Annotated IPF Guidelines

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Annotated IPF Guidelines

Current guidelines for IPF

An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-Based Guidelines For Diagnosis And Management. 
 
Raghu G, Collard HR, Egan JJ et al.
Am J Respir Crit Care Med. 2011;183(6):788-824.

Note: this document was published in 2011 and is currently in revision. Certain aspects of this document may be out of date and caution should be used when applying these in clinical practice or other usages.

Definition of IPF

Definition
IPF is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of UIP defined below. The definition of IPF requires the exclusion of other forms of interstitial pneumonia including other idiopathic interstitial pneumonias and ILD associated with environmental exposure, medication, or systemic disease.

IPF (n.)2,3: a chronic, progressive form of fibrotic interstitial pneumonia of unknown cause; associated with UIP patterns on HRCT and histopathology; requires exclusion of other forms of IP.
 
Learn more in:About IPF: Disease Course

UIP, usual interstitial pneumonia; ILD, interstitial lung disease; HRCT, high-resolution computed tomography; IP; interstitial pneumonia.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
2. ATS. Am J Respir Crit Care Med. 2000;161(2 Pt 1):646-664.;
3. ATS/ERS. Am J Respir Crit Care Med. 2002;165(2 Pt 1):277-304.

Clinical presentation

Clinical Presentation
IPF should be considered in all adult patients with unexplained chronic exertional dyspnea, and commonly presents with cough, bibasilar inspiratory crackles, and finger clubbing. The incidence of the disease increases with older age, with presentation typically occurring in the sixth and seventh decades. Patients with IPF aged less than 50 years are rare; such patients may subsequently manifest overt features of an underlying connective tissue disease that was subclinical at the time IPF was diagnosed. More men have been reported with IPF than women, and the majority of patients have a history of cigarette smoking.

Clinical Presentation1,4,5
  • Chronic, exertional dyspnea
  • Cough
  • Bibasilar crackles
  • Digital clubbing  
Learn more in:Diagnosing IPF: Clinical Presentation

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
4. King TE, Jr. et al. Am J Respir Crit Care Med. 2001;164(7):1171-1181.
5. Douglas WW et al. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1172-1178.

Incidence and prevalence

Incidence and Prevalence
There are no large-scale studies of the incidence or prevalence of IPF on which to base formal estimates. The incidence of IPF was estimated at 10.7 cases per 100,000 per year for men and 7.4 cases per 100,000 per year for women in a population-based study from the county of Bernalillo, New Mexico. A study from the United Kingdom reported an overall incidence rate of only 4.6 per 100,000 person-years, but estimated that the incidence of IPF increased by 11% annually between 1991 and 2003. This increase was not felt to be attributable to the aging of the population or increased ascertainment of milder cases. A third study from the United States estimated the incidence of IPF to be between 6.8 and 16.3 per 100,000 persons using a large database of healthcare claims in a health plan… 

Incidence of IPF6,7
4.6-16.3/100,000 people/yr
 
Learn more in:About IPF: Epidemiology
 
1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
6. Raghu G et al. Am J Respir Crit Care Med. 2006;174(7):810-816.
7. Gribbin J et al. Thorax 2006;61(11):980-985.

Risk factors for IPF

Potential Risk Factors
Cigarette smoking. Smoking is strongly associated with IPF, particularly for individuals with a smoking history of more than 20 pack-years. This applies to familial as well as sporadic IPF. 
Environmental exposures. Increased risk for IPF has been found to be associated with a variety of environmental exposures. A significantly increased risk has been observed after exposure to metal dusts…
Gastroesophageal reflux. Several studies have suggested that abnormal acid gastroesophageal reflux (GER), through its presumed association with microaspiration, is a risk factor for IPF. Abnormal GER…
Genetic factors. Although accounting for less than 5% of total patients with IPF, familial forms of IPF (i.e., those affecting two or more  members of the same primary biological…

Risk Factors1
  • Cigarette smoking
  • Environmental factors (eg, various dusts)
  • GERD
  • Genetics
Learn more in:About IPF: Risk Factors

GERD, gastroesophageal reflux disease.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824. 

HRCT: UIP pattern

UIP Pattern: HRCT Features
HRCT is an essential component of the diagnostic pathway in IPF. The optimal HRCT technique for evaluation of ILD is provided in the online supplement. UIP is characterized on HRCT by the presence of reticular opacities, often associated with traction bronchiectasis. Honeycombing is common, and is critical for making a definite diagnosis. Honeycombing is manifested on HRCT as clustered cystic airspaces, typically of comparable diameters on the order of 3–10 mm but occasionally as large as 2.5 cm. It is usually subpleural and is characterized by well-defined walls. Ground glass opacities are common, but usually less extensive than the reticulation. The distribution of UIP on HRCT is characteristically basal and peripheral, though often patchy. The presence of coexistent…

Definite UIP Pattern8-10
  • Reticular opacities
  • Honeycombing
  • Traction bronchiectasis
  • Basal, peripheral distribution  
A definite UIP pattern on HRCT has a 90%-100% PPV for IPF11-16

Learn more in:Diagnosing IPF: Radiology

PPV, positive predictive value.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
8. Nishimura K et al. Radiology. 1992;182():337-342.
9. Johkoh T et al. Radiology 1999;211():555-560.
10. Hansell DM et al. Radiology 2008;246(3):697-722
11. Mathieson JR et al. Radiol. 1989;171(1):111-116.
12. Hunninghake GW et al. Am J Respir Crit Care Med. 2001;164(2):193-196. 
13. Raghu G et al. Chest. 1999;116(5):1168-1174.
14. Grenier P et al. Radiology. 1991;179(1):123-132.
15. Lee KS et al. Radiology. 1994;191(3):669-673.
16. Swensen SJ et al. Radiology. 1997;205(1):229-234.

Histopathology: UIP pattern

UIP Pattern: Histopathology Features
The histopathologic hallmark and chief diagnostic criterion is a heterogeneous appearance at low magnification in which areas of fibrosis with scarring and honeycomb change alternate with areas of less affected or normal parenchyma. These histopathologic changes often affect the subpleural and paraseptal parenchyma most severely. Inflammation is usually mild and consists of a patchy interstitial infiltrate of lymphocytes and plasma cells associated with hyperplasia of type 2 pneumocytes and bronchiolar epithelium. The fibrotic zones are composed mainly of dense collagen, although scattered convex subepithelial foci of proliferating fibroblasts and myofibroblasts (so-called fibroblast foci) are a consistent finding. Areas of honeycomb change are composed of cystic fibrotic airspaces that…

Definite UIP pattern2
  • Heterogeneous appearance at low magnification
  • Areas of fibrosis with scarring and honeycomb change alternate with areas of less affected parenchyma
Learn more in:Diagnosing IPF: Histopathology

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
2. ATS. Am J Respir Crit Care Med. 2000;161(2 Pt 1):646-664.

Diagnostic criteria for IPF

Diagnostic Criteria
The diagnosis of IPF requires the following:
  1. Exclusion of other known causes of ILD (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity). 
  2. The presence of a UIP pattern on HRCT in patients not subjected to surgical lung biopsy.
  3. Specific combinations of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy.
Thus, the accuracy of diagnosis of IPF increases with clinical, radiologic, and histopathologic correlation and can be accomplished with a multidisciplinary discussion among experienced clinical experts in the field of ILDs. This is particularly…

Diagnostic Criteria1
  1. Exclude other known causes of ILD
  2. UIP pattern on HRCT
  3. Specific combinations of HRCT and histopathologic patterns
Learn more in:Diagnosing IPF: Diagnostic criteria and algorithm

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.

Serologic testing

Question: Should serologic testing for connective tissues disease be used in the evaluation of suspected IPF?
There are no reliable data on the role of screening serologies in patients with suspected IPF. Connective tissue disease can present with a UIP pattern, and ILD has been described as the sole clinical manifestation of these conditions and can precede the overt manifestation of a specific connective tissue disease.
Recommendation: Serologic testing for connective tissue disease should be performed in the evaluation of IPF in the majority of patients, but may not be appropriate in a minority (weak recommendation, very low-quality evidence).
Values: This recommendation places a high  value on distinguishing connective tissue…

Serologic Testing
Ruling out other known causes of ILD (eg, CTD) is critical to diagnosing IPF1
 
The guidelines recommend performing testing for CTD in the majority of patients with suspected IPF1
 
Learn more in:Diagnosing IPF: Clinical Signs

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.

Multidisciplinary discussion

Question: Should a multi-disciplinary discussion be used in the evaluation of suspected IPF?
The diagnosis of IPF is, by definition, multidisciplinary, drawing on the expertise of experienced clinicians, radiologists, and pathologists. Proper communication between the various disciplines involved in the diagnosis of IPF (pulmonary, radiology, pathology) has been shown to improve inter-observer agreement among experienced clinical experts as to the ultimate diagnosis. 
Recommendation: We recommend that a multi-disciplinary discussion should be used in the evaluation of IPF (strong recommendation, low-quality evidence). 
Values: This recommendation places a high value on the accurate diagnosis of IPF and a…

MDD1
The guidelines recommend the use of an MDD to evaluate IPF, which includes:
  • Pulmonologists
  • Radiologists
  • Pathologists
Learn more in:Diagnosing IPF: MDD

MDD, multidisciplinary discussion.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824. 

Natural history

Natural History of IPF
The natural history of IPF has been described as a progressive decline in subjective and objective pulmonary function until eventual death from respiratory failure or complicating comorbidity. Available longitudinal studies do not allow a clear assessment of median survival in IPF. Several retrospective longitudinal studies suggest a median survival time from 2 to 3 years from the time of  diagnosis. However, recent data from clinical trials of patient with preserved pulmonary function suggest this may be an underestimate. 

There appear to be several possible natural histories for patients with IPF. For a given patient, the natural history is unpredictable at the time of the diagnosis. The majority of patients demonstrate a slow, gradual progression over many years. Some…

Natural History
Median survival: 2-3 years4,17-20
 
The course of IPF is unpredictable.4,21,22
 
Comorbidities and other unidentified factors likely affect the disease course.23,24
 
Learn more in:About IPF: Disease course

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
4. King TE, Jr. et al. Am J Respir Crit Care Med. 2001;164(7):1171-1181.
17. Bjoraker JA et al. Am J Respir Crit Care Med. 1998;157(1):199-203.
18. Flaherty KR et al. Eur Respir J. 2002;19(2):275-283.
19. Nicholson AG et al. Am J Respir Crit Care Med. 2000;162(6):2213-2217.
20. Rudd RM et al. Thorax. 2007;62(1):62-66.
21. Selman M et al. PLoS One. 2007;2(5):e482.
22. Ley B et al. Am J Respir Crit Care Med. 2011;183(4):431-440.
23. Mejia M et al. Chest. 2009;136(1):10-15.
24. Lettieri CJ et al. Chest. 2006;129(3):746-752.

Acute exacerbations of IPF

Acute Exacerbation of IPF
Recent observations have suggested that acute respiratory worsening occurs in a small minority of patients with IPF annually (approximately 5–10%). These episodes may occur secondary to common conditions such as pneumonia, pulmonary embolism, pneumothorax, or cardiac failure. When a cause cannot be identified for the acute respiratory decline, the term acute exacerbation of IPF has been used. It is presently unclear if acute exacerbation of IPF is simply a manifestation of an unidentified respiratory complication (such as pulmonary emboli, infection) contributing to an acute worsening in a patient with IPF or represents an inherent acceleration in the pathobiological processes involved in IPF. Recent data from gene expression profiling of patients with acute…

AE-IPF25
  • No identifiable cause of acute worsening of dyspnea
  • Increased hypoxemia
  • New radiologic abnormalities
  • Can occur at any time
Learn more in:About IPF: AE-IPF

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
25. Collard HR et al. Am J Respir Crit Care Med. 2007;176(7):636-643.  

Staging and prognosis

Staging and Prognosis
The extent of disease and the severity of functional impairment of patients with IPF at the time of diagnosis are variable. The reasons for this are thought to be variation in subjective perception of symptoms and differences in providers’ awareness. Recent studies have clarified predictors of survival in IPF. However, the accuracy of these predictors is limited by the retrospective nature of some of these studies and variations in study design.
Terms such as ‘‘mild,’’ ‘‘moderate,’’ ‘‘severe,’’ ‘‘early,’’ and ‘‘advanced’’ have been suggested for staging disease. Proposed stages are commonly based on resting pulmonary function test measurements and/or extent of radiologic abnormalities. However, it is unknown if these staging approaches are relevant to clinical decision making. The committee recognizes the importance of…

Staging and Prognosis1
There are no officially recognized stages of IPF at this time.
 
Learn more in:About IPF: Disease course

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824. 

Emphysema and IPF

Emphysema
Recent retrospective data suggest that patients with IPF and coexisting emphysema have a poorer outcome than those without emphysema. Patients with coexisting IPF and emphysema may require treatment for both conditions. Limited data suggest that patients with IPF and emphysema are likely to require long-term oxygen therapy and may have significant pulmonary hypertension. When controlling for these differences, the presence of emphysema was not significantly predictive of survival. Thus, it is not clear if IPF with coexisting emphysema represents a distinct clinical phenotype (combined pulmonary fibrosis and emphysema) with a distinct prognosis or whether emphysema in these cases is simply a comorbidity.

Emphysema
Cases of CPFE are becoming increasingly recognized.26
 
Patients with CPFE generally have worse prognosis and outcomes.23
 
Learn more in:Managing IPF: Comorbidities

CPFE, combined pulmonary fibrosis and emphysema.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
23. Mejia M et al. Chest. 2009;136(1):10-15.
26. Lin H et al. J Thorac Dis 2015;7(4):767-779.

Nonpharmacologic treatments for IPF

Question: Should patients with IPF and resting hypoxemia receive long-term oxygen therapy?
There are no data that directly inform the use of long-term oxygen therapy in patients with IPF. One study has retrospectively compared survival in a cohort of patients with IPF, many of whom (27%) received oxygen therapy. In multivariate analysis, no survival benefit was demonstrated with oxygen use. This study was limited by its retrospective design…
Recommendation: We recommend that patients with IPF and clinically significant resting hypoxemia should be treated with long-term oxygen therapy (strong  recommendation, very low-quality evidence).
Values: This recommendation places a high value on evidence from other chronic lung diseases and a low value on inconvenience…

Oxygen Therapy1
The guidelines recommend long-term oxygen supplementation for patients with IPF and clinically significant hypoxemia.
 
Learn more in:Managing IPF: Symptoms

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824. 

Nonpharmacologic treatments for IPF (cont.)

Question: Should appropriate patients with IPF undergo lung transplantation?
Five-year survival rates after lung transplantation in IPF are estimated at 50 to 56%. A single-center study of 46 patients referred for lung transplantation with IPF demonstrated a reduced risk of death at 5 years in patients receiving lung transplantation. Additional evidence suggests that patients with pulmonary fibrosis undergoing lung transplantation have favorable long-term survival compared with other disease indications… 
Recommendation: We recommend that appropriate patients with IPF should undergo lung transplantation (strong recommendation, low-quality evidence).
Values: This recommendation places a high value on low-quality evidence showing a…

Lung Transplantation1
The guidelines recommend lung transplantation for appropriate patients with IPF.
 
Learn more in:Managing IPF: Symptoms

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824. 

Nonpharmacologic treatments for IPF (cont.)

Question: Should patients with respiratory failure due to IPF receive mechanical ventilation?
There are several small studies of mechanical ventilation in patients with IPF and respiratory failure, all of which show a high hospital mortality rate. The inclusion criteria varied among studies, with some only including patients with respiratory failure of unknown etiology…
Recommendation: The majority of patients with respiratory failure due to IPF should not receive mechanical ventilation, but mechanical ventilation may be a reasonable
intervention in a minority (weak recommendation, low-quality evidence).
Values: This recommendation places a high value on the high mortality observed in this patient population and on reducing…

Mechanical Ventilation1
The guidelines do not recommend mechanical ventilation for the majority of patients with IPF and respiratory failure.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824. 

Nonpharmacologic treatments for IPF (cont.)

Question: Should patients with IPF receive pulmonary rehabilitation?
Pulmonary rehabilitation programs involve aerobic conditioning, strength and flexibility training, educational lectures, nutritional interventions, and psychosocial support. Pulmonary rehabilitation has recently been studied in patients with ILD. Two controlled trials of pulmonary rehabilitation in IPF have demonstrated an improvement in walk distance and symptoms or quality of life…
Recommendation: The majority of patients with IPF should be treated with pulmonary rehabilitation, but pulmonary rehabilitation may not be reasonable in a minority (weak recommendation, low-quality evidence).
Values: This recommendation places a high value on moderate-quality data demonstrating improvement in functional status and …

Pulmonary Rehab1
The guidelines recommend that the majority of patients with IPF receive pulmonary rehabilitation.
 
Learn more in:Managing IPF: Symptoms

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824. 

Treating comorbidities

Treatment of Selected Complications and Comorbid Conditions
There is an increasing awareness of complications and comorbid conditions frequently associated with IPF. These include acute exacerbation of IPF, pulmonary hypertension, gastroesophageal reflux disease, obesity, emphysema, and obstructive sleep apnea. It is unknown if treating these comorbidities influences clinical outcomes. There are no data on which to make recommendations for treatment of obesity, emphysema, and obstructive sleep apnea in the setting of IPF.

Treating Complications and Comorbidities1
Treating comorbidities may or may not affect outcomes for patients with IPF. Check the guidelines for recommendations on treating individual comorbidities.
 
Learn more in:Managing IPF: Comorbidities

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824. 

Palliative care

Palliative Care
Palliative care focuses on reducing symptoms and providing comfort to patients, rather than treating patients’ disease. Specific goals for palliative care include relief from physical and emotional suffering and consideration for psychological and spiritual support for patients and caregivers. Such care will need to be individualized. Palliative care should be considered an adjunct to disease-focused care. 

Worsening of symptoms such as cough and dyspnea are common and difficult to treat. Limited data suggest that corticosteroids and thalidomide may be beneficial for chronic cough in IPF. Chronic opioids may be used for severe dyspnea and cough; careful monitoring for side effects should be  performed. Advanced directives and end-of-life care issues should be addressed…

Palliative Care1
Individualized care should focus on relieving physical and emotional suffering, as well as psychological and spiritual support for patients and caregivers.
 
It should be used as an adjunct to disease-based care.

Learn more in:About IPF: Disease course

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824. 

Monitoring disease progression

Monitoring the Clinical Course of Disease
Monitoring of patients with IPF is necessary to proactively identify patients with progressive disease, to appreciate worsening of symptoms and oxygenation, and to detect the development of disease or treatment complications. In addition, careful assessment of the clinical course is useful in helping patients understand their disease course and in initiating timely, appropriate therapeutic interventions, including consideration of lung transplantation.

Disease Monitoring1
Patients should be monitored regularly to detect worsening symptoms and oxygenation, as well as developing comorbidities (disease- or treatment-based).
 
Learn more in:About IPF: Disease course

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824. 

Monitoring disease progression

Monitoring for Progressive Disease
Disease progression may be manifested by increasing respiratory symptoms, worsening pulmonary function test results, progressive fibrosis on HRCT, or acute respiratory decline. In the absence of another identifiable cause, the presence of any of the following changes is consistent with progressive disease: 
  • Progressive dyspnea (objectively assessed)
  • Progressive, sustained decrease from baseline in absolute FVC
  • Progressive, sustained decrease from baseline in absolute DLCO (corrected for hemoglobin)
  • Progression of fibrosis from baseline on HRCT
  • Acute exacerbation
  • Death from respiratory failure
These parameters were developed based on data from clinical trials (see STAGING AND PROGNOSIS). While progressive dyspnea is an important subjective variable, objective…

Disease Progression1
Changes associated with disease progression include:
  • Progressive dyspnea
  • Progressive, sustained decrease from baseline in absolute FVC or Dlco
  • Progressive fibrosis from baseline on HRCT
  • Acute exacerbation
  • Death from respiratory failure
Learn more in:About IPF: Disease course

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824. 

Monitoring for worsening symptoms

Monitoring for Worsening Symptoms
Identifying patients with worsening respiratory symptoms (e.g., dyspnea) has important management implications. Patients experiencing worsening respiratory symptoms require evaluation for progressive disease, assessment of oxygenation at rest and with exertion, and prompt detection of secondary complications (e.g., development of deep venous thrombosis and pulmonary embolus). In addition, some patients may benefit from symptom-based therapies. There are several research tools available for the quantification of dyspnea. It is unclear if any of these tools have clinical utility.

Worsening Symptoms1
Identifying patients with worsening symptoms is important to properly manage their treatment.
 
Learn more in:About IPF: Disease course

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.

Monitoring for oxygenation

Monitoring for Worsening Oxygenation
Oxygen saturation by pulse oximetry should be measured at rest and with exertion in all patients regardless of symptoms to assure adequacy of oxygenation and identify the need for supplemental oxygen at baseline and during follow-up evaluation. Careful attention to the pulse oximetry tracing and signal is required to overcome potential problems related to poor circulation and inadequate signal quality. Generally, desaturation below 88% during a formal 6MWT or equivalent has been used to prescribe supplemental oxygen. Such measurements should be performed at baseline and during follow up at 3- to 6-month intervals. Formal  cardiopulmonary exercise testing does not have a defined role and is not recommended for routine monitoring.

Worsening Oxygenation1
Monitoring oxygenation levels is critical to a timely prescription for supplemental oxygen.
  • Oxygenation should be measured at rest and exertion at baseline and follow-up appointments
  • Desaturation of ≤88% should generally lead to use of supplemental oxygen
Learn more in:Managing IPF: Symptoms

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824. 

Monitoring for comorbidities

Monitoring for Complications and Comorbidities
Comorbidities including pulmonary hypertension, pulmonary embolism, lung cancer, and coronary artery disease are known to occur in IPF. While the development of these comorbidities may influence survival, the role of routine screening to identify such complications in patients with IPF (e.g., annual HRCT for lung cancer surveillance) is unknown. Thus, a recommendation for routine screening cannot be made. In patients demonstrating progressive disease, the identification of pulmonary hypertension may impact consideration for lung transplantation in eligible patients, and evaluation is indicated. Echocardiography is inaccurate in estimating pulmonary hemodynamics in patients with fibrotic lung disease and should not be relied upon to assess the presence and severity of…

Monitoring Complications and Comorbidities1
The guidelines do not provide recommendations for routine screening for comorbidities.
  • Acute respiratory worsening should lead to evaluation for AE-IPF
Learn more in:Managing IPF: Comorbidities

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824. 

References

1.Raghu G et al. Am J Respir Crit Care Med2011; 183(6):788-824.
2.ATS. Am J Respir Crit Care Med. 2000;161(2 Pt 1):646-664.
3.ATS/ERS. Am J Respir Crit Care Med. 2002;165(2 Pt 1):277-304.
4.King TE, Jr. et al. Am J Respir Crit Care Med. 2001;164(7):1171-1181.
5.Douglas WW et al. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1172-1178
6.Raghu G et al. Am J Respir Crit Care Med. 2006;174(7):810-816.
7.Gribbin J et al. Thorax 2006;61(11):980-985.
8.Nishimura K et al. Radiology. 1992;182():337-342.
9.Johkoh T et al. Radiology 1999;211():555-560.
10.Hansell DM et al. Radiology 2008;246(3):697-722.
11.Mathieson JR et al. Radiol. 1989;171(1):111-116.
12.Hunninghake GW et al. Am J Respir Crit Care Med. 2001;164(2):193-196.
13.Raghu G et al. Chest. 1999;116(5):1168-1174.
14.Grenier P et al. Radiology. 1991;179(1):123-132.
15.Lee KS et al. Radiology. 1994;191(3):669-673.
16.Swensen SJ et al. Radiology. 1997;205(1):229-234.
17.Bjoraker JA et al. Am J Respir Crit Care Med. 1998;157(1):199-203.
18.Flaherty KR et al. Eur Respir J. 2002;19(2):275-283.
19.Nicholson AG et al. Am J Respir Crit Care Med. 2000;162(6):2213-2217.
20.Rudd RM et al. Thorax. 2007;62(1):62-66.
21.Selman M et al. PLoS One. 2007;2(5):e482.
22.Ley B et al. Am J Respir Crit Care Med. 2011;183(4):431-440.
23.Mejia M et al. Chest. 2009;136(1):10-15.
24.Lettieri CJ et al. Chest. 2006;129(3):746-752.
25.Collard HR et al. Am J Respir Crit Care Med. 2007;176(7):636-643.
26.Lin H et al. J Thorac Dis 2015;7(4):767-779