11th January 2024

Diagnosis

History

Due to the wide variety of aetiologies, a detailed history is the key to establishing ILD diagnosis.

Symptoms

When enquiring about symptoms, particular attention should be paid to their onset (days/weeks/years), timing (time of day/day of the week/seasonal variation) and locations at which they occur (work/home).

Past medical history

• History of chronic illnesses, especially of connective tissue disorders, cardiac disorders or autoimmune conditions, could point towards a cause for ILD – either the disorder itself or medications used to treat it.
• It is also important to ask about any recent acute illnesses, including respiratory and urinary tract infections. Patients might not bring these up, deeming them irrelevant, but ILD can occasionally follow chest infections or be a consequence of an antibiotic treatment. Additionally, frequent infections might suggest immunocompromised state and possible infectious aetiology of ILD.
• Note any atopic history, e.g. asthma and allergic rhinitis, as they suggest eosinophilic pneumonia or Churg-Strauss syndrome.

Drug history

• As discussed above, many medications have been implicated in pulmonary toxicity, so it is important to take full drug history of both current and previous medications. History should include over-the-counter (OTC) drugs, birth control, and any supplements. Always establish a clear timeline of when medications were taken relative to the symptoms.
• Enquire about other treatments, such as radiotherapy.

Family history

• Family history can be useful, as certain ILDs have a clear inheritance pattern, e.g. autosomal dominant in familial pulmonary fibrosis and tuberous sclerosis and autosomal recessive in many metabolic disorders.
• Sarcoidosis seems to occur more in certain families, suggesting a genetic component, although the pattern of inheritance is less clear.

Social history

• Illicit drug use, alcohol and smoking history are all very relevant in ILD history. Both smoking and certain recreational drugs are well-established causes of ILD, while excessive alcohol use might lead to recurrent aspiration or pulmonary hypertension secondary to liver disease.
• Occupational history – lifelong occupational history should be elicited. If exposure to harmful materials (e.g. silica, asbestos) is suspected but not clear from history, a patient should be advised to seek a Safety Data Sheet (SDS) from the employer, which documents hazardous materials at workplace. Remember that a patient might be eligible for compensation if they develop occupation-related pneumoconiosis.
• Environmental exposures – respiratory symptoms with fevers occurring at workplace or during particular activity, and disappearing in other environments, should raise suspicion of HP. Ask about any regular exposure to common triggers such as birds, pets and hot tubs (see Table). Note that symptoms might develop secondary to a passive exposure to the causative antigen from another family member, so good exposure history should include that of all close contacts of the patient.

Examination

Respiratory examination

• Fine late inspiratory crackles at bases are typical of ILDs but may not be present in the early stages and in granulomatous disease, e.g. sarcoidosis. Note the location (i.e. basal/widespread/apical), as it might give a clue towards a diagnosis.
• Wheeze may be present in certain types of ILDs, e.g. HP

Cardiovascular examination

• Usually normal, especially in early disease
• Long -standing ILD may lead to core pulmonale and pulmonary hypertension signs (loud S2, raised JVP, peripheral oedema, occasionally pulmonary valve regurgitation), but this is usually only found in advanced, severe disease. If present early in the course, consider alternative diagnosis.

Systemic features

• Clubbing is a useful feature to note, as it is common in certain ILDs but rare in others (see image below). In particular, it is associated with asbestosis and IPF. It is also strongly linked to many non-ILD diseases, such as cyanotic heart disease, cystic fibrosis, and inflammatory bowel disease (IBD), so should be considered in the context of patient’s history. In ILD, clubbing usually points to advanced fibrosis.
• Examine joints and skin for any evidence of CTD-ILD. Rheumatoid arthritis, dermatomyositis, myositis, SLE, and scleroderma can all present with typical skin or articular signs (see images). Saddle nose deformity might point towards GPA or chronic illicit drug use (see image below).

Image Source: Wikimedia Commons (2013). Clubbing of fingers in IPF, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Clubbing_of_fingers_in_IPF.jpg (Accessed: 24 January 2023).

Image Source: Wikimedia Commons (2010). Dermatomyositis, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Dermatomyositis.jpg (Accessed: 24 January 2023).

Image Source: Wikimedia Commons (2013). Lupusfoto, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Lupusfoto.jpg (Accessed:24 January 2023).

Image Source: Wikimedia Commons (2011). Raynaud’s syndrome, Licensed under a creative commons licence. Available for free at: https://upload.wikimedia.org/wikipedia/commons/4/43/Raynaud-Syndrom.JPG (Accessed: 24 January 2023).

Image Source: Wikimedia Commons (2016). Saddle_nose_38, Licensed under a creative commons licence. Available for free at: https://upload.wikimedia.org/wikipedia/commons/e/ee/Saddle_nose_38.jpg  (Accessed: 24 January 2023).

Investigations

All patients with suspected ILD should have biochemistry, pulmonary function testing, chest x-ray and computer tomography (CT) of chest done. Multi-disciplinary team (MDT) should be involved at that stage, consisting of respiratory physician, ILD specialty nurse, and radiologist. Sometimes, a diagnosis can be made at that point; otherwise, MDT will decide whether histology is needed by means of bronchoalveolar lavage (BAL) or/and lung biopsy.

Biochemistry

• Full blood count
  • WCC and neutrophils: high in infection, low in immune compromise
  • Hb: evidence of anaemia (anaemia of chronic disease; microcytic anaemia suggestive of malignancy; large Hb drop in pulmonary haemorrhage) or polycythaemia (secondary to chronic hypoxia)
  • Eosinophils: high in eosinophilic pneumonia, fungal infection, ABPA
• Renal profile
  • Kidney involvement in vasculitis, SLE, sarcoidosis
  • Baseline prior to starting treatment
• Liver function tests
  • Baseline prior to starting treatment
• CRP and ESR – might be raised due to inflammatory nature of ILD, especially during flare
• Rheumatoid factor (RF) and antinuclear antibody (ANA): screen for rheumatic disease
• Urinalysis: check for proteinuria (e.g. SLE) and haematuria (e.g. anti-GBM, WGA, SLE).

Selected patients will require additional tests depending on suspected diagnosis:

• Suspected systemic disease: connective tissue screen including anti-neutrophil cytoplasmic (ANCA), anti-topoisomerase (Scl-70), anti-PM-1 (PM-Scl), anti-double stranded (ds) DNA
• Sicca features: Sjogren antibodies (anti-RO (SS-A), anti-La (SS-B))
• Mechanic’s hands, muscle weakness: myositis antibodies (anti-tRNA synthetase), creatinine kinase (CK)
• Sclerodactyly, Raynaud’s syndrome, prominent GORD: scleroderma antibodies (anti-centromere, anti-Scl-70)
• Suspected sarcoidosis: blood ACE level, bone profile
• Haemoptysis: anti-GBM antibodies, coagulation profile, ANCA
• Suspected HP: serum antibody IgG precipitins depending on history of exposures
• Suspected pulmonary hypertension: brain natriuretic peptide (BNP)
• Risk factors for HIV: HIV test

Pulmonary function testing

• Spirometry – spirometry typically demonstrates a restrictive pattern with reduced full volume capacity (FVC) and forced expiratory volume in one second (FEV1); FVC/FEV1 ratio is normally preserved. Total lung volume (TLV) is gradually reduced as fibrosis progresses. Obstructive pattern (reduced FEV1 and FVC/FEV1 ratio) can sometimes be observed in ILDs with pronounced involvement of airways, e.g. sarcoidosis, HP, and pulmonary Langerhans cell histiocytosis. It can also occur when ILD is accompanied by emphysema.
• Diffusing capacity of the lungs for carbon monoxide (DLCO) – in ILD, both DLCO and TLV are reduced. This is in contrast to low TLV with normal DLCO, which would point towards an extrapulmonary cause of lung restriction, such as obesity, kyphosis, or neuromuscular weakness. These conditions would also cause decreased lung volume due to compression, yet gas exchange would remain unimpaired.
• Oximetry and arterial blood gas (ABG) – often normal at rest, especially early in the course of the disease. These tests are most useful when done during exercise testing, e.g., a six-minute walking test (6MWT). Several studies showed correlation between end-of-exercise oxygen saturation and distance walked in 6 minutes, as well as with survival. Significant desaturation on exertion might point towards pulmonary hypertension (PH).

Cardiac investigations

• ECG – typically obtained during the work up to screen for evidence of right heart strain and pulmonary hypertension, and cardiac comorbidities.
• Echocardiogram – allows investigation for pulmonary hypertension, which is associated with severe disease and shorter survival in ILD patients, especially in IPF cases. Right heart catheterisation may be performed in cases with a normal echocardiogram, if suspicion of PH remains high, e.g. where significant desaturation on exertion is present.

Imaging

• Chest X-ray (CXR) – typically shows reticular, nodular (see images below), or reticulo-nodular (mixed) pattern. Note that the CXR is normal in up to 10% of patients with ILDs, for example, if taken between HP flares. It is rarely diagnostic, and so most patients go on to have a computer tomography scan (CT). A CXR is, however, a useful tool to quickly assess disease status, especially in combination with previous films.

Image Source: Wikimedia Commons (2011). Silicosis simple, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Silicosis_simple.jpg#/media/File:Silicosis_simple.jpg (Accessed: 4 January 2023).

Image Source: Wikimedia Commons (2005). CSilicosis.ILO Classification 2-2 R-R, Licensed under a creative commons licence.  https://commons.wikimedia.org/wiki/File:Silicosis.ILO_Classification_2-2_R-R.jpg (Accessed: 27 December 2022).

• CT – allows for much more detailed views of the lung fields and can narrow the ILD differentials. Classically, high-resolution CT (HRCT) is used for ILD diagnosis, which produces images of ≤1.5 mm slice thickness. Certain patterns on CT (and, to a limited extent, CXR) are associated with particular conditions.
  • Nodular pattern: multiple rounded opacities 1-10mm in diameter (see images below). Associated with HP, sarcoidosis, silicosis, and coal worker’s pneumoconiosis.
  • Reticular (linear) pattern: HP, IPF, asbestosis, CTD-ILD.
  • ‘Ground glass’: increased lung density with visible pulmonary vasculature; associated with inflammation. Seen in HP, drug toxicity, pulmonary haemorrhage, infections, Pneumocystis jirovecii (PCP). (See images below)
  • Consolidation: air-filled bronchi on background of opacified, fluid-filled alveoli (air bronchograms). Occurs as disease infiltrates alveolar airspaces. Associated with eosinophilic pneumonia, COP, and pulmonary oedema.
  • Honeycombing: cystic spaces with irregular walls composed of thick fibrous tissue. Occurs secondary to emphysema and traction bronchiectasis in advanced fibrosis (See image below).
  • Pleural plaques: asbestos lung.
  • Bilateral hilar adenopathy: sarcoidosis, TB (See image below).
  • ‘Eggshell calcified’ hilar lymph nodes: silicosis, coal worker’s pneumoconiosis
  • Normal: HP, sarcoidosis, asbestosis.
  • Usual Interstitial Pneumonia (UIP). UIP refers to radiologic pattern seen in fibrotic ILDs, which includes loss of lung volume, honeycombing and septal thickening secondary to scarring and fibrosis. It is pathognomonic for IPF; however, can also be seen in other fibrotic subtypes such as fibrotic HP, CTD-ILD, advanced asbestosis, etc.

Image Source: Wikimedia Commons (2009). Ground glass stopper, Licensed under a creative commons licence. Available for free at: Available from https://upload.wikimedia.org/wikipedia/commons/6/61/Ground_glass_stopper.jpg (Accessed: 4 January 2023).

Image Source: Wikimedia Commons (2010). Corte_axial_con_patron_de_ground_glass_diseminado, Licensed under a creative commons licence. Available for free at: https://upload.wikimedia.org/wikipedia/commons/6/65/Corte_axial_con_patron_de_ground_glass_diseminado.jpg  (Accessed : 4 January 2023).

Image Source: Wikimedia Commons (2014). CT scan in usual interstitial pneumonia (UIP), Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:CT_scan_in_usual_interstitial_pneumonia_(UIP).jpg  (Accessed: 4 January 2023).

Image Source: Wikimedia Commons (2016).  HilarAdenopathyNo, Licensed under a creative commons licence. courtesy of James Heilman, MD.  Available for free at: https://commons.wikimedia.org/wiki/File:HilarAdenopathyNo.png  (Accessed: 24 December 2022).

In addition to the nature of radiological changes, their distribution is also important to note. Certain conditions classically affect specific areas within the lung:

Note that in sarcoidosis, radiological appearance is used to establish stage of the disease, which has implications for its management (see list below).

• Stage 0 – normal
• Stage I – hilar or mediastinal lymphadenopathy
• Stage II – lymphadenopathy and parenchymal infiltrate
• Stage III – parenchymal infiltrates only
• Stage IV – fibrosis

Bronchoalveolar lavage

Bronchoalveolar lavage (BAL) is sampling of cells and fluid from bronchioles and alveoli during bronchoscopy. The sample is sent for culture, cell counts and cytology.

BAL is only performed in selected groups of patients. It is most useful when history and imaging are suggestive of the following conditions:

• HP – the cell count will show lymphocytosis
• Infection – positive culture (mycobacterial, viral, fungal)
• Eosinophilic pneumonia – eosinophilia
• Malignancy – malignant cells

BAL is almost always performed in someone with acute onset of ILD and in patients with haemoptysis1. It is not usually needed when history and imaging allow for a confident diagnosis. However, it could be useful in borderline cases; for example, to differentiate IPF and chronic, fibrotic HP. Lymphocytosis of >40% on BAL would suggest HP, while high mixed cellularity would typically be seen in IPF.

Lung biopsy

Lung biopsy is performed when the diagnosis cannot be established with confidence based on the available information, for example, when patients’ symptoms suddenly change or there is unexplained rapid deterioration. It is also useful when non-invasive tests seemingly contradict each other, for example, when imaging shows minimal changes yet respiratory function tests and patient’s symptoms point to severe ILD. Benefits of having exact diagnosis should always be weighed against the risks involved in the procedure.

Biopsy can be obtained via transbronchial route during bronchoscopy or surgically by thoracotomy or video-assisted thoracoscopic surgery (VATS). Choice of technique depends on the location of disease, suspected diagnosis, and fitness of the patient.

References

• Talmadge E King, Jr, MD, Approach to the adult with interstitial lung disease: Diagnostic testing. Uptodate.com accessed on 08/01/2023.
• Idiopathic pulmonary fibrosis in adults: diagnosis and management. NICE clinical guideline, www.nice.org.uk/guidance/cg163, ISBN: 978-1-4731-0179-1
• Flaherty KR, Andrei AC, Murray S, Fraley C, Colby TV, Travis WD, Lama V, Kazerooni EA, Gross BH, Toews GB, Martinez FJ. Idiopathic pulmonary fibrosis: prognostic value of changes in physiology and six-minute-walk test. Am J Respir Crit Care Med. 2006 Oct 1;174(7):803-9. doi: 10.1164/rccm.200604-488OC. Epub 2006 Jul 6. PMID: 16825656; PMCID: PMC2648064.
• Hallstrand TS, Boitano LJ, Johnson WC, Spada CA, Hayes JG, Raghu G. The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis. Eur Respir J. 2005 Jan;25(1):96-103. doi: 10.1183/09031936.04.00137203. PMID: 15640329.
• Charlotte U. Andersen, Søren Mellemkjær, Ole Hilberg, Jens Erik Nielsen-Kudsk, Ulf Simonsen, Elisabeth Bendstrup, Pulmonary hypertension in interstitial lung disease: Prevalence, prognosis and 6 min walk test, Respiratory Medicine, Volume 106, Issue 6, 2012, ISSN 0954-6111
• k S. Ley, L. Fidler, H. Schenk, M. Durand, T. Marras, N. Paul, S. Shapera, S. Mittoo, Low dose computed tomography of the lung for detection and grading of interstitial lung disease: A systematic simulation study, Pulmonology, Volume 27, Issue 1, 2021, ISSN 2531-0437