Examine individual changes

'{{Infobox disease | Name = Idiopathic pulmonary fibrosis | Image = Ipf NIH.jpg | Caption = '''Figure A''' shows the location of the lungs and airways in the body. The inset image shows a detailed view of the lung's airways and air sacs in cross-section. <br>'''Figure B''' shows fibrosis (scarring) in the lungs. The inset image shows a detailed view of the fibrosis and how it damages the airways and air sacs.<ref name="NIH_IPF">{{cite web|title=Idiopathic Pulmonary Fibrosis|url=http://www.nhlbi.nih.gov/health/health-topics/topics/ipf/|website=http://www.nhlbi.nih.gov/|accessdate=5 August 2014}}</ref><!-- PD source --> | DiseasesDB = 4815 | ICD10 = {{ICD10|J|84|112|j|80}} | ICD9 = {{ICD9|516.31}} | ICDO = | OMIM = 178500 | MedlinePlus = 000069 | eMedicineSubj = radio | eMedicineTopic = 873 | MeshID = D011658 }} <!-- Definition and symptoms --> '''Idiopathic pulmonary fibrosis''' ('''IPF''') is a [[chronic condition|chronic]] and ultimately fatal disease characterized by a progressive decline in lung function.<ref name=RaghuCollard /><ref name=ATS/ERS /> The term [[pulmonary fibrosis]] means scarring of lung tissue and is the cause of worsening [[dyspnea]] (shortness of breath). [[Fibrosis]] is usually associated with a poor [[prognosis]].<ref name=RaghuCollard /><ref name=ATS/ERS /><ref name=MeltzerNoble /> <!-- Cause and diagnosis --> IPF belongs to a large group of more than 200 lung diseases known as [[interstitial lung disease]]s (ILDs), characterized by the involvement of lung [[interstitium]].<ref name=ATS/ERS /> The interstitium, the tissue between the [[Alveoli|air sacs in the lung]], is the primary site of injury in ILDs. However, these disorders frequently affect not only the [[interstitium]], but also the airspaces, peripheral airways, and vessels.<ref name=ATS/ERS /> Lung tissue from people with IPF shows a characteristic histopathologic pattern known as [[usual interstitial pneumonia]] (UIP). UIP is therefore the pathologic counterpart of IPF.<ref name=RaghuCollard /><ref name=PulmonaryFibrosis /> The term '[[idiopathic]]' is used because the cause of pulmonary fibrosis is still unknown.<ref name=RaghuCollard /> IPF usually occurs in adult individuals of between 50 and 70 years of age, particularly those with a history of [[cigarette smoking]], and affects more men than women.<ref name=RaghuCollard /><ref name=PulmonaryFibrosis /> The diagnosis of IPF requires exclusion of other known causes of ILDs and the presence of a typical radiological pattern identified through [[high resolution computed tomography]] (HRCT). In the right clinical setting, it is possible to make the diagnosis of IPF by HRCT alone, obviating the need for surgical lung biopsy.<ref name=RaghuCollard /><ref name=ATS/ERS /> <!-- Prevention and treatment --> Treatment may include [[nintedanib]] or [[pirfenidone]].<ref>{{cite journal|last1=Raghu|first1=Ganesh|last2=Rochwerg|first2=Bram|last3=Zhang|first3=Yuan|last4=Garcia|first4=Carlos A. Cuello|last5=Azuma|first5=Arata|last6=Behr|first6=Juergen|last7=Brozek|first7=Jan L.|last8=Collard|first8=Harold R.|last9=Cunningham|first9=William|last10=Homma|first10=Sakae|last11=Johkoh|first11=Takeshi|last12=Martinez|first12=Fernando J.|last13=Myers|first13=Jeffrey|last14=Protzko|first14=Shandra L.|last15=Richeldi|first15=Luca|last16=Rind|first16=David|last17=Selman|first17=Moisés|last18=Theodore|first18=Arthur|last19=Wells|first19=Athol U.|last20=Hoogsteden|first20=Henk|last21=Schünemann|first21=Holger J.|title=An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline|journal=American Journal of Respiratory and Critical Care Medicine|date=15 July 2015|volume=192|issue=2|pages=e3–e19|doi=10.1164/rccm.201506-1063ST}}</ref> ==Classification== [[File:Diffuse Parenchymal Lung Diseases.jpg|thumb|New classification of IIPs.<ref>{{cite journal|last1=Travis|first1=WD|last2=Costabel|first2=U|last3=Hansell|first3=DM|last4=King TE|first4=Jr|last5=Lynch|first5=DA|last6=Nicholson|first6=AG|last7=Ryerson|first7=CJ|last8=Ryu|first8=JH|last9=Selman|first9=M|last10=Wells|first10=AU|last11=Behr|first11=J|last12=Bouros|first12=D|last13=Brown|first13=KK|last14=Colby|first14=TV|last15=Collard|first15=HR|last16=Cordeiro|first16=CR|last17=Cottin|first17=V|last18=Crestani|first18=B|last19=Drent|first19=M|last20=Dudden|first20=RF|last21=Egan|first21=J|last22=Flaherty|first22=K|last23=Hogaboam|first23=C|last24=Inoue|first24=Y|last25=Johkoh|first25=T|last26=Kim|first26=DS|last27=Kitaichi|first27=M|last28=Loyd|first28=J|last29=Martinez|first29=FJ|last30=Myers|first30=J|last31=Protzko|first31=S|last32=Raghu|first32=G|last33=Richeldi|first33=L|last34=Sverzellati|first34=N|last35=Swigris|first35=J|last36=Valeyre|first36=D|last37=ATS/ERS Committee on Idiopathic Interstitial|first37=Pneumonias|title=An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.|journal=American Journal of Respiratory and Critical Care Medicine|date=15 September 2013|volume=188|issue=6|pages=733–48|pmid=24032382|doi=10.1164/rccm.201308-1483ST}}</ref>]] Idiopathic pulmonary fibrosis (IPF) belongs to a large group of more than 200 lung diseases known as [[interstitial lung disease]]s (ILDs), which are characterized by the involvement of the lung [[interstitium]],<ref name=ATS/ERS /> the tissue between the air sacs of the lung. IPF is one specific presentation of [[idiopathic interstitial pneumonia]] (IIP), which is in turn a type of ILD, also known as [[diffuse parenchymal lung disease]] (DPLD). The 2002 [[American Thoracic Society]]/[[European Respiratory Society]] (ATS/ERS) classification of IIPs was updated in 2013.<ref name=ATS/ERS /> In this new classification there are three main categories of [[idiopathic]] interstitial pneumonias (IIPs): major IIPs, rare IIPs, and unclassifiable IIPs. The major IIPs are grouped into [[chronic condition|chronic]] fibrosing IPs (this includes IPF and [[non-specific interstitial pneumonia]] [NSIP]); smoking-related IPs (i.e. respiratory bronchiolitis–interstitial lung disease [RB-ILD] and [[desquamative interstitial pneumonia]] [DIP]); and acute/subacute IPs (i.e. [[cryptogenic organizing pneumonia]] [COP] and [[acute interstitial pneumonia]] [AIP].<ref name=ATS/ERS /> The diagnosis of IIPs requires exclusion of known causes of ILD. Examples of ILD of known cause include [[hypersensitivity pneumonitis]], pulmonary [[Langerhan’s cell histiocytosis]], [[asbestosis]], and [[collagen vascular disease]]. However, these disorders frequently affect not only the interstitium, but also the airspaces, peripheral airways, and blood vessels.<ref name=ATS/ERS /> ==Signs and symptoms== [[File:Clubbing of fingers in IPF.jpg|thumb|right|Clubbing of the fingers in idiopathic pulmonary fibrosis]] In many patients, symptoms are present for a considerable time before diagnosis.<ref name=MeltzerNoble /> The most common clinical features of IPF include the following:<ref name=RaghuCollard /><ref name=ATS/ERS /><ref name=FlahertyMumford /> * Age over 50 years * Dry, non-productive cough on exertion * Progressive exertional dyspnea (shortness of breath with exercise) * Dry, inspiratory bibasilar "velcro-like" [[crackles]] on [[auscultation]] (a crackling sound in the lungs during inhalation similar to Velcro being torn apart slowly, heard with a stethoscope).<ref name=RaghuCollard /><ref name=RaghuWeycker /><ref name=CottinCordier /> * Clubbing of the digits, a disfigurement of the finger tips or toes (see image) * Abnormal [[pulmonary function test]] results, with evidence of restriction and impaired gas exchange. These features are due to chronic [[oxygen deficiency]] in blood and can occur in a wide variety of other pulmonary disorders and not be specific for IPF. However, IPF should be considered in all patients with unexplained chronic exertional dyspnea who present with cough, inspiratory bibasilar crackles, or finger clubbing.<ref name=RaghuCollard /> Assessment of "velcro" crackles on lung auscultation is a practical way to improve the earlier diagnosis of IPF. Fine crackles are easily recognized by clinicians and are characteristic of IPF.<ref name=BaughnmanShipley /> {{listen |filename=IPF Lung Sound.ogg |title=IPF Lung Sound |description=velcro crackles on auscultation in a patient with IPF }} If bilateral fine crackles are present throughout the inspiratory time and are persisting after several deep breaths, and if remaining present on several occasions several weeks apart in a subject aged ≥60 years, this should raise the suspicion of IPF and lead to consideration of an HRCT scan of the chest which is more sensitive than a [[chest X-ray]].<ref name=CottinCordier /> As crackles are not specific for IPF, they must prompt a thorough diagnostic process.<ref name=RaghuCollard /> == Causes== The cause of IPF is unknown but certain environmental factors and exposures have been shown to increase the risk of getting IPF.<ref name=OlsonSwigris /> [[Cigarette smoking]] is the best recognized and most accepted risk factor for IPF, and increases the risk of IPF by about twofold.<ref name=OlsonSwigris /> Other environmental and occupation exposures such as exposure to metal dust, wood dust, coal dust, silica, stone dust, biologic dusts coming from hay dust or mold spores or other agricultural products, and occupations related to farming/livestock have also been shown to increase the risk for IPF.<ref name=OlsonSwigris /> There is some evidence that viral infections may be associated with idiopathic pulmonary fibrosis and other [[fibrotic lung disease]]s.<ref name=Williams /> ==Pathogenesis== Despite extensive investigation, the cause of IPF remains unknown.<ref name=RaghuCollard /> The fibrosis in IPF has been linked to cigarette smoking, environmental factors (e.g. occupational exposure to gases, smoke, chemicals or dusts), other medical conditions including [[gastroesophageal reflux disease]] (GERD), or to genetic predisposition (familial IPF). However, none of these is present in all people with IPF and therefore do not provide a completely satisfactory explanation for the disease.<ref name=RaghuCollard /><ref name=GarciaBuendia /> IPF is believed to be the result of an aberrant wound healing process including/involving abnormal and excessive deposition of [[collagen]] (fibrosis) in the pulmonary [[interstitium]] with minimal associated [[inflammation]].<ref name=HarariCaminati /> It is hypothesized that the initial or repetitive injury in IPF occurs to the lung cells, called alveolar epithelial cells (AECs, pneumocytes), which line the majority of the alveolar surface.<ref name=LoomisFlaherty /> When type I AECs are damaged or lost, it is thought that type II AECs undergo proliferation to cover the exposed basement membranes. In normal repair, the hyperplastic type II AECs die and the remaining cells spread and undergo a differentiation process to become type I AECs. Under pathologic conditions and in the presence of [[transforming growth factor beta]] (TGFβ), [[fibroblasts]] accumulate in these areas of damage and differentiate into [[myofibroblasts]] that secrete collagen and other proteins.<ref name=LoomisFlaherty /> In the past, It was thought that [[inflammation]] was the first event in initiating lung tissue scarring. According to the most recent findings, however, the development of fibroblastic foci precedes the accumulation of inflammatory cells and the consequent deposition of collagen.<ref name=PardoSelman /> [[File:Concepts of IPF.jpg|thumb|right|alt=Etiology and pathobiology of Idiopathic Pulmonary Fibrosis (IPF)]] This pathogenetic model is indirectly supported by the clinical features of IPF, including an insidious onset, progression over several years, relatively infrequent acute exacerbations, and failure to respond to [[immunosuppressive therapy]].<ref name=HarariCaminati /><ref name=SelmanKing /> A number of therapies that target fibroblast activation or the synthesis of extracellular matrix are currently in early testing or are being considered for development. Familial IPF accounts for less than 5% of the total of patients with IPF and is clinically and histologically indistinguishable from sporadic IPF.<ref name=RaghuCollard /> Genetic associations include mutations in [[pulmonary surfactant]] proteins A1, A2, C ([[SFTPA1]], [[SFTPA2B]]) and [[mucin]] ([[MUC5B]]).<ref name=OMIM /> A remarkable aspect of the MUC5B variant is its high frequency of detection, as it is found in approximately 20% of individuals with Northern and Western European ancestry and in 19% of the Framingham Heart Study population.<ref name=Mathai /> Mutations in human [[telomerase]] genes are also associated with familial pulmonary fibrosis and in some patients with sporadic IPF (e.g. the [[TERT]], [[Telomerase RNA component|TERC]] genes).<ref name=OMIM /> Recently an X-linked mutation in a third telomerase-associated gene, dyskerin (DKC1), has been described in a family with IPF.<ref name=KropskiMitchell /> ==Diagnosis== An earlier diagnosis of IPF is a prerequisite for earlier treatment and, potentially, improvement of the long-term clinical outcome of this progressive and ultimately fatal disease.<ref name=RaghuCollard /> If IPF is suspected, diagnosis can be challenging but a multidisciplinary approach involving a pulmonologist, radiologist and pathologist expert in interstitial lung disease has been shown to improve the accuracy of IPF diagnosis.<ref name=RaghuCollard /><ref name=FlahertyKing /><ref name=FlahertyAndrei /> A Multidisciplinary Consensus Statement on the Idiopathic Interstitial Pneumonias published by the [[American Thoracic Society]] (ATS) and the [[European Respiratory Society]] (ERS) in 2000 proposed specific major and minor criteria for establishing the diagnosis of IPF.<ref name=RaghuCollard /> However, in 2011, new simplified and updated criteria for the diagnosis and management of IPF were published by the ATS, ERS, together with the Japanese Respiratory Society (JRS) and Latin American Thoracic Association (ALAT).<ref name=RaghuCollard /> Currently, a diagnosis of IPF requires: * Exclusion of known causes of ILD, e.g., domestic and occupational environmental exposures, connective tissue disorders, or drug exposure/toxicity * The presence of a typical radiological UIP pattern on HRCT. In the right clinical setting, it is possible to make the diagnosis of IPF by HRCT alone, obviating the need for surgical lung biopsy.<ref name=RaghuCollard /><ref name=ATS/ERS /> Recognizing IPF in clinical practice can be challenging as [[symptoms]] often appear similar to those of more common diseases, such [[asthma]], [[chronic obstructive pulmonary disease]] (COPD) and [[congestive heart failure]] ([http://www.diagnoseipf.com www.diagnoseipf.com]). The key issue facing clinicians is whether the presenting history, [[symptoms]] (or signs), [[radiology]], and [[pulmonary function testing]] are collectively in keeping with the diagnosis of IPF or whether the findings are due to another process. It has long been recognized that patients with ILD related to [[asbestos]] exposure, [[drugs]] (such as [[chemotherapeutic]] agents or [[nitrofurantoin]]), [[rheumatoid arthritis]] and [[scleroderma]]/[[systemic sclerosis]] may be difficult to distinguish from IPF. Other differential diagnostic considerations include interstitial lung disease related to [[mixed connective tissue disease]], advanced [[sarcoidosis]], chronic [[hypersensitivity pneumonitis]], pulmonary [[Langerhan’s cell histiocytosis]] and [[radiation-induced lung injury]].<ref name=RaghuCollard /><ref name=ATS/ERS /> ===Radiology=== [[Chest X-rays]] are useful in the follow up routine of IPF patients. Plain chest X-rays are unfortunately not diagnostic but may reveal decreased [[lung volumes]], typically with prominent reticular interstitial markings near the lung bases.<ref name=RaghuCollard /> [[File:Radiological evaluation through HRCT.jpg|thumb|right|A chest radiograph of a patient with Idiopathic Pulmonary Fibrosis (IPF).|A chest radiograph of a patient with IPF. Note the small lung fields and peripheral pattern of reticulonodular opacification.]]The radiological evaluation through HRCT is an essential point in the diagnostic pathway in IPF. HRCT is performed using a conventional [[X-ray computed tomography|computed axial tomographic scanner]] without injection of contrast agents. Evaluation slices are very thin, 1–2&nbsp;mm. Typical HRCT of the chest of IPF demonstrates fibrotic changes in both lungs, with a predilection for the bases and the periphery. According to the joint ATS/ERS/JRS/ALAT 2011 guidelines, HRCT is an essential component of the diagnostic pathway in IPF which can identify UIP by the presence of:<ref name=RaghuCollard /> * Reticular opacities, often associated with [[traction bronchiectasis]] * [[Honeycombing]] manifested as cluster cystic airspaces, typically of comparable diameters (3–10&nbsp;mm) but occasionally large. Usually sub-pleural and characterized by well-defined walls and disposed in at least two lines. Generally one line of cysts is not sufficient to define honeycombing * [[Ground-glass opacities]] are common but less extensive than the reticulation * Distribution characteristically basal and peripheral though often patchy. [[File:HR tomography of the chest of an IPF patient.jpg|frame|center|High-resolution computed tomography scans of the chest of a patient with IPF|High-resolution computed tomography scans of the chest of a patient with IPF. The main features are of a peripheral, predominantly basal pattern of coarse reticulation with honeycombing]] ===Histology=== According to the updated 2011 guidelines, in the absence of a typical UIP pattern on HRCT, a surgical lung biopsy is required for confident diagnosis.<ref name=RaghuCollard /> Histologic specimens for the diagnosis of IPF must be taken at least in three different places and be large enough that the pathologist can comment on the underlying lung architecture. Small biopsies, such as those obtained via transbronchial lung [[biopsy]] (performed during bronchoscopy) are usually not sufficient for this purpose. Hence, larger biopsies obtained surgically via a [[thoracotomy]] or [[thoracoscopy]] are usually necessary.<ref name=RaghuCollard /><ref name=ATS/ERS /> Lung tissue from people with IPF usually show a characteristic histopathologic UIP pattern and is therefore the pathologic counterpart of IPF.<ref name=RaghuCollard /><ref name=PulmonaryFibrosis /> Although a pathologic diagnosis of UIP often corresponds to a clinical diagnosis of IPF, a UIP histologic pattern can be seen in other diseases as well, and fibrosis of known origin (rheumatic diseases for example).<ref name=NIH_IPF /><ref name=RaghuCollard /> There are four key features of UIP including interstitial fibrosis in a ‘patchwork pattern’, interstitial scarring, honeycomb changes and fibroblast foci. Fibroblastic foci are dense collections of myofibroblasts and scar tissue and, together with honeycombing, are the main pathological findings that allow a diagnosis of UIP. [[File:Photomicrograph of usual interstitial pneumonia.jpg|frame|center|Photomicrograph of the histopathological appearances of usual interstitial pneumonia.|Photomicrograph of the histopathological appearances of usual interstitial pneumonia. High-power magnification (on the right) shows a focus of fibroblastic proliferation, close to an area of fibrosis within which a mild, non-specific, chronic inflammatory cell infiltrate can be observed. In the subpleural space, a typical honeycombing aspect can be recognized.]] ===Bronchoalveolar lavage=== [[Bronchoalveolar lavage]] (BAL) is a well-tolerated diagnostic procedure in ILD.<ref name=FlahertyMumford /> BAL cytology analyses (differential cell counts) should be considered in the evaluation of patients with IPF at the discretion of the treating physician based on availability and experience at their institution. BAL may reveal alternative specific diagnoses: [[malignancy]], [[infections]], [[eosinophilic pneumonia]], [[histiocytosis X]], or [[alveolar proteinosis]]. In the evaluation of patients with suspected IPF, the most important application of BAL is in the exclusion of other diagnoses. Prominent [[lymphocytosis]] (>30%) generally allows excluding a diagnosis of IPF.<ref name=OhshimoBonella /> ===Pulmonary function tests=== [[Spirometry]] classically reveals a reduction in the [[vital capacity]] (VC) with either a proportionate reduction in airflows, or increased airflows for the observed vital capacity. The latter finding reflects the increased lung stiffness (reduced lung compliance) associated with pulmonary fibrosis, which leads to increased lung elastic recoil.<ref name=PellegrinoViegi /> Measurement of static lung volumes using [[body plethysmography]] or other techniques typically reveals reduced lung volumes (restriction). This reflects the difficulty encountered in inflating the fibrotic lungs. The diffusing capacity for carbon monoxide (DL<small>CO</small>) is invariably reduced in IPF and may be the only abnormality in mild or early disease. Its impairment underlies the propensity of patients with IPF to exhibit oxygen desaturation with exercise which can also be evaluated using the 6-minute walk test (6MWT).<ref name=RaghuCollard /> Terms such as ‘mild’, ‘moderate’, and ‘severe’ are sometimes used for staging disease and are commonly based on resting pulmonary function test measurements.<ref name=RaghuCollard /> However, there is no clear consensus regarding the staging of IPF patients and what are the best criteria and values to use. Mild-to-moderate IPF has been characterized by the following functional criteria:<ref name=NobleAlbera /><ref name=MartinezSafrin /><ref name=KingBradford /><ref name=RicheldiduBois /> * Forced Vital Capacity (FVC) of ≥50% * DL<small>CO</small> of ≥30% * 6MWT distance ≥150 meters. ==Treatment== The goals of treatment in IPF are essentially to reduce the symptoms, stop disease progression, prevent acute exacerbations, and prolong survival. Preventive care (e.g. vaccinations) and symptom-based treatment should be started early in every patient.<ref name=LeeMcLaughlin /> ===Pharmacologic interventions=== A number of treatments have been investigated in the past for IPF, including [[Interferon beta 1a|interferon gamma-1β]],<ref name=KingAlberaBradford /> [[bosentan]],<ref name=KingBrown /> [[ambrisentan]],<ref name=RaghuBehr /> and [[anticoagulants]],<ref name=NothAnstrom /> but these are no longer considered effective treatment options. Many of these earlier studies were based on the hypothesis that IPF is an inflammatory disorder. ;Pirfenidone [[Pirfenidone]] is a small molecule that combines both anti-inflammatory, anti-oxidant, and anti-fibrotic effects in experimental models of fibrosis.<ref name=SchaeferRuhrmund /> Pirfenidone marketed under the trade name [http://www.intermune.com/pirfenidone Esbriet®], is approved in Europe for the treatment of patients with mild-to-modetate IPF. It is also approved in Japan and South Korea (trade name Pirespa®), as well as in Canada, China, India, Argentina and Mexico. In October 2014 it was approved for use in IPF in the United States of America by the Food and Drug Administration (FDA).<ref>http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418991.htm</ref> Pirfenidone was approved in the European Union based on the results of three Phase III, randomized, double-blind, placebo-controlled studies, one conducted in Japan and the other two in Europe and the USA ([http://www.ncbi.nlm.nih.gov/pubmed/21571362 CAPACITY] trials).<ref name=NobleAlbera /><ref name=TaniguchiEbina /> A Review on the [[Cochrane Library]] (the journal of the Cochrane Collaboration for evidence-based Medicine) based on four trials involving 1155 patients comparing pirfenidone with placebo, demonstrated a significantly reduced risk of disease progression in patients treated with pirfenidone by 30%.<ref name=SpagnoloDelGiovane /> FVC or VC was also significantly improved by pirfenidone, even if a mild slowing in FVC decline could be demonstrated only in one of the two CAPACITY trials.<ref name=NobleAlbera /> On the basis of these mixed results, the American Federal [[Food and Drug Administration]] (FDA) requested a third multinational Phase III clinical study, [http://www.ncbi.nlm.nih.gov/pubmed/24836312 ASCEND] (NCT01366209). This study, which was completed in 2014 and published on-line in the New England Journal of Medicine, showed that pirfenidone significantly reduced decline in lung function and IPF disease progression.<ref name=KingBradford /> The data from the ASCEND study were also pooled with data from the two CAPACITY studies in a pre-specified analysis which showed that pirfenidone reduced the risk of death by almost 50% over one year of treatment.<ref name=KingBradford /> Based on these results, pirfenidone has been granted Breakthrough Therapy Designation from the U.S. FDA, a designation reserved for drugs that are intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.<ref name=IntermunePress /> The company that has developed pirfenidone, InterMune Inc., is providing compassionate use of pirfenidone through a multi-center Expanded Access Program (EAP) in the United States during the pre-approval period.<ref name=IntermuneAnnounces /> ;N-acetylcysteine and triple therapy [[N-Acetylcysteine|''N''-Acetylcysteine]] (NAC) is a precursor to glutathione, an [[antioxidant]]. It has been hypothesized that treatment with high doses of NAC may repair an oxidant–antioxidant imbalance that occurs in the lung tissue of patients with IPF. In the first clinical trial of 180 patients (IFIGENIA), NAC was shown in previous study to reduce the decline in VC and DLCO over 12 months of follow-up when used in combination with [[prednisone]] and [[azathioprine]] (triple therapy).<ref name=DemedtsBehr /> More recently, a large randomized, controlled trial (PANTHER-IPF) was undertaken by the [[National Institutes of Health]] (NIH) in the USA to evaluate triple therapy and NAC monotherapy in IPF patients. This study found that the combination of prednisone, azathioprine, and NAC increased the risk of death and hospitalizations<ref>Raghu G, Anstrom KJ, King TE, Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. NEnglJMed. 2012 May 24;366:1968–77.</ref> and the NIH announced in 2012 that the triple-therapy arm of the PANTHER-IPF study had been terminated early.<ref name=NIHApril2013 /> This study also evaluated NAC alone and the results for this arm of the study were published in May 2014 in the New England Journal of Medicine, concluding that "as compared with placebo, acetylcysteine offered no significant benefit with respect to the preservation of FVC in patients with idiopathic pulmonary fibrosis with mild-to-moderate impairment in lung function".<ref name=IPFCRN /> ;Nintedanib (formerly BIBF 1120) One treatment in development has completed two Phase III trials (INPULSIS-1 and INPULSIS-2).<ref name=RicheldiduBois/> Nintedanib is an investigational orally-administered triple angiokinase inhibitor that targets receptor tyrosine kinases involved in the regulation of angiogenesis: fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR),<ref name=BIBF /> which have also been implicated in the pathogenesis of fibrosis and IPF. In both phase III trials, nintedanib significantly reduced the decline in lung function by approximately 50% over one year.<ref name=RicheldiduBois/> With regards to the secondary endpoints, only in INPULSIS-2 trial, there was a significant increase in the time (delayed onset) of the first acute exacerbation (seeabove) in the nintedanib group as compared with the placebo group. In INPULSIS-1 trial this increase was not seen. Nintedanib, like pirfenidone, was approved for the treatment of Idiopathic Pulmonary Fibrosis by the U.S. FDA in October 2014.<ref>http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418994.htm</ref> ;Future therapeutic options A number of agents are currently being investigated in Phase II clinical trials for IPF, including the monoclonal antibodies simtuzumab, tralokimab, lebrikizumab and FG-3019, a lysophosphatidic acid receptor antagonist (BMS-986020). A Phase II study of STX-100 is also ongoing.<ref name=CoalitionForPF /> These molecules are directed against several growth factors and cytokines that are known to play a role in the proliferation, activation, differentiation or inappropriate survival of fibroblasts. [[mir-29 microRNA precursor]] investigations in mice have produced reversal of induced IPF. MRG-201 is currently being tested as-of 2016, but not in IPF patients yet, and no human trials for IPF use have been scheduled as-of January, 2016.<ref>{{cite web|title=Research Demonstrates Reversal Of Pulmonary Fibrosis With miRagen Therapeutics Synthetic microRNA-29 Mimic (promiR-29)|url=http://pulmonaryfibrosisnews.com/2014/09/23/research-demonstrates-reversal-of-pulmonary-fibrosis-with-miragen-therapeutics-synthetic-microrna-29-mimic-promir-29/}}</ref> More information can be found at [http://ClinicalTrials.gov ClinicalTrials.gov], a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. ===Non pharmacological interventions=== ;Lung transplantation [[Lung transplantation]] may be suitable for those patients physically eligible to undergo a major transplant operation. In IPF patients, lung transplant has been shown to reduce the risk of death by 75% as compared with patients who remain on the waiting list.<ref name=RussoIribarne /> Since the introduction of the [[lung allocation score]] (LAS), which prioritizes transplant candidates based on survival probability, IPF has become the most common indication for lung transplantation in the USA.<ref name=SpagnoloTonelli /> Symptomatic patients with IPF younger than 65 years of age and with a body mass index (BMI) ≤26&nbsp;kg/m² should be referred for lung transplantation, but there are no clear data to guide the precise timing for LTx. Although controversial, the most recent data suggest that bilateral lung transplantation is superior to single lung transplantation in patients with IPF.<ref name=GeorgeArnaoutakis /> Five-year survival rates after lung transplantation in IPF are estimated at between 50 to 56%.<ref name=RaghuCollard /><ref name=MasonBrizzio /><ref name=KeatingLevvey /> ;Long-term oxygen therapy (LTOT) In the 2011 IPF guidelines, [[oxygen therapy]], or supplementary oxygen for home use, became a strong recommendation for use in those patients with clinically significant resting hypoxemia. Although oxygen therapy has not been shown to improve survival in IPF, some data indicate an improvement in exercise capacity.<ref name=RaghuCollard /><ref name=MorrisonStovall /> ;Pulmonary rehabilitation Fatigue and loss of muscular mass are common and disabling problems for patients with IPF. [[Pulmonary rehabilitation]] may alleviate the overt symptoms of IPF and improve functional status by stabilizing and/or reversing the extrapulmonary features of the disease.<ref name=SpagnoloTonelli /><ref name=Lee /> The number of published studies on the role of pulmonary rehabilitation in idiopathic pulmonary fibrosis is small, but most of these studies have found significant short-term improvements in functional exercise tolerance, quality of life, and dyspnea on exertion.<ref name=KennGloeckl /> Typical programs of rehabilitation include exercise training, nutritional modulation, occupational therapy, education and psychosocial counseling. In the late phase of disease, IPF patients tend to discontinue physical activity due to increasing dyspnea. Whenever possible, this should be discouraged. ===Palliative care=== [[Palliative care]] focuses on reducing symptoms and improving the comfort of patients rather than treating the disease. This may include treatment of worsening symptoms with the use of chronic [[opioids]] for severe dyspnea and cough. Further, oxygen therapy may be useful for palliation of dyspnea in hypoxemic patients. Palliative care also includes relief of physical and emotional suffering and psychosocial support for patients and caregivers.<ref name=RaghuCollard /> With disease progression, patients may experience fear, anxiety and depression and psychological counseling should therefore be considered. In a recent study of outpatients with ILDs, including IPF, depression score, functional status (as assessed by walk test), as well as pulmonary function, all contributed to the severity of dyspnea.<ref name=RyersonBerkeley /> In selected cases of particularly severe dyspnea [[morphine]] could be considered. It can reduce dyspnea, anxiety and cough without significant decrease in oxygen saturation.<ref name=AllenRaut /> ===Follow-up=== IPF is often misdiagnosed, at least until physiological and/or imaging data suggest the presence of an ILD leading to delay in accessing appropriate care.<ref name=SpagnoloTonelli /> Considering that IPF is a disease with a median survival of three years after diagnosis, early referral to a center with specific expertise should therefore be considered for any patient with suspected or known ILD. On the basis of the complex differential diagnostic, multidisciplinary discussion between pulmonologists, radiologists, and pathologists experienced in the diagnosis of ILD is of the utmost importance to an accurate diagnosis.<ref name=RaghuCollard /> After diagnosis of IPF, and the appropriate treatment choice according to symptoms and stage of disease, a close follow-up should be applied. Due to the high variable course of disease, the higher incidence of complications such as lung cancer (up to 25% of patients has been reported in IPF) a routine evaluation every 3 to 6 months, including spirometry (body plethysmography), diffusion capacity testing, chest X-rays, 6MWT, assessment of dyspnea, quality of life, oxygen requirement is mandatory. In addition, the increasing awareness of complications and common concomitant conditions frequently associated with IPF requires a routinely evaluation of comorbidities, most of them simply reflecting concurrent diseases of aging, and medications with their interaction and side effects. ===Acute exacerbations=== Acute exacerbations of IPF (AE-IPF) are defined as an unexplained worsening or development of dyspnea within 30 days with new radiological infiltrates at HRCT abnormality often superimposed on a background consistent with UIP pattern. The yearly incidence of AE-IPF is between 10 and 15% of all patients. The prognosis of AE-IPF is poor, with mortality ranging from 78% to 96%.<ref name=AgarwalJindal /> Other causes of AE-IPF such as pulmonary embolism, congestive heart failure, pneumothorax, or infection need to be excluded. Pulmonary infection have to be ruled out by endotracheal aspirate or BAL. Many patients experiencing acute deterioration require intensive care treatment, particularly when respiratory failure is associated with hemodynamic instability, significant co-morbidities or severe hypoxemia.<ref name=SternMal /> However, mortality during hospitalization is high.<ref name=AgarwalJindal /> Mechanical ventilation should be introduced only after carefully weighing the patient’s long-term prognosis and, whenever possible, the patient’s wishes. However, current guidelines discourage the use of mechanical ventilation in patients with respiratory failure secondary to IPF.<ref name=RaghuCollard /> ==Prognosis== [[File:Comparison of the 5-year survival rate for IPF.jpg|thumb|rightComparison of the 5-year survival rate for Idiopathic Pulmonary Fibrosis (IPF) and common malignancies.|Comparison of the 5-year survival rate for IPF and common malignancies. Adapted from Bjoraker et al. 1998.<ref name=BjorakerRyu />]] The clinical course of IPF can be unpredictable.<ref name=RaghuCollard /><ref name=BjorakerRyu /><ref name=KimCollard /> IPF progression is associated with an estimated median survival time of 2 to 5 years following diagnosis.<ref name=NIH_IPF /><ref name=RaghuCollard /> The 5-year survival for IPF ranges between 20–40%,<ref name=KimCollard /> a mortality rate higher than that of a number of malignancies, including colon cancer, multiple myeloma and bladder cancer.<ref name=BjorakerRyu /><ref name=KimCollard /> Recently a multidimensional index and staging system has been proposed to predict mortality in IPF.<ref name=LeyRyerson /> The name of the index is GAP and is based on gender [G], age [A], and two lung physiology variables [P] (FVC and DL<small>CO</small> that are commonly measured in clinical practice to predict mortality in IPF. The highest stage of GAP (stage III) has been found to be associated with a 39% risk of mortality at 1 year.<ref name=LeyRyerson /> This model has also been evaluated in IPF and other ILDs and shown good performance in predicting mortality in all main ILD subtypes. A modified ILD-GAP Index has been developed for application across ILD subtypes to provide disease-specific survival estimates.<ref name=RyersonVittinghoff /> In IPF patients, the overall mortality at 5 years rate is high but the annual rate of all-cause mortality in patients with mild to moderate lung impairment is relatively low. This is the reason why change in lung function (FVC) is usually measured in 1-year clinical trials of IPF treatments rather than survival.<ref name=KingAlbera /> In addition to clinical and physiological parameters to predict how rapidly patients with IPF might progress, genetic and molecular features are also associated with IPF mortality. For example, it has been shown that IPF patients who have a specific genotype in the mucin MUC5B gene polymorphism (see above) experience slower decline in FVC and significantly improved survival.<ref name=PeljtoZhang /><ref name=StockSato /> Even if such data are interesting from a scientific point of view, the application in the clinical routine of a prognostic model based on specific genotypes is still not possible. ==Epidemiology== Although rare, IPF is the most common form of IIP.<ref name=ATS/ERS /> The prevalence of IPF has been estimated between 14.0 and 42.7 per 100,000 persons based on a USA analysis of healthcare claims data, with variation depending on the case definitions used in this analyses.<ref name=PulmonaryFibrosis /><ref name=RaghuWeycker /> IPF is more common in men than in women and is usually diagnosed in people over 50 years of age.<ref name=RaghuCollard /> The [[incidence (epidemiology)|incidence]] of IPF is difficult to determine as uniform diagnostic criteria have not been applied consistently.<ref name=RaghuCollard /><ref name=RaghuWeycker /> A recent study from the USA estimated the incidence of IPF to be between 6.8 and 16.3 per 100,000 persons. In the 27 European Union countries, a range of sources estimate an incidence of 4.6–7.4 people per 100,000 of the population,<ref name=GribbinHubbard /><ref name=NavaratnamFleming /> suggesting that approximately 30,000–35,000 new patients will be diagnosed with IPF each year.<ref name=PulmonaryFibrosis /><ref name=EurostatNewsJuly2010 /> A recent single-centre, retrospective, observational cohort study including incident patients diagnosed with ILD at Aarhus University Hospital (Denmark) between 2003 and 2009 revealed an incidence of 4.1 per 100,000 inhabitants/year for ILD. IPF was the most common diagnosis (28%) followed by connective tissue disease-related ILD (14%), hypersensitivity pneumonitis (7%) and non-specific interstitial pneumonia (NSIP) (7%). IPF incidence was 1.3 per 100,000 inhabitants/year.<ref name=HyldgaardHilberg /> Due to a heterogeneous distribution of the disease across European countries, epidemiological data needs to be updated through a Europe-wide registry for ILD and IPF. ==Other animals== IPF has been recognized in several breeds of both dogs and cats,<ref name=WilliamsMalarkey /> and has been best characterized in [[West Highland White Terriers]].<ref name=Webb /> Veterinary patients with the condition share many of the same clinical signs as their human counterparts, including progressive exercise intolerance, increased respiratory rate, and eventual respiratory distress.<ref name=Canine /> Prognosis is generally poor. ==References== {{reflist|2| refs= <ref name=RaghuCollard>{{cite journal |vauthors=Raghu G, Collard HR, Egan JJ, etal | title = An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management | journal = Am. J. Respir. Crit. 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Retrieved 2013-04-11.</ref> }} ==External links== {{Commons category|Idiopathic pulmonary fibrosis}} * {{DMOZ|Health/Conditions_and_Diseases/Respiratory_Disorders/Pulmonary_Fibrosis/}} * [http://www.pulmonaryfibrosis.org/Treatment/ Pulmonary fibrosis foundation] * [http://www.blf.org.uk/IPF/ IPF - British Lung Foundation] * [http://www.pulmonary-fibrosis.net/ The European IPF Registry (eurIPFreg) has become Europe's leading database of longitudinal data from IPF patients, including control groups of patients with other lung diseases] * [http://www.coalitionforpf.org/ Coalition for Pulmonary Fibrosis] * [http://www.ildcare.nl/index.php?id=19/ ILD CARE FOUNDATION´s activity is focused to increase knowledge, support research, contribute to prevention and provide counselling for interstitial lung diseases] * [http://www.diagnoseipf.com/ www.diagnoseipf.com] * [http://knowipfnow.com/ KnowIPFNow.com ] * [http://www.inipf.com/ inIPF] * [http://ipftoday.com/ IPFtoday.com] * [http://www.ipfcharter.org ipfcharter.org] * [https://www.youtube.com/channel/UCrtHfxmJFXuG8u87RUkTJNw/featured/ YouTube playlist of patient interviews] {{Respiratory pathology}} {{DEFAULTSORT:Idiopathic Pulmonary Fibrosis}} [[Category:Respiratory diseases principally affecting the interstitium]] [[Category:Idiopathic diseases]] [[de:Idiopathische interstitielle Pneumonie#Idiopathische pulmonale Fibrose (IPF)]]'