Rheumatoid disease

It was the association of pulmonary fibrosis with rheumatoid arthritis that first drew attention to the fact that this disease is not confined to the joints, and led to the use of the term ‘rheumatoid disease’ (rather than arthritis) to indicate the generalised nature of the disorder.¹⁴ It is now recognised that rheumatoid disease has many pleuropulmonary manifestations (see Table 10.1 and Box 10.1), some of which are dealt with in the appropriate chapters.

Although rheumatoid disease is commoner in women, pulmonary complications are more frequent in men, possibly reflecting the prevalence of smoking, which may increase pulmonary vascular permeability and aggravate the inflammatory process in the lung. As with many connective tissue disorders, the pulmonary manifestations of rheumatoid disease may precede other clinical or serological evidence of the disease, although in most cases there are other features, such as arthritis, subcutaneous nodules, digital vasculitis and positive serology.

Rheumatoid nodules

Nodules identical to those found in the subcutis of patients with rheumatoid disease occasionally develop in the substance of the lung or the trachea.^23–26 They may be the only manifestation of rheumatoid disease, developing before there is any arthritis or seroconversion.²³ Thus, they may herald generalised disease. As they may develop in any part of the body, the occasional involvement of the major airways should occasion no surprise.²⁵

The nodules in the lungs may be recurrent or appear first in one lung and then the other. They may be solitary or multiple and may enlarge, remain static or shrink to an insignificant scar. Resolution is usually by absorption but occasionally a nodule cavitates and discharges its necrotic contents through an airway. Erosion of both an airway and the pleura establishes a bronchopleural fistula, and perhaps pyopneumothorax.^21,22 Direct involvement of the pleura by rheumatoid nodules is considered on page 714.

Patients with rheumatoid nodules may present with haemoptysis, or chest pain if there is pleural involvement, or they may have no symptoms. The radiographic findings may be suspected of representing malignant disease. Rheumatoid nodules have a tendency to develop in the subpleural regions of the upper and mid zones.²⁴ They are round and typically measure up to 3 cm across but larger nodules are sometimes found, particularly when synergistic factors such as mine dust are also present (see Caplan’s syndrome, p. 341).²⁷ As elsewhere, the nodules have a necrotic centre of finely granular eosinophilic debris surrounded by a capsule of chronic inflammatory granulation tissue (Fig. 10.1A). The boundary between dead and viable tissue is marked by a characteristic palisade of radially oriented macrophages (Fig. 10.1B). The inflammatory cells include a small number of giant cells as well as plentiful lymphocytes and plasma cells. Fungal colonisation is a rare complication of rheumatoid nodules.²⁸

Figure 10.1 A pulmonary rheumatoid nodule. (A) The nodule consists of a necrotic centre surrounded by a thick fibrous capsule and an intervening inflammatory zone. (B) As in the subcutaneous nodules of rheumatoid disease, a palisade of radially oriented macrophages borders the central necrosis.

The differential diagnosis is principally from infection and Wegener’s granulomatosis (see Table 8.3.3, p. 443). The satellite granulomas seen in tuberculosis are not a feature of rheumatoid nodules, and special stains for mycobacteria and fungi give negative results. However, staining for these organisms should always be undertaken if there is any doubt about the diagnosis. Less common infective granulomas that enter the differential diagnosis include syphilis and dirofilariasis, the former requiring serological investigation and the latter step sections to identify fragments of the worm (see pp. 216 and 258 respectively). In Wegener’s granulomatosis there is also vasculitis whereas blood vessels near rheumatoid nodules show intimal fibrosis and a cuff of lymphocytes, but not a true vasculitis.

Follicular bronchiolitis

Rheumatoid disease is characterised by widespread lymphoid hyperplasia. This is best seen in lymph nodes but the bronchopulmonary lymphoid tissue is also involved in this process, resulting in the development of lymphoid follicles alongside the bronchioles, a process termed follicular bronchiolitis (Fig. 10.2).^42,43 Patients complain of breathlessness with cough, fever or recurrent pneumonia. They have bilateral reticulonodular radiographic opacities and lung function tests show an obstructive, restrictive or combined defect. When follicular bronchiolitis accompanies an interstitial pneumonia it suggests that the latter is part of a systemic connective tissue disorder.¹⁰

Figure 10.2 Follicular bronchiolitis as a manifestation of rheumatoid disease. Several lymphoid follicles are seen, particularly bordering the central bronchiole.

Constrictive bronchiolitis obliterans

Rare patients with rheumatoid disease and other connective tissue disorders develop a bronchiolar disorder that is of considerably greater clinical consequence than follicular bronchiolitis, one that is characterised by a severe ventilatory disturbance that often proves fatal. This is the constrictive form of obliterative bronchiolitis (Fig. 10.3).^44–46 The primary lesion appears to involve continuing autoimmune damage to the respiratory epithelium. This is replaced by granulation tissue, which is laid down in a circumferential pattern and gradually narrows and finally obliterates the airway lumen. It has been suggested that the process is a consequence of penicillamine^47,48 or gold⁴⁹ antirheumatoid therapy rather than a direct result of the connective tissue disease but as rheumatoid patients who have not received these drugs have also developed constrictive obliterative bronchiolitis this appears unlikely. Furthermore, constrictive obliterative bronchiolitis has not been reported in patients treated with penicillamine for disorders such as Wilson’s disease and primary biliary cirrhosis. Alternatively, it has been suggested that the bronchiolitis may have an infective basis. However, the obliterative process has the constrictive pattern seen when there is constant attrition of the respiratory epithelium rather than the proliferative intraluminal form of the disease seen after brief viral or chemical injury (see p. 121). It is notable that a case of obliterative bronchiolitis attributed to the domestic inhalation of a common cleansing agent concerned a patient with rheumatoid disease and that the airway obliteration was of the constrictive variety,⁵⁰ suggesting that the process was the result of continuing injury rather than an isolated episode of fume inhalation.

Figure 10.3 Constrictive obliterative bronchiolitis in a patient with rheumatoid disease. The mucosa of the bronchiole seen to the left is thickened by granulation tissue so that the airway lumen is reduced to a pinpoint.

Rheumatic fever

Rheumatic fever is now rare in developed countries but remains common in many parts of the world. It involves serosal surfaces and often results in pleurisy, which is generally manifest as a sterile exudative effusion. Less commonly, there is a fibrinous alveolar exudate, organisation of which results in Masson bodies, hyaline membrane formation, chronic interstitial pneumonia or a focal necrotising process involving alveoli and pulmonary blood vessels.^63–66

Systemic sclerosis

Systemic sclerosis (also known as scleroderma) is a multisystem disease that is subclassified according to the degree of skin involvement as diffuse or limited cutaneous. The former is associated with a greater degree of visceral disease and carries a worse prognosis. The limited cutaneous form is more often associated with the CREST syndrome (calcinosis cutis, Raynaud’s phenomenon, oesophageal dysfunction, sclerodactyly and telangiectasia) and has a better prognosis, although it is the form that is more often associated with pulmonary hypertension.⁶⁷ Parenchymal pulmonary involvement in systemic sclerosis may take the form of interstitial pneumonia^3,7,68 or diffuse alveolar haemorrhage,^69,70 whilst oesophageal involvement may result in aspiration pneumonia and centriacinar fibrosis.⁷¹ Constrictive bronchiolitis is also reported^72,73 and there is an increased risk of lung cancer, particularly adenocarcinoma, which is often of lepidic (bronchioloalveolar) pattern.^74,75

Interstitial pneumonia

Interstitial pneumonia is the commonest pulmonary manifestation of systemic sclerosis (Fig. 10.4), the prevalence at autopsy being approximately 70%.^76,77 However, many of these cases have subclinical involvement⁷⁸ and the prognosis is better than in idiopathic interstitial pneumonia.^7,79–81 NSIP is the commonest pattern, accounting for 55–77% of cases.^2–4,8,82 The second commonest pattern is UIP but the adverse prognosis associated with this pattern in idiopathic disease is not so marked.^3,4,10,82 This may be related to differences in neutrophil numbers and degranulation in the lung.⁸³ Other histological patterns seen in systemic sclerosis include desquamative interstitial pneumonia and respiratory bronchiolitis although, it is likely that these patterns are related to smoking more than systemic sclerosis.^72,84 Organising pneumonia has been reported in occasional patients,⁸⁵ as has diffuse alveolar damage.^33,70,86 Sarcoid granulomas have also been noted but whether they relate to systemic sclerosis or are incidental is unknown.^3,87

Figure 10.4 Pulmonary fibrosis as a manifestation of systemic sclerosis. (A) The fibrosis is seen as a subpleural band of pallor, chiefly affecting the base and posterior of the lung. (B) Microscopy shows non-specific interstitial pneumonia. (C) Malignant change may complicate the fibrosis. Here there is both non-specific interstitial pneumonia and adenocarcinoma.

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic multisystem disorder associated with antinuclear autoantibodies and immune complex deposition. Women of child-bearing age are most commonly affected, the female-to-male ratio being approximately eight. Particularly common manifestations include arthropathy, skin lesions, renal disease and serositis. There are also several pleuropulmonary manifestations,⁹⁸ in addition to which reactions to drugs such as methotrexate and cyclophosphamide used to treat SLE may affect the lungs. Respiratory disease is commoner in SLE than in any other connective tissue disease but the prognosis is more dependent upon renal than pleuropulmonary involvement.

Polymyositis and dermatomyositis

These inflammatory disorders of skin and skeletal muscle affect women more frequently than men and have a peak onset in the sixth decade. The most common pleuropulmonary complication of these diseases is aspiration pneumonia due to a depressed cough reflex and weakness of pharyngeal and intercostal muscles and the diaphragm, which may result in ventilatory failure.¹²⁹

Mixed connective tissue disease

Mixed connective tissue disease is characterised by overlapping features of other connective tissue disorders, notably SLE, systemic sclerosis and polymyositis, in association with high titres of an antinuclear antibody that gives a speckled pattern of immunofluorescence.¹⁴² The frequency of pulmonary involvement has ranged from 25 to 85%, the commonest form being interstitial pneumonia, followed by pleuritis, pulmonary hypertension, vasculitis and diffuse alveolar damage.^33,143–147 Pulmonary hypertension is especially seen when features of systemic sclerosis are prominent but the pathological features are those of plexogenic arteriopathy rather than the myxoid intimal thickening seen in systemic sclerosis.¹⁴⁸

Ankylosing spondylitis

Ankylosing spondylitis typically affects the spine of young men with an HLA-B27 haplotype. Pulmonary associations include apical fibrosis. This develops in 1–2% of patients with ankylosing spondylitis, typically many years after the onset of the joint disease.^149,150 Whereas the spinal lesions typically appear early in adult life, it is not until the fifth decade or so that pulmonary disease develops, often being discovered incidentally on chest radiographs. Initially, the changes may be unilateral but they have often become bilateral if cough or dyspnoea first draws attention to pulmonary involvement. As the disease progresses, cystic changes develop and the appearances resemble those of tuberculosis, but mycobacteria do not appear to play a causal role. However, like all cavities in the lungs, those of ankylosing spondylitis are liable to secondary saprophytic infection by Aspergillus species or colonisation by opportunistic mycobacteria.¹⁵¹

At necropsy, there is bilateral apical fibrosis (Fig. 10.5), which may be associated with bronchiectasis and bulla formation. Secondary infection may be found but generally microscopy shows only fibrosis and lymphocytic infiltration. The process is not granulomatous and the aetiology is unknown. The changes cannot be attributed to the irradiation that was formerly used to treat ankylosing spondylitis as this was confined to the spine and the pulmonary changes may develop without such therapy. Occasionally, identical changes are found in association with rheumatoid disease³⁵ or with psoriatic spondylitis.¹⁵²

Figure 10.5 Gross apical fibrosis in a patient with ankylosing spondylitis.

Sicca syndrome and Sjögren’s syndrome

Bronchial disease

The sicca syndrome of dry eyes and dry mouth, due respectively to keratoconjunctivitis sicca and xerostomia, may be combined with one of the connective tissue disorders, usually rheumatoid disease, to form Sjögren’s syndrome. The dryness of the eyes and mouth is due to inflammatory destruction of the lacrimal and salivary glands. The same process may extend into the lower respiratory tract to destroy the tracheobronchial glands and lead to dryness of the trachea and bronchi.^153–156 Airway clearance is impaired and bronchitis, bronchiectasis, bronchiolitis and pneumonia may develop. The destruction of the glands is of unknown cause. In both sicca and the full Sjögren’s syndrome, the glands show a heavy lymphoid infiltrate with destruction of the secretory acini (Fig. 10.6).¹⁵⁷ Further extensions of the sicca syndrome are encapsulated in the term TASS syndrome (thyroiditis, Addison’s disease, Sjögren’s and sarcoidosis).¹⁵⁸ The association with rheumatoid disease, thyroiditis and Addison’s disease suggests an autoimmune aetiology. The immunoparesis associated with human immunodeficiency virus infection is also reported in the sicca syndrome.¹⁵⁹

Figure 10.6 Sjögren’s syndrome. The bronchial glands show an intense lymphoid infiltrate.

Parenchymal disease

Parenchymal disease occurs in both primary and secondary Sjögren’s disease but is more common in the latter, where it often reflects the pulmonary manifestations of the associated connective tissue disease. Parenchymal disease includes amyloidosis and the formation of bullae (Fig. 10.7).^160–164 Interstitial pneumonia of NSIP pattern is the commonest manifestation of primary Sjögren’s disease.¹⁶⁵ Pulmonary hypertension, LIP, UIP and organising pneumonia are also reported.^165–172

Figure 10.7 Sjögren’s syndrome. (A) The lung shows amyloidosis, lymphoid hyperplasia and air space destruction. (B) High-resolution computed tomography scan showing cystic destruction and peripheral nodules, the latter probably reflecting the focal amyloid deposition.

Relapsing polychondritis

Relapsing polychondritis is a rare systemic disorder affecting connective tissues with a high content of glycosaminoglycans, notably cartilage, the aorta, the sclera and cornea.^176–180 It is associated with rheumatoid arthritis in about 20% of cases. Autoantibodies to cartilage and type III collagen are sometimes found¹⁸¹ and there may be vasculitis, glomerulonephritis, rheumatoid disease, Sjögren’s syndrome, SLE or other autoimmune disease.^180,182,183

Constitutional symptoms are common while involvement of the pinnae and nasal cartilage leads to crumpled ears and a saddle-nose deformity.^178,179 Involvement of the lower respiratory tract is uncommon, especially in isolation, but may result in life-threatening tracheobronchial narrowing (see p. 95).^184–186

Histologically, there is erosion of the edges of the affected cartilages by a dense lymphocytic, plasma cell and giant cell infiltrate (see Fig. 3.4, p. 95). Immunoglobulins and complement components have been demonstrated at the chondrofibrous junction.¹⁸⁷ Resolution of the inflammation, which may be spontaneous, may leave a deformed cartilage showing fibrosis and metachromasia of its ground substance.¹⁸⁶

Behçet’s syndrome and Hughes–Stovin syndrome

Behçet’s syndrome combines recurrent orogenital ulceration with a variety of systemic disorders. A family history is sometimes obtained and the disease is associated with HLA-B51, suggesting that it has a genetic basis. Pulmonary involvement occurs in up to 8% of cases, most commonly as multiple pulmonary artery aneurysms due to a necrotising arteritis (see Fig. 8.3.19, p. 447).¹⁸⁸ Arteries of any size may be affected. Leakage or rupture of the aneurysms causes pulmonary haemorrhage, which may be fatal. Alternatively, the arteritis may result in widespread pulmonary thrombosis.¹⁸⁹ Other respiratory manifestations include pulmonary embolism, pleurisy, pulmonary fibrosis, bronchial ulceration and stenosis, and chyloptysis.^{188,190–197} The Hughes–Stovin syndrome of haemoptysis due to pulmonary artery aneurysms probably represents a limited form of Behçet’s syndrome.^198–200

Cutis laxa

Cutis laxa is a rare hereditary disease of connective tissue in which the skin lacks its normal elasticity and hangs in folds like the dewlaps of a bloodhound. It may be associated with dissection of the aorta and pulmonary emphysema.²⁰¹

Ehlers–Danlos syndrome

Ehlers–Danlos syndrome is another hereditary defect of connective tissue, one caused by mutation of the gene that encodes the chains of type III procollagen. There are 10 recognised subtypes, with corresponding clinical heterogeneity. The syndrome is generally characterised by soft, hyperextensible skin and hyperextensibility of the joints. Visceral abnormalities include fragility of blood vessels with consequent haemorrhage, hernias, visceral rupture, mitral valve prolapse and premature rupture of the membranes in pregnancy. Respiratory complications include tracheobronchomegaly, pulmonary laceration with subsequent haemorrhage, cystic change, fibrous pseudotumours that frequently show osseous metaplasia (Fig. 10.8), pneumothoraces and haemothorax.^202–205 Occasionally some of these respiratory features are seen in isolation. Ehlers–Danlos syndrome and cutis laxa have both been associated with Mounier–Kuhn’s and Klippel–Trenaunay syndromes (see pp. 163 and 482).

Figure 10.8 Ehlers–Danlos syndrome. (A) Fibrous scars, shown red in this van Gieson stain, are probably the result of spontaneous tearing of the lung. (B) Fibrous pseudotumours may represent a development of the same process.

Pseudoxanthoma elasticum

Pseudoxanthoma elasticum is a further generalised connective tissue disorder that has its principal manifestations in the skin but may involve the lung. As in other tissues the pulmonary elastic tissue is damaged and the site of dystrophic calcification.²⁰⁶

Marfan’s syndrome

Marfan’s syndrome is a further hereditary disorder of connective tissue. It is an autosomal disorder caused by mutation of the gene encoding fibrillin-1, which is a major component of the microfibrillar part of elastin.²⁰⁷ Dysregulation of transforming growth factor-β (TGF-β) signalling due to mutations in the TGF-β genes has also been implicated in certain patients with Marfan’s syndrome.²⁰⁸ Patients with Marfan’s syndrome are of a tall, thin build and have arachnodactyly, a high arched palate, pectus excavatum, scoliosis, flat feet, dislocation of the lens, aortic incompetence, dissection of the aorta and mitral valve prolapse. Pulmonary complications of the connective tissue fragility include recurrent pneumothoraces and emphysema.^209–211

Hypertrophic pulmonary osteoarthropathy

Hypertrophic pulmonary osteoarthropathy is characterised by digital clubbing associated with arthropathy and periostitis that mainly affects the distal long bones in a symmetrical manner and causes painful swelling of the ankles, wrists, knees and elbows. Scans show abundant periosteal new bone. The condition is mainly associated with primary carcinoma of the lung, of which it may be the presenting feature. The tumour is usually peripheral and may be of any cell type but is rarely small cell. The numerous other associations include bronchopulmonary carcinoid, carcinoma of the oesophagus, thymus and thyroid, thoracic lymphoma, localised fibrous tumour of the pleura, leiomyoma of the oesophagus, pleuropulmonary sepsis, cystic fibrosis, sarcoidosis, cyanotic congenital heart disease, thyrotoxicosis and inflammatory bowel disease. The aetiology is obscure. Vagal stimulation, hormonal and immune mechanisms have all been suggested while the digital clubbing has been attributed to the release of growth factors following the impaction of platelet aggregates in distal blood vessels.

Anomalies of the great vessels compressing the trachea

Four vascular anomalies are liable to compress the trachea. These are the left pulmonary artery sling syndrome and three varieties of vascular ring.

The left pulmonary artery sling syndrome

In this syndrome,²¹³ the left pulmonary artery crosses to the right in front of the trachea, curls around it above the origin of the right main bronchus and runs to the left between the trachea and the oesophagus (Fig. 10.10). The lower trachea is liable to be compressed, causing stridor or wheeze.

Figure 10.10 Left pulmonary artery sling syndrome. In comparison with the normal arrangement shown on the left, the left pulmonary artery passes to the right and then backwards over the origin of the right main bronchus before crossing to the left side behind the trachea just above its bifurcation and in front of the oesophagus. The arrow indicates the course of the left pulmonary artery.

(Reproduced from Brewis RAL, Corrin B, Geddes DM et al. (eds) Respiratory Medicine, 2nd edn. London: Saunders, 1995, with permission.)

Vascular rings

Certain congenital anomalies of the great vessels result in a ring of arteries surrounding and possibly compressing the trachea. Three conditions are liable to do this:

1 a double aortic arch in which the ring is formed by the heart to the front, the twin arches to either side and the common descending aorta behind

2 an anomalous right subclavian artery. Here the ring consists of the heart to the front, the aortic arch to the left, an anomalous right subclavian artery behind and a ductus (or ligamentum) arteriosus connecting the anomalous right subclavian artery to the right pulmonary artery to the right

3 a right-sided aortic arch with an anomalous left subclavian artery. This is the mirror image of the above and here the vascular ring is formed by the heart in front, the aortic arch to the right, an anomalous left subclavian artery behind and a ductus (or ligamentum) arteriosus connecting the left subclavian artery to the left pulmonary artery to the left (Fig. 10.11).²¹⁴

Figure 10.11 Right-sided aortic arch with anomalous left subclavian artery. In this condition a vascular ring is formed by the heart in front, the aortic arch (AA) to the right, an anomalous left subclavian artery (ALS) behind and a left ductus arteriosus (LD) connecting the left subclavian artery to the left pulmonary artery to the left. Arrows indicate aortic flow; DA, descending aorta; PT, pulmonary trunk; RCC, right common carotid artery; LCC, left common carotid artery; RS, right subclavian artery.

(Reproduced from Stewart et al. (1966)²¹⁴ with permission from the American Journal of Roentgenology.)

It will be noted that in two of these conditions there is a right-sided aortic arch. This can be identified radiologically and in a child thought to have corticosteroid-resistant asthma is a valuable indication that the true cause of the child’s wheezing is a vascular ring compressing the trachea.²¹⁵

Hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu disease)

Hereditary haemorrhagic telangiectasia is an autosomal-dominant condition characterised by multiple telangiectases in the skin and mucous membranes, often resulting in distressing and sometimes life-threatening haemorrhage.^216–218 Epistaxis and gastrointestinal haemorrhage are common manifestations while there may be haemoptysis, haematuria and iron-deficiency anaemia. Viscera such as the lungs, liver and brain may also be involved. The telangiectases connect arteries and veins, bypassing the normal resistance vessels so that they are subject to arterial pressure.²¹⁹ They act as arteriovenous fistulae and increase cardiac output. About 15% of patients have large pulmonary arteriovenous fistulae (see p. 76).²²⁰ These permit paradoxical embolisation with the danger of infarction and abscesses in sites such as the brain.

Genetic mutations have been identified at three loci involving cell surface receptors for TGF-β. Two, which are located at 9q33-34 and 3p22 and respectively encode for endogline and ALK1, are found in families in whom pulmonary arteriovenous fistulae are common.^221–223 The third mutation, which is less common, has been mapped to the long arm of chromosome 12.²²⁴ This mutation is associated with primary (plexogenic) pulmonary hypertension rather than pulmonary arteriovenous fistulae.^224–226 Thus, two mechanisms underlie the development of pulmonary hypertension in hereditary haemorrhagic telangiectasia: there may be either high-output left-sided cardiac failure or primary pulmonary vasoconstriction.²²⁷

Klippel–Trenaunay syndrome

This is a congenital disorder characterised by a triad of cutaneous vascular lesions, venous abnormalities of the extremities and soft-tissue or bony hypertrophy. Venous thromboembolism is a common complication, sometimes leading to pulmonary hypertension and right heart failure.^228–231 Occasionally, there are also pulmonary angiomas.

Idiopathic arterial calcification of infancy

In this condition there is calcification of the arterial internal elastic laminae, generally involving systemic vessels but also pulmonary arteries on occasion.²³² Affected babies usually die in infancy and the diagnosis is often made at autopsy. Medium-sized arteries are rigid and as well as showing calcification of the internal elastic lamina they are often obliterated by secondary thrombosis and fibrosis.

Blue rubber bleb disease

Blue rubber bleb disease is characterised by cavernous haemangiomas involving the skin and gastrointestinal tract. Rarely the lesions extend into the trachea and bronchi where they are seen as discrete bluish mucosal nodules.²³³

Yellow-nail syndrome

This syndrome is characterised by lymphatic hypoplasia, lymphoedema, chylous effusions and yellow discoloration of the nails. It is described more fully on page 709.

Aortic fistula

Fistulas between the aorta and the tracheobronchial tree may complicate previous thoracic vascular surgery, aortic aneurysm, bacterial aortitis or radiation therapy. They often present as recurrent episodes of haemoptysis but the initial event may be a catastrophic flooding of the airways.²³⁴

Renal failure

The commonest respiratory conditions encountered in renal failure are infection and pulmonary oedema. The latter is often described as ‘uraemic lung’ but is indistinguishable from pulmonary oedema of other cause, described in full on page 401. Several mechanisms may contribute to the development of pulmonary oedema in renal failure. They include fluid retention; hypertensive left ventricular failure secondary to chronic glomerulonephritis, chronic pyelonephritis and polycystic renal disease; and hypoproteinaemia, which is a prominent feature of the nephrotic syndrome.²³⁶ Cytotoxic factors may also operate.²³⁷ Pleural effusion may develop for the same reasons.

Renal failure may be complicated by secondary hyperparathyroidism, leading to absorption of bone and a secondary rise in serum calcium levels. This may be followed by metastatic calcification, in which the lungs are amongst the most commonly affected organs (see below). Pulmonary hypertension is also reported in chronic renal failure, affecting 29% of such patients in one study; its etiology is poorly understood but it appears to be unrelated to secondary hyperparathyroidism or pulmonary vascular calcification.²³⁸

The treatment of renal failure introduces further respiratory hazards. The immunosuppression involved in renal transplantation is associated with azathioprine-associated interstitial pneumonitis, opportunistic infection and posttransplantation lymphoproliferative disease, while dialysis has its own detrimental effects on lung function. Peritoneal dialysis entails a reduction in diaphragmatic excursions so that a low vital capacity and hypoxaemia are regularly seen with this form of dialysis. Haemodialysis may be accompanied by hypoxaemia, probably because the filters employed activate complement and lead to the sequestration of neutrophils in the pulmonary capillaries, as in shock (see Figs 4.20 and 4.21, p. 144).

Autosomal-dominant polycystic kidney disease

The association of bronchiectasis with this renal disorder is described on page 65.

Familial Fanconi syndrome (renal tubular acidosis)

An unexplained association of bilateral diffuse pleural fibrosis has been described in two siblings with renal tubular acidosis.²³⁹

Anaemia

Anaemia from any cause is liable to give rise to breathlessness because of impaired oxygen transport, even when cardiorespiratory function is normal. More specific is an association of autoimmune haemolytic anaemia with idiopathic pulmonary fibrosis.²⁴¹

Hypercoaguability

Hypercoaguability of the blood gives rise to pulmonary thromboembolism, pulmonary thrombosis and pulmonary infarction, conditions that are accordingly seen in association with polycythaemia,²⁴² thrombocythaemia,²⁴² myelomatosis, macroglobulinaemia,²⁴³ cryoglobulinaemia,²⁴⁴ cryofibrinogenaemia,²⁴⁵ the antiphospholipid syndrome (see p. 489),^246–249 the hypereosinophilic syndrome (see p. 467) and haemoglobinopathies such as sickle cell disease,^250–255 spherocytosis,²⁵⁶ thalassaemia^258,259 and paroxysmal nocturnal haemoglobinuria.²⁶⁰ The thrombosis and subsequent organisation may be widespread and lead to pulmonary hypertension of the pattern seen in thromboembolic disease (see p. 404).²⁶⁰

Sickle cell disease

Sickle cell disease is a serious haemolytic disorder caused by homozygosity for haemoglobin S. The sickle cell trait is its milder heterozygous counterpart in which there is both haemoglobin S and A. The gene is found in Africa and Mediterranean countries. Whenever oxygen tension drops, haemoglobin S is liable to alter its molecular shape and deform the red blood cell, causing haemolysis and thrombosis. Infarction is widespread and may involve the lungs. Two major clinical forms of pulmonary involvement are recognised: an acute chest syndrome and sickle cell chronic lung disease. Acute chest syndrome is characterised by fever, chest pain and the appearance of new radiographic opacities. It represents an acute pulmonary vaso-occlusive crisis leading to acute right ventricular failure and sometimes death. Histologically, this may mimic veno-occlusive disease by causing patchy congestion through capillary sludging of the abnormal red blood cells (Fig. 10.12). Exchange transfusion has been shown to be effective.²⁶¹ Chronic lung disease on the other hand is manifest as radiographic infiltrates, impaired pulmonary function and, in its most severe form, pulmonary hypertension.^262–264 The pulmonary hypertension is due to pulmonary thrombosis (Fig. 10.13).^250–255 In severe cases there is plexogenic arteriopathy.^265,266 Veins as well as arteries thrombose and, when the venous thrombus organises, the appearances are similar to those seen in veno-occlusive disease. Rarely, pneumococcal septicaemia is also seen in sickle cell disease, possibly because of the splenic infarction that occurs in this condition. Fatal bone marrow embolism is a further occasional complication of sickle cell disease.^259,267

Figure 10.12 Sickle cell disease. (A) In a patient who died of an acute vaso-occlusive crisis the lungs show differential congestion similar to that seen in veno-occlusive disease but here due to sludging of the abnormal red blood cells (B) rather than postcapillary obstruction.

Figure 10.13 Sickle cell disease. A pulmonary artery shows recanalisation, following thrombosis.

Thalassaemia

Thalassaemia is another serious haemoglobinopathy, in this case caused by persistence of fetal haemoglobin because of a genetic inability to form adult haemoglobin A. Again there is haemolysis coupled with hypercoaguability of the blood, leading to thrombosis and infarction. Pulmonary hypertension may develop but is not as common as in sickle cell disease.²⁵⁸ Haemosiderin deposition is a prominent pulmonary change and may lead to interstitial fibrosis.^{258,259,268,269} Hypoxaemia is often noted in thalassaemia; this is possibly due to arteriovenous anastomoses in the form of ‘spider naevi’ that have been demonstrated in the periphery of the lung by postmortem injection techniques in thalassaemia patients that also have cirrhosis, which is a further complication of this disease.²⁵⁸ Such anastomoses are recorded in the lungs of other patients with liver disease (see below). Mixed sickle cell thalassaemia has led to fatal bone marrow embolism.²⁵⁹

Myeloproliferative disease

Myeloproliferative disease may extend from the bone marrow to the lung, generally involving the pulmonary interstitium. Pulmonary involvement in myelofibrosis is seen as interstitial fibrosis accompanied by foci of extramedullary haemopoiesis.^270–272 In rare cases there is also air space and vascular involvement leading to pulmonary haemorrhage and pulmonary hypertension.^242,273 Thus, in diseases such as polycythaemia and thrombocythaemia, pulmonary hypertension may be the result of either thromboembolism or plugging of pulmonary blood vessels by haemopoietic cells.²⁴² Leukaemic processes also infiltrate the interstitial compartment of the lung, but generally as a terminal event²⁷⁴: before the lungs are directly involved they are liable to be the seat of opportunistic infection. Alveolar lipóproteinosis is also described (see p. 316). Pulmonary fibrosis is recorded in occasional patients with human T-cell lymphotropic virus type I-associated myelopathy²⁷⁵ and leukaemia.²⁷⁶ The pulmonary effects of treating leukaemia with cytotoxic drugs and by bone marrow transplantation are discussed on page 668.

Chronic granulomatous disease

Chronic granulomatous disease is characterised by opportunistic infections, both bacterial and fungal, with Staphyloccus aureus, Nocardia and Aspergillus species being particularly implicated.^277,278 It is due to a genetic disorder that impairs the production of oxygen metabolites by neutrophils, eosinophils and macrophages. Over 400 gene defects are recognised, involving both mutations and inactivating recombinations. They are all recessive and may be either X-linked or autosomal.

Phagocytic cells lack nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and ingested microbes are therefore not killed following phagocytosis. Abscesses develop throughout the body in the first year of life, and the lung is only one of many organs affected. Within the lung, the granulomatosis may affect the lung parenchyma or be centred on the airways.^279,280 Often a balance is arrived at whereby viable microbes survive within granulomas composed of lymphocytes and yellow-brown, foamy macrophages centred on collections of neutrophils and eosinophils (Fig. 10.14).

Figure 10.14 Chronic granulomatous disease. A collection of neutrophils is surrounded by epithelioid and giant cells and beyond that chronic inflammatory granulation tissue. Eosinophils are prominent throughout.

(Courtesy of Dr K Dhaene, Ghent, Belgium.)

Sea-blue histiocytosis

Sea-blue histiocytosis takes its name from the appearance of macrophages laden with cytoplasmic granules of this colour in Giemsa-stained preparations. In haematoxylin and eosin-stained sections the macrophages have an abundant pale, granular cytoplasm. Such cells are seen in Niemann–Pick disease (see below) and occasionally within the pulmonary interstitium and air spaces in a variety of acquired haematological disorders, including myelofibrosis.²⁸¹

Mastocytosis

Mastocytosis is a rare disease of uncertain aetiology, characterised by infiltration and proliferation of mast cells in the skin (urticaria pigmentosa), bone marrow, gastrointestinal tract and lymph nodes. Pulmonary mast cell infiltration is particularly rare.²⁸²

IgG₄-related systemic sclerosing disease

The term ‘IgG4-related systemic sclerosing disease’ has been applied to lymphoproliferative lesions found in various sites throughout the body in association with high serum levels of IgG₄.283–285c The lesions contain abundant IgG₄-positive cells, generally accompanying exuberant fibrous tissue, which progresses to dense hyalinosis. Idiopathic retroperitoneal fibrosis and sclerosing pancreatitis are archetypal examples. The lungs have been involved in some cases of multisystem disease^286,287 and in a few instances pulmonary pseudotumours (plasma cell granulomas) have represented the sole evidence of hyper-IgG₄ disease.^288,289 Such patients have ranged from 42 to 78 years in age and shown an equal sex distribution. Several were asymptomatic at presentation. Imaging varies from ill-defined infiltrative lesions to nodular or multifocal opacities. Histology shows varying degrees of fibrosis with intense infiltration by lymphocytes, plasma cells, scattered neutrophils and occasional aggregates of eosinophils (Fig. 10.15A). Obliterative venulitis and obliterative arteritis (mimicking lymphomatoid granulomatosis) are common and there is sometimes a stenosing peribronchiolar infiltrate (see Fig. 10.15B, C). Immunohistochemistry shows polyclonality and many IgG₄-positive plasma cells, identification of which distinguishes the condition from its principal mimics, lymphatoid granulomatosis and NSIP. Most patients have been treated surgically but it is becoming apparent that the condition responds well to systemic corticosteroids.^288,290 The cases that have been classified as plasma cell granuloma or inflammatory pseudotumour need to be distinguished from inflammatory myofibroblastic tumour, a further condition to which these terms have been applied but which is now considered to be neoplastic (see p. 620). The distinction may be difficult as inflammatory myofibroblastic tumours also contain IgG₄-positive plasma cells, as do conditions such as Rosai–Dorfman disease.²⁹¹ The precise relationship of the IgG₄-related sclerosing disease to various lung disorders requires further elucidation.

Figure 10.15 IgG₄ disease. (A) Lung biopsy showing bronchiolocentric and subpleural consolidation. (B) The infiltrate narrows the airway lumen. (C) The infiltrate mainly consists of plasma cells, many of which stain for IgG₄.

Splenectomy

Splenectomy results in lowered immunity, particularly to pneumococcal infection. Many patients who have lost their spleen have died of pneumococcal pneumonia or septicaemia and all who have undergone this operation should be offered pneumococcal immunisation. Splenectomy also appears to be a risk factor for chronic thromboembolic pulmonary hypertension.²⁹²

Disorders of the upper alimentary tract

A variety of upper alimentary tract disorders may be associated with pulmonary disease, chiefly the consequence of aspiration of ingested material or of alimentary tract secretions (Box 10.3). The patient may be unaware of such aspiration. Otherwise asymptomatic gastro-oesophageal reflux has been associated with several respiratory disorders.²⁹³ Complications of aspiration include chronic cough, asthma, recurrent infections, aspiration pneumonia, abscess, empyema, bronchiectasis, exogenous lipid pneumonia, Mendelson’s syndrome (see p. 145) and chronic interstitial pneumonia and fibrosis.

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