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[MEDSCAPE]:特发性肺间质纤维化
2017年12月14日 时讯速递, 进展交流 暂无评论

Idiopathic Pulmonary Fibrosis: Killer Without a Cause

Mehran Farid-Moayer, MD; Mark P Brady, PA-C | December 5, 2017

Image courtesy of author's practice database.

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)?

Image courtesy of Radiopaedia.org.

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?

Images courtesy of Radiopaedia.org (left) and author's practice database (right).

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?

Images courtesy of Radiopaedia.org.

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?

Image courtesy of Radiopaedia.org.

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?

Image courtesy of Wikimedia Commons.

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.

In these circumstances, does the diffusing capacity of the lung for carbon monoxide (DLCO) have any prognostic value?

Image courtesy of Latsi PI et al.[3]

Answer: Yes. A DLCO of less than 35% is associated with a worse prognosis. [3]

What are the most important risk factors for IPF?

Table adapted from Raghu et al.[4]

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. [4]

Image courtesy of Wikimedia Commons | Table adapted from Bjoraker JA et al.[5]

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]

As of 2017, what are the treatment options for IPF?

Image courtesy of Medscape.

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?

Image courtesy of the National Institutes of Health (NIH).

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. [6,7] 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.

What are the treatment options for acute exacerbations of IPF?

Image courtesy of Wikimedia Commons.

Answer: Treatment options for acute IPF exacerbations include the following [8]:

  • Broad-spectrum antibiotics
  • High-dose steroids
  • Possibly, cytotoxic agents and mechanical ventilation

The mortality exceeds 70%.

What, if any, specific medical therapies are available for IPF?

Image courtesy of Medscape.

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 [9,10]; in addition, it may increase the time to first exacerbation. [10] 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.

The 2015 update of the 2011 clinical practice guideline published by the American Thoracic Society (ATS), the European Respiratory Society (ERS), the Japanese Respiratory Society (JRS), and the Latin American Thoracic Association (ALAT) included a conditional recommendation for the use of nintedanib to treat IPF. [11]

Image courtesy of Sam Shlomo Spaeth / Medscape.

The second medication approved by the FDA for the treatment of IPF is pirfenidone, an antifibrotic agent that slows down the lung function decline. [12] It is more effective in a subset of patients with mild-to-moderate disease. [13,14] 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. [11] 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?

Image courtesy of Wikimedia Commons.

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. [15] 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. [16,17]

Image courtesy of Wikipedia.

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. [18] 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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