20th February 2025

Idiopathic interstitial pneumonias

Overview of idiopathic interstitial pneumonias

Idiopathic interstitial pneumonias (IIP) are a group of lung diseases affecting the interstitium of the lung. This is comprised of support tissues, including the alveolar epithelium, pulmonary capillary endothelium, basement membrane, perivascular and perilymphatic tissues.

The most common IIP is idiopathic pulmonary fibrosis (IPF). Others are rarer and this chapter will review them briefly.

Idiopathic pulmonary fibrosis (IPF)

Overview of IPF

Idiopathic pulmonary fibrosis is the most prevalent IIP. The pathogenesis is poorly understood, but the characteristic histological pattern is usual interstitial pneumonia (UIP). It is more common in older men.

Signs and symptoms include:

• Progressive exertional dyspnoea
• Cough (typically dry)
• Bi-basal, fine, end-inspiratory crackles which do not clear on coughing
• Clubbing

Diagnosis of IPF

Key investigations include:

• Blood tests (mostly to exclude alternative diagnoses): ANA, RF (rheumatoid factor), anti-centromere, anti-Ro, anti-La, anti-RNP, anti-dsDNA, anti-smith, anti tRNA synthetase, anti-PM-Scl, anti-Th/To, anti-U3 RNP, ANCA panel, anti-topoisomerase (Scl-70)
• Lung function tests: classically show a restrictive pattern and reduced transfer factor (TLCO). Should be performed at the time of diagnosis, 6 and 12 months
• Chest X-ray: bilateral, peripheral and basal interstitial reticulation. Sometimes, honeycombing is visible
• High-resolution CT (HRCT) thorax: the investigation of choice. Features include bilateral, subpleural, predominantly basal reticulation and honeycombing (must be present for a definite radiological diagnosis of UIP)
• Histology: UIP – alternating areas of normal lung, interstitial inflammation, fibroblast foci and honeycombing

NICE recommends that a bronchoalveolar lavage, transbronchial biopsy or surgical lung biopsy should be considered if the multidisciplinary team cannot make a confident diagnosis from clinical features, lung function tests and radiological findings. The risks and benefits should be discussed with the patient.

Management of IPF

General management includes:

• Pulmonary rehabilitation: assessment includes a 6-minute walk test and a quality-of-life assessment
• Anti-fibrotic agents (pirfenidone and nintedanib): there is no conclusive evidence to support the use of any drugs to increase survival of people with IPF. However, anti-fibrotic agents have been shown to slow the decline in FVC. NICE restricts their use to patients who fulfil certain criteria: for pirfenidone, FVC must be 50-80% of predicted, whereas for nintedanib, FVC should be ≥50% of predicted. Both drugs can cause LFT derangement, and therefore, LFTs and FBC should be monitored monthly for the first 6 months, then 3 monthly. Effectiveness is monitored through FVC and TLCO
• Ambulatory or long-term oxygen therapy may be needed

Lung transplantation may be considered.

However, ultimately, management often must trend towards best supportive care, including giving information and support, symptom relief, management of comorbidities, withdrawal of ineffective therapies, and holistic end of life care.

Acute exacerbations

These are defined as worsening or acute-onset dyspnoea (<30 days) in a patient with known IPF.

As well as the chronic UIP appearances of IPF, HRCT in this context may show more acute areas of ground glass and/or extensive consolidation.

Treatment usually involves high-dose steroids with broad-spectrum antibiotic cover, as it is difficult to confidently exclude infection. Invasive ventilation of patients with known IPF is often not appropriate as outcomes are very poor.

Non-specific interstitial pneumonia (NSIP)

Non-specific interstitial pneumonia refers to a histological pattern which is poorly understood and can be observed in a wide variety of clinical settings. It typically affects younger patients and has a better prognosis than IPF. It can be idiopathic or associated with connective tissue disease, infection, drugs or immunodeficiency.

HRCT shows basal ground-glass opacification, often without honeycombing. Relative subpleural sparing may be a helpful sign to differentiate NSIP from other IIPs. Histology is often necessary for diagnosis. Findings are variable and range from an inflammatory, cellular pattern with no fibrosis to a more fibrotic pattern.

NSIP responds better to steroids than IPF and these are the mainstay of treatment, followed by other immunosuppressants if steroids fail.

Acute interstitial pneumonia (AIP)

This form of IIP has an acute onset and is characterised by idiopathic, rapidly developing diffuse alveolar damage, possibly leading to fulminant respiratory failure.

It is often preceded by a viral-like illness. Examination reveals widespread crepitations. Profound hypoxia and respiratory failure are often present.

Investigations include:

• CXR: shows a non-specific pattern, often similar to ARDS with bilateral air-space diffuse opacities. This can progress to reticular shadowing and ground-glass appearance, often sparing the hila, heart borders and costophrenic angles
• HRCT: again, features are similar to ARDS in the initial stages with bilateral, diffuse ground glass and airspace consolidation. This can develop into traction bronchiectasis and cystic changes
• Lung biopsy is essential for diagnosis and histology typically shows diffuse alveolar damage

Management usually consists of high-dose steroids and antibiotics, as well as supportive measures such as high-flow O2 and often mechanical ventilation.

Cryptogenic organising pneumonia (COP)

This is a type of ILD where alveoli become congested with granulation tissue. Organising pneumonias can be cryptogenic (of uncertain origin) or secondary to other insults (infection, drugs, malignancy, etc).

Symptoms of breathlessness and cough typically develop in less than three months and patients may complain of an unresolved chest infection. Clubbing is not present on examination.

Diagnosis is usually made based on clinical features, HRCT and biopsy results.

• HRCT usually shows patchy consolidation with or without ground glass, in a predominantly subpleural and/or peribronchial distribution. Nodules or masses ranging in size might be seen, which can occasionally lead to an erroneous suspicious of malignancy 
• Histology reveals patchy ‘plugging’ of alveolar spaces, and sometimes bronchioles, with granulation tissue

Prognosis is generally good and most patients respond well to steroids, which are the mainstay of treatment. Steroid courses of 6-12 months are usually indicated. If steroid therapy fails, other immunosuppressants such as azathioprine or cyclophosphamide might be used.

Lymphoid interstitial pneumonia (LIP)

This is a rare IIP characterised by lymphocytic infiltration of the interstitium and alveolar spaces. There is often an underlying cause (such as CTD [connective tissue disease], immunodeficiency, infection or autoimmune disease), but it can also be idiopathic.

Dyspnoea and cough develop over years.

Investigations include:

• Blood tests: a polyclonal (or occasionally monoclonal) IgM gammopathy in serum immunoglobulins
• HRCT: predominantly ground-glass change, with mid-to-lower-lobe predominance
• BAL: often reveals lymphocytosis
• Histology: lymphocytic infiltration of alveolar septa

Steroids are the mainstay of management.

Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD)

This is a smoking-related form of ILD associated with the accumulation of pigment-laden macrophages in the bronchioles.

Symptoms include dyspnoea and cough. Examination reveals inspiratory crackles and clubbing is rare.

HRCT shows poorly defined centrilobular nodules, ground-glass opacities and other changes related to smoking, such as airway wall thickening and centrilobular emphysema. Diagnosis is made on clinical and HRCT findings, however biopsy or BAL may be needed to exclude differentials.

Management primarily involves smoking cessation, but steroids are sometimes used.

Desquamative interstitial pneumonia (DIP)

Often considered the end stage of RB-ILD, in DIP pigmented alveolar macrophages accumulate in alveolar spaces.

Dyspnoea and cough develop over weeks to months and clubbing may be seen on examination.

Investigations include:

• HRCT: ground-glass opacities, predominantly in the bases or peripheries
• Biopsy: usually required for diagnosis; diffuse accumulation of pigmented macrophages in alveolar spaces

As with RB-ILD, the mainstay of treatment is smoking cessation, but steroids may also be used.

Note on nintedanib

In November 2021, NICE recommended nintedanib as a treatment option for chronic progressive fibrosing interstitial lung diseases. This group of diseases includes but is not limited to IIP, autoimmune ILD and hypersensitivity pneumonitis.

References

• Natalini MEKJG. Idiopathic Pulmonary Fibrosis: BMJ Best Practice; 2021 [accessed 26/11/2021]. Available from: https://bestpractice.bmj.com/topics/en-gb/446.
• Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174(7):810-6
• Mikolasch TA, Garthwaite HS, Porter JC. Update in diagnosis and management of interstitial lung disease. Clin Med (Lond). 2017;17(2):146-53
• Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2018;198(5):e44-e68
• Rabeyrin M, Thivolet F, Ferretti GR, Chalabreysse L, Jankowski A, Cottin V, et al. Usual interstitial pneumonia end-stage features from explants with radiologic and pathological correlations. Ann Diagn Pathol. 2015;19(4):269-76
• NICE. Idiopathic pulmonary fibrosis in adults: diagnosis and management. National Institute for Health and Care Excellence; 2013 [accessed 27/11/2021]
• NICE. Nintedanib for treating progressive fibrosing interstitial lung diseases. National Institute for Health and Care Excellence, 2021 [accessed 18/03/2024]
• NICE. Nintedanib for treating idiopathic pulmonary fibrosis when forced vital capacity is above 80% predicted. National Institute for Health and Care Excellence; 2023 [accessed 18/03/2023]
• Chapman SJR, G. V.; Shrimanker, R. S.; Turnbull, C. D.; Wrightson, J. M. Oxford Handbook of Respiratory Medicine. Fourth Edition ed. Oxford, United Kingdom: Oxford University Press; 2021