A raised serum level of KL-6 is known to exist in active pulmonary fibrosis and KL-6 may be produced and secreted by type II pneumocytes. A case is described of pulmonary alveolar proteinosis with high serum KL-6 levels. The serum KL-6 level decreased after whole lung washing and correlated with symptoms, opacities on the chest radiograph, and arterial blood gas measurements. The serum KL-6 level may represent a useful marker for pulmonary alveolar proteinosis.
- pulmonary alveolar proteinosis
- tumour marker
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KL-6 is a mucin-like high molecular weight glycoprotein which is now classified as cluster 9 (MUC-1).1 The serum level of KL-6 is known to be an indicator of disease activity in pulmonary fibrosis.2-4 We have previously reported that KL-6 is produced and secreted in the serum by pulmonary type II pneumocytes.5 Pulmonary alveolar proteinosis is characterised by deposition of proteinaceous material in air spaces. This material consists of lipid bilayer membranes separated by amorphous proteinaceous material containing phospholipids and proteins similar to surfactant or one of its components. The cause of this condition remains unclear, but it is probably related to either overstimulation of type II pneumocytes and/or an impairment in the mechanisms for removal of alveolar phospholipids.6-10 We describe a patient with pulmonary alveolar proteinosis who had high serum KL-6 levels which were monitored before and after whole lung washings.
A 40 year old man who presented with exertional dyspnoea was found to have non-segmental bilateral reticular infiltration shadows in the middle and lower lung fields on the chest radiograph (fig 1A). A chest CT scan revealed diffuse ground glass opacity with thickening of the interlobular septum and a peripheral clear zone (fig 1B). In October 1991 a diagnosis of pulmonary alveolar proteinosis was confirmed by the grossly milky opacity of the bronchoalveolar lavage (BAL) fluid, histopathological findings of a transbronchial lung biopsy specimen (fig 2A), a biochemical analysis of phospholipids, and an electron microscopic study of the lavage fluid. With the patient breathing room air, his arterial blood gas values were as follows: pH 7.45; Pao 2 8.53 kPa. Other laboratory data revealed a haemoglobin level of 15.6 g/dl, a white blood cell count of 4500/μl with normal differentials, an erythrocyte sedimentation rate of 3 mm/h, and C reactive protein (CRP) of 0.3 mg/dl. Blood chemical analysis demonstrated a high serum lactate dehydrogenase (LDH) level of 198 IU/l. Analysis of bronchoalveolar lavage fluid revealed total cells of 24.5 × 105 cells/ml. The percentages of macrophages, lymphocytes and neutrophils from the recovered cells were 99%, 1% and 0%, respectively. Whole lung washing alleviated his symptoms, affected the shadows on his chest radiographs, and brought his blood gas values towards normal. However, in 1992, 1993, 1994, and 1996 he was admitted to hospital with dyspnoea and the ground glass opacities on the chest radiographs were consistent with recurrence of pulmonary alveolar proteinosis. Total bilateral whole lung lavages were performed on two different occasions, about two weeks apart. We examined the KL-6 levels with a sandwich-type enzyme linked immunosorbent assay (EIA) using KL-6 monoclonal antibody (IgG1) in serum and whole lung washing fluids (fig 2B). The serum KL-6 levels were extremely high before whole lung washing, but decreased and were within the normal range after whole lung washing in December 1994 and February 1996. The level of KL-6 in whole lung washing fluid was 100 000 U/ml. The serum levels of KL-6 correlated with symptoms, opacities on the chest radiographs, and Pao 2 levels (fig 3). Immunostaining with monoclonal KL-6 antibody (mouse IgG) was performed on transbronchial lung biopsy specimens using the avidin-biotin-peroxidase complex (ABC) method. There was strongly positive immunoreactivity for KL-6 to the alveolar epithelium. This was confirmed using a positive control of pulmonary fibrosis with type II cell hyperplasia and negative controls of paraquat lung in which type II cells are completely lost as well as those of omission of primary antisera.
Pulmonary alveolar proteinosis is a disease of unknown cause with accumulation of surfactant-like substance in alveolar and bronchiolar lumina.6-10 Pulmonary surfactant is a complex mixture of lipids and proteins which are produced and secreted by pulmonary type II pneumocytes. Interstitial fibrosis is not usually seen.10 BAL and whole lung washing are useful treatments for pulmonary alveolar proteinosis. Some patients with pulmonary alveolar proteinosis do not require more than one or two lavages or whole lung washings and few patients require them to be repeated semi-annually or annually.
KL-6 has been reported as a new serum marker for indicating the disease activity in patients with pulmonary fibrosis.2-4 We have previously reported that KL-6 is produced and secreted by pulmonary type II pneumocytes.5 However, the mechanism of the production of KL-6 from pulmonary type II pneumocytes is still unknown, and further studies are necessary.
We have reported that some glycoproteins and tumour markers such as carcinoembryonic antigen (CEA), sialyl LeX (SLX), and carbohydrate antigen 15–3 (CA 15–3) are found in high levels in whole lung washing fluid, and that they were produced by type II pneumocytes in a patient with pulmonary alveolar proteinosis.11 Serum KL-6 levels were extremely high before whole lung washing and correlated with dyspnoea, arterial blood gas analysis (Pao 2), and the degree of opacities on the chest radiographs before and after whole lung washing. In this case serum carcinoembryonic antigen (CEA) and CA 15–3 levels were also examined and were found to be slightly raised before washing and decreased afterwards. These findings suggest that type II cell pneumocytes could produce not only glycoproteins such as CEA and CA 15–3, but also a high molecular glycoprotein such as KL-6. As a result, the serum KL-6 level could be a useful indicator and monitoring marker for pulmonary alveolar proteinosis.
Variable indicating markers in pulmonary alveolar proteinosis including chest radiographic findings, serum LDH levels, and blood gas analysis results have been reported. The level of Pao 2correlated with symptoms, but serum LDH levels did not and there was a high LDH level after the first whole lung washing in 1996. In this case, serial measurements of serum KL-6 and LDH levels revealed that KL-6 correlated more closely with disease activity than serum LDH levels.
Previous reports have shown that the serum KL-6 level is a useful marker for pulmonary fibrosis.2-5 However, in this case pulmonary fibrosis was not prominent because the chest radiographic findings, pulmonary function test results, and blood gas analysis results were almost normal after whole lung lavage. We have shown that the serum KL-6 level can be raised in pulmonary alveolar proteinosis without pulmonary fibrosis. Although pulmonary alveolar proteinosis is a rare disease, we should be aware that a high serum KL-6 level exists in the disease and that it could be an indicator and a good monitoring marker.