Acute pneumonitis associated with low dose methotrexate treatment for rheumatoid arthritis: report of five cases and review of published reports.

BACKGROUND: Low dose methotrexate has become established in the treatment of refractory rheumatoid arthritis. Until recently it has been considered that the use of a low dose regimen (< 20 mg/week) would avoid the pulmonary toxicity associated with the higher doses prescribed in malignant disease. Although initial experience with low dose methotrexate was encouraging, an increasing number of cases of an acute, life threatening pneumonitis are being reported in patients with refractory rheumatoid arthritis. PATIENTS: Since 1984 43 patients with refractory rheumatoid arthritis have been established on low dose methotrexate in the Oxford Health District. Five of these patients have subsequently developed acute methotrexate induced pneumonitis. The clinical and radiological features of these cases are described and previous reports reviewed. RESULTS: Five patients having low dose methotrexate treatment developed acute pneumonitis. Presentation was subacute and dominated by constitutional features. Respiratory symptoms developed insidiously but progressed rapidly with increasing dyspnoea associated with severe hypoxia. Chest radiographs were non-specific, showing diffuse interstitial infiltration and alveolar shadowing. Microbiological investigation gave negative results. In all cases methotrexate was discontinued and high dose corticosteroids started, with rapid clinical and radiological improvement. After withdrawal of steroid both clinical and radiological resolution was maintained at follow up. CONCLUSION: Acute pneumonitis is an uncommon but serious adverse effect of low dose methotrexate treatment for refractory rheumatoid arthritis. The initial presentation is non-specific and a high index of suspicion is required as respiratory failure may develop rapidly. Management depends on exclusion of infection, withdrawal of methotrexate, and high dose corticosteroid treatment. Full supportive treatment is indicated as the prognosis in such patients is good.     

Lymphocyte dynamics: caution in interpreting BAL numbers

In various allergic and inflammatory lung diseases the number and subset composition of lymphocytes in the bronchoalveolar lavage (BAL) fluid are taken as indicators of the state of the disease. The number of lymphocytes in the BAL fluid depends on three main parameters: (1) entry into the bronchoalveolar space from the different compartments of the lung, (2) persistence in the bronchoalveolar space which is modified by the rate of local proliferation and apoptosis, and (3) exit into the draining bronchial lymph node via the lymphatic system. In healthy individuals lymphocytes in the BAL fluid seem to be a stable pool: each day there is hardly any entry, local cell division or cell death and few lymphocytes emigrate from this compartment. In contrast, during inflammatory, toxic and allergic reactions all parameters can increase rapidly with more lymphocytes entering, proliferating and/or undergoing apoptosis locally. Very little is known about factors such as cytokines and chemokines which may regulate these parameters. When interpreting data on lymphocyte numbers in patients, lymphocyte dynamics in the bronchoalveolar space have to be considered, and in the future it may be possible to manipulate these lymphocyte fluxes for therapeutic purposes.


     

Analysis of T cell subsets and beta chemokines in patients with pulmonary sarcoidosis

BACKGROUND: Sarcoidosis is a systemic granulomatous disorder of unknown origin characterised by accumulation of T lymphocytes and macrophages in multiple organs. Several cytokines and adhesion molecules may contribute to the accumulation of T lymphocytes in pulmonary sarcoidosis. The distribution of T lymphocyte subsets, T cell bearing CD11a and beta chemokines such as regulated on activation normal T expressed and secreted (RANTES), macrophage inflammatory peptide 1 alpha (MIP-1 alpha), and macrophage chemoattractant protein 1 (MCP-1) in bronchoalveolar lavage (BAL) fluid and peripheral blood were compared in untreated patients with sarcoidosis and normal subjects. METHODS: Flow cytometric analysis with monoclonal antibodies to cell surface antigens was used to identify T lymphocyte subsets in the BAL fluid of untreated patients with sarcoidosis (n = 40)--either without (group A, n = 12) or with (group B, n = 28) radiological evidence of pulmonary involvement--and in 22 normal subjects. The level of different beta chemokines was estimated by enzyme linked immunosorbent assay (ELISA). RESULTS: A high percentage of CD3+ cells, CD4+ cells expressing HLA-DR antigen, and a high CD4/CD8 ratio were detected in the BAL fluid of patients compared with normal subjects. In particular, CD4+ CD29+ memory T cells were significantly increased in patients with sarcoidosis. Furthermore, these cells were higher in those in group B than group A. The level of RANTES in the BAL fluid of patients was significantly higher than in normal subjects and correlated well with the percentage, number, and expression of CD29 on CD4 cells. The expression of CD11a (alpha chain of lymphocyte function associated antigen-1, LFA-1) on CD3+ cells in the BAL fluid of patients with sarcoidosis was not different from that of normal subjects. However, the expression of CD11a on CD3+ cells in the BAL fluid of patients in group A was significantly lower than that of patients in group B and normal subjects. CONCLUSIONS: These results suggest a possible interaction between activated memory T cells bearing CD11a and RANTES which may contribute to the pulmonary involvement in patients with sarcoidosis.


     

Gamma/delta cells in tissue from patients with sarcoidosis.

BACKGROUND: Because gamma/delta T lymphocytes (gamma delta cells) respond to myco-bacterial antigens in vitro and accumulate in the skin lesions of patients with certain granulomatous infections (leprosy, leishmaniasis), it was hypothesised that these cells might have a role in the pathogenesis of sarcoidosis, a disease also characterised by granuloma formation. Having failed to demonstrate an increase in gamma delta cells in the blood of patients with sarcoidosis, the aim of this study was to examine samples of bronchoalveolar lavage (BAL) fluid and biopsy tissue. METHODS: Samples from 23 patients (13 women) with newly diagnosed sarcoidosis, of mean age 31 years and median percentage of lymphocytes in the BAL fluid of 31%, were studied. Controls included normal subjects and patients with other interstitial lung diseases (ILD). Cytopreparations of BAL fluid (n = 13) and cryostat sections (five mediastinal nodes, 14 transbronchial biopsies) were stained with alkaline phosphatase-antialkaline phosphatase and monoclonal antibodies to CD3, CD4, CD8, CD25, and gamma delta T cell receptor (TCR). RESULTS: All patients had typical chest radiographs (16 stage I, four stage II, three stage III). All were Mantoux negative with negative tuberculosis cultures. Compared with normal controls and patients with other interstitial lung diseases there was no increase in gamma delta cells in the BAL fluid (sarcoidosis, 1% (range 0-4%) total cells; ILD, 1% (0-2%); controls, 0.5% (0-2%); p > 0.05, Kruskal-Wallis). Likewise, there was no increase in gamma delta cells in the transbronchial biopsy specimens (sarcoidosis, 1/high power field (hpf) (range 0-2); ILD, < 1/hpf (0-4); controls < 1/hpf (0-2); p > 0.05). gamma delta cells were rarely seen in the lymph nodes in spite of the presence of numerous granulomas. CONCLUSION: These results provide further evidence that gamma delta cells are not increased in most patients with sarcoidosis.     

Interstitial pneumonitis during murine cytomegalovirus infection and graft-versus-host reaction. Characterization of bronchoalveolar lavage cells

Acute murine cytomegalovirus (MCMV) infection alters the course of graft-vs-host (GVH) disease involving major histocompatibility (MHC) antigens and induces interstitial pneumonitis. F1 (B10 x B10.BR) mice given 20 x 10(6) B10.BR spleen cells and MCMV (1 x 10(5) plaque-forming units [PFU]) develop severe, diffuse pneumonitis not seen with either MCMV or GVH alone. As one index of the host immune processes operating in the lungs during MCMV/GVH pneumonitis, we examined the types of cells recovered from the lung by bronchoalveolar lavage (BAL) during pneumonitis. During MCMV/GVH pneumonitis, the total cells recovered significantly increased, due primarily to an influx of Thy 1.2 lymphocytes. Characterization of cells using multiparameter flow cytometric analysis revealed that greater than 80% of all BAL cells were Thy 1.2-positive lymphocytes of donor origin. In addition, donor Thy 1.2-positive cells were of both the L3T4+ (43% of BAL cells) and Lyt 2+ (38% of BAL cells) phenotype. Thus, MCMV infection during GVH to MHC antigens induces interstitial pneumonitis, characterized by an influx of T lymphocytes (both helper and suppressor/cytotoxic) from the donor. The antigenic specificity of these cells is not known.     

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.     

Interstitial pneumonitis in patients infected with the human immunodeficiency virus.

BACKGROUND--A study was performed to identify the clinical, radiographic, and histopathological features of interstitial pneumonitis in patients infected with the human immunodeficiency virus. METHODS--A retrospective review was made of the case notes, chest radiographs, and histopathological results of seven HIV-1 antibody positive patients with symptomatic diffuse pulmonary disease and a pathological diagnosis of non-specific interstitial pneumonitis. RESULTS--All patients had dyspnoea, with or without cough, and chest radiographs showing diffuse infiltrates. The arterial oxygen tension ranged widely from 5.9 to 13.1 kPa. The initial clinical diagnosis was Pneumocystis carinii pneumonia in most cases. The pathological diagnosis was made by transbronchial biopsy in one case and by open lung biopsy in six cases. The interstitial pneumonitis consisted of a patchy lymphocytic infiltrate composed of B cells in focal aggregates and T cells in a more diffuse distribution. The T cell population was a mixture of CD4+ and CD8+ cells. The histological findings contrast with the more extensive infiltrate of predominantly CD8+ lymphocytes seen in HIV-associated lymphocytic interstitial pneumonitis which occurs mainly in children. The condition ran a subacute course. Three patients spontaneously improved and three improved with steroid therapy. Long term survival was less than three years, the prognosis being determined by other infective or neoplastic complications. CONCLUSIONS--Non-specific interstitial pneumonitis usually presents with an illness resembling Pneumocystis carinii pneumonia but occurs when the CD4 and total lymphocyte counts are still preserved. The pneumonitis resolves spontaneously or responds to steroids, and does not itself lead directly to the patient's death. It does, however, appear to mark a downturn in the course of HIV infection.     

Phenotypic analysis of lymphocytes and monocytes/macrophages in peripheral blood and bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis

BACKGROUND: The granulomatous inflammation in sarcoidosis is driven by the interplay between T cells and macrophages. To gain a better understanding of this process the expression by these cells of cell surface activation markers, co-stimulatory molecules, and adhesion molecules was analysed. METHODS: CD4+ and CD8+ T lymphocytes from peripheral blood (PBL) or bronchoalveolar lavage (BAL) fluid, as well as paired peripheral blood monocytes and alveolar macrophages from 27 patients with sarcoidosis were analysed by flow cytometry. RESULTS: CD26, CD54, CD69, CD95, and gp240 were all overexpressed in T cells from BAL fluid compared with those from PBL in both the CD4+ and CD8+ subsets, while CD57 was overexpressed only in BAL CD4+ cells. In contrast, CD28 tended to be underexpressed in the BAL T cells. Monocyte/macrophage markers included CD11a, CD11b, CD11c, CD14, CD16, CD54, CD71, CD80 and CD86 and HLA class II. CD11a expression in alveolar macrophages (and peripheral blood monocytes) was increased in patients with active disease and correlated positively with the percentage of BAL lymphocytes. Expression of CD80 in macrophages correlated with the BAL CD4/CD8 ratio. CONCLUSIONS: Our data indicate substantial activation of both CD4+ and CD8+ lung T cells in sarcoidosis. There were also increased numbers of BAL lymphocytes whose phenotypic characteristics have earlier been associated with clonally expanded, replicatively senescent cells of the Th1 type.     

Immunopathological changes in the airways of stable lung transplant recipients

BACKGROUND: Pathological obliterative bronchiolitis, characterised by inflammation and occlusion of airways, is a serious complication of lung transplantation. Endobronchial biopsy (EBB) provides a means of examining transplanted airways. This study aimed to investigate the role of EBB samples in revealing early signals of airway injury. METHODS: In 18 stable lung transplant recipients with close to maximal lung function (median FEV1, best after transplantation 100%, interquartile range 98-100%) EBB samples were taken simultaneously with transbronchial biopsy samples and bronchoalveolar lavage (BAL) fluid (median 195 days after transplantation). OCT embedded specimens were snap frozen on an isopentane slurry made with liquid nitrogen and 7 microns sections were stained with monoclonal antibodies using a three stage immunoperoxidase method. RESULTS: Compared with nine non- transplanted control subjects, EBB specimens from the stable transplant group had significantly increased CD8 positivity (median 53 versus 27 cells/mm basement membrane, p = 0.04; 95% CI for the difference 1 to 46)) and increased HLA-DR positivity (median 84 versus 26 cells/mm basement membrane, 95% CI for the difference 6 to 115). There was an increase in CD68 positive cells in the EBB specimens from transplant recipients of borderline significance (median 92 versus 68, p = 0.08, 95% CI for the difference 1 to 84). CD3, CD4, and CD25 counts were similar in the two groups. EBB findings were not influenced by age, sex, indication for transplant, immunosuppression doses or levels, nor the presence of airway commensals in the BAL fluid. CONCLUSIONS: EBB is practicable in a transplant setting and provides information about bronchial inflammatory changes. It is likely that there is ongoing inflammation, possibly rejection mediated, even in healthy lung transplant recipients despite triple immunosuppression.


     

Clinical Utility of Cytomegalovirus Viral Load in Bronchoalveolar Lavage in Lung Transplant Recipients

The utility of cytomegalovirus (CMV) viral load (VL) by quantitative hybrid capture assay (Q-HCA) was investigated in bronchoalveolar lavage (BAL) from lung transplant recipients and compared with BAL cultures and blood VL. Forty-three consecutive BAL samples from 27 lung transplant recipients were analyzed. All samples had shell vial (SV) cultures in addition to Q-HCA. Histopathology was done on all lung tissues, and immunohistochemistry (IHC) in those with positive CMV cultures. Fifteen (56%) lung transplant recipients had both positive BAL SV cultures and BAL VL. Five of 15 had CMV pneumonitis with a VL in BAL >500 000 copies/mL (mean: 1638 450). Ten patients without CMV pneumonitis had VL in BAL <500 000 copies/mL (mean 81 820, p = 0.002). High VL in BAL and blood invariably meant CMV pneumonitis, but 2 patients with CMV pneumonitis had high BAL VL but relatively low blood VL. Initial CMV seronegativity was associated with pneumonitis (4/5 vs. 1/10; p = 0.004) and higher BAL CMV VL (p = 0.03). High CMV BAL or blood VL did not correlate with acute rejection or development of bronchiolitis obliterans syndrome (BOS). High CMV VL in BAL in lung transplant recipients is strongly associated with CMV pneumonitis, and may be more predictive than peripheral blood viral load.     

T lymphocytes and silica-induced pulmonary inflammation and fibrosis in mice.

BACKGROUND: Silica-induced pulmonary inflammation and fibrosis in animals provides a good model for chronic pulmonary inflammation and fibrosis. Although lymphocytes are implicated in the pathogenesis of pulmonary fibrosis, experimental models using silica-treated athymic nude mice have not been successful in showing the fibrogenic mechanism regulated by T cells. The aim of this study was to re-evaluate the role of T lymphocytes in the development of silicosis by comparing the response to silica administration of nude athymic mutants with that of euthymic animals. METHODS: Suspensions of silica particles were transnasally administered to nude athymic mice (Balb/c nu/nu) as well as to their euthymic littermates (Balb/c nu/+). The degree of pulmonary inflammation and fibrosis was assessed on days 14, 28, and 56 based upon histological observation, analysis of collagen deposition in the lungs, and analysis of the cellular constituent, protein, and phospholipid content in the bronchoalveolar lavage fluid. RESULTS: Histologically, athymic mice developed less severe interstitial pneumonitis than euthymic mice. In euthymic mice the lung hydroxyproline content increased with time after silica administration from 6.48 (0.38) micrograms hydroxyproline/mg dry lung weight on day 0 to 8.87 (0.41) micrograms/mg on day 56. A gradual increase in lung hydroxyproline content was also observed in athymic mice but the increase was significantly smaller than in euthymic mice (6.63 (0.43) micrograms/mg on day 0, 7.90 (0.19) micrograms/mg on day 56). Administration of silica resulted in an increase in the number of macrophages and neutrophils and in the total protein and phospholipid content of the bronchoalveolar lavage (BAL) fluid in both mouse strains. No significant difference was detected between athymic and euthymic mice in the numbers of macrophages, but the increase in neutrophils in the BAL fluid of athymic mice was significantly smaller than in euthymic mice on days 14 and 56. The total protein and phospholipid content of the BAL fluid from athymic mice was lower than that from euthymic mice. CONCLUSIONS: T lymphocytes appear to be involved in the pathogenesis of silica-induced pneumonitis. Since pulmonary fibrosis develops even in nude athymic mice, T cells do not seem to play a primary part in fibrogenic response but they regulate, at least to some extent, the response of inflammatory cells and fibrogenesis of the lung.     

Bronchoalveolar lavage in patients with mild and severe rheumatoid lung disease.

The reported prevalence of interstitial lung disease in patients with rheumatoid arthritis has varied from 10% to 50%, yet less than 5% of patients with arthritis develop severe fibrosing interstitial lung disease. This suggests that subclinical disease may not always presage progressive disease. Bronchoalveolar lavage fluid from patients with rheumatoid arthritis and either clinically evident interstitial lung disease or subclinical disease was examined for the presence of factors with a putative role in the development of interstitial fibrosis. Patients with subclinical disease were identified by prospective radiographic and lung function screening of 93 patients with rheumatoid arthritis. Fourteen patients were identified in this manner and an association between subclinical disease and smoking history was noted. Eleven patients with established interstitial lung disease had increased neutrophils (p less than 0.05), collagenase, and type III procollagen N terminal peptide levels (p less than 0.01) in the bronchoalveolar lavage fluid. Preliminary characterisation of the bronchoalveolar lavage collagenase suggested that it originated from neutrophils. Ten patients with subclinical interstitial lung disease underwent bronchoalveolar lavage. Of these, one had increased neutrophils and two had increased collagenase concentrations--abnormalities associated with advanced interstitial lung disease and a poor prognosis. These results suggest that in arthritis patients with evidence of subclinical pulmonary interstitial disease bronchoalveolar lavage might be useful in identifying those who may require careful monitoring in the hope that early treatment will prevent severe fibrosis.     

Variation of bronchoalveolar lymphocyte phenotypes with age in the physiologically normal human lung

BACKGROUND: Changes in T lymphocyte subsets have been observed in various forms of pulmonary disease. However, bronchoalveolar lymphocyte subsets have not been well characterised for healthy individuals differing in age. A study was undertaken to investigate the bronchoalveolar lavage (BAL) and peripheral blood lymphocyte subsets in clinically normal volunteers of two different age groups (19-36 and 64-83 years). METHODS: Bronchoalveolar lavage was performed on all individuals in both age groups and peripheral venous blood was drawn just prior to BAL. Bronchoalveolar cell profiles were characterised by morphological criteria, and cell surface antigen expression of lymphocytes was determined by flow cytometry. RESULTS: A significant increase in total BAL lymphocytes was observed for the oldest group compared with the youngest age group. Mean lymphocyte subset (CD4+/CD8+) ratios were significantly increased in BAL fluid from the older group compared with the younger group (mean (SE) 7.6 (1.5) vs 1.9 (0.2); p<0.0001). The increase in the BAL CD4+/CD8+ T cell ratio was mostly due to an increase in relative numbers of CD4+ lymphocytes, and the BAL CD4/CD8 ratio was disproportionately increased compared with peripheral blood in the older group. Increased expression of HLA-DR and CD69 on CD4+ T lymphocytes was observed in the oldest age group. Relative numbers of natural killer (NK) cells did not vary with age, and gammadelta T cells and CD5+ B cells were present in very low numbers in both age groups. CONCLUSIONS: CD4+ T cells accumulate in air spaces of the lower respiratory tract with age in healthy adults and express increased amounts of HLA-DR and CD69 on their surfaces, suggesting a relative degree of CD4+ T lymphocyte activation for healthy older individuals who have normal lung function.     

Preventive effect of erythromycin on experimental bleomycin-induced acute lung injury in rats

BACKGROUND—Erythromycin has been reported to havean inhibitory effect on chronic inflammatory airway disease and chronicinfiltration of neutrophils into the airway. Bleomycin (BLM) ofteninduces interstitial lung fibrosis following acute lung injury. A study was undertaken to investigate the effects of erythromycin (EM) onexperimental bleomycin-induced acute lung injury in rats.
METHODS—Bleomycin-induced lung injurywas assessed by light microscopic examination, measurement ofneutrophil elastase activity and of the interleukin 8 (IL-8) content inbronchoalveolar lavage (BAL) fluid. The potential inhibitory effect oferythromycin was assessed by overall comparison of erythromycinuntreated (BLM alone), concurrently treated (BLM + EM), andpretreated (BLM +pre-EM) groups.
RESULTS—The neutrophil count and concentration ofneutrophil-derived elastase in BAL fluid were significantly differentin the three groups. The morphological changes of lung injury were alsoless extensive in rats pretreated with erythromycin. However, these protective effects were not marked in the group concurrently treated with erythromycin. Moreover, the concentration of IL-8 in the BALfluid tended to be less in the erythromycin treated groups; however,there were no significant differences between the bleomycin-treated groups.
CONCLUSION—Erythromycin exhibits a prophylacticeffect on acute lung injury induced by intratracheal administration ofbleomycin, which is possibly associated with a downregulation ofneutrophil-derived elastase.

     

Longitudinal comparisons of lymphocytes and subtypes between airway wall and bronchoalveolar lavage after human lung transplantation

BACKGROUND: T lymphocytes are crucial in lung allorejection. The contribution of lymphocyte subtypes to the pathogenesis of chronic rejection (bronchiolitis obliterans syndrome [BOS]) remains unclear. METHODS: Twenty-nine initially healthy lung transplant recipients underwent 136 bronchoscopic assessments, including bronchoalveolar lavage (BAL) (with flow cytometry) and endobronchial biopsies (EBB) (with immunohistochemistry) over 3 years of follow-up. RESULTS: Of the 29 patients studied over 3 years, 23 developed BOS category 0 p and 17 went on to BOS 1. Compared with controls, the BAL percentage of CD4 cells was lower and the percentage of CD8 cells was increased significantly early posttransplant. Subsequent BAL lymphocyte subtype changes with time, or with the development of BOS, were minimal. By contrast, the early posttransplant EBB lymphocyte numbers were normal (P>0.05 vs. controls); subsequently, CD3 and CD8 (but not CD4) cells were increased with time in patients who did not develop BOS (P<0.05) and, more strikingly, in patients who eventually developed BOS (P<0.01). Multivariate analyses suggested an association between BAL lymphocytes (percentage) and azathioprine dose, female gender, rejection grade A on transbronchial biopsies, and pre-BOS status, whereas EBB CD8 cell counts were associated with time posttransplant, pretransplant diagnosis, and rejection grade B on TBB. CONCLUSIONS: There is an early, persistent low percentage of BAL CD4 T cells, high BAL CD8 T cells, and progressively increasing airway wall CD3 and CD8 T cells with time posttransplant in healthy patients (but more predominantly in BOS patients) after transplantation. These immunopathologic changes may suggest that CD8 T cells could escape current immunosuppression and participate in chronic lung rejection.     

Infection à cytomégalovirus chez un patient atteint de polyarthrite rhumatoïde

Background. – Pulmonary dysfunction in rheumatoid arthritis patients treated with low-dose methotrexate is usually caused by bacterial infection and less frequently by an immunoallergic reaction to the drug (acute hypersensitivity pneumonitis). Opportunistic infections are a rare cause. We report a case of cytomegalovirus pneumonia during bone marrow aplasia in a patient with rheumatoid arthritis taking methotrexate and cyclosporine.Conclusions. – Cytomegalovirus infection is a rarely reported cause of pulmonary dysfunction. This diagnosis should be considered in immunocompromised rheumatoid arthritis patients with no other satisfactory explanation to pulmonary dysfunction.     

Release of prostaglandin E2 and leukotriene B4 by alveolar macrophages from patients with sarcoidosis

BACKGROUND: Mediators released by alveolar macrophages, as well as by T cells, play an important part in modulating local immune processes in sarcoidosis. Among alveolar macrophage secretory products, arachidonic acid metabolites are known to regulate inflammatory and immune reactions. It has been suggested that cyclo-oxygenase and lipoxygenase pathway metabolites of arachidonic acid modulate the evolution of the granulomatous inflammatory response in the lung differently. METHODS: Alveolar macrophages recovered from the bronchoalveolar lavage (BAL) fluid of 32 patients with sarcoidosis in different states of disease activity and 10 normal subjects were evaluated for their ability to release prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). Alveolar macrophages were cultured in the presence or absence of opsonised zymosan (500 micrograms/ml), and PGE2 and LTB4 levels in the culture supernatants were determined by enzyme immunoassay (EIA). RESULTS: Stimulated alveolar macrophages from patients with active sarcoidosis released higher LTB4 levels than those from normal subjects, but no differences in PGE2 release were observed between the two groups. The time course of LTB4 release by activated alveolar macrophages showed that normal cells produced similar levels of the hydroxyacid during the early and late times of culture while LTB4 release by activated cells from patients with sarcoidosis increased markedly after 60 minutes of culture, remaining elevated until 24 hours. Indomethacin (3 x 10(6) M) caused the expected inhibition of PGE2 formation without affecting LTB4 release. CONCLUSIONS: These results suggest that alveolar macrophages from the BAL fluid of patients with active sarcoidosis are primed to release LTB4, which may contribute to the locally heightened immune response.




     

Cellular profiles in asthmatic airways: a comparison of induced sputum, bronchial washings, and bronchoalveolar lavage fluid

BACKGROUND: Analysis of bronchoalveolar lavage fluid has improved our understanding of the pathogenesis of asthma. Safety issues and access to expert resources limit this techniques as a research tool. Induced sputum is a non-invasive method of collecting airway fluid which is applicable to subjects with a range of severity of airflow obstruction. The method of sputum collection and processing differs between groups. A study was undertaken to compare induced sputum with bronchoscopically collected fluid. METHODS: Sixteen patients with mild stable asthma underwent both sputum induction and bronchoscopic examination with bronchial washings and bronchoalveolar lavage (BAL) in random order, with each procedure being separated by an interval of 12 days. Airway fluid was processed and stained for differential cell counting. RESULTS: Induced sputum was relatively rich in neutrophils and eosinophils compared with bronchial washings and BAL fluid (mean (SE) 1.3 (0.4)%, 5.0 (2.7)%, and 36.4 (3.7)% neutrophils and 0.6 (0.1)%, 1.6 (0.6)%, and 3.3 (1.1)% eosinophils in BAL fluid, bronchial washings, and induced sputum, respectively). The proportions of cells obtained at sputum induction correlated with those in bronchial washings but not BAL fluid (r = 0.6 and 0.7 for neutrophils and eosinophils, respectively, p < 0.05). By contrast, induced sputum had a lower proportion of lymphocytes and macrophages than bronchial washings or BAL fluid, without any correlation. CONCLUSION: Induced sputum is rich in neutrophils and eosinophils and poor in lymphocytes, suggesting an origin in the larger airways. Induced sputum adequately reflects the findings in fluid collected by direct bronchoscopy.


     

Role of heat shock proteins in the pathogenesis of cystic fibrosis arthritis

BACKGROUND: Arthritis is a well recognised complication of cystic fibrosis. The cause of this arthritis is not yet clear but it is likely to be an immunological reaction to one of the many bacterial antigens to which the lungs are exposed. One such group, the heat shock proteins, (hsp), was investigated. These are immunodominant antigens of a wide variety of infectious microorganisms and have varying amino acid chain sequences, some of which are similar to those found in human tissues. METHODS: Antibodies to human hsp 27 and hsp 90 in the serum of patients with cystic fibrosis, with and without arthritis, and in normal age and sex matched healthy controls were measured. The severity of the cystic fibrosis was assessed by lung function tests and chest radiographs. The nature of the organisms colonising the lungs was determined by bacteriological examination of sputum. RESULTS: Higher mean titres of serum IgG anti-human hsp 27 and hsp 90 antibodies were found in 50 patients with cystic fibrosis than in healthy controls (hsp 27, 0.25 (95% CI 0.19 to 0.33) versus 0.05 (95% CI 0.04 to 0.07); hsp 90, 0.27 (95% CI 0.22 to 0.32) versus 0.11 (95% CI 0.08 to 0.14)). These antibodies were higher in patients in whom the lungs were colonised with Pseudomonas aeruginosa than in those without infection (hsp 27, 0.41 (95% CI 0.17 to 0.63) versus 0.18 (95% CI 0.10 to 0.27); hsp 90, 0.37 (95% CI 0.18 to 0.57) versus 0.22 (95% CI 0.16 to 0.29)). The eight patients with cystic fibrosis with arthritis had higher anti- hsp 27 antibodies (0.48 (95% CI 0.13 to 0.92)) than the 42 patients without arthritis (0.22 (95% CI 0.17 to 0.30)). CONCLUSIONS: These findings suggest that the arthritis associated with cystic fibrosis, despite being seronegative for rheumatoid factor, was associated with more severe lung disease and with a greater inflammatory response to heat shock proteins.