Pulmonary fibrosis and honeycomb lung Pulmonary fibrosis is the end result of many diseases of the respiratory tract. It may be: localized (e.g. following unresolved pneumonia) bilateral (e.g. in tuberculosis) widespread (e.g. in cryptogenic fibrosing alveolitis, in industrial lung disease, or due to drugs such as busulphan, bleomycin and cyclophosphamide). Sometimes with widespread fibrosis a typical radiological appearance is seen that is known as ‘honeycomb lung’. This refers to the presence, often diffusely in both lungs, of cysts 0.5–2.0 cm diameter that are thick-walled and do not fill with opaque material on bronchography. The cystic air spaces probably represent dilated and thickened terminal and respiratory bronchioles. The main causes are shown in Table 12.16. Cryptogenic fibrosing alveolitis (CFA) This relatively rare disorder causes diffuse fibrosis throughout the lung fields, usually in late middle age. It is thought that the disease, at least in some, is the result of occupational exposure to metal or wood dust and that the term ‘cryptogenic’ should be dropped in these cases. PATHOGENESIS The pathogenesis of damage and fibrosis is complex and several factors are involved (Fig 12.42). Macrophages activated by several factors (see p. 161) produce growth factors. These include fibronectin, platelet-derived growth factor, transforming growth factor ß, and insulin-like growth factor 1. This leads to the deposition of collagens type I and III. Histologically there are two main features: cellular infiltration with lymphocytes and plasma cells and thickening and fibrosis of the alveolar walls alveolitis – increased cells within the alveolar space (mainly shed type II pneumocytes and macrophages). Pathogenesis of pulmonary fibrosis. Macrophages can be activated by several factors, such as soluble immune complexes and sensitized T-lymphocytes, resulting in the release of various cytokines leading to fibrosis Clinical features The cardinal features are progressive breathlessness and cyanosis, which eventually lead to respiratory failure, pulmonary hypertension and cor pulmonale. Gross clubbing occurs in two- thirds of cases and bilateral fine end-inspiratory crackles are heard on auscultation. An acute form known as the Hamman–Rich syndrome occurs in about 20%. The chest X-ray appearance initially is of ground-glass appearance, progressing to obvious small nodular shadows with streaky fibrosis and finally a honeycomb lung. A number of autoimmune diseases are seen in association with this condition. For example, autoimmune hepatitis occurs in 5–10% of cases. Similar lung changes are also seen in rheumatoid arthritis, systemic sclerosis and Sjögren’s syndrome, often associated with Raynaud’s phenomenon. CFA has also been reported in association with coeliac disease, ulcerative colitis and renal tubular acidosis. INVESTIGATIONS Chest X-ray shows irregular reticulonodular shadowing, maximal in the lower zones. High-resolution CT scan shows characteristic changes of peripheral reticular and ground-glass opacification, seen best in the basal regions but extending all over the lungs (Fig 12.43). Respiratory function tests show a restrictive ventilatory defect – the lung volumes are reduced, the FEV1 and FVC ratio is normal to high (with both values being reduced), and gas transfer is reduced. Peak flow rates may be normal. Blood gases show an arterial hypoxaemia with normal Paco2. Blood tests The antinuclear factor and rheumatoid factor are positive in one-third of patients. The ESR is mildly elevated. Bronchoalveolar lavage shows increased numbers of cells (particularly neutrophils). Histological confirmation is necessary in some patients, requiring a transbronchial lung biopsy or even an open lung biopsy to obtain a larger specimen. CT scan showing cryptogenic fibrosing alveolitis DIFFERENTIAL DIAGNOSIS The diagnosis of CFA is usually made in a patient presenting with the above signs and characteristic CT changes. The differential diagnosis of chest X-ray appearance includes extrinsic allergic alveolitis, bronchiectasis, chronic left heart failure, sarcoidosis, industrial lung disease, and lymphangitis carcinomatosa. PROGNOSIS AND TREATMENT The median survival time for patients with CFA is approximately five years, although mortality is very high with the acute form. Treatment with prednisolone (30 mg daily) is usually prescribed for disabling disease, though its benefit has still to be proved by appropriate controlled trials. Azathioprine or cyclophosphamide may be added if there is no response. Supportive treatment includes domiciliary oxygen therapy. In severe disease, single lung transplantation can be offered. Extrinsic allergic alveolitis In this disease there is a widespread diffuse inflammatory reaction in both the small airways of the lung and 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 12.17. 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 poor, wet areas around the world. In the West the incidence is almost certainly declining as more mechanized farming procedures are introduced. PATHOGENESIS Histologically there is an initial infiltration of the small airways and alveolar walls with neutrophils followed by lymphocytes and macrophages, leading to the development of non- caseating granulomas. These comprise multi-nucleated giant cells, occasionally containing the inhaled antigenic material. The major allergic response to the inhaled antigens is through cellular immunity, though there is evidence in some cases of an additional immediate hypersensitivity reaction involving specific IgE antibody and the deposition of immune complexes. All these mechanisms can attract and activate alveolar macrophages, so that continued antigenic exposure results in the development of pulmonary fibrosis. CLINICAL FEATURES The typical history is that of the onset of fever, malaise, cough and shortness of breath several hours after exposure to the causative antigen. For example, a farmer forking hay in the morning may notice symptoms only during the late afternoon and evening that resolve by the following morning. On examination the patient may have a fever, tachypnoea and coarse end-inspiratory crackles and wheezes throughout the chest. Cyanosis may be severe even at rest. Continuing exposure leads to a chronic illness characterized by severe weight loss, effort dyspnoea and cough, and the features of fibrosing alveolitis (see p. 813). 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 is seen. Polymorphonuclear leucocyte count is raised in acute cases. Precipitating antibodies are present in the serum. One-quarter of pigeon fanciers have precipitating antibody against pigeon protein and droppings in their serum, but only a small proportion have lung disease. Precipitating antibodies are evidence of exposure, not disease. Lung function tests show a restrictive ventilatory defect with a decrease in gas transfer. Bronchoalveolar lavage shows increased cells (lymphocytes and granulocytes). DIFFERENTIAL DIAGNOSIS Although an extrinsic allergic bronchiolar alveolitis 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. The common ones are Lepidoglyphus domesticus, L. destructor and Acarus siro. Symptoms of asthma resulting from inhalation of these allergens are often mistaken for farmer’s lung. Pigeon fancier’s lung is quite common, but alveolitis from budgerigars 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. It is difficult to control pigeon fancier’s lung, since individuals remain addicted to their hobby. Prednisolone, initially in large doses of 30–60 mg daily, is necessary to cause regression of 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 on their degree of disability. Humidifier fever Humidifier fever may present with the typical features of extrinsic allergic alveolitis 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. The cause remains unknown but probably involves several bacteria or even amoebae. Humidifier fever is prevented by sterilization of the recirculating water used in the very large humidifying plants in industry. Drug-induced lung disease Drugs may produce a wide variety of disorders of the respiratory tract. 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 greater than 450 mg, but will regress in some cases if the drug is stopped. The most sensitive test is a decrease in gas transfer, and therefore gas transfer should be measured repeatedly during treatment with the drug. The use of corticosteroids may help resolution. Some of the most important drugs affecting the respiratory tract are shown in Table 12.18, together with the types of reaction they produce. The list is not exhaustive; for example, over 20 different drugs are known to produce a systemic lupus erythematosus-like syndrome, sometimes complicated by pulmonary infiltrates and fibrosis. Paraquat ingestion (see p. 879) can cause severe pulmonary oedema and death, and fibrosis develops in many of those who survive. Radiation damage Irradiation of the lung during radiotherapy can cause a radiation pneumonitis. Patients complain of breathlessness and a dry cough. Radiation pneumonia results in a restrictive lung defect. Corticosteroids should be given in the acute stage.
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