Diagnosing IPF: Clinical features of IPF

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Diagnosing IPF: Clinical features of IPF

A patient with suspected IPF should have a full workup performed

Clinical signs of IPF may be found during1-3:
–Physical examination
–Pulmonary function testing
–A full medical history
 
1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
2. Meltzer EB et al. Orphanet J Rare Dis. 2008;3:1-15.
3. Pellegrino R et al. Eur Respir J. 2005;26(5):948-968.

Physical examination

Signs of IPF are often present on physical examination

Common signs of IPF1,4-7
-Dyspnea
-Dry, nonproductive cough
-Crackles on auscultation
-Digital clubbing

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
4. Bjoraker JA et al. Am J Respir Crit Care Med. 1998;157(1):199-203.
5. King TE Jr. et al. Am J Respir Crit Care Med. 2001;164(7):1171-1181.
6. Douglas WW et al. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1172-1178.
7. American Thoracic Society. Am J Respir Crit Care Med. 2000;161(2 Pt 1):646-664.

Signs of IPF are often present on physical examination (cont.)

Rare signs of IPF8,9
-Cyanosis
-Signs of right heart failure

8. Kim DS et al. Proc Am Thorac Soc. 2006;3(4):285-292.
9. Panos RJ et al. Am J Med. 1990;88(4):396-404.
 

Signs of IPF are often present on physical examination (cont.)

Constitutional signs and CTDs are rare in IPF2,8
-Fever
-Weight loss
-Arthritis or other CTDs

These signs should prompt investigation into secondary causes of pulmonary fibrosis2

CTD, connective tissue disorder.

2. Meltzer EB et al. Orphanet J Rare Dis. 2008;3:1-15.
8. Kim DS et al. Proc Am Thorac Soc. 2006;3(4):285-292.

Dyspnea is nearly universal in IPF

Dyspnea is one of the prominent and disabling symptoms of IPF7
 
7. American Thoracic Society. Am J Respir Crit Care Med. 2000;161(2 Pt 1):646-664.

Most patients have experienced dyspnea for more than 6 months before presentation

Some patients expect shortness of breath to be part of normal aging, especially during or after physical activity, and may not seek medical attention until much later10
 
IPF should be considered in all patients with unexplained, gradual onset of chronic dyspnea (either exertional or at rest)4,7

4. Bjoraker JA et al. Am J Respir Crit Care Med. 1998;157(1):199-203.
7. American Thoracic Society. Am J Respir Crit Care Med. 2000;161(2 Pt 1):646-664.
10. Castriotta RJ et al. Chest. 2010;138(3):693-703.

Cough is a nearly universal symptom of IPF

  • Most – if not all – patients with IPF have a chronic, dry/nonproductive cough7,11
  • Wheezing is not common in IPF and suggests airway disease rather than interstitial disease12
 
7. American Thoracic Society. Am J Respir Crit Care Med. 2000;161(2 Pt 1):646-664.
11. Ryerson CJ et al. Respirology. 2011;16(6):969-975.
12. Kritek P, Choi MK. In: Longo DL, Fauco AS, Kasper DL et al, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill Companies, Inc. 2012:2094-2101.

Cough is a nearly universal symptom of IPF (cont.)

  • Chronic cough significantly impairs patients’ QOL13
  • Persistent and excessive cough may cause serious complications, including14:
    • Cough-related syncope
    • Pneumothorax
    • Cardiac arrhythmias
    • Seizures
QOL, quality of life.

13. Swigris JJ et al. Health Qual Life Outcomes. 2005;3:61.
14. Irwin RS et al. Chest .1998;114(2):133S-181S.

At least 80% of patients with IPF have crackles on auscultation

  • The crackles of IPF are pan- or end-inspiratory, have a “Velcro-like” character, and are heard predominantly in lower posterior lung zones2,15 
  • With disease progression, crackles may extend toward the mid- and upper-lung zones16

2. Meltzer EB et al. Orphanet J Rare Dis. 2008;3:1-15.
4. Bjoraker JA et al. Am J Respir Crit Care Med. 1998;157(1):199-203.
5. King TE, Jr. et al. Am J Respir Crit Care Med. 2001;164(7):1171-1181.
6. Douglas WW et al. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1172-1178.
15. Kraman SS. Arch Intern Med. 1986;146(7):1411-1412.
16. Cottin V et al. Eur Respir J. 2012;40(3):519-521.

Some experts believe that crackles are essentially universal in the diagnosis of IPF

However, the correlation of crackles and IPF has not been validated in the current diagnostic criteria1,16

If crackles are absent, other forms of lung disease (eg, granulomatous disease) should be considered17

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
16. Cottin V et al. Eur Respir J. 2012;40(3):519-521.
17. Epler GR et al. Chest. 1978;73(3):333-339.

Digital clubbing may be present in up to 50% of patients with IPF

Clubbing is commonly seen in other pulmonary diseases, including lung cancer and pulmonary tuberculosis, as well as in congestive heart failure18

4. Bjoraker JA et al. Am J Respir Crit Care Med. 1998;157(1):199-203.
5. King TE Jr. et al. Am J Respir Crit Care Med. 2001;164(7):1171-1181.
6. Douglas WW et al. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1172-1178.
18. Spicknall KE et al. J Am Acad Dermatol 2005; 52(6):1020.
19. NHLBI. Signs and Symptoms of IPF. Available at https://www.nhlbi.nih.gov/health/health-topics/topics/ipf/signs. Accessed June 7, 2017.

Pulmonary function testing

Patients with suspected IPF should undergo full pulmonary function testing

  • Spirometry
  • Complete lung volume assessment
    • TLC
    • FVC
    • FEV1
  • Evaluation of DLco
TLC, total lung capacity; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second; DLco, diffusing capacity of carbon monoxide.

20. Ley B et al. Am J Respir Crit Care Med. 2011;183(4):431-440.

Patients with IPF generally show reduced total lung capacity

TLC generally decreases in IPF because parenchymal scar tissue accumulates, resulting in reduced intrinsic elasticity and subsequent distortion of normal lung architecture2
 
2. Meltzer EB et al. Orphanet J Rare Dis. 2008;3:1-15.

Patients with IPF often show a restrictive pattern on spirometry

Restrictive defect
  • TLC is low
  • Low FVC
  • Higher FEV1/FVC ratio
  • Flows are higher than expected at a given lung volume
Obstructive defect
  • TLC is normal
  • Normal FVC but lower FEV1
  • Lower FEV1/FVC ratio
  • Flows are lower than expected over the entire volume range
Used with permission from Pellegrino R et al. Eur Respir J 2005;26(5):948-968.
PEF, peak expiratory flow.

2. Meltzer EB et al. Orphanet J Rare Dis. 2008;3:1-15.
3. Pellegrino R et al. Eur Respir J. 2005;26(5):948-968.

Patients with IPF also tend to have impaired gas exchange

Fibrosis during IPF affects how well the lungs exchange gases, which can be seen by measuring the diffusion capacity of the lungs, particularly carbon monoxide (DLco)2
 
2. Meltzer EB et al. Orphanet J Rare Dis. 2008;3:1-15.

Reduced DLco may occur before reduced lung volumes

Reduced DLco can be found during the early stages of IPF2,7 
 
In patients with concomitant IPF and emphysema, spirometric measures and lung volumes may be normal, but DL will invariably be low21,22
 
2. Meltzer EB et al. Orphanet J Rare Dis. 2008;3:1-15.
7. American Thoracic Society. Am J Respir Crit Care Med. 2000;161(2 Pt 1):646-664.
21. Portillo CK et al. Arch Bronconeumol. 2010;46(12):646-651.
22. Cottin V et al. Eur Respir J. 2005;26(4):586-593.

Most patients with IPF will experience hypoxemia on exertion

Patients may or may not show decreased blood gas exchange/oxygen saturation at rest2

2. Meltzer EB et al. Orphanet J Rare Dis. 2008;3:1-15.

Other clinical evaluations

Patients with IPF or suspected IPF should have a cardiovascular workup

  • Pulmonary hypertension is a common comorbidity in IPF23
  • Patients with IPF or suspected IPF should be evaluated for potential pulmonary vascular abnormalities, such as right ventricular hypertrophy or right bundle branch block patterns24
23. Collard HR et al. J Med Econ. 2012;15(5);829-835.
24. Han MK et al. Circulation. 2007;116(25):2992-3005.

Patients should be evaluated for signs and symptoms of CTD

The ATL/ERS/JRS/ALAT 2011 guidelines recommend evaluating patients with suspected IPF for1:
  • Rheumatoid factor
  • Anti-CCP
  • ANA titer and pattern
Patients with ILD and clinical signs or symptoms that meet the diagnostic criteria for CTD do not have IPF1

CCP, cyclic citrullinated peptide; ANA, anti-nuclear antibody; ILD, interstitial lung disease.

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

Other tests should be ordered based on the patient's specific symptoms

Possible symptoms and associated tests include1,25-27:
 
Morning stiffness
Arthritis
Rash
 >  ANA
RF
Anti-CCP
Dry mouth (Sicca syndrome)
Dry eyes
 >  SS-A
SS-B
Skin thickening
Esophageal symptoms
Raynaud’s phenomenon
 >  Scl-70
Mechanic’s hands
Proximal muscle pain/weakness
Heliotrope rash
Raynaud’s phenomenon
 >  CK
Aldolase
Anti-Jo1















CK, creatine kinase; RF, rheumatoid factor; SS-A/SS-B, Sjögren’s antibodies.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
25. Kinder BW et al. Am J Respir Crit Care Med. 2007;176(7):691-697.
26. Vij R et al. Chest. 2013;143(3):814-824.
27. Satoh M, et al. Mod Rheumatol. 2009;19:219-228.

High titers of autoantibodies suggest the presence of CTD

Approximately 10%-20% of patients with IPF have low-level titers of ANA ( <1:160) or rheumatoid factor7 
  • Such patients should be screened for signs and symptoms of CTD (eg, arthritis, Raynaud's phenomenon, skin changes, abnormal esophageal motility)1
 
1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
7. American Thoracic Society. Am J Respir Crit Care Med. 2000;161(2 Pt 1):646-664.

Patients with suspected CTD but low titers should be retested

If CTD is strongly suspected but the tests do not show strong evidence of CTD, the panel may be repeated after initial testing1,28 
 
1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
28. British Columbia Medical Association. Antinuclear antibody (ANA) testing protocol. Available at www.bcguidelines.ca. Accessed June 7, 2017.

Medical history

A detailed medical history is essential to diagnosing IPF

In all cases of potential ILD, a detailed medical history should be taken that covers1:
  • Comorbidities
  • Social history
  • Occupational and environmental exposures
  • Drug exposures
  • Family history

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

IPF has several common comorbidities

  • Common comorbidities seen with IPF include23:
    • GERD
    • Emphysema
    • Coronary artery disease
    • Congestive heart failure
    • Obstructive sleep apnea 
    • Pulmonary hypertension, either due to chronic hypoxia or as a result of ILD
    • Lung cancer
  • See Managing IPF: Comorbidities for more information
 
GERD, gastroesophageal reflux disease.

23. Collard HR et al. J Med Econ. 2012;15(5);829-835.

Many patients are former smokers at the time of IPF diagnosis

Cigarette smoking is strongly associated with IPF, especially among patients with a history of smoking more than 20 pack-years29

4. Bjoraker JA, et al. Am J Respir Crit Care Med. 1998;157(1):199-203.
29. Baumgartner KB et al. Am J  Respir Crit Care Med. 1997;155(1):242-248.

Certain occupational and environmental exposures are associated with IPF

  • Occupational and environmental exposures that are associated with increased risk of IPF include30:
    • Varied sources of dust and/or particulate matter
    • Agriculture-related and livestock-related exposures
    • Raising birds
  • Although these exposures are associated with IPF, they have not been found to be causative31
  • See About IPF: Risk Factors for more information

30. Baumgartner KB et al. Am J Epidemiol 2000;152(4):307-315.
31. Taskar VS et al. Proc Am Thorac Soc. 2006;3:293–298.

IPF can look like hypersensitivity pneumonitis but differs by environmental exposures

  • HP is typically caused by an inflammatory reaction to inhaled organic particles32
  • Specific fungi:
    • Bird feathers (eg, household bedding)
    • Atypical mycobacterium (eg, those that colonize hot tubs) 
HP, hypersensitivity pneumonitis.

32. Selman M et al. Am J Respir Crit Care Med. 2012;186(4):314-324.

It is essential to distinguish between IPF and HP

  • The workup and treatment for IPF and HP are vastly different32,33
  • HP is treated with systemic corticosteroids,32 which is strongly discouraged when treating IPF1
1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
32. Selman M et al. Am J Respir Crit Care Med. 2012;186(4):314-324.
33. Morell F. Lancet Respir Med. 2013;1(9):685-694.

Serologic workup should be performed for suspected cases of HP

Patients whose exposure history suggests HP should undergo a serologic workup including fungal antigen panels and immunoglobulin G levels toward the suspected offending antigen32
 
32. Selman M et al. Am J Respir Crit Care Med. 2012;186(4):314-324.

Numerous drugs have been associated with development of ILD

The website Pneumotox (www.pneumotox.com) is freely available and accessible to help in diagnosing potential drug-induced ILD by drug name or pathologic condition34

34. Camus P. The drug-induced respiratory disease website. 2012.  Pneumotox website. www.pneumotox.com. Accessed December 12, 2017.
35. Schwaiblmair M et al. Open Respir Med J. 2012;6:63-74.

Family history of IPF or young age should lead to suspicion of familial IPF

  • Familial IPF is generally indistinguishable from sporadic cases based on clinical and/or histologic characteristics36,37
Both familial and sporadic cases of IPF have been linked with genetic mutations38-41
  • For more information on the genetic mutations associated with IPF, see About IPF: Molecular Understanding
36. Marshall RP et al. Thorax. 2000;55(2):143-146.
37. Hodgson U et al. Thorax. 2002;57(4):338-342.
38. Thomas AQ et al. Am J Respir Crit Care Med. 2002;165(9):1322-1328.
39. van Moorsel CH et al. Am J Respir Crit Care Med. 2010;182(11):1419-1425.
40. Wang Y et al. Am J Hum Genet. 2009;84(1):52-59.
41. Seibold MA et al. N Engl J Med. 2011;364(16):1503-1512.

Summary

  • Patients with suspected IPF should undergo a full set of examinations1-3
    • Physical exam, respiratory evaluation, full medical history
  • Pulmonary function tests will often show abnormalities that add evidence to support a diagnosis of IPF1,2
  • Taking a detailed medical history is essential for identifying risk factors and potential alternative diagnoses1
1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
2. Meltzer EB et al. Orphanet J Rare Dis. 2008;3:1-15.
3. Pellegrino R et al. Eur Respir J. 2005;26(5):948-968.

References

1.Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
2.Meltzer EB et al. Orphanet J Rare Dis. 2008;3:1-15.
3.Pellegrino R et al. Eur Respir J. 2005;26(5):948-968.
4.Bjoraker JA et al. Am J Respir Crit Care Med. 1998;157(1):199-203.
5.King TE Jr. et al. Am J Respir Crit Care Med. 2001;164(7):1171-1181.
6.Douglas WW et al. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1172-1178.
7.American Thoracic Society. Am J Respir Crit Care Med. 2000;161(2 Pt 1):646-664.
8.Kim DS et al. Proc Am Thorac Soc. 2006;3(4):285-292.
9.Panos RJ et al. Am J Med. 1990;88(4):396-404.
10.Castriotta RJ et al. Chest. 2010;138(3):693-703.
11.Ryerson CJ et al. Respirology. 2011;16(6):969-975.
12.Kritek P, Choi MK. In: Longo DL, Fauco AS, Kasper DL et al, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill Companies, Inc. 2012:2094-2101.
13.Swigris JJ et al. Health Qual Life Outcomes. 2005;3:61.
14.Irwin RS et al. Chest. 1998;114(2):133S-181S.
15.Kraman SS. Arch Intern Med. 1986;146(7):1411-1412.
16.Cottin V et al. Eur Respir J. 2012;40(3):519-521.
17.Epler GR et al. Chest. 1978;73(3):333-339.
18.Spicknall KE et al. J Am Acad Dermatol 2005; 52(6):1020.
19.NHLBI. Signs and Symptoms of IPF. Available at https://www.nhlbi.nih.gov/health/health-topics/topics/ipf/signs. Accessed June 7, 2017.
20.Ley B et al. Am J Respir Crit Care Med. 2011;183(4):431-440.
21.Portillo CK et al. Arch Bronconeumol. 2010;46(12):646-651.
22.Cottin V et al. Eur Respir J. 2005;26(4):586-593.
23.Collard HR et al. J Med Econ. 2012;15(5);829-835.
24.Han MK et al. Circulation. 2007;116(25):2992-3005.
25.Kinder BW et al. Am J Respir Crit Care Med. 2007;176(7):691-697.
26.Vij R et al. Chest. 2013;143(3):814-824.
27.Satoh M, et al. Mod Rehumatol. 2009;19:219-228.
28.British Columbia Medical Association. Antinuclear antibody (ANA) testing protocol. Available at www.bcguidelines.ca. Accessed June 7, 2017. 
29.Baumgartner KB et al. Am J  Respir Crit Care Med. 1997;155(1):242-248.
30.Baumgartner KB et al. Am J Epidemiol. 2000;152(4):307-315.
31.Taskar VS et al. Proc Am Thorac Soc. 2006;3:293-298.
32.Selman M et al. Am J Respir Crit Care Med. 2012;186(4):314-324.
33.Morell F. Lancet Respir Med. 2013;1(9):685-694.
34.Camus P. The drug-induced respiratory disease website. Pneumotox website. 2012. Available at www.pneumotox.com. Accessed June 21, 2017.
35.Schwaiblmair M et al. Open Respir Med J. 2012;6:63-74.
36.Marshall RP et al. Thorax. 2000;55(2):143-146.
37.Hodgson U et al. Thorax. 2002;57(4):338-342.
38.Thomas AQ et al. Am J Respir Crit Care Med. 2002;165(9):1322-1328.
39.van Moorsel CH et al. Am J Respir Crit Care Med. 2010;182(11):1419-1425.
40.Wang Y et al. Am J Hum Genet. 2009;84(1):52-59.
41.Seibold MA et al. N Engl J Med. 2011;364(16):1503-1512.