[Pulmonary complications of Chronic Granulomatous Disease]. / Complications pulmonaires de la granulomatose septique chronique.

Chronic Granulomatosis Disease (CGD) is an inherited immune deficiency due to a mutation in the genes coding for the subunits of the NADPH oxidase enzyme that affects the oxidative capacity of phagocytic cells. It is characterized by increased susceptibility to bacterial and fungal infections, particularly Aspergillus, as well as complications associated with hyperinflammation and granulomatous tissue infiltration. There exist two types of frequently encountered pulmonary manifestations: (1) due to their being initially pauci-symptomatic, possibly life-threatening infectious complications are often discovered at a late stage. Though their incidence has decreased through systematic anti-bacterial and anti-fungal prophylaxis, they remain a major cause of morbidity and mortality; (2) inflammatory complications consist in persistent granulomatous mass or interstitial pneumoniae, eventually requiring immunosuppressive treatment. Pulmonary complications recurring since infancy generate parenchymal and bronchial sequelae that impact functional prognosis. Hematopoietic stem cell allograft is a curative treatment; it is arguably life-sustaining and may limit the morbidity of the disease. As a result of improved pediatric management, life expectancy has increased dramatically. That said, new challenges have appeared with regard to adults: difficulties of compliance, increased inflammatory manifestations, acquired resistance to anti-infectious therapies. These different developments underscore the importance of the transition period and the need for multidisciplinary management.

Screening protocols to monitor respiratory status in primary immunodeficiency disease: findings from a European survey and subclinical infection working group.

Many patients with primary immunodeficiency (PID) who have antibody deficiency develop progressive lung disease due to underlying subclinical infection and inflammation. To understand how these patients are monitored we conducted a retrospective survey based on patient records of 13 PID centres across Europe, regarding the care of 1061 adult and 178 paediatric patients with PID on immunoglobulin (Ig) G replacement. The most common diagnosis was common variable immunodeficiency in adults (75%) and hypogammaglobulinaemia in children (39%). The frequency of clinic visits varied both within and between centres: every 1-12 months for adult patients and every 3-6 months for paediatric patients. Patients diagnosed with lung diseases were more likely to receive pharmaceutical therapies and received a wider range of therapies than patients without lung disease. Variation existed between centres in the frequency with which some clinical and laboratory monitoring tests are performed, including exercise tests, laboratory testing for IgG subclass levels and specific antibodies, and lung function tests such as spirometry. Some tests were carried out more frequently in adults than in children, probably due to difficulties conducting these tests in younger children. The percentage of patients seen regularly by a chest physician, or who had microbiology tests performed following chest and sinus exacerbations, also varied widely between centres. Our survey revealed a great deal of variation across Europe in how frequently patients with PID visit the clinic and how frequently some monitoring tests are carried out. These results highlight the urgent need for consensus guidelines on how to monitor lung complications in PID patients.

[The effects of inhaled steroids withdrawal in COPD]. / Impact du sevrage des corticostéroïdes inhalés dans la BPCO.

The key pathophysiological feature of chronic obstructive pulmonary disease (COPD) is an abnormal inflammatory bronchial reaction after inhalation of toxic substances. The priority is the avoidance of such toxic inhalations, but the use of anti-inflammatory drugs also seems appropriate, especially corticosteroids that are the sole anti-inflammatory drug available for this purpose in France. The risks associated with the prolonged use of these parenteral drugs are well known. Inhalation is therefore the optimal route, but inhaled drugs may also lead to adverse consequences. In COPD, there is an inhaled corticosteroids overuse, and a non-satisfactory respect of the guidelines. Consequently, their withdrawal should be considered. We reviewed seven clinical studies dealing with inhaled corticosteroids withdrawal in patients with COPD and found that included populations were heterogenous with different concomitant treatments. In non-frequent exacerbators receiving inhaled corticosteroids outside the recommendations, withdrawal appears to be safe under a well-managed bronchodilator treatment. In patients with severe COPD and frequent exacerbations, the risk of acute respiratory event is low when they receive concomitant optimal inhaled bronchodilators. However, other risks may be observed (declining lung function, quality of life) and a discussion of each case should be performed, especially in case of COPD and asthma overlap.

[The place of inhaled corticosteroids in COPD]. / Place des corticostéroïdes inhalés dans la BPCO.

INTRODUCTION: Clinical trials have provided some evidence of a favorable effect of inhaled corticosteroids on the frequency of exacerbations and on the quality of life of patients with chronic obstructive pulmonary disease (COPD). In contrast, ICS have little or no impact on lung function decline and on mortality. STATE OF THE ART: Inhaled corticosteroids are recommended only in a minority of COPD patients, those with severe disease and repeated exacerbations and probably those with the COPD and asthma overlap syndrome. However, surveys indicate that these drugs are inappropriately prescribed in a large population of patients with COPD. Overtreatment with inhaled corticosteroids exposes these patients to an increased risk of potentially severe side-effects such as pneumonia, osteoporosis, and oropharyngeal candidiasis. Moreover, it represents a major waste of health-care spending. CONCLUSION: Primary care physicians as well as pulmonologists should be better aware of the benefits as well as the side-effects and costs of inhaled corticosteroids.

Efficacy and safety of gefitinib during pregnancy: case report and literature review.

The incidence of lung cancer is rising in pregnancy, which is diagnosed on stage III-IV in 98%. Almost half of these patients are non-smokers, who are associated with more epidermal growth factor receptor (EGFR)-mutated lung cancer. As cytotoxic chemotherapy is associated with poor outcome for mothers and prematurity for children this will probably lead to repeatedly question the use of EGFR-Tyrosine kinase inhibitors (TKI) (i.e. gefitinib and erlotinib) during pregnancy for EGFR-mutated lung cancer. EGFR-TKIs are recommended as the first line targeted therapy in case of advanced non small cell lung carcinoma (NSCLC) with an activating EGFR mutation but not recommended during pregnancy due to lack of data. We report clinical and pharmacological data for gefitinib during pregnancy in both the mother and fetus and resume the literature on the subject. A 33-year-old pregnant mother exhibited a disseminated EGFR-mutated lung carcinoma with respiratory distress at 26 weeks of pregnancy. Gefitinib administration was associated with rapid maternal respiratory improvement allowing a planned cesarian section on week 35, giving birth to a healthy baby (2575g) with regular development at 24 months of follow-up. The mother exhibited a progression-free survival of 42 weeks with an overall survival of 22 months. Gefitinib residual concentration was found in cord blood at 25.7ng/mL, confirming a transplacental transfer, but at only 20% of the maternal concentration measured at the same time (i.e. 127.1ng/mL). Gefitinib concentration in amniotic fluid, which represents chronic fetal exposure to the drug, was also 20% of the maternal residual concentration (16.9ng/mL) and reflected no fetal accumulation of the drug, despite both long half time elimination of gefitinib (i.e. 48h) and long time exposure (i.e. 55 days). This low transplacental transfer is an important report, as potential side effect toxicity on the fetus is likely correlated to gefitinib blood concentration.

[Pulmonary involvement due to HHV-8 virus during the course of HIV infection]. / Atteintes pulmonaires liées au virus HHV-8 au cours de l'infection VIH.

HHV-8 is a herpes virus discovered in 1994 in Kaposi sarcoma cells. Its involvement was later demonstrated in multicentric Castleman disease and in primary lymphoma effusion lymphoma. These diseases arise almost exclusively in immunocompromised patients, mostly in association with HIV infection. Apart from Kaposi's sarcoma, combined antiretroviral therapy does not seem to have reduced the incidence of these diseases, which remain rare. In these three diseases, pulmonary involvement is common and may be the presenting feature. Kaposi's sarcoma of the lung is usually asymptomatic but may require specific therapy. Pulmonary involvement is mostly associated with cutaneous disease. Patients with Castleman disease typically present with fever and lymphadenopathy, associated with interstitial lung disease without opportunistic infection. Patients with primary lymphoma effusion presents with fever and an exudative lymphocytic pleural effusion, without a pleural mass on the CT-scan. Rapid diagnosis of these conditions avoids unnecessary invasive examinations and leads to prompt specific treatment.

Mucormycosis after allogeneic haematopoietic stem cell transplantation: a French Multicentre Cohort Study (2003-2008).

We conducted a nationwide retrospective study to evaluate clinical characteristics and outcome of mucormycosis among allogeneic haematopoietic stem cell transplant recipients. Twenty-nine patients were diagnosed between 2003 and 2008. Mucormycosis occurred at a median of 225 days after allogeneic haematopoietic stem cell transplant, and as a breakthrough infection in 23 cases. Twenty-six patients were receiving steroids, mainly for graft-versus-host disease treatment, while ten had experienced a prior post-transplant invasive fungal infection. Twenty-six patients received an antifungal treatment; surgery was performed in 12. Overall survival was 34% at 3 months and 17% at 1 year.

[Pneumocystis jirovecii pneumonia in non-HIV infected patients: a study of 41 cases]. / Pneumocystose pulmonaire chez des patients immunodéprimés non infectés par le VIH : étude de 41 cas.

BACKGROUND: The increasing use of immunosuppressive and cytotoxic therapies leads to a growing number of opportunistic infections especially Pneumocystis jirovecii pneumonia (PCP). The purpose of our study was to describe the population involved, and to assess clinical, biological, and mortality data. METHODS: We collected retrospectively the whole medical file of all PCP cases diagnosed in non-HIV infected patients, in two French University Hospitals in the last decade (1999-2009). Diagnosis was made on standard coloration and/or immunofluorescence analysis of bronchoalveolar lavage fluid (BAL). RESULTS: Forty-one patients were included in the study, mean age 56 (±12.5) years, sex ratio 0.71 men/woman. Underlying diseases were as follow: 12 patients (29%) were renal transplant recipients, 13 (32%) were treated for solid cancers, and 16 (39%) suffered from various diseases (three allogenic bone-marrow transplantation, 11 hematological malignancies, one pulmonary transplantation, one vasculitis). Twelve patients died (i.e. 29%). Median lymphocyte count was 542/mm(3). More than 85% patients received corticosteroids at a median cumulative 6-month dose of 2700mg. Seven patients (17%) had a PCP prophylaxis. Clinical worsening at day 5 (P<0.003), poor control of the underlying disease (P<0.015), WHO performans status superior than 2 (P<0.025), high temperature (P<0.04), and high oxygen flow (P<0.042) were linked to a poor prognosis. DISCUSSION/CONCLUSION: The prognosis factors found are mostly linked to the patients' clinical severity. We would like to highlight: first, near to 30% mortality rate, secondly, a lack of prophylaxis in 34 patients, reflecting the difficulty to define PCP's risk in non HIV-infected patients.

[H1N1 (2009) influenza A infection in transplant recipient patients: a comparative study versus non-transplanted patients]. / Grippe A/H1N1 2009 chez des patients transplantés : étude comparative versus des patients non transplantés.

OBJECTIVE: To compare H1N1 (2009) influenza A infection characteristics between transplant recipient patients and non-transplanted patients. To assess the evolution of transplanted patients up to 6 months following infection. METHODS: Patients diagnosed with confirmed influenza A infection from three Parisian transplant centers between September 1st, 2009 and February 15th, 2010. Clinical symptoms, biological, and radiological findings, and management were analysed and retrospectively compared between transplanted (T) and non-transplanted patients (NT). The evolution was assessed by a follow-up questionnaire, CT results 1 to 3 months after influenza infection and FEV1 variation. RESULTS: Seventy patients were included. Thirteen patients had an allograft (lung: eight, kidney: four, stem cells: one): (1) hospitalization: 100% (13 out of 13) in group T, 54% (31 out of 57) in group NT (P=0.0013); (2) pneumonia: 62% (eight out of 13) in group T, 26% (eight out of 57) in group NT (P=0.004); (3) mortality rate among hospitalized patients: 7.7% (one out of 13) in the group T, 9.7% (three out of 57) in group NT (P=NS); (4) chest CT scan abnormalities remained in four lung transplanted patients; (5) a minimum 10% decrease in FEV1 was detected in four lung transplant recipients. CONCLUSION: Our results suggest that H1N1(2009) influenza A infection in transplant recipient patients compared to non-transplanted patients: (1) more often leads to hospitalization; (2) is more frequently associated with pneumonia; (3) is responsible for a persistent graft functional impairment in lung transplant recipients; (4) has a low mortality rate similar to admitted non-transplanted patients.

[Pulmonary non-infectious diseases in common variable immunodeficiency]. / Manifestations pulmonaires non infectieuses du déficit immunitaire commun variable.

Few studies have described pulmonary non-infectious diseases (PNID) in patients with common variable immunodeficiency (CVID). Indeed the most frequent complications in these patients are infectious. The aim of our study is to analyze the characteristics of PNID in a retrospective study of patients with CVID of two pneumology departments in Paris (France), from 1990 to 2008. PNID was observed in 11 patients. Mean immunoglobulin serum level was 3.46g/L. The PNID observed were: arteriovenous pulmonary fistula: three; interstitial lung disease: three; asthma: two; mediastinal lymphadenopathy: four; emphysema: one; mesothelioma: one. Our study outlines the broad spectrum of pulmonary manifestations related to CVID. Clinicians should be aware of the diagnosis of PNID even in patients without classic infectious manifestations.

[Lung surgery in haematological patients: useful? hazardous?]. / Chirurgie pulmonaire chez le malade d'hématologie : pourquoi ? Pour qui ?

Respiratory complications are frequent in haematological patients. Lung surgery, either for diagnosis or treatment, is considered useful but hazardous in these patients. We performed a reappraisal study of this purpose; retrospective study in a university centre, located in the Paris area, France. We analysed the entire records of all the haematological patients admitted in the Thoracic Surgery department from October 2001 to January 2009, among 400 haematological patients with pulmonary complications admitted to the Respiratory Diseases department. Seventeen patients (male: n=13, mean age 47 ± 15 years) underwent lung surgery. Underlying haematological disease was acute (n=7) or chronic (n=5) leukaemia, lymphoma (n=4), and eight have had stem cell transplantation. Thirteen patients had been exposed to a cytotoxic chemotherapy with known pulmonary toxicity. Respiratory diseases have been evolving for 112 days (10-663 days), and 14 patients received previously antibiotic and/or antifungal therapy. One patient was neutropenic and three had thrombopenia. Five patients underwent curative surgery for a residual pulmonary nodule after medical treatment of invasive aspergillosis, and 12 had a diagnostic procedure (open lung biopsy by video-assisted thoracoscopy [n=2]; thoracotomy [n=8]). Surgery permitted a final diagnosis in all 12 cases: non-specific infiltrative pneumonia (n=4), pulmonary graft versus host disease (n=3), granulomatous pneumocystosis (n=1), invasive aspergillosis (n=1), bronchial carcinoma (n=1), EBV-related lymphoproliferation (n=1), and tuberculosis (n=1). Therapeutic regimens were modified according to the surgical results in ten cases (84%). All patients were extubated at the end of surgery. Post-operative complications were: prolonged air leaks (n=3), pneumonia (n=1), parenchymal hematoma (n=1), acute coronary syndrome (n=1). Seven patients were admitted in the Intensive Care Unit, and five had non-invasive ventilation. Three patients died from respiratory failure: NSIP (n=2), pneumocystosis (n=1). Lung surgery for selected haematological patients has two indications: (1) curative surgery, for a residual pulmonary nodule after medical treatment of invasive aspergillosis; (2) diagnostic procedure, leading frequently to modifications of therapeutic regimens, with low rate of complications, in highly selected patients.

[Radiofrequency treatment of lung tumours]. / Le traitement par radiofréquence des tumeurs pulmonaires.

Formal surgical resection is the standard treatment for patients with an operable non-small cell lung tumour and for selected patients with limited lung metastases, even if only a small number of patients are suitable for formal surgical resection due to comorbidities. CT-guided radiofrequency treatment is a minimally invasive therapeutic option that has been successfully applied to different organs, and for the lung is considered to be an alternative to surgery for patients who are not candidates for surgery. The procedure is well-tolerated and the complication rate is acceptable.

[Pulmonary arterial hypertension related to HIV: is inflammation related to IL-6 the cornerstone?]. / Hypertension artérielle pulmonaire liée à l'infection VIH : de la pression artérielle pulmonaire à l'interleukine-6.

Vascular diseases have become the leading cause of mortality in the population treated for HIV infection. Pulmonary arterial hypertension (PAH) related to HIV (PAH-HIV), the fourth cause of PAH in France, has the same histological pattern as other PAH from the group 1 of Dana Point classification. But, conversely to idiopathic PAH in the general population, PAH-HIV is particular by its high frequency in HIV-infected population. This raises the question for the role of inflammation in the PAH-HIV pathophysiology. Its constant occurrence over the decades, despite introduction of combination antiretroviral therapy (CAT), does not preclude the hypothesis of an involvement of inflammation in the genesis of PAH-HIV. Indeed, it is well known that normalization of CD4+ by the CAT does not mean no inflammation. Especially, it persists an increased and continuous production of IL-6, a main cytokine in the genesis of PAH lesions. This inflammation mainly involves the endothelin-1 pathway, which has an action on endothelium and macrophages, leading to high production of IL-6. Moreover, plasmatic level of IL-6 has a prognostic value in PAH-HIV, independently from conventional (functional or hemodynamic) parameters. The use of endothelin receptor antagonist permits major effect on IL-6 production and dramatic effect on PAH in so-called "bosentan responders".