Abstract
Interstitial lung diseases (ILDs) encompass a wide range of diffuse pulmonary disorders, characterized by a variable degree of inflammatory and fibrotic changes of the alveolar wall and eventually the distal bronchiolar airspaces. ILDs may occur in isolation or in association with systemic diseases. The clinical evaluation of a patient with ILD includes a thorough medical history and detailed physical examination; obligatory diagnostic testing includes laboratory testing, chest radiography, and high-resolution computed tomography and comprehensive pulmonary function testing and blood gas analysis. To optimize the diagnostic yield, a dynamic interaction between the pulmonologist, radiologist, and pathologist is mandatory.
Keywords
Diagnosis, Idiopathic interstitial pneumonia, Idiopathic pulmonary fibrosis, Interstitial lung disease, Pulmonary function testing, Radiologic assessment
Key Points
- •
A comprehensive patient history taking is of crucial importance for the diagnosis of interstitial lung diseases (ILDs).
- •
Dyspnea with exertion or at rest is the predominant symptom in most ILDs.
- •
There are no specific laboratory tests that allow for the diagnosis of an ILD, but, in an appropriate clinical setting, laboratory test results may be strongly supportive of a specific diagnosis.
Interstitial lung diseases (ILDs) are a heterogeneous group of more than 150 disease entities that differ significantly with respect to prevention, therapy, and prognosis. The current classification scheme of ILDs is shown in Fig. 7.1 .
The diagnostic strategy in a patient with ILD is based on considerations regarding the dynamic time course (acute, subacute, chronic), the cause (known or unknown), and the context of the disease at presentation (presence of extrapulmonary/systemic disease manifestations). Fig. 7.2 summarizes the main disease categories that have to be differentiated during the diagnostic process.
Once an interstitial disease process has been recognized in a patient, there are three crucial questions that have to be addressed in the diagnostic workup:
- 1.
Is there a discernible cause for the disease?
- 2.
If no cause is identifiable, is it idiopathic pulmonary fibrosis (IPF)?
- 3.
If there is no cause of the disease and if it is not IPF, should surgical lung biopsy be recommended?
After a diagnosis has been established, the severity and dynamics of the disease have to be assessed and monitored, with or without therapy. Diagnosis and disease severity/dynamics are fundamental for treatment decisions and to predict prognosis. The diagnostic approach to ILD may have to be adapted to different clinical scenarios that eventually lead to presentation of a patient:
- 1.
A patient presents with clinical symptoms (e.g., dry cough, dyspnea).
- 2.
A patient is at risk of ILD because of known exposures (e.g., amiodarone, asbestos).
- 3.
A patient is at risk of ILD because of family history.
- 4.
A patient is asymptomatic but presents with chance finding on chest radiography or computed tomography.
- 5.
A patient is asymptomatic but presents with chance finding on a pulmonary functioning test (e.g., restrictive pattern, reduced gas transfer).
This article deals with diagnostic approaches suitable for patients presenting with clinical symptoms of ILD in the first place.
Clinical evaluation
History Taking
A comprehensive history taking of a patient is of crucial importance for the diagnosis of ILD. There are four main questions to be answered: (1) When did respiratory symptoms start? (2) How did the disease develop over time to the present? (3) Are there or have there been any exposures to etiologic agents known to cause ILD? and (4) What is the severity of symptoms at presentation?
The disease chronology can be subdivided into four categories: (1) acute, days up to a few weeks; (2) subacute, 4 to 12 weeks; (3) chronic, longer than 12 weeks; and (4) episodic, that is, symptomatic phases that are followed by asymptomatic phases. In addition, all available radiographs of the lung should be reviewed to characterize the nature and development of the radiologic pattern. Flitting opacities on chest imaging studies may drive the differential diagnosis to focus on eosinophilic pneumonia, hypersensitivity pneumonitis (HP), vasculitis, or organizing pneumonia.
Assessment of Symptoms
Dyspnea with exertion or at rest is the predominant symptom in most ILDs. It is of importance to accurately assess the degree of exercise limitation and dyspnea in a reproducible manner by asking specific questions: after what distance, after how many steps, or after how many stairs or floors does dyspnea occur and for how long has the patient experienced this degree of dyspnea and how fast did it develop or when was the most recent change? The degree of dyspnea is linked to disease severity and prognosis. It is also necessary to exclude nonrespiratory symptoms as a cause of the exercise limitation, for example, joint pains, muscle pains, or weakness.
Cough is the second most frequent symptom in patients with ILD and sometimes becomes really bothersome. Although a dry cough is common in IPF, cough is generally an airway symptom and therefore more indicative of airway-centered diseases such as sarcoidosis, HP, or organizing pneumonia. Increased secretions from ILD-associated bronchitis or bronchiectasis cause productive cough. Wheezing is another airway-associated symptom that is infrequent in ILD but may occur in certain entities such as Churg-Strauss syndrome, HP (e.g., pigeon breeder’s lung), or airway-stenotic sarcoidosis.
Pleural pain and effusion in the context of an ILD indicate connective tissue disease (e.g., systemic lupus erythematosus or rheumatoid arthritis) or drug-induced or asbestos-related disease. Differential diagnoses include complications such as infections or pulmonary embolism. Hemoptysis is always an alarming signal and may indicate manifestation of pulmonary hemorrhagic syndromes, for example, Goodpasture syndrome or granulomatosis with polyangiitis (GPA, previously called Wegener disease). Alternatively, infections, lung cancer, and pulmonary embolism have to be considered. Gastroesophageal reflux is another common symptom in patients with ILD that is suspected of causing or at least exacerbating ILD. A history of acid reflux should, therefore, be taken in all patients with ILD.
Extrapulmonary features of associated diseases may provide important hints to the correct diagnosis. Therefore joint pain and swelling (rheumatoid arthritis), cutaneous thickening, Raynaud phenomenon and dysphagia (systemic sclerosis), oculocutaneous albinism and colitis (Hermansky-Pudlak syndrome), chronic granulomatous sinusitis (GPA and Churg-Strauss syndrome), renal failure (Goodpasture syndrome), renal angiomyolipoma (lymphangioleiomyomatosis), and Crohn disease should be carefully asked about and sought for.
Next Step Is a Comprehensive Investigation of Possible Causes for Interstitial Lung Diseases
Causative agents
A comprehensive history taking of all respiratory risk factors and exposures in the past and present is of utmost importance. Because history taking is a very complex and time-consuming task, it is often helpful to use a standardized questionnaire, such as that available from the American College of Chest Physicians. The following items have to be checked: (1) smoking history, (2) hobbies, (3) travel, (4) occupations, and (5) drug history and treatments (e.g., radiation therapy). Of special interest in this context is the family history as it becomes more and more clear that a considerable subset of patients and diseases do have hereditary traits.
Comorbid diseases
There are several diseases that mimic or that are associated with ILDs: (1) Infectious agents such as mycobacteria, cytomegalovirus, Pneumocystis jiroveci , and human immunodeficiency virus (HIV) and parasite infestations are able to cause an ILD-like condition. (2) Connective tissue diseases are frequently associated with ILDs. This is especially the case for systemic sclerosis and rheumatoid arthritis. (3) Vasculitides, for example, GPA, Churg-Strauss syndrome, and microscopic polyangiitis, are able to manifest in the lungs as ILD.
Physical Examination
On physical examination, inspection of the integument may reveal valuable findings: skin thickening and acral necrosis (scleroderma), oculocutaneous albinism (Hermansky-Pudlak syndrome), clubbing (up to 40% in all ILDs, up to 66% in IPF), livedo racemosa (systemic lupus erythematosus), cutaneous vasculitis (Churg-Strauss syndrome), and edematous-cyanotic skin (dermatomyositis, “disease lilac”). Palpation may reveal lymphadenopathy, hepatosplenomegaly pointing at sarcoidosis, HIV infection, or connective tissue disease.
On auscultation of the lungs, symmetric fine “Velcro-like” inspiratory crackles are found in more than 90% of patients with IPF and in about 60% of patients with connective tissue disease–associated ILD. Crackles are less frequent in HP and rare in sarcoidosis. Wheezing and inspiratory squeaks reflect bronchiolitis and/or bronchial obstruction and are associated with Churg-Strauss syndrome, HP, and rarely nonspecific interstitial pneumonia. Cyanosis may be present and should be confirmed by pulse oximetry, which can be easily performed in clinics.
Laboratory Testing
There are no specific laboratory tests that allow for the diagnosis of an ILD, but, in an appropriate clinical setting, laboratory test results may be strongly supportive of a specific diagnosis. Routine laboratory testing should include a complete blood cell count; leukocyte differential; platelet count; erythrocyte sedimentation rate; determination of serum electrolyte levels, including calcium, serum urea nitrogen, and creatinine; liver function tests; and urinary sediment. These laboratory values allow the exclusion or suggestion of an associated hematologic, liver, or kidney disease in a potential context of systemic disease (e.g., sarcoidosis, vasculitis, amyloidosis), malignancy (e.g., lymphoma), or infection (e.g., tuberculosis, HIV). To further evaluate the presence of connective tissue disease, systemic disease (e.g., sarcoidosis), or HP, additional measures may be appropriate as summarized in Table 7.1 .
| Laboratory Test | Indication | Interpretation |
|---|---|---|
| ANA; rheumatoid factor; ANA differentiation, including Jo-1 or ScL-70 antibodies | Suspected CTD or idiopathic ILD for which CTD cannot be excluded | Low titers occur in up to 20% of patients with IPF, high titers suggest underlying CTD |
| Creatine kinase activity, myoglobin, aldolase | Suspected myositis | Elevated values support a diagnosis of dermatomyositis |
| Immunoglobulins | Suspicion of immunodeficiency | Decreased serum immunoglobulins suggest common variable immunodeficiency syndrome or LIP |
| c-ANCA, p-ANCA | Suspected vasculitis | c-ANCA suggestive of GPA (Wegener syndrome), microscopic polyangiitis; p-ANCA suggestive of CSS or MPA |
| Antiglomerular basement membrane antibody | Hemoptysis due to DAH, renal failure | Positive result is diagnostic of Goodpasture syndrome |
| Serum angiotensin-converting enzyme activity, serum-soluble interleukin-2 receptor | Sarcoidosis | Low sensitivity and specificity |
| Specific serum IgG antibodies | Exposure to antigens that cause HP | Valid only within an appropriate clinical context |
There have been multiple attempts to find biomarkers to monitor disease activity or to predict prognosis in different ILDs. Intraindividual changes of serum angiotensin-converting enzyme activity or of serum concentration of the soluble interleukin-2 receptor are to some extent helpful in monitoring disease activity in sarcoidosis. The serum lactate dehydrogenase activity is to some extent predictive of prognosis in IPF. Limited data are available for serum levels of Krebs von der Lungen 6, a high-molecular-weight glycoprotein representing human MUC1 mucin, surfactant proteins A and D, matrix metalloproteinases, and CCL-18. However, none of these biomarkers has been validated sufficiently to be recommended for the routine use in the monitoring and follow-up of patients with ILD.
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