Fortnightly Review: Diffuse lung disease: an approach to managementBMJ 1994; 309 doi: https://doi.org/10.1136/bmj.309.6948.175 (Published 16 July 1994) Cite this as: BMJ 1994;309:175
The term diffuse (interstitial) lung disease embraces a large number of disorders characterised by distinct cellular and extracellular infiltrates in the acinar regions of the lung (that is, distal to the terminal bronchiole). Some of these diseases present acutely whereas others have a subacute or chronic course: the infiltrate may result in tissue injury, as in cryptogenic fibrosing alveolitis, or cause little damage to the lung architecture, as in pulmonary eosinophilia. Because diffuse lung disease particularly affects the peripheral part of the lung, chest radiographs usually show widespread shadows of various types, and in clinical practice this is the commonest starting point for diagnostic evaluation: a clinician is consulted by a (usually breathless) patient with a chest radiograph that shows widespread pulmonary shadows.
About one in every 3000-4000 of the population in Britain has diffuse lung disease, and about 3000 people die each year from it.1 Cryptogenic fibrosing alveolitis is the most common diffuse lung disease and carries the worst prognosis: in all studies half of patients are dead within five years of presentation despite treatment, and only a quarter show an apparent response to treatment.*RF 1a4* In the United Kingdom mortality from fibrosing alveolitis is increasing and approaching 1500 a year.5
Diffuse (interstitial) lung disease
Organic dusts (extrinsic allergic alveolitis)
Inorganic dusts (pneumoconioses)
Gases or fumes
Drugs or radiation
Cryptogenic fibrosing alveolitis
Interstitial lung disease associated with rheumatological diseases (such as rheumatoid arthritis and systemic sclerosis)
Granulomatous diseases (such as sarcoidosis and Langerhans' cell histiocytosis)
Neoplasia (such as lymphoproliferative diseases, metastases, and lymphangitis carcinomatosa)
Miscellaneous (such as amyloidosis and alveolar proteinosis)
Inherited diseases (such as neurofibromatosis)
Despite these disturbing figures, a recent survey of the management of fibrosing alveolitis in three regions in Britain revealed that few patients underwent investigations to confirm the diagnosis.6 Transbronchial biopsy was performed in one third of 200 patients (and was believed to be diagnostic in 40% of these); diagnosis was confirmed by open lung biopsy in 7.5%; and bronchalveolar lavage was undertaken in 17.5%; and treatment was started at the time of diagnosis in only 66%. In contrast, in a review of practice in the United States transbronchial biopsy was performed in two thirds of cases, and 42% of patients underwent open lung biopsy if a “non-specific” answer was obtained from the transbronchial sample.7 These different approaches to the same problem are also evident in comparisons of management of other diffuse lung diseases and highlight the need for clear management plans. Guidelines on standards of care, particularly regarding appropriate investigation and timing of treatment, have never been agreed. A strategy of conservative management has come to be the most commonly chosen option for these relatively uncommon and often slowly progressive diseases even though this has not improved our understanding of the diseases or long term outcome.
However, more sophisticated investigations are now available that can provide greater information about diagnosis and prognosis and thus a more logical approach to questions of managment, which have not changed over the past 20 years. The most striking innovation has been the use of high resolution computed tomography to define better the diffuse lung diseases. This technique, used in concert with some established investigations, can provide the framework for designing properly controlled evaluative studies of management. The purpose of this article is to show how improvements might be made in the diagnostic approach to diffuse lung disease in general and also, using cryptogenic fibrosing alveolitis as an example, how prognostic indices may be derived that could refine our approach to treatment.
Diagnosis of diffuse lung disease
Figure 1 shows a protocol for the diagnosis of diffuse lung disease. An initial phase of investigation is followed by more specific tests to arrive at a precise diagnosis and, in the case of fibrosing alveolitis, a more refined prediction of prognosis. The key “tools” in the process are bronchoalveolar lavage, high resolution computed tomography, and biopsy (usually thorascopic).
Bronchoalveolar lavage has been used to sample cells and non-cellular material from the lower respiratory tract in the evaluation of diffuse lung disease for more than 15 years.8 Initial hopes that this would provide an alternative to lung biopsy with high specificity for diagnosis have generally not been realised. Although the technique can provide diagnostic samples for rare disorders such as alveolar proteinosis (bilameller bodies in lavage fluid) and occupational diseases (energy dispersive x ray analysis to identify inorganic particulate matter) and can help to exclude infection and malignancy, such precise information is not obtained for most diffuse lung diseases.
Value of bronchoalveolar lavage in assessing diffuse lung disease
Extrinsic allergic alveolitis
Adult respiratory distress syndrome
Cryptogenic fibrosing alveolitis
Good response to corticosteroids if increased numbers of lymphocytes
Poor response to corticosteroids if increased numbers of eosinophils or neutrophils alone
More likely response to cyclophosphamide if numbers of neutrophils increased
Despite this, a case can be made for lavage in the evaluation of all patients suspected of having diffuse lung disease because the type of inflammatory cell in the lower respiratory tract helps to confirm the diagnosis.9 The presence of abnormal numbers of granulocytes, particularly neutrophils and eosinophils, is typical for a patient with fibrosing alveolitis; excess lymphocytes are associated with granulomatous diseases and drug induced causes of lung disease; and a CD4:CD8 (helper: suppressor T cells) ratio of more than 3.5 increases the probability that the diagnosis is sarcoidosis. The predominant inflammatory cell obtained by lavage therefore provides a useful indication of the nature of the underlying disease, particularly when the diagnosis is not clear from other investigations. Results from lavage may also throw into question a diagnosis made purely on clinical grounds.
High resolution computed tomography
The use of high resolution computed tomography over the past five years has revolutionised the approach to diffuse lung disease.*RF 10-12* The pattern of abnormality may be characteristic in several diseases and is virtually pathognomonic in most cases of cryptogenic fibrosing alveolitis. Several studies have shown that high resolution computed tomography can identify disease before abnormality is apparent in a chest radiograph13 and that computed tomography is superior to chest radiography in diagnostic accuracy.14, 15 Mathieson et al studied 118 patients with diffuse lung disease with diagnosis confirmed by biopsy.14 Independent observers attempted to make diagnoses based on paired chest radiographs and tomograms: they made a “definite” diagnosis with 23% of the chest radiographs and 49% of the tomograms, the diagnoses being correct in 77% and 93% of cases respectively. A correct diagnosis irrespective of the degree of confidence was made with 57% of the radiographs and 76% of the tomograms.
Tung et al reported the accuracy of diagnosing fibrosing alveolitis with computed tomography in a paired study of 86 patients (41 with fibrosing alveolitis and 45 with other diffuse lung diseases).15 Computed tomography was found to discriminate accurately between fibrosing alveolitis and other diseases in 88% of cases compared with 76% of cases when chest radiography was used. False negative results for fibrosing alveolitis fell from 29% with chest radiography to 11% with computed tomography.
High resolution computed tomography
Characteristic patterns of abnormality shown by:
Langerhans' cell histiocytosis
Extrinsic allergic alveolitis
Diagnosis of a diffuse lung disease should generally be confirmed by biopsy if computed tomography is not diagnostic (computed tomography can also help to determine the site and type of biopsy needed). Transbronchial biopsy will often confirm the diagnosis of bronchocentric disease such as sarcoidosis,16 but with other diffuse lung diseases it will only be helpful in excluding some disorders since, although it commonly provides evidence of inflammation, this is of a non-specific nature. At this stage a decision has to be made about a more invasive biopsy procedure, which in practice means minithoracotomy or thoracoscopic biopsy. If the diagnosis is uncertain biopsy is clearly indicated. More controversial is the need for an open biopsy in cases of fibrosing alveolitis in which tomographic appearances may be pathognomonic. Here a decision to perform open lung biopsy depends on assessment of individual cases. A patient aged over 65 or with poor lung function, especially with hypoxia at rest, is at high risk from any operation. In these circumstances it is reasonable to make a clinical diagnosis reinforced by computed tomography. With a younger patient, provided computed tomography shows a predominantly reticular pattern, confirmation of diagnosis and prognosis by biopsy is usually unnecessary. However, if computed tomography provides an equivocal prognosis in a younger patient, for whom prolonged treatment with potentially toxic drugs is being considered, it is important to perform a biopsy before treatment is started.
Choice of biopsy procedure
Extrinsic allergic alveolitis
Open lung (or thoracoscopic)
Other diffuse fibrosing lung disease
Langerhans' cell histiocytosis
Need for biopsy - It is often argued that treatment will be the same with or without confirmation of the diagnosis by biopsy and that biopsy therefore changes little and carries a risk of mortality. This view would be acceptable if empirical treatment always produced an improvement, but when the reverse is the case the next step in managment is more difficult. This is made worse if drug induced side effects have developed, particularly those related to treatment with high doses of corticosteroids. A clear diagnosis confirmed by biopsy allows clinicians and patients to discuss fully the implications of the disease, to develop a clear plan of treatment, and to weigh up the advantages and disadvantages of treatment. Morbidity and mortality from open biopsy are low. In a series of 101 patients in whom minithoracotomy was performed four patients died, but in three the cause of death was progression of the disease for which the biopsy was undertaken and the fourth patient was already in severe respiratory failure of unknown cause.17
Prognosis for fibrosing alveolitis
Many studies have examined which clinical factors and results of investigations predict a good prognosis for fibrosing alveolitis, but the data are confusing because of the variety of factors analysed and because mixed groups of treated and untreated patients were often studied. Turner- Warwick et al retrospectively analysed data on 220 patients, of whom 77 had received no treatment.2 Factors that predicted better survival in the untreated group were being female and younger age at presentation or start of symptoms. Median survival in these patients was 4 1/2 years. In the treated group factors associated with a better survival were younger age at presentation or start of symptoms, less dyspnoea, less profuse radiographic abnormality, a more cellular histological appearance on lung biopsy, and a good early response to corticosteroids. Responsiveness to steroids was closely linked with a more cellular appearance on biopsy. Median survival in the patients who responded to corticosteroids approached nine years.
In a large series of 100 treated patients longer survival was associated with younger age, a shorter duration of symptoms before presentation, less radiographic abnormality, less impairment of carbon monoxide transfer factor, and an early response to corticosteroids.18
Correlating the histological appearance of biopsy specimens with indices such as survival is difficult because the disease process is patchy and it is never certain that a specimen is representative of the overall condition. It seems clear, however, that early disease, especially of a more cellular variety, carries a much more favourable prognosis and that improved survival is determined largely by the factors predicting a good response to treatment. If overall prognosis is to be improved new strategies of management need to be devised; this would include identification of less advanced disease, prediction of cellularity, and estimates of probable response to treatment and probable progression of disease in individual patients. Computed tomography can provide this information in many cases.
High resolution computed tomography Prediction of appearance of biopsy specimens
Because computed tomography has improved the diagnostic accuracy of non-invasive investigation of fibrosing alveolitis, the main indication for lung biopsy now is to assess the relative degrees of cellularity and fibrosis. If computed tomography could predict pathological appearances the need for lung biopsy would be further reduced, and advances have been made in this area. Two distinct patterns of disease may be seen in tomograms: a ground glass increase in attenuation (fig 2) and a reticular pattern (fig 3). The ground glass pattern is associated with a cellular histological appearance of that area of lung whereas the reticular pattern is found in patients whose subsequent lung biopsy confirms fibrosis.*RF 19-21* A recent study reports the value of using computed tomography to predict the relative proportions of cellular to fibrotic disease in patients who underwent biopsy after examination by computed tomography.20 In 12 out of 13 cases a mainly reticular pattern accurately predicted a predominantly fibrotic histology, but only four out of seven predictions of at least equivalent amounts of cellularity and fibrosis were correct. The overinterpretation of more cellular disease might be due to two reasons. Firstly, the presence of fine fibrosis is beyond the resolution of the computed tomographic scanner and would be indistinguishable from cellular infiltrate. Secondly, the overall scoring of relative degrees of cellularity and fibrosis made on the basis of the tomographic appearance of the lung as a whole might give a more accurate assessment than biopsy, which samples only a small piece of peripheral lung. Possibly computed tomography is the more reliable investigation, but until this issue is clearer patients whose tomograms show at least equivalent cellularity and fibrosis should still undergo biopsy to complete evaluation.
Prediction of response to treatment and outcome
Computed tomography can also be used to predict response to treatment and outcome, based on the pattern of disease, and has been shown to be more accurate than chest radiography.22 In this study radiologists were more likely to agree on the pattern of disease with computed tomography (81%) than with chest radiography (54%). A predominantly ground glass appearance was associated with more cellular disease and with greater improvement in lung function and reduction in the extent of the disease in response to treatment than if computed tomography showed increasing amounts of reticular change.23, 24 In a study of 76 patients 43% of those with predominantly ground glass appearance in tomograms obtained significant (>15%) improvement in measures of lung function compared with 33% of patients with a mixed appearance and 9% with a mainly reticular pattern.23 This improved response rate was matched by survival figures A mainly ground glass pattern was associated with 100% survival at 50 months after diagnosis compared with a 50% survival for patients with more reticular disease. These observations are identical to survival figures observed after biopsy was used to categorise patients on the basis of relative degrees of cellularity and fibrosis. Lastly, a decrease in the extent of disease in response to treatment was due entirely to a diminution of ground glass pattern; a reticular pattern never reduced.24
Computed tomography can therefore not only improve diagnostic certainty with diffuse lung disease but also substantially improve the assessment of prognosis for fibrosing alveolitis without recourse to biopsy. Although biopsy will still be required in some cases, fewer biopsies will be needed, and this is already the position in our institution. This has important implications for improved management of patients and health economies - computed tomography is less invasive and considerably cheaper than open biopsy.
High resolution computed tomography as a guide to prognosis for fibrosing alveolitis
Greater sensitivity and diagnostic accuracy than chest radiography
Can predict histological appearance of lung biopsy specimens
Can predict response to treatment and survival
Bronchoalveolar lavage may be of prognostic value. The presence of increased numbers of lymphocytes is usually associated with a good response to corticosteroids and thus a better overall prognosis, whereas the presence of increased numbers of eosinophils or neutrophils without increased numbers of lymphocytes predicts a poorer response to corticosteroids in established fibrosing alveolitis but a better response to cyclophosphamide.25 There is, however, considerable individual variation, and many patients with persistently increased numbers of granulocytes in lavage fluid have a stable disease course.
Technetium (99mTc) diethylenetriamine pentaacetate
Although computed tomography can provide indicators of good prognosis, it is less helpful in predicting deterioration. The clearance of inhaled nebulised technetium (99mTc) diethylenetriamine pentaacetate has now been shown to be of value not only in identifying early fibrosing alveolitis but also in predicting which patients are more likely to deteriorate.26 The speed of clearance of the isotope from the lung is dependent on the integrity of the epithelial barrier, and anything that disrupts this, either inflammation or fibrosis, will therefore increase the rate of clearance. Clearance of the isotope is highly sensitive; cigarette smoking will produce increased rates of clearance so that the test is of value only for non-smokers or people who have given up smoking for at least one month before assessment.
The rate of clearance of isotope, particularly the change in rate of clearance, can predict subsequent changes in pulmonary function. In one study, patients with persistently abnormal rates of clearance over 12 months were more likely to show deterioration in pulmonary function at subsequent follow up.26 Of 33 patients with abnormal clearance on two occasions, 10 suffered a decline in pulmonary function of more than 15% over the next 20 months. In contrast persistently normal clearance of isotope predicted stable disease and therefore provided a further index of good prognosis. Significant improvement in pulmonary function tests occurred in six out of eight patients whose clearance returned to the normal range, whereas similar improvements were not seen in patients whose clearance remained normal or abnormally fast.
The most important issue is when to start treatment. Most of the drugs used to treat diffuse lung disease have the potential for serious side effects, and this is often a powerful disincentive to using them until there is “no other option.” By the time a patient has developed unequivocal breathlessness, however, a considerable proportion of functional lung capacity has already been lost. Diseases affecting the acinar regions of the lungs reduce lung function piecemeal, which may not be perceived as abnormal by the patient for some time because there is considerable pulmonary reserve capacity and because some breathlessness is regarded as normal in middle age. By this stage considerable irreversible changes have probably occurred. In this situation it is not surprising that meaningful improvements (>15% of baseline) in lung function are uncommon and that the best that can be achieved is often only stabilisation of the disease to prevent further deterioration. It is this lack of substantial improvement, often compounded by a failure to treat the disease until symptoms of breathlessness are more severe, that has given rise to the misconception that treatment is ineffective - a severely breathless patient whose disease has been stabilised will still be severely breathless.
It is therefore critical that any increase in exercise intolerance or any abnormality seen in a chest radiograph, no matter how mild this may appear, is investigated. Detection of early disease when symptoms are trivial or absent would provide an opportunity to prevent more severe symptoms, but confidence to treat at this stage requires reliable predictors of likely disease progression that would justify the use of potentially toxic drugs. We now have such predictors for fibrosing alveolitis.
The appearance of the lungs on high resolution computed tomography can predict the degree of the inflammatory component (which is responsive to treatment) in lung biopsies, and this is of considerable help when making a decision about starting treatment. This can be used in conjunction with measurements of clearance of technetium (99mTc) diethylenetriamine pentaacetate to try to predict disease progression and response to treatment. I have used an assessment protocol based on these indices for fibrosing alveolitis occurring alone or in the context of the rheumatological diseases (fig 4). Clinical trials are being designed to test this approach. These long term evaluative studies are urgently needed to provide universal guidelines for the management of this most aggressive diffuse lung disease (which could be adapted for use in the other diseases in this group).
Diffuse lung disease kills 3000 people each year in the United Kingdom
No guidelines on standards of care exist
Present treatment approaches are often unsuccessful
New technologies, particularly high resolution computed tomography, have improved our appreciation of type, stage, and prognosis of disease
These investigations can be used to define strategies for diagnosis, treatment, and long term evaluative studies
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