Abstract
The care of patients with idiopathic pulmonary fibrosis requires multidisciplinary management integrating disease-specific therapy with treatment of comorbidities as well as symptom palliation. This review focuses on the role of nonpharmacologic therapy in the care of patients with idiopathic pulmonary fibrosis and describes the integration of this aspect of care in the overall patient-centered model. Nonpharmacologic care in idiopathic pulmonary fibrosis (IPF) is focused primarily on symptom management and falls in the realm of palliative care. This includes interventions to abate disease-specific symptoms such as cough and dyspnea, as well as more general comorbidities such as gastroesophageal reflux disease, fatigue, depression, and anxiety. Another aspect of nonpharmacologic therapy for IPF is lung transplantation for carefully selected individuals. Patient-centered care for IPF requires thoughtful consideration of disease-specific management, symptom management, and management of comorbidities. Central to this process are communication between the patient and provider and engagement of the patient to determine individualized goals of treatment. This approach should include nonpharmacologic therapies, as well as consideration of lung transplantation in a small group of patients.
Keywords
Cough, Depression, Dyspnea, Fatigue, Gastroesophageal reflux disease, Lung transplantation, Palliation
Key Points
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A patient with idiopathic pulmonary fibrosis (IPF) requires multidisciplinary care.
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Symptomatic hallmarks of IPF include dyspnea, often driven by hypoxemia, and cough.
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Proper integration of nonpharmacologic management is imperative to improve quality of life and potentially increases survival.
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Nonpharmacologic treatment of IPF is largely focused on symptom management and falls under the umbrella of palliative care.
Idiopathic pulmonary fibrosis (IPF) is a complex disease, for which there is currently no cure. There are exciting emerging new therapies that will hopefully change the prognosis of this devastating disease. However, at present, the medical community must treat the multiple symptoms, manage comorbidities, and guide patients through difficult decisions regarding lung transplantation and end of life. A multidisciplinary approach is essential in providing patient-centered care to improve quality of life and includes the physician, nurse, respiratory therapist, oxygen specialist, social worker, palliative care specialist, and, in certain circumstances, lung transplant team. Thus a multidisciplinary approach to the nonpharmacologic treatment of IPF is both a mainstay of care and essential to provide optimal patient outcomes. Nonpharmacologic treatment of IPF is largely focused on symptom management and, thus, falls under the umbrella of palliative care. Palliative care encompasses treating all the symptoms of IPF, including cough, dyspnea, depression, anxiety, and fatigue, as well as assisting the patient in identifying his/her individual goals and using those values to guide therapeutic decision-making.
Symptomatic hallmarks of IPF include dyspnea, often driven by hypoxemia, and cough. Treating hypoxemia with supplemental oxygen has been shown to improve exercise tolerance and quality of life in various pulmonary diseases, and these findings have been extrapolated to IPF in clinical practice. Dyspnea often improves with oxygen supplementation and, in some individuals, cough improves as well. Cough is a predominant symptom in patients with IPF and one of the most challenging to treat, but effective therapy can provide highly valued relief to patients. Pulmonary rehabilitation is a keystone of therapy for those with exercise intolerance who have become more sedentary as the disease progresses, allowing patients to become more active again. Gastroesophageal reflux disease (GERD) is a common comorbidity in patients with IPF and potentially plays a role in the disease pathophysiology as well.
Comorbidities in IPF include high rates of depression and anxiety. Similarly, fatigue, related both to the disease and to comorbid sleep-disordered breathing, ischemic heart disease and cardiac arrhythmias, emphysema/chronic obstructive pulmonary disease (COPD), and tobacco use disorder are common, all of which are important to manage to improve the patient’s quality of life and life expectancy. It is valuable to establish resuscitative status with the patient when the patient is prepared to discuss it, as mechanical ventilation outcomes in IPF are dismal if not in the setting of bridge to transplantation. When the disease progresses to the end stage, hospice care is a critical service, which can be provided in the home or in-patient setting. Lung transplantation is a potential option for a subset of patients who do not have comorbidities that preclude it and is a potential life-saving therapy ( Fig. 5.1 ).
Palliative Care
Palliative care is defined in a recent ATS statement as interventions that “prevent and relieve suffering by controlling symptoms” as well as “to provide other support to patients and families in order to maintain and improve their quality of living.” In this context, virtually all of the care provided to patients with IPF can be considered palliative as, clearly, the goals are to control symptoms and maintain quality of life. Although palliative care was once considered synonymous with end of life, it is now more broadly considered as all interventions that focus on the symptoms of the patient as opposed to the disease. This reframing of palliative care is demonstrated by the schematics in Fig. 5.2 taken from this statement. In Fig. 5.2A and B , palliative care is shown as an alternative to disease-focused care engaged toward the end of life or as an incrementally increasing component of care in patients with progressive disease. An alternative concept illustrated in Fig. 5.2C is that of palliative care as a dynamic part of patient management, which varies dynamically based on the need of the patient and follows along from the earliest point of diagnosis to the end of life and beyond. This model most accurately reflects the typical engagement of symptom management in the care of patients with IPF, which might not have been explicitly considered to be palliation. The first component of palliative care is the management of symptoms directly related to IPF such as cough and dyspnea. However, the scope of symptoms experienced by patients with IPF may extend beyond these disease-specific symptoms to those more broadly related to fatigue, decreased endurance, pain, depression, and anxiety ( Fig 5.2 ). All of these areas are considered in detail in the following text. Several recent studies focused on perception of needs of the patient and the caregiver in IPF care have identified palliation as a critical deficiency. Indeed, a recent statement by patients, caregivers, support networks, and providers in Europe entitled “The European IPF Patient Charter” lists the availability of palliative and end-of-life care as a critical “right” for all IPF patients.
Integral to palliation is addressing the needs of the patient and his/her support system at the end of life. Because IPF is a progressive and often fatal disorder, it is critical to engage patients regarding their preferences and goals should the IPF lead to death. This may include the location of death, the availability of symptom control (hospice), as well as the desires/needs for family support after the death of the patient. A 2016 Swedish study of 285 patients with ILD on supplemental oxygen at the time of death found that only 41% of patients had engaged in end-of-life discussion before death. Nearly half of patients with ILD died in an acute hospital setting as opposed to about 30% in hospice. This contrasted with findings regarding patients with lung cancer on oxygen at the time of death where 59% had discussed end of life and 45% died in hospice. This highlights the importance of having not just a single but instead a series of conversations on end of life as a part of the continuum of care for IPF patients.
Dyspnea
Dyspnea is the most common symptom reported by patients with IPF. Although dyspnea may occur initially only with significant exertion, over time dyspnea becomes a frequent and disabling symptom. Typically, dyspnea on exertion in IPF is associated with hypoxemia. The use of supplemental oxygen has been studied primarily in pulmonary patients with COPD and the benefits extrapolated to IPF. British Thoracic Society guidelines suggest supplemental long-term oxygen therapy is indicated in patients with chronic hypoxemia defined by Pa o 2 < 7.3 kPa or between 7.3 and 8 kPa with polycythemia or evidence of pulmonary hypertension (PH). Current Medicare guidelines ( http://www.medicare.gov/Pubs/pdf/11045.pdf ) require evidence that the supplemental oxygen level is adequate to maintain an ambulatory saturation above 88%. Oxygen supplementation has been demonstrated to be beneficial in terms of increasing exercise capacity in IPF. However, there have been no systematic studies on the impact of supplemental oxygen use on the IPF patient’s or caregiver’s quality of life. The potential advantages of supplemental oxygen include relieving dyspnea and increasing activity. These benefits are balanced by a number of burdens associated with use of supplemental oxygen, including making the patient’s disease public and need for extensive planning (to allow for adequate supply) as well as financial burden.
For some patients, dyspnea and hypoxemia will eventually exceed the capacity for oxygen at home. In this situation, the use of opiates to lower the perception of dyspnea has been shown to be effective. Interestingly, a recent study of patients requiring oxygen at the end of life in Sweden showed that over 70% of ILD patients report dyspnea at or near the time of death. This suggests that attention to this symptom may not be sufficient. However, further study in this area is clearly needed.
Cough
Cough is a very common and distressing symptom for patients with IPF and has been associated with disease progression and death, as well as decreased quality of life. The cough is typically persistent and nonproductive, often disabling, and occurs in up to 80% of patients with IPF. By cough monitor data, it has been observed that the cough is predominantly a daytime symptom, with nocturnal cough being uncommon. The cause of the cough is unknown, but studies have found a functional upregulation of sensory fibers within the respiratory tracts of patients with IPF and studies have also demonstrated a dysregulated and disrupted epithelium. Other potential contributors to cough in IPF include postnasal drip, gastroesophageal reflux, and architectural distortion of the airways, known as traction bronchiectasis.
Treatment of cough in IPF is problematic for both patients and physicians, especially in the advanced stages of the disease when breathlessness can be significantly worsened by cough. There have been few studies demonstrating effective therapy, and there is no currently approved treatment for IPF-related cough. There are a number of options for treating chronic cough associated with IPF ( Box 5.1 ). Benzonatate can be given up to four times per day and is well tolerated, but is not effective for many patients. Opiate-derived medications come in liquid or pill forms and may be coupled with guaifenesin in those who have a productive cough, but the use may be limited by side effects such as constipation and sedating effects. Corticosteroids have not been shown to be effective in treatment of IPF, but their use in the palliation of cough can be quite effective. A small, uncontrolled open-label study found that cough sensitivity to capsaicin and cough symptoms were reduced after 1 month of oral corticosteroids. This is in line with clinical experience: some patients have significant improvement in cough with the use of oral corticosteroids, while others have little or no relief. The symptomatic benefits of corticosteroids have to be weighed with the risks of long-term use. Finally, airway nerve–active agents including thalidomide and gabapentin may provide relief from cough. A single-center study showed that the use of thalidomide for IPF-related cough over 24 months improved cough and respiratory quality of life. However, there has not been a follow-up multicenter trial conducted, which limits the generalizability of the conclusions. The potential antitussive effects of thalidomide certainly warrant further investigation, but may be limited by potentially serious side effects, which include constipation, bradycardia, dizziness, and peripheral neuropathy. Long-term use of thalidomide is often limited by these side effects. Gabapentin at a maximum tolerable dose of 1800 mg was found to be effective in treating refractory chronic cough in subjects without active respiratory disease in a randomized, double-blind, placebo-controlled trial, as measured by a significant difference in Leicester cough questionnaire score. Although gabapentin may be effective for a minority of IPF patients, its use is often limited by side effects, especially fatigue, particularly given the high rates of preexisting fatigue in this population.
Cough—Pharmacologic Options
Benzonatate
Opiate-containing medications (e.g., guaifenesin with codeine)
Corticosteroids
Airway nerve–acting medications (thalidomide, gaba-pentin)
Postnasal drip medication (nasal ipratropium, fluticasone)
Treatment of gastroesophageal reflux disease (lifestyle modification, protein pump inhibitors, H2-blockers)
Cough—Other Options
Hot tea
Honey
Menthol lozenges
N -Acetycysteine
Number of other supplements
Other, less well-studied options can be helpful, with little downside, and include hot tea, menthol lozenges, which are a natural cough suppressant (range of 2–10 mg/lozenge of menthol; suggest the higher dose lozenge works best), and clothing around the neck area such as a scarf. Some patients report the use of N -acetylcysteine (NAC) and serrapeptase in helping with cough. The use of NAC for treatment of IPF has not been found to be beneficial and may potentially be harmful in accelerating the rate of decline in FVC in the general population, although there may be a subset of patients who may benefit. There are no data to support the use of serrapeptase in IPF-related cough; however, there is some concern for safety. Serrapeptase has been reported in three cases of acute eosinophilic pneumonia and acute pneumonitis and one case of acute granulomatous hepatitis. It can decrease blood clotting, so it should be used with caution and avoided in those on anticoagulation medication or who have issues with bleeding. Other supplements have been suggested to help with cough, but there are limited data regarding their efficacy. The lack of regulation of herbal supplements makes it impossible to recommend one over another and adds concerns for safety profile and drug interactions.
Gastroesophageal Reflux Disease
GERD can present with esophageal symptoms or with mucosal damage produced by the abnormal reflux of gastric contents into the esophagus or beyond, including the lung. GERD is a common comorbidity in patients with IPF and potentially plays a role in the pathophysiology. Addressing GERD and microaspiration may be important in treating and controlling the progression of disease, both with medication and with lifestyle modification. However, who should be treated and how is not entirely clear, nor is evaluation standardized. Symptoms of heartburn and acid regurgitation have a very high specificity (89% and 95%, respectively), but low sensitivity (38% and 6%) for GERD, in the general population. By contrast, patients with IPF are largely asymptomatic. In those with symptoms, resolution of symptoms with a trial of antacids provides additional evidence for pathologic esophageal acid exposure and essentially confirms a diagnosis of GERD. Other testing available includes ambulatory pH monitoring, either by 24 h transnasal catheter with impedance to diagnose nonacidic reflux or by a wireless capsule. Upper endoscopy can diagnose the mucosal damage caused by esophageal acid exposure, but may, nevertheless, be normal in some with GERD. Barium swallow study can diagnose a hiatal hernia, but is no longer recommended in the evaluation of GERD because of poor sensitivity and specificity. Esophageal manometry is useful when esophageal dysmotility is suspected, but not recommended in the diagnosis of GERD.
Gastroesophageal reflux is common in IPF, affecting 87–94% of patients. The majority of IPF patients are asymptomatic, with “silent reflux,” and the incidence of GERD is significantly higher than in the general population and in patients with other advanced lung diseases. The presence of hiatal hernias has also been found to be increased in those with IPF. Laboratory models have demonstrated harmful effects when human alveolar epithelial cells are exposed to gastric materials or its individual components leading to immune stimulation, airway inflammation, increased cell membrane permeability, and lung remodeling. Several retrospective observational studies have shown favorable effects of proton pump inhibitors (PPIs) at improving or preventing deterioration of lung function. Together, this evidence led to the 2015 ATS guideline recommendation that clinicians use regular antacid treatment for patients with IPF. However, the expert panel did not unanimously agree, and it is currently a conditional recommendation, with low confidence. Reasonable options for medication therapy for GERD in IPF include PPIs as well as H2-blockers, although the PPIs may have appealing nonacid suppressant mechanisms that may be advantageous in IPF. However, recent retrospective analysis of the pirfenidone trials does not support an effect of PPIs and suggests that their use increases risk of respiratory infections. These studies have raised skepticism regarding the 2015 guidelines. Lifestyle modifications are a cornerstone to addressing gastroesophageal reflux in patients with IPF ( Box 5.2 ). These include recommendations to elevate the head of the bed (e.g., risers placed under the feet of the headboard), weight and abdominal girth reduction, smoking cessation, and dietary modifications including not eating 3–4 h before bedtime and avoiding foods or drinks that cause distal esophageal sphincter relaxation such as coffee, wine, chocolate, high-fat foods, and citrus fruits. However, weight reduction has been the only therapy shown to consistently improve GERD in studies. There is some evidence to support surgical correction of hiatal hernias and Nissen fundoplication, not only to correct acid reflux, but also to prevent the nonacid component of reflux, also known to be associated with lung injury; however, this is a retrospective observational study with intrinsic selection bias. Currently, a phase II clinical trial “WRAP-IPF” is recruiting patients to prospectively test the hypothesis that treatment with laparoscopic antireflux surgery in subjects with IPF and abnormal gastroesophageal reflux will slow the decline of forced vital capacity (FVC).
