desaturation may benefit from AOT [36, 37]. The 6MWT shows responsiveness to change with acute oxygen administration [14] and is used to titrate the flow of oxygen needed to correct hypoxaemia. However, the 6MWT is time- and space-consuming, due to the need for a 30-min break between the two tests and a 30-m corridor [34]. Of late, the 1-min sit-to-stand test (1STS) has gained popularity. Significant correlations were seen between distance walked during 6MWT and number of repetitions on 1STS, as well similarities in maximal oxygen uptake, nadir S_pO2 and frequency of desaturation [38–40], suggesting that the 1STS may offer a simpler alternative to the 6MWT, with potential for primary care use. However, responsiveness to acute oxygen administration has not been demonstrated.

The “DeOx” score is a simple score (from 0 to 2) to predict exertional desaturation to ≤88% in ILD patients. A score of 2, reached when resting saturation is ≤95% and the diffusing factor for carbon monoxide (D_LCO) is ≤40%, successfully predicted exertional desaturation in 78.5% of patients in a cohort of 300 [41]. In busy outpatient clinics, this simple score could be used to screen patients requiring exertional desaturation tests.

What about nocturnal oxygen?

Nocturnal hypoxaemia is common in patients with ILD and is not tightly related to daytime hypoxaemia or ILD severity [42]. It can occur with or without obstructive sleep apnoea syndrome. Troy et al. [43] observed that nocturnal hypoxaemia, defined as >10% total sleep time spent with S_pO2 <90%, was associated with development of PH, as measured by echocardiography, and with worse survival. Future studies are needed to assess the impact of different thresholds of nocturnal hypoxaemia on ILD progression, development of PH and survival, and to investigate the impact of treating nocturnal hypoxaemia in ILD patients.

Future recommendations

Given the limited evidence base specific to ILD, clinical trials and quasi-experimental trial designs are necessary to better define the use of supplemental oxygen in ILD (table 1). Studies are needed to assess whether treatment of nocturnal hypoxaemia could prevent/reduce the development of PH and improve survival. Importantly, research into more effective and user-friendly ambulatory oxygen delivery systems is urgently needed for ILD patients whose life is significantly restrained by the practicalities of AOT, to allow independent and active lives, with fewer burdens despite the respiratory limitations [44].