Interstitial lung diseases (ILDs) are characterised 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 (HRCT), and comprehensive pulmonary function testing and blood-gas analysis. To optimise the diagnostic yield, a dynamic interaction between the clinician, radiologist and pathologist is mandatory. 

ILDs are a heterogeneous group of more than 150 disease entities that differ significantly with respect to prevention, therapy and prognosis. 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).

Once an interstitial disease process has been recognised in a patient, there are three crucial questions that have to be addressed in the diagnostic work-up: 

• Is there a discernible cause for the disease?
• If no cause is identifiable, is it idiopathic pulmonary fibrosis (IPF)?
• 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: 

• Patient presents with clinical symptoms (eg. dry cough, dyspnoea)
• Patient is at risk of ILD due to known exposures (eg. amiodarone, asbestos)
• Patient is at risk of ILD due to family history
• Patient is asymptomatic, but presents with chance finding on chest radiography or computed tomography
• Patient is asymptomatic, but presents with chance finding on pulmonary functioning test. 

History taking 

A comprehensive patient history taking is of crucial importance for the diagnosis of ILD. There are four main questions to be answered. When did respiratory symptoms start? How did the disease develop over time to the present? Are there or have there been any exposures to aetiologic agents known to cause ILD? What is the severity of symptoms at presentation?

The disease chronology can be subdivided into four categories: acute – days up to a few weeks; subacute – four to 12 weeks; chronic – longer than 12 weeks; and episodic – symptomatic phases that are followed by asymptomatic phases. In addition, all available radiographs of the lung should be reviewed to characterise the nature and development of the radiological pattern. Flitting opacities on chest imaging studies may drive the differential diagnosis to focus on eosinophilic pneumonia, hypersensitivity pneumonitis (HP), vasculitis or organising pneumonia. 

Assessment of symptoms 

Dyspnoea on exertion or at rest is the predominant symptom in most ILDs. 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-centred diseases such as sarcoidosis, HP or organising pneumonia. 

Pleural pain and effusion in the context of an ILD indicate connective tissue disease (eg. systemic lupus erythematosus [SLE] or rheumatoid arthritis [RA]) or drug-induced or asbestos-related disease. Differential diagnoses include complications such as infections or pulmonary embolism. 

Haemoptysis is always an alarming signal and may indicate manifestation of pulmonary haemorrhagic syndromes, for example, Goodpasture syndrome or granulomatosis with polyangiitis (GPA, previously called Wegener disease). 

Alternatively, infections, lung cancer or pulmonary embolism have to be considered. Gastro-oesophageal 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, the following should be carefully sought:

• Joint pain and swelling (RA) and cutaneous thickening
• Raynaud’s 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)
• Crohn’s disease. 

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 (SLE)
• Cutaneous vasculitis (Churg-Strauss syndrome)
• Oedematous-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, non-specific interstitial pneumonia. 

Laboratory testing 

There are no specific laboratory tests that allow for the diagnosis of an ILD. 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
• Urinary sediment. 

These laboratory values allow the exclusion or suggestion of an associated haematological, liver or kidney disease in a potential context of systemic disease (eg. sarcoidosis, vasculitis, amyloidosis), malignancy (eg. lymphoma) or infection (eg. tuberculosis, HIV). To further evaluate the presence of connective tissue disease, systemic disease (eg. sarcoidosis, connective tissue disease) or HP, additional measures may be appropriate as summarised in Table 1.

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Pulmonary function testing 

Patients with ILD should undergo comprehensive pulmonary function testing (PFT). This includes:

• Arterial or capillary blood gas analysis at rest and eventually under exertion
• Spirometry and body plethysmography
• Measurement of the diffusion capacity using carbon monoxide as a tracer in the single-breath method (DLco). 

In addition, measurement of compliance may be helpful in objectifying the elevated stiffness of the lung. PFTs are in general not able to support a specific ILD diagnosis, but they are necessary to assess the respiratory limitations and to monitor the disease during follow-up. 

Radiological assessment 

An abnormal chest radiograph is often the initial finding in patients with ILD. A diffuse reticulonodular pattern, ground-glass opacities or both are the most common findings on a chest radiograph in patients with ILD. The pattern and distribution of radiological appearances contribute to initial diagnostic considerations as summarised in Table 2.

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Bronchoscopy 

In patients with ILD, bronchoscopy can be performed to obtain materials for microbiological, cytological and histological analyses. The applied techniques encompass bronchoalveolar lavage (BAL), transbronchial lung biopsy (TBLB) and transbronchial needle aspiration (TBNA) for cytological or histological (Wang needle) analyses. 

However, bronchoscopy is associated with some morbidity, and even a very low rate of mortality, and therefore is not an obligatory diagnostic procedure for all patients with ILD. Moreover, to make bronchoscopy and BAL/TBLB a valuable tool in the work-up of patients with ILD, each clinical site must establish routine methods for handling and analysis of the materials. 

If these obligatory prerequisites are fulfilled, bronchoscopy and BAL with or without TBLB are valuable tools in the diagnostic work-up of patients with ILD. The use of BAL, TBLB and/or TBNA (eventually endobronchial ultrasonography guided), can be used to diagnose:

• Sarcoidosis
• Lymphangitis carcinomatosa
• Eosinophilic pneumonia
• Alveolar proteinosis
• Langerhans cell histiocytosis
• Lymphoid interstitial pneumonia
• Several bacterial, viral and fungal infections.

This avoids using more invasive procedures such as mediastinoscopy, video-assisted thoracoscopic (VATS) biopsy or open surgical lung biopsy. 

In several patients with probable or possible IPF, bronchoscopic techniques may be used to rule out alternative diagnoses, such as HP in selected patients, especially if VATS biopsy seems too risky or has to be performed in elderly patients. However, especially in patients with IPF, bronchoscopy and BAL have the potential of triggering acute exacerbation of IPF, so that the indication for bronchoscopic evaluation should be discussed critically in every individual patient. 

Surgical lung biopsy 

Surgical lung biopsy, nowadays preferentially performed during video-assisted thoracic surgery (VATS), is the most invasive diagnostic procedure used for diagnosis of ILD. It is associated with significant morbidity and mortality and should be reserved for those patients in whom the management and treatment could change depending on the result of biopsy. 

In IPF, histological analysis from a surgical lung biopsy is no longer the gold standard of diagnosis because it has become clear that because of sampling error and uniformity of disease pattern in patients with advanced disease, histological examination will not provide the diagnostic clue in many patients. 

Consequently, in IPF, the multidisciplinary discussion (MDD) involving the clinician, radiologist and pathologist has become the gold standard for diagnosis. Because IPF is one if not the most important differential diagnosis in most patients with ILD, an MDD seems to be the most promising approach to reach a confident diagnosis.