Fig.13.15 ).Overtimetheseareasbecomemorecollagenousandlesscellular.Quitetypicalistheexistenceofbothearlyandlatelesions. ThedensefibrosiscausescollapseofalveolarwallsandformationofcysticspaceslinedbyhyperplastictypeIIpneumocytesorbronchiolarepithelium(honeycomb fibrosis). Theinterstitialinflammationusuallyispatchyandconsistsofanalveolarseptalinfiltrateofmostlylymphocytesandoccasionalplasmacells,mastcells,andeosinophils.Secondarypulmonaryhypertensivechanges(intimalfibrosisandmedialthickeningofpulmonaryarteries)areoftenpresent.
IPF usually presents with the gradual onset of a nonproductive cough and progressive dyspnea. On physical examination, most patients have characteristic “dry” or “Velcrolike” crackles during inspiration. Cyanosis, cor pulmonale, and peripheral edema may develop in later stages of the disease. The characteristic clinical and radiologic findings (subpleural and basilar fibrosis, reticular abnormalities, and “honeycombing”) often are diagnostic. Anti-inflammatory therapies have proven to be of little use, in line with the idea that inflammation is of secondary pathogenic importance. By contrast, anti-fibrotic therapies such as nintedanib, a tyrosine kinase inhibitor, and pirfenidone, an inhibitor of TGF-β, have produced positive outcomes in clinical trials and are now approved for use in patients with IPF. The overall prognosis remains poor, however; survival is only 3 to 5 years, and lung transplantation is the only definitive treatment.
Fig. 13.15 Usualinterstitialpneumonia.Fibroblasticfocuswithfibersrunningparalleltosurfaceandbluishmyxoidextracellularmatrix.Honey-combingispresenttotheleft.
Other rare pulmonary diseases associated with fibrosis need to be considered in the differential diagnosis of IPF, several of which are worthy of brief mention. One is nonspecific interstitial pneumonia (NSIP). NSIP is a chronic bilateral interstitial lung disease of unknown etiology, which (despite its name) has distinct radiologic, histologic, and clinical features, including a frequent association with collagen vascular disorders such as rheumatoid arthritis. It is important to recognize NSIP because it has a much better prognosis than IPF. It is characterized by mild to moderate interstitial chronic inflammation and/or fibrosis that is patchy but uniform in the areas involved. A second uncommon entity associated with fibrosis is cryptogenic organizing pneumonia. It presents with cough and dyspnea, and chest radiographs demonstrate subpleural or peribronchial patchy areas of airspace consolidation which are due to intraalveolar plugs of loose organizing connective tissue. Some patients recover spontaneously while most require treatment, usually with oral steroids. Also in the differential diagnosis of fibrosing pulmonary disorders are several rheumatologic entitiies, such as systemic sclerosis, rheumatoid arthritis and systemic lupus erythematosus, which may be complicated by diffuse pulmonary fibrosis.
Diffuseinterstitialfibrosisofthelunggivesrisetorestrictivelungdiseasescharacterizedbyreducedlungcomplianceandreducedforcedvitalcapacity(FVC).TheratioofFEVtoFVCisnormal.
Diseasesthatcausediffuseinterstitialfibrosisareheterogeneous.TheunifyingpathogenicfactorisinjurytothealveolileadingtoactivationofmacrophagesandreleaseoffibrogeniccytokinessuchasTGF-β.