Exercise limitation is a cardinal feature of interstitial lung disease (ILD), resulting in reduced ability to undertake daily activities and poor quality of life [1]. Reduced peak oxygen uptake (VO₂peak) [2–4] and exercise-induced hypoxemia [2, 5] during the cardiopulmonary exercise test (CPET) are sensitive markers of mortality. Results from the CPET can also inform exercise prescription in people with ILD undergoing pulmonary rehabilitation. However, the CPET is not currently recommended as part of routine monitoring [6] and may not be available in all centres.

The six-minute walk test (6MWT) is a practical and inexpensive test of exercise tolerance that is commonly used to stage disease and evaluate treatment responses in people with ILD [2, 7]. A reduced 6-minute walk distance (6MWD) is a predictor of mortality for people with idiopathic pulmonary fibrosis (IPF) in some [8, 9] but not all [10] studies. Although the 6MWD has a significant relationship with other measures of outcome such as forced vital capacity (FVC) and diffusing capacity for carbon monoxide (TLCO) across a range of ILDs, these relationships are poor to modest in strength. [2, 7, 11, 12] Some investigators have been reluctant to recommend the use of the 6MWT as it is unclear what it actually measures in people with ILD [13]. Whilst it is often considered a submaximal test, perhaps partially reflecting functional exercise tolerance [13], one previous study has suggested that the VO₂peak achieved during a 6MWT may be equivalent to that during CPET in people with ILD [14], although this study may not have been sufficiently powered to detect differences between the tests.

It is possible that the 6MWT provides unique information that is not available from CPET. Oxyhemoglobin desaturation, a marked feature of the 6MWT in ILD, is a more consistent predictor of reduced survival than distance walked [2, 15, 16]. Data from people with other respiratory diseases have shown greater desaturation during walking compared to cycling [17], suggesting that the full extent of exercise-induced desaturation may only be visible during a walking test. However, an adequately powered comparison of the cardiorespiratory responses to CPET and 6MWT in ILD has not been undertaken.

The aims of this study were (1) to assess cardiorespiratory responses to the 6MWT in people with ILD; and (2) to compare cardiorespiratory responses with those obtained during CPET.

Patients with documented ILD of any etiology were recruited from a tertiary hospital in Melbourne, Australia. Diagnosis was made according to established criteria [6, 18]. Patients were eligible to participate if they were ambulant and able to ride a stationary cycle ergometer. Exclusion criteria were clinical instability, history of syncope on exertion and presence of comorbidities that precluded exercise testing (for example, orthopedic or neurological disease). Patients were also excluded if they had resting oxygen saturation (SpO₂) <88% on room air, as supplemental oxygen was not used during the metabolic monitoring. Measurements of spirometry and TLCO were obtained to quantify disease severity. Right ventricular systolic pressure was estimated on transthoracic echocardiogram. The research protocol was approved by the hospital and university Human Research Ethics Committees and written informed consent was obtained from each participant prior to testing (H2008/03363, FHEC08-021).

Our direct comparison of the cardiorespiratory responses during the 6MWT and CPET in people with ILD provides novel physiological data to explain the different performance characteristics of these important tests. This study has shown that, on average, the 6MWT elicits a high but submaximal VO₂ in people with ILD that reaches a plateau after the third minute of the test. This supports the conceptualization of the 6MWT as a submaximal, steady state exercise test. However there is variability in responses that is related to disease stage. The 6MWT imposes a greater cardiorespiratory load on those with greater disease severity, where the peak VO₂ can equal or exceed the VO₂peak seen during a CPET. Oxyhaemoglobin desaturation was significantly greater during the 6MWT than the CPET and this was unrelated to the physiological load imposed by the test. These findings may assist in explaining the superior performance of oxyhaemoglobin desaturation compared to 6MWD as prognostic indicator in people with ILD.

It has previously been suggested that the self-paced nature of the 6MWT may contribute to the reduced predictive value of the 6MWD [3]. Our results show pronounced differences between 6MWT and CPET in VCO₂peak and VEpeak, indicating a much lower physiological load for the 6MWT. This is similar to previous findings in COPD [23–26] and may reflect a smaller exercising muscle mass and greater lactate production during the CPET. More importantly, our results indicate that the 6MWT protocol frequently allows people with mild disease to exercise at a much lower percentage of their CPET VO₂peak than those with more advanced disease. Not surprisingly, we found that a lower VO₂peak was associated with lower 6MWD. This variability in the load imposed by the 6MWT across the range of disease severity may contribute to the inconsistency of 6MWD as a marker of prognosis across study populations [8–10].

In contrast, the degree of desaturation during exercise was unaffected by the VO₂ elicited during the test. Although there was desaturation during both exercise tests, it was significantly greater during walking than during cycling for the vast majority of participants (Table 2). This is consistent with previous findings in COPD [17], which showed increased alveolar ventilation during cycling compared to treadmill walking, with a concomitant increase in partial pressure of oxygen in arterial blood (PaO₂) which minimized the magnitude of oxyhaemoglobin desaturation during cycling. The increase in PaO₂ during cycling compared to walking occurred prior to the anabolic threshold, which suggests that both neurogenic feedback from exercising muscles andearlier onset of anaerobic metabolism were contributors to better maintained oxyhaemoglobin saturation [17]. Whilst previous studies have found a consistent relationship between desaturation on 6MWT and poor prognosis, [2, 15, 16] the relationship between desaturation on CPET and prognosis is less consistent [2, 3, 27]. This may be because the lesser degree of desaturation on the CPET was not sufficient to discriminate those at risk of a poor outcome. Our data suggest that a greater degree of desaturation occurs during a 6MWT regardless of the physiological load imposed by the test, and this may be the most robust outcome of the 6MWT.

To date this is the largest study to compare the physiological responses to the CPET and 6MWT in individuals with any form of chronic lung disease. This may explain differences in our findings compared to others. One previous study included 13 individuals with ILD (12 IPF) and did not find a difference in VO₂peak on 6MWT compared to CPET [14]. However, the small numbers of participants may have reduced the ability to detect small differences and did not allow the authors to assess effects attributable to disease severity. Their study also excluded people with pulmonary hypertension and thus the findings cannot be generalized to patients with more severe disease, where pulmonary hypertension is relatively common [28]. Studies which have examined the physiological load associated with the 6MWT in COPD have also found no difference in VO₂peak between 6MWT and CPET [23–26]. This may represent a real difference in response across disease groups, or may reflect the smaller subject numbers in those studies (n = 12 to 26). It should be noted that we did not find a difference in mean VO₂peak between tests when the subgroup of participants with IPF was examined separately (n = 27), however this study was not powered to assess differences in this subgroup and results should be interpreted with caution.

Other limitations to this study include conducting the exercise tests on the same day, such that fatigue may have impacted on results; however the order of testing was randomized to account for any potential order effects. Our exclusion criteria did not allow participation by patients with resting SpO₂ of less than 88%, as supplemental oxygen was not applied during metabolic monitoring; our results therefore may not apply to patients with ILD and severe resting hypoxemia. Finally, a number of participants (n = 8) stopped during the 6MWT due to intolerable dyspnea, which occurs commonly in this group. This may have affected the physiological data collected and a steady state may not have been achieved. However, the difference between tests persists when these individuals are excluded from analysis.

This study shows that the 6MWT elicits high but submaximal cardiorespiratory responses in people with ILD. There is wide variability across the range of disease severity, such that the 6MWT may elicit a higher VO₂peak for those with more severe disease. Exertional desaturation is greater on 6MWT than CPET and this is unaffected by the physiological load. These data suggest that desaturation during a 6MWT may provide unique and consistent information across the range of disease severity in ILD.