
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
A 71-year-old man comes to the office with complaints of shortness of breath and a dry cough for the last 8 months. His cough has not improved with antibiotics or albuterol inhalers. His other main symptom is fatigue. He reports no significant past medical history, takes no medications, and has no known allergies. He denies recreational drug use. He is a social drinker with no history of smoking. His initial pulmonary examination reveals fine bibasilar crackles. Jugular veins are not distended, and no leg edema is present. His ejection fraction is 60% on echocardiography.
What is the radiologic description of this patient's chest radiograph (shown)?
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
Answer: The patient's chest radiograph shows bilateral reticular (a fine network or netlike) opacities.
What is the most appropriate next step in the workup?
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
Answer: The most appropriate next step is to obtain a high-resolution computed tomography (HRCT) scan of the lungs.
Accordingly, the patient undergoes HRCT, which yields the scans shown in the slide. What do these scans reveal?
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
Answer: The HRCT scan shows basal and peripheral reticular opacities with honeycombing and traction bronchiectasis.
What are the signal features of honeycombing on pathologic analysis and HRCT?
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
Answer: Pathologically, honeycombing includes cystic spaces that are air-filled, are lined by bronchiolar epithelium, and have thick walls composed of dense fibrous tissue. On HRCT, honeycombing includes cystic spaces a few millimeters to a few centimeters in diameter that are air-filled and have clear definable walls ranging from 1 to 3 mm in thickness.[1] Adjacent honeycomb cysts share the same walls.
Honeycombing is differentiated from intralobular interstitial thickening on the basis of the material in the cyst-shaped spaces. In honeycombing, the contents of the cystic spaces appear black (air), but in intralobular interstitial thickening, the contents of the spaces appear gray (lung parenchyma). Honeycombing is due to pulmonary fibrosis, and pathologically, it is a terminal process.
What is the main histopathologic feature of IPF?
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
Answer: Fibroblastic foci. Usual interstitial pneumonia (UIP) is the pathologic finding in IPF, and fibroblastic foci and honeycombing are the characteristic histopathologic features of UIP.[2] A fibroblastic focus includes clusters of fibroblasts and myofibroblasts.
Does IPF progress? And if yes, how fast?
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
Answer: The rate of decline in forced vital capacity (FVC) is around 150-200 ml annually.[3]
Among other changes seen in pulmonary function testing is a decline in the diffusing capacity of the lung for carbon monoxide (DLCO), which has prognostic significance.
A DLCO of less than 35% is associated with a worse prognosis.[4]
What are the most important risk factors for IPF?
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
Although IPF is, by definition, a disease of unknown etiology, a number of potential risk factors have been described, including smoking, environmental exposure, infection, gastroesophageal reflux, familial IPF, and genetic factors.[5,6]
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
IPF should be considered in all adult patients with unexplained chronic exertional dyspnea. Common presenting symptoms include cough, bibasilar inspiratory crackles, and finger clubbing (25-50%). Prevalence estimates for IPF have ranged from 2 to 29 cases per 100,000 in the general population. Patients most often present in the sixth and seventh decades of life, and there is a slight male preponderance. Only 20-30% of patients are still alive after 5 years. The median survival is in the range of 2.5-3.5 years.[5]
What are the treatment options for IPF?
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
Answer: Current treatment options for IPF are as follows:
- Supportive care and nonspecific therapies, including oxygen supplementation, pulmonary rehabilitation, vaccinations for influenza, and pneumococcal vaccines
- Treatment of exacerbations
- Medical therapy
- Lung transplant
What are the features of an IPF exacerbation?
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
Answer: In an IPF exacerbation (which occurs in 10-57% of patients with IPF), acute or subacute worsening of respiratory symptoms develops with no clear identifiable cause.[8,9] No viral or bacterial infection is apparent, and no heart failure is detected. The HRCT scan in the slide shows areas of honeycombing with new ground-glass opacities or consolidation. Heart failure or volume overload do not explain the worsening of the patient's condition.[10]
What are the treatment options for acute exacerbations of IPF?
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
Answer: Treatment options for acute IPF exacerbations include the following[11]:
- Maintaining oxygen saturation of 88% or greater by administration of oxygen supplementation or high-flow oxygen.
- Palliative care strategies to improve dyspnea.
- Anti-acid therapy, based on a hypothesis that acid reflux may contribute to the acute exacerbations.
- Broad-spectrum antibiotics.
- Pirfenidone and nintedanib. They can be continued during the course of acute exacerbations. For new patients, they can be started after improvement of acute exacerbation.
- Possibly, cytotoxic agents and mechanical ventilation.
The mortality exceeds 70%.
What, if any, specific medical therapies are available for IPF?
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
Although no curative therapies for IPF are available, two medications have been approved by the US Food and Drug Administration (FDA) for treatment of this condition. One of these agents is the tyrosine kinase receptor blocker nintedanib, which reduces the fibrogenesis and slows down the decline in lung function[12,13]; in addition, it may increase the time to first exacerbation.[13] The dosage is 150 mg twice daily with food. Liver function test (LFT) results should be checked both before the initiation of nintedanib therapy and during treatment. In clinical trials, diarrhea was reported in 62% of patients taking nintedanib, compared with 18% of those taking placebo; nausea was observed in 24% of those taking nintedanib, compared with 7% of those taking placebo.
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
The second medication approved by the FDA for the treatment of IPF is pirfenidone, an antifibrotic agent that slows down the lung function decline.[14] It is more effective in a subset of patients with mild-to-moderate disease.[15,16] Recommended dosing for pirfenidone is as follows:
- Days 1-7: 267 mg (one capsule) orally q8hr with food
- Days 8-14: 534 mg (two capsules) orally q8hr with food
- Day 15 and thereafter: 801 mg (three capsules) orally q8hr with food
LFT results should be checked both before and during treatment with pirfenidone. In clinical trials, nausea was observed in 36% of patients taking pirfenidone, compared with 16% of those taking placebo; diarrhea was reported in 26% of those taking pirfenidone, compared with 20% of those taking placebo. Rash and photosensitivity are common; accordingly, patients must use sunscreen and avoid direct sun exposure.
The 2015 update of the 2011 ATS/ERS/JRS/ALAT clinical practice guideline included a conditional recommendation for the use of pirfenidone to treat IPF.[17] The 2015 guideline also contained conditional recommendations against the use of macitentan, bosentan, or sildenafil, as well as strong recommendations against the use of warfarin, imatinib, ambrisentan, or prednisone + azathioprine + N-acetylcysteine.
Surgical treatment (ie, lung transplant) may be an option for some, but not all, IPF patients. What are the indications for lung transplant in the setting of IPF?
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
With regard to an IPF patient's candidacy for a lung transplant, the criteria for referral differ from the criteria for placement on the transplant list.[18] For the referral, the DLCO should be less than 40% of the predicted value, and the functional vital capacity (FVC) should be less than 80% of the predicted value. Oxygen saturation at baseline or during an exacerbation should be less than 89%. Many people get worse and die while on the transplant waiting list.
Palliative care and end-of-life discussions should be started when the FVC is reduced to less than 50% of the predicted value. The adequacy of end-of-life management in IPF is deserving of further study.[19,20]
Idiopathic Pulmonary Fibrosis: Killer Without a Cause
Herazo-Maya from Yale University and collaborators from six academic centers recruited 425 participants and carried out analysis of a 52-gene signature in mononuclear cells from the blood of IPF patients.[21] They were able to predict transplant-free survival on the basis of changes in the gene profile, and they demonstrated changes in the gene profile after the initiation of antifibrotic therapy. This approach may eventually play a role in prioritization of transplant or in stratification of patients in drug studies.
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