Mrs. N is a 57-year-old, nonsmoker, obese, black schoolteacher who had complained of progressive dyspnea and dry intermittent cough for the past 2 years. A recent chest X-ray at an urgent care center revealed increased linear markings in the lower lobes, and enlarged shadow of the pulmonary artery (see Figure 1). The urgent care physician entertained the possibility of pneumonia and started her on oral antibiotics and referred her to a pulmonologist for further testing.
Mrs. N has a past medical history of systemic hypertension, gastroesophageal reflux disorder (GERD), and osteoporosis. Her current medications include metoprolol and hydrochlorothiazide for hypertension; vitamin D and calcium supplementation for bone health; and omeprazole for GERD, although she admits to stopping this medication on her own.
Upon presentation, the patient reported recent difficulty in walking up the stairs at her school building. She denied any previous history of dyspnea or family history of lung disease. Her physical examination showed 2+ pedal edema up to the shin. Lung auscultation revealed fine crackles predominant in the lung bases without any cyanosis or clubbing.
Pulmonary function testing demonstrated a moderate to severe restrictive ventilatory defect and severe decrease in diffusing capacity (see Table 1). Pulse oximeter at rest showed oxygen saturation of 93%. Mrs. N also underwent a 6-minute walk test (6MWT) and was able to walk 337 meters, with a fall in oxygen saturation to 90% during the walk.
Table 1. Pulmonary Function Test Results
Figure 2. High-Resolution Computed Tomography Scan of the Chest
The patient was advised to undergo high-resolution computerized tomography imaging of the chest. The scan revealed an enlarged pulmonary artery, ground glass opacities with peripheral interstitial thickening, mild traction bronchiectasis, and honeycombing findings, which were consistent with interstitial lung disease, particularly usual interstitial pneumonia (see Figure 2). With the presence of this finding it was understood that the patient has some interstitial process most likely consistent with idiopathic pulmonary fibrosis (IPF).
In addition, the patient underwent further work-up to rule out any cardiac causes of dyspnea and was found to be mildly hypertensive despite her current antihypertensive medications. A transthoracic echocardiography showed an enlarged right atrium and an estimated pulmonary artery systolic pressure of 90 mmHg.
The patient did not demonstrate any manifestation of connective tissue disease; however, connective tissue serologies were performed. Her antinuclear antibody titer was 1:40 and the remaining serologies were also negative (see Table 2).
Table 2. Connective Tissue Serology Tests
Clinical Decision Point 1: Follow-Up to Initial Diagnostic Testing
Question 1: Which of the following is the best next step regarding this patient’s pulmonary hypertension?
- Order right heart catheterization
- Order transesophageal echocardiography
- Order Holter monitoring
- Begin medication for pulmonary hypertension
Answer: (a) The presence of pulmonary hypertension secondary to IPF impacts patient outcomes and survival and informs treatment decisions, including decisions regarding lung transplant.1 Therefore, prior to making decisions regarding medication, it is important to accurately confirm the presence and severity of pulmonary hypertension in this patient using right heart catheterization.
Listen as Dr. Talwar discusses what factors contribute to the development of pulmonary hypertension in the setting of IPF.
Audio Commentary 1
Transthoracic echocardiography is commonly used to screen for pulmonary hypertension, but it may either overestimate or underestimate right-sided pressures in up to approximately 60% of patients and miss the diagnosis completely in up to one third of patients.2,3 Echocardiography, therefore, cannot be used alone in the assessment of pulmonary hypertension.3 Right heart catheterization remains the gold standard for the diagnosis of pulmonary hypertension in patients with IPF.3 Transesophageal echocardiography is not necessary for the diagnosis of pulmonary hypertension, and Holter monitoring should be conducted only when a rhythm disorder is suspected.
Pulmonary hypertension is defined as a resting mean pulmonary arterial pressure of 25 mmHg or greater.4 It has been reported in up to 41% to 46% of patients with IPF, although severe pulmonary hypertension is relatively infrequent in these patients (less than 10%).5,6
Distinguishing symptoms of pulmonary hypertension from those of IPF is difficult in this patient population; for example, dyspnea and fatigue are symptoms of IPF as well as pulmonary hypertension.2 Due to its high prevalence and overlapping symptomatology, clinicians should consider the possibility of pulmonary hypertension in all patients with IPF.2 In particular, patients with any of the signs or symptoms shown in Table 3 should be evaluated for pulmonary hypertension.1,2
Table 3. Indicators of Pulmonary Hypertension in Patients with IPF1,2
The patient underwent right cardiac catheterization to determine pulmonary artery pressures. She was found to have a resting mean pulmonary arterial pressure of 47 mmHg, confirming the diagnosis of pulmonary hypertension, and a pulmonary capillary wedge pressure of 12 mmHg.
Listen as Dr. Talwar addresses the role that this patient’s obesity may play in her pulmonary hypertension secondary to IPF.
Audio Commentary 2
Clinical Decision Point 2: Addressing Pulmonary Hypertension
Question 2: In addition to evaluation for lung transplant, which of the following is the best next step, given the patient’s confirmed pulmonary hypertension in the setting of IPF?
- Start sildenafil
- Enroll in a clinical trial
- Start supplemental oxygen
- “a” and/or “b”
Answer: (d) In some patients the majority of symptoms may be due to pulmonary hypertension alone and not the interstitial process, which may be mild at presentation.7 Our patient has been identified to have both—an interstitial process and pulmonary hypertension—and a therapeutic decision needs to be made. Sildenafil is an approved treatment option for World Health Organization (WHO) Group I pulmonary arterial hypertension, but is not approved for pulmonary hypertension secondary to IPF, a WHO Group III pulmonary hypertension.8,9 Although pulmonary artery pressures have not been shown to decrease, improvement in exercise tolerance has been demonstrated with sildenafil in the setting of IPF.10 In addition, this patient should be evaluated for lung transplant, as per recent treatment guidelines for IPF from the American Thoracic Society (ATS).11
Pulmonary hypertension in the context of IPF is associated with decreased exercise capacity, decreased overall survival, and increased mortality following lung transplant.1,12 Treatment of pulmonary hypertension in patients with IPF presents a clinical challenge, because no medication is approved by the FDA for either IPF alone or IPF associated with pulmonary hypertension (Group III).13 Although ATS guidelines recommend that pulmonary hypertension should not be treated in the majority of patients with IPF, the guidelines do suggest that a trial of vasodilator treatment should be considered in a selective minority of patients, including those with moderate to severe pulmonary hypertension as indicated by a mean pulmonary arterial pressure of greater than 35 mmHg.11
A small open-label trial of sildenafil in patients with IPF and pulmonary hypertension showed that a single oral dose improved gas exchange and caused preferential pulmonary vasodilation, with a decrease in the pulmonary vascular resistance index.14 A 3-month open-label phase II trial of sildenafil in 14 patients with IPF and pulmonary hypertension found that 57% of patients had at least a 20% improvement in 6MWT distance.10 Overall, sildenafil was well tolerated, although two patients discontinued due to treatment side effects.10
Trials of other drugs approved for pulmonary arterial hypertension have been unsuccessful.15,16 A recent randomized, double-blind, placebo-controlled phase III trial (N = 492) of ambrisentan in patients with IPF, including 10% with pulmonary hypertension, was cut short due to increased disease progression and respiratory hospitalizations.15 A phase II trial of macitentan failed to reach its primary endpoint of improved forced vital capacity compared with placebo.16
Due to the lack of any FDA approved therapy for IPF, patients should be encouraged to participate in clinical trials.11
Supplemental Home Oxygen
According to ATS guidelines, supplemental oxygen should be reserved for patients with clinically significant resting hypoxemia, defined as oxygen saturation of less than 88%.11 In the case of our patient, she does not exhibit hypoxemia at rest, and she desaturated only to 90% during her 6MWT.
After discussion with the patient, she was started on sildenafil 20 mg three times a day, off label. The fact that sildenafil is approved in patients with Group I pulmonary hypertension, but not approved for patients with Group III pulmonary hypertension, was discussed with the patient. She was referred for lung transplant candidacy evaluation and was encouraged to participate in a clinical trial for pulmonary hypertension and interstitial lung disease.
Clinical Decision Point 3: Managing Comorbidities
Question 3: Given the need to address comorbid conditions in patients with IPF, which of the following is the best next step for this patient?
- Start antidepressants
- Initiate nighttime continuous positive airway pressure treatment
- Reassess her treatment for GERD
Answer: (c) In addition to pulmonary hypertension, a number of comorbidities are associated with IPF, including pulmonary infection, bronchitis, and asthma; heart disease, including heart failure, myocardial infarction, atrial fibrillation, and coronary artery disease; cerebrovascular disease; depression; GERD; sleep apnea; lung cancer; pulmonary embolism and deep vein thrombosis; rib fracture; and obesity.17 Whether associated comorbidities have a shared pathology with IPF or whether they are unrelated but common to an aging population is currently unknown.13 Relevant comorbidities, when present, should be addressed because they may have an impact on mortality, functional status, quality of life, disease progression, symptoms, and treatment response.13,18 In addition, comorbidities may affect eligibility for clinical trials and lung transplant and also survival while on the transplant waiting list.13
GERD in IPF
GERD has long been known to be associated with worsening or exacerbation of a range of lung diseases.19 In IPF, chronic microaspiration may play a role in disease pathogenesis and progression resulting from repeated injury to the lung.20 GERD is present in up to 90% of patients with IPF, yet more than half of these patients lack symptoms of GERD.21
Use of GERD medications is associated with improved or stabilized pulmonary function tests, and reduced fibrosis and increased survival in this patient population.20,22 Some clinicians advocate that all patients with IPF should be evaluated with pH monitoring, esophageal manometry, and impedance testing.19 Other clinicians suggest that invasive testing be avoided and GERD treatment be given empirically.18 Dietary and lifestyle modifications, such as sleeping with one’s head raised, also should be employed.18 Current guidelines recommend GERD treatment for the majority of asymptomatic patients with GERD.11 Antireflux surgery may be an option in some patients.23
Depression in IPF
Depression has been observed in approximately 24% of patients with IPF.24 It is associated with increased dyspnea, increased pain, poor sleep quality, and decreased forced vital capacity.24 All patients with IPF should be routinely screened for clinical depression.18 Patients in whom depression is identified should be referred for treatment, particularly if the depression accounts for functional impairment and is considered to contribute to a decreased quality of life.18,25 The widespread use of antidepressants in patients with IPF in the absence of a diagnosis of depression is not in the literature, however. In fact, certain depressive medications have been linked to pneumonitis.26
Although depression is a common comorbidity, our patient currently is not exhibiting depressive symptoms. In addition, starting an antidepressant at this time would not help her underlying pulmonary disease.
Obstructive Sleep Apnea in IPF
Obstructive sleep apnea (OSA) has been reported in up to 88% of patients with IPF.18,27 A prospective study in patients with IPF showed that the sleep-disordered breathing in this population most often took the form of hypopneas rather than apneas.27 Importantly, it could not be predicted on the basis of desaturation, forced volume capacity, lung volumes, or diffusing capacity for carbon monoxide.27 Furthermore, the predictive value of questionnaires, including the Epworth sleepiness scale questionnaire or the sleep apnea scale of sleep disorders questionnaire, is insufficient to support their use as screening tools.27
Although ATS guidelines do not make any recommendations of treatment for OSA in the setting of IPF, clinicians should consider referring patients with IPF who have clinical features of OSA for overnight polysomnographic study.11 Some clinicians refer all patients with IPF for polysomnography, particularly patients with functionally or radiologically advanced disease.18,27,28 Patients in whom obstructive sleep apnea is identified should start nocturnal continuous positive airway pressure treatment.18,27
Other Selected IPF-Related Comorbidities
Lung cancer. Patients with IPF have more than a 7-fold risk of developing lung cancer.29 The prevalence of lung cancer in this population is estimated between 4% and 38%.18 Tumors are located primarily in the peripheral portion or the lower lobes.30 Squamous cell carcinoma is the most common histologic type.30
Thromboembolic conditions. Venous thromboembolism occurs among patients with IPF at an incidence 34% higher than the general population (1.74% versus 1.31%).31 Pulmonary embolism accounts for approximately 3.4% of deaths in patients with IPF.32
Listen as Dr. Talwar comments on this patient’s comorbid osteoporosis and the effect that osteoporosis and IPF may have on each other.
Audio Commentary 3
Listen as Dr. Talwar comments on this patient’s mild systemic hypertension and how it should be managed in the context of her IPF and pulmonary hypertension.
Audio Commentary 4
Mrs. N is advised to restart omeprazole for GERD and to take it consistently as prescribed. She is also advised to be compliant with her bone health supplementations. A bone density (DEXA) scan should be ordered; if osteoporosis is confirmed, she should be started on osteoporosis treatment. Although she has not exhibited any classical signs or symptoms of depression or anxiety, she underwent mental health assessment, including screening for depression. An additional referral was made for polysomnography.
Clinical Decision Point 4: Improving Quality of Life
Question 4: What can be done to further help this patient?
- Start the patient on corticosteroid monotherapy
- Start the patient on combination corticosteroid and immunomodulator therapy
- Enroll the patient in a structured pulmonary rehabilitation program
- Start the patient on a combination of acetylcysteine, corticosteroid, and azathioprine
Answer: (c) In the absence of specific proven pharmacotherapies for IPF, the clinician should make management decisions that will improve the patient’s health-related quality of life (HRQOL) and functional status as much as possible.11,33 For our patient, decisions that will address HRQOL include continuing her on sildenafil and starting her on pulmonary rehabilitation. Importantly, she should complete evaluation for lung transplantation and be listed when deemed appropriate.
Instruments to Measure QOL
In the absence of IPF-specific HRQOL measures, trial investigators have used generic or non-IPF respiratory-specific instruments to measure HRQOL in clinical trials. The instrument most used to measure HRQOL in IPF is the Medical Outcomes Study Short-Form 36-item Questionnaire (SF-36).33 The SF-36 includes eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health.33 The Physical Component Summary reflects the first four physical domains, and the Mental Component Summary reflects the last four mental health domains.33
The St. George’s Respiratory Questionnaire (SGRQ) is also used in the setting of IPF but is specific to obstructive respiratory diseases.33 It includes the domains of Symptoms (eg, cough, dyspnea), Activity (ie, physical activity limited by dyspnea), and Impacts (eg, effect on emotional well-being).33 In fact, it has been adapted to an IPF-specific instrument (SGRQ-I).34 In addition, the Cambridge Pulmonary Hypertension Outcome Review is an instrument specific to pulmonary hypertension.35 There is an urgent unmet need to develop similar assessment tools to assess HRQOL in patients with the clinical phenotype of IPF and associated pulmonary hypertension.
Listen as Dr. Talwar discusses how patient and provider perspectives on HRQOL compare and suggests ways that clinicians can better target interventions that will improve a patient’s perceived HRQOL.
Audio Commentary 5
ATS guidelines recommend that the majority of patients with IPF be treated with pulmonary rehabilitation.11 Pulmonary rehabilitation programs include exercise for aerobic conditioning, strength, and flexibility; nutritional counseling; psychosocial support; and other educational interventions.11 Randomized controlled trials have shown that both 6MWT distance and patient-reported HRQOL outcomes are improved with pulmonary rehabilitation.36 It is important to note that 6MWT distance is itself associated with HRQOL in the setting of IPF and may be used as a prognostic factor.38 Importantly, the correlation between dyspnea, functional status, and depression has been found to be significant, suggesting that patients who can walk greater distances may have less dyspnea, and in turn, improved depressive symptoms.39
Two recent prospective trials have also demonstrated improved patient outcomes with pulmonary rehabilitation.39,40 A German study of 402 consecutive patients with interstitial lung disease, including 202 patients with IPF and 111 with pulmonary hypertension, found that pulmonary rehabilitation significantly improved 6MWT distance compared with baseline after a mean duration of 30 days.40 Vital capacity also improved, although dyspnea did not change.40 The SF-36 questionnaire showed an increase in the eight domains and the Physical and Mental Component Summary scores also increased.40 Among the 111 patients with pulmonary hypertension, the increase in 6MWT distance was also significant, although the absolute increase was lower compared with patients without pulmonary hypertension.40 In this subset, only improvement in the SF-36 mental summary score was observed.40
A smaller prospective study recruited 54 patients with interstitial lung disease, including 22 with IPF, for a pulmonary rehabilitation program for an average period of 7 weeks.41 Compared with baseline, improvements following rehabilitation were observed in 6MWT distance, 4-meter walk time, and physical activity, as well as in patient perceptions of HRQOL (as measured by SGRQ), depression, and dyspnea.41 Improvement in 6MWT distance was sustained at the 6-month follow-up evaluation, as were improvements in depression and HRQOL.41
Pharmacotherapy and HRQOL
Sildenafil. A 3-month phase III randomized placebo-controlled trial, enrolling 180 patients with advanced IPF, evaluated sildenafil’s impact on walking distance (primary outcome) and on dyspnea, oxygenation measures, and HRQOL (secondary outcomes).42 This trial included many types of patients, including patients with pulmonary hypertension.43 HRQOL was assessed using the SF-36, SGRQ, and the EuroQol Group 5-Dimension Self-Report Questionnaire.42 The primary outcome was not met, with 10% of patients in the sildenafil group responding with at least a 20% improvement in the 6MWT distance compared with 7% of patients in the placebo group.42 A clinically significant, albeit small, improvement was seen in HRQOL and dyspnea with sildenafil, however.42 Further study is needed.
Corticosteroid monotherapy and corticosteroid immunomodulator combination therapy. Current ATS treatment guidelines strongly recommend that patients with IPF should not be treated with corticosteroid monotherapy.11 Retrospective uncontrolled studies have reported no survival benefits with steroids in the setting of IPF.11 Long-term corticosteroid treatment resulted in substantial morbidity in at least one study.44
Similarly, ATS guidelines strongly recommend against treating with a corticosteroid combined with an immunomodulator, such as azathioprine or cyclophosphamide.11
Combination acetylcysteine, corticosteroid, and azathioprine therapy. The use of acetylcysteine has been debated in IPF patients. Data have shown that acetylcysteine at a dose of 600 mg three times daily, added to prednisone and azathioprine, for 1 year preserves vital capacity and diffusing capacity for carbon monoxide in patients with IPF compared with placebo plus prednisone and azathioprine.45 HRQOL, a secondary endpoint assessed using SGRQ, dyspnea, and exercise capacity, was similar between the two groups.45 Based on these findings, ATS guidelines recommend that most patients with IPF should not be treated with the combination of acetylcysteine, corticosteroid, and azathioprine, although a minority of patients may benefit.11 A more recent randomized placebo-controlled trial, however, offered strong evidence against the use of this combination in patients with well-defined IPF, demonstrating its association with increased all-cause mortality and all-cause hospitalizations.46
Pirfenidone. Two randomized placebo-controlled phase III international trials evaluated pirfenidone in patients with IPF (CAPACITY 004 and 006), with the primary endpoint in both trials being percentage predicted forced vital capacity at week 72.47 In CAPACITY 004, pirfenidone 2403 mg/day significantly improved the percentage predicted forced vital capacity compared with placebo, whereas this endpoint was not met in CAPACITY 006.47 A recent Cochrane review evaluated these trials plus two additional trials. Based on the three trials of the four that provided data on progression-free survival, the review concluded that pirfenidone was associated with a 30% improvement in progression-free survival.48 Although pirfenidone is approved in Europe for mild-to-moderate IPF, it is not yet approved in the United States but is pending results of a phase III trial.49,50
More recently preliminary data from pirfenidone’s phase III ASCEND trial in IPF demonstrated that pirfenidone significantly improved percent predicted FVC from baseline to week 52.51 Furthermore, significant benefits were observed in the secondary endpoints of 6MWT distance and progression-free survival.
Nintedanib. A novel tyrosine kinase inhibitor, nintedanib 150 mg BID reduced the decline in forced vital capacity and improved HRQOL compared with placebo in a 1-year phase II trial in patients with IPF.52 Two phase III trials have been completed: IMPULSIS-1 and IMPULSIS-2.53,54 Results are expected to be reported at the 2014 ATS annual conference (BM-IPF-IMPULSIS). A phase III extension trial of IMPULSIS-1 and IMPULSIS-2 is ongoing.55
Listen as Dr. Talwar discusses the role of palliative care in patients with IPF and gives advice on when and how it should be delivered.
Audio Commentary 6
Mrs. N was enrolled in a structured 12-week pulmonary rehabilitation program. In addition, she continued on sildenafil and also was offered pneumococcal and influenza vaccination. Her mental health assessment found no signs or symptoms of depression and polysomnography showed no evidence of OSA.
After 12 weeks of monitored physical activity, she showed an increase of 138 meters in her 6MWT and overall improvement in her physical activities and mood. Compared with baseline, her SF-36 showed an improvement in her Physical Component Summary score and a greater improvement in her Mental Component Summary score after pulmonary rehabilitation. She also reported that her nocturnal cough was improved after becoming more compliant with daily omeprazole. She continues to be dyspneic, however, and experiences increasing frustration at its persistence, despite utilizing all treatment measures.
Listen as Dr. Talwar addresses the value in utilizing a team approach (ie, laboratory, radiology, cardiology, pulmonology, respiratory medicine and rehabilitation, social work) to managing patients with IPF, particularly patients with relevant comorbidities.
Audio Commentary 7
Pulmonary hypertension secondary to IPF is common and presents a negative prognostic factor. Currently there are no medications approved for the treatment of pulmonary hypertension in the setting of IPF. Lung transplant is the most viable option for these patients. In addition, these patients should be actively enrolled in clinical trials.
Treatment of IPF is centered on increasing subjective HRQOL and utilizing mainly supportive measures to manage comorbidities. Addressing underlying medical issues, such as GERD and depression may improve patient outcomes. The role of pulmonary rehabilitation is evolving but appears to significantly improve HRQOL.
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