IPF Clinical Features

Clinical Presentation

IPF commonly presents with a chronic dry, nonproductive cough and/or unexplained chronic exertional dyspnea.35810 Chest pain is not a typical manifestation of IPF.

IPF should be considered in all patients with unexplained, chronic exertional dyspnea.358 Dyspnea is one of the prominent and disabling symptoms of idiopathic pulmonary fibrosis. Most patients have experienced dyspnea for more than 6 months before presentation.310 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 later.11

The cough associated with IPF is often paroxysmal and dry, and can be debilitating.3512

The patient's age at presentation is an important consideration. IPF typically occurs in individuals between 508 and 70 years of age,12 but infrequently in patients younger than 40 years of age.812 IPF is rare in children and therefore other diagnostic possibilities for ILD should be considered in pediatric patients.12 If an older adult develops an interstitial lung disease, IPF is commonly the ultimate diagnosis, with positive predictive value (PPV) based on age alone being 95% for those age 70 or older and close to 100% for those age 75 or older.13 Although no formal recommendations exist, surgical lung biopsy may be deferred in patients over 75 with evidence of a UIP or probable UIP pattern on HRCT and no evidence for connective tissue disease.8

Physical Examination

Crackles are detected on auscultation of the lungs in at least 80% of patients with IPF, though these data are not validated in the current diagnostic criteria.3514 Some experts believe that crackles are essentially universal in the diagnosis of IPF.15 If crackles are absent, other forms of lung disease (eg, granulomatous disease) should be considered.16

The crackles of IPF are pan- or end-inspiratory, have a “Velcro-like” character, and are heard predominantly in lower posterior lung zones.1217 With disease progression, crackles may extend toward the mid- and upper-lung zones.15 To learn more about the respiratory sounds associated with IPF and how they differ from normal lung sounds and sounds associated with COPD, see Resource Center.

Digital clubbing is present in up to 50% of patients with IPF (Figure 1).35814

Figure 1.
An example of digital clubbing that may be present in patients with IPF. Used with permission from National Heart, Lung, and Blood Institute, National Institutes of Health. Available at www.nhlbi.nih.gov.

Digital Clubbing in Patient with IPF

Other physical manifestations of IPF are rare, but may include cyanosis, and/or signs of pulmonary hypertension or right heart failure.1018

Constitutional symptoms are rare.10 Notably, fever, weight loss, and arthritis are unusual in IPF and should prompt investigation for secondary causes of pulmonary fibrosis such as connective tissue disease.12 By definition, patients with pulmonary fibrosis and a connective tissue disease diagnosis do not have IPF.8

Medical History

In all cases of potential ILD, a detailed medical history is essential, focusing on social history, occupational and environmental exposures, drug exposures, family history, comorbidities, and a comprehensive review of systems.8

Social History

Cigarette smoking is strongly associated with IPF, especially among patients with a history of smoking more than 20-pack-years.19 Many patients are former smokers at the time of IPF diagnosis.319 For more information about smoking as a potential risk factor for IPF, see Natural History and Potential Risk Factors.

Environmental Exposures

Case-controlled studies have examined the association between various environmental or occupational exposures and the risk of developing IPF.20 Several of these studies observed an increased risk of developing IPF among patients with exposure to certain environmental factors, including metal dust exposure, wood dust exposure, sand, stone, and silica exposure, as well as agriculture/farming-related and livestock-related exposures.

While such exposures are associated with IPF, they have not been found to be causative. In contrast, hypersensitivity pneumonitis (HP), a granulomatous inflammatory lung disorder, is typically caused by inflammatory reaction to inhaled organic particles.21 Common exposures associated with HP are specific fungi, bird feathers (such as in household bedding), and atypical mycobacterium (such as those that colonize hot tubs),21 though a myriad of causes have been described. Potential etiologic agents of HP are shown in Table 1.22

Table 1.
Etiologic agents of hypersensitivity pneumonitis. Adapted from: Selman M. Hypersensitivity pneumonitis. In: Schwarz M, King TE, Jr., eds. Interstitial lung disease. 5th ed. Shelton, CT: People's Medical Publishing House; 2011:597-625.

Disease Source
Fungal and Bacterial
Farmer's lung Moldy hay, grain, silage
Ventilation pneumonitis; humidifier lung; air conditioner lung Contaminated forced-air systems; water reservoirs
Bagassosis Moldy sugarcane (ie, bagasse)
Mushroom worker's lung Moldy mushroom compost
Enoki mushroom worker's lung (Japan) Moldy mushroom compost
Suberosis Moldy cork
Detergent lung; washing powder lung Detergents (during processing or use)
Malt worker's lung Moldy barley
Sequoiosis Moldy wood dust
Maple bark stripper's lung Moldy maple bark
Cheese washer's lung Moldy cheese
Woodworker's lung Oak, cedar, and mahogany dust, pine and spruce pulp
Hardwood worker's lung Kiln-dried wood
Paprika slicer's lung Moldy paprika pods
Sauna taker's lung Contaminated sauna water
Familial HP Contaminated wood dust in walls
Wood trimmer's lung Contaminated wood trimmings
Composter's lung Compost
Basement shower HP Mold on unventilated shower
Hot tub lung Hot tub mists; mold on ceiling
Wine maker's lung Mold on grapes
Woodsman's disease Oak and maple trees
Thatched roof lung Dead grasses and leaves
Tobacco grower's lung Tobacco plants
Potato riddler's lung Moldy hay around potatoes
Summer-type pneumonitis Contaminated old houses
Dry rot lung Rotten wood
Stipatosis Esparto dust
Machine operator's lung Aerosolized metalworking fluid
Residential provoked pneumonitis Amebae Residential exposure
Humidifier lung Contaminated water from home humidifier, ultrasonic misting fountains
Shower curtain disease Moldy shower curtain
Animal Proteins
Pigeon breeder's or pigeon fancier's disease Parakeets, budgerigars, pigeons, chickens, turkeys
Pituitary snuff taker's lung Bovine and porcine pituitary proteins
Fish meal worker's lung Fish meal dust
Bat lung Bat droppings
Furrier's lung Animal pelts
Animal handler's lung; laboratory worker's lung Urine, serum, pelts, proteins
Insect Proteins
Miller's lung Dust-contaminated grain
Lycoperdonosis Lycoperdon puffballs

HP = hypersensitivity pneumonitis

Differentiation between IPF and HP can be difficult, but is essential, as the workup and treatment are vastly different.23 In HP, allergen avoidance is mandatory and can be curative, which differs from IPF. Systemic corticosteroids are recommended for treatment in HP21 but are strongly discouraged as IPF treatment.8 If HP is suspected by history, serologic workup including fungal antigen panels and immunoglobulin G levels toward the suspected offending antigen are suggested.21

For more information about environmental exposures, see Natural History and Potential Risk Factors.

Drug Exposures

Numerous drugs have been associated with development of ILD.24 Drugs commonly associated with the development of ILD include bleomycin and other chemotherapeutic agents, nitrofurantoin, amiodarone, and methotrexate.25 The website Pneumotox (www.pneumotox.com) is freely available and accessible as an aid in the diagnostic process of potential drug-induced ILD and can be indexed by drug name or pathologic pattern.

Patients with suspected IPF should be carefully evaluated for other known causes of ILD (domestic and occupational environmental exposures, connective tissue disease, and drug toxicity).8

Family History

Genetic factors have been investigated in both familial and sporadic cases of IPF.8 Familial and sporadic IPF, may be clinically and/or histologically indistinguishable, with familial forms being suspected based on family history or in patients younger than 50 years of age.8 While routine genetic testing cannot be recommended at this time in patients with sporadic IPF8 the rapid accumulation of genetic information and the changes in understanding of their functional consequences makes this a rapidly changing field. For more information on the genetic abnormalities associated with IPF, see Pathogenesis.

Comorbidities

Gastroesophageal reflux disease (GERD) is strongly associated with IPF, although a cause-and-effect relationship has not been established.8 The estimated prevalence may be as high as 90% in patients with IPF but may be present without symptoms.26 For more information about GERD as a potential risk factor for IPF, see Natural History and Potential Risk Factors.

Because IPF occurs in older individuals, it is not uncommon for comorbid conditions (such as emphysema, coronary artery disease, congestive heart failure, or obstructive sleep apnea) to also be present.827 Pulmonary hypertension, either due to chronic hypoxia28 or as a result of interstitial lung disease29 may also be present.

The incidence of lung cancer is seven times higher in IPF patients compared to patients without IPF; this finding persists even when controlling for smoking history.30

Rheumatologic Review of Symptoms

Patients with suspected IPF should be carefully evaluated for signs and symptoms suggestive of a potential connective tissue disease, such as arthralgias, synovitis, joint effusions, morning joint stiffness, proximal muscle weakness, fever, photosensitivity, Raynaud's phenomenon, pleuritis, or sicca symptoms (ie, dry eyes).31 Patients with ILD and clinical signs or symptoms that meet the diagnostic criteria for connective tissue disease do not have IPF.8

Laboratory Testing

No specific laboratory abnormalities are associated with, or diagnostic for, IPF.12

Serologic testing should be performed in the evaluation of patients with suspected IPF to exclude occult connective tissue disease.8 The ATS/ERS/JRS/ALAT 2011 guidelines recommend evaluating rheumatoid factor, anti-cyclic citrullinated peptide (CCP), and anti-nuclear antibody (ANA) titer and pattern, even if the patient has no symptoms that would suggest connective tissue disease.8

Antisynthetase antibodies, creatine kinase and aldolase, Sjögren's antibodies, and scleroderma antibodies should be evaluated based on symptoms (Table 2).832

Table 2.
Suggested Connective Tissue Disease Workup for Patients with Suspected IPF832

Signs and Symptoms Laboratory Test Disease
All patients with suspected IPF
Pleurisy/effusions
Morning stiffness
Arthritis
Rash
ANA
RF
Anti-CCP
Rheumatoid arthritis
Multiple others
Dry mouth (Sicca syndrome)
Dry eyes
SS-A (Anti-Ro)
SS-B (Anti-La)
Sjögren's
Skin thickening
Esophageal symptoms
Raynaud's phenomenon
Sclerodactyly
Scl-70 Systemic sclerosis
Proximal muscle pain or weakness
Heliotrope rash
CK
Aldolase
Anti-Jo1
Dermatomyositis
Polymyositis
Mechanic's hands
Raynaud's phenomenon
Muscle pain
CK
Aldolase
Anti-Jo1 (anti-synthetase)
Antisynthetase syndrome

Low-level titers of ANA (less than 1:160) or rheumatoid factor occur in 10% to 20% of patients with IPF.7 Such patients should be screened for signs and symptoms of connective tissue disease (eg, arthritis, Raynaud's phenomenon, skin changes, abnormal esophageal motility).8 If there is no additional serologic and/or clinical evidence to support a connective tissue diagnosis, a diagnosis of IPF is appropriate.8 A high titer of autoantibodies suggests an alternative diagnosis.12

Notably, in up to 10% of patients with signs or symptoms suggestive of connective tissue disease, initial serologic testing may be non-revealing.33 If a strong clinical suspicion of connective tissue disease exists, repeating a serologic panel 6 to 12 months after initial testing may be warranted.834 At each clinical encounter, a re-evaluation of targeted symptoms and physical exam should be performed to ensure no new rheumatologic findings have emerged.8

An electrocardiogram in patients with suspected IPF may reveal pulmonary vascular abnormalities.35 Patients with pulmonary hypertension may demonstrate right ventricular hypertrophy or right bundle branch block patterns.35 Those with concurrent cardiac disease may have abnormalities on electrocardiogram which may be present prior to the development of respiratory symptoms.

Physiologic Changes

Patients with suspected IPF should undergo full pulmonary function testing, which includes spirometry, complete lung volume assessment, and evaluation of diffusing capacity for carbon monoxide.1

Measurement of lung volumes typically shows a reduction in total lung capacity (TLC) in patients with IPF, confirming restrictive physiology.712 Decreased TLC is due to accumulation of parenchymal scar tissue, loss of intrinsic elasticity, and subsequent distortion of normal lung architecture.12

Routine spirometry without full lung volumes may be appropriate in the initial evaluation of patients with unexplained exertional dyspnea. In patients with IPF, spirometry typically shows the following:

  • Decreased measures of forced vital capacity (FVC) and forced expiratory volume (FEV) in 1 second (FEV1)12
  • Increased ratio of FEV1/FVC, consistent with restrictive physiology12

Measurement of diffusion capacity of the lungs (DL) often reveals impaired gas exchange in patients with IPF.12 The reduction in DL can occur prior to a reduction in lung volume and can be found during the early stages of IPF.12

In patients with concomitant IPF and COPD, spirometric measures (FEV1, FVC, and FEV1/FVC) and lung volumes (TLC) may be normal; however, DL will invariably be low.3637 Abnormal pulmonary function tests need not be present when establishing a diagnosis of IPF.2

The resting arterial blood gas may be normal or abnormal in patients with IPF. Oftentimes relative or absolute hypoxia precedes hypercapnia in those with IPF.12 While the oxygen saturation may be normal at rest, oxygen desaturation is commonly observed during exercise.12

For more information about FVC and other measures of pulmonary function see Clinical Assessments.

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Content contributed by:
Ryan Hadley, MD
University of Michigan