Background

The term ‘interstitial lung disease’ (ILD), synonymous with ‘diffuse parenchymal lung disease’ (DPLD), is used to describe a large number of lung disorders sharing similar clinical, radiological and pathological features. They are all characterised by a degree of fibrosis and/or inflammation of parenchymal interstitium, which results in impaired gas exchange. There are more than 200 different subtypes of ILDs, the commonest being idiopathic pulmonary fibrosis (IPF), sarcoidosis, and extrinsic allergic alveolitis (EAA), also known as hypersensitivity pneumonitis (HP).

Classification

Classification of ILDs has been a subject of much debate. This is hardly surprising, given the sheer amount of disorders covered by the term. However, classifying ILD is clinically important, as management and prognosis often depend on its specific subtype.

The most widely used classification model is based on ILD aetiology. It can be established in approximately 35% of cases. Up to 65% fall under the ‘unknown aetiology’ category, which is then further subdivided into idiopathic interstitial pneumonias (IIPs) and ‘rare’/’ others’ (see below)

Adjusted from ‘Approach to the adult with interstitial lung disease: Clinical evaluation’. Talmadge E King, Jr, MD, ed. By Kevin R Flaherty, MD, MS. UpToDate.com [Internet]. https://www.uptodate.com/contents/approach-to-the-adult-with-interstitial-lung-disease-clinical-evaluation  

CTD-ILD: connective tissue disease-ILD; IIP: idiopathic interstitial pneumonia; IPF: idiopathic pulmonary fibrosis

Another way to classify ILDs has been proposed:

Native parenchymal disorders

• IPF
• Non-specific interstitial pneumonia (NSIP)
• Acute interstitial pneumonia (AIP)
• Cryptogenic organising pneumonia (COP)

Systemic disease-related ILD

• Connective tissue-related ILD (CTD-ILD), e.g. myositis, rheumatoid arthritis (RA), scleroderma, systemic lupus erythematosus (SLE)
• Vasculitides, e.g. granulomatosis with polyangiitis (GPA), Churg-Strauss syndrome (EGPA), anti-glomerular basement membrane (anti-GBM) disease

Exposure related CTD

• Drug-related
• Radiation related
• Hypersensitivity pneumonitis
• Post infective

Vascular disorders

• Diffuse pulmonary haemorrhage

Epidemiology

Registries of various ILDs have been initiated in many countries, yet it remains challenging to determine incidence accurately due to differences in diagnostic criteria used and rarity of many of these conditions. In England alone, between 2,000 and 4,000 individuals are diagnosed with ILD every year. The most common subtypes are sarcoidosis, HP and IPF, accounting for 50-75% of all cases. Sarcoidosis incidence is estimated to be between 3 to 5 cases per 100,000 people per year in the UK, and it seems to be more common in patients of Afro-Caribbean descent. 

The majority of ILDs are more common in older individuals, but sarcoidosis, connective tissue disease-associated ILD, pulmonary Langerhans cell histiocytosis, and inherited forms of ILD typically present between the ages of 20 and 40. Pneumoconiosis and IPF occur more frequently in men, while CTD-ILD is more common in women. 

Pathophysiology

ILD subtypes all share similar pathophysiological mechanisms, and all primarily affect the same part of the lung: its interstitium. Lung interstitium contains a complex mixture of connective tissue elements, which together create a matrix supporting the respiratory tree and alveoli. It can be subdivided into parenchymal, axial and peripheral compartments. Axial interstitium surrounds primary bronchi and pulmonary arteries and is continuous with interlobular septa. The peripheral compartment contains strong supportive fibres between the visceral pleura and the lung parenchyma. In ILDs, it is the parenchymal interstitium that is mainly affected. It represents the ‘interface’ between alveolar epithelial cells and capillary endothelium, thus supporting the intralobular, gas-exchanging part of the lung. 

The two key mechanisms by which the parenchymal interstitium is damaged in ILD are fibrosis and inflammation. Initial insult, be it by an environmental agent, drug, or an autoimmune process, leads to an influx of inflammatory cells; fibroblasts and type II pneumocytes get activated in order to repair the damage. Both processes result in accumulation of extracellular matrix components, which distort the alveolar/capillary interface and impair the gas exchange. As the disease progresses, the architecture of alveolar lumens and bronchi gets distorted as well. Mechanisms at play include alveolar infiltration with proliferating fibroblasts, traction bronchiectasis due to the scarred tissue ‘pulling’ the airways apart, and alveolar haemorrhage due to damaged capillary walls.

It is worth noting that some ILDs are predominantly fibrotic (e.g. IPF), while others are mainly inflammatory (e.g. ILDs in vasculitis), although many demonstrate some combination of the two. Diseases on each end of the spectrum share certain characteristics. For example, fibrotic ILDs tend to have a slower onset, poor response to therapy, and progressive course. In contrast, inflammatory ILDs tend to present acutely or sub-acutely, are mostly treated with immunosuppressive medications, and can be reversible. This distinction is clinically important, as knowing where the disease lies on the fibrosis-inflammation spectrum allows us to predict disease behaviour and response to therapy, even when specific diagnosis is challenging to establish.

Specific conditions

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF), also known as cryptogenic fibrosing alveolitis (CFA), is a chronic, progressive fibrosis of the lungs with an unknown cause. It is currently thought that an unknown antigen, e.g. a virus, tobacco or environmental pollution, causes activation of mesenchymal cells and subsequent secretion of extracellular matrix. Genetic factors are important in pathogenesis; predisposing mutations described so far include mucin 5B (MUC5B; present in up to 35% of IPF cases), surfactant protein C (SPC), surfactant protein A (SPA), and telomerase (TERT, TERC). Fibrosis in IPF is always progressive and has been compared to cancer in this regard. Indeed, it has been observed that, in contrast to what happens in normal healing process, fibroblasts in IPF acquire resistance to apoptosis and an ability to invade surrounding tissues – features usually associated with malignant processes. Eventually, progressive fibrosis leads to respiratory failure. 

Extrinsic allergic alveolitis

Extrinsic allergic alveolitis (EAA), or hypersensitivity pneumonitis (HP), is a term for a subset of ILD disorders caused by an abnormal immunological reaction to an organic antigen. It is not an atopic disease and is not characterised by a rise in tissue eosinophils or IgE. 

HP can be acute, subacute and chronic. Acute HP is an example of type III hypersensitivity reaction, in which antigen-antibody complexes deposit in lung interstitium, causing influx of inflammatory cells. Between flares, patients are asymptomatic, and their imaging is usually clear. 

The chronic form of HP is a type IV, delayed hypersensitivity reaction in which T cells play a key role. It is also called ‘fibrotic’ HP, as persistent inflammation leads to progressive scarring of the lung. It is not clear why some individuals develop fibrotic HP. Notably, it can persist even after removal of causative antigen exposure. It can present and look similar to IPF, which is why histology is often required to distinguish the two. The most common triggers are outlined in Table 1.

Condition	Source	Antigen
Farmer’s lung	Mouldy hay	Thermophilic actinomycetes (e.g. Micropolyspora faeni and Thermoactinomyces vulgaris)
Mushroom worker’s lung	Mouldy compost; mushrooms	Thermophilic actinomycetes
Compost lung	Compost	Aspergillus species
Cheese worker’s lung	Cheese mould	Penicillium casei
Malt worker’s lung	Mouldy malt	Aspergillus clavatus
Bird/pigeon fancier’s lung	Pigeons, parakeets, rodents	Avian or animal proteins
Woodworker’s lung	Wood dust	Alternaria species
Hot tub lung Swimming pool lung	Mould on ceiling, in tub water, pool water, fountains	Mycobacterium avium complex

Table 1: Antigen causes of hypersensitivity pneumonitis (not exhaustive). Adapted from Mudawi et al. (2021). An update on interstitial lung disease. British Journal of Hospital Medicine.

Pneumoconiosis

Pneumoconiosis is a group of diseases caused by inhalation of inorganic dust, usually in occupational context. Particles of <5 microns in size are small enough to reach terminal bronchioles and alveoli. Inflammation is triggered by a combination of direct toxicity to pneumocytes and alveolar macrophages (in particular asbestos, silica) and cell-mediated hypersensitivity reaction (e.g. berylliosis) in genetically predisposed individuals. Repeated exposure leads to a variety of clinical manifestations (Table 2). 

Inorganic dust	Source	Related conditions
Asbestos	Mining, milling, installation and removal of insulation	Benign pleural disease Asbestosis Mesothelioma Lung cancer
Beryllium	Ceramics, aerospace, nuclear weapon industries	Acute berylliosis  Beryllium granulomatosis
Silica	Quarrying, tunnelling, sandblasting, stone cutting, rock mining	Silicosis Caplan’s syndrome
Coal	Coal mining	Simple pneumoconiosis Progressive fibrosis Caplan’s syndrome
Aluminium dust	Mining, fireworks, painting	Aluminium dust pneumoconiosis

Table 2: common types of pneumoconiosis. Adapted from Chapman, S.J. Oxford Handbook of Respiratory Medicine, 4th ed, 2021

Sarcoidosis

Sarcoidosis is a multisystem condition which involves lungs in 90% of all cases. It is believed to be caused by an abnormal immunological response to a benign antigen in a genetically predisposed host. The antigen triggers T-cell mediated response, which includes macrophage activation and production of interferon-γ. As a consequence, non-caseating granulomas are formed, and raised angiotensin converting enzyme (ACE) levels can often be detected in these patients, secondary to high macrophage activity. Macrophages also contain 1α-hydroxylase, the enzyme that catalyses the conversion from inactive to active vitamin D. As a result, sarcoidosis is often associated with hypercalcemia, which is occasionally significant enough to cause symptoms. In up to 60% of cases, sarcoidosis resolves in 2-5 years, often requiring no treatment. Some patients, however, progress to developing progressive lung fibrosis.

Connective tissue disease-related ILD

Connective tissue diseases (CTDs) can cause a variety of pulmonary complications, and ILD is one of the most serious ones. It is common for both conditions to be diagnosed simultaneously or for patients to develop ILD years after their CTD diagnosis. However, occasionally, the opposite occurs, and CTD patients present with pulmonary symptoms alone. Thus, it is important to consider systemic disease in any patient with new diagnosis of ILD (see ‘presentation’). 

Pathophysiology of CTDs is beyond the scope of this section. The most common conditions leading to ILD are SLE, RA, Sjogren’s, systemic sclerosis, myositis and dermatomyositis.

Drug-induced ILD

Drug-related ILD can present either acutely (e.g. with certain antibiotics) or years after discontinuing the causative agent (e.g. cytotoxics). Full list of drugs which have been reported to cause pulmonary toxicity is available on ‘Pneumotox’ database: https://www.pneumotox.com/drug/index/. However, it is useful to be familiar with the most common examples (Table 3). 

Radiation-related ILD can present as an acute radiation pneumonitis (weeks to months after exposure), fibrotic radiation pneumonitis (6 to 12 months) or radiation recall pneumonitis (years).

Antimicrobials	Nitrofurantoin, ethambutol, cephalosporins, amphotericin B, isoniazid
Immunosuppressive drugs	Methotrexate, azathioprine, cyclophosphamide, thalidomide, sulfasalazine, gold
Cytotoxic drugs	Busulfan, bleomycin, etoposide, paclitaxel
Antiarrhythmics	Amiodarone, tocainide
Illicit	Cocaine, heroin, methadone, talc

Table 3: common medications linked to pulmonary toxicity. Adapted from Chapman, S.J. Oxford Handbook of Respiratory Medicine, 4th ed. 

References

• Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax 2008;63(Suppl V):v1–v58. doi:10.1136/thx.2008.101691
• Talmadge E King, MD. Approach to the adult with interstitial lung disease: Clinical evaluation. UpToDate Inc. http://www.uptodate.com (accessed on 15th of December, 2022)
• Gibson GJ, Loddenkemper R, Lundbäck B, Sibille Y. Respiratory health and disease in Europe: the new European Lung White Book. Eur Respir J. 2013 Sep;42(3):559-63. doi: 10.1183/09031936.00105513. PMID: 24000245.
• Griese M. Etiologic Classification of Diffuse Parenchymal (Interstitial) Lung Diseases. J Clin Med. 2022 Mar 21;11(6):1747. doi: 10.3390/jcm11061747. PMID: 35330072; PMCID: PMC8950114.
• Interstitial Lung Disease Service specification, NHS England, published 19th of June 2017. https://www.england.nhs.uk/publication/interstitial-lung-disease-adults-service-specification/
• Marvin I. Schwarz & Talmadge E. King. Interstitial Lung Disease, fifth edition. Published by PMPH-USA, 2011. IBSN 1607950243
• Dr. T. Simpson. ‘Diagnostics in ILD’. Lecture given at Interstitial Lung Disease Interdisciplinary Network annual conference, 2021
• Chapman, S.J. Oxford Handbook of Respiratory Medicine, 4th ed. Oxford Medical Handbooks, 2021, ISBN: 9780198837114
• Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol. 2014;9:157-79. doi: 10.1146/annurev-pathol-012513-104706. Epub 2013 Sep 13. PMID: 24050627; PMCID: PMC4116429.
• Talmadge E King, Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Treatment, prognosis, and prevention. uptodate.com, accessed on 10/01/2023.
• Knott, L. Hypersensitivity Pneumonitis. patient.info, accessed on 10/01/2023
• Mudawi, Dalia & Heyes, K & Hastings, R & Rivera Ortega, Pilar & Chaudhuri, Nazia. (2021). An update on interstitial lung disease. British Journal of Hospital Medicine. 82. 1-14. 10.12968/hmed.2020.0556.

Presentation

Initial symptoms of ILD are often very unspecific, which can present a significant diagnostic challenge. Up to 49% of patients with IPF, for example, are diagnosed more than a year after initial presentation, with up to 23% of these – more than 3 years after.

Breathlessness

The most common presenting complaint is progressive breathlessness, or dyspnoea, on exertion. Timing of progression is diagnostically important, although some ILDs can present both acutely and chronically (see Table 4). Particular care should be taken to differentiate ILDs with indolent presentation from other common causes of dyspnoea, such as chronic obstructive pulmonary disease (COPD) and heart failure. 

It is important to check if the breathlessness is continuous or episodic. If episodic with asymptomatic periods in between, ascertain whether there is a clear pattern, e.g. symptoms are worse in the morning/on weekdays/in winter, which could point towards an environmental trigger. On the other hand, episodic breathlessness in the absence of a clear pattern could be suggestive of EGPA, COP or allergic bronchopulmonary aspergillosis (ABPA). Continuous symptoms are more suggestive of fibrotic ILDs such as IPF.

Breathlessness onset	Aetiology	Examples
Acute (days-weeks)	Infection	Bacterial, fungal (aspergillosis, Pneumocystis jirovecii pneumonia (PCP)), viral (varicella, measles)
	Miscellaneous	Acute Respiratory Distress Syndrome (ARDS), Acute interstitial pneumonia
Acute or chronic	Drug-related	Antimicrobials, immunosuppressive drugs, cytotoxic Drugs, antiarrhythmics, illicit
	Toxins	Radiation
	Vasculitis	GPA, EGPA, anti-glomerular basement membrane (anti-GBM) disease
	Miscellaneous	Sarcoidosis, COP, eosinophilic pneumonia
Chronic  (months-years)	IIIPs	IPF, NSIP, desquamative interstitial pneumonia (DIP)
	Connective tissue disease	RA, SLE, scleroderma, myositis, dermatomyositis, ankylosing spondylitis, Sjögren’s syndrome, Behçet’s disease
	Pneumoconioses	Asbestosis, silicosis, coal worker’s pneumoconiosis
	Hypersensitivity pneumonitis (HP)	Farmer’s lung, bird fancier’s lung
	Miscellaneous	Amyloidosis, LAM, alveolar proteinosis, microlithiasis

Table 4: diffuse lung disease and time of onset. Adjusted from Oxford Handbook of Respiratory Medicine, 4th ed. 

Other features 

• Another common feature of ILD is persistent, non-productive cough. It is particularly common in conditions affecting airways, such as sarcoidosis, bronchiolitis obliterans, COP, eosinophilic pneumonia and HP. Productive cough is unusual.
• Haemoptysis can occur in vasculitis-related ILD, pulmonary venous hypertension and diffuse alveolar haemorrhage. First episode in a patient with a known ILD may sometimes point towards a malignancy – a well-recognised complication of ILD. 
• Chest pain is uncommon; note that acute onset chest pain might point towards an ILD complication such as pneumothorax or pulmonary embolism (PE).
• Extrapulmonary symptoms can occur in connective tissue disorders and vasculitides. In particular, enquire about headaches, changes in vision or photosensitivity, skin rashes, dry mouth and eyes, joint pains or swelling, muscle aches, fatigue, night sweats and fevers. Absence of these symptoms does not rule out a systemic disorder, which may manifest as respiratory symptoms alone at the start. If present, however, they might provide a useful clue. In addition, clear documentation of negative findings at the baseline will help in patient assessment at later stages.
• Lofgren syndrome – specific acute presentation of systemic sarcoidosis, characterised by a triad of fever, erythema nodosum (see below) and bilateral hilar lymphadenopathy on chest X-ray. This is more common in Caucasians. It is usually self-limiting and carries a good prognosis – 80% of cases will resolve spontaneously over 1-2 years.

Image Source: Wikimedia Commons (2010). ENlegs, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:ENlegs.JPG#/media/File:ENlegs.JPG. (Accessed: 3 January 2023).

References

1. Snyder LD, Mosher C, Holtze CH, et al. Time to diagnosis of idiopathic pulmonary fibrosis in the IPF-PRO Registry. BMJ Open Respiratory Research 2020; 7:e000567. doi: 10.1136/bmjresp-2020-000567
2. Oxford Handbook of Respiratory Medicine, 4th ed. Stephen Chapman. Oxford University Press, 2014. ISBN: 9780198837114
3. Talmadge E King, MD. Approach to the adult with interstitial lung disease: Clinical evaluation. UpToDate Inc. http://www.uptodate.com (accessed on 20th of December, 2022)

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 1). 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:

Peripheral	Central	Upper	Lower
IPF	Sarcoidosis	Silicosis	Asbestosis
Asbestosis	Pneumocystis pneumonia (PCP)	Coal lung disease	CTD-ILD
CTD-ILD		Ankylosing spondylitis	Rheumatoid arthritis
Eosinophilic pneumonia		Chronic HP	IPF
COP		TB

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

Management

ILD management is led by respiratory physicians, but it is important to understand general principles of management and to familiarise yourself with the most commonly used medications. The general principle of management is that inflammatory ILDs are mainly treated with immunosuppressive drugs, while fibrotic ones are treated with fibrinolytics; a combination of the two can be used when both elements are present.

Conservative measures

Supportive care plays a crucial role and should be considered in all patients at the time of diagnosis.

• Pulmonary rehabilitation – every patient diagnosed with ILD should be assessed for the need for pulmonary rehabilitation. It should be offered to those whose quality of life is significantly affected by the disease, e.g. those with low exercise tolerance. Sessions include information on the condition, nutritional advice, breathing exercises, psychological support, and social network opportunities.
• Long-term oxygen therapy (LTOT) – many patients with ILD may require supplemental oxygen if/as the disease progresses; this is particularly relevant for IPF patients who almost universally develop hypoxia. It is important to recognise the point where it needs to be initiated in order to preserve patient’s quality of life, as well as avoid or minimise complications of chronic hypoxia, such as pulmonary hypertension and polycythaemia.
• Smoking cessation – should be advised to all patients with ILD
• Minimising risk of chest infections – annual flu vaccination and pneumococcal vaccination should be offered to all patients. Those with frequent exacerbations can be offered prophylactic antibiotics. Whenever possible, antibiotic choice should be guided by sensitivities of patient’s sputum culture.

Idiopathic pulmonary fibrosis

Fibrinolytics 

• Pirfenidone and Nintedanib are the only two drugs approved for treatment of ILD in the UK. 
• Pirfenidone has both anti-inflammatory and anti-fibrotic properties. It inhibits the production of transforming growth factor-β1 (TGF-β1), a cytokine involved in differentiation of human lung fibroblasts into myofibroblasts, thereby attenuating excess collagen and extracellular matrix deposition. Its anti-inflammatory properties come from its inhibition of several pro-inflammatory cytokines, including TNF-α, interleukin-1 (IL-1) and interferon-gamma (IFN-γ).
• Nintedanib is a tyrosine kinase inhibitor which inhibits multiple growth factors. Consequently, it prevents the proliferation and activation of fibroblasts and attenuates angiogenesis within the lungs. The result is a slowing down of fibrosis as well as associated complication of pulmonary hypertension. 
• Both drugs were shown to slow down deterioration in FVC and DLCO when compared to non-treated cohort with IPF2. Patients with FVC of 50% to 80% are offered one of the medications. Treatment is stopped if FVC declines by >10% in 12 months while on the drug.
• They are generally well tolerated by patients; main side effect is gastrointestinal upset, which settles after a couple of months in most patients.
• Both medications are contraindicated in pregnancy and severe liver impairment.

Lung transplantation 

• Patients with IPF should be referred for consideration of lung transplant soon after the diagnosis if there are no absolute contraindications and the patient is deemed to be fit enough for the procedure.

Hypersensitivity pneumonitis 

• Avoidance of the causative antigen – for many patients, avoiding the culprit antigen is enough to alleviate symptoms, especially if the disease is caught early in acute stage. The time between antigen avoidance and symptom improvement is antigen and patient-dependant; re-evaluation should be done at 8-12 weeks.
• Corticosteroids – typically given during the acute HP flare for a short period of time. In chronic HP, trial of long-term steroids is recommended but is more likely to be successful in patients with inflammatory features, such as characteristic ground-glass opacities on CT or lymphocytosis on BAL.
• Lung transplantation

Sarcoidosis

About half of patients with sarcoidosis require treatment, which depends on stage of the condition.

• Asymptomatic, stage 1: usually only observation is required
• Symptomatic, stage 1: oral corticosteroids. Consider gastric protection and osteoporosis prophylaxis if steroids are used long-term. However, vitamin D and calcium supplementation are often avoided due to risk of hypercalcaemia in sarcoidosis
• Symptomatic, stage 2 and above: oral corticosteroids are a mainstay of treatment. Cytotoxic medications such as methotrexate or azathioprine may be considered, but this should always be discussed with a respiratory consultant. If symptoms persist, or there is evidence of progression, biological therapies can also be given, e.g. infliximab.
• Lung transplantation

References

• Idiopathic pulmonary fibrosis in adults: diagnosis and management. NICE clinical guideline. www.nice.org.uk/guidance/cg163, ISBN: 978-1-4731-0179-1
• Stefania Cerri et al., Real-life comparison of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis: A 24-month assessment. Respiratory Medicine, Volume 159, 2019, 105803, ISSN 0954-6111
• Talmadge E King, Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Treatment, prognosis, and prevention. Uptodate.com, accessed on 17/01/2023.
• Leslie Grammer. Hypersensitivity pneumonitis. BMJ Best Practice, last updated on 01/11/2022, accessed on 17/01/2023.
• Dr Colin Tidy, Sarcoidosis. Edited on 15/08/2022, accessed on 01/01/2023. https://patient.info/doctor/sarcoidosis-pro

Complications

Many ILD complications are common to all subtypes, while others are specific to certain conditions.

Lung cancer

• ILD is an independent risk factor for developing lung malignancy, which could be partially secondary to increased cell damage due to inflammatory nature of the condition. An estimated 15-20% of ILD patients develop lung cancer.
• It is often challenging to diagnose, as emerging symptoms are often contributed to the already-known diagnosis of ILD. Constitutional symptoms such as new weight and appetite loss, new haematemesis or chest pain should prompt further investigations with imaging +/- bronchoscopy. 
• Mesothelioma is a rare but highly aggressive type of lung cancer. Up to 90% of all cases are linked to asbestos exposure. Note that asbestos exposure also increases the risk of other types of cancer.
• Perhaps not surprisingly, lung malignancy is associated with higher morbidity and mortality in patients with ILD compared to patients without ILD. 

Infections

• Chest infections are commoner in patients with ILD. They are important to avoid, and if they do occur, they should be treated swiftly as they are linked to ILD progression.
• All infections are more common in ILD (bacterial, viral, fungal); incidence of tuberculosis, in particular, was shown to be up to 4-5 times higher than in patients without ILD. 
• Impaired defence mechanisms due to lung injury and scarring, as well as immunosuppressive medications with which ILD is often treated, both predispose this cohort of patients to chest infections.
• Fibrotic conditions such as IPF are not treated with immunosuppression; thus, patients with exacerbation should always be covered with broad-spectrum antibiotics for a potential infective cause.
• In non-IPF ILD, however, acute deterioration might present a clinical dilemma. It is important to distinguish between non-infective and infective exacerbation, as it might call for either increase in immunosuppression or reduction of it in combination with antibiotic treatment. BAL and/or sputum culture are key investigations to make this distinction in unclear cases.

Pulmonary arterial hypertension

• This is a frequent late-stage complication of many ILDs, in particular IPF, sarcoidosis and CTD-ILD.
• As fibrosis progresses, affected parts of the lung become hypoxic. This leads to reactive vasoconstriction and redistribution of the blood to better-ventilated parts of the lung. These processes, in turn, lead to rise in intravascular pressure, wall stress and further release of inflammatory and proliferative cytokines. It also puts stress on the right heart, which has to pump against the high pressures, eventually leading to right heart failure.
• ILD-related PAH is associated with reduced exercise capacity, poorer quality of life, and shorter life span. 
• It can be difficult to diagnose, as symptoms are similar to those of ILD. It should be suspected in any patient showing significant clinical deterioration, especially when it seems to be out of proportion to their lung function tests, and in any patient showing signs/symptoms of heart failure.
• Echocardiogram is usually the first investigation as it is a great non-invasive test to screen for the condition. Right heart catheterisation (RHC) remains the gold standard; mean pulmonary artery pressure more than 20 mm Hg is diagnostic.
• Treatment options include supportive management, including supplemental oxygen, and heart failure therapy. There are currently no medical therapies approved for ILD-PAH (note that this is different from the primary pulmonary hypertension, which has multiple treatment options).

Pneumothorax

• Pneumothorax occurs more commonly in patients with respiratory diseases, and up to 20% of ILD patients develop this complication at some point.
• All ILD patients with pneumothorax should be admitted for at least 24 hours. 
• Pneumothorax size should be measured using distance between hilum and ribcage. This will determine further steps:
  1. If the patient is breathless at presentation, or their pneumothorax is >2cm, chest drain should be inserted
  2. If the patient is not breathless, and their pneumothorax is 1-2cm, aspirate up to 2.5L of air with a cannula and assess response with a chest x-ray. If pneumothorax is still >1cm, chest drain should be inserted. If it reduces to <1cm, admit for 24hrs with high-flow oxygen
  3. If the patient is not breathless, and their pneumothorax is <1cm, admit for 24hrs with high-flow oxygen
• Such patients should always be discussed with a chest physician on admission, and if air leak persists at 48hrs after drain insertion – with thoracic surgeons for consideration of surgical management.

Caplan syndrome

• Rare complication of pneumoconiosis (in particular, coal worker’s lung and silicosis), which occurs in patients with rheumatoid arthritis (RA)
• In this condition, rheumatoid nodules develop on the periphery of lungs, with the background of pnemoconiotic changes.
• These nodules can develop rapidly within weeks. In this case, they can either lead to acute worsening of the known ILD or manifest as its first presentation.

References

• Brown SW, Dobelle M, Padilla M, Agovino M, Wisnivesky JP, Hashim D, Boffetta P. Idiopathic Pulmonary Fibrosis and Lung Cancer. A Systematic Review and Meta-analysis. Ann Am Thorac Soc. 2019 Aug;16(8):1041-1051. doi: 10.1513/AnnalsATS.201807-481OC. PMID: 30892054.
• Naccache JM, Gibiot Q, Monnet I, Antoine M, Wislez M, Chouaid C, Cadranel J. Lung cancer and interstitial lung disease: a literature review. J Thorac Dis. 2018 Jun;10(6):3829-3844. doi: 10.21037/jtd.2018.05.75. PMID: 30069384; PMCID: PMC6051867.
• George A. Margaritopoulos, Katerina M. Antoniou, Athol U. Wells. Comorbidities in interstitial lung diseases. European Respiratory Review March 2017, 26 (143) 160027; DOI: 10.1183/16000617.0027-2016
• Watanabe T, Tanahashi M, Suzuki E, Yoshii N, Tsuchida H, Yobita S, Iguchi K, Uchiyama S, Nakamura M. Treatment of secondary pneumothorax with interstitial lung disease: the surgical indications at the start of treatment is important. J Thorac Dis. 2022 May;14(5):1393-1400. doi: 10.21037/jtd-21-1851. PMID: 35693624; PMCID: PMC9186251.
• MacDuff A, Arnold A, Harvey J. Management of spontaneous pneumothorax: British Thoracic Society pleural disease guideline 2010. Thorax 2010;65:ii18-ii31.
• Stark P. Imaging of occupational lung diseases. Ed. Dieffenbach P. UptoDate.com, update 08/11/22, accessed on 01/01/2023.