Perception of bronchial obstruction in asthmatic patients. Relationship with bronchial eosinophilic inflammation and epithelial damage and effect of corticosteroid treatment.

We studied the perception of bronchoconstriction in asthmatic subjects who were randomly treated with inhaled beta 2 agonist given either alone (n = 9) or associated with inhaled corticosteroids (n = 9). Methacholine and bradykinin challenges, bronchoalveolar lavage, and bronchial biopsies were performed in all subjects. After each dose of agonist, breathlessness was assessed using a visual analog scale (VAS) and the forced expiratory volume in 1 s (FEV1) was measured. The relationship between VAS scores and FEV1 and the slope of the regression line of VAS scores on the corresponding FEV1 (VAS/FEV1 slope) were analyzed for each agonist. Subjects without corticosteroids had good perception of methacholine but poor perception of bradykinin-induced bronchoconstriction. In subjects with corticosteroids, bronchoconstriction was well perceived whatever the agonist. VAS/FEV1 slopes for bradykinin but not for methacholine correlated negatively with the magnitude of eosinophilic inflammation in airway mucosa. VAS/FEV1 slopes for each agonist correlated positively with the percentage of basement membrane covered by airway epithelium. We conclude that in asthmatic patients perception of bronchoconstriction is related to eosinophilic inflammation and to epithelial damage in airways and that corticosteroid treatment is associated with improved perception of bronchoconstriction induced by bradykinin, a mediator endogenously produced in asthma.

Pulmonary lymphangioleiomyomatosis. A study of 69 patients. Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P).

Pulmonary lymphangioleiomyomatosis (LAM) is a rare disorder of unknown cause characterized by peribronchial, perivascular, and perilymphatic proliferation of abnormal smooth muscle cells leading to cystic lesions. The hypothesis of hormonal dependence and the effectiveness of hormonal therapy have not yet been demonstrated conclusively, and the prevalence of extrathoracic manifestations and the survival of patients with LAM are somewhat contradictory. A multicentric retrospective study was conducted in an attempt to describe better the initial features, the diagnostic procedures, the associated lesions, and, above all, the management and course of LAM in a large homogeneous series of 69 stringently selected patients, with a majority of cases diagnosed since 1990. The aim of the study, based on a review of the literature, also was to provide a comprehensive view of this uncommon disease. The clinical features were in keeping with previous studies, but we found that exertional dyspnea and pneumothorax were the most common features, and chylous involvement was less frequent. LAM was diagnosed after menopause in about 10% of cases. The onset of LAM occurred during pregnancy in 20% of cases, and a clear exacerbation of LAM was observed in 14% of cases during pregnancy. Pulmonary LAM was diagnosed on lung histopathology in 83% of cases, but renal angiomyolipoma, observed in 32% of our patients, may be a useful diagnostic criterion when associated with typical multiple cysts on chest CT scan or with chylous effusion. Chest CT scan was more informative than chest X-ray (normal in 9% of cases), and may be indicated in spontaneous pneumothorax or renal angiomyolipoma in women of childbearing age. About 40% of the patients had a normal initial spirometry, while an obstructive ventilatory defect (44%), a restrictive ventilatory defect (23%), was observed in other patients. Initial diffusing capacity for carbon monoxide was frequently decreased (82%). Hormonal therapy was administered in 57 patients, but a clear > or = 15% improvement of FEV1 was observed in only 4 evaluable patients, treated with tamoxifen and progestogens (n = 2), progestogen (n = 1), and oophorectomy (n = 1). Probably 1 of the most urgent needs for clinical research in LAM is to test the currently available hormonal treatments in the context of international multicenter prospective controlled studies. Pleurodesis was performed in 40 patients. Lung transplantation was performed in 13 patients, 7.8 +/- 5.2 years after onset of LAM, in whom the mean FEV1 was 0.57 +/- 0.15 L. After a follow-up of 2.3 +/- 2.2 years, 9 patients were alive. Mean follow-up from onset of disease to either death or closing date was 8.2 +/- 6.3 years. Overall survival was better than usually reported in LAM, and Kaplan-Meier plot showed survival probabilities of 91% after 5 years, 79% after 10 years, and 71% after 15 years of disease duration.

Pulmonary lymphangiomyomatosis. Follow-up and long-term outcome with antiestrogen therapy; a report of eight cases.

Lymphangiomyomatosis is a rare disease which affects young women of childbearing age. Eight women with pulmonary LAM were treated with antiestrogen therapy and were monitored by blood estrogen measurements along with clinical hypoestrogenic symptoms. Treatment ranged from three to nine years. The response to therapy was evaluated by the clinical course, chest x-ray films, pulmonary function tests and overall long-term outcome. Three patients died of respiratory failure after three, five and nine years of treatment. Of the five patients remaining alive, respiratory function deteriorated in four cases, after a transient period of mild improvement lasting three years in two cases. The last patient appeared stable after three years of follow-up. Time course ranged from 4 to 17 years. However, without a control group, we cannot determine whether or not the apparent improvement of the natural time course was due to the hormonal treatment.

Immunochemical characterization of corticosteroid-binding globulin in human bronchoalveolar fluid.

The corticosteroid-binding globulin (CBG) is a plasma protein which is present both in liver, where it is mainly synthesized, and in cells of different target tissues for glucocorticoids. Using monospecific antibodies raised against human CGB, we could demonstrate the antigenic identity of the protein in human bronchoalveolar fluid. We found that the bronchoalveolar fluid/serum concentration ratio of CBG was similar to that of albumin. Since albumin is not synthesized in pulmonary cells, it was concluded that, in healthy human, CBG enters bronchoalveolar fluid by diffusion through alveolar cells. It is suggested that the expression of the CBG gene in pulmonary cells could occur during the pathological state.

[Clinical judgment and decision, pedagogy and practice]. / Jugement et décision clinique, pédagogie et pratique.

The interactive systems of logical interference represent but one of the computer applications to medicine. While the potential of computers in medical practice is beyond question, their actual use is not widespread. After the stage of practical demonstration of the working features of the hardware, one needs to define accurately the purpose to which the computer is intended in order to perform efficiently in its everyday use. To a certain extent, this unavoidable specialisation contrasts with the ubiquitous presence of computers and the availability of software the use of which does not, in principle, require particular training. A teaching experience directed to a number of different user groups in various fields has prompted us to examine the bases of the difficulties we met with. While some of them are related to cultural (or even religious) grounds, other, being of more technical nature, are more readily amendable to a methodological inquiry. Briefly, this analysis has led us to suggest a revision of various computer applications, including the interactive systems of logical interference, in the field of clinical research. A minimal theoretical training is essential in order to prevent delusions caused by an improvident autodidactic approach. The formal analysis of decision making appears as an excellent teaching guideline since it allows to refresh the elementary statistical concepts and then to approach economical aspects of health management (especially the cost/benefit and cost/effectiveness studies), as well as the sciences of administration as applied to health problems. Oncology represents a particularly suitable field of application on several accounts. It covers various and complex clinical domains, constant conceptual developments and finally, owing to the need for a systematic organisation of the data collection, it offers persuasive applications whose lasting features should warrant the necessary initial effort of investment.

[Hydatid cyst of the heart. Apropos of 9 cases]. / Le kyste hydatique du coeur. A propos de 9 cas

The authors report 9 cases of hydatic cyst of the heart which they have encountered over an 8 year period. They illustrate the variable nature of this parastic illness, which may stimulate almost and cardiovascular disorder. The various clinical presentations and the methods of diagnosis and treatment are presented: the clinical picture is of little help in establishing the diagnosis. This is made at three levels: the history (country of origin where the disease is endemic, or other associated cyst), the presence of Xray of a swelling of the heart which is later calcified, and the presence on the electrocardiograph of ischaemic changes, which may be severe enough for necrosis. They emphasise the importance of serological tests to make a formal diagnosis of the condition, and a repetition of such tests as part of the postoperative follow-up. Surgical treatment (usually by an open heart technique) is the rule. It may be coupled with medical treatment with anti-malarials (paludrin of flavoquin).

[Oral and inhaled corticoid therapy. Rivals or partners?]. / Corticothérapie orale et corticothérapie inhalée. Concurrents ou partenaires?

Although steroids have been prescribed as antiinflammatory preparation for the treatment of asthma for many years, fear of side effects has limited their wider use. The development of new steroid derivatives administered by inhalation has reduced these risks. Oral and inhaled steroids can be used in a separate way, oral steroids being reserved for the control of acute exacerbations and inhaled steroids for the baseline treatment of chronic asthma. Inhaled and oral steroids can also be used concurrently in the same patient. Studies have shown a reduction in the dose of oral steroids in patients taking inhaled steroids. Works carried out by the Canadian research worker Toogood have addressed the question of the equivalent clinical dosing potency of inhaled and oral steroids. Finally, the reversibility of airway obstruction in subjects affected by non-specific chronic obstructive diseases might worth be assessed by using an inhaled steroid preparation.

[Bronchoceles. Apropos of a case]. / Les bronchocèles. A propos d'un cas.

Bronchoceles form bronchial cul-de-sacs in normal or destroyed walls, post-stenotic or secondary to congenital bronchial atresia or infections in infancy. Because of their rarity they frequently go unrecognised. A precise history may sometimes reveal the cause as post-infectious. The differential diagnosis includes mucoid impaction and bronchial tumors. The most common radiological appearance of a bronchocele is a pulmonary opacity, posing problems of differential diagnosis with cancer; such a case is presented in this article.

[Mechanism of action and effects of corticoids in asthma]. / Mécanismes d'action et effets des corticoïdes dans l'asthme.

The value of oral or inhaled glucocorticoids (GCS) in asthma is well recognized. Their use has remained empirical for a long time. However, some progress has been achieved recently in the understanding of their general mode of action and of their bronchial effects suggesting that in the near future ther may be some new therapeutic perspectives. The fundamental action of GCS involves a close intracellular interaction between the specific glucocorticoid hormone receptor and the cellular genome which results in the activation of the genes coding the proteins responsible for the phenotypic response of the cell and thus for their biological action. The place of the extra-genomic mechanisms remains ill understood. The immunomodulating action of GCS is difficult to dissociate from their anti-inflammatory and anti-allergic effects which seem to predominate in asthma. They inhibit all stages of the inflammatory reaction in acting on the key mediators of the inflammatory response, the pharmacologically active lipids (LPA: prostaglandins, leukotrienes, PAF-acether) which are a result of the catabolism of arachidonic acid which occurs during the course of membrane activation. The phospholipid A2 (PLA2), a membrane enzyme responsible for the splitting of the phospholipids in the presence of calcium and leading to the liberation of LPA is the driving force of the reaction in such a way that the products of the nuclear activation subsequently reactivated. GCS is considered as a natural modulator of inflammation, inducing the synthesis of lipocortin, an inhibitory protein of PLA2, which explains the blockage in the generation of LPA and thus the inflammatory reaction. The regulation of the activity of these or of the lipocortin seems to lead to the intervention of the phosphorylation. But numerous questions remain concerning the precise action of PLO2, the existence of endogenous lipocortin, their secretion and their extra-cellular action. In spite of these unknown facts it is not impossible to envisage a clinical potential for lipocortin, once sequenced and produced, when the pharmacological and immunological problems have been surmounted. In asthma the effect of GCS essentially involve: the inhibition of all the bronchial components of inflammation: the synthesis, liberation and peripheral action of the mediators; the oedema and mucous congestion.(ABSTRACT TRUNCATED AT 400 WORDS)

[Characteristics and specificities of cystic fibrosis in adults: evolutive disease of childhood or recently diagnosed disease?]. / Caractéristiques et spécificités de la mucoviscidose chez l'adulte: évolution d'une maladie de l'enfance ou maladie de découverte récente?

We have studied the characteristics of 202 cystic fibrosis adult patients, all with chronic respiratory symptoms, with a median age of 27 yrs (18 to 55 yrs) and a male predominance (56%). At genetic analysis, delta F508 homozygotes were 41%, delta F508 heterozygotes 42% and 17% had no delta F508. The respiratory disease was more severe and complications were more frequent in adults: hemoptysis in 14%, pneumothorax in 15%, lung transplantation in 25 patients. Chronic bronchial colonisation with Pseudomonas aeruginosa, in 76% of patients, contributed to making treatments more severe because of antibiotic i.v. courses and nebulised antibiotics. Respiratory function showed a mean FVC of 62 +/- 22% and a mean FEVI of 48 +/- 94%. External pancreatic insufficiency was found in 83%, diabetes in 14%. Intestinal occlusion syndromes were observed in 11% of patients and hepatic cirrhosis in 8%. In spite of the severity of the respiratory disease, theses patients succeeded in social and occupational insertion; 62% were independent, 18% had children and 77% were working or studying. Analysis of the patients according to age at diagnosis showed that, in 38 patients diagnosed after the age of 18 yrs, the respiratory disease was less severe, pancreatic insufficiency and non-respiratory complications were less frequent (34% had pancreatic insufficiency, 5% had diabetes and none had cirrhosis). This may partly be due to the presence of milder CFTR mutations. In conclusion, cystic fibrosis in adulthood frequently looks like an evolutive form of cystic fibrosis in childhood. Nevertheless, some late diagnosed forms in adults, with better prognosis, have been recently identified.

[Multifocal epithelioid hemangioendothelioma with partial remission after interferon alfa-2a treatment]. / Hémangioendothéliome épithélioïde multifocal en rémission partielle sous traitement par interféron alpha 2a.

INTRODUCTION: Epithelioid hemangioendothelioma (EHE) is a rare vascular tumour of the soft tissue having an intermediate malignancy. Cutaneous presentations have exceptionally been reported. OBSERVATION: A young woman, initially affected by an EHE with cutaneous and bone involvement, then with pulmonary and hepatic localizations, was in partial remission after one year of treatment with alpha 2a interferon. DISCUSSION: In a critical review of the literature, we describe the main features of this tumour and the difficulties to classify this entity in the vascular tumors' spectrum. Histologically, epithelioid hemangioendothelioma has a very characteristic appearance and is clearly different from other vascular tumors as angiolymphoid hyperplasia with eosinophilia and Kimura's disease. The assumption of a multicentric or a metastatic origin when multiple tumor deposits are found, is still not elucidated. Different therapeutic approaches are proposed: surgery, interferon, interleukin-2, retinoids. Randomized studies would be necessary to confirm our results with alpha 2a interferon but are probably difficult to realize because of the lack of cases.

[Primum non nocere: inhaled corticoids]. / Primum non nocere: les corticoïdes inhalés.

Several studies have been devoted to the possible deleterious effects of inhaled corticosteroids. These products are effective and have been widely used for longer and longer periods. Tests used to detect systemic effects are now quite sensitive allowing us to identify infraclinical purely biological effects resulting from minimal doses. The real value of these tests in predicting long-term deleterious effects such as adrenal failure, osteoporosis or growth retardation are now recognized. However, it is difficult to incriminate corticosteroids alone in certain cases because "parasite" conditions are often created by systemic corticosteroid therapy and because asthma alone can lead to deleterious extrapulmonary effects which should not be considered to result from treatment alone, emphasizing the need for carefully controlled studies. Despite the description of multiple systemic effects, the clinical consequences of long-term inhaled corticosteroids are not at all in the same range as oral corticosteroids. Nevertheless, there is some debate as to the strict indications for inhaled corticosteroids in adults and in children. The use of minimal effective doses in asthma is a primum non nocere.

[Primum non nocere...inhaled glucocorticosteroids in 2003]. / Primum non nocere...les glucocorticostéroïdes inhalés en 2003.

The use of inhaled glucocorticosteroids for the treatment of asthma raises the important question of short- and long safety. Thus the assessment of the benefit-risk ratio is an essential part of the development of powerful agents with reinforced topical activity. Several factors determine the optimal profile for an inhaled glucocorticoid: topical activity, systemic bioavailability (influence of the first-pass liver metabolism, inhalation device, patient- and disease-related factors), and pharmacokionetic behavior, liposolubility being one of the determining elements. Taken together these different factors produce a therapeutic index expressing the topical and systemic effects of inhaled glucocorticosteroids and their variability under the particular conditions of each patient. Al high-dose inhaled glucocorticoids have an impact on the adrenal gland which is easy to demonstrate but with rather insignificant clinical relevance. In children for example, there is a transient inhibition of bone growth with no impact on final height in adulthood. In adults; the effect on bone metabolism raises the risk of osteoporosis which must be prevented and detected in patients at risk. More data must be acquired concerning the ocular risk. Overall, significant adverse systemic effects are not observed with administration of inhaled glucocorticoids, but there remains a certain degree of uncertainty concerning the effects of long-term administration of low effective doses.

[Current aspects of lymphangioleiomyomatosis]. / Aspects actuels de la lymphangioléiomyomatose.

Lymphoangioleiomyomatosis (LAM) is a characteristic diffuse proliferation of abnormal smooth muscle fibers predominantly developing in the lung and leading to cystic destruction. An almost totally specific marker, HMB45, is available. This monoclonal antibody labels cells of the melanocyte line, LAM cells and renal angiomyolipoma cells. The antigen carried by all these cell lines is probably gp-100 involved in melanogenesis. Two gene loci are formally implicated in the pathogenesis of Bourneville tuberous sclerosis (BTS): TSC1 (9q 34.3) and TSC2 (16p 13.3). The TSC2 locus could be implicated in the pathogenesis of pulmonary LAM. LAM and BTS have similar clinical and histological features and could be two different phenotypic forms, distinguished strictly on a nosological basis, of the same disease. The hormone-dependence theory is suggested on the basis of purely clinical arguments, particularly the almost exclusive female predominance, generally during the period of genital activity. Certain counter arguments have also been put forward and consequently, since no in vitro cell culture model or animal model of LAM is available, it is not really possible to verify the hypothesis. Epidemiological data have been recently acquired in France with the constitution of the GERM"O"P registry of LAM cases in France. Recent technological progress in imaging techniques has also been helpful for earlier, more precise diagnosis. HMB45 immunolabeling improves diagnostic sensitivity on small tissue fragments obtained with transbronchial biopsies. The course of LAM appears to be different in certain patient subgroups. Certain patients develop rapidly fatal disease in months or years while in the majority of patients the disease is much less aggressive for years. A minority of patients also have very slowly evolving disease sometimes diagnosed after menopause. Lung transplantation remains the ultimate treatment in case of life-threatening prognosis.

[Langerhans cell pulmonary granulomatosis]. / La granulomatose pulmonaire à cellules de Langerhans.

Langerhans' cell granulomatosis, formerly known as histiocytosis X include several granulomatosis of unknown aetiology. The original pathological finding is a Langerhans' cell granuloma. Recent progress has improved our understanding of the pathogenesis of this group of diseases and facilitated the diagnosis. We describe here the cell populations involved, the general pathology of Langerhans' cells, proposed pathogenesis, and the relationship between Langerhans' cell pulmonary granulomatosis and other localizations of Langerhans' cell granulomatosis. Finally, the clinical manifestations, elements of diagnosis and changing attitudes of current therapy are discussed.

[Pulmonary lymphangiomyomatosis. Long-term benefit of anti-estrogen treatments remains uncertain]. / Lymphangiomyomatose pulmonaire. Le bénéfice des traitements anti-oestrogènes reste incertain à long terme.

Lymphangiomyomatosis is a rare disease which affects young women of childbearing age. Ten women with pulmonary lymphangiomyomatosis were treated with antiestrogen therapy from 3 to 9 years (mean time of treatment: 5.3 years). Efficacy of treatment was evaluated by clinical, radiological, pulmonary function testing response as well as the overall long-term outcome. Four patients died of respiratory failure after 3, 5, 5 and 9 years of treatment. Of the 6 patients remaining alive, respiratory function deteriorated in 4 cases after a transient period of mild improvement lasting 3 years in 2 cases. Two patients appeared stable after 3 and 7 years of treatment. Without a control group, although a longer time of survival along these last years, it seems difficult to impute this benefit to the sole antiestrogen treatment and the overall long term prognosis of the disease remains really uncertain.

[Asthma with permanent obstructive ventilation disorder]. / Asthme avec trouble ventilatoire obstructif permanent.

Asthma accompanied by chronic airways obstruction (CAO) is frequent and raises difficult clinical problems. Persistent inflammation of the airways is the main factor responsible for obstruction. There are no symptoms that distinguish this form of asthma from non-asthmatic chronic obstructive lung disease, and only respiratory function tests can confirm the diagnosis of CAO. Pharmacological tests with bronchodilators evaluate the bronchomotor part of CAO which is substantial in asthma as opposed to other causes of obstructive lung diseases. A negative test cannot exclude the diagnosis and suggests that the obstructive component due to bronchial inflammation is predominant. In such case a reversibility test performed with corticosteroids is of considerable interest as it reduces the partly reversible inflammatory part of the obstruction. Peak flow curves provide more precise date on the evolutive type of CAO and therefore contribute to a great extent to the monitoring and education of patients. Severe chronic asthma with high annual systemic corticosteroid consumption requires special care and justifies the current attempts made to replace corticosteroids by other anti-inflammatory drugs.

[Eosinophilic pleural effusion related to taking valproic acid]. / Une pleurésie à éosinophiles liée à la prise d'acide valproïque.

Eosinophilic pleural effusions have multiple aetiologies. We report on the case of a 40-year-old man who experienced an eosinophilic pleural effusion with blood hypereosinophilia that occurred nine weeks after a treatment with valproic acid was introduced. Usual aetiologies of eosinophilic pleural effusion were excluded. Once valproic acid was discontinued, both pleural effusion and blood eosinophilia decreased rapidly. The persistence of a residual pleural effusion required the introduction of oral corticosteroids, which resulted in the effusion disappearing completely and rapidly. Valproic acid is a rare cause of eosinophilic pleural effusion. The effusion usually regresses when treatment is discontinued but short-term oral corticotherapy may be necessary in order to heal the patient.