In search of a cause of cryptogenic fibrosing alveolitis (CFA): one initiating factor or many?

The history of patients with idiopathic pulmonary fibrosis (IPF) shows that the disease may be preceded by a viral-like illness. Although viruses have not been demonstrated, it is possible that viruses were not detected in culture because they do not replicate during latency. We investigated the presence of adenovirus in IPF and interstitial pneumonia associated with collagen vascular disease (CVD-IP), using the nested polymerase chain reaction (PCR) and in situ hybridization (ISH) for the E1A region of the adenovirus genome. Studies were performed on lung tissues obtained by transbronchial lung biopsy from 19 patients with IPF, 10 patients with CVD-IP and, for comparison, 20 patients with sarcoidosis. The E1A DNA was present in 3 out of 19 (16%) cases of IPF, in 5 of 10 (50%) cases of CVD-IP, and in 2 of 20 (10%) cases of sarcoidosis. The incidence of E1A DNA in CVD-IP was significantly higher than that in sarcoidosis (p < 0.05). In patients with IPF and CVD-IP, E1A DNA was more prevalent in patients treated with corticosteroids (6 out of 9 cases; 67%) than in those without it (2 out of 20 cases; 10%) (p < 0.01). ISH studies showed that 1 out of 8 cases of IPF and CVD-IP, in which E1A DNA was detected by PCR, was positive for E1A DNA. We conclude that adenovirus E1A is unlikely to be aetiologically involved in the pathogenesis of idiopathic pulmonary fibrosis or interstitial pneumonia associated with collagen vascular disease. However, a latent adenovirus infection may be reactivated or may newly infect the host following corticosteroid administration.

Patient/doctor relationships in the new NHS.

In spite of the radical changes in the delivery of health care, patients still need a high quality, professional individual relationship with their doctor. As modern medicine increases in complexity, this need becomes more crucial. It must not be eroded by pressures on time, manpower restrictions or financial expediency. Teamwork with other skilled health-care workers is complementary and greatly enhances the quality of care, but it is not a substitute.

Extrinsic allergic alveolitis and asthma in a sawmill worker: case report and review of the literature.

A 34 year old sawmill maintenance engineer developed a dry cough that was associated with widespread wheezes and crackles in his lungs. His symptoms worsened, with work related lethargy, fever, and breathlessness, and the loss of a stone in weight. At that time, while still at work, he had a neutrophil leucocytosis and increased concentration of gamma globulins. When seen subsequently some two months after stopping work, his chest radiograph and lung function tests were normal, but the cells recovered at bronchoalveolar lavage showed an increase in lymphocytes and mast cells, a pattern consistent with extrinsic allergic alveolitis. Serum precipitins were identified to extracts of sawdust, wood chips, and bark from the sawmill, and to eight species of mould grown from these samples. Specific IgG binding inhibition studies suggested that a common epitope present on Trichoderma koningii might be responsible for the cross reactivity of the patient's serum with the wood and fungal extracts. A diagnosis of wood associated extrinsic allergic alveolitis was made and since changing his job the patient has remained well. Wood associated allergic alveolitis has not previously been described in British sawmill workers, but has been reported in Sweden, with a prevalence of 5%-10% in exposed workers. A review of published data suggests extrinsic allergic alveolitis in wood workers is primarily caused by inhalation of the spores of contaminating fungi, but inhaled wood dust may exert a synergistic effect.

Structural features of interstitial lung disease in systemic sclerosis.

Most studies of lung histology in systemic sclerosis have been based on autopsy specimens and consequently emphasize end-stage fibrotic disease. Although occasional pathologic descriptions of open-lung biopsies have recognized the presence of inflammatory cells, suggesting a similarity to "lone" cryptogenic fibrosing alveolitis, the two conditions have never been formally compared. In this study we describe the morphologic features of 49 open-lung biopsies from 34 systemic sclerosis patients with interstitial lung disease, many of whom had their lung disease diagnosed at an early stage. None had pulmonary hypertension. Examination of lung tissue by light microscopy showed the earliest changes to include patchy lymphocyte and plasma cell infiltration of the alveolar walls, interstitial fibrosis, and increased macrophages but only occasional polymorphonuclear cells and lymphocytes in the alveolar spaces. Alveolitis was not observed without fibrosis. Comparison of 22 biopsies with a similar number from patients with lone cryptogenic fibrosing alveolitis, matched for age and sex, revealed no qualitative or quantitative differences, other than a higher prevalence of focal lymphoid hyperplasia (follicular bronchiolitis) in the systemic sclerosis patients than in the lone cryptogenic fibrosing alveolitis controls (23 and 5%, respectively). There was an inverse correlation between the extent of interstitial inflammation and patients' age (p less than 0.05), disease duration (p less than 0.05), and age at onset of systemic sclerosis (p less than 0.01). There was also an inverse correlation between DLCO and interstitial fibrosis (p less than 0.01) and loss of lung architecture (p less than 0.05). Ultrastructural studies of eight systemic sclerosis biopsies showed evidence of endothelial and epithelial injury together with interstitial edema and excess collagen deposition. Occasional mast cells were observed, often in close contact with interstitial fibroblasts, but there were no tubuloreticular structures or evidence of immune complexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Can asthma be cured?

1. There is much evidence that many asthmatics lose their symptoms for long periods and are in this sense 'cured'. 2. The factors leading to restitution of normally reactive healthy airways are multiple and only partially understood. 3. Attempts at cure are likely to require a multi-faceted approach where inducers and sensitizers of asthma are reduced as far as possible at the same time as stimulating biological factors whose function is to preserve normal patho-physiology of the airways. 4. Identification of these controlling factors requires intensive study using naturally occurring models of individuals who have and have not gone into remission. 5. Whether anti-asthma medication will help usefully in redressing the balance or whether by inhibiting the stimulus for the production of inherent biological controlling factors, they actually mitigate against persisting remission (i.e. 'cure') needs urgent study. Such a possibility might account for some of the remarkable inconsistencies in epidemiological studies currently being reported. In particular, while medications for the control of asthma have improved dramatically over the last twenty years, the prevalence and perhaps mortality rates from asthma are actually rising. However until evidence is much firmer, the dangers of undertreating asthma must be recognized.

Combined cryptogenic fibrosing alveolitis and emphysema: the value of high resolution computed tomography in assessment.

Simple tests of lung function may be misleading in the assessment of patients with interstitial lung disease. Eight patients are described with cryptogenic fibrosing alveolitis (histologically proven in four) with severe breathlessness and low gas transfer (median DLCO 32.4%, range 9.2 to 35.3%, % predicted) in whom lung volumes were preserved [median VC 98.7, range 67.5-131.1%; median TLC 92.5, range 88.1 to 121.2, (% predicted)], and in whom there was no evidence of airflow obstruction [median FEV1/FVC 84.6, range 68-116 (% predicted)]. All were current or ex-heavy smokers. Thoracic high resolution computed tomography revealed upper zone emphysema, the extent of which was not appreciated using conventional chest radiography. The atypical physiological and radiological features can be explained by coincidental cryptogenic fibrosing alveolitis and emphysema and high resolution computed tomography was valuable in the assessment of these patients.

Computed tomography in adult obliterative bronchiolitis.

Fifteen adults with obliterative bronchiolitis (OB) were investigated with computed tomography (CT). CT was considered to be abnormal in 13/15 patients (87%) showing widespread areas of increased attenuation of a patchy nature and variable proportion. CT revealed more extensive changes than the chest radiograph or bronchogram. It is a non-invasive well-tolerated and easily repeatable technique and may have an important role in the radiological evaluation of adults with OB.

Pulmonary involvement in systemic sclerosis: the detection of early changes by thin section CT scan, bronchoalveolar lavage and 99mTc-DTPA clearance.

Systemic sclerosis is frequently complicated by fibrosing alveolitis although clinical and radiological abnormalities are not usually apparent until the lung disease is well established. The aim of this study was to investigate pulmonary involvement in systemic sclerosis by thin section CT scan, bronchoalveolar lavage (BAL) and 99mTc-DTPA clearance studies, and assess the value of these tests in defining pulmonary abnormalities in patients with a normal chest radiograph. Patients were divided into those with an abnormal chest radiograph (Group I, n = 14) and those with a normal chest radiograph (Group II, n = 16). CT scans were abnormal in all patients in Group I and 7 of 16 (44%) in Group II. BAL inflammatory cell counts were raised in all 12 (100%) patients studied in Group I and 11 of 15 (73%) in Group II. There was no difference in the type of inflammatory cells observed between the two groups. 99mTc-DTPA clearance was faster than normal controls in ten of 14 patients (71%) in Group I and seven of 15 (47%) in Group II and correlated with carbon monoxide transfer factor (P less than 0.05). Lung biopsies were performed on nine patients in Group I and three in Group II all of whom had abnormal CT scans. Fibrosing alveolitis was confirmed in every case. Group II biopsies could not be distinguished from Group I biopsies; both showed fibrosis as well as inflammation suggesting that pulmonary fibrosis is an early abnormality in systemic sclerosis. Our results indicate that CT scans, BAL and 99mTc-DTPA are frequently abnormal in asymptomatic patients with systemic sclerosis who have normal chest radiographs. When the CT scan is normal abnormalities of BAL and/or 99mTc-DTPA (99mTechnetium diethylenetriamine pentacetate) clearance may indicate lung disease at a still earlier stage. This observation requires further investigation.

Advanced cryptogenic fibrosing alveolitis: preliminary report on treatment with cyclosporin A.

Seven patients with fibrosing alveolitis who failed to respond to prednisolone and cyclophosphamide and were deteriorating, were treated with cyclosporin A. An initial favourable response was seen but was not maintained. When compared to a control population, matched for the extremely severe disease present in the treated group, survival was doubled from 2.5 to 5 months. With growing awareness of the possibility of heart-lung transplantation in this disease, even this trivial increase in survival may be of crucial importance in individual patients.

Lung permeability in adult obliterative bronchiolitis.

There is histopathological evidence that, in certain inflammatory disorders involving the smaller airways, extension of the inflammatory process may occur distally into the respiratory bronchioles, alveolar ducts and alveoli (1,2). The objective of this study was to perform a non-invasive evaluation of the possible involvement of gas exchanging regions of the lung in obliterative bronchiolitis presenting with severe airways obstruction. We measured the clearance of technetium 99m-labelled diethylene triamine penta-acetate (99m Tc-DTPA) with time from the lungs to the blood, in 11 normal, non-smoking subjects (mean age 30 years), ten non-smoking patients with cryptogenic fibrosing alveolitis (CFA, mean age 57 years) and ten patients who were non-smokers with obliterative bronchiolitis (mean age 51 years). There was a substantial increase in clearance in patients with CFA, (mean T1/2 19.9 min), compared with either patients with obliterative bronchiolitis (mean T1/2 52.2 min; mean difference 32.3; 95% confidence intervals (CI) 18.40; P less than 0.001) or normal controls (mean T1/2 84.3; mean difference 64.4; 95% CI 55, 74; P less than 0.001). Clearance was also significantly faster in patients with obliterative bronchiolitis than in normal controls (mean difference 32.1; 95% CI 18.48; P less than 0.001). Peripheral deposition of 99m Tc-DTPA was uniform in normal subjects and patients with CFA, but patchy in patients with obliterative bronchiolitis, possibly resulting from altered patterns of ventilation associated with patchy distribution of bronchiolitis within affected lungs. Increased clearance of 99m Tc-DTPA from the lungs in these patients suggests that subtle derangement of the alveolar-capillary membrane occurs in adult obliterative bronchiolitis.

Nocturnal asthma: a study in general practice.

Symptoms of nocturnal asthma were studied using questionnaires returned by 1199 general practitioners throughout the United Kingdom. Of 7729 asthmatic patients seen consecutively and prescribed a bronchodilator aerosol, 73% woke with asthma at least once a week and 39% woke nightly. The percentage of asthmatics waking at night at least once a week in this population, where 48% were prescribed corticosteroid aerosols, was very similar to the 74% found to have asthma attacks at night in an earlier study of new hospital referrals at a time when such medication was not available. While sampling bias cannot be excluded, the clinical characteristics and profile of medications found in this study are similar to other reports and the evidence suggests that the general practitioners were managing these patients carefully. There was an overall association between the patients' perception of the severity of their asthma and frequency of waking at night (P less than 0.001). However, 26% of 2928 patients waking every night regarded their asthma as mild. These patients were taking significantly less medication than those also waking nightly but assessing their asthma as severe (P less than 0.001). The seriousness of nocturnal symptoms may be underestimated by asthmatics and they should be asked specifically about the frequency of nocturnal waking. Those with nocturnal asthma had a generally higher frequency of allergic and non-allergic provoking factors, but no single factor distinguished these patients from those without nocturnal symptoms. There was a strong correlation between the frequency of nightly waking and the number of medications used (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Are the results of early long-term trials of sodium cromoglycate valid?

The first long-term study of sodium cromoglycate, reported in 1972, demonstrated the effectiveness of sodium cromoglycate in controlling asthma. The trial had various limitations, but more recent trials have been designed so that they overcome some of these problems. Results of these trials validate the results obtained in the first long-term trial.

Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis.

In a randomised, controlled study alternate day prednisolone with an initial high dose phase ("prednisolone only series") has been compared with cyclophosphamide plus alternate day low dose prednisolone ("cyclophosphamide-prednisolone series") in 43 patients with previously untreated fibrosing alveolitis (five patients had received prednisolone in minimal dosage). In the prednisolone only series prednisolone 60 mg daily was given for one month and then reduced by 5 mg a week to 20 mg on alternate days or the minimum dose to maintain early improvement. Patients in the cyclophosphamide-prednisolone series received 100, 110, or 120 mg cyclophosphamide daily (depending on body weight) plus 20 mg prednisolone on alternate days. Treatment was continued indefinitely, or changed to the alternative regimen if the patient deteriorated, failed to improve, or developed drug toxicity. For response to treatment (as judged by change in breathlessness score, radiographic appearance, and lung function) patients were classified as improved, stable, or deteriorating. Deaths from cryptogenic fibrosing alveolitis were also analysed. Improvement had occurred at one or more assessments in seven of the 22 patients in the prednisolone only series and in five of the 21 patients in the cyclophosphamide-prednisolone series. At three years, however, only two of the 22 patients in the prednisolone only series were still improved and three stable, compared with one and seven of the 21 patients in the cyclophosphamide-prednisolone series (three of the seven had stopped treatment because of toxicity). Life table analysis suggested better survival in patients in the cyclophosphamide-prednisolone series but this was not significant. At three years 10 of 22 patients in the prednisolone only series had died compared with three of 21 patients in the cyclophosphamide-prednisolone series. With death or failure of first treatment regimen as outcome there was a significant advantage to the patients having cyclophosphamide-prednisolone. This advantage was explained in part by the better lung volumes in this group on admission. After allowance had been made for total lung capacity (TLC), no other factor was predictive of outcome. Analyses of subgroups according to TLC on admission showed that patients with a TLC below 60% predicted did badly and those with a TLC of 80% or more predicted did well with both regimens. Patients with an initial TLC of 60-79% predicted did better with the cyclophosphamide-prednisolone regimen. Side effects were uncommon in both series and those due to cyclophosphamide resolved when treatment was stopped. The combination of cyclophosphamide with prednisolone may be an alternative to prednisolone alone with an initial high dose phase. Many patients, however, failed to respond to either treatment.

Observations on sputum production in patients with variable airflow obstruction; implications for the diagnosis of asthma and chronic bronchitis.

There are few clinical studies on hypersecretion in asthma, defined as variable airflow obstruction. One hundred and thirty defined asthmatics were questioned in detail about their clinical features, with special reference to sputum production. Other clinical and laboratory data were obtained from the hospital notes. Thirty (23%) denied sputum production at any time. Of the hundred patients reporting sputum, 55 reported the largest volume when an attack of asthma was at its worst and 42 reported most sputum during recovery. Three patients reported unchanging sputum volumes regardless of asthma attacks. There was an association between greater sputum volumes and increased absenteeism due to respiratory symptoms (P less than 0.01) and negative prick skin tests (P less than 0.001). Cigarette smoking and bronchopulmonary aspergillosis were uncommon among our patients, and did not alone account for the sputum production rates. Sixty-eight per cent of patients reported that their pattern or volume of sputum production during attacks had not changed substantially since the onset of their asthma. Patients also fulfilling the Medical Research Council (MRC) criteria for chronic bronchitis (n = 56) were more likely to have smoked than those who did not (P less than 0.005), although 32 (57%) of the asthmatics with chronic bronchitis had smoked little or not at all. Moreover the lability of peak flow measurements was similar in asthmatic patients with and without chronic bronchitis (Lability index 43 and 42% respectively). The prevalence of persistent airflow limitation (PAL) in addition to a variable component related to duration of asthma but not to smoking. The relation between PAL and sputum production was complex.(ABSTRACT TRUNCATED AT 250 WORDS)