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After reading this article, the reader should be able to:
• Discuss the clinical presentation and usual clinical course of idiopathic pulmonary fibrosis (IPF).
• Describe the comorbidities and complications commonly associated with IPF.
• Compare and contrast traditional and current IPF pharmacotherapy.
• Summarize the role of lung transplantation for IPF.
• Explain how extracorporeal membrane oxygenation (ECNO) can improve lung transplant outcomes.
Activity Launch Date: November 2017
Expiration Date: November 2018
This CME activity does not have any commercial support.
A 62-year-old white male with hypertension, hypercholesterolemia, a nonproductive cough, and progressive shortness of breath is hospitalized for pneumonia and placed on a short course of prednisone and supplemental oxygen. He improves on steroids but now requires around-the-clock oxygen. A former smoker (1.5 packs/day for seven years; quit at age 28), he has no family history of lung disease. Current medications are losartan, hydrochlorothiazide, atorvastatin, aspirin, albuterol inhaler, and oxygen at 3.0 L/minute per nasal cannula.
During a visit to his primary care physician, the patient complains of increasing dyspnea while mowing his lawn but reports no chest pain or palpitations. Interstitial changes are seen on chest X-ray (Figure 1). On pulmonary function testing, his forced vital capacity is 1.83 L (58 percent of predicted), and diffusion capacity for carbon monoxide (DLCO) and lung capacity are 41 percent and 42 percent of predicted, respectively.
The patient is referred to a local pulmonologist, who notes mild clubbing of the fingers and diffuse chest crackles on physical examination. High-resolution computed tomography (HRCT) shows scattered coarse reticular opacities, mild ground glass opacifications in the mid lung and lower lobes, thickened interlobular septa throughout both lungs, and traction bronchiectasis (Figure 2)—all consistent with a diagnosis of pulmonary fibrosis.
Overview of Idiopathic Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia of unknown etiology characterized by the progressive loss of lung function.1 Its prevalence (14 to 42 cases per 100,000) increases with age, the majority of patients being males 55 to 80 years with a current or previous smoking history.2 While the clinical course is highly variable and unpredictable, IPF has a poor prognosis: median survival time after diagnosis is just two to five years.3
Comorbidities and Complications
Because IPF generally affects older adults, comorbidities are common. These include emphysema, concurrent with IPF in approximately 30 percent of cases;4 obstructive sleep apnea, identified in 60 to 88 percent of affected persons;5,6 and gastroesophageal reflux disease (GERD), diagnosed in up to 90 percent of individuals with IPF.7 Pulmonary hypertension is a severe complication of IPF that significantly contributes to morbidity and mortality.8 Also impacting survival is the development of lung cancer, primarily squamous cell carcinoma followed by adenocarcinoma and independent of smoking history, which occurs in an estimated 10 percent of patients with IPF.9
Clinical Presentation, Risk Factors, and Diagnosis
IPF typically presents with the gradual onset of non-specific symptoms, in particular a nonproductive cough and exertional dyspnea. Finger clubbing is common, and bibasilar crackles are virtually a universal finding.2 Pulmonary function tests usually demonstrate restriction, but this may be masked by emphysema.
“Although the underlying causes of idiopathic pulmonary fibrosis remain unclear, an increased risk of the disease has been reported in persons with any smoking history or other types of particulate exposure (e.g., metal and wood dusts, stone, silica),” reports David Roe, MD, assistant professor of clinical medicine at Indiana University School of Medicine and medical director of Indiana University Health lung transplant program. “Genetic tendencies are increasingly recognized and currently account for about five to seven percent of IPF cases.”
The diagnosis of IPF requires the exclusion of other known causes of interstitial lung disease and the presence of a usual interstitial pneumonia (UIP) pattern on lung HRCT or surgical biopsy.1 The UIP pattern comprises basal, subpleural reticulation associated with architectural distortion, in particular honeycombing (Figure 3, see page 4),* and traction bronchiectasis, and its demonstration on HRCT may be sufficient to establish the diagnosis without the need for lung biopsy. Pulmonary function testing, particularly forced vital capacity and DLCO, is an important surrogate of disease progression and predictor of mortality (Table 1, see page 5) and correlates with the extent of radiologic disease.10
The management of IPF is multifaceted (Figure 4, see page 5), with the goals of: 1) slowing disease progression, 2) preserving quality of life (QoL), and 3) improving survival.
For several decades, glucocorticoids and immunosuppressants were the mainstays of IPF therapy because chronic inflammation was believed to cause persistent fibrosis in the early stages of the disease. This theory and treatment regimen were abandoned after a randomized, double-blind clinical trial found that compared with placebo, combination therapy with prednisone, azathioprine, and N-acetylcysteine actually increased the risk of hospitalization and death in patients with mild-to-moderate IPF.12
Current consensus is that fibrosis results from aberrant wound healing, specifically, the abnormal repair of alveolar epithelial injury. 2
Antifibrotics. Two recently approved antifibrotic drugs—pirfenidone (Esbriet®), which inhibits transforming growth factor and also has anti-inflammatory and antioxidant effects; and nintedanib (Ofev®), an inhibitor of platelet-derived growth factor, vascular endothelial growth factor, and fibroblast growth factor—have been shown to safely slow declining lung function and reduce acute exacerbations in IPF.13-15 Clinical practice guidelines recommend initiating treatment with one of these drugs in cases of mild-tomoderate disease.16 At the present time, data are insufficient to choose between pirfenidone and nintedanib, and selection may be guided by drug availability and patient preference and tolerance.
Antacids. “The vast majority of patients with IPF have concomitant gastroesophageal reflux disease, a risk factor for aspiration that can cause pneumonitis and worsen idiopathic pulmonary fibrosis,” Dr. Roe explains. “The empiric use of antacids, such as proton pump inhibitors or histamine-2 blocker receptor antagonists, may decrease this risk.”
IPF has become the most common indication for referral to a lung transplant service,17 with transplantation shown to improve QoL and extend survival: median post-transplant survival is 4.5 years.18 Patients with IPF are increasingly receiving bilateral rather than single lung transplant, and accumulating evidence suggests that this trend is linked to longer survival.19
“According to international guidelines, patients with idiopathic pulmonary fibrosis should be considered for lung transplantation at the time of diagnosis,”20 Dr. Roe says. “Early referral is warranted, given the high mortality of the disease and the often lengthy waiting time for suitable donor organs.”
The number of patients with IPF referred to Dr. Roe and his team for transplant evaluation is growing, and these individuals are being transplanted at a higher rate owing to the severity of their disease. Of the 52 patients who received lung transplants at IU Health last year, more than half were patients with IPF.
Oxygen Therapy and Pulmonary Rehabilitation
Pronounced hypoxia during physical exertion is a frequent finding in IPF. Although no longterm data support the use of supplemental oxygen in this patient population, limited information suggests it may improve exercise capacity.
“Pulmonary rehabilitation, including aerobic conditioning, strength and flexibility training, nutrition counseling and other education, and psychosocial support is also beneficial for patients with idiopathic pulmonary fibrosis, alleviating symptoms and improving exercise tolerance, activities of daily living, and quality of life,” emphasizes Dr. Roe. “In patients undergoing lung transplantation at IU Health, pulmonary rehabilitation is a component of care before and after transplant.”
Because of the patient’s advanced lung disease (as demonstrated on HRCT and pulmonary function testing), he is referred to IU Health lung transplant program at Methodist Hospital for evaluation and is subsequently placed on the waiting list for a donor organ. Two months later, he successfully undergoes bilateral lung transplantation and is supported by venovenous extracorporeal membrane oxygenation (ECMO) during the immediate post-transplant period.
Despite improvements in donor lung preservation and surgical technique, 10 to 25 percent of patients undergoing lung transplantation experience primary graft dysfunction (PGD), the leading cause of early death.21 Survivors of PGD tend to have a longer duration of mechanical ventilation, extended hospital stays, and lower lung function over time.
DPGD reflects the summation of injuries inflicted on the donor lung(s) by the transplant process—retrieval, preservation, implantation, and reperfusion—and by factors such as acid aspiration, pneumonia, and microtrauma from mechanical ventilation. Recipient factors also play a role: persons with IPF have a higher incidence of PGD than do those with emphysema.
“Perioperative venovenous ECMO, which provides pulmonary support only, has the capacity to support gas exchange and stabilize the patient’s condition until the new lungs recover,” Dr. Roe explains. “Enhanced safety combined with increased experience has led to earlier deployment of ECMO following lung transplantation, thereby avoiding or minimizing the detrimental effects of ventilator support for primary graft dysfunction secondary to elevated airway pressures or high inspired oxygen concentrations.”
The venovenous ECMO technique used by IU Health transplant specialists involves placement of a dual-lumen catheter (Avalon Elite®) in the right internal jugular vein (Figure 5, see page 6). The catheter is designed to increase the efficiency of blood gas exchange by draining blood from both the upper and lower body while simultaneously reinfusing it directly into the heart. Bleeding, often related to the need for systemic anticoagulation and the most common complication of ECMO, is reduced by the use of modern circuitry.22
The patient is hospitalized for three weeks. Following discharge home, he is enrolled for one month at the Center of Life for Thoracic Transplant (COLTT).* After completing the rehabilitation program, his overall lung function has normalized, supplemental oxygen is no longer required, and he is able to resume all daily activities. He returns to IU Health for weekly follow-up during the first post-transplant month, every two weeks for the next three months, and monthly thereafter for the first year.
Future Management of IPF
Enhanced understanding of the pathogenic mechanisms of IPF (e.g., genetic susceptibility, abnormalities in telomere biology, increased epithelial apoptosis, cell senescence23) together with the efficacy of pirfenidone and nintedanib in slowing deteriorating lung function have raised hopes of finding a curative therapy. Ongoing investigational drug trials are focused on modifying disease progression via disparate targets, including the immune system, proinflammatory cascade, intracellular signaling, and myofibroblast activation. Strategies directed toward modulating the alveolar microenvironment (the lung microbiome) may represent another avenue for treatment, while the identification of specific IPF biomarkers may lead to more tailored therapies. For the near future, however, lung transplantation will remain the only treatment for IPF with the potential to increase long-term survival.
“Early disease detection and referral to a transplant center for initial consultation, even if lung transplantation is not yet needed, is key to improving outcomes for patients with idiopathic pulmonary fibrosis,” Dr. Roe concludes.
Dr. Roe received his medical degree from Southern Illinois University in Springfield, did a residency in internal medicine and pediatrics at Michigan State University, and completed a fellowship in pulmonary/critical care medicine at IU School of Medicine. He is currently medical director of the lung transplant and ECMO programs at IU Heath and medical director of the critical care unit and advanced heart and lung care clinic at Methodist Hospital. His clinical interests focus on lung transplantation, ECMO, and interventional bronchoscopy. Among his research interests are frailty in lung transplant recipients, chronic lung allograft dysfunction, and lung transplantation protocol development.
A fellow of the American College of Physicians and the American College of Chest Physicians and member of the American Thoracic Society and other professional organizations, Dr. Roe is a reviewer for the Journal of Intensive Care Medicine and serves as a co-investigator for two ongoing clinical trials. The author of several peer-reviewed journal articles, he is frequently invited to lecture on lung transplantation and ECMO at local and national medical conferences.
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