Epstein-Barr virus replication within pulmonary epithelial cells in cryptogenic fibrosing alveolitis.

BACKGROUND--Cryptogenic fibrosing alveolitis (synonymous with idiopathic pulmonary fibrosis) is a clinically heterogeneous condition in which the precipitating factor is unclear. Both environmental and infective factors have been implicated. An association between Epstein-Barr virus (EBV) and cryptogenic fibrosing alveolitis was suggested over a decade ago by a study based on EBV serology, but the significance of this has been unclear. METHODS--Lung tissue obtained surgically from patients (n = 20) with cryptogenic fibrosing alveolitis was investigated for evidence of EBV replication and compared with lung tissue from 21 control patients. Fourteen of the 20 patients had received no specific therapy for cryptogenic fibrosing alveolitis at the time of biopsy. Monoclonal antibodies directed against the EBV viral antigens, EBV viral capsid antigen (VCA) and gp 340/220 antigen, which are expressed during the lytic phase of the EBV life cycle, were studied. RESULTS--Fourteen (70%) of the 20 patients with cryptogenic fibrosing alveolitis were positive for both EBV VCA and gp 340/220 compared with two (9%) of the 21 controls. In the patients with cryptogenic fibrosing alveolitis viral replication was localised to pulmonary epithelial cells using epithelial cell markers, and immunohistochemical analysis confirmed the staining to be within type II alveolar cells. CONCLUSIONS--This is the first report of in vivo EBV replication within epithelial cells of the lower respiratory tract in an immunocompetent human host. Furthermore, this suggests that EBV may be an immune trigger or contribute to lung injury in cryptogenic fibrosing alveolitis, thus offering a potential new avenue of treatment.     

Detection of anti-cytokeratin 8 antibody in the serum of patients with cryptogenic fibrosing alveolitis and pulmonary fibrosis associated with collagen vascular disorders

BACKGROUND: It has been suggested that the humoral immune system plays a role in the pathogenesis of cryptogenic fibrosing alveolitis (CFA). Although circulating autoantibodies to lung protein(s) have been suggested, none of the lung proteins have been characterised. The purpose of this study was to determine the antigen to which the serum from patients with pulmonary fibrosis reacted. METHODS: The anti-A549 cell antibody was characterised in a patient with CFA using Western immunoblotting and immunohistochemical staining of A549 cells. As we identified that one of the antibodies against A549 cells was anti-cytokeratin 8, the expression of mRNA of cytokeratin 8 in A549 cells was evaluated. In addition, we attempted to establish an enzyme linked immunosorbent assay to measure the levels of anti-cytokeratin 8 antibody in the serum of patients with CFA and pulmonary fibrosis associated with collagen vascular disorders (PF-CVD). RESULTS: Initially two anti-A549 cell antibodies were detected in the serum of patients with pulmonary fibrosis, one of which was characterised as anticytokeratin 8 antibody by Western immunoblotting. We were able to establish an ELISA to measure anti-cytokeratin 8 antibody and found significantly higher levels in patients with CFA and PF-CVD than in normal volunteers, patients with sarcoidosis, pneumonia, and pulmonary emphysema. CONCLUSIONS: One of the anti-A549 cell antibodies in the serum of patients with CFA was against cytokeratin 8. The serum levels of anti-cytokeratin 8 antibody were increased in patients with CFA and PF-CVD. These results suggest that anticytokeratin 8 antibody may be involved in the process of lung injury in pulmonary fibrosis.     

The significance of antinuclear and DNA antibodies in cryptogenic fibrosing alveolitis

The roles of antinuclear and DNA antibodies in the pathogenesis of cryptogenic fibrosing alveolitis were investigated in 53 patients. Twenty-two patients who had antinuclear antibodies detected in their serum had a significantly higher proportion of women, a higher prevalence of Raynaud phenomenon and digital vasculitis, and higher erythrocyte sedimentation rates, paralleled by raised serum globulin and IgG levels, than patients with no antinuclear antibodies detected. Serum antibodies to double-strand DNA (DS-DNA), assayed by a Farr binding technique, were significantly raised in 25% of patients with cryptogenic fibrosing alveolitis. Serum binding of single-strand DNA (SS-DNA) was greatly increased in all the patients with cryptogenic fibrosing alveolitis, achieving levels similar to those found in systemic lupus erythematosus. Serum DS-DNA binding correlated with IgA levels but not with disease activity. Thus, unlike in systemic lupus erythematosus, antibodies to DS-DNA and SS-DNA with their capacity to form immune complexes are unlikely to be of major importance in the pathogenesis of cryptogenic fibrosing alveolitis.     

Cryptogenic fibrosing alveolitis with preserved lung volumes

BACKGROUND: Cryptogenic fibrosing alveolitis (CFA) is an uncommon disorder of unknown aetiology characterised by interstitial fibrosis which typically shows a restrictive pattern on pulmonary function testing. Some patients with CFA and relative preservation of lung volumes have been described and it has been suggested that their volume preservation may be due to concomitant emphysema. In a retrospective study the relative frequency of preserved lung volumes in CFA, its relationship to emphysema determined by CT scanning, its clinical features, and its subsequent natural history were investigated. METHODS: Using predefined characteristics 48 patients with CFA were identified from pulmonary function records over a three year period. Volume preservation was defined as a forced vital capacity (FVC) of > 80% predicted at presentation. Patients with relative volume preservation were compared with those with more typical pulmonary restriction and clinical data at presentation, and details of their subsequent prognosis, treatment and loss of lung function with time were obtained. Where available, computed tomographic (CT) scans for the two groups were compared in a blinded fashion to score the extent of fibrosis and the presence of concomitant emphysema. RESULTS: Twenty one (44%) of the patients with CFA had a FVC of > 80% predicted. They were more likely to be male (76% versus 48%) and to be current smokers (57% versus 22%) with a heavier life time cigarette consumption than the restricted patients (mean (SE) 38 (4.6) versus 25 (4.5) pack years). There were no significant differences in prognosis and subsequent treatment between the groups. Comparable HRCT scans were available in 23 subjects (seven preserved, 16 restricted). They showed no difference in extent of the pulmonary fibrosis but patients with volume preservation were more likely to show concomitant emphysema (86% versus 19%). Patients with emphysema on HRCT scans were heavier smokers (41(10) versus 21(17) pack years) than those without emphysema but there was no difference in the extent of CFA score between the two groups. CONCLUSIONS: In this area of high smoking prevalence a significant number of patients with CFA presented with relative preservation of lung volumes and FEV1/FVC ratio. In many of these subjects this appears to reflect coincidental emphysema. This may make interpretation of gas transfer factor used to monitor progression in CFA difficult. However, there was no evidence that lung volumes at presentation were of prognostic significance.


     

Cryptogenic fibrosing alveolitis and the fibrosing alveolitis of systemic sclerosis: morphological differences on computed tomographic scans

BACKGROUND: The purpose of this study was to identify morphological differences on the computed tomographic (CT) scan between cryptogenic fibrosing alveolitis (CFA) and the fibrosing alveolitis associated with systemic sclerosis (FASSc), and to examine their biological relevance. METHODS: One hundred and seven patients with CFA (n = 55) or FASSc (n = 52) who had undergone thin section CT scanning were included. Multivariate analysis was used to identify morphological differences on the CT scans between lone CFA and FASSc, and to determine whether the pattern and distribution of disease on the CT scans were functionally significant (as judged by the lung transfer factor (TLCO), forced vital capacity (FVC), and arterial oxygen tension (PaO2)) or predictive of survival (independent of the type and extent of fibrosing alveolitis, age, sex, and smoking history). RESULTS: Increasingly extensive disease on CT scans was associated with a coarser reticular pattern (increase in reticular score per percentage increase in disease extent = 0.06, 95% confidence interval (CI) 0.03 to 0.09, p < 0.0005) and increasing upper zone involvement (increase in ratio of upper zone to total disease per percentage increase in disease extent = 0.002, 95% CI 0.000 to 0.003, p < 0.04). Patients with CFA were characterised by a higher upper zone ratio (difference = 0.08, 95% CI 0.02 to 0.13, p < 0.004) and a weak trend towards a coarser reticular pattern (p = 0.09), independent of disease extent. Smokers with CFA had more upper zone involvement (difference = 0.11, 95% CI 0.05 to 0.16, p < 0.0005) and a coarser reticular pattern (difference in reticular score = 1.92, 95% CI 0.27 to 3.55, p < 0.02) than smokers with FASSc. The extent of disease on the CT scan was predictive of lung function impairment and survival but the pattern and distribution of disease were not. CONCLUSIONS: Patients with CFA have relatively more upper zone involvement than those with FASSc independent of the extent of disease on the CT scan. This finding may result from smoking related damage but is not functionally significant.


     

Decreased nitric oxide in the exhaled air of patients with systemic sclerosis with pulmonary hypertension

BACKGROUND: Systemic sclerosis (SSc) may be complicated by pulmonary hypertension (PHT), which can occur both in the setting of fibrosing alveolitis or as lone pulmonary vascular disease. Nitric oxide (NO) is a powerful vasodilator and is produced by various cells in the respiratory tract including pulmonary vascular endothelial cells and can be measured in expired air. A study was undertaken to test the hypothesis that exhaled NO levels would be decreased in patients with SSc with PHT and to assess the utility of this measurement in discriminating between patients with and without PHT, regardless of concurrent fibrosing alveolitis. METHODS: Exhaled NO was measured with a chemiluminescence analyser in 23 patients with SSc (six with PHT, 17 subjects without) and in 67 normal individuals. Doppler echocardiography was used to assess pulmonary artery pressure in subjects with SSc, and lung function tests were performed at the same visit as NO measurements. Thin section CT scans were analysed for the presence of abnormality consistent with fibrosing alveolitis. RESULTS: Patients with SSc with PHT had a greater reduction in arterial oxygen tension (PaO2) and carbon monoxide gas transfer (TLCO) than patients with SSc without PHT. Exhaled NO was significantly higher in patients with SSc without PHT than in normal individuals, and was significantly decreased in patients with SSc with PHT (mean (SD) 20 (6) ppb) compared with 149 (19) ppb in those with SSc without PHT (mean difference 129 (95% CI 112 to 146) ppb) and 80 (7) ppb in normal individuals (mean difference 60 (95% CI 54 to 66) ppb). CONCLUSION: Exhaled NO is decreased in patients with SSc with PHT compared with both normal individuals and patients with SSc without PHT.


     

Circulating antibodies to lung protein(s) in patients with cryptogenic fibrosing alveolitis.

BACKGROUND--It has been hypothesised that cryptogenic fibrosing alveolitis has an immunological pathogenesis mediated by T lymphocytes. It is, however, recognised that patients may show dysregulation of the humoral immune system and that the presence of large numbers of B lymphocytes in open lung biopsies may be associated with a poor prognosis. Evidence of a role for the humoral immune system in the pathogenesis of cryptogenic fibrosing alveolitis has been suggested, but attempts to demonstrate circulating immunoglobulin to antigen within the lung have been inconclusive. METHODS--Plasma samples from 22 patients with cryptogenic fibrosing alveolitis, 22 patients with sarcoidosis, and 17 healthy controls were screened by SDS-PAGE and Western blotting for the presence of autoantibodies to lung proteins derived from cryptogenic fibrosing alveolitis, sarcoid and control lung tissue, as well as four normal non-pulmonary tissues. Possible site(s) of target protein(s) within the lung tissue were identified by immunohistochemical examination using IgG purified from the plasma of six patients and two controls. RESULTS--Eighteen of the plasma samples from patients with cryptogenic fibrosing alveolitis had reactive IgG to lung protein(s) in the 70-90 kDa molecular weight range compared with five of 18 plasma samples from patients with sarcoidosis and one of 17 controls. Plasma from patients with cryptogenic fibrosing alveolitis recognised antigen(s) of the same molecular weight in control and sarcoid lung tissue, but not non-pulmonary tissues, with a similar frequency. Immunohistochemical staining of cryptogenic fibrosing alveolitis biopsy material using IgG purified from plasma samples from patients with cryptogenic fibrosing alveolitis, but not control samples, revealed fine linear positivity in the lung parenchyma in a pattern suggestive of reaction with alveolar lining cells. The pattern was cytoplasmic/membranous and not nuclear. CONCLUSIONS--Patients with cryptogenic fibrosing alveolitis have a high frequency of plasma IgG autoantibodies to protein(s) within lung tissue associated with alveolar lining cells. This is believed to be the site where immunological injury occurs in cryptogenic fibrosing alveolitis, but the significance of these antibodies to the aetiology and pathogenesis is as yet unclear.     

Accuracy of diagnostic coding of hospital admissions for cryptogenic fibrosing alveolitis.

To determine the accuracy of diagnostic coding of cryptogenic fibrosing alveolitis, the case notes of 166 admissions to four hospitals were reviewed. These consisted of all admissions that had been coded as "idiopathic fibrosing alveolitis" (ICD code 516.3: 97 admissions) or as "postinflammatory pulmonary fibrosis" (ICD code 515.9: 69 admissions). Of 88 available records of admissions coded as idiopathic fibrosing alveolitis, 70 (80%) patients had definite cryptogenic fibrosing alveolitis, and six (7%) possible cryptogenic fibrosing alveolitis according to predetermined conventional clinical criteria. Only seven (8%) admissions were clearly coded wrongly. Sixty four records were available for patients coded as having postinflammatory pulmonary fibrosis; 16 (25%) of these patients had definite cryptogenic fibrosing alveolitis, a further 12 (19%) had possible cryptogenic fibrosing alveolitis or fibrosing alveolitis with a connective tissue disorder, and the remainder had a very wide range of diagnoses. In this study the idiopathic fibrosing alveolitis (ICD 516.3) code was relatively reliable, but a substantial proportion of admissions coded under postinflammatory pulmonary fibrosis (ICD 515.9) also had cryptogenic fibrosing alveolitis and code 515.9 was of little diagnostic value. The data are inadequate for case finding, though in respect of cryptogenic fibrosing alveolitis may be adequate for planning purposes. There continues to be a need for more medical input into the process of diagnostic coding.     

British Thoracic Society study of cryptogenic fibrosing alveolitis: current presentation and initial management. Fibrosing Alveolitis Subcommittee of the Research Committee of the British Thoracic Society

BACKGROUND: Mortality due to cryptogenic fibrosing alveolitis (CFA) is increasing, particularly in the elderly. Optimum management remains uncertain and previous studies of the disease have largely been from specialist centres. A national study was carried out of the presentation and initial management of CFA in the UK. METHODS: All respiratory physicians in England, Scotland and Wales were invited to enter patients with newly diagnosed CFA over a two year period. CFA was diagnosed on histological grounds or according to clinical criteria which included the absence of a defined connective tissue disorder or pneumoconiosis. Participating physicians (n = 150) completed a questionnaire at patient entry and at all subsequent follow up visits and death. RESULTS: A total of 588 patients (373 men, 63%) were studied of whom 441 (75%) were referrals from primary care. Their mean (SD) age was 67.4 (10.0) years and median duration of symptoms at presentation was 9.0 months. Clubbing was more common in men (203/373; 54%) than in women (86/ 215; 40%); 209 patients (36%) were graded as severely breathless at presentation. A history of dust exposure (organic or inorganic) was present in 274 patients (47%) of whom 87 had had some exposure to asbestos. Subjects exposed to dust were more likely to have smoked and had slightly higher mean lung volumes, but were otherwise indistinguishable from those not exposed in terms of clinical presentation, management, and outcome. Transbronchial biopsy specimens were taken in 164 patients (28%) and open lung biopsy specimens in 73 (12%), but 60% had no histological diagnostic procedure. Biopsy procedures were more likely to be performed in younger patients, those with better lung function, and those with a history of asbestos exposure. At presentation a decision not to initiate specific treatment was made in 284 cases (48%). The decision to initiate treatment was made predominantly on symptomatic grounds. Two years after the close of entry to the study 266 patients (45%) had died. CONCLUSIONS: CFA is predominantly a disease of elderly patients and has a poor prognosis. Physicians generally considered CFA to be a clinical diagnosis and did not initiate treatment in up to half of patients at presentation.


     

Expression of bcl-2 and Epstein-Barr virus LMP1 in lymphocytic interstitial pneumonia

BACKGROUND: Epstein-Barr virus (EBV) genome has been demonstrated in lung tissues of patients with lymphocytic interstitial pneumonia (LIP) but its role in the pathogenesis of this condition is unclear. In vitro studies have shown that EBV can immortalise and transform cells by upregulation of the cellular proto-oncogene, B cell leukaemia-2 (bcl- 2), via the viral latent membrane protein, LMP1. The purpose of this study was to determine whether bcl-2 expression is upregulated in the lungs of patients with LIP and whether EBV LMP1 has a role in this bcl- 2 expression. METHODS: Immunohistochemical analysis using alkaline phosphatase anti-alkaline phosphatase (APAAP) was performed on formalin fixed, paraffin embedded lung tissues from 13 patients with LIP using anti-LMP1 and anti-bcl-2 monoclonal antibodies. Lung tissues from nine patients with idiopathic pulmonary fibrosis (IPF) and nine necropsy cases without pulmonary disease served as controls. LMP1 positivity was estimated as the number of LMP1 positive cells per unit area of lung tissue. Immunostaining for bcl-2 expression was assessed by a pictorial- based semiquantitative grading system. RESULTS: Positive immunostaining for LMP1 was localised to airway epithelial cells of lung tissue. Ten out of 13 (77%) patients with LIP were positive for LMP1 compared with three of nine cases (33%) in each control group. LMP1 positivity of LIP cases was significantly greater than that of non-LIP cases: LIP versus IPF (mean difference, 95% confidence interval (CI)) 2.39 (1.54 to 3.24); LIP versus necropsy controls 2.62 (1.77 to 3.47). bcl-2 immunostaining was localised to lymphocytes within the alveolar septa and lymphoid aggregates of patients with LIP. The cumulative score for bcl-2 immunostaining was significantly higher in the lungs of patients with LIP than in those of patients with IPF and necropsy controls: LIP versus IPF and LIP versus necropsy controls (mean difference, 95% CI) 7.55 (7.18 to 7.92). CONCLUSIONS: These immunohistochemical studies have shown the presence of EBV LMP1 protein in airway epithelial cells and overexpression of the cellular bcl-2 protein in lymphoid cells of lung tissue in patients with LIP. These geographically distinct staining patterns of immunostaining suggest that the involvement of EBV LMP1 in the upregulation of cellular bcl-2 is more complex in LIP than was thought from previous in vitro observations. The respective roles of EBV LMP1 and bcl-2 in the pathogenesis of LIP require further studies.


     

Non-Hodgkin's lymphoma arising in cryptogenic fibrosing alveolitis

The case report is presented of a patient with longstandingcryptogenic fibrosing alveolitis who developed a high grade B cellnon-Hodgkin's lymphoma in an area of fibrosis.

     

Response to methotrexate in fibrosing alveolitis associated with connective tissue disease.

Methotrexate by intermittent intramuscular injection was used to treat three patients with fibrosing alveolitis complicating connective tissue diseases. All three patients had improvement of symptoms, two had radiological improvement, and one had significant improvement of pulmonary function. Two patients whose pulmonary symptoms, function, and chest radiographs had deteriorated on penicillamine improved when treated with methotrexate. Methotrexate may be a useful treatment for fibrosing alveolitis complicating connective tissue diseases.     

Adult familial cryptogenic fibrosing alveolitis in the United Kingdom

BACKGROUND: Familial cases of cryptogenic fibrosing alveolitis (CFA) have previously been reported; however, the prevalence and genetic background of this disorder are not known. The clinical and epidemiological findings of 25 families identified within the UK are reported. METHODS: Adult pulmonary physicians in the UK were asked to identify all families under their care in which two or more individuals had been diagnosed with fibrosing alveolitis of unknown cause. A detailed structured questionnaire was sent to each proband to delineate possible environmental/occupational exposures and to obtain complete pedigree data. Physicians were also asked to provide clinical and diagnostic information. RESULTS: Twenty five families were identified comprising 67 cases. Suitable data for analysis were available for 21 families (57 cases). The male:female ratio was 1. 75:1 (p<0.05). A high resolution computed tomographic (HRCT) scan was performed in 93% and a diagnosis of CFA confirmed on biopsy specimens in 32%. The mean age at diagnosis was 55.5 (2.5) years. Fifty percent of cases were ever smokers and 18% had been diagnosed as asthmatic. Exposure to known fibrogenic agents was recorded by 36% of patients. Clinical signs/symptoms and histological findings were indistinguishable from non-familial cases. CONCLUSIONS: This study represents the largest cohort of familial CFA cases reported to date and confirms a prevalence of 1.34 cases per 10(6) in the UK population. Although rare, such cases represent an important subgroup in which a genetic susceptibility to pulmonary fibrosis is particularly evident. Familial patients are younger at diagnosis but otherwise indistinguishable from non-familial cases. The mode of inheritance is as yet unclear but a number of genetic loci are likely to be involved and are the subject of ongoing studies.     

High resolution computed tomographic assessment of asbestosis and cryptogenic fibrosing alveolitis: a comparative study.

BACKGROUND: The aim of this study was to compare the distribution and configuration of lung opacities in patients with cryptogenic fibrosing alveolitis and asbestosis by high resolution computed tomography. METHODS: Eighteen patients with cryptogenic fibrosing alveolitis and 24 with asbestosis were studied. Two independent observers assessed the type and distributions of opacities in the upper, middle, and lower zones of the computed tomogram. RESULTS: Upper zone fibrosis occurred in 10 of the 18 patients with cryptogenic fibrosing alveolitis and in six of the 24 patients with asbestosis. A specific pattern in which fibrosis was distributed posteriorly in the lower zones, laterally in the middle zones, and anteriorly in the upper zones was seen in 11 patients with cryptogenic fibrosing alveolitis and in four with asbestosis. Band like intrapulmonary opacities, often merging with the pleura, were seen in 19 patients with asbestosis but in only two with cryptogenic fibrosing alveolitis. Areas with a reticular pattern and a confluent or ground glass pattern were the commonest features of cryptogenic fibrosing alveolitis (15 and 14 patients respectively) but were uncommon in asbestosis (four and three patients). Pleural thickening or plaques were seen in 21 patients with asbestosis and in none with cryptogenic fibrosing alveolitis. CONCLUSION: Apart from showing pleural disease high resolution computed tomography showed that confluent (ground glass) opacities are common in cryptogenic fibrosing alveolitis and rare in asbestosis whereas thick, band like opacities are common in asbestosis and rare in cryptogenic fibrosing alveolitis.     

Localisation of a pulmonary autoantigen in cryptogenic fibrosing alveolitis.

BACKGROUND--Cryptogenic fibrosing alveolitis (CFA) is believed to have an immunological pathogenesis with a persisting inflammatory reaction to an as yet unidentified pulmonary antigen(s). A high frequency of IgG autoantibodies has previously been found in the plasma of patients with CFA to an extractable 70-90 kDa lung antigen by Western blotting. Preliminary immunohistochemical studies with patient IgG had indicated that the target protein(s) might be associated with alveolar epithelial lining cells which have previously been suggested as the site of immunological attack in CFA. METHODS--In order to confirm this finding immunohistochemical analysis and Western blotting were performed on a human type II alveolar cell line (A549) using CFA patient plasma. In order to study further the distribution of the antigen, antibodies were raised in a rabbit to the partially purified 70-90 kDa CFA lung protein. RESULTS--The results showed that the human CFA autoantibody recognised a 70-90 kDa protein with a cytoplasmic distribution present in the A549 cells, confirming previous observations. The immune rabbit IgG recognised a protein of similar molecular weight by Western blotting of protein derived from lung biopsy samples of patients with CFA and A549 cells. In addition it immunoprecipitated protein(s) of this molecular weight from lung biopsy protein extracts from patients with CFA. The precipitated protein(s) were found to cross-react with the autoantibody found in the plasma of patients with CFA. Immunohistochemical analysis with immunised rabbit antibody revealed positive staining of type I and II alveolar epithelial lining cells in CFA. A similar pattern of epithelial staining was also observed with the rabbit IgG on biopsy specimens of lung from patients with sarcoidosis and control lung tissue, although this was more focal and less intense. No positive staining was seen on sections from a number of non-pulmonary tissues (colon, liver, kidney, tonsil, lymph node, skin, cervix). Cytoplasmic staining of the A549 cell line was also detected. CONCLUSIONS--The 70-90 kDa protein recognised by autoantibodies in patients with CFA is associated with pulmonary epithelial lining cells. The immune rabbit IgG produced appears to recognise antigen by Western blotting and immunohistochemical staining of lung tissue in a similar pattern to the patient autoantibodies. Immunohistochemical data obtained with this antibody suggest that the putative autoantigen against which patients with CFA mount a humoral immune response may be endogenous and specific to the lung.     

Pulmonary gamma interferon production in patients with fibrosing alveolitis.

Patients with fibrosing alveolitis have active inflammation within their lung interstitium. Previous studies have focused on the humoral (immune complex) driven processes. In this study increased pulmonary gamma interferon production has been evaluated. Bronchoalveolar lavage cells were obtained from 40 patients with fibrosing alveolitis, 22 with cryptogenic fibrosing alveolitis, and 18 with connective tissue disease associated (CTD) fibrosing alveolitis. Increased gamma interferon production was seen in 12 (30%) patients and was similar in the two study groups. Up to 512 units/10(6) cells were released over 24 hours, showing that the amounts of gamma interferon released could be as large as those seen in other pulmonary diseases associated with active cellular immune processes, such as sarcoidosis. Spontaneous gamma interferon production was related to increased serum concentrations of IgG and IgM but not to serum IgA, antinuclear antibody, or rheumatoid factor titres. There was no relation between gamma interferon production and pulmonary uptake of gallium-67 citrate. The ratio of helper-inducer (Leu-3) to suppressor-cytotoxic (Leu-2) cells in bronchoalveolar lavage fluid was similar in the two study groups and was similar in patients whose cells produced gamma interferon and those whose cells did not. These data suggest that gamma interferon is released in the lungs of a proportion of individuals with cryptogenic fibrosing alveolitis and CTD-fibrosing alveolitis, suggesting a role for this cytokine in mediating these diseases.     

Thoracic epidural anesthesia for modified radical mastectomy in a patient with cryptogenic fibrosing alveolitis: a case report

A case of advanced cryptogenic fibrosing alveolitis (CFA) with multiple bullae and extensive pulmonary fibrosis, scheduled for modified radical mastectomy for carcinoma of breast, is presented. This patient had ischemic heart disease, corticosteroid-induced hypertension, diabetes mellitus, and a difficult airway. Thoracic epidural segmental anesthesia was successfully given to this patient. Preoperative problems, perioperative management, and alternative anesthetic techniques are discussed.     

Accuracy of the typical computed tomographic appearances of fibrosing alveolitis.

BACKGROUND--Open lung biopsy is often performed to confirm the diagnosis in patients with suspected fibrosing alveolitis. The superior sensitivity and specificity of high resolution computed tomography (CT) over chest radiography in various diffuse lung diseases suggest that the characteristic appearance of fibrosing alveolitis on high resolution CT might render biopsy confirmation unnecessary. METHODS--The chest radiographs and high resolution CT scans of 86 patients (41 with fibrosing alveolitis and 45 with various other diffuse lung diseases) were examined individually and independently by two observers. No clinical information was given and the observers gave a level of confidence when the diagnosis was thought to be fibrosing alveolitis. RESULTS--The observers correctly and confidently discriminated between fibrosing alveolitis and other diffuse lung diseases on high resolution CT with an accuracy of 88% and on chest radiography with an accuracy of 76%. The false negative rate for fibrosing alveolitis diminished from 29% on chest radiography to 11% on high resolution CT. The false positive rate on chest radiography was 19% and on high resolution CT 13%; the false positive diagnoses on CT were the result of a few conditions (extrinsic allergic alveolitis, sarcoidosis, cryptogenic organising pneumonia, and pulmonary eosinophilia) which mimicked some of the CT features of fibrosing alveolitis. The superficial similarity of the CT patterns of these conditions are discussed. CONCLUSIONS--High resolution CT is superior to chest radiography in establishing the diagnosis of fibrosing alveolitis and the typical CT appearances are virtually pathognomonic. The diagnostic advantages of CT over chest radiography should further reduce the need for open lung biopsy in this condition.     

Capsaicin induced cough in cryptogenic fibrosing alveolitis

BACKGROUND: Cough is a common and troublesome symptom in cryptogenic fibrosing alveolitis (CFA) but the mechanisms responsible are not known. The cough threshold to inhaled capsaicin is increased in asthma and chronic obstructive pulmonary disease (COPD) where lung volumes are increased, but the relationship between cough response and symptom intensity has not been studied in CFA where lung volumes are reduced. METHODS: Capsaicin challenge tests were performed on 15 subjects with proven CFA and 96 healthy controls. Symptoms, as assessed by daily diary card cough score and by visual analogue scale (VAS), were related to the capsaicin sensitivity (C5) and compared with lung volumes. Volume restriction was produced in a group of 12 normal healthy subjects by a plastic shell tightly strapped to the chest wall. Capsaicin challenge tests were performed in these subjects, both strapped and unstrapped, to determine whether volume restriction altered the cough reflex. RESULTS: The median C5 response in normal subjects was more than 500 microM compared with 15.6 microM in those with CFA (p<0.001). The C5 response of the CFA patients was not related to symptoms of cough (whether measured by diary card or by VAS), nor was it related to percentage predicted total lung capacity (TLC) or forced vital capacity (FVC). Volume restriction of normal subjects with chest strapping successfully restricted lung volumes to levels similar to that of the CFA patients but did not change the sensitivity to capsaicin. CONCLUSIONS: The cough reflex measured using capsaicin is markedly increased in patients with CFA. This increase is not the result of alterations in the deposition of inhaled particles of capsaicin brought about by volume restriction. It could be related to reduced lung compliance leading to sensitisation of rapidly adapting receptors, other mechanical changes, or to destruction of pulmonary C fibres secondary to interstitial inflammation. The capsaicin test may be a useful method of objectively monitoring cough propensity in CFA.     

Aerosolised ribavirin in patients with advanced cryptogenic fibrosing alveolitis: a pilot study.

BACKGROUND: A report has recently been published concerning a patient with a cryptogenic fibrosing alveolitis who showed a striking improvement after being treated with the antiviral drug ribavirin (tribavirin, Virazid). The objective of this study was to further evaluate, in an open trial, the efficacy of rivabirin in cryptogenic fibrosing alveolitis. METHODS: Ten patients (eight women) with advanced cryptogenic fibrosing alveolitis received aerosolised ribavirin (6 g/day for 15 days). Chest radiographs, lung function, and severity of dyspnoea were evaluated before and after two weeks of rivabirin treatment and also at three and 12 months. RESULTS: No differences in radiographs, lung function impairment, or severity of dyspnoea were found after treatment. No side effects were detected. CONCLUSIONS: Administration of high doses of aerosolised ribavirin has no beneficial effects in patients with advanced cryptogenic fibrosing alveolitis.