Dominique Israel-Biet

Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients.

Background. Sirolimus, a promising new immunosuppressive drug for organ transplantation, is currently associated with side effects, such as thrombocytopenia and hyperlipidemia. Methods. Eight renal transplant recipients, who developed unexplained interstitial pneumonitis during sirolimus therapy, were extensively re-screened for all causes of pneumonitis. Results. Interstitial pneumonitis was constantly characterized by bilateral interstitial infiltrates on chest x-rays and lung computed tomography scans, with marked general symptoms in all patients but one. Bronchoalveolar lavage (BAL) disclosed lymphocytic alveolitis (mainly of the CD4 type) in seven patients and alveolar hemorrhage in one. Transbronchial lung biopsies, performed in two patients, showed bronchiolitis obliterans with organizing pneumonia combined with lymphocytic interstitial pneumonitis. Pulmonary infections were ruled out by specific stainings and cultures of BAL, bronchial aspirates, and blood cultures. After the elimination of all possible causes, sirolimus-induced pneumonitis was considered probable. Discontinuation of sirolimus in seven cases and dose reduction in the remaining case dramatically improved clinical and radiological status within a few weeks and led to complete resolution within 3 months. Conclusions. Sirolimus is very probably responsible for interstitial pneumonitis on the following grounds: (a) occurrence of pneumonitis during sirolimus therapy; (b) absence of any other causes; and (c) resolution within 3 months of sirolimus discontinuation or dose reduction. Sirolimus should now be added to the list of possible causes of pulmonary complications after renal transplantation. Discontinuation or dose reduction of sirolimus led to complete and lasting resolution of symptoms.

Circulating Endothelial Cells A New Candidate Biomarker of Irreversible Pulmonary Hypertension Secondary to Congenital Heart Disease

Background— Congenital heart disease can be complicated by pulmonary arterial hypertension (PAH), the reversibility of which is often difficult to predict. We recently reported a lung biopsy study showing impaired apoptotic regulation of endothelial cells in irreversible PAH. The objective of the present study was to identify noninvasive biomarkers of endothelial turnover that could be used to identify congenital heart disease patients at risk of irreversible PAH. Methods and Results— Circulating endothelial cells (CECs) isolated with CD146-coated beads and circulating CD34+CD133+ progenitor cells (CPCs) were quantified in peripheral vein, pulmonary artery, and pulmonary vein blood samples from 26 patients with congenital heart disease (16 with reversible PAH [median age 2 years] and 10 with irreversible PAH [median age 9 years]) and 5 control patients. Surgical lung biopsy was performed in 19 cases. As expected, endothelial remodeling was observed in irreversible PAH but not in reversible PAH. CEC and CPC numbers were each similar in the 3 types of blood samples. CEC numbers were significantly higher in patients with irreversible PAH (median 57 CEC/mL) than in patients with reversible PAH and control subjects (median 3 CEC/mL in the 2 groups). In contrast, CPC numbers did not differ among patients with irreversible or reversible PAH and control subjects (median 84, 64, and 44 CPC/105 lymphocytes, respectively, in the 3 groups). Conclusions— Irreversible PAH in congenital heart disease is associated with endothelial damage and with increased circulating endothelial cell counts. The present study suggests that CECs could be a valuable tool to define therapeutic strategies in congenital heart disease patients with PAH.

Local increase in the number of mast cells and expression of nerve growth factor in the bronchus of asthmatic patients after repeated inhalation of allergen at low-dose.

Background Repeated inhalation of allergen at low‐dose induces an increase in bronchial hyper‐responsiveness, without any associated symptom. The concomitant events in the bronchus have not been described.

Elevation of IgE in HIV-infected subjects: A marker of poor prognosis

The IgE synthesis is tightly controlled by a complex network of T and B cells. Because human immunodeficiency virus (HIV) disease associates T cell activation and depletion, polyclonal B cell activation, atopic symptoms, drug hypersensitivity, and autoimmune activity, we have evaluated IgE, as well as IgA, IgG, and IgM, in 315 HIV-seropositive individuals with or without acquired immunodeficiency syndrome (AIDS) and compared the results to those of 100 HIV-seronegative subjects. IgE levels were higher in HIV-infected subjects as a whole, compared to levels in seronegative control subjects (p less than 0.05). This difference was particularly marked between patients with AIDS and control subjects (p less than 0.005). A strong relationship appeared between IgE and the immune status as assessed by CD4 cell counts (p less than 0.001 between IgE values in patients with CD4 less than 300 or greater than 300/microliters). In addition, we assessed the predictive value of IgE elevation over disease progression: in subjects with a CD4 count less than 300/microliters, the survival analysis disclosed a 24-month occurrence rate of AIDS of 83% in individuals with IgE greater than 150 KIU/L versus 44% in individuals with IgE less than 150 (p = 0.016). In subjects with an AIDS-related complex, IgE greater than 150 indicated a 100% rate of AIDS versus 9% in individuals with IgE less than 150 (p = 0.003). Thus, IgE levels appear to be a very discriminative marker between patients in late stages of HIV infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of cyclosporin on T-cell subsets in human immunodeficiency virus disease.

Cyclosporin (7.5 mg/kg daily) was given to 8 AIDS patients for 17-66 days and to 25 HIV-seropositive non-AIDS patients, 15 with stage II (T4 cells/microliter greater than or equal to 300, less than 600) and 10 with stage III (T4/microliter less than 300), for 3-6 months with the hypothesis that the drug could inhibit both HIV replication and the potential autoimmune component of HIV disease. A sustained increase over 600 T4/microliter occurred in 7 patients with stage II and 1 with stage III. T8 cells significantly decreased in most patients and lymphadenopathy disappeared in 14/16. After cyclosporin withdrawal T4 and T8 cells as well as lymphadenopathy returned to pretreatment status. Cyclosporin side effects (hypertension, creatinine increase, and anemia) were moderate and reversible. These results might stimulate biological research as well as clinical trials with cyclosporin in selected groups of HIV-seropositive subjects with the aim of delaying or preventing AIDS occurrence.

Peaks of transforming growth factor-beta mRNA in alveolar cells of lung transplant recipients as an early marker of chronic rejection.

BACKGROUNDnChronic lung rejection (CLR) induces a fibroproliferative disorder leading to the occlusion of small airways. It has emerged as the major factor limiting the survival of lung transplant recipients. Predictive markers of CLR are lacking, and its diagnosis is generally ascertained when the fibrosis process is irreversible.nnnMETHODSnWe have quantified the expression of transforming growth factor-beta (TGF-beta), a critical mediator of fibrogenesis, in alveolar cells from lung transplant recipients using a competitive reverse transcriptase polymerase chain reaction method.nnnRESULTSnWe have shown that patients with CLR presented marked peaks of TGF-beta mRNA expression, in contrast with patients without CLR. These peaks preceded the diagnosis of CLR by several months in two of three patients who died within 2 years of diagnosis.nnnCONCLUSIONSnOur data suggest that TGF-beta expression in alveolar cells could serve as an early predictive and prognostic marker of chronic lung rejection.

Perforin And Granzyme B Expression Is Associated With Severe Acute Rejection: Evidence for In Situ Localization in Alveolar Lymphocytes of Lung-transplanted Patients

To evaluate rejection episodes in lung-transplanted patients, we analyzed 31 bronchoalveolar lavage specimens for lymphocyte levels and lymphocyte expression of two intracytoplasmic activation markers, perforin, the pore-forming lytic protein, and granzyme B, a member of the serine esterase family. Using anti-human granzyme B and perforin mAbs, we show that their expression in alveolar lymphocytes is correlated with the severity of rejection as assessed by histological parameters and the patients clinical status. The presence of these molecules may provide a prognostic parameter that will facilitate the patients monitoring, particularly in cases with minimal acute lung rejection susceptible to rapid progression to severe rejection.

Serial computed tomography and lung function testing in pulmonary Langerhans’ cell histiocytosis

Little is known about longitudinal lung function variation in patients with pulmonary Langerhans’ cell histiocytosis (LCH). The contribution of serial lung computed tomography (CT) to managing these patients has not been evaluated. This long-term retrospective study included 49 patients who were serially evaluated by lung CT and pulmonary function tests. The lung function variation was categorised as improvement or deterioration. The extent of the CT lesions was correlated with lung function. Lung function deteriorated in ∼60% of the patients. Forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (DL,CO) were the parameters that most frequently deteriorated. A subgroup of patients experienced a dramatic decline in FEV1 within 2 yrs of diagnosis. Airway obstruction was the major functional pattern observed. In a multivariate analysis, % predicted FEV1at diagnosis was the only factor associated with the incidence of airway obstruction. The increase in cystic lesions on the lung CTs was associated with impaired lung function but did not anticipate the decline in FEV1 or DL,CO. Serial lung function tests are essential for following patients with pulmonary LCH, who frequently develop airway obstruction. A lung CT at diagnosis is informative, but routine sequential CTs seem less useful. A prospective study is needed to characterise those patients with early progressive disease.

Diagnosis and management of idiopathic pulmonary fibrosis: French practical guidelines.

Idiopathic pulmonary fibrosis (IPF) is the most frequent chronic idiopathic interstitial pneumonia in adults. The management of rare diseases in France has been organised by a national plan for rare diseases, which endorsed a network of expert centres for rare diseases throughout France. This article is an overview of the executive summary of the French guidelines for the management of IPF, an initiative that emanated from the French National Reference Centre and the Network of Regional Competence Centres for Rare Lung Diseases. This review aims at providing pulmonologists with a document that: 1) combines the current available evidence; 2) reviews practical modalities of diagnosis and management of IPF; and 3) is adapted to everyday medical practice. The French practical guidelines result from the combined efforts of a coordination committee, a writing committee and a multidisciplinary review panel, following recommendations from the Haute Autorité de Santé. All recommendations included in this article received at least 90% agreement by the reviewing panel. Herein, we summarise the main conclusions and practical recommendations of the French guidelines.

Developmental Changes in Endothelial Vasoactive and Angiogenic Growth Factors in the Human Perinatal Lung

Little is known of the mechanisms underlying the marked fall in pulmonary vascular resistance that occurs at birth, but changes in the expression of endothelial vasoactive and angiogenic factors during lung development might play a key role. Nitric oxide, endothelin-1, and vascular endothelial growth factor have critical effects on vascular tone and cell growth. Here, we investigated the protein expression of endothelial nitric oxide synthase, endothelin-1 and its receptors, and vascular endothelial growth factor in pulmonary necropsy samples from 14 fetuses of different gestational ages and from 5 infants. Expression of endothelin-1 and its receptor endothelin-A was strong and stable. In contrast, expression of the endothelin-B receptor was weak in early gestation, then increased markedly in mid-gestation and remained high thereafter. The expression of endothelial nitric oxide synthase and vascular endothelial growth factor fell markedly after mid-gestation and remained low thereafter. These data point to a discrepancy between maturational and functional changes in human pulmonary vascular structures. The weak perinatal expression of endothelial nitric oxide could suggest that other potent vasodilatory mediators are responsible for the marked vasodilation observed at birth.