Diffuse diseases of the lung parenchyma

Diffuse parenchymal lung disorders (DPLD, also referred to as interstitial lung diseases) are a heterogeneous group of disorders accounting for about 15% of respiratory clinical practice. There is diffuse lung injury and inflammation that can progress to lung fibrosis. The classification is shown in Box 15.17.

Box 15.17

Diffuse parenchymal lung diseases (DPLDs)

Granulomatous lung disease, e.g. sarcoid

Granulomatous lung disease with vasculitis, e.g. Wegener, Churg–Strauss, microscopic vasculitis

Pulmonary autoimmune rheumatic diseases, e.g. rheumatoid arthritis, systemic lupus erythematosus

Idiopathic interstitial pneumonias, see Box 15.18

Drugs, see Table 15.22

Other forms:

– Langerhans’ cell histiocytosis

– Goodpasture’s syndrome

– Diffuse alveolar haemorrhage

– Idiopathic pulmonary haemosiderosis

– Lymphangioleiomyomatosis

– Pulmonary alveolar proteinosis

Granulomatous lung disease

A granuloma is a mass or nodule composed of chronically inflamed tissue formed by the response of the mononuclear phagocyte system (macrophage/histiocyte) to an insoluble or slowly soluble antigen or irritant. If the foreign substance is inert (e.g. an inhaled dust), the phagocytes turn over slowly; if the substance is toxic or reproducing, the cells turn over faster, producing a granuloma. A granuloma is characterized by epithelioid multinucleate giant cells, as seen in tuberculosis. Granulomas are also seen in other infections, including fungal and helminthic, in sarcoidosis, and in hypersensitivity pneumonitis, and can also be due to foreign bodies (e.g. talc). Granulomatous lung disease with pulmonary vasculitis is discussed on page 847.

Sarcoidosis

Sarcoidosis is a multisystem granulomatous disorder, commonly affecting young adults and usually presenting with bilateral hilar lymphadenopathy, pulmonary infiltration and skin or eye lesions. Beryllium poisoning can produce a clinical and histological picture identical to sarcoidosis, though contact with this element is now strictly controlled.

Epidemiology and aetiology

Sarcoidosis is a common disease of unknown aetiology that is often detected by routine chest X-ray. There is great geographical variation. The prevalence in the UK is approximately 19/100 000. Sarcoidosis is common in the USA but is uncommon in Japan. The course of the disease is much more severe in American blacks than in whites. The peak incidence is in the 3rd and 4th decades, with a female preponderance. There is no relation with any histocompatibility antigen, but 1st degree relatives (particularly in Caucasians) have an increased risk of developing sarcoidosis. Other proposed aetiological factors are an atypical mycobacterium or fungus, the Epstein–Barr virus, and occupational, genetic, social or other environmental factors (sarcoidosis is commoner in rural than in urban populations). None of these has been substantiated.

Immunopathology

Typical sarcoid granulomas consist of focal accumulations of epithelioid cells, macrophages and lymphocytes, mainly T cells.

There is depressed cell-mediated reactivity to tuberculin and other antigens such as Candida albicans.

There is overall lymphopenia: circulating T lymphocytes are low but B cells are slightly increased.

Bronchoalveolar lavage shows a great increase in the number of cells; lymphocytes are greatly increased (particularly CD4⁺ T-helper cells). The number of alveolar macrophages is increased but they represent a reduced percentage of the total number of bronchoalveolar lavage cells.

Transbronchial biopsies show infiltration of the alveolar walls and interstitial spaces with leucocytes, mainly T cells, prior to granuloma formation.

It seems likely that the decrease in circulating T lymphocytes and changes in delayed hypersensitivity responses are the result of sequestration of lymphocytes within the lung. There is no evidence to suggest that patients with sarcoidosis suffer from an overall defect in immunity, since the frequency of fungal, viral and bacterial infections is not increased and there is no evidence of any increased risk of developing malignant neoplasms.

FURTHER READING

Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007; 357: 2153–2165.

Clinical features

Sarcoidosis can affect many different organs of the body. The most common presentation is with respiratory symptoms or abnormalities found on chest X-ray (50%). Less common presentations include fatigue or weight loss (5%), peripheral lymphadenopathy (5%) and fever (4%). Neurological presentations are rare but well recognized and can mimic a variety of conditions. Chest X-ray may be normal in up to 20% of non-respiratory cases, though pulmonary lesions may be detected later.

There are four stages of pulmonary involvement based on radiological stage of the disease, which is helpful in prognosis:

Stage I: bilateral hilar lymphadenopathy (BHL) alone

Stage II: BHL with pulmonary infiltrates

Stage III: pulmonary infiltrates without BHL

Stage IV: fibrosis.

Bilateral hilar lymphadenopathy

This is a characteristic feature of sarcoidosis which is usually symptomless and only detected on chest X-ray. Occasionally, the bilateral hilar lymphadenopathy is associated with a dull ache in the chest, malaise and a mild fever.

Although the lung fields may appear normal on plain chest X-ray, the lung parenchyma is nearly always involved as shown by CT scanning (Fig. 15.38), transbronchial biopsies and bronchoalveolar lavage.

Figure 15.38 HRCT scan in sarcoidosis. Note bilateral hilar lymphadenopathy and reticular shadowing.

The differential diagnosis of bilateral hilar lymphadenopathy includes:

Lymphoma: though this rarely affects only the hilar lymph nodes

Pulmonary tuberculosis: though it is rare for the hilar lymph nodes to be symmetrically enlarged

Carcinoma of the bronchus with malignant spread to the contralateral hilar lymph nodes: again this is rarely symmetrical.

Pulmonary infiltration

Parenchymal sarcoidosis may be asymptomatic. The combination of pulmonary infiltration and normal lung function tests is highly suggestive of sarcoidosis. Other cases are progressive leading to increasing effort dyspnoea and eventually cor pulmonale and death. The chest X-ray shows mottling in the mid-zones evolving over time to generalized fine nodular shadows. Eventually, widespread linear shadows develop, reflecting the underlying fibrosis. A honeycomb appearance can occasionally occur. In progressive disease, lung function tests show a typical restrictive defect with reduced gas transfer (see below).

The principal differential diagnoses are tuberculosis, pneumoconiosis, idiopathic pulmonary fibrosis and alveolar cell carcinoma.

Extrapulmonary manifestations

Skin and ocular sarcoidosis are the most common extrapulmonary presentations.

Skin lesions occur in 10% of cases. Sarcoidosis is the most common cause of erythema nodosum (see p. 1216). The association of bilateral symmetrical hilar lymphadenopathy with erythema nodosum occurs only in sarcoidosis. A chilblain-like lesion known as lupus pernio is also seen, as are skin nodules (see p. 1219).

Eye lesions. Anterior uveitis is common and presents with misting of vision, pain and a red eye, but posterior uveitis may present simply as progressive loss of vision. Although ocular sarcoidosis accounts for about 5% of uveitis presenting to ophthalmologists, asymptomatic uveitis may be found in up to 25% of patients with sarcoidosis. Conjunctivitis and retinal lesions have also been reported. Uveoparotid fever is a syndrome of bilateral uveitis and parotid gland enlargement together with occasional development of facial nerve palsy and is sometimes seen with sarcoidosis.

Keratoconjunctivitis sicca and lacrimal gland enlargement also occurs.

Metabolic manifestations. It is rare for sarcoidosis to present with problems of calcium metabolism, though hypercalcaemia is found in 10% of established cases. Hypercalcaemia and hypercalciuria can lead to the development of renal calculi and nephrocalcinosis. The cause of the hypercalcaemia is an increase in circulating 1,25-dihydroxyvitamin D₃, with 1 α-hydroxylation occurring in sarcoid macrophages in the lung in addition to that taking place in the kidney.

Central nervous system. CNS involvement is rare (2%) but can lead to severe neurological disease (see p. 1130).

Bone and joint involvement. Arthralgia without erythema nodosum is seen in 5% of cases. Bone cysts are found, particularly in the digits, with associated swelling. In the absence of swelling, routine X-rays of the hands are unnecessary.

Hepatosplenomegaly. Sarcoidosis is a cause of hepatosplenomegaly, though it is rarely of any clinical consequence. Liver biopsy is occasionally performed when the diagnosis is in doubt and will show granulomas.

Cardiac involvement is rare (3%) but can be serious. Ventricular dysrhythmias, conduction defects and cardiomyopathy with congestive cardiac failure are seen.

Investigations

Imaging. Chest X-ray (see above). High-resolution CT is useful for assessment of diffuse lung parenchymal involvement.

Full blood count. There may be a mild normochromic, normocytic anaemia with raised ESR.

Serum biochemistry. Serum calcium is often raised and there is hypergammaglobulinaemia.

Transbronchial biopsy is the most useful investigation, with positive results in 90% of cases of pulmonary sarcoidosis with or without X-ray evidence of lung parenchymal involvement. Pulmonary non-caseating granulomas are found in approximately 50% of patients with extrapulmonary sarcoidosis in whom the chest X-ray is normal.

Serum angiotensin-converting enzyme (ACE) level is raised by two standard deviations above the normal mean value in over 75% of patients with untreated sarcoidosis. Raised (but lower) levels are also seen in patients with lymphoma, pulmonary tuberculosis, asbestosis and silicosis, limiting the diagnostic value of the test. However, the test is useful in assessing disease activity and response to treatment. Reduction of serum ACE during corticosteroid treatment does not, however, imply complete resolution of the disease.

Lung function tests show a restrictive lung defect in patients with pulmonary infiltration or fibrosis. There is a decrease in TLC, FEV₁ and FVC, and gas transfer. Lung function is usually normal in patients who present with extrapulmonary disease or who only have hilar adenopathy on chest X-ray.

Treatment

Both the need to treat and the value of corticosteroid therapy are contested in many aspects of this disease. Hilar lymphadenopathy alone does not require treatment. Persisting infiltration visible on the chest X-ray with normal lung function tests should be monitored carefully. Patients with abnormal lung function tests are unlikely to improve without corticosteroid treatment. If the disease is not improving spontaneously 6 months after diagnosis, treatment should be started with prednisolone 30 mg for 6 weeks, reducing to alternate-day treatment with prednisolone 15 mg for 6–12 months. Although there have been no controlled trials of corticosteroids, they are indicated when there is continuing deterioration of lung function. Eye involvement or persistent hypercalcaemia are mandatory indications for systemic steroids.

If the erythema nodosum of sarcoidosis is severe or persistent it will respond rapidly to a 2-week course of prednisolone 5–15 mg daily, as will patients with uveoparotid fever. Myocardial sarcoidosis and neurological manifestations are also treated with prednisolone.

Prognosis

Sarcoidosis is a much more severe disease in certain racial groups, particularly American blacks, where death rates of up to 10% have been recorded. It is probable that the disease is fatal in fewer than 5% of cases in the UK, either as a result of respiratory failure and cor pulmonale or, more rarely, from myocardial sarcoidosis and renal damage. The initial chest X-ray provides a guide to prognosis. The disease remits within 2 years in over two-thirds of patients with hilar lymphadenopathy alone (stage I), in approximately one-half with hilar lymphadenopathy plus chest X-ray evidence of pulmonary infiltration (stage II), but in only one-third of patients with X-ray evidence of infiltration without any demonstrable lymphadenopathy (stage III). Lung volumes and gas transfer are the most useful way to monitor progression.

Granulomatous lung disease with vasculitis

The classification of pulmonary vasculitis and granulomatous disorders is unsatisfactory. In broad terms there are two main groups: the respiratory manifestations of systemic diseases, and disorders associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCAs).

Anti-neutrophil cytoplasmic antibodies (ANCAs) (see also p. 587) are found in the acute phase of vasculitides, particularly Wegener’s granulomatosis, Churg–Strauss syndrome and microscopic polyangiitis (polyarteritis) associated with neutrophil infiltration of the vessel wall.

Two major ANCA reactivities are recognized: proteinase-3 (PR₃) ANCA and myeloperoxidase (MPO) ANCA.

Some 10–15% cases of progressive glomerulonephritis with anti-glomerular basement membrane (GBM) antibodies Goodpasture’s syndrome (see below) are also MPO-ANCA-positive and these are the most likely to suffer pulmonary haemorrhage.

Wegener’s granulomatosis (granulomatosis with polyangiitis)

This granulomatous disease (see p. 544) of unknown aetiology predominantly affects small arteries. It is characterized by lesions involving the upper respiratory tract, lungs and kidneys. It often starts with severe rhinorrhoea, with subsequent nasal mucosal ulceration followed by cough, haemoptysis and pleuritic pain. Occasionally, the skin and nervous system are involved. Single or multiple nodular masses or pneumonic infiltrates with cavitation are seen on chest X-ray. These appear to migrate, with large lesions clearing in one area and new lesions appearing elsewhere. The typical histological changes are usually best seen on renal biopsy, which shows necrotizing microvascular glomerulonephritis. This disease responds well to treatment with cyclophosphamide 150–200 mg daily. Rituximab is also being used. A variant of Wegener’s granulomatosis called ‘midline granuloma’ affects the nose and paranasal sinuses and is particularly mutilating; it has a poor prognosis.

Churg–Strauss syndrome

This condition classically occurs in males in their 4th decade, who present with rhinitis and asthma, eosinophilia and systemic vasculitis. The aetiology is uncertain, with some believing that it is an unusual progression of allergic disease while others regard it as a primary vasculitis which presents like asthma because of the involvement of eosinophils.

There is an eosinophilic infiltration with a characteristic high blood eosinophil count, vasculitis of small arteries and veins, and extravascular granulomas. Typically, it involves the lungs, peripheral nerves and skin, but renal involvement is uncommon. Transient patchy pneumonia-like shadows may occur, but sometimes these can be massive and bilateral. Skin lesions include tender subcutaneous nodules as well as petechial or purpuric lesions. ANCA is usually positive. The disease responds well to corticosteroids. Occasionally, Churg–Strauss syndrome is revealed when oral steroids are withdrawn in patients being treated for asthma. There is no evidence that anti-asthma drugs precipitate the condition.

Microscopic vasculitis (polyangiitis)

This involves the kidneys and the lungs where it results in recurrent haemoptysis. ANCA is usually positive.

Pulmonary autoimmune rheumatic disease

Rheumatoid disease (see also p. 521)

The lungs can be affected by rheumatoid disease and also by some anti-rheumatic drugs used in its treatment (Fig. 15.39).

Pleural adhesions, thickening and effusions are the most common lesions. The effusion is often unilateral and tends to be chronic. It has a low glucose content but this is not specific.

Figure 15.39 Respiratory manifestations of rheumatoid disease. Many drugs affect the lungs, see text, page 1231.

Several forms of parenchymal disease can occur in patients with rheumatoid arthritis. These include fibrosing alveolitis, rheumatoid nodules, cryptogenic organizing pneumonia, lymphoid interstitial pneumonia and bronchiectasis; other pulmonary problems include pulmonary hypertension and fibrosis (Fig. 15.39). Some patients will have modified presentations because they are already on disease-modifying drugs such as prednisolone or methotrexate for their arthritis.

Fibrosing alveolitis occurring in rheumatoid arthritis can be considered as a variant of the cryptogenic form of the disease (see p. 848). The clinical features and gross appearance are the same but the disease is often more chronic.

Rheumatoid nodules appear on the chest X-ray as single or multiple nodules ranging in size from a few millimetres to a few centimetres. The nodules frequently cavitate. They usually produce no symptoms but can give rise to a pneumothorax or pleural effusion.

Obliterative disease of the small bronchioles is rare. It is characterized by progressive breathlessness and irreversible airflow limitation. Corticosteroids may prevent progression.

Cricoarytenoid joint involvement by rheumatoid arthritis gives rise to dyspnoea, stridor, and hoarseness. Occasionally severe obstruction necessitates tracheostomy.

Caplan’s syndrome is due to a combination of dust inhalation and the disturbed immunity of rheumatoid arthritis. It occurs particularly in coal-worker’s pneumoconiosis but it can occur in individuals exposed to other dusts, such as silica and asbestos. Typically the lesions appear as rounded nodules 0.5–5.0 cm in diameter, though sometimes they become incorporated into large areas of fibrosis that are indistinguishable radiologically from progressive massive fibrosis. There may not be much evidence of simple pneumoconiosis prior to the development of the nodule. These lesions may precede the development of the arthritis. Rheumatoid factor is always present in the serum.

Drugs used in the treatment of rheumatoid arthritis can cause pulmonary problems: e.g. pneumonitis with methotrexate, gold, NSAIDs; fibrosis, with methotrexate; bronchospasm with NSAIDs, aspirin; infections due to corticosteroids, methotrexate; reactivation of tuberculosis with anti-TNF therapy.

FURTHER READING

King TE, Pards A, Selman M. Idiopathic pulmonary fibrosis. Lancet 2011; 378:1949–1961.

Systemic lupus erythematosus (see also p. 536)

The most common respiratory manifestation of this disease is pleurisy, occurring in up to two-thirds of cases, with or without an effusion. Effusions are usually small and bilateral. Basal pneumonitis is often present, perhaps as a result of poor movement of the diaphragm, or restriction of chest movements because of pleural pain. Pneumonia also occurs because of either infection or the disease process itself. In contrast to rheumatoid arthritis, diffuse pulmonary fibrosis is rare.

Systemic sclerosis (see pp.538 and 1218)

Autopsy studies have indicated that there is almost always some diffuse fibrosis of alveolar walls and obliteration of capillaries and the alveolar space. Severe changes result in nodular then streaky shadowing on the chest X-ray, followed by cystic changes, ending up with a honeycomb lung. Lung function tests reveal a restrictive defect and poor gas transfer. Dilation of the oesophagus increases the risk of aspiration pneumonia (see p. 243). Breathlessness may be worsened by restriction of chest wall movement owing to thickening and contraction of the skin and trunk.

Idiopathic interstitial pneumonia (IIP)

A current international classification is shown in Box 15.18. IIP is characterized by diffuse inflammation and fibrosis in the lung parenchyma.

Box 15.18

Classification of idiopathic interstitial pneumonias

Clinical diagnosis	Pathological pattern
Idiopathic pulmonary fibrosis (IPF)	Usual interstitial pneumonia (UIP)
Desquamative interstitial pneumonia (DIP)	Desquamative interstitial pneumonia (DIP)
Respiratory bronchiolitis interstitial lung disease (RBILD)	Respiratory bronchiolitis interstitial lung disease (RBILD)
Acute interstitial pneumonia (AIP)	Diffuse alveolar damage (DAD)
Nonspecific interstitial pneumonia (NSIP)	Nonspecific interstitial pneumonia (NSIP)
Cryptogenic organizing pneumonia (COP)	Organizing pneumonia (OP)
Lymphoid interstitial pneumonia (LIP)	Lymphoid interstitial pneumonia (LIP)

ATS/ERS. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. American Journal of Respiratory and Critical Care Medicine 2002; 165:277.

Idiopathic pulmonary fibrosis (IPF)

This is also known as usual interstitial pneumonia (UIP) and was previously known as cryptogenic fibrosing alveolitis (CFA).

It is relatively rare with a prevalence of about 20/100 000 population, mean onset is in the late 60s and it is more common in males. The cause is unknown but possible contributory factors include cigarette smoking, chronic aspiration, antidepressants, wood and metal dusts and infections, e.g. Epstein–Barr virus.

Pathology

The key features are patchy fibrosis of the interstitium (often with intervening normal lung), subpleural and paraseptal changes, minimal or absent inflammation, acute fibroblastic proliferation and collagen deposition (fibroblastic foci) and honeycombing.

Pathogenesis

Several hypotheses have been proposed but it seems likely that injury results from repeated exogenous and endogenous unknown stimuli. It is now understood that inflammation plays little or no part. Multiple micro-injuries to the alveolar cells cause them to secrete growth factors that recruit fibroblasts in a fibrotic environment. These fibroblasts differentiate into myofibroblasts under the influence of TGF-β, synthesize collagen and aggregate to form ‘fibrotic foci’ (Fig. 15.40). In familial pulmonary fibrosis, several mutations have been identified, suggesting a genetic disposition. Genes over-expressed in IPF include matrix metalloproteinases (MMP1, 7), cyclin A₂ (CLNA₂), α-defensins, surfactant protein A1 and the gene encoding mucinSB (MUCSB). There is an absence of type 1 pneumocytes with a lack of differentiation of type 2 into type 1 pneumocytes resulting in a dysfunctional alveolar epithelium.

Figure 15.40 Pathogenesis of pulmonary fibrosis (see text).

Clinical features

The main features are progressive breathlessness, a non-productive cough and cyanosis, which eventually lead to respiratory failure, pulmonary hypertension and cor pulmonale. Fine bilateral end-inspiratory crackles are heard on auscultation and gross finger clubbing occurs in two-thirds of cases. An acute form known as the Hamman–Rich syndrome occasionally occurs. Various autoimmune diseases are associated with IPF (see also Box 15.17). IPF has also been reported in association with coeliac disease, ulcerative colitis and renal tubular acidosis.

Investigations

Chest X-ray initially shows a ground glass appearance, followed by irregular reticulonodular shadowing (often maximal in the lower zones) and finally a honeycomb lung.

High-resolution CT scan (HRCT) shows characteristic bilateral changes mainly involving the lower lobes (Fig. 15.41). There may be subpleural reticular abnormalities with minimal or no ground glass changes, honeycombing, i.e. thick-walled cysts 0.5–2 cm in diameter in terminal and respiratory bronchioles, and traction bronchiectasis.

Respiratory function tests show a restrictive ventilatory defect – lung volumes are reduced, the FEV₁ to FVC ratio is normal to high (with both values being reduced), and carbon monoxide gas transfer is reduced. Peak flow rates may be normal.

Blood gases show arterial hypoxaemia, caused by a combination of alveolar-capillary block and ventilation–perfusion mismatch with normal or low P_aCO₂ owing to hyperventilation.

Blood tests. Anti-nuclear antibodies and rheumatoid factors are present in one-third of patients. The ESR and immunoglobulins are mildly elevated.

Bronchoalveolar lavage shows increased numbers of cells, particularly neutrophils and macrophages.

Histological confirmation is necessary in some patients. Transbronchial lung biopsy is rarely diagnostic, but can exclude other conditions which present similarly, e.g. sarcoidosis or lymphangitis carcinomatosa. Video-assisted thoracoscopic lung biopsy is used to obtain a larger specimen, which will allow a clear histological diagnosis to be made.

Figure 15.41 CT scan showing idiopathic pulmonary fibrosis with reticular nodular shadowing and a honeycomb appearance.

Differential diagnosis

The diagnosis of IPF is usually made in a patient presenting with the above signs and characteristic HRCT changes. The differential diagnosis of the chest X-ray appearance includes hypersensitivity pneumonitis, bronchiectasis, chronic left heart failure, sarcoidosis, industrial lung disease and lymphangitis carcinomatosa.

Prognosis and treatment

The median survival time for patients with IPF is approximately 5 years, although mortality is very high in the more acute forms. Treatment with prednisolone (30 mg daily) is usually prescribed for disabling disease although it produces little benefit. Azathioprine or cyclophosphamide is added if there is no response. A number of other treatments have been tried. Pirfenidone, an anti-fibrotic anti-inflammatory drug, has reduced lung funtion deterioration in two randomized controlled trials. A tyrosine kinase inhibitor, BIBF1120, has shown the same benefit in a phase II study. Supportive treatment includes domiciliary oxygen therapy. In younger patients with severe disease, lung transplantation is offered.

Desquamative interstitial pneumonia (DIP)

This occurs mainly in middle-aged male smokers and is less severe but similar to usual interstitial pneumonia (UIP). Pathologically there are more mononuclear cells than in UIP, due to smoking (pigmented macrophages). The prognosis is good with corticosteroid therapy.

Respiratory bronchiolitis interstitial lung disease (RBILD)

Clinically, RBILD is like DIP. Pathologically, pigmented macrophages are seen in the lumen of respiratory bronchioles. It has a better prognosis than UIP.

Acute interstitial pneumonia (AIP)

There is a very acute onset of pneumonia, often preceded by an upper respiratory tract infection, and progressive respiratory failure. Diffuse alveolar damage (DAD) is seen on lung biopsy. The prognosis is poor.

Nonspecific interstitial pneumonia (NSIP)

The onset is subacute with a fever in 30%. Men and women are equally affected and finger clubbing does not occur. Biopsy reveals a chronic interstitial pneumonia with mononuclear inflammatory cells and some fibrosis. Prognosis is variable (depending on amount of fibrosis).

Cryptogenic organizing pneumonia (COP)

This condition, previously called bronchiolitis obliterans organizing pneumonia (BOOP), is an organizing pneumonia of unknown aetiology. Typically, patients present with single or recurrent episodes of malaise associated with cough, breathlessness and fever. Pleuritic chest pain is sometimes present but finger clubbing is very rare. Chest X-rays show confluent bilateral parenchymal shadowing. Lung function tests are usually normal but may show a restrictive defect. The white blood count is normal, but the ESR may be raised. The diagnosis is usually made on history and X-ray appearances. Lung biopsy reveals characteristic buds of connective tissue (Masson’s bodies) in respiratory bronchioles and in alveolar ducts. Open biopsy has now been replaced by video-assisted thorascopic lung biopsy. COP responds rapidly to corticosteroid treatment but can recur episodically, especially in older women.

Lymphoid interstitial pneumonia

This condition is more common in children than in adults and is characterized by infiltration with lymphocytes, plasma cells and immunoblasts. It is thought to be a viral pneumonia and causes diffuse reticulonodular infiltrates on the chest X-ray. Corticosteroid therapy appears to be of benefit, as is zidovudine.

Drugs

Drugs causing diffuse parenchymal lung disease are shown on page 854 and in Table 15.22.

Table 15.22 Some drug-induced respiratory reactions

Disease	Drugs
Bronchospasm	Penicillins, cephalosporins
	Sulphonamides
	Aspirin/NSAIDs
	Monoclonal antibodies, e.g. infliximab
	Iodine-containing contrast media
	β-Adrenoceptor-blocking drugs, (e.g. propranolol)
	Non-depolarizing muscle relaxants
	Intravenous thiamine
	Adenosine
Diffuse parenchymal lung disease and/or fibrosis	Amiodarone
	Anakinra (IL-1 receptor antagonist)
	Nitrofurantoin
	Paraquat
	Continuous oxygen
	Cytotoxic agents (many, particularly busulfan, CCNU, bleomycin, methotrexate)
Pulmonary eosinophilia	Antibiotics:
	Penicillin
	Tetracycline
	Sulphonamides, e.g. sulfasalazine
	NSAIDs
	Cytotoxic agents
Acute lung injury	(Paraquat – a weedkiller)
Pulmonary hypertension	Fenfluramine, dexfenfluramine, phentermine
SLE-like syndrome including pulmonary infiltrates, effusions and fibrosis	Hydralazine
	Procainamide
	Isoniazid
	Phenytoin
	ACE inhibitors
	Monoclonal antibodies
Reactivation of tuberculosis	Immunosuppressant drugs, e.g. steroids
Reactivation of tuberculosis	Biological agents, e.g. tumour necrosis factor blockers

CCNU, chloroethyl-cyclohexyl-nitrosourea (lomustine); NSAIDs, non-steroidal anti-inflammatory drugs; SLE, systemic lupus erythematosus.

Other types of diffuse lung disease

Langerhans’ cell histiocytosis (LCH)

This rare disease (prevalence 1/50 000) is characterized histologically by proliferation of Langerhans’ cells, identified by the presence of Birbeck granules on electron microscopy or the CD1a antigen on the surface of the cells. There is a wide variation in clinical presentation, from unifocal bone lesions in older children (which may regress spontaneously), to more disseminated disease in younger children (with a high mortality). Pulmonary LCH occurs almost exclusively in smokers. Chest X-rays (and HRCT) show multiple small cysts (honeycomb lung), fibrosis or widespread nodular shadows. Treatment involves stopping smoking, with regression of disease, corticosteroids and immunosuppressive therapy. For advanced progressive disease, lung transplantation is the only option. Five-year and 10-year survivals are 75% and 65%, respectively.

Goodpasture’s syndrome

This disease (see also p. 585) often starts with symptoms of an upper respiratory tract infection followed by cough and intermittent haemoptysis, tiredness and eventually anaemia, although massive bleeding may occur. The chest X-ray shows transient blotchy shadows that are due to intrapulmonary haemorrhage. These features usually precede the development of an acute glomerulonephritis by several weeks or months. The course of the disease is variable: some patients spontaneously improve while others proceed to renal failure.

The disease usually occurs in individuals over 16 years of age. It is due to a type II cytotoxic reaction driven by antibodies directed against the basement membrane of both kidney and lung. It has been proposed that there is a shared antigen. ANCA may be positive. An association with influenza A₂ virus has been reported.

Treatment is with corticosteroids, but in some cases dramatic improvement has been seen with plasmapheresis to remove the autoantibodies.

Diffuse alveolar haemorrhage

This is clinically similar to Goodpasture’s syndrome, but anti-basement-membrane antibodies are absent and the kidneys are less frequently involved. Most cases occur in children under 7 years of age. The child develops a chronic cough and anaemia. The chest X-ray shows diffuse shadows that are due to intrapulmonary bleeding, and eventually miliary nodulation. Characteristically, haemosiderin-containing macrophages are found in the sputum. There is an association with sensitivity to cow’s milk, and an appropriate diet is usually tried.

The general prognosis is poor but treatment with corticosteroids or azathioprine is usually given.

Lymphangioleiomyomatosis

This is a rare disorder of young women with hamartomatous smooth muscle infiltration of the lungs. Gene mutations in the hamartin–tuberin complex are present; the gene products regulate the activity of rapamycin complex 1. Patients present with dyspnoea, chylous pleural effusions, haemoptysis and pneumothorax. Treatment with hormones/oophorectomy has shown little benefit. Sirolimus (rapamycin) treatment has shown benefit.

Pulmonary alveolar proteinosis

This is a rare disease in which there is accumulation of lipoproteinaceous material within the alveoli. It can be congenital, but most cases are acquired and appear to have an autoimmune basis, with antibodies directed against the cytokine GM-CSF. The disease mostly affects men and presents with progressive exertional dyspnoea and cough. Inspiratory crackles are present in only about 50%. Diagnosis is made by bronchial lavage, which reveals a milky appearance and many large, foamy macrophages but few other inflammatory cells.

FURTHER READING

Chen M, Kallenberg CG. ANCA-associated vasculitides–advances in pathogenesis and treatment. Nat Rev Rheumatol 2010; 6:653–664.

Danoff SK, Terry PB, Horton MR. A clinician’s guide to the diagnosis and treatment of interstitial lung disease. South Med J 2007; 100:579–587.

King TE. Clinical advances in the diagnosis and therapy of interstitial lung disease. Am J Respir Crit Care Med 2005; 172:268–279.

Tazi A. Adult pulmonary Langerhans’ cell histiocytosis. Eur Respir J 2006; 27:1272–1285.

Pulmonary infiltration with eosinophilia

The common types and characteristics of these diseases are shown in Table 15.23. They range from very mild, simple, pulmonary eosinophilias to the often fatal hypereosinophilic syndrome.

Table 15.23 Common types and characteristics of pulmonary infiltration with eosinophilia

Simple and prolonged pulmonary eosinophilia

Simple pulmonary eosinophilia is a relatively mild illness with a slight fever and cough and usually lasts for less than 2 weeks. Occasionally, the disease becomes more prolonged, with a high fever lasting for over a month. There is usually an eosinophilia in the blood and this condition is then called prolonged pulmonary eosinophilia. In both conditions the chest X-ray shows either localized or diffuse opacities. The simple form is probably due to a transient allergic reaction in the alveoli. Many allergens have been implicated, including Ascaris lumbricoides, Ankylostoma, Trichuris, Trichinella, Taenia and Strongyloides. Drugs such as aspirin, penicillin, nitrofurantoin and sulphonamides have been implicated. Often, no allergen is identified. The disease is self-limiting and no treatment is required, apart from treating the cause. In the more chronic form all unnecessary treatment should be withdrawn and, where appropriate, worms are treated. Corticosteroid therapy is indicated, with resolution of the disease over the ensuing weeks.

Asthmatic bronchopulmonary eosinophilia

This is characterized by the presence of asthma, transient fleeting shadows on the chest X-ray, and blood or sputum eosinophilia. By far the most common cause worldwide is allergy to A. fumigatus (see below), although Candida albicans and other mycoses may be the allergen in a small number of patients. In many, no allergen can be identified. Whether these cases are intrinsic or driven by an unidentified extrinsic factor is uncertain.

Diseases caused by Aspergillus fumigatus

The various types of lung disease caused by A. fumigatus are illustrated in Figure 15.42.

Figure 15.42 Diseases caused by Aspergillus fumigatus. Allergic aspergillosis (initial and later) and three other forms.

The spores of A. fumigatus (diameter 5 mm) are readily inhaled and are present in the atmosphere throughout the year, though they are at their highest concentration in the late autumn. They can be grown from the sputum in up to 15% of patients with chronic lung disease in whom they do not produce disease. They are a cause of extrinsic asthma in atopic individuals.

Allergic bronchopulmonary aspergillosis (asthmatic pulmonary eosinophilia)

This rare disease is caused by a hypersensitivity reaction when the bronchi are colonized by Aspergillus. It can complicate asthma and cystic fibrosis. Proximal bronchiectasis occurs.

Clinical features. There are episodes of eosinophilic pneumonia throughout the year, particularly in late autumn and winter. The episodes present with a wheeze, cough, fever and malaise. They are associated with expectoration of firm sputum plugs containing the fungal mycelium, which results in the clearing of the pulmonary infiltrates on the chest X-ray. Occasionally large mucus plugs obliterate the bronchial lumen, causing collapse of the lung.

Left untreated, repeated episodes of eosinophilic pneumonia can result in progressive pulmonary fibrosis that usually affects the upper zones and can give rise to a chest X-ray appearance similar to that produced by tuberculosis.

Investigations. The peripheral blood eosinophil count is usually raised, and total levels of IgE are usually extremely high, at >1000 ng/mL (both that specific to Aspergillus and nonspecific). Skin-prick testing to protein allergens from A. fumigatus gives rise to positive immediate skin tests. Sputum may show eosinophils and mycelia. Precipitating antibodies in the serum are usually, but not always, found in the serum.

Lung function tests show a decrease in lung volumes and gas transfer in more chronic cases, but there is evidence of reversible airflow limitation in all cases.

Treatment is with prednisolone 30 mg daily, which causes rapid clearing of the pulmonary infiltrates. Frequent episodes of the disease can be prevented by long-term treatment with prednisolone, but doses of 10–15 mg daily are usually required. Antifungal agents (itraconazole, voriconazole) should be used in patients on high doses of steroids; there is evidence that treatment with itraconazole improves pulmonary function. The asthma component responds to inhaled corticosteroids, although these do not influence the occurrence of pulmonary infiltrates. Omalizumab, a humanized monoclonal antibody against IgE, is being trialled.

FURTHER READING

Zmeili OS, Soubani AO. Pulmonary aspergillosis – update. Quarterly Journal of Medicine 2007; 100:317–334.

Aspergilloma and invasive aspergillosis

Aspergilloma is the growth of A. fumigatus within previously damaged lung tissue where it forms a ball of mycelium within lung cavities. Typically the chest X-ray shows a round lesion with an air ‘halo’ above it. Continuing antigenic stimulation gives rise to large quantities of precipitating antibody in the serum. The aspergilloma itself causes little trouble, though occasionally massive haemoptysis may occur, requiring resection of the area of damaged lung containing the aspergilloma. The antifungal agent voriconazole is the drug of choice. Amphotericin is used if patients are intolerant of voriconazole. Invasive aspergillosis is a well-recognized complication of immunosuppression and requires aggressive antifungal therapy; immunosuppression should be reduced if possible.

Tropical pulmonary eosinophilia

This term is reserved for an allergic reaction to microfilaria from Wuchereria bancrofti. The condition is seen in the Indian subcontinent and presents with cough and wheeze together with fever, lassitude and weight loss. The typical appearance of the chest X-ray is of bilateral hazy mottling that is often uniformly distributed in both lung fields. Individual shadows may be as large as 5 mm or may become more confluent, giving the appearance of pneumonia.

The disease is characterized by a very high eosinophil count in peripheral blood. The filarial complement fixation test is positive in almost every case, although the microfilaria are seldom found. The treatment of choice is diethylcarbamazine (see p. 154 for details).

The hypereosinophilic syndrome

This disease is characterized by eosinophilic infiltration in various organs, sometimes associated with an eosinophilic arteritis. The heart muscle is particularly involved, but pulmonary involvement in the form of a pleural effusion or interstitial lung disease occurs in about 40% of cases. Typical features are fever, weight loss, recurrent abdominal pain, persistent non-productive cough and congestive cardiac failure. Corticosteroid treatment may be of value in some cases.

Hypersensitivity pneumonitis

In this disease there is a widespread diffuse inflammatory reaction in both the small airways of the lung and the alveoli. It is due to the inhalation of a number of different antigens, the most common being microbial spores contaminating vegetable matter (e.g. straw, hay, mushroom compost). Some examples are illustrated in Table 15.24. By far the most common of these diseases worldwide is farmer’s lung, which affects up to 1 in 10 of the farming community in disadvantaged, wet communities around the world. Cigarette smokers have a lower risk of developing the disease due to decreased antibody reaction to the antigen.

Table 15.24 Hypersensitivity pneumonitis – some causes

Disease	Situation	Antigens
Farmer’s lung	Forking mouldy hay or any other mouldy vegetable material	Thermophilic actinomycetes, e.g. Micropolyspora faeni
Farmer’s lung	Forking mouldy hay or any other mouldy vegetable material	Fungi, e.g. Aspergillus umbrasus
Bird fancier’s lung	Handling pigeons, cleaning lofts or budgerigar cages	Proteins present in the ‘bloom’ on the feathers and in excreta
Maltworker’s lung	Turning germinating barley	Aspergillus clavatus
Humidifier fever	Contaminated humidifying systems in air conditioners or humidifiers in factories (especially in printing works)	Possibly a variety of bacteria or amoeba (e.g. Naegleria gruberi)
Humidifier fever		Thermoactinomyces
Mushroom workers	Turning mushroom compost	Thermophilic actinomycetes
Cheese washer’s lung	Mouldy cheese	Penicillin casei
Cheese washer’s lung	Mouldy cheese	Aspergillus clavatus
Winemaker’s lung	Mould on grapes	Botrytis

Pathogenesis

Histologically there is an initial infiltration of the small airways and alveolar walls with neutrophils followed by T lymphocytes and macrophages, leading to the development of small non-caseating granulomas. These comprise multinucleated giant cells, occasionally containing the inhaled antigenic material. The allergic response to the inhaled antigens involves both cellular immunity and the deposition of immune complexes causing foci of inflammation through the activation of complement via the classical pathway. Some of the inhalant materials may also lead to inflammation by directly activating the alternative complement pathway. These mechanisms attract and activate alveolar and interstitial macrophages, so that continued antigenic exposure results in the progressive development of pulmonary fibrosis.

Clinical features

Typically fever, malaise, cough and shortness of breath come on several hours after exposure to the causative antigen. Thus, a farmer forking hay in the morning may notice symptoms during the late afternoon and evening with resolution by the following morning. On examination, the patient may have a fever, tachypnoea, and coarse end-inspiratory crackles and wheezes throughout the chest. Cyanosis caused by ventilation–perfusion mismatch may be severe even at rest. Continued exposure leads to a chronic illness characterized by severe weight loss, effort dyspnoea and cough as well as the features of idiopathic pulmonary fibrosis (see p. 848).

Investigations

Chest X-ray shows fluffy nodular shadowing with the subsequent development of streaky shadows, particularly in the upper zones. In very advanced cases, honeycomb lung occurs.

High-resolution CT shows reticular and nodular changes with ground glass opacity, which can be further categorized with multislice CT.

Lung function tests show a restrictive ventilatory defect with a decrease in carbon monoxide gas transfer.

Polymorphonuclear leucocyte count is raised in acute cases. Eosinophilia is not a feature.

Precipitating antibodies are present in the serum. One-quarter of pigeon fanciers have precipitating IgG antibodies against pigeon protein and droppings in their serum, but only a small proportion have lung disease. Precipitating antibodies are evidence of exposure, not disease.

Bronchoalveolar lavage shows increased T lymphocytes and granulocytes.

Differential diagnosis

Although hypersensitivity pneumonitis due to inhalation of the spores of Micropolyspora faeni is common among farmers, it is probably more common for these individuals to suffer from asthma related to inhalation of antigens from a variety of mites that infest stored grain and other vegetable material. These include Lepidoglyphus domesticus, L. destructor and Acarus siro. Symptoms of asthma resulting from inhalation of these allergens are often mistaken for farmer’s lung. Lung function tests will effectively discriminate between the disorders. Pigeon fancier’s lung is quite common, but alveolitis from budgerigars, parrots and parakeets is very rare.

Management

Prevention is the aim. This can be achieved by changes in work practice, with the use of silage for animal fodder and the drier storage of hay and grain. Pigeon fancier’s lung is more difficult to control since affected individuals remain strongly attached to their hobby. Prednisolone, initially in large doses of 30–60 mg daily, may achieve regression during the early stages of the disease. Established fibrosis will not resolve and in some patients the disease may progress inexorably to respiratory failure in spite of intensive therapy. Farmer’s lung is a recognized occupational disease in the UK and sufferers are entitled to compensation, depending upon their degree of disability.

Humidifier fever

Humidifier fever (Table 15.24), one cause of building-related illnesses (p. 936), may present with the typical features of hypersensitivity pneumonitis without any radiographic changes. This disease has occurred in outbreaks in factories in the UK, particularly in printing works. In North America it is more commonly found in office blocks with contaminated air-conditioning systems. Humidifier fever may be effectively prevented by sterilization of the re-circulating water used in large humidifying plants.

Drug and radiation-induced respiratory reactions

Drugs may produce a wide variety of disorders of the respiratory tract (Table 15.22). The mechanisms are varied and include direct toxicity (e.g. bleomycin), immune complex formation with arteritis, hypersensitivity (involving both T cell and IgE mechanisms) and autoimmunity. Tuberculosis reactivation is seen with immunosuppressive drugs.

Pulmonary infiltrates with fibrosis may result from the use of a number of cytotoxic drugs used in the treatment of cancer. The most common cause of these reactions is bleomycin. The pulmonary damage is dose-related, occurring when the total dosage is >450 mg, but will regress in some cases if the drug is stopped. The most sensitive test is a decrease in carbon monoxide gas transfer, and therefore gas transfer should be measured repeatedly during treatment with the drug. The use of corticosteroids may help resolution. Drugs affecting the respiratory system are shown in Table 15.22, together with the types of reaction they produce. Anaphylaxis with bronchospasm can occur with many drugs. The list is not exhaustive; e.g. over 20 different drugs are known to produce a systemic lupus erythematosus-like syndrome, sometimes complicated by pulmonary infiltrates and fibrosis. Paraquat ingestion causes severe pulmonary oedema and death, and pulmonary fibrosis develops in many of the few who survive.

Irradiation of the lung during radiotherapy can cause a radiation pneumonitis. Patients complain of breathlessness and a dry cough. Radiation pneumonitis results in a restrictive lung defect. Corticosteroids should be given in the acute stage.

Occupational lung disease

Exposure to dusts, gases, vapours and fumes at work can cause several different types of lung disease:

Acute bronchitis and even pulmonary oedema from irritants such as sulphur dioxide, chlorine, ammonia or the oxides of nitrogen

Pulmonary fibrosis due to mineral dust

Occupational asthma (see Table 15.13) – this is now the commonest industrial lung disease in the developed world

Hypersensitivity pneumonitis (see Table 15.24)

Bronchial carcinoma due to industrial agents (e.g. asbestos, polycyclic hydrocarbons, radon in mines).

The degree of fibrosis that follows inhalation of mineral dust varies. While iron (siderosis), barium (baritosis) and tin (stannosis) lead to dramatic dense nodular shadowing on the chest X-ray, their effect on lung function and symptoms is minimal. In contrast, exposure to silica or asbestos leads to extensive fibrosis and disability. Coal dust has an intermediate fibrogenic effect and used to account for 90% of all compensated industrial lung diseases in the UK. The term ‘pneumoconiosis’ means the accumulation of dust in the lungs and the reaction of the tissue to its presence. The term is not wide enough to encompass all occupational lung disease and is now generally used only in relation to coal dust and its effects on the lung.

Coal-worker’s pneumoconiosis

The disease is caused by dust particles approximately 2–5 µm in diameter that are retained in the small airways and alveoli of the lung. The incidence of the disease is related to total dust exposure, which is highest at the coal face, particularly if ventilation and dust suppression are poor. Improved ventilation and working conditions have reduced the risk of this disease.

Two very different syndromes result from the inhalation of coal.

Simple pneumoconiosis

This simply reflects the deposition of coal dust in the lung. It produces fine micronodular shadowing on the chest X-ray and is by far the most common type of pneumoconiosis. It is graded on the chest X-ray appearance according to standard categories set by the International Labour Office (see below). Considerable dispute remains about the effects of simple pneumoconiosis on respiratory function and symptoms. In many cases, the symptoms are due to COPD related to cigarette smoking, but this is not always the case. Changes to UK workers’ compensation legislation means that coal miners who develop COPD are compensated for their disability regardless of their chest X-ray appearance.

Categories of simple pneumoconiosis are as follows:

1. Small round opacities definitely present but few in number

2. Small round opacities numerous but normal lung markings still visible

3. Small round opacities very numerous and normal lung markings partly or totally obscured.

Simple pneumoconiosis can progress to the development of progressive massive fibrosis (PMF) (see below). PMF virtually never occurs on a background of category 1 simple pneumoconiosis but occurs in about 7% of those with category 2 and in 30% of those with category 3. Miners with category 1 pneumoconiosis are unlikely to receive compensation unless they also have evidence of COPD. Those with more extensive radiographic changes are compensated solely on the basis of their X-ray appearances.

Progressive massive fibrosis

In PMF, patients develop round fibrotic masses several centimetres in diameter, almost invariably in the upper lobes and sometimes having necrotic central cavities. The pathogenesis of PMF is still not understood, though it seems clear that some fibrogenic promoting factor is present in individuals developing the disease, leading to the formation of immune complexes, analogous to the development of large fibrotic nodules in coal miners with rheumatoid arthritis (Caplan’s syndrome). Rheumatoid factor and anti-nuclear antibodies are both often present in the serum of patients with PMF, and also in those suffering from asbestosis or silicosis. Pathologically there is apical destruction and disruption of the lung, resulting in emphysema and airway damage. Lung function tests show a mixed restrictive and obstructive ventilatory defect with loss of lung volume, irreversible airflow limitation and reduced gas transfer.

The patient with PMF suffers considerable effort dyspnoea, usually with a cough. The sputum may be black. The disease can progress (or even develop) after exposure to coal dust has ceased and may lead to respiratory failure.

Silicosis

This disease is uncommon though it may still be encountered in stonemasons, sand-blasters, pottery and ceramic workers and foundry workers involved in fettling (removing sand from metal castings made in sand-filled moulds). Silicosis is caused by the inhalation of silica (silicon dioxide). This dust is highly fibrogenic. For example, a coal miner can remain healthy with 30 g of coal dust in his lungs but 3 g of silica is sufficient to kill. Silica seems particularly toxic to alveolar macrophages and readily initiates fibrogenesis (see Fig. 15.40). The chest X-ray appearances and clinical features of silicosis are similar to those of PMF, but distinctive thin streaks of calcification may be seen around the hilar lymph nodes (‘eggshell’ calcification).

Asbestos

Asbestos is a mixture of silicates of iron, magnesium, nickel, cadmium and aluminium, and has the unique property of occurring naturally as a fibre. It is remarkably resistant to heat, acid and alkali, and has been widely used for roofing, insulation and fireproofing. Asbestos has been mined in southern Africa, Canada, Australia and Eastern Europe. Several different types of asbestos are recognized: about 90% of asbestos is chrysotile, 6% crocidolite and 4% amosite. Chrysotile or white asbestos is the softest asbestos fibre. Each fibre is often as long as 2 cm but only a few microns thick. It is less fibrogenic than crocidolite.

Crocidolite (blue asbestos) is particularly resistant to chemical destruction and exists in straight fibres up to 50 mm in length and 1–2 µm in width. Crocidolite is the type of asbestos most likely to produce asbestosis and mesothelioma. This may be due to the fact that it is readily trapped in the lung. Its long, thin shape means that it can be inhaled, but subsequent rotation against the long axis of the smaller airways, particularly in turbulent airflow during expiration, causes the fibres to impact. Crocidolite is also particularly resistant to macrophage and neutrophil enzymatic destruction.

Exposure to asbestos occurred particularly in shipbuilding yards and in power stations, but it was used so widely that low levels of exposure were very common. Up to 50% of city dwellers have asbestos bodies (asbestos fibres covered in protein secretions) in their lungs at post mortem. Regulations in the UK prohibit the use of crocidolite and severely restrict the use of chrysotile. Careful dust control measures are enforced, which should eventually abolish the problem. Workers continue to be exposed to blue asbestos in the course of demolition or in the replacement of insulation, and it should be remembered that there is a considerable time lag between exposure and development of disease, particularly mesothelioma (20–40 years).

The risk of primary lung cancer (usually adenocarcinoma) is increased in people exposed to asbestos, even in non-smokers. This risk is about 5–7-fold greater in those who have parenchymal asbestosis and about 1.5-fold in those with pleural plaques without parenchymal fibrosis. A synergistic relationship exists between asbestosis and cigarette smoking with the risk of bronchial carcinoma multiplied about five-fold above the risk attributable to smoking alone.

Diseases caused by asbestos are summarized in Table 15.25. Bilateral diffuse pleural thickening, asbestosis, mesothelioma and asbestos-related carcinoma of the bronchus are all eligible for industrial injuries benefit in the UK.

Table 15.25 The effects of asbestos on the lung

Asbestosis

Asbestosis is defined as fibrosis of the lungs caused by asbestos dust, which may or may not be associated with fibrosis of the parietal or visceral layers of the pleura. It is a progressive disease characterized by breathlessness and accompanied by finger clubbing and bilateral basal end-inspiratory crackles. Minor degrees of fibrosis that are not seen on chest X-ray are often revealed on high-resolution CT scan. No treatment is known to alter the progress of the disease, though corticosteroids are often prescribed.

FURTHER READING

Lin RT, Takahashi K, Karjalainen A et al. Ecological association between asbestos-related diseases and historical asbestos consumption. Lancet 2007; 369:844–849.

Mesothelioma

The number of cases of mesothelioma has increased progressively since the mid-1980s and has now reached 2100 deaths/year in the UK, which has the highest per capita death rate from this condition. Rates of mesothelioma in the UK are expected to peak around 2020 at about 2300/year. The most common presentation of mesothelioma is a pleural effusion, typically with persistent chest wall pain, which should raise the index of suspicion even if the initial pleural fluid or biopsy samples are non-diagnostic. Video-assisted thoracoscopic lung biopsy is often needed to obtain sufficient tissue for diagnosis. Some early promise is emerging from clinical trials of chemotherapy, sometimes combined with surgery, but the outlook for most patients remains very limited.

Byssinosis

This disease occurs worldwide but is declining rapidly in areas where the number of people employed in cotton mills is falling. Typically symptoms start on the first day back at work after a break (Monday sickness), with improvement as the week progresses. Tightness in the chest, cough and breathlessness occur within the first hour in dusty areas of the mill, particularly in the blowing and carding rooms where raw cotton is cleaned and the fibres are straightened.

The exact nature of the disease and its aetiology remain disputed. Pure cotton does not cause the disease, and cotton dust has some effect on airflow limitation in all those exposed. Individuals with asthma are particularly badly affected by exposure to cotton dust. The most likely aetiology is endotoxins from bacteria present in the raw cotton causing constriction of the airways of the lung. There are no changes on the chest X-ray and there is considerable dispute as to whether the progressive airflow limitation seen in some patients with the disease is due to cotton dust or to other factors such as cigarette smoking or co-existent asthma.

Berylliosis

Beryllium-copper alloy has a high tensile strength and is resistant to metal fatigue, high temperature and corrosion. It is used in the aerospace industry, in atomic reactors and in many electrical devices.

When beryllium is inhaled, it can cause a systemic illness with a clinical picture similar to sarcoidosis. Clinically there is progressive dyspnoea with pulmonary fibrosis. However, strict control of levels in the working atmosphere has made this disease a rarity.

Tumours of the respiratory tract

Malignant tumours

Bronchial carcinoma

Bronchial carcinoma is the most common malignant tumour worldwide, with around 1.4 million deaths annually.

It is the third most common cause of death in the UK after ischaemic heart disease and cerebrovascular disease and is now the commonest cause of cancer-related death in both men and women.

Rates are declining in men but still increasing overall reflecting increasing incidence in women.

The ratio in men-to-women is now 1.2 : 1.

Cigarette smoking (including passive smoke exposure) accounts for >90% of lung cancer. There remains a higher incidence of bronchial carcinoma in urban compared with rural areas, even when allowance is made for cigarette smoking. Other aetiological factors include:

Environmental: radon exposure, asbestos, polycyclic aromatic hydrocarbons and ionizing radiation. Occupational exposure to arsenic, chromium, nickel, petroleum products and oils

Host factors: pre-existing lung disease such as pulmonary fibrosis; HIV infection; genetic factors.

Legislative control over smoking in public places in many parts of the world has been introduced to reduce ill health related to cigarette smoke.

Pathophysiology

Historically, lung cancers are broadly divided into small cell carcinoma and non-small cell carcinoma based upon the histological appearances of the cells seen within the tumour. This distinction is necessary with respect to the behaviour of the tumour, providing prognostic information and determining best treatment. Non-small cell carcinoma is further divided into a number of cell types (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, large cell neuroendocrine (see Table 15.26).

Table 15.26 Lung cancer cell types and clinical features

Cell type	Incidence in UK (%)	Features
Squamous cell carcinoma	35	Remains the most common cell type in Europe
		Arises from epithelial cells, associated with production of keratin
		Occasionally cavitates with central necrosis
		Causes obstructing lesions of bronchus with post-obstructive infection
		Local spread common, metastasizes relatively late
Adenocarcinoma	27–30	Likely to become the most common cell type in the UK in the near future (most common cell type in the USA)
		Increasing incidence over last 10 years possibly linked to low tar cigarettes
		Originate from mucus-secreting glandular cells
		Most common cell type in non-smokers
		Often causes peripheral lesions on chest X-ray/CT
		Subtypes include bronchoalveolar cell carcinoma (associated with copious mucus secretion, multifocal disease)
		Metastases common: pleura, lymph nodes, brain, bones, adrenal glands
Large cell carcinoma	10–15	Often poorly-differentiated
Large cell carcinoma	10–15	Metastasize relatively early
Small cell carcinoma	20	Arise from neuroendocrine cells (APUD cells)
		Often secrete polypeptide hormones
		Often arise centrally and metastasize early

Clinical features

The presentation and clinical course vary between the different cell types (Table 15.26). Symptoms and signs may vary depending on the extent and site of disease.

Common presenting features can be divided into those caused by direct/local tumour effects, metastatic spread and non-metastatic extrapulmonary features.

Local effects

Cough: this is the most commonly encountered symptom in lung cancer. Because evidence suggests this symptom is neglected by both patients and healthcare professionals, campaigns in the UK have highlighted the ‘three week cough’ as a symptom that merits a chest X-ray.

Breathlessness: central tumours occlude large airways resulting in lung collapse and breathlessness on exertion. Many patients with lung cancer have co-existent COPD which is also a cause of breathlessness.

Haemoptysis: coughing up fresh or old blood due to tumour bleeding into an airway.

Chest pain: peripheral tumours invade the chest wall or pleura (both well innervated), resulting in sharp pleuritic pain. Large volume mediastinal nodal disease often results in a characteristic dull central chest ache.

Wheeze: monophonic when due to partial obstruction of an airway by tumour.

Hoarse voice: mediastinal nodal or direct tumour invasion of the mediastinum results in compression of the left recurrent laryngeal nerve.

Nerve compression: Pancoast tumours in the apex of the lung invade the brachial plexus causing C8/T1 palsy with small muscle wasting in the hand and weakness as well as pain radiating down the arm. An associated Horner’s syndrome due to compression of the sympathetic chain with classic features of miosis, ptosis and anhidrosis also occurs.

Recurrent infections: tumour causing partial obstruction of an airway results in post-obstructive pneumonia.

Bronchial carcinoma can also directly invade the phrenic nerve, causing paralysis of the ipsilateral hemidiaphragm. It can involve the oesophagus, producing progressive dysphagia, and the pericardium, resulting in pericardial effusion and malignant dysrhythmias.

Superior vena caval obstruction: see p. 449.

Tracheal tumours present with progressive dyspnoea and stridor. Flow volume curves show dramatic reductions in inspiratory flow (see Fig. 15.7c).

FURTHER READING

Goldstraw P et al. Non-small cell lung cancer. Lancet 2011; 378:1727–1740.

Van Meerbeeck JP et al. Small cell lung cancer. Lancet 2011; 378:1741–1755.

Metastatic spread

Bronchial carcinoma commonly spreads to mediastinal, cervical and even axillary or intra-abdominal nodes. In addition, the liver, adrenal glands, bones, brain and skin are frequent sites for metastases:

Liver: common symptoms are anorexia, nausea and weight loss. Right upper quadrant pain radiating across the abdomen is associated with liver capsular pain.

Bone: bony pain and pathological fractures as a result of tumour spread occur. If the spine is involved, there is a risk of spinal cord compression, which requires urgent treatment.

Adrenal glands: metastases to the adrenals do not usually result in adrenal insufficiency and are usually asymptomatic.

Brain: metastases present as space-occupying lesions with subsequent mass effect and signs of raised intracranial pressure. Less common presentations include carcinomatous meningitis with cranial nerve defects, headache and confusion.

Malignant pleural effusion: this presents with breathlessness and is commonly associated with pleuritic pain.

Non-metastatic extrapulmonary manifestations of bronchial carcinoma (Table 15.27)

Minor haematological extrapulmonary manifestations of lung cancer such as normocytic anaemia and thrombocytosis are reasonably common. Apart from finger clubbing and HPOA, most other non-metastatic complications are relatively rare. Approximately 10% of small cell tumours produce ectopic hormones giving rise to paraneoplastic syndromes (see Box 9.2).

Table 15.27 Non-metastatic extrapulmonary manifestations of bronchial carcinoma (percentage of all cases)

Metabolic (universal at some stage)

Loss of weight

Lassitude

Anorexia

Endocrine (10%) (usually small cell carcinoma)

Ectopic adrenocorticotrophin syndrome

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

Hypercalcaemia (usually squamous cell carcinoma)

Rarer: hypoglycaemia, thyrotoxicosis, gynaecomastia

Neurological (2–16%)

Encephalopathies – including subacute cerebellar degeneration

Myelopathies – motor neurone disease

Neuropathies – peripheral sensorimotor neuropathy

Muscular disorders – polymyopathy, myasthenic syndrome (Eaton–Lambert syndrome)

Vascular and haematological (rare)

Thrombophlebitis migrans

Non-bacterial thrombotic endocarditis

Microcytic and normocytic anaemia

Disseminated intravascular coagulopathy

Thrombotic thrombocytopenic purpura

Haemolytic anaemia

Skeletal

Clubbing (30%)

Hypertrophic osteoarthropathy (± gynaecomastia) (3%)

Cutaneous (rare)

Dermatomyositis

Acanthosis nigricans

Herpes zoster

Investigations

Investigations are necessary:

to stage the extent of disease

to make a tissue diagnosis (differentiate small cell from non-small cell lung cancer (NSCLC) as well as to detail the cell type in NSCLC – increasingly relevant with newer targeted biological agents) and

to assess fitness to undergo treatment.

Staging and diagnosis

Chest X-ray

Plain chest radiographs show obvious evidence of lung cancer or nonspecific appearances (Box 15.19). In some cases, the initial radiograph is normal, either because the lesion is small, or the disease is confined to central structures.

Box 15.19

Lung cancer presentations on a chest X-ray


Mass lesion	Pleural effusion	Mediastinal widening or hilar adenopathy
Lesions visible if greater than 1 cm diameter. Spiculate, cavitating or smooth edged. Often an incidental finding, usually asymptomatic if small. By the time symptoms are present, chest X-ray almost always abnormal	Usually unilateral; commonly large, which can cause obscuration of an underlying mass or pleural tumour. Mesothelioma is a differential diagnosis	Lymphadenopathy evident on the plain film, manifested by splayed carina, hilar enlargement or paratracheal shadowing

Slow resolving consolidation	Collapse	Reticular shadowing
Tumour causes partial obstruction of a bronchus. This results in retention of secretions, bacterial overgrowth and subsequent infection. (Persistent right upper lobe consolidation due to tumour in right upper lobe.)	Endoluminal tumour causes complete collapse of a lung and associated mediastinal shift, or collapse of a lobe or segment resulting in volume loss on the affected side with raised hemidiaphragm/deviated trachea	Carcinoma spreads through the lymphatic channels of the lung to give rise to lymphangitis carcinomatosa; in bronchial carcinoma this is usually unilateral and associated with striking dyspnoea. Bilateral lymphangitis should prompt investigation for a primary site other then lung, such as breast, stomach or colon
	Normal
	A normal film does not rule out an underlying tumour. A minority of tumours are confined to the central airways and mediastinum without obvious change on the plain chest X-ray. Although investigation of isolated haemoptysis with a normal chest X-ray is often negative, a normal chest X-ray should not deter from further investigation, especially in smokers over the age of 40 years

Computed tomography

CT indicates the extent of disease. Imaging should include the liver and adrenal glands which are common sites for metastases. The International Association for the Study of Lung Cancer (IASLC) has devised the most widely used staging definitions which are based upon CT imaging of tumour size (T), nodal involvement (N) and metastases (M) along with prognostic data. These have been recently updated based upon an extensive review of survival in over 80 000 patients (Table 15.28).

Table 15.28 TNM staging system for lung cancer

T – primary tumour
TX	Primary tumour cannot be assessed, or tumour proven by the presence of malignant cells in sputum or bronchial washings, but not visualized by imaging or bronchoscopy
T0	No evidence of primary tumour
Tis	Carcinoma in situ
T1	Tumour ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e. not in the main bronchus)
T1a	Tumour ≤2 cm in greatest dimension
T1b	Tumour >2 cm but not more than 3 cm in greatest dimension
T2	Tumour >3 cm but not more than 7 cm; or tumour with any of the following features:
	Involves main bronchus, 2 cm or more distal to the carina
	Invades visceral pleura
	Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung
T2a	Tumour >3 cm but not more than 5 cm in greatest dimension
T2b	Tumour >5 cm but not more than 7 cm in greatest dimension
T3	Tumour >7 cm or one that directly invades any of the following: chest wall (including superior sulcus tumours), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumour in the main bronchus <2 cm distal to the carina but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumour nodule(s) in the same lobe as the primary.
T4	Tumour of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina; separate tumour nodule(s) in a different ipsilateral lobe to that of the primary.
N – regional lymph nodes
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension
N2	Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3	Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)
M – distant metastasis
M0	No distant metastasis
M1	Distant metastasis
M1a	Separate tumour nodule(s) in a contralateral lobe; tumour with pleural nodules or malignant pleural or pericardial effusion
M1b	Distant metastasis
The resultant stage groupings are:
Occult carcinoma	TX, N0, M0
Stage 0	TisN0M0
Stage IA	T1a,bN0M0
Stage IB	T2aN0M0
Stage IIA	T2bN0M0; T1a,bN1M0; T2aN1M0
Stage IIB	T2bN1M0; T3N0M0
Stage IIIA	T1a,b, T2a,b, N2M0; T3N1, N2M0; T4N0, N1M0
Stage IIIB	T4N2M0; any T N3M0
Stage IV	Any T any NM1

Adapted from: Goldstraw P, Crowley J, Chansky K et al.; International Association for the Study of Lung Cancer International Staging Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (7th) edition of the TNM Classification of malignant tumours. Journal of Thoracic Oncology 2007; 2(8):706–714. Erratum in: Journal of Thoracic Oncology 2007; 2(10):985.

Using CT criteria, lymph nodes that are less than 1 cm in diameter are not classed as being enlarged, yet they can still contain malignant cells. With increasing size, the positive predictive value of CT in detecting malignant nodes increases; however, it cannot be assumed that enlarged nodes are definitely malignant and further staging tests should be performed if there are no distant metastases and the primary tumour is thought to be eligible for curative treatment. These tests would include direct sampling of affected nodes and positron emission tomography to assess for distant spread of cancer.

Positron emission tomography (PET) imaging/CT

This is the investigation of choice for characterizing extent of mediastinal nodal involvement and highlighting distant metastases either not visualized or indeterminate on CT (see p. 797). Most commonly, PET images are combined with CT for best correlation. Negative predictive value is high but a positive node on PET-CT should prompt sampling for confirmation of presence of malignant cells as the positive predictive value is relatively low.

Other imaging modalities

MRI is not useful for the diagnosis of primary lung tumours other than in Pancoast tumours with nerve invasion or when assessing for chest wall involvement prior to surgery.

Fibreoptic bronchoscopy (see also this chapter, Fig. 15.43)

This technique is used to define the bronchial anatomy and to obtain biopsy and cytological specimens. If the carcinoma involves the first 2 cm of either main bronchus, the tumour is inoperable as there would be insufficient resection margins for pneumonectomy. Widening and loss of the sharp angle of the carina indicates the presence of enlarged subcarinal lymph nodes, either malignant or reactive. These can be biopsied ‘blind’ by passage of a needle through the bronchial wall.

Figure 15.43 Bronchoscopic view of a bronchial carcinoma obstructing a large bronchus.

Percutaneous aspiration and biopsy

Peripheral lung lesions cannot be seen by fibreoptic bronchoscopy. Samples are obtained by aspiration or biopsy through the chest wall under CT guidance. The commonest complication is pneumothorax (around 10% patients), especially if the mass is deep in the lung, as opposed to lesions next to the parietal pleura. Mild haemoptysis occurs in <5%. Implantation metastases do not occur.

Endobronchial ultrasound

A fibreoptic scope with ultrasound probe is used in staging of lung cancer, to visualize the majority of mediastinal nodes (not all of which are accessible surgically via mediastinoscopy or mediastinotomy) and then allow fine needle aspiration.

Endoscopic ultrasound via the oesophagus can also be used with the added advantage of enabling sampling of the left adrenal gland, posterior and inferior mediastinal lymph node groups. Figure 15.44 shows the lymph node areas which are commonly involved and sampled in the staging investigations.

Figure 15.44 Lymph node stations commonly involved in lung cancer and sampled during staging investigations.

FURTHER READING

Xie Y, Minna D. A lung cancer molecular prognostic test ready for prime time. Lancet 2012; 379:785–787.

Ultrasound-guided supraclavicular node sampling

In selected cases, where staging suggests N3 nodes to be involved, even where supraclavicular nodes are not palpable, ultrasound fine needle aspiration can be diagnostic.

Video-assisted thoracoscopic surgery

Large effusions with evidence of pleural thickening are amenable to biopsy and drainage via minimally invasive surgery. This technique is particularly useful as pleurodesis to prevent recurrence of effusion can be performed at the same time.

Other investigations

These include a full blood count for the detection of anaemia, and biochemistry for liver involvement, hypercalcaemia and hyponatraemia.

Assessing fitness for treatment

Before radical treatment, an assessment of fitness for treatment should be carried out. This work-up should include full lung function testing with transfer capacity, and if cardiovascular disease is present, cardiopulmonary exercise testing, stress echo or occasionally preoperative angiography.

Treatment (see also p. 471)

Treatment of lung cancer involves several different modalities and should be planned by a multidisciplinary team. Unfortunately, the majority of patients have incurable disease at presentation, or have significant co-morbidities which preclude radical treatment. Table 15.29 shows the mean survival based on tumour stage for NSCLC and SCC: only 25–30% patients are still alive one year after diagnosis and only 6–8% after 5 years.

Table 15.29 Mean 5-year survival in small cell and non-small cell cancer based upon clinical stage of disease

Stage of disease	Mean 5-year survival (%)	Mean survival time (months)
Non-small cell lung cancer
IA	50	60
IB	43	43
IIA	36	34
IIB	25	18
IIIA	19	14
IIIB	7	10
IV	2	6
Small cell lung cancer
Limited	10–13	15–20
Extensive	1–2	8–13

Data from: Goldstraw P, Crowley J, Chansky K et al.; International Association for the Study of Lung Cancer International Staging Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (7th) edition of the TNM Classification of malignant tumours. Journal of Thoracic Oncology 2007; 2(8):706–714. Erratum in: Journal of Thoracic Oncology 2007; 2(10):985.

Surgery

Surgery is performed in early stage non-small cell lung cancer (stage I, II and in selected IIIA) with curative intent. Many patients with stage III disease are treated with chemoradiation with a view to ‘downstaging’ disease and render it amenable to surgical resection. Where surgical staging of resected lung cancer demonstrates nodal involvement, patients require adjuvant chemotherapy.

Radiation therapy for cure

In selected patients with adequate lung function and early stage NSCLC, high-dose radiotherapy or continuous hyperfractionated accelerated regimens (CHART) provide a good alternative to surgical resection with almost comparable outcomes. It is the treatment of choice if surgery is not possible due to co-morbidities. Radiation pneumonitis (defined as an acute infiltrate precisely confined to the radiation area and occurring within 3 months of radiotherapy) develops in 10–15% of cases. Radiation fibrosis, a fibrotic change occurring within a year or so of radiotherapy and not precisely confined to the radiation area, occurs to some degree in all cases. These complications usually cause no problems.

In patients with significant cardiovascular or respiratory co-morbidities and early stage I disease, stereotactic radiotherapy can be used. In the same patient group radiofrequency ablation is used – an image-guided technique using heat to destroy small peripheral tumours.

Radiation treatment for symptoms

Radiation therapy has a role in palliation of symptoms from lung cancer. Bone and chest wall pain from metastases or direct invasion, haemoptysis, occluded bronchi and superior vena cava obstruction respond favourably to irradiation in the short term. Radiotherapy is also given at the end of chemotherapy to consolidate treatment in small cell lung cancer.

Chemotherapy

This is discussed on page 471. Adjuvant chemotherapy with radiotherapy improves response rate and extends median survival in non-small cell cancer. Newer targeted agents against epidermal growth factor receptors and tyrosine kinases in NSCLC (in particular adenocarcinoma) offer better outcomes in selected patients and can also be used where intravenous chemotherapy offers unacceptable toxicity or as second-line chemotherapy.

Laser therapy, endobronchial irradiation and tracheobronchial stents

These techniques are used in the palliation of inoperable lung cancer in selected patients with tracheobronchial narrowing from intraluminal tumour or extrinsic compression causing disabling breathlessness, intractable cough and complications, including infection, haemoptysis and respiratory failure.

A neodymium-Yag (Nd-Yag) laser passed through a fibreoptic bronchoscope can be used to vaporize inoperable fungating intraluminal carcinoma involving short segments of trachea or main bronchus. Benign tumours, strictures and vascular lesions can also be treated effectively with immediate relief of symptoms.

Endobronchial irradiation (brachytherapy) is useful for the treatment of both intraluminal tumour and malignant extrinsic compression. A radioactive source is afterloaded into a catheter placed adjacent to the carcinoma under fibreoptic bronchoscope control. Radiation dose falls rapidly with distance from the source, minimizing damage to adjacent normal tissue. Reduction in endoscopically assessed tumour size occurs in 70–95% of cases.

Tracheobronchial stents made of silicone or as expandable metal springs are available for insertion into strictures caused by tumour or from external compression or when there is weakening and collapse of the tracheobronchial wall.

Palliative care

Patients dying of cancer of the lung need attention to their overall wellbeing (see Ch. 10, p. 485). Much can be done to make the patient’s remaining life symptom-free and as active as possible. Furthermore, compared with patients with fatal cancers at other sites, patients with lung cancer tend to remain relatively independent and pain-free, but they die more rapidly once they reach the terminal phase. Both the patient and the relatives require psychological and emotional support, a task that should be shared between the respiratory teams, the primary care team and the nurses, social workers, hospital chaplains and doctors, who make up the palliative care team.

FURTHER READING

Aberle DR, Adams AM, Berg CD et al.; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365(5):395–409.

Rusch VW, Asamura H, Watanabe H et al.; Members of IASLC Staging Committee. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2009; 4(5):568–577.

Temel JS, Greer JA, Muzikansky A et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 2010; 363(8):733–742.

SIGNIFICANT WEBSITE

National Institute of Health and Clinical Excellence. The diagnosis and treatment of lung cancer (update): http://www.nice.org.uk/nicemedia/live/13465/54199/54199.pdf

Secondary tumours

Metastases in the lung are very common and usually present as round shadows (1.5–3.0 cm diameter). They are usually detected on chest X-ray in patients already diagnosed as having carcinoma, but can be the first presentation. Typical sites for the primary tumour include the kidney, prostate, breast, bone, gastrointestinal tract, cervix or ovary.

Metastases nearly always develop in the parenchyma and are often relatively asymptomatic even when the chest X-ray shows extensive pulmonary metastases. Rarely metastases develop within the bronchi, when they often present with haemoptysis.

Carcinoma, particularly of the stomach, pancreas and breast, can involve mediastinal glands and spread along the lymphatics of both lungs (lymphangitis carcinomatosis), leading to progressive and severe breathlessness. On the chest X-ray, bilateral lymphadenopathy is seen together with streaky basal shadowing fanning out over both lung fields.

Occasionally, a pulmonary metastasis is detected as a solitary round shadow on chest X-ray in an asymptomatic patient. The most common primary tumour to do this is a renal cell carcinoma.

The differential diagnosis includes:

Primary bronchial carcinoma

Tuberculoma

Benign tumour of the lung

Hydatid cyst.

Single pulmonary metastases can be removed surgically but, as CT scans usually show the presence of small metastases undetected on chest X-ray, detailed imaging including PET scanning and assessment is essential before undertaking surgery.

Investigation of solitary pulmonary nodules

With the increased use of CT scanning for other conditions, there has been increasing incidental detection of asymptomatic small sub-centimetre nodules. The majority of these are benign; however, radiological follow-up should be arranged at intervals, determined by the size of the nodule in millimeters and the risk of developing malignancy (i.e. high risk associated with either current or previous smoking history, occupational exposure to carcinogens or family history of lung cancer; low risk if never smoked and no occupational exposure to potential carcinogens or relevant family history).

Screening for lung cancer

A large trial carried out in the USA has demonstrated a 20% mortality benefit from low-dose helical CT screening for lung cancer in high-risk populations of smokers/ex-smokers between the ages of 55–74. A similar trial is underway in Europe. It is likely that CT screening will be employed in the future.

Benign tumours

Pulmonary hamartoma

This is the most common benign tumour of the lung and is usually seen on the X-ray as a very well-defined round lesion 1–2 cm in diameter in the periphery of the lung. Growth is extremely slow, but the tumour can reach several centimetres in diameter. Rarely it arises from a major bronchus and causes obstruction.

Bronchial carcinoid

This rare tumour resembles an intestinal carcinoid tumour and is locally invasive, eventually spreading to mediastinal lymph nodes and finally to distant organs. It is a highly vascular tumour that projects into the lumen of a major bronchus causing recurrent haemoptysis. It grows slowly and eventually blocks the bronchus, leading to lobar collapse. As foregut derivatives, bronchial carcinoids produce ACTH but do not usually produce the 5-hydroxytryptamine that is seen in midgut or hindgut carcinoid tumours. Staging of carcinoid tumours is the same as for NSCLC.

Cylindroma, chondroma and lipoma

These are extremely rare tumours that grow in the bronchus or trachea, causing obstruction.

Tracheal tumours

Benign tumours include squamous papilloma, leiomyoma, haemangiomas and tumours of neurogenic origin.

Diffuse diseases of the lung parenchyma

Granulomatous lung disease

Sarcoidosis

Epidemiology and aetiology

Immunopathology

Clinical features

Bilateral hilar lymphadenopathy

Pulmonary infiltration

Extrapulmonary manifestations

Investigations

Treatment

Prognosis

Granulomatous lung disease with vasculitis

Wegener’s granulomatosis (granulomatosis with polyangiitis)

Churg–Strauss syndrome

Microscopic vasculitis (polyangiitis)

Pulmonary autoimmune rheumatic disease

Rheumatoid disease (see also p. 521)

Systemic lupus erythematosus (see also p. 536)

Systemic sclerosis (see pp.538 and 1218)

Idiopathic interstitial pneumonia (IIP)

Idiopathic pulmonary fibrosis (IPF)

Pathology

Pathogenesis

Clinical features

Investigations

Differential diagnosis

Prognosis and treatment

Desquamative interstitial pneumonia (DIP)

Respiratory bronchiolitis interstitial lung disease (RBILD)

Acute interstitial pneumonia (AIP)

Nonspecific interstitial pneumonia (NSIP)

Cryptogenic organizing pneumonia (COP)

Lymphoid interstitial pneumonia

Drugs

Other types of diffuse lung disease

Langerhans’ cell histiocytosis (LCH)

Goodpasture’s syndrome

Diffuse alveolar haemorrhage

Lymphangioleiomyomatosis

Pulmonary alveolar proteinosis

Pulmonary infiltration with eosinophilia

Simple and prolonged pulmonary eosinophilia

Asthmatic bronchopulmonary eosinophilia

Diseases caused by Aspergillus fumigatus

Allergic bronchopulmonary aspergillosis (asthmatic pulmonary eosinophilia)

Aspergilloma and invasive aspergillosis

Tropical pulmonary eosinophilia

The hypereosinophilic syndrome

Hypersensitivity pneumonitis

Pathogenesis

Clinical features

Investigations

Differential diagnosis

Management

Humidifier fever

Drug and radiation-induced respiratory reactions

Occupational lung disease

Coal-worker’s pneumoconiosis

Simple pneumoconiosis

Progressive massive fibrosis

Silicosis

Asbestos

Asbestosis

Mesothelioma

Byssinosis

Berylliosis

Lung cysts

Tumours of the respiratory tract

Malignant tumours

Bronchial carcinoma

Pathophysiology

Clinical features

Local effects

Metastatic spread

Non-metastatic extrapulmonary manifestations of bronchial carcinoma (Table 15.27)

Investigations

Staging and diagnosis

Chest X-ray

Computed tomography