Respiratory - Interstitial lung disease

Question 1

What is interstitial lung disease?

Answer 1

This is an imprecise term for a number of conditions with bilateral diffuse pulmonary involvement by cellular or non cellular deposits. They can involve the interstitium, the alveoli or both.

They are characterised by inflammation and fibrosis.

Question 2

What are the common clinical features of ILD?

Answer 2

Patients typically present with progressive breathlessness, a dry cough, lung crackles (fine crepitations), and diffuse infiltrates on chest x ray.

Question 3

What do lung function tests typically show in ILD?

Answer 3

Lung function tests usually show a restrictive defect (reduced TLC and VC with a normal FEV1/ FVC ratio), impaired gas diffusion (reduced CO transfer factor) and hypoxaemia with hypocapnia (due to hyperventilation).

Question 4

What differential diagnoses should be considered in a patient with suspected ILD?

Answer 4

At presentation the differential diagnosis includes:

• pneumonia
• pulmonary oedema
• bronchiectasis
• malignancy

Once the clinical features suggest ILD then a cause must be searched for.

Question 5

What are the potential causes of ILD? Specifically what drugs can lead to ILD?

Answer 5

Note that the majority of ILD is idiopathic but particular attention should be made to exposures to:

• environmental antigens (e.g. parrots, pigeons)
• toxins (e.g. paraquat)
• dusts (e.g. asbestos - ports!)
• systemic diseases (e.g. RA, SLE commonly involve the lung parenchyma)
• drugs (e.g. amiodarone, nitrofurantoin, methotrexate, bleomycin)
• eosinophilic reactions in the alveoli (e.g. sulphonamides, naproxen)

Question 6

What is honeycomb lung?

Answer 6

This is a generalized cystic or honeycomb appearance of the lung parenchyma that is a feature of certain interstitial lung diseases. It is best regarding as end stage lung resulting from a wide variety of interstitial pulmonary diseases with fibrosis.

Question 7

What is the macroscopic appearance of honeycomb lung?

Answer 7

The affected areas show a firm sponge like appearance with a coarse texture due to cystic spaces with fibrous walls. The pleural surface is typically nodular.

Question 8

Describe the microscopic appearance of honeycomb lung?

Answer 8

The cystic spaces are lined by flattened or cuboidal epithelium. The walls are irregular, thick and fibrous and contain hypertrophic smooth muscle. The muscular arteries show muscle hypertrophy and fibrosis. There may be also disease specific changes.

Question 9

What are the common causes of honeycomb lung?

Answer 9

Note that “honeycomb” lung is not a feature of ALL interstitial lung diseases, but many of them do share this feature.

Common causes include:

• pneumoconiosis - e.g. asbestosis
• sarcoidosis
• cryptogenic fibrosing alveolitis/ idiopathic pulmonary fibrosis

Question 10

Give some less common causes of honeycomb lung?

Answer 10

• Diffuse alveolar damage (DAD)/ ARDS - e.g. radiation
• drugs reactions (amiodarone, busulphan)
• EAA (most commonly causes ground glass opacification)
• chronic pulmonary venous congestions - e.g. mitral stenosis
• infections - e.g. TB
• histiocytosis X
• GVHD
• recurrent gastric reflux

Question 11

What are the consequences of honeycomb lung?

Answer 11

1) Impaired respiratory function: the diseases are “restrictive” in type
2) Respiratory failure and cor pulmonale: due to severe loss of alveolar capillary units. Pulmonary hypertension is due to hypoxia, fibrous obliteration of vessels and anastomoses

Question 12

What is idiopathic pulmonary fibrosis?

Answer 12

IPF (also known as cryptogenic fibrosing alveolitis) is a progressive chronic inflammatory disease of the lung of unknown cause which results in diffuse interstitial fibrosis and honeycomb change.

It comes under the umbrella term of indiopathic interstitial pneumonias.

Question 13

Who is affected by IPF?

Answer 13

IPF is more common in men (male:female = 2:1) and in the older age groups (mean age is 70 years). Although not that common, it does cause 2500 deaths per year.

Question 14

What are the clinical features of IPF?

Answer 14

Patients present with the usual features of interstitial lung disease - i.e. progressive dyspnoea, dry cough, crackles, restrictive defect in lung function and reticulonodular infiltrates on chest x ray. About 60-70% of patients have clubbing.

Question 15

What is the pathogenesis of IPF?

Answer 15

The aetiology of IPF is unknown. One theroy suggests that an unidentified antigen (possibly metal or wood dust as suggested by some studies) stimulates B cells to secrete immunoglobulin. These bind to antigen to form immune complexes which bind to and activate macrophages.

These secrete a wide range of cytokines - e.g. IL-1, FGF. Polymorphs and eosinophils are attracted to the lung and release reactive oxygen species, proteases and other toxic compounds. These produce local lung damage. Additional factors promote fibrous scarring of the damaged lung.

Question 16

What is the histological feature of IPF?

Answer 16

Histology shows a characteristic pattern of usual interstitial pneumonia (UIP). This has a heterogenous appearance with alternating areas of normal lung, interstitial inflammation, fibrosis and honeycombing.

Question 17

What is the imaging modality of choice in suspected cases of IPF and what does it show?

Answer 17

High resolution CT typically shows evidence of advanced fibrosis with extensive areas of reticulation and honeycombing. This predominantly affects the sub- pleural areas of the lower zones.

Question 18

How is IPF treated?

Answer 18

Patients are usually treated with a combination of low dose prednisolone, azothioprine, and N-acetyl cysteine.

Unfortunately the response to treatment is usually poor, and 50% of patients die within 3 years of diagnosis. For younger patients, lung transplantation may be an option. N-acetyl cysteine is an antioxidant which suggests that IPF may be caused by an imbalance between oxidant-antioxidant systems in the lung.

Question 19

What are the results of IPF?

Answer 19

1) Clinically: a restrictive type of lung disease mostly in middle age, with progressive dyspnoea, cough, fine inspiratory crackles, finger clubbing, weight loss and basal mottling on chest x ray
2) Respiratory dysfunction: this is progressive ending in respiratory failure and cor pulmonale
3) Death
4) Lung carcinoma: increased incidence in 13% of advanced disease, usually a peripheral adenocarcinoma

Question 20

What are idiopathic interstitial pneumonias?

Answer 20

This term is used to describe a spectrum of inflammatory and infiltrative fibrotic lung diseases of unknown cause, including IPF (which is probably the most important to know about).

Question 21

What is non specific interstitial pneumonia?

Answer 21

This is a subtype of idiopathic interstitial pneumonias. Unlike IPF, non specific interstitial pneumonia is characterised by more uniform inflammatory changes and less fibrosis on lung biopsy. This corresponds with more ground glass opacification on CT.

It responds more favourably to corticosteroids and has a better prognosis than IPF.

Question 22

Histology showing intralveolar buds of organising fibrosis is characteristic of which type of idiopathic interstitial pneumonia?

Answer 22

Cryptogenic organising pneumonia (BOOP). This seems to be a pattern of response in the lungs to a variety of insults. It particularly occurs in association with some drugs (e.g. amiodarone) connective tissue diseases (e.g. RA) or ulcerative colitis. Often no cause can be identified.

Clinically patients often have a cough, malaise, fever, dyspnoea with chest X ray infiltrates and a raised ESR.

Quite often patients are thought to have an infective pneumonia but the differential is widened when no pathogen is identified and the patient fails to respond to antibiotics.

Question 23

What are rarer idiopathic interstitial pneumonias that affect smokers?

Answer 23

Desquamative interstitial pneumonia and respiratory bronchiolitis interstitial lung disease affect smokers. They have particular features of desquamation of alveolar macrophages or bronchiolitis on histology.

Question 24

What idiopathic interstitial pneumonia may complicate HIV infection?

Answer 24

Lymphoid interstitial pneumonia is characterised by the presence of lymphoid cells in the interstitium. It may occur as a complication of HIV infection or connective tissue disease.

Question 25

What type of interstitial lung disease typically occurs with connective tissue diseases?

Answer 25

The typical clinical features of IPF with the histopathological pattern of usual interstitial pneumonia can occur in association with a connective tissue disease.

When a patient presents with interstitial lung disease a careful search for features of connective tissue disease - e.g. Raynaud’s, inflammatory arthritis, sicca syndrome, myositis and skin changes - should be undertaken.

Question 26

Summarise the pulmonary complications of rheumatoid arthritis?

Answer 26

1) Cricoarytenoid arthritis - hoarseness
2) Rheumatoid nodules - same histology as subcutaneous nodules
3) Caplans syndrome - cavitating nodules in rheumatoid arthritis with coal miners pneumoconiosis
4) Obliterative airway disease
5) Pleurisy and pleural effusion
6) Diffuse pulmonary fibrosis

Question 27

Why can diffuse infiltrates on chest x ray in a patient with RA be confusing?

Answer 27

Fibrotic lung diseases complicating rheumatoid arthritis are managed in the same way as IPF but the prognosis is generally better.

Drugs (e.g. methotrexate) used to treat RA may cause inflammatory reactions in the lungs and may also give rise to infections. In these circumstances, diffuse infiltration may be a result of a i) a drug reaction, ii) lung involvement by the connective tissue disease iii) infection or iv) co-incidental lung disease.

Bronchoalveolar lavage is useful in detecting infection.

Question 28

What are the pulmonary features of systemic sclerosis?

Answer 28

Diffuse lung fibrosis is a common complication of systemic sclerosis.

• Aspiration pneumonia may occur due to oesophageal dysmotility in CREST
• Pulmonary hypertension may also develop in patients with CREST syndrome as a primary vascular phenomenon (often in the absence of significant pulmonary fibrosis)

Question 29

Summarise the pulmonary complications of SLE?

Answer 29

• pleural effusions are common and may cause pleural thickening
• “shrinking lungs”: chest x ray shows high hemi diaphragms with small lungs, probably caused by myopathy of the diaphragm
• lung fibrosis
• immunosuppressive treatment may predispose to opportunistic infections (e.g. Pneumocystis pneumonia)

Question 30

What is hypersensitivity pneumonitis (or EAA)?

Answer 30

These are a group of diseases characterised by immunologically mediated interstitial granulomatous inflammation resulting from inhalation of various antigens, usually organic dust.

Question 31

What are the important types of EAA?

Answer 31

1) Farmers lung: due to inhalation of fungal spores of actinomycetes present in mouldy hay
2) Pigeon/ bird fanciers lung: due to inhalation of avian protein antigen in bird droppings
3) Others: include bagassosis, mushroom workers lung etc

Question 32

What are the macroscopic changes in EAA?

Answer 32

Initially the lung may appear normal but chronic exposure leads to the development of diffuse interstitial fibrosis progressing to honeycomb lung. Changes are most marked in the upper lobes.

Question 33

What are the features of lung biopsy in EAA?

Answer 33

There is a diffuse interstitial infiltrate of inflammatory cells including lymphocytes, plasma cells and macrophages.

Small non caseating granulomas similar to those found in sarcoidosis are also present. Some cases also show bronchiolitis obliterans organising pneumonia (BOOP).

Question 34

What is the pathogenesis of EAA?

Answer 34

The mechanism is probably a combined type III immune complex hypersensitivity reaction and type IV cell mediated delayed hypersensitivity reaction to inhaled antigen.

The disease only occurs in a small % of those exposed, suggesting that individual susceptibility is important. Dose of antigen and the effects of cigarette smoke are also important (less common in smokers due to immunosuppressive effect). Precipitating antibodies in the serum and a positive skin test are useful in the diagnosis.

Question 35

What are the two forms of hypersensitivity pneumonitis?

Answer 35

1) Acute form - recurrent dyspnoea, dry cough, pyrexia, myalgia, and flu like sensation about 4-8 hours after antigen exposure
- X ray may show diffuse infiltrates
- often misdiagnosed as pneumonia

2) Chronic form - insidious development of dyspnoea and lung fibrosis

Question 36

What is sarcoidosis?

Answer 36

A multisystem disease of unknown cause characterised by non caseating granulomas. It occurs worldwide, being more common in Africa and Asia.

Females are slightly more affected than males with a peak age of onset between 20 and 40 years.

Question 37

What sites are affected in sarcoidosis?

Answer 37

Sarcoid may present in one or more organs but many organs are usually subclinically involved.

Pulmonary involvement is seen in 90% of cases. Other common sites are: skin, spleen, lymph node, eye, liver, bones and salivary glands.

Question 38

What is microscopic appearance of sarcoidosis?

Answer 38

The non caseating granuloma is the fundamental lesion of sarcoidosis. It is composed of a central collection of epithelioid histiocytes and some helper T lymphocytes. There is occasionally a multinucleated giant cell of Langhans type, outside this there is a rim of suppressor T lymphocytes.

There is NO caseation.

Intracellular inclusions may be seen in giant cells including asteroid and Schaumann bodies.

Question 39

What are the clinical features of sarcoidosis?

Answer 39

The clinical features of sarcoidosis are very varied but it is useful to consider two broad categories of disease:

1) an acute form that is usually transient and often resolves spontaneously
2) a chronic form that is persistent and may cause fibrosis

Question 40

What are the features of the acute form of sarcoidosis?

Answer 40

Acute sarcoidosis typically develops abruptly in young adults with:

• erythema nodosum
• bilateral hilar lymphadenopathy
• uveitis
• arthritis
• parotitis

Question 41

Other than sarcoidosis, what else can cause bilateral hilar lymphadenopathy?

Answer 41

• lymphoma
• metastatic carcinoma
• TB
• fungal infections - e.g. coccidiodomycosis and histioplasmosis
• berylliosis

NB sarcoidosis is the most common cause of BHL in the UK

Question 42

What are the features of chronic sarcoidosis?

Answer 42

The chronic form of sarcoidosis follows a more indolent course, often in an older age group with involvement of many tissues of the body.

Chronic pulmonary sarcoidosis involves the lung parenchyma with reticular shadowing often distributed in a perihilar fashion on chest x ray. There may be little other findings on clinical examination of the chest but the disease may progress in some patients causing progressive fibrosis.

Chronic extrapulmonary sarcoidosis can involve:

• occular sarcoidosis - pain and redness due to anterior uveitis
• parotid gland enlargement
• CNS involvement: CN palsies, chronic meningitis, obstructive hydrocephalus, posterior pituitary involvement
• cardiac: conduction abnormalities and arrhythmias
• hypercalcaemia: increased bone resorption (–> nephrocalcinosis, hypercalcuria, renal calculi)

Question 43

How is sarcoidosis diagnosed?

Answer 43

The diagnosis of sarcoidosis can often be made on clinical grounds especially if a young patient presents with erythema nodosum and BHL.

In less typical cases it can be helpful to obtain a biopsy of the affected organ. Bronchial and transbronchial biopsies are particularly useful and may be combined with bronchoalveolar lavage. This demonstrates evidence of CD4 lymphocyte alveolitis.

Serum ACE are elevated in about 2/3’s of cases with active sarcoidosis.

Question 44

How is sarcoidosis treated?

Answer 44

More than 70% of cases resolve with minimal or no pulmonary fibrosis. In 25% there is permanent disability due to varying degrees of diffuse interstitial fibrosis with honeycomb lung change leading to respiratory failure and cor pulmonale.

Steroids can suppress inflammation in the affected organs.

Question 45

What is the pathogenesis of sarcoidosis?

Answer 45

The exact cause of sarcoidosis remains unclear. Antigenic exposure may activate T cells stimulating IL-1 secretion. This causes macrophage migration and activation.

IL-2 release stimulates T helper cell and alveolar macrophage activation. Macrophages stimulate fibroblast proliferation leading to progressive fibrosis due to collagen deposition. Granuloma form.

Question 46

What is pulmonary eosinophilia?

Answer 46

These are a group of conditions characterised by a patchy pulmonary inflammatory cell infiltrate rich in eosinophils that is often associated with a blood eosinophilia.

Question 47

What causes pulmonary eosinophilia?

Answer 47

1) Allergic bronchopulmonary mycosis: aspergillus infection
2) Helminth infections: ascariasis, microfilariasis, schistosomiasis
3) Drugs: nitrofurantoin, aspirin, sulphonamides
4) Unknown: cryptogenic chronic pulmonary eosinophilia, Churg-Strauss, hypereosinophilic syndrome

Some forms (e.g. Helminth infection) are self limiting with fleeting X ray pulmonary shadows.

Cryptogenic pulmonary eosinophilia is characterised by marked systemic symptoms of appetite loss, malaise, weight loss and fever. Chronic asthma is often present. Transient pulmonary shadows are seen together with eosinophilia.

Question 48

What is Histiocytosis X?

Answer 48

This is otherwise known as Langerhans cell granulomatosis/ histiocytosis and is a proliferative disorder of histiocytes (macrophages) and Langerhans cells (dendritic cells) which can occur in an isolated pulmonary form or be part of a systemic histiocytosis.

Question 49

What is the clinical presentation of histiocyctosis X?

Answer 49

Patients present with cough and dyspnoea. Recurrent pneumothoraces are common. It is more common in females and smokers.

There is patchy but widespread bilateral, nodular pulmonary parenchymal interstitial infiltrate of Langerhans cells, eosinophils and mononuclear inflammatory cells. Fibrosis occurs after.

50% of patients stabilize and the others have slowly progressive disease from which half die usually in respiratory failure from honeycomb lung.

Question 50

Lymphangioleiomyomatosis

Answer 50

A rare disease in which there is haphazard proliferation of smooth muscle through the interstitium of the lung leading to respiratory failure. Similar changes occur in tuberose sclerosis.

Question 51

Pulmonary alveolar proteinosis

Answer 51

A rare disorder usually in adults characterised by progressive pulmonary infiltrates, dyspnoea, cough and fever.

The affected lung is firm and yellow. Histologically there is intra-alveolar eosinophilic, granular, muco-polysaccharide lipid material derived from type 2 pneumocytes. No inflammatory cells are seen.

It is usually idiopathic but can be seen after silica exposure, immunodeficiency (e.g. HIV) and underlying malignancy. Spontaneous resolution occasionally occurs.

Question 52

What are the x ray features of interstitial lung disease?

Answer 52

Pulmonary fibrosis has distinct features on chest x ray:

• reduced lung volumes: fibrosis causes scarring, shrinkage and loss of elasticity
• mediastinal shift: volume loss causes the mediastinum to be pulled towards the fibrosis if unilateral
• reticular/ reticulonodular shadowing: the fibrotic tissue appears as either a light grey meshwork pattern (reticular) or with additional light grey nodular densities (reticulonodular)
• ground glass appearance: in the early stages a thin, “veil-like” light grey shadowing covers all or part of the lung
• Honeycombing: framework of multiple light grey-ring like structures may be seen

So, reduced lung volumes, mediastinal shift, reticular/reticulonodular shadowing, ground glass appearance and honeycombing are all features of pulmonary fibrosis.

Question 53

What are the CT features of interstitial lung disease?

Answer 53

HRCT is the imaging modality of choice for interstitial lung disease. Features include:

• peripheral and subpleural intralobular septal thickening
• loss in lung volume
• honeycombing
• traction bronchiectasis

Question 54

Is a biopsy always needed to diagnose interstitial lung disease?

Answer 54

In some cases, HRCT scan is sufficient to diagnose ILD. However, chest x ray and lung function studies should also be performed.

Biopsy is needed to confirm some variants of idiopathic interstitial pneumonia or in sarcoidosis and EAA. There are 2 ways of performing a lung biopsy:

• transbronchial biopsy using a flexible bronchoscope: good for small biopsy’s
• surgical biopsy: under general anaesthesia by video assisted thoracoscopy