Diffuse parenchymal pulmonary diseases

01Definition and overview

Diffuse parenchymal lung disease (DPLD), or interstitial lung disease (ILD), is a heterogeneous group of conditions that cause inflammation, fibrosis or both in the lung parenchyma: the alveolar walls, the tissue around the airways and vessels, and often the air spaces too. "Interstitial" is a little misleading, because many of them fill the alveoli with cells or protein, and some affect small airways and vessels.

They share a pattern. The patient is breathless on exertion with a dry cough; the lungs are stiff, so the lung volumes fall and the FEV1/FVC ratio is normal or high (a restrictive defect in most, though sarcoidosis with airway disease, LAM and LCH can give an obstructive or mixed one); the gas transfer (DLCO) is low; and the film shows diffuse shadowing, though it can be normal early on. The diseases are grouped by what is known of their cause:

This topic also covers the small-vessel vasculitides, anti-GBM disease, alveolar haemorrhage and eosinophilic lung disease, at the end of each section below.

The names of the IIPs have changed. The current classification (2013) keeps six major IIPs (IPF, NSIP, RB-ILD, DIP, COP and AIP) and moves LIP and pleuroparenchymal fibroelastosis to a rare group, with an "unclassifiable" category for the cases that fit nowhere. Since 2022 the guidelines also use progressive pulmonary fibrosis (PPF): any fibrosing ILD other than IPF that is getting worse, shown by at least two of three features in the past year with no other explanation: worse symptoms, physiological decline (an absolute fall in FVC of at least 5 per cent predicted, or in DLCO of at least 10 per cent predicted), and progression on imaging. Such a disease behaves like IPF in that it keeps getting worse, and nintedanib is conditionally recommended for it (pirfenidone awaits more research).

02Etiology and pathophysiology

The common pathway

1. 1

   Injury

   An inhaled antigen or dust, a drug, radiation, an autoimmune attack or an unknown trigger damages the alveolar epithelium and the capillary endothelium.
2. 2

   Inflammation

   The injury recruits lymphocytes, macrophages, neutrophils or eosinophils into the walls and air spaces (an alveolitis), or forms granulomas. If the cause goes away, this stage can resolve completely.
3. 3

   Abnormal repair

   When the injury is repeated or the repair goes wrong, fibroblasts and myofibroblasts multiply and lay down collagen and matrix in the interstitium.
4. 4

   Fibrosis

   The lung loses its elasticity, so it is stiff and the volumes fall. The gas-exchange membrane thickens and capillaries are lost, so the DLCO falls and the oxygen saturation drops on exertion. The airways are pulled open as traction bronchiectasis, cysts form as honeycombing, and pulmonary hypertension follows.

Sarcoidosis

The cause is unknown. The best account is that a genetically susceptible person mounts an exaggerated T-helper cell response to an unidentified antigen, which is not cleared. The typical sarcoid granuloma is a focal collection of epithelioid cells, macrophages (often fused into giant cells) and lymphocytes, mainly CD4 T cells, without caseation. Two features follow:

• the T cells are concentrated in the lung, so the lavage has a lymphocytosis with a high CD4:CD8 ratio, while the blood has a lymphopenia and depressed cell-mediated reactivity (the Mantoux test is usually negative); and
• the activated macrophages hydroxylate vitamin D directly, independent of the parathyroid hormone, which raises the absorption of calcium and gives hypercalcaemia and hypercalciuria.

The epithelioid cells also make angiotensin-converting enzyme (ACE), so the serum level is raised in many patients.

First-degree relatives have a raised risk, and several HLA types are linked to the risk of the disease and to its course: HLA-DRB1*03, for example, predicts resolution in Löfgren syndrome.

Idiopathic pulmonary fibrosis

The cause is unknown. The accepted model is that repeated injury of the alveolar epithelium by unidentified environmental stimuli leads to uncontrolled wound healing, with too many fibroblasts, too much extracellular matrix, and little inflammation, which explains why anti-inflammatory drugs fail. Risk factors are:

• age, male sex, and cigarette smoking;
• genes: the MUC5B promoter polymorphism is the commonest strong risk factor, and rarer variants affect telomere maintenance (TERT, TERC) and surfactant proteins (SFTPC), which is why some families have several cases;
• gastro-oesophageal reflux with micro-aspiration; and
• occupational dust (metal and wood) and chronic viral infection, with weaker evidence.

The histological pattern is usual interstitial pneumonia (UIP): patchy, with normal lung beside dense scar, subpleural honeycombing, and fibroblastic foci (dense collections of fibroblasts and myofibroblasts). UIP and IPF are not synonyms, since UIP is also found in rheumatoid lung disease, chronic hypersensitivity pneumonitis and asbestosis.

The other idiopathic interstitial pneumonias

Strictly, only the idiopathic forms of COP and LIP are IIPs; organising pneumonia and LIP with a known cause look the same but are not.

Hypersensitivity pneumonitis

Hypersensitivity pneumonitis (HP) is an allergic reaction in the small airways and alveoli to an inhaled antigen, or occasionally a drug. The reaction involves both cellular immunity (T cells, giving a lymphocytic infiltrate and poorly formed granulomas) and immune complexes that activate complement. Long exposure leads to fibrosis and honeycombing. Smokers are less likely to develop HP (a weaker antibody response), but if they do, the disease is more chronic and more severe.

Humidifier fever is a self-limited febrile illness that usually leaves the lung undamaged; the HP form is humidifier lung.

Connective tissue disease, drugs and dusts

The lung is involved in many autoimmune rheumatic diseases, and in different ways:

• Rheumatoid arthritis: fibrosis (UIP, NSIP or OP), pleural effusion (chronic, often unilateral, with a low glucose), cavitating rheumatoid nodules, obliterative bronchiolitis, cricoarytenoid arthritis (stridor and hoarseness), and Caplan syndrome (rounded nodules of 0.5 to 5 cm in a coal miner or other dust-exposed worker with arthritis).
• Systemic sclerosis: involved in most patients, and the leading cause of death. Interstitial fibrosis (usually NSIP) and pulmonary arterial hypertension are the commonest, and a dilated oesophagus leads to aspiration.
• SLE: pleurisy (in up to two-thirds), usually small bilateral effusions, and pneumonia; fibrosis is uncommon, which is the difference from rheumatoid disease.
• Others: Sjögren syndrome (LIP, NSIP), and myositis (NSIP and OP, especially the antisynthetase syndrome with anti-Jo-1 antibodies).

Drugs include methotrexate (pneumonitis and fibrosis; stop it and use another agent), amiodarone, nitrofurantoin, bleomycin and immune checkpoint inhibitors, as well as radiation. Dusts cause the pneumoconioses (asbestosis, silicosis), and beryllium causes a granulomatous disease that is easily mistaken for sarcoidosis.

Rare interstitial lung diseases

• Langerhans cell histiocytosis (LCH): proliferation of Langerhans cells, strongly associated with cigarette smoking, affecting the lungs in about 10 per cent of cases of the whole disease. Many cases carry activating mutations in the MAPK pathway, such as BRAF V600E, and it is now classed as a neoplasm.
• Lymphangioleiomyomatosis (LAM): a hamartomatous infiltration of the lung by smooth-muscle-like cells with TSC gene mutations, which over-activate mTOR. It occurs in premenopausal women, sporadically or with tuberous sclerosis (about 15 per cent in some series).
• Pulmonary alveolar proteinosis (PAP): lipoproteinaceous material fills the alveoli. Most cases are autoimmune, with antibodies against GM-CSF, which the alveolar macrophages need in order to clear surfactant; others are secondary (haematological disease, dust) or congenital.

Vasculitis, anti-GBM disease and alveolar haemorrhage

The ANCA-associated small-vessel vasculitides are caused by antibodies to neutrophil enzymes, which activate neutrophils and damage the walls of small vessels (a necrotising capillaritis in the lung and a glomerulonephritis in the kidney). Granulomatosis with polyangiitis (GPA) has c-ANCA to proteinase 3 (PR3) and granulomas. Microscopic polyangiitis (MPA) has p-ANCA to myeloperoxidase (MPO) and no granulomas. Eosinophilic granulomatosis with polyangiitis (EGPA) begins as asthma and eosinophilia, with a later vasculitis.

Anti-GBM disease (Goodpasture syndrome) is the triad of pulmonary haemorrhage, glomerulonephritis and circulating antibodies to an antigen of the basement membrane in both organs. The antigen is the NC1 domain of the alpha-3 chain of type IV collagen, in the alveolar and glomerular basement membranes, and smoking, solvent inhalation and infection expose it in the lung. Diffuse alveolar haemorrhage (DAH) is the common endpoint, with causes that include vasculitis, SLE, anti-GBM disease, drugs, infection, and bland bleeding (clotting disorders, mitral stenosis), and sometimes no cause is found.

Eosinophilic lung disease

Eosinophils are drawn into the lung in an allergic reaction to helminths, drugs, or fungi. The classic grouping:

Allergic bronchopulmonary aspergillosis (ABPA) is the hypersensitivity reaction to Aspergillus colonising the bronchi of a patient with asthma or cystic fibrosis. It damages the proximal airways, causing proximal bronchiectasis. Two further forms complete the group: chronic eosinophilic pneumonia (weeks of cough, fever and weight loss, often in a person with asthma, with peripheral opacities) and acute eosinophilic pneumonia (a few days of fever and respiratory failure, often after starting to smoke), both with many eosinophils in the lavage.

03Clinical features

The shared picture is an insidious, progressive breathlessness on exertion with a dry cough, fatigue and weight loss. On examination there are fine, late-inspiratory ("Velcro") crackles at the bases, clubbing in some diseases, and later signs of pulmonary hypertension and right heart failure. Wheeze is uncommon, but squeaks suggest bronchiolitis. Findings elsewhere point to the cause: a rash, joint disease, Raynaud phenomenon, tight skin, mechanic's hands, dry eyes. Haemoptysis suggests a vasculitis, alveolar haemorrhage, LAM or a cancer.

Sarcoidosis

Sarcoidosis can involve any organ, with the lungs in up to 90 per cent. It is often found by chance on a chest film, or presents with cough, breathlessness and vague chest discomfort, and fatigue is frequent and hard to treat. The chest is often clear to auscultation even with marked changes on the film. The radiographic stages inform the outlook:

Patients can present at any stage and do not pass through them in order, and the extent on the film does not match the lung function. Symmetrical bilateral hilar lymphadenopathy is characteristic. Lymphoma, tuberculosis and bronchial cancer cause hilar enlargement too, but it is usually asymmetrical.

Löfgren syndrome (bilateral hilar lymphadenopathy, erythema nodosum, arthralgia and fever) usually resolves without treatment. Heerfordt syndrome (uveoparotid fever) combines uveitis, parotid swelling, fever and often a facial palsy. The other organs:

• skin (10 to 30 per cent): erythema nodosum, lupus pernio (violaceous plaques on the nose, cheeks and ears), infiltrated scars and tattoos;
• eyes (anterior uveitis in 5 per cent, asymptomatic uveitis in up to 25 per cent): a painful red eye or misting of vision, and dry eyes; every new patient needs an eye examination;
• calcium: hypercalcaemia (10 to 20 per cent) and hypercalciuria (30 to 50 per cent), leading to stones, nephrocalcinosis and renal failure; sarcoid can also cause a granulomatous tubulointerstitial nephritis;
• heart (clinically in about 3 per cent): ventricular arrhythmia, heart block, cardiomyopathy and sudden death; and
• nervous system (about 2 per cent): cranial nerve palsies (especially the facial nerve), meningitis, a neuropathy, seizures; and the liver and spleen (abnormal liver tests, granulomas), joints and bones.

Idiopathic pulmonary fibrosis

The patient is usually in their sixties, with an insidious progressive dyspnoea, often a dry cough, bibasal end-inspiratory crackles and clubbing in 25 to 50 per cent. The crackles do not clear with diuretics or antibiotics, but patients are often treated for heart failure or recurrent chest infection first. The course is a steady decline, interrupted by complications: pulmonary hypertension, pneumothorax, pulmonary embolism, infection, lung cancer (the risk is raised), and acute exacerbations (an acute worsening over days to weeks, with new bilateral ground-glass opacity or consolidation on the fibrotic background that heart failure or fluid overload does not explain; they were once defined as having no identifiable cause, but infection, aspiration or a procedure can trigger one), which carry a high mortality.

Hypersensitivity pneumonitis

The picture depends on the exposure, and the symptoms (cough, breathlessness, malaise, weight loss and fever) tend to recur with exposure and ease away from it, on holiday or at the weekend. The classic time courses are:

• acute: onset 4 to 6 hours after exposure, with fever, so it is often mistaken for a chest infection; it settles within 24 to 48 hours of leaving the antigen;
• subacute: lower-level or intermittent exposure; better in weeks to months after removal; and
• chronic: insidious respiratory and constitutional symptoms with no acute episodes, and clubbing may be present; irreversible fibrosis raises the mortality.

Current guidelines describe it instead as non-fibrotic or fibrotic HP, since the presence of fibrosis decides the outlook. Examination shows fine crackles and inspiratory squeaks.

The other diseases

04Diagnosis and management

The approach

1. 1

   History

   Ask about the exposures (birds, hay, mould, humidifiers, hot tubs, dusts, asbestos, occupations over a lifetime), drugs including old ones, radiation, smoking, family members with lung fibrosis, and the symptoms of connective tissue disease. Note the tempo: weeks suggests AIP, COP, HP or eosinophilic pneumonia, and years suggests IPF, NSIP or sarcoidosis.
2. 2

   Physiology and bloods

   Lung function shows a restrictive defect with a low DLCO. Exertional desaturation can be shown by a walk test. Bloods are the full blood count with eosinophils, ESR, calcium, liver and renal tests, and autoantibodies: ANA, rheumatoid factor and anti-CCP, ENA, myositis antibodies, ANCA and anti-GBM. Precipitins to a suspected antigen show exposure, not disease (a quarter of pigeon fanciers have them).
3. 3

   Imaging

   The film may be normal early on. HRCT is the imaging test, and the pattern is often enough to narrow the diagnosis (see the table).
4. 4

   Lavage and biopsy

   Bronchoalveolar lavage is used when the cause is unclear: lymphocytes (HP, sarcoidosis, NSIP), eosinophils over 25 per cent (eosinophilic pneumonia), neutrophils (IPF), a milky fluid (PAP) or blood (DAH). Transbronchial or cryobiopsy, EBUS of nodes and surgical (VATS) lung biopsy are used when HRCT and the clinical picture do not give a confident diagnosis. A skin or other lesion may be an easier site.
5. 5

   Multidisciplinary discussion

   The clinician, radiologist and pathologist (with a rheumatologist when relevant) agree on the diagnosis. In the right clinical setting a UIP pattern, and often a probable UIP pattern, on HRCT is enough to diagnose IPF without a biopsy.

The commonest HRCT patterns:

Other conditions to consider on the film are interstitial pulmonary oedema, infection and lymphangitis carcinomatosa.

Sarcoidosis

The diagnosis rests on a compatible picture, non-caseating granulomas on tissue, and the exclusion of other causes (tuberculosis, fungal infection, beryllium, drugs, lymphoma). Lymph nodes need not be sampled in a typical Löfgren syndrome (hilar adenopathy with erythema nodosum or ankle arthritis). Otherwise the yield is highest with EBUS-guided sampling of the nodes and transbronchial lung biopsy (positive in up to 90 per cent of lung disease in older series), and a skin lesion is the easiest site. Other tests:

• HRCT to stage and to find the beading of nodules along airways and fissures; the lung function shows a restrictive defect with a low gas transfer, or can be normal with isolated hilar nodes;
• calcium, including a 24-hour urinary calcium, a full blood count (a mild normocytic anaemia and a raised ESR), and renal and liver tests;
• serum ACE, raised in many untreated patients but also in tuberculosis, lymphoma and silicosis, so neither reliable for diagnosis nor for monitoring;
• an ECG and echocardiogram for everyone, with cardiac MRI if they raise concern;
• an eye examination; and
• lavage with a lymphocytosis and a raised CD4:CD8 ratio, supportive but not required.

Management: the natural history is unpredictable and many cases resolve in the first 6 months, and although steroids improve the film, the effect on lung function is not consistent. So many patients need only observation and review. Treat when there is:

• troublesome symptoms, falling lung function or progression on imaging; or
• hypercalcaemia, or major extrathoracic disease, especially cardiac, neurological or ocular disease that does not respond to topical treatment.

The first line is prednisolone, classically 0.5 mg/kg for 4 to 6 weeks, tapered to a maintenance dose for at least 12 months; European guidance finds no extra benefit in pulmonary disease above 20 mg a day, and strongly recommends steroids only for patients at higher risk of death or permanent disability. Methotrexate is the usual steroid-sparing drug, azathioprine, mycophenolate and leflunomide are alternatives, and an anti-TNF agent such as infliximab is used for refractory disease. Hydroxychloroquine is a standard choice for skin disease and hypercalcaemia. Löfgren syndrome needs only an NSAID. Cardiac sarcoidosis may need a pacemaker or defibrillator as well as immunosuppression. Relapse on withdrawal is common, and lung transplantation is considered for stage 4 disease with respiratory failure.

Idiopathic pulmonary fibrosis

Diagnosis: lung function shows a restrictive defect with a low gas transfer (spirometry can be normal early, or the volumes preserved when emphysema coexists). Blood tests (ANA, RF) exclude a connective tissue disease, but no blood test is specific. The HRCT hallmarks are the basal subpleural distribution, reticulation, traction bronchiectasis and honeycombing, and lavage is only needed if infection or malignancy is suspected (a neutrophilic pattern is common in IPF). Biopsy is used when the HRCT and the multidisciplinary meeting leave doubt.

Treatment:

• Antifibrotic drugs: pirfenidone and nintedanib (a tyrosine kinase inhibitor) roughly halve the yearly fall in FVC, but do not reverse the scarring. Pirfenidone causes a reversible photosensitive rash and gastrointestinal upset, and nintedanib mostly diarrhoea; both need liver tests. In the UK, pirfenidone is funded when the FVC is between 50 and 80 per cent predicted and nintedanib when it is 50 per cent or more, and treatment is stopped if the predicted FVC falls by 10 percentage points or more in a year. A third drug, nerandomilast (a PDE4B inhibitor), slowed the decline in two trials published in 2025, by less than the older drugs did (about 70 mL a year against placebo), and was licensed in the US in 2025 and in the UK and EU in 2026; UK funding guidance on it is awaited.
• No immunosuppression: steroids are no longer recommended in confirmed IPF. In a trial, prednisone with azathioprine and N-acetylcysteine caused more deaths and admissions than placebo.
• Supportive care: ambulatory oxygen, pulmonary rehabilitation, vaccination, stopping smoking, treating reflux when symptomatic (though antacids and antireflux surgery are not given to slow the disease), and treating pulmonary hypertension, sleep apnoea and other comorbidity. A palliative care referral should be made early.
• Acute exacerbation: oxygen or non-invasive ventilation, treatment for any infection, and often high-dose steroids on weak evidence.
• Lung transplantation is the only curative option, so assessment should begin early in suitable patients; antifibrotics slow the decline and may lower mortality.

In progressive fibrosis of other causes (PPF), nintedanib and nerandomilast also slow the fall in FVC.

Hypersensitivity pneumonitis

A careful exposure history with the typical HRCT and a lymphocytic lavage (a low CD4:CD8 ratio helps to tell it from sarcoidosis, though the two overlap) can make the diagnosis without a biopsy. Lung function is not diagnostic: it shows a restrictive defect with a low gas transfer in chronic disease. The biopsy shows a lymphocytic infiltrate with varying fibrosis.

The key to treatment is avoiding the antigen, which may need a change of work, a mask, or getting rid of the birds. Pigeon fancier's lung is hard to control because owners are attached to the hobby. Prednisolone is given if symptoms persist after removal of the antigen or if the disease is severe. Mycophenolate or azathioprine is often added in fibrotic HP, and nintedanib in progressive fibrosis. Established fibrosis does not resolve. Farmer's lung is a recognised occupational disease in the UK, with compensation.

Other idiopathic pneumonias and connective tissue disease

The treatment of each IIP is in the table above. A diagnosis of NSIP or organising pneumonia means a search for a connective tissue disease, a drug or an exposure, and treatment of that cause. For connective tissue disease ILD, immunosuppression (mycophenolate, azathioprine, rituximab or cyclophosphamide) is guided by the underlying disease, and nintedanib slows the loss of FVC in systemic sclerosis. Stop any drug that is responsible. Older advice was to replace methotrexate if there is fibrosis in rheumatoid arthritis; current practice is to stop it when pneumonitis or progression is suspected, and mild, stable lung disease is not an absolute bar. In systemic sclerosis and myositis, lung function and HRCT are used to screen for ILD.

Rare ILDs

• LCH: stop smoking, which is essential and can lead to remission; steroids, chemotherapy and cladribine have been used with variable success, and BRAF inhibitors in some patients; lung transplantation in advanced disease.
• LAM: HRCT shows diffuse thin-walled cysts, and a serum VEGF-D level of at least 800 pg/mL supports the diagnosis without a biopsy. Sirolimus (an mTOR inhibitor) stabilises the lung function; other measures are treatment of pneumothorax and chylous effusion, avoiding oestrogens, and transplantation.
• PAP: HRCT shows crazy-paving, lavage a milky fluid and foamy macrophages, and serum anti-GM-CSF antibodies are found. The initial treatment is whole-lung lavage; inhaled GM-CSF (molgramostim) has been tested in a phase 3 trial but is not yet part of standard care.

ANCA vasculitis, anti-GBM disease and alveolar haemorrhage

Diagnose with ANCA (c-ANCA/PR3 for GPA, p-ANCA/MPO for MPA, though the overlap is common and a minority are ANCA-negative), a biopsy of the active site (kidney, nose, lung), urine tests for blood and protein, and imaging (nodules that cavitate, consolidation, ground glass). In a sick patient with haemorrhage or renal failure, treatment starts before the biopsy.

• GPA and MPA: induction with glucocorticoids and rituximab or cyclophosphamide (methotrexate in milder disease); maintenance with rituximab or azathioprine for some years; co-trimoxazole prophylaxis against Pneumocystis. Plasma exchange is no longer routine, since a large trial found no overall benefit; it may still be considered when the creatinine is above 300 µmol/L from active glomerulonephritis, but is not used routinely for alveolar haemorrhage. Avacopan, a C5a-receptor blocker, was used to cut the steroid dose. But the paper on its main trial was retracted in June 2026, after the primary-endpoint assessments of a few patients were re-adjudicated following unblinding, without the academic authors' knowledge; the manufacturer disputes any wrongdoing. The EU authorisation has been revoked, so it is not started in new patients there, and the US regulator has proposed withdrawing its approval. This was a data-integrity retraction, which does not show that the drug fails, but the evidence for it is now in doubt.
• EGPA: steroids, with cyclophosphamide or rituximab for organ-threatening disease, and mepolizumab for relapsing or refractory disease (benralizumab is an alternative).
• Anti-GBM disease: the antibody is detected in the serum or on the kidney biopsy, and treatment is plasma exchange to remove the antibody, cyclophosphamide and prednisolone to stop its production, and stopping smoking. The kidney recovers only if treatment is early.
• Alveolar haemorrhage: the lavage becomes more bloody with each aliquot, with haemosiderin-laden macrophages, and the KCO is raised. Intensive care and ventilatory support may be needed, with pulsed methylprednisolone and treatment of the cause.

Eosinophilic lung disease

Remove the cause: stop the drug or treat the helminth. Simple eosinophilia resolves untreated. Prolonged, chronic and acute eosinophilic pneumonia respond quickly to corticosteroids, and chronic eosinophilic pneumonia often relapses when they are reduced. ABPA is treated initially with oral prednisolone or with itraconazole (itraconazole where steroids are unsuitable, and as a steroid-sparing agent in treatment-dependent disease), and a monoclonal antibody (omalizumab, mepolizumab and others) in treatment-dependent cases. ABPA is diagnosed by fungal sensitisation (Aspergillus-specific IgE) with a total IgE of at least 500 IU/mL and two of: Aspergillus-specific IgG, blood eosinophilia, and suggestive imaging. Tropical eosinophilia is treated with diethylcarbamazine.

05Epidemiology

06Prognosis

Follow-up depends on the disease. In fibrotic ILD, repeat the FVC and DLCO every 3 to 6 months with a walking saturation, and do an HRCT if there is a change; progression by the 2022 criteria brings antifibrotic treatment into view. In sarcoidosis, review calcium, ECG, eyes and lung function while on treatment and after remission, since relapse is common. All patients should be offered vaccination, help to stop smoking, pulmonary rehabilitation, and, where the disease is progressive and unlikely to be cured, early palliative care and an assessment for transplantation.