Question: Does distance covered during a six-minute walk test impact prognosis?

Answer: Dr. Flaherty: In general, a shorter walk distance is associated with an increased risk of subsequent mortality.¹ The six-minute walk test has the advantage of being a very simple and relatively inexpensive test to perform. It also mimics a daily activity, and thus is highly relevant to the patient's quality of life. However, the test has high variability due to both test methodology and subject factors. Some of the elements that can impact the walk distance are:^2,3

Test variables

• use of supplemental oxygen
• criteria for termination of the test (SpO₂ 88% or 85%)
• circular vs linear walk paths

Subject variables

• motivation
• age
• height
• gender
• comorbidities
• fitness

1. Lederer DJ, Arcasoy SM, Wilt JS, D'Ovidio F, Sonett JR, Kawut SM. Six-minute-walk distance predicts waiting list survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174(6):659-664.
2. Hallstrand TS, Boitano LJ, Johnson WC, Spada CA, Hayes JG, Raghu G. The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis. Eur Respir J. 2005;25(1):96-103.
3. Enright PL. The six-minute walk test. Respir Care. 2003;48(8):783-785.

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Question: What factors are associated with the presence of pulmonary hypertension in patients with IPF?

Answer: As pulmonary fibrosis progresses, the odds of having pulmonary hypertension increase. Low PaO₂, the need for supplemental oxygen and decreased diffusion capacity for carbon monoxide (DL_CO) have all been associated with increased risk for pulmonary hypertension.^1-4 Estimated by echocardiography, pulmonary artery pressures correlated with DL_CO and PaO₂ but not FVC or FEV₁.² A subsequent publication identified the risk of pulmonary hypertension as 10.2 times higher in patients requiring supplemental oxygen and with a DL_CO of < 40% predicted while a third study identified a threshold for DL_CO of < 30% predicted.^1,3 In aggregate these data suggest that hypoxemia and decreased DL_CO are the most important predictors of the presence of pulmonary hypertension. Brain natriuretic peptide levels may also be predictive. In one study, a cut-off 33.3 pg/mL could distinguish moderate-severe pulmonary hypertension (mPAP > 35 mmHg) from no or mild PAH with a sensitivity of 100% and specificity of 89%.⁵

1. Lettieri CJ, et al. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest. 2006;129:746-752.
2. Nadrous HF, et al. Pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Chest. 2005;128:2393-9.
3. Nathan SD, et al. Pulmonary hypertension and pulmonary function testing in idiopathic pulmonary fibrosis. Chest. 2007;131:657-663.
4. Hamada K, et al. Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognositicator in patients with idiopathic pulmonary fibrosis. Chest. 2007;131:650-656
5. Leuchte H, et al. Brain natriuretic peptide and exercise capacity in lung fibrosis and pulmonary hypertension. Am J Respir Care Med. 2004;170:360-365.

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Question: Does echocardiography accurately estimate pulmonary arterial pressure?

Answer: Echocardiography (Echo) has fair sensitivity and negative predictive value and poor specificity and positive predictive value for the presence of pulmonary hypertension. In a study of 374 patients undergoing evaluation for lung transplantation, patients were evaluated with both Doppler echocardiography and right heart catheterization performed within 72 hours.¹ Echo was not able to estimate pulmonary artery pressures in the majority of patients (208/374, 56%). In addition, the performance of echocardiography by either pressure estimates or qualitative assessment of right ventricular structural/functional abnormalities compared to right heart catheterization was moderate at best (Table 1). These data suggest that echocardiography should be used with caution as a screening or diagnostic tool for pulmonary hypertension in patients with interstitial lung disease.

	Sensitivity (95% CI)	Specificity (95% CI)	PPV (95% CI)	NPV (95% CI)
sPAP	85% (73-93%)	55% (45-64%)	52% (41-62%)	87% (76-94%)
RV findings	82% (73-89%)	57% (51-62%)	39% (32-46%)	90% (85-94%)

PPV=positive predictive value, NPV=negative predictive value, sPAP=systolic pulmonary arterial pressure estimated by Doppler echocardiography, RV findings=qualitative right ventricular findings of pulmonary hypertension. Right heart catheterization is used as the comparator

1. Arcasoy SM, et al. Echocardiographic assessment of pulmonary hypertension in patients with advance lung disease. Am J Resp Crit Care Med. 2005;171:1040-1047.

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Question: Should I order routine (ie, every 6 or 12 months) follow-up HRCT studies for my patients with IPF?

Answer: HRCT plays a pivotal role in the diagnosis of diffuse parenchymal lung disease and, in some cases, can supplant the need for a surgical lung biopsy. That said, the role of regular HRCT follow-up is less clear. Few longitudinal studies are available and most show some change in ground glass and/or interstitial abnormalities with weak correlations with survival.^1-3 Differences in HRCT patterns have also been reported between treatment arms in clinical trials; however, the details of analysis were not clearly specified.⁴ There is also recent heightened awareness about the possible radiation risks associated with the increased numbers of CT scans.⁵ With these thoughts in mind, we do not recommend routine follow-up HRCT studies to monitor patients with IPF. We do perform follow-up CT studies when there is a change, particularly an abrupt change, in clinical status to look for evidence of infection (especially in patients on immunosuppressive therapy), pulmonary edema, pulmonary embolism, malignancy, or acute exacerbation of IPF.

1. Xaubet A, Agusti C, Luburich P, et al. Pulmonary function tests and CT scan in the management of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;158:431-436.
2. Hartman TE, Primack S, Kang EY, et al. Disease progression in usual interstitial pneumonia compared with desquamative interstitial pneumonia. Assessment with serial CT. Chest. 1996;110:378-382.
3. Nagao T, Nagai S, Hiramoto Y, et al. Serial evaluation of high-resolution computed tomography findings in patients with idiopathic pulmonary fibrosis in usual interstitial pneumonia. Respiration. 2002;69:413-419.
4. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Resp Crit Care Med. 2005;171:1040-1047.
5. Brenner DJ, Hall EJ. Computed tomography--an increasing source of radiation exposure. N Eng J Med. 2007;357:2277-2284.