Idiopathic Pulmonary Fibrosis (IPF; Cryptogenic Fibrosing Alveolitis, Usual Interstitial Pneumonitis)

Epidemiology

  • Incidence: 3-5 cases per 100k
  • Age Distribution
    • Mean Age of Onset: 60’s
    • Peak Incidence: 50-70 y/o (uncommonly occurs before age 40)
  • Relationship to Smoking: 66% of cases are smokers

Familial Idiopathic Pulmonary Fibrosis

  • xxx

Physiology

MUC5B Promoter Polymorphism (rs35705950)

  • MUC5B Promoter Polymorphism (rs35705950) is Associated with IPF in Europeans and Asians [MEDLINE]

    • MUC5B Promoter Polymorphism (rs35705950) is Also Associated with Interstitial Lung Disease in the General Population [MEDLINE]: the association appears to be more prevalent in patients >50 y/o
      • Cigarette smoking does not appear to be associated
  • Unclear etiology

  • Viral infection (no virus has been found in tissue, secretions): possible role of EBV (increased anti-EBV Ab and IgA against viral capsid Ag are present) or HCV
  • Genetic factors: familial cases occur (See ILD (1))
  • Alveolar inflammation: predominantly neutrophils and macrophages (possibly elicited by immune complexes formed in response to some injury/ immune complexes have been found on the surface of alveolar macrophages) in some studies while others show mostly lymphocytes and mast cells (inflammation is factor in predicting therapeutic response)
    • Immune deposits found in 50% of cases, along alveolar epitheilial surface and luminal side of capillary walls (all with immune deposits had circulating immune complexes or positive findings by IF microscopy)
    • Increased fibroblast number with more type I and less type III collagen (type III procollagen can be monitored as a marker by examining BAL, serum, and tissue in IPF) and disordered array of the collagen
  • Role of surfactant: abnormal quantity and composition of phospholipid (decreased total recovery of surfactant phos-pholipid with decreased percentage of PG and slight increase in PI/ PG: PI ratio correlates with histopathologic cellularity and degree of fibrosis)/ similar findings for surfactant pro-teins (SP-A is decreased in IPF/ decreased SP-A: phospho-lipid ratio predicts adverse outcome in IPF and other ILD’s)
  • Pulmonary HTN (due to primary vasculitic lesions of pulm-onary vessels/ compression and destruction of vessels/ acidosis, autocoid, and hypoxia-induced vasoconstriction/ pulmonary blood volume changes/ decreased PA compliance/ pulmonary edema/ decreased LV function/ temperature changes): rarely occurs at rest (occurrence at rest is predicted by VC <50% predicted or DLCO <45% predicted), but is common during exercise (even in early stages of IPF)
    • At rest, mean PA: 23-28 mm Hg (rarely >40)
  • Effects of IPF on sleep (especially in those with daytime hypoxemia or snoring): persistent tachypnea, decreased REM, lighter and more fragmented sleep, REM-associated hypoxemia (hypoxemia may be severe in absence of apnea, hypovent)

Pathology

  • UIP

Pathologic patterns (vasculitis, granulomas, signs of pneumoconioses suggest diagnoses other than IPF/inflammatory or obliterative airway narrowing, obstructive pneumonitis are usually mild-moderate and are seen in <25% of cases):
1) Organizing pneumonia:
2) Usual interstitial pneumonitis (UIP): probably represents intermediate stage of IPF between DIP and honecombing
-Broadened alveolar inter-stitium with fibrosis and fibroblastic proliferation/ type II pneumocyte hyper-plasia
3) Desquamative interstitial pneumonia (DIP): probably is earliest stage of IPF
-Alveolitis: alveoli are filled with alveolar macro-phages (previously thought to be sloughed epithelial cells) and lymphocytes/intact alveolar walls/probably represents the early cellular phase of UIP (and can occur in many lung diseases)/ more steroid-responsive
4) Giant Cell Interstitial Pneumonitis: variant of DIP with multinucleated giant cells also in alveoli (may be idiopathic or associated with hard metal pneumoconiosis)
5) Cellular interstitial pneumonia (CIP):
6) Honeycombing: end-stage, irre-versible IPF
-Disruption of lung architecture with cysts lined by metaplastic cuboidal epi-thelium (has potential for malignant tranformation into adeno or alveolar cell carcinoma) and filled with mucous-containing acute inflammatory cells/ proliferation of interstitial smooth muscle/ intimal smooth muscle proliferation and medial hypertrophy in vessels (indicate long-standing hypoxic pulmonary vasoconstriction)


Diagnosis

Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]])

Erythrocyte Sedimentation Rate (ESR) (see Erythrocyte Sedimentation Rate, [[Erythrocyte Sedimentation Rate]])

  • Elevated

Arterial Blood Gas (ABG) (see Arterial Blood Gas, [[Arterial Blood Gas]])

  • Respiratory Alkalosis (see Respiratory Alkalosis, [[Respiratory Alkalosis]])
  • Increased A-a Gradient Hypoxemia (see Hypoxemia, [[Hypoxemia]])
    • hypoxemia may occur only with exercise in some cases)/ hypercapnia is unusual (except late)
  • Hypoxemia is due to V/Q mismatch and not due to shunt or diffusion limitation (except during heavy exercise, when short transit time may be responsible for 20-30% of A-a gradient widening)

CXR/Chest CT Patterns (see Chest X-Ray, [[Chest X-Ray]] and Chest Computed Tomography, [[Chest Computed Tomography]])

  • Normal CXR (in 5-10% of all ILD cases at presentation): HRCT may be positive in some but not all of these cases/especially common pattern in DIP cases
  • Diffuse reticular or reticulonodular interstitial infiltrates (most common pattern): typically lower-lobe predominance with decreased lung volumes
    • CXR findings are not specific (diganosis is correct <50% of time) and do not correlate well with physiologic impairment
    • Absence of pleural involvement
  • Alveolar infiltrates (due to alveolar filling with alveolar macrophages): seen mainly in cases early in course, typically in DIP cases
  • Honeycombing (only radiographic pattern that correlates well with biopsy path): small cystic changes (seen best in lower lobes), seen late in course

High-Resolution Chest CT (HRCT) (see High-Resolution Chest Computed Tomography, [[High-Resolution Chest Computed Tomography]])

  • 2-3 mm cuts/not adequately studied to replace biopsy): early IPF demonstrates peripheral patchy reticular opacities, thickened interlobular septa, prominent centrilobular core structures/ later IPF demon-strates traction bronchiectasis, lower zone subpleural honeycombing (with 2-4 mm cysts)
  • With normal CXR: superior to conventional CT (10 mm cuts: add little to CXR findings) for early diagnosis of ILD
    -With abnormal CXR: improves diagnostic accuracy
  • Prone/supine views: maximize detection, minimize mimicking of septal thickening by dependent vascular engorgement
  • Presence of airspace involvement: suggests DIP or CIP on path and correlates with degree of cellularity on biopsy

  • Radiographic Features Which Best Differentiate Chronic HP from Idiopathic Pulmonary Fibrosis (IPF) and Non-Specific Interstitial Pneumonia (NSIP) [MEDLINE]

    • Lobular Areas with Decreased Attenuation and Vascularity
    • Centrilobular Nodules
    • Absence of Lower-Zone Predominance of Abnormalities

The features that best differentiated NSIP were relative subpleural sparing, absence of lobular areas with decreased attenuation, and lack of honeycombing
The features that best differentiated IPF were basal predominance of honeycombing, absence of relative subpleural sparing, and absence centrilobular nodules

Gallium Scan (see Gallium Scan, [[Gallium Scan]])

  • Not sensitive or specific in IPF/ poor correlation with histopathology): diffuse uptake in IPF/ localizes in inflammatory alveolar foci (within alveolar macrophages>neutrophils), but minimally in normal lung tissue

Ventilation/Perfusion (V/Q) Scan (see Ventilation-Perfusion Scan, [[Ventilation-Perfusion Scan]])

  • Not routinely recommended (reveals patchy areas of high and low V/Q matching, consistent with decreased VD/VT ratio)
  • If ruling out concomitant PE, CT pulmonary angiogram is usually required

6-Minute Walk Test (see 6-Minute Walk Test, [[6-Minute Walk Test]])

  • Utility of 6-Minute Walk Distance in IPF (2011) [MEDLINE]
    • 6-minute walk distance was weakly correlated with measures of physiologic function and health-related quality of life
    • A 24-week decline of >50 m in 6-minute walk distance in IPF was associated with a 4x-increase in the 1-year mortality rate

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]])

  • TLC, VC, RV, and FRC: decreased (VC <50% pred correlates with pulmonary HTN and decreased 2 year survival/TLC not correlated with pathology, prognosis, or survival)
    • Lower than expected TLC and VC with normal FRC and higher than expected RV suggests superimposed obstruction or poor effort
  • Expiratory flow rates: normal-decreased (but depend on lung volume, higher than expected at any given volume due to increased elastic recoil)
    • Obstructive component: increased peripheral upstream resistance may also occur: as in IPF, hypersensitivity pneumonitis, asbestosis
  • FEV1/FVC ratio: normal-increased
  • DLCO (no correlation with pathology): decreased, even early due to decreased pulmonary capillary blood volume, V/Q mismatch (Note: recent DAH may transiently elevate DLCO measurements)
  • Elastic recoil: increased (seen on plot of static transpulmonary pressure, at no flow, vs. volume)
    • Correlation between degree of fibrosis and alteration in elastic recoil is poor in IPF and Sarcoid, due to confounding effects of smoking (smoking: shifts PV curve downward to the right in Sarcoid, while shifts it upward to the left in IPF)
  • Compliance: decreased (correlates with fibrosis, does not exclude cellularity on pathology)
    Exercise testing (tolerance correlates with CXR and decrease in VC): exercise gas exchange is best correlate with pathologic severity (resting abnormalities do not predict exercise abnormalities)
  • Exercise response: increased VE (with increase in RR > VT), increased ventilation to high V/Q areas, resting increased VD/VT ratio decreases or stays same during exercise, decreased VO2max, worsened hypoxemia (due to worsened V/Q matching/ due partly to diffusion impairment only with heavy exercise, when pulmonary circulation transit time is short)

Bronchoscopy (see Bronchoscopy, [[Bronchoscopy]])

  • TBB: usually not diagnostic in IPF
  • BAL (Note: macrophage and eosinophils are increased in smokers, even without IPF): low-grade eosinophilia (<40%) may be seen/ low-grade lymphocytosis (15-35%) may be seen (lymphocytosis suggests cellular histology, better treatment response and survival)
    • Neutrophilia/ low-grade eosinophilia/ absence of lymphocytosis: predicts more fibrosis with progressive unresponsive disease

Thoracoscopic/Open Lung Biopsy

  • Sampling: recommended to biopsy multiple sites
    • Avoid dependent areas of lingula and right middle lobe
  • Relative Contraindications
    • Elderly (>70 y/o)
    • Cardiovascular Disease
    • Diffuse Honeycombing
    • Severe Lung Dysfunction
    • Major Surgical Risk
  • Operative Mortality Rate: <1%

Other Testing

  • Hypergammaglobulinemia: may be seen
  • ANA: positive at low titer (21%)
  • RF: may be positive
  • Serum Immune Complexes: may be positive (only serum test that correlates with disease stage and prognosis)
  • Cryoglobulins: may be positive

Clinical Manifestations

General Comments

  • Onset: typically insidious onset
  • 91% of IPF pts have associated GERD (Raghu, 2006)
  • IPF Exacerbation: rapid decline with HRCT-ground glass changes

Pulmonary Manifestations

  • General Comments
    • Flu-like illness may precede symptom onset
    • Symptoms usually present for months-2 years before diagnosis
    • Pathology provides best estimate of disease stage
  • Acute Respiratory Failure (see Respiratory Failure, [[Respiratory Failure]])
  • Dry Cough (see Cough, [[Cough]])
  • Dyspnea (insidious onset): degree of dyspnea at presentation correlates with CXR profusion score
  • Increased Risk of Lung Cancer (see Lung Cancer, [[Lung Cancer]])
    • Epidemiology: 14x increased risk
    • Physiology: arising from metaplastic bronchiolar epithelium
    • Clinical: bronchioloalveolar, adenocarcinoma, and small cell have all been seen
  • Late Inspiratory Fine Crackles (Velcro Crackles)
  • Pneumothorax (see Pneumothorax, [[Pneumothorax]])
  • Pulmonary Hypertension/Cor Pulmonale (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
    • Epidemiology: usually seen late in course
    • Pulmonary hypertension is present in 35-59% of IPF pts
    • Diagnosis
      • Echocardiogram has poor sens/spec for pulmonary hypertension in IPF
      • BNP >33 has 87% sens for pulmonary hypertension in IPF [Leuchte, 2006]
  • Tachypnea with Decreased Tidal Volume: due to altered mechanical reflexes (caused by increased elastic load and vagal mechanism, but not by chemical mechanisms)

Rheumatologic Manifestations

  • Clubbing (see Clubbing, [[Clubbing]]): 40-75% of cases
    • More common later in course
  • Hypertrophic Pulmonary Osteoarthropathy: rare
  • Raynaud’s Phenomenon (see Raynaud’s Phenomenon, [[Raynauds Phenomenon]])

Other Manifestations

  • Cyanosis (see Cyanosis, [[Cyanosis]]): more common later in course
  • Fever (see Fever, [[Fever]])
  • Fatigue
  • Myalgias (see Myalgias, [[Myalgias]])
  • Weight Loss (see Weight Loss, [[Weight Loss]])

Complications

  • Infection: increased risk due to disease and therapy
  • PE: 3-7% mortality in IPF
  • Progressive respiratory failure: 39% mortality in IPF

Prognosis

  • 5-year survival: 50%/ 10-year survival: 25%
  • Median survival (even with treatment): <5 years
  • Resting PA pres-sure at rest >30 poorer prognosis
  • Decreased SP-A: phospholipid ratio in surfactant predicts adverse clinical outcome
  • Cellular pathol-ogy (as compared to fibrosis) is more steroid-responsive and has better prognosis
  • Younger patients tend to have less fibrosis
  • Younger patients and females survive longer than older patients and men
  • Less severe CXR at presentation predicts better survival
  • DLCO >45% predicted have better survival (markedly de-creased DLCO and resting hypox-emia correlates with pulmonary HTN and decreased survival)

  • Monitors of disease activity

    • Serial exercise gas exchange measurements: best test to monitor response
    • BAL cell counts: nor-malize in cases with sustained improvement (prednisolone-respon-ders have a decrease in neutrophils while cytoxan-responders have a decrease in eosinophilia/ some non-responders with persis-tent BAL neutrophilia had clinically stable disease)
    • CXR: poor monitor of degree of inflammation

Treatment

General Measures

  • Avoidance of Tobacco Exposure (see Tobacco, [[Tobacco]])
  • Oxygen Therapy (see Oxygen, [[Oxygen]])
    • Rest and exercise supplemental oxygen improves pulmonary hemodynamics, exercise tolerance, and prognosis
  • Pulmonary Rehabilitation (see Pulmonary Rehabilitation, [[Pulmonary Rehabilitation]])
  • Vaccination
  • Treat Concomitant Sleep-Related Breathing Disorders: may decrease morbidity and improve survival

Pirfenidone (Esbriet) (see Pirfenidone, [[Pirfenidone]])

  • Mechanism: pirfenidone is an anti-fibrotic agent
  • CAPACITY 004 and 006 Trials (2011) [MEDLINE]
    • Main Findings: pirfenidone reduced the decline in FVC
    • Adverse Effects
      • Gastrointestinal Adverse Effects: nausea/vomiting, dyspepsia, anorexia
      • Other Adverse Effects: photosensitivity, rash, dizziness
  • ASCEND Trial (2014) [MEDLINE]
    • Trial: randomized, multi-center, placebo-controlled phase 3 trial (n = 555), 52 week duration, pirfenidone dose: 2403 mg qday
    • Main Findings
      • 47.9% decrease in patients who had at least a 10% decline in FVC or who died
      • 132.5% increase in patients with no decline in FVC
      • Improvement in progression-free survival
      • No change in all-cause mortality, death from IPF, or dyspnea scores
        • In pooled analysis with data from prior trials: decreased all-cause mortality and death from IPF
      • Decreased decline in 6-minute walk distance
    • Adverse Effects
      • Gastrointestinal Adverse Effects: elevated LFT’s, nausea/vomiting, anorexia, weight loss, GERD, dyspepsia
      • Dermatologic Adverse Effects: rash
      • Other Adverse Effects: insomnia

Nintedanib (Ofev) (see Nintedanib, [[Nintedanib]])

  • Mechanism: nintedanib is a tyrosine kinase inhibitor
  • INPULSIS 1/2 Trials (2014) [MEDLINE]:
    • Main Findings
      • Slowed the decline in FVC
      • In INPULSIS-2, nintedanib increased time to first exacerbation
    • Adverse Effects
      • Diarrhea: occurred in 61.5% of cases, as compared 18.6% of placebo-treated controls

Treatments with No Demonstrated Clinical Benefit

Azathioprine (Imuran) (see Azathioprine, [[Azathioprine]])

  • Dose: imuran 2-3 mg/kg/day
  • PANTHER-IPF Trial (2012) [MEDLINE]: prednisone + azathioprine + N-acetylcysteine increased risk of death and hospitalization, as compared to placebo

Bosentan (see Bosentan, [[Bosentan]])

  • BUILD1 Trial (2008) [MEDLINE]: no significant clinical benefit (although there was a positive trend in favour of bosentan observed in time to death or disease progression in an arbitrary subset of patients diagnosed by surgical lung biopsy)

Chlorambucil (see Chlorambucil, [[Chlorambucil]])

  • No Clinical Benefit

Colchicine (see Colchicine, [[Colchicine]])

  • Mechanism: decreases alveolar macrophage release of fibronectin/alveolar macrophage growth factor
  • Lung Study Group (1998) [MEDLINE]: no clinical benefit

Corticosteroids (see Corticosteroids, [[Corticosteroids]])

  • Dose: start prednisone 1-1.5 mg/kg IBW/day, then 0.5 mg/kg/day at 3 months, then 0.25 mg/kg/day at 6 months, then taper to off (or lowest effective dose) at 1 year
  • PANTHER-IPF Trial (2012) [MEDLINE]: prednisone + azathioprine + N-acetylcysteine increased risk of death and hospitalization, as compared to placebo

Coumadin (see Coumadin, [[Coumadin]])

  • ACE-IPF Trial (2012) [MEDLINE]: coumadin increased mortality in an IPF population who lacked other indications for anticoagulation

Cyclophosphamide (Cytoxan) (see Cyclophosphamide, [[Cyclophosphamide]])

  • Trial Comparing Prednisolone Alone with Prednisolone + Cyclophosphamide in IPF 1989) [MEDLINE]: no clinical benefit

Etanercept (Enbrel) (see Anti-TNF Therapy, [[Anti-TNF Therapy]])

  • No Clinical Benefit

Imatinib (Gleevec) (see xxxx, [[xxxx]])

  • No Clinical Benefit

Interferon Gamma-1b (Actimune) (see Interferon Gamma-1b, [[Interferon Gamma-1b]])

  • Dose: 200 µg SQ 3x/week
  • Raghu 2004 study: probable mortality benefit in subset of patients with mild-mod IPF (FVC >60%), INSPIRE trial
  • May continue steroids with Actimmune (bring to lower doses, if possible)

N-Acetylcysteine (Mucomyst) (see N-Acetylcysteine, [[N-Acetylcysteine]])

  • Dose: 600 mg PO TID
  • IFIGENIA Trial (2005): in addition to prednisone + azathioprine, N-Acetylcysteine slowed progression of DLCO/VC in IPF
  • PANTHER-IPF Trial (2012) [MEDLINE]: prednisone + azathioprine + N-acetylcysteine increased risk of death and hospitalization, as compared to placebo
  • Idiopathic Pulmonary Fibrosis Clinical Research Network Randomized Double-Blind Placebo-Controlled Trial of N-Acetylcysteine (2014) [MEDLINE]: N-acetylcysteine had no significant benefit in terms of FVC preservation in patients with mild-moderate IPF, as compared to placebo

Penicillamine (see Penicillamine, [[Penicillamine]])

  • No Clinical Benefit

Vincristine (see Vincristine, [[Vincristine]])

  • No Clinical Benefit

Experimental Treatments

Thalidomide (see Thalidomide, [[Thalidomide]])

  • xxx

Lung Transplant (see Lung Transplant, [[Lung Transplant]])

  • Indications: severe end-stage disease with life expectancy <18 months
    • Indicators of end-stage disease: NYHA class 3 or 4/ honeycombing or pulmonary HTN/ TLC <60%/ resting A-a gradient >30/ severe exercise-associated desats/ clinical-radiographic-physiologic score >70
  • Relative Contraindications
    • Systemic Diseases
    • Psychiatric
    • Previous major chest surgery
    • Prednisone >15 mg per day

Prognosis

  • Prediction of IPF Mortality Rate with 6-Minute Walk Distance (2011) [MEDLINE]: a 24-week decline of >50 m in 6-minute walk distance in IPF was associated with a 4x-increase in the 1-year mortality rate

References

General

  • ATS/ERS/JRS/ALAT statement: Idiopathic Pulmonary Fibrosis: Evidence- based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788-824 [MEDLINE]

  • Six-minute-walk test in idiopathic pulmonary fibrosis: test validation and minimal clinically important difference. Am J Respir Crit Care Med 2011;183:1231-1237 [MEDLINE]

  • MUC5B promoter polymorphism and interstitial lung abnormalities. N Engl J Med 2013;368:2192-2200 [MEDLINE]

  • Bedside to gene and back in IPF. N Engl J Med 2013;368:2228-2229
  • A meta-analysis examining the association between the MUC5B rs35705950 T/G polymorphism and susceptibility to idiopathic pulmonary fibrosis. Inflamm Res. 2015 Jun;64(6):463-70. doi: 10.1007/s00011-015-0829-6. Epub 2015 Apr 30 [MEDLINE]

Treatment

  • Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis. Thorax 1989;44(4):280–8 [MEDLINE]
  • Lung Study Group. Colchicine versus prednisone in the treatment of idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 1998;158 (1):220–5 [MEDLINE]
  • Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest 2004;125(6): 2169-2174 [MEDLINE]
  • IFIGENIA Trial. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:229-242 [MEDLINE]
  • Chronic hypersensitivity pneumonitis: differentiation from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section CT. Radiology. 2008;246(1):288-297 [MEDLINE]
  • BUILD-1: A randomized placebo- controlled trial of bosentan in idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 2008;177(1):75–81 [MEDLINE]
  • Non-steroid agents for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev. 2010 Sep 8;(9):CD003134. doi: 10.1002/14651858.CD003134.pub2 [MEDLINE]
  • Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011;365(12):1079-1087 [MEDLINE]
  • CAPACITY 004 + 006 Trials: Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011 May 21;377(9779):1760-9. doi: 10.1016/S0140-6736(11)60405-4. Epub 2011 May 13 [MEDLINE]
  • ACE-IPF Trial: A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;186:88-95 [MEDLINE]
  • PANTHER-IPF Trial: Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012 May 24;366(21):1968-77. doi: 10.1056/NEJMoa1113354. Epub 2012 May 20 [MEDLINE]
  • Anti-fibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmcol Exp Ther 2014;349:209-230 [MEDLINE]
  • Idiopathic Pulmonary Fibrosis Clinical Research Network. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2093-101. doi: 10.1056/NEJMoa1401739. Epub 2014 May 18 [MEDLINE]
  • Design of the INPULSIS trials: two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis. Respir Med. 2014 Jul;108(7):1023-30. doi: 10.1016/j.rmed.2014.04.011. Epub 2014 Apr 29 [MEDLINE]
  • INPULSIS Trial: Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2071-82 [MEDLINE]
  • ASCEND Trial: A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2083-92 [MEDLINE]
  • Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J. 2015 May;45(5):1434-45. doi: 10.1183/09031936.00174914. Epub 2015 Mar 5 [MEDLINE]
  • Safety, tolerability and appropriate use of nintedanib in idiopathic pulmonary fibrosis. Respir Res. 2015 Sep 24;16:116. doi: 10.1186/s12931-015-0276-5 [MEDLINE]
  • Efficacy of Nintedanib in Idiopathic Pulmonary Fibrosis Across Pre-specified Subgroups in INPULSIS®. Am J Respir Crit Care Med. 2015 Sep 22 [MEDLINE]