Rituximab-induced lung disease: A systematic literature review.

The anti-CD20 antibody rituximab has been reported to induce a heterogeneous spectrum of lung disorders. The aim of the present study was to critically review data on the clinical presentations, causality assessments and management strategies of lung diseases possibly related to rituximab. A systematic literature review was performed on English-language reports in PubMed until September 2008. Cases of lung diseases ascribed to rituximab (n = 45) were identified, with three time-to-onset patterns. The most common presentation was acute/subacute hypoxaemic organising pneumonia (n = 37), starting 2 weeks after the last infusion (often around the fourth cycle) and resolving, in most cases, provided glucocorticoid therapy was given early. Acute respiratory distress syndrome occurred in five patients, within a few hours and usually after the first infusion. In the remaining three patients, macronodular organising pneumonia developed insidiously long after rituximab therapy and responded to steroids. Eight patients died. Based on time to onset, symptoms, and responses to discontinuation and rechallenge with rituximab and other drugs, 13 cases were highly compatible and 32 compatible with rituximab-induced lung disease. Knowledge of these presentations of rituximab-induced lung disease should prove helpful for diagnosis and causality assessment purposes. Time-to-onset data, suggesting different pathogenic mechanisms, support closer clinical and perhaps radiological monitoring between infusions, particularly in patients with a history of reversible respiratory symptoms.

Characterisation of severe obliterative bronchiolitis in rheumatoid arthritis.

The characteristics of patients with rheumatoid arthritis (RA) who develop obliterative bronchiolitis characterised by severe airflow obstruction have been hitherto poorly investigated. A retrospective study of 25 patients with RA and functional evidence of obliterative bronchiolitis (forced expiratory volume in one second (FEV(1))/forced vital capacity (FVC) <50% and/or residual volume (RV)/total lung capacity (TLC) >140% predicted) was conducted. Patients (mean+/-SD age 64+/-11 yrs) included 17 never-smokers and eight ex-smokers (10.5+/-5.4 pack-yrs). The diagnosis of RA preceded respiratory symptoms in 88% of cases. Dyspnoea on exertion was present in all patients and bronchorrhea in 44%. High-resolution computed tomography findings included: bronchial wall thickening (96%), bronchiectasis (40%), mosaic pattern (40%), centrilobular emphysema (56%), and reticular and/or ground-glass opacities (32%). Pulmonary function tests showed: FEV(1) 41+/-12% pred, FEV(1)/FVC 49+/-14%, FVC 70+/-20% pred, RV 148+/-68% pred and RV/TLC 142+/-34% pred. Lung biopsy, available in nine patients, demonstrated constrictive, follicular and mixed bronchiolitis. Patients were followed for 48.2+/-49 months. Treatment was poorly effective. Chronic respiratory failure occurred in 40% of patients, and four patients died. Obliterative bronchiolitis associated with rheumatoid arthritis is a severe and under-recognised condition leading to respiratory failure and death in a high proportion of patients.

[Tuberculosis, anti-TNF agents and other immunosuppressants: evolution of preventitive strategies]. / Tuberculose, agents anti-TNF et autres immunosuppresseurs: évolution des stratégies de prévention.

The occurrence of tuberculosis (TB) in patients treated with immunosuppressive drugs (ISD) is an old problem that has been highlighted by cases occurring in patients using anti-TNFalpha drugs. After a brief review of anti-tuberculosis immunity to highlight the immunosuppressant targets, we show how an epidemiological approach allows the control of risk in patients with drug-induced immunosuppression. The assessment and the control of this risk are usually complicated by underlying immunosuppressant disease, co-morbidities, associated drugs and local disease prevalence. Steroid therapy in systemic diseases and ISD protocols in graft rejection prevention illustrate this problem particularly well. The management strategy adopted to combat anti-TNF related tuberculosis in rheumatoid arthritis (RA) has allowed these biases to be avoided. The incidence of TB in RA has been recorded in some national databases (USA, Spain). A four fold increase was registered after the introduction of anti-TNF agents in 2001 which could be considered as the true risk of the drug. Several national health agencies proposed guidelines to screen and prevent TB risk in these patients. Their effectiveness was confirmed by the incidence of TB returning the level prior to the introduction of these agents. Recommendations could be improved by using interferon-gamma screening tests and a better benefit/risk prophylaxis. They should be observed and if possible extended to new and other ISD.

[Pulmonary manifestation of rheumatoid arthritis]. / Manifestations respiratoires spécifiques de la polyarthrite rhumatoïde: "le poumon rhumatoïde"

INTRODUCTION: Lung disease is the most frequent and among the most severe extra-articular manifestation of rheumatoid arthritis (RA). Several interesting advances have been made in recent years in our understanding of this respiratory disease. STATE OF ART: 1. The induction of BALT responsible for follicular lymphoid infiltrates has been demonstrated in the wall of respiratory bronchioles. These lymphoid infiltrates are similar to synovial and skin cellular infiltrates and secrete specific markers of RA (citrullinated proteins). These data strongly suggest a common pathogenic mechanism for RA in the joints and in other sites, such as the lung. 2. Improvements in high resolution computed tomography (HR- CT) increased the sensitivity of diagnosis. CT evidence of pulmonary disease is present in 50% of RA patients, but only 10% of these patients have clinical symptoms. The different lung manifestations, frequently combined, have been clearly described: pulmonary nodules (20%); small airways disease (30%): bronchiolitis, bronchiolectasis, and bronchiectasis; diffuse interstitial pneumonia of various types (20%). 3. Predictors of progression and therapeutic response remain unknown. Therefore treatment is empirical and based on usual indications and on drugs used in idiopathic fibrosis and other connective tissue pulmonary pathologies. CONCLUSIONS: New biological drugs such as TNF blocking agents or anti CD20 antibody could be beneficial. Infections and drug-induced pneumonitis are not described in this review but must be considered systematically when an RA patient presents with lung involvement.

[PneumoDoc: a computer-based decision-making system for drug-related pulmonary disease]. / Formalisation de la démarche diagnostique des pneumopathies médicamenteuses: le système PneumoDoc.

Establishing the diagnosis of drug-related pulmonary disease (DRPD) remains a difficult task because of the large number of drug-related toxic situations and the variety of clinical presentations. PneumoDoc is a computer-based support system designed to facilitate the diagnosis of lung disease using chronological, clinical, imaging, and cytological (alveolar lavage) input. These intrinsic items are crosschecked against extrinsic items reported in the literature (Pneumotox). Data input is in the form of yes-no questions. The final output displays the characteristic features of the observed clinical situation and calculates the probability of DRPD defined in five categories: incompatible, doubtful, compatible, suggestive, and highly suggestive. Use of multiple drugs, interaction with cardiopulmonary disease, and the absence of reported cases are limitations of the system.

Late pleuropulmonary metastases of a cerebral ependymoma.

A patient with a 12-year history of occipital ependymoma was found to have late pleuropulmonary metastases without recurrence of the primary tumor. The pleural metastases were diagnosed by histologic, ultrastructural features and finally by glial fibrillary acidic protein (GFAP) labeling positive reaction. This case is unique because of the long interval between occurrence of the initial tumor and the metastases, and because of the apparent quiescence of the cerebral lesion when the pleuropulmonary metastases were discovered.

Leukocyte migration inhibition in amiodarone-associated pneumonitis.

Amiodarone-associated pneumonitis is now a well-known clinical entity, but the mechanism for the induction of the pulmonary disease is ill defined. In four patients with this disorder, evidence was obtained for elaboration of a lymphokine, leukocyte inhibitory factor (LIF), by peripheral blood lymphocytes after incubation with amiodarone in the direct leukocyte migration inhibition test. Control lymphocytes from normal subjects, as well as from patients receiving amiodarone but without pneumonitis, failed to elaborate LIF in the presence of the drug in this test. This production of LIF suggests that pneumonitis associated with amiodarone therapy is also associated with a specific cellular immune response to the drug.

Provocation test coupled with bronchoalveolar lavage in diagnosis of drug (nilutamide)-induced hypersensitivity pneumonitis.

A 79-year-old man was given a cumulative dose of 16.5 g of nilutamide for treatment of prostate cancer. He then presented with a respiratory illness having clinical, radiologic and functional characteristics of interstitial pneumonitis. No other cause of pneumonitis was found. Bronchoalveolar lavage showed a lymphocytic alveolitis with an inverted lymphocyte subset ratio. After an 11-week period of drug withdrawal, clinical, radiologic and functional improvement was observed along with a normal alveolar lymphocytosis. Nilutamide therapy was then resumed for five weeks and induced the recurrence of clinical, functional and alveolar abnormalities. Nilutamide treatment was finally stopped and two months later, clinical and functional abnormalities resolved. This observation seems to exemplify the possible diagnostic value of coupling provocation test with BAL cell data in hypersensitivity pneumonitis induced by drugs. In addition, these data support the role of a cell-mediated immunologic mechanism in the pathogenesis of nilutamide-induced pneumonitis.

Pleural T-lymphocyte subsets in amiodarone-associated pleuropneumonitis.

Two male patients presented with lung disorders with all the characteristics of amiodarone-related pneumonitis. Bilateral exudative pleural effusions were associated with pneumonitis. High lymphocytosis was present in the pleural fluid with a ratio of T-lymphocyte subsets close to that found in peripheral blood; in the blood T-lymphocyte subset ratio was nearly normal. By contrast, and as is usual in similar cases, lymphocytic alveolitis with T-lymphocyte subset imbalance was found in bronchoalveolar lavage fluid. These findings, never published so far to our knowledge, would favor a compartmentalization of the immune response inside the lung.

The relationship between introduction of American society of clinical oncology guidelines and the use of colony-stimulating factors in clinical practice in a Paris university hospital.

BACKGROUND: Clinical practice guidelines are issued periodically by professional medical societies or committees to assist practitioners in clinical decision making. However, it is unclear whether such guidelines have any lasting impact on clinical practice. OBJECTIVE: The purpose of this study was to assess the impact of the American Society of Clinical Oncology (ASCO) guidelines regarding use of hematopoietic colony-stimulating factors (CSF) on cancer care in a university hospital in Paris. METHODS: The study was performed at Hjpital Tenon, an 830-bed university hospital in Paris, in 1996 and 1997, both before and after the ASCO guidelines were implemented. The guidelines were first disseminated as a continuing medical education program and then actively implemented using a CSF prescription order form summarizing the guidelines. This form had to be used during the patient consultation and was sent to the Hjpital Tenon pharmacy for CSF dispensation. Even if CSF use did not comply with the ASCO guidelines, the pharmacy filled the prescription. Seven other university hospitals in Paris, where the ASCO guidelines were not actively implemented, comprised the control group. The main outcome measure was the proportion of prescriptions in compliance with the 1996 update of the ASCO guidelines. Secondary outcome measures were the proportions of prescriptions in compliance with ASCO guidelines regarding primary prophylactic, secondary prophylactic, and therapeutic CSF administration. RESULTS: Before implementation of the ASCO guidelines, CSF use in compliance with the guidelines was 39% (41/105) at the study site and 31% (16/51) at the control sites (P > 0.05). Six months after dissemination and implementation of the guidelines, the proportion of CSF prescriptions complying with ASCO guidelines increased significantly versus baseline (P = 0.003) in the study group, to 61% (50/82). However, even after the guidelines were implemented, compliance with guidelines on primary prophylactic CSF administration did not change significantly versus before implementation in the study group (12% [5/41] before implementation vs 6% [2/33] after implementation; P > 0.05). CONCLUSIONS: The results suggest an association between the active implementation strategy (continuing medical education and CSF prescription reminder form) and physician compliance with the ASCO guidelines. Implementation of the ASCO guidelines appears to have had some impact on medical practice.

[Respiratory complications of new treatments for rheumatoid arthritis]. / Complications respiratoires des nouveaux traitements de la maladie rhumatoïde.

INTRODUCTION: Treatment of rheumatoid arthritis (RA) has changed with the release of more efficient disease-modifying anti-inflammatory drugs (DMARDs) and biologicals, such as methotrexate, leflunomide and TNF blockers, respectively. However they are prone to trigger potential pulmonary side effects. STATE OF KNOWLEDGES: Diffuse interstitial pneumonitis with alveolar lymphocytosis are induced by methotrexate. This drug increases also the risk of opportunistic infections (Pneumocyctis carinii) and of delayed lymphomas. Many intracellular bacterial infections, about 80 cases of diffuse pneumonitis, and rare vasculitis are attributable to leflunomide. PERSPECTIVES: The TNF blocking agents (infliximab, etanercept and adalimumab) trigger immunization and consequently, rare type I and III hypersensitivity pneumonitis, serological lupus-like reactions usually without any clinical manifestations. Indeed the risk of infection with intracellular agents remains the first concern. Several hundreds of cases of pulmonary and non pulmonary tuberculosis (TB) have been described. They present as disseminated forms, with pulmonary manifestations present in half cases; of note, other sites are atypical, namely meningitis, lymph node, and digestive involvement. Pathological diagnosis can be difficult since granulomas are sparse or absent. Therefore TB can be lethal because of delayed diagnosis and treatment. CONCLUSION: To prevent this major risk when using TNF blockers, the French agency AFFSAPS recommends to screen and treat susceptible patients such as latent tuberculosis. Specifically, antituberculous drugs have to be started three weeks before anti-TNF agents. During biological therapy, physicians must regularly look for usual and unusual symptoms of TB. When TB is diagnosed, anti -TNF agents have to be discontinued, probably definitively, and appropriate antituberculosis treatment started in order to achieve an uneventful course.

[Protein-poor pleurisy and mesothelioma. Apropos of 2 cases]. / Pleurésie pauvre en protides et mésothéliome. A propos de 2 cas.

We report two cases of protein poor pleural effusions secondary to malignant mesothelioma which were proven histologically. In the absence of any extra pulmonary cause, in particular cardiac, the associated investigations carried out led to the exclusion of either a chylothorax or a mechanical effusion due to atelectasis. Pulmonary venous obstruction by the mesothelial masses which had developed on the mediastinal pleura were shown in the two cases. The high pressure in the pulmonary capillaries which resulted could be the origin of the low level of protein observed in the pleural fluid.

[Acute, reversible, interstitial pneumopathy induced by melphalan]. / Pneumopathie interstitielle, aiguë, réversible, induite par le melphalan.

A case of acute interstitial pneumonia with hypoxaemia is described; this occurred after the cessation of cortico steroids in a patient suffering from myeloma treated with melphalan. The absence of any microbes and the lymphocytosis in the bronchoalveolar lavage and the rapid and favourable improvement on cortico steroids led to a diagnosis of melphalan induced pneumonia. This acute form is probably due to a hypersensitivity mechanism and should be distinguished from the majority of cases of sub-acute fibrosing pneumonitis due to melphalan which have been published before. Urgent treatment with glucocorticoids is justified as well as the immediate and final cessation of the medication responsible, because it is this which will affect prognosis.

[Bronchiolitis obliterans, pneumocystosis and HIV infection]. / Bronchiolite oblitérante, pneumocystose et infection par le V.I.H.

A 39 year old man who was HIV positive and was treated with trimethoprim-sulfamethoxazole for pneumocystis with hypoxaemia. During the acute episode he had a persistent fever of 38 degrees and hypoxaemia with a PaO2 of 65 mm/Hg and bilateral opacities both radiologically and on a CT scan, which were of alveolar type, with bronchograms identical to those observed before the treatment of the pneumocystis. In view of the negative evidence for a respiratory or extra respiratory infection, a surgical biopsy was performed and this revealed lesions of bronchiolitis obliterans with an organising pneumonia (BOOP). After the thoracotomy, there was a spontaneous clinical cure in a few days and radiological clearance in a month. This very rare diagnosis should be added to the list of causes of alveolar pneumopathy with infiltration and fever occurring during the course of an HIV infection.

[Prevention of venous thromboembolism in a non-surgical medical ward. Proposed indications for low molecular weight heparin]. / Prévention de la maladie thromboembolique veineuse en milieu hospitalier non chirurgical. Propositions d'indications des héparines de bas poids moléculaire.

OBJECTIVE: The efficiency of venous thromboembolism prophylaxis with low molecular weight heparins (LMWH) has not been established in non surgical patients, so their official preventive use has been limited in France since 1995 to surgery. However, a survey conducted in 5 university hospitals in non surgical patients showed that 21-29% of patients still received a LMWH prescription. It seemed necessary to define the medical conditions for which the practical use of these heparins would be justified. We contacted external experts to obtain a consensus by using the Delphi method. METHODS: The Delphi method, created by the "Rand Corporation" in the USA and used in medicine since the nineteen seventies, is based on a light logistic, with questionnaires been sent by mail with a feed-back report A total of 48 experts were chosen by local staff teams in the 5 hospitals. For the 3 rounds, from March to October 1998, questions were devised by a multicentred staff team. RESULTS: Among the 48 experts contacted, 32 completed the 3 questionnaires, 7 of them did for 2, and 43 did for at least one questionnaire. The experts first defined a list of 12 risk or high risk situations and 11 aggravating factors. For any high risk situation, prescription is justified. For other cases, 2 risk situations are required, or one risk situation with at least 2 aggravating factors, to justify a prescription. If no risk situation is present, prescription is, according to experts, usually not justified. CONCLUSION: The maximal agreement defines the situations in which one use of low molecular weight heparins is proposed to prevent deep venous thrombosis in non surgical inpatients, in most current hospital situations and for more than 24 hours of hospitalization. Clinical trials are needed, to validate their effectiveness and define the optimal dose in these indications. To date, epidemiological studies should be conducted to evaluate the experts proposals by estimating risk factors for deep venous thrombosis.

[Prophylactic prescription of low-molecular-weight heparin in the non-surgical setting: impact of recommendations]. / Prescription préventive des héparines de bas poids moléculaire en milieu non chirurgical: l'impact de recommandations.

OBJECTIVE: Low-molecular-weight heparins (LMWH) had official approval for use for venous thromboembolism prophylaxis only for surgery patients when this survey was conducted, but were nevertheless often used in non-surgery patients. We conducted this "before and after" survey from May 1998 to April 1999 to assess the impact of the recommendations implemented in the beginning of 1999. METHODS: Data on the use of LMWH were collected on three different days within a three week interval in all non-surgery departments at the Tenon hospital before distribution of expert recommendations early in 1999. Published in La Presse Médicale in January 2000, these recommendations issued from an external panel of 43 experts who were contacted to establish a consensus opinion using the Delphi method. Data were again collected on three different days after implementation of the recommendations. Implementation was based on a patient-specific prescription order form requested by the hospital pharmacy for delivery to the department. RESULTS: Data were collected for 121 prescriptions prior to the recommendations and for 158 after. Sex-ratio, mean age and percentage of LMWH prescriptions did not differ significantly between the two periods. There was a lower number of non-appropriate prescriptions after implementation of the recommendations from 54.5% to 35.4% (p = 0.01) with better conformity for recommendation A (high-risk patients) (36% versus 43%, NS) and for recommendation B (= 2 risk situations or = 1 risk situation and = 2 aggravating factors) (10% versus 22%, p = 0.01). Better conformity of LMWH prescriptions in oncology and radiotherapy departments partially explained this general improvement, but the difference remained significant when excluding these two departments (p = 0.04). CONCLUSION: This study shows that physician compliance with recognized expert recommendations can improve their implementation. This procedure is now in general use in the Tenon hospital.

[Etiological work-up for bronchectasia in adults]. / Enquête étiologique devant des bronchectasies de l'adulte.

Search for an etiology of bronchiectasis consists in identifying constitutional or acquired defense mechanisms of the respiratory mucosa. The question is timely because causes change. In developing countries, presumed sequelae of infection account for about 30% of the cases despite vaccination campaigns, control of endemic tuberculosis, and widespread use of antibiotics. Genetic diseases account for 20% of the causes when identified by high-performance prospective diagnostic tests (CFTR mutation). Computed tomography enables the identification of frequent associations between bronchiectasis and rheumatoid disease or ulcerative colitis. Recent diseases such as HIV infection or GVHD can also lead to bronchiectasis. Nevertheless, the cause remains unknown in 30-50% of patients. After a detailed analysis of the clinical presentation and diagnostic criteria specific for each etiology, we propose a two-phase diagnostic procedure. The first step, used for all patients (careful history taking, physical examination, imaging, bronchofibroscopy, limited blood tests) enables detecting localized bronchial obstacles and obvious etiologies (situs inversus of primary ciliary dyskinesia, known systemic disease, HIV...). If the first step is negative, the second phase is oriented by the clinical context. Sequelae of infection (tuberculosis...) in older subjects or migrants, a genetic cause in younger subjects, particularly if there is a familial history and/or infertility, a systemic disease or allergic bronchopulmonary aspergillosis if there is an extra-respiratory context. This etiological search should help improve patient management and provide a better prognosis and prevention of bronchiectasis.

[Pulmonary aspergilloma appearing early]. / Aspergillome pulmonaire d'apparition précoce.

A 62-year old smoker and alcoholic woman with chronic obstructive lung disease was admitted for suppurative pneumonia with cavitation and developed an intracavitary aspergilloma less than 2 months after the first signs of pneumonia. In view of the short time elapsed between the aspergilloma and the onset of suppurative pneumonia, 2 possibilities are discussed: either an aspergilloma developed unusually early in the cavity of a recent pulmonary abscess, or the patient had a chronic necrotizing pulmonary aspergillosis diagnosed at an early stage, which would account for all the manifestations observed.

[Endobronchial metastases of cancer. Apropos of 29 cases]. / Les métastases endo-bronchiques des cancers. A propos de 29 observations.

In a retrospective study covering a 3-year period, 29 cases were reviewed. All concerned patients with endoscopic abnormalities resembling those of a primary carcinoma and histologically of the same type as a previously known tumour affecting areas as diverse as the E.N.T. region (31%), the colorectal region (20.6%), the mammary gland (13.7%) or the bladder (10.3%). There was nothing particular in the clinical, radiological or endoscopic signs. In the vast majority of cases (27/29) the histological diagnosis was provided by bronchofibroscopy. Thus, not only does endoscopy frequently visualizes abnormalities in obviously secondary carcinomas, but it also diagnoses cancers with clinical, radiological and endoscopic features of primary cancers from which they are sometimes almost undistinguishable.

[Thoracic metastases of ependymoma. Apropos of a case and review of the literature]. / Les métastases thoraciques des épendymomes. A propos d'un cas, revue de la littérature.

A 27-year old woman with occipital ependymoma treated by surgery and radiotherapy for multiple recurrences developed a right lymphocytic pleural effusion. After 3 inconclusive needle biopsies of the pleura, pleurectomy was performed. Pathological examination with a specific immunohistochemical marker provided a diagnosis of pleuro-pulmonary metastases from the ependymoma. This rare case of extraneuraxial metastasis from a cerebral ependymoma is discussed in the light of published data. Its originality lies in that a positive diagnosis of pleural metastases was obtained with an immunohistochemical marker, the gliofibrillary antiprotein serum (anti-GFAP) specific of glial tissue.