Biomedical subjects
Publications and source records attributed to D G James.
Certain syndromes develop because of regression or shrinkage of essential pathways. This account draws attention to six conditions in which different mechanisms and pathways give rise to a scorched-earth policy and to strange clinical syndromes.
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The Kveim-Siltzbach (KS) skin test has been in use worldwide for fifty years. It is a safe, simple and specific out-patient technique to confirm the diagnosis of sarcoidosis and to provide evidence of activity of the disease. It is most helpful in delineating sarcoidosis as a cause of erythema nodosum, uveitis, liver granulomas, hypercalciuria and meningitis. It is the patient's preference when he is confronted with the choice between a skin test or alternatively bronchoscopy, lung biopsy or aspiration liver biopsy. It also creates considerable academic interest for it reflects granuloma formation vividly when viewed by modern immunopathology techniques. Its disadvantage is that it takes a month to provide a result; a critical month in which systemic steroids are avoided for this would suppress the test. The immunopathology of the KS test is similar to spontaneous sarcoid granuloma formation, and evolution of the KS granuloma may provide clues to the cause of sarcoidosis and other granulomatous disorders.
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Sarcoidosis wears many different faces, depending upon the viewer, who may be clinician, radiologist, pathologist or immunologist. This Thomé Villar Memorial lecture salutes the charismatic chest physician who pioneered studies of the disorder in Lisbon and transmitted this knowledge internationally. The four main themes of this Lisbon Conference are granuloma formation, granulomatous vasculitis, markers of activity and occupational granulomatous lung diseases; these four faces of sarcoidosis are delineated in the way that they are recognised today and as they might unfold tomorrow. Sarcoid granuloma formation is the result of a complex interplay of invading antigen, prolonged antigenaemia, macrophage presentation, T4 response, B cell overactivity, circulating immune complexes and a cascade of several biological mediators. This spider's web progresses to fibrosis which represents a process of reparation leaving a scarred hyalinised remains of the previous battlefield. Granulomatous vasculitis embraces a group of disorders which mimic sarcoidosis. Assessment must include markers of activity to decide whether sarcoidosis is active and progressive. Lisbon is an international centre for the study of occupational granulomatous lung disease and its differentiation from sarcoidosis. Finally four important remaining problems concerning sarcoidosis are faced. They are: 1. What is the aetiology? 2. Who develops it and why? 3. What are the best ways of assessing activity? 4. How is it best treated?
Sixty seven patients with biopsy proven pulmonary sarcoidosis were prospectively studied to determine whether single point bronchoalveolar lavage cell counts were a useful indicator of functional outcome and whether repeated lavage helped in management. The mean follow up period was 25 (range 13-37) months. No patient was having corticosteroid treatment at the time of initial bronchoalveolar lavage. "High intensity alveolitis" (lymphocyte count greater than or equal to 28%) was present at the initial lavage in 42 patients. These patients showed a significant improvement in their pulmonary function and chest radiographs over the follow up period whereas patients with "low intensity alveolitis" did not. Of the 42 patients with high intensity alveolitis, 31 had chronic sarcoidosis (duration over two years, mean 80 months). These patients showed a significant improvement in FVC but not in TLCO. Corticosteroids resulted in greater functional and radiological improvement in the patients with high intensity alveolitis than in those with low intensity alveolitis. Repeat bronchoalveolar lavage in 34 patients, mean 8.4 months after the original lavage, showed a weak inverse relation between a reduced lymphocyte count and change in forced vital capacity and isotope uptake on a gallium scan. These correlations were too weak to make repeated cell counts useful in management. Our results suggest that high intensity alveolitis may be a favourable prognostic factor for lung function in pulmonary sarcoidosis, even in patients with chronic disease, but that repeat lavage adds little to the management of the individual patient.
The late and great Thomé Villar established a basic understanding of sarcoidosis in Lisbon, and his successors have added scholarly contributions to this firm foundation. He recognised its worldwide distribution and prevalence, the several interwoven patterns of presentation, the importance of histological confirmation, and the value of corticosteroid therapy. His successors have clarified our understanding of extrinsic allergic alveolitis (hypersensitivity pneumonitis), shown us how to differentiate the two disorders and expanded our knowledge of immunology and markers of activity of both disorders. Although we do not know the cause, we can recognise the terrain or soil in which it flourishes; factors which includes age, sex, race, HLA affinity and hormonal status. The road which will lead us to the cause(s) is in immunology, particularly macrophages and lymphocytes and the chemical mediators which influence the development of granuloma formation and ultimate fibrosis. Professor Thomé George Villar was a Man of Lisbon in every sense of the word - by birth, education, and academic achievement. He would have rejoiced that Lisbon was chosen for an International Conference on Sarcoidosis and he would have approved of his successor's choice of four topics--granuloma formation, granuloma vasculitis, markers of activity and occupational granulomatous lung disease. These are all important growing points in our advances in knowledge.
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