Treatment of chronic rhinosinusitis with high-dose oral terbinafine: a double blind, placebo-controlled study.

OBJECTIVES: To evaluate antifungal terbinafine in patients with chronic rhinosinusitis. STUDY DESIGN: Randomized, double-blind, placebo-controlled multicenter pilot study. METHODS: Fifty-three adults with chronic rhinosinusitis received terbinafine 625 mg/day (n = 25) or placebo (n = 28) once daily for 6 weeks. Sinus secretions were collected at screening for mycology. Computed tomography was graded for extent of opacification at baseline and at week 6 using a modification of the Lund-Mackay scoring system. Patients recorded rhinosinusitis symptoms on a visual analogue scale and completed the Rhinosinusitis Disability Index. RESULTS: Positive fungal cultures were found in 41 of 53 patients (17 terbinafine, 24 placebo). (Two subjects from the Terbinafine group and one subject from the control group had no week 6 data). The mean opacification scores pre- and posttreatment for the entire study group improved from 24.2 to 22.5 in placebo (n = 26) and from 26.3 to 24.2 in terbinafine group (n = 23). The least squares means for percent change from baseline (SE) were -6.0 (8.7) for placebo compared with -7.2 (8.1) for terbinafine; 95% confidence interval for treatment difference (-18.9, 21.1); P = .91. Results were similar when only patients with positive fungal cultures were evaluated in the efficacy analysis. Investigator therapeutic evaluations and sinus symptom scores were not significantly different between the two groups at baseline or at treatment completion. CONCLUSION: Treatment with terbinafine failed to improve the symptoms or radiographic appearance of chronic rhinosinusitis even when nasal irrigation samples were positive for fungus on culture. One consideration is that the fungi isolated were not a major pathologic factor in this cohort. It is also possible that, even at high dose, terbinafine may not have maintained therapeutic levels in the nasal secretions.

Core body temperature is normal in chronic fatigue syndrome.

BACKGROUND: Subjects with chronic fatigue syndrome (CFS) frequently report symptoms of subnormal body temperature and low-grade fever. We conducted a study to determine whether CFS subjects manifest any abnormality of core body temperature (CBT) that might help explain their fatigue. METHODS: Continuous 24-hour recordings of CBT measured every 5 min were performed in 7 subjects meeting the Centers for Disease Control definition of CFS. Three additional groups were studied: normal controls, subjects with seasonal allergy, and subjects with major depression. Subjects (n = 7) in each group were age-, sex-, and weight-matched to the CFS group and had normal basal metabolic rates, thyroid function, and 24-hour urinary free cortisol excretions. CBT was measured with an ingestible radio frequency transmitter pill and a belt-worn receiver-logger. Each pill was factory-calibrated to +/- 0.1 degree C and field-calibrated with a water bath calibration prior to use. RESULTS: The 24-hour mean calibration-adjusted CBTs of each group were not significantly different (control: 37.00 +/- 0.17 degrees C; CFS: 37.04 +/- 0.31 degrees C; allergy: 37.15 +/- 0.18 degrees C; depression: 37.16 +/- 0.18 degrees C). Similarly, the mean peak and trough circadian temperatures were not statistically different. The mean 24-hour profile of CBT for each group showed a similar circadian rhythm. In simultaneously collected blood samples, each group showed a similar circadian profile of serum cortisol with a peak occurring at 08:00. CONCLUSIONS: Subjects with CFS have normal CBT despite frequent self-reports of subnormal body temperature and low-grade fever.

Antigen presenting cells.

A great deal has been learned over the past few years regarding the molecular biology of antigen presentation. These discoveries have been possible in part because of acquisition of protein sequencing data regarding class I and class II MHC molecules and in part because of X-ray crystallographic analysis of the three-dimensional structures of these molecules. These discoveries have merged nicely with detailed immunologic studies delineating the 'minimal antigenic peptides' of complex protein antigens. All of these studies strongly confirm the belief that the antigen-specific interaction of T cells with antigen in the context of antigen presenting cells is exquisitely specific. The process of 'trimolecular complex' formation involves binding interactions between antigenic peptide, class I or class II MHC molecules and the antigen-specific T cell receptor. One of the key functions of antigen presenting cells involves the 'processing' of complex protein antigens so as to allow for the interaction of the 'minimal antigenic peptide' with the appropriate class I or class II MHC molecule. A substantial body of evidence now indicates that the interaction of processed antigenic peptides and class II MHC molecules involves a binding interaction with a significant binding affinity and a slow dissociation constant. In addition to antigen-specific binding interactions which govern antigen presentation, there are a variety of antigen-independent and MHC-independent factors which greatly augment the process of antigen presentation. Along with differences in antigen processing, these factors probably account for the qualitative and quantitative differences seen between the various cell types involved in antigen presentation. There may be a substantial amount of antigen which associates with the antigen presenting cell surface in an MHC-independent fashion associated with so-called 'non-MHC peptide binding structures'. However, if the trimolecular complex theory is to be satisfied, antigen bound to these structures ultimately must become associated with the MHC restricting element in order to effectively engage the antigen-specific T cell receptor. Antigen presenting cells differ in their sensitivity to lymphokines and inflammatory mediators which augment antigen presentation. In addition, antigen presenting cells differ in their capacity to secrete or express membrane-bound costimulatory molecules, such as interleukin 1. Finally, factors which promote the cellular adherence of antigen presenting cells with T cells greatly augment the process of antigen presentation.(ABSTRACT TRUNCATED AT 400 WORDS)

Distal airway bronchomalacia resulting in severe obstructive airway physiology.

A 24-year-old woman, referred for treatment of presumed severe steroid-dependent asthma, was found to have generalized bronchomalacia. The diagnosis was based on an abnormal collapsibility of the bronchi on bronchoscopic examination and a lack of bronchial reversibility with aggressive bronchodilator therapy.

Pleural effusion in Churg-Strauss syndrome.

A 33-year-old man with a two-year history of asthma and sinusitis presented with wheezing, pleuritis, bilateral pleural effusions, and patchy basilar infiltrates on chest roentgenogram. Laboratory studies revealed peripheral blood eosinophilia, and pulmonary function studies showed an obstructive pattern which was bronchodilator responsive. Thoracocentesis yielded an acidotic exudative effusion with low glucose, low C3, eosinophilia, and a markedly increased rheumatoid factor. Open lung biopsy revealed extensive eosinophilic interstitial pneumonitis with necrotizing eosinophilic vasculitis. Although pleural effusions are present in 29 percent of Churg-Strauss patients, these effusions have not been well described. This report describes the pleural fluid findings in a case of Churg-Strauss syndrome.

Benefits of high-dose i.v. immunoglobulin in patients with severe steroid-dependent asthma.

STUDY OBJECTIVE: To determine the efficacy of IV immunoglobulin (IVIg) in severe asthma to reduce steroid requirements. DESIGN: Pre- and posttreatment measurements were analyzed using Dunnett's multiple comparison procedure. SETTING: Hospital clinical research center. PATIENTS: Eleven adolescents and adults with severe, steroid-dependent asthma enrolled over a 14-month period. INTERVENTIONS: IVIg was administered at a dose of 2 g/kg every 4 weeks for a total of seven infusions. MEASUREMENTS AND RESULTS: Steroid requirements, pulmonary function including lung volumes, symptom scores, bone densitometry, and airway reactivity monitored by methacholine challenge were followed over the course of 7 months. A significant decrease in steroid usage was achieved. Despite substantial steroid reduction, the patients demonstrated improvement in their pulmonary function and symptom scores. The responses to methacholine challenge were unaffected by IVIg treatment. CONCLUSIONS: IVIg provides a potentially important adjunctive therapy in severe asthma, reducing oral steroid requirements and steroid side effects without deterioration of lung function.

Gastroesophageal reflux and sinusitis in asthma.

The evidence that links gastroesophageal reflux (GER) and sinusitis to asthma from a pathophysiologic viewpoint is reviewed. The clinical relationships are explored in disease prevalence and studies assessing whether interventions that treat either GER or sinusitis improve asthma. An overview of patient evaluation and treatment is presented.

Chronic sinusitis.

Sinusitis is a very common chronic illness with a substantial health care impact. This review focuses on factors contributing to sinusitis pathogenesis and chronicity, including anatomic factors, disturbances in mucociliary clearance, microbial pathogens, and inflammatory factors. A distinction is made between "infectious" and "noninfectious" types of inflammation in chronic sinusitis. The inflammatory characteristics of noninfectious inflammation are reviewed primarily in the context of chronic hyperplastic sinusitis with nasal polyposis. Key features of this type of inflammation include the presence of chronic inflammatory cells, large numbers of eosinophils, and IL-5-producing T lymphocytes. Allergic fungal sinusitis is discussed as a special type of chronic sinusitis. Published studies on the outcomes of medical management are reviewed. Finally, algorithms for medical management of chronic sinusitis and allergic fungal sinusitis are presented.

The role of glutathione in lymphocyte activation. I. Comparison of inhibitory effects of buthionine sulfoximine and 2-cyclohexene-1-one by nuclear size transformation.

The role of glutathione (GSH) in lectin-induced lymphocyte activation can be studied by quantitating lectin-induced nuclear size transformation in the presence of variable degrees of GSH depletion. Buthionine sulfoximine (BSO) inhibits intracellular GSH synthesis by inhibition of the enzyme gamma-glutamyl-cysteine synthetase. By combining endogenous GSH depletion in cell cultures with BSO-induced inhibition of GSH synthesis, lectin-induced lymphocyte activation can be studied at various concentrations of soluble intracellular GSH. With this approach, the percentage of lymphocytes undergoing a nuclear size transformation is minimally affected despite depletion of soluble intracellular GSH to 0.27 nmol/10(7) cells (PBL), which represents approximately 95% depletion of intracellular GSH. When soluble intracellular GSH is depleted to undetectable levels (less than 0.10 nmol/10(7) cells) there is a 10 to 12% reduction in the number of cell nuclei transformed. However, in all BSO-pretreated cultures the lectin-induced nuclear size transformation is intermediate between resting and blast-transformed lymphocytes, suggesting only partial (or aborted) activation. The partial activation response observed in BSO-pretreated cultures may be due to mobilization of the protein-bound pool of GSH, which is relatively resistant to depletion by BSO. That the inhibition of full blast transformation is truly due to GSH depletion was proven by experiments in which GSH was repleted exogenously and a full blast transformation was restored. The results of previous work in our laboratory had shown that the sulfhydryl-reactive agent 2-cyclohexene-1-one (2-CHX) was a potent inhibitor of activation at soluble intracellular GSH concentrations well above 0.27 nmol/10(7) PBL. In the present study, the dose-dependent inhibition of activation by 2-CHX was confirmed, but it was shown that the degree of inhibition caused by 2-CHX could be at least partially dissociated from the level of intracellular GSH present at the time of lectin addition and that the inhibitory potential of 2-CHX exceeded that of BSO at comparable levels of soluble intracellular GSH. Thus, the inhibitory properties of 2-CHX cannot be accounted for solely on the basis of GSH depletion.

The role of glutathione in lymphocyte activation--II. Effects of buthionine sulfoximine and 2-cyclohexene-1-one on early and late activation events.

Depletion of intracellular glutathione (GSH) inhibits the lectin-induced activation response of human T lymphocytes. GSH-depleted lymphocytes undergo a partial activation response to lectins but fail to undergo blast transformation. Several lines of evidence indicate that the inhibition of lymphocyte activation in GSH-depleted lymphocytes involves relatively late activation events. Firstly, lectin stimulation induces significant 14C-AIB uptake, IL-2 production and expression of IL-2 receptor but a near complete inhibition of 3H-uridine and 3H-thymidine incorporation. Comparable levels of IL-2 production and IL-2 receptor expression are seen in GSH-depleted lymphocytes allowed to recover from GSH depletion during lectin stimulation. However, in the latter case, 3H-uridine and 3H-thymidine incorporation are normal, and activation is completely restored. Exogenous IL-2 cannot restore activation in GSH-depleted lymphocytes. Furthermore, lymphocytes remain highly susceptible to inhibition by GSH depletion even after 48 h of lectin stimulation which is sufficient to induce early activation events in the Go----G1 transition, such as IL-2 receptor expression and IL-2 production. Exogenous GSH partially restores intracellular GSH levels and completely restores lymphocyte activation in GSH-depleted lymphocytes. Despite comparable degrees of GSH depletion, DL-buthionine-SR-sulfoximine and 2-cyclohexene-1-one inhibit lymphocyte activation to different degrees. The inhibition by 2-cyclohexene-1-one is consistently greater than would be predicted based on glutathione depletion per se. We conclude that GSH-dependent processes are important in relatively late steps of the activation sequence characterized by nuclear events with relative sparing of essential early steps in activation, such as IL-2 receptor expression and IL-2 production. The approximate minimal intracellular GSH concentration necessary to sustain a normal activation response is 2 nmol per 10(7) lymphocytes.

Lymphocyte proliferation in glutathione-depleted lymphocytes: direct relationship between glutathione availability and the proliferative response.

Lymphocyte proliferation in response to mitogenic lectins is directly dependent upon glutathione (GSH) availability. Thus, proliferation can be enhanced by providing lymphocytes with excess glutathione, and strongly inhibited by limiting the quantity of intracellular GSH available during the mitogenic stimulation. Exogenous GSH, cysteine and 2-mercaptoethanol (2-ME) can all significantly enhance lymphocyte proliferation and augment intracellular GSH levels. Lymphocytes depleted of GSH by buthionine sulfoximine (BSO) fail to undergo a full blast transformation response to mitogenic lectins. In lymphocytes stimulated with mitogen in the presence of BSO, the time profile of intracellular GSH levels shows a rapid decline over the first 24-48 h and a subsequent gradual decline to levels less than 0.5 nmol/10(7) lymphocytes by 72-96 h. Exogenous GSH partially sustains intracellular GSH levels and completely restores lymphocyte proliferation even in the presence of 2000 microM BSO. Other thiols, such as cysteine and 2-ME, do not significantly alter the time profile of intracellular GSH in mitogen-stimulated lymphocytes in the presence of 2000 microM BSO, and their capacity to enhance proliferation is greatly diminished albeit not completely abolished under these conditions. Ongoing GSH synthesis is clearly essential to maintain a normal proliferative response. If intracellular GSH levels are depleted initially and lymphocytes are then stimulated with mitogen in the presence of BSO, there is a diminished capacity of cysteine and 2-ME to restore proliferation relative to exogenous GSH. There is also a diminished capacity of exogenous GSH to restore proliferation with higher concentrations of BSO. This suggests that the restoration of lymphocyte proliferation by exogenous GSH is more closely linked to effects on intracellular rather than extracellular GSH. These studies confirm the importance of intracellular GSH in lymphocyte proliferation. The essential role for intracellular GSH can be demonstrated even in the presence of other exogenous thiols, such as cysteine and 2-ME. The enhancement of lymphocyte proliferation by exogenous cysteine appears to be directly linked to effects on intracellular GSH, whereas the enhancement by 2-ME is probably more complex but clearly linked to effects on intracellular GSH.

Distribution and severity of bronchiectasis in allergic bronchopulmonary aspergillosis (ABPA).

The purpose of this paper was to quantitate the distribution and severity of computed tomography (CT) and radiographic findings in patients with allergic bronchopulmonary aspergillosis (ABPA), probable ABPA, and asthmatic controls. Chest radiographs and high-resolution CT images were evaluated in 19 patients with documented ABPA and 18 asthmatic controls. Ten patients with probable ABPA were also evaluated. On CT examination 17 patients (89%) with ABPA had central cystic or varicoid bronchiectasis in at least one lobe. One patient had no evidence for bronchiectasis. Three asthmatic patients (17%) had findings of cylindrical bronchiectasis. All 10 patients with probable ABPA had evidence of bronchiectasis on high-resolution CT (HRCT). The majority of patients with ABPA have diffuse disease at the time of diagnosis, manifested by central cystic and/or varicoid bronchiectasis in four or five lobes. Evaluation with HRCT can facilitate a diagnosis of ABPA and probable ABPA, allowing for earlier treatment which may prevent progression to fibrosis.

Effect of intranasal fluticasone on cellular infiltration, endothelial adhesion molecule expression, and proinflammatory cytokine mRNA in nasal polyp disease.

BACKGROUND: Nasal polyp (NP) disease demonstrates a gradual response to treatment with intranasal steroids. We hypothesized that various inflammatory features that promote NP eosinophilia would show a differential sensitivity to treatment with intranasal fluticasone. OBJECTIVES: We conducted a double-blind, placebo-controlled trial of 4 weeks of intranasal fluticasone propionate or matching placebo to assess their effectiveness in reducing NP inflammatory cells, expression of endothelial vascular cell adhesion molecule (VCAM)-1 and P-selectin, and expression of cytokines involved in induction of a group of adhesion molecules (ie, IL-4, IL-13, TNF-alpha, and IL-1beta). METHODS: Twenty subjects (9 women and 11 men) with severe chronic sinusitis and NP were studied. Systemic and intranasal steroids were withheld for a minimum of 1 month and 2 weeks, respectively, before the study. Biopsy specimens of NPs were obtained 1 week before and 4 weeks after treatment with intranasal fluticasone 100 microg or placebo per nostril administered twice daily. Biopsy specimens were snap frozen for immunostaining or fixed in paraformaldehyde for in situ hybridization. Pretreatment to posttreatment results were analyzed with Wilcoxon's signed-rank test. RESULTS: Fluticasone treatment significantly reduced NP eosinophilia (P =.02) and CD4(+) T lymphocytes (P =.02). Eosinophils expressing the marker EG2 were more significantly reduced (P =.007). Fluticasone also reduced the expression of P-selectin (P =.005) and the number of IL-4 and IL-13 mRNA+ cells (P =.02 and.05, respectively). In contrast, fluticasone did not significantly reduce expression of endothelial VCAM-1 or the number of TNF-alpha or IL-1beta mRNA+ cells in the polyps. CONCLUSIONS: We conclude that intranasal fluticasone reduced NP inflammation but that expression of proinflammatory cytokines and endothelial VCAM-1 were relatively unaffected by fluticasone treatment. These latter inflammatory features may contribute to the persistence of NP disease despite intranasal steroid treatment.

The role of dendritic cells as stimulators of minor lymphocyte-stimulating locus-specific T cell responses in the mouse. I. Differential capacity of dendritic cells to stimulate minor lymphocyte-stimulating locus-reactive T cell hybridomas and the primary anti-minor lymphocyte-stimulating locus mixed lymphocyte reaction.

The response of T cells to minor lymphocyte-stimulating locus (Mls) determinants remains poorly understood with respect to the antigenic determinants responsible for T cell stimulation and the types of APC capable of stimulating the response. In this report, we demonstrate that highly purified dendritic cells (DC) as well as B cells have the capacity to stimulate Mls-specific responses. Unseparated spleen cells, purified DC, resting B cells, and activated B cells were compared for their capacity to stimulate several Mls-reactive T cell hybridomas. Whereas the entire panel of Mls-reactive T cell hybridomas was stimulated strongly by unseparated spleen cells and activated B cells, the hybridomas responded only weakly to purified DC or resting B cells. Activation of resting B cells with either B cell stimulatory factor-1 (1 day pre-treatment) or LPS/dextran (2 or 3 day pre-treatment) greatly augmented their Mls-stimulatory capacity. In contrast, the Mls-stimulatory capacity of DC was not augmented by a 1-day pre-treatment with either B cell stimulatory factor-1 or supernatant from the DC-induced primary anti-Mls-MLR. In the primary anti-Mls-MLR, both purified DC and LPS/dextran-stimulated B blasts were found to elicit vigorous T cell proliferative responses. Much weaker responses were elicited by unseparated spleen cells. The stimulation of the primary anti-Mls-MLR by purified DC was further confirmed by producing Mls-specific T cell clones which were preferentially stimulated by DC. Autologous (Mlsb) DC were found to markedly enhance the primary anti-Mls-MLR response to small numbers of Mlsa B blasts. Thus, DC possess other "accessory cell" properties that augment the primary anti-Mls-MLR despite the predicted low level of Mls determinant expression on DC based on the results obtained with Mls-reactive hybridomas. Possible accessory cell properties of DC relevant to this phenomenon are discussed.

Hypogammaglobulinemia in asthmatic patients.

We measured quantitative immunoglobulins (IgG, IgA, IgM, and IgG subclasses) in 101 unselected asthmatic patients. We identified hypogammaglobulinemia in 12 patients primarily involving IgG (dose-related) without a strong prediction for any IgG subclass. IgA and IgM were also suppressed but to a lesser extent. This prevalence of hypogammaglobulinemia (.12 +/- standard error of .03) is significantly greater than that seen in the normal population (approximately .025 +/- .017, P = .01). Hypogammaglobulinemia was strongly associated with use of systemic corticosteroids (P = .0001). A cumulative steroid dose of greater than or equal to 5 mg/day for at least 2 years was found in 10/12 patients with hypogammaglobulinemia compared with 37/89 patients without hypogammaglobulinemia (P = .024). No significant increase in the number of infectious episodes was seen in the hypogammaglobulinemic patients. To assess the significance of hypogammaglobulinemia in asthmatics, we assessed responses to tetanus and pneumococcal vaccine in three groups of asthmatics: (1) those with total IgG less than 400 mg/dL who had been on chronic oral steroids, (2) those with total IgG between 855 and 1199 mg/dL who were currently receiving oral steroids, and (3) those with total IgG between 855 and 1199 mg/dL who were not receiving oral steroids. All patients responded normally to tetanus vaccine, but three of eight patients in the hypogammaglobulinemic group showed impaired responses to pneumococcal vaccine. Patients with impaired pneumococcal responses were not clearly distinguishable on the basis of sinus disease or pneumonia. We conclude that although many patients with severe, steroid-dependent asthma experience repeated episodes of bronchitis or exacerbations of sinusitis, these problems are rarely associated with an impairment in specific antibody production. IgG subclass deficiencies are not common in this patient population. A very small subgroup of patients manifest a more severe hypogammaglobulinemia (IgG less than 400 mg/dL) or an inordinate frequency of infectious episodes. Given that bronchitis or sinusitis can be attributed to factors other than hypogammaglobulinemia in these patients, an assessment of specific antibody production in response to pneumococcal vaccination is warranted. A small but significant percentage of such patients will demonstrate impaired responses. These patients should be considered at increased risk for bacterial infections and should, therefore, be monitored closely for infectious episodes.

Gamma delta T lymphocytosis associated with common variable immunodeficiency.

We present the case of a 28-year-old Caucasian female with common variable immunodeficiency (CVID) since age 5 who had a long history of hospitalizations for unexplained fevers and pulmonary infiltrates. The patient developed mild lymphocytosis 7 months prior to our evaluation. Flow cytometry of peripheral blood revealed an expansion of gamma delta T lymphocytes, mild CD4 T lymphocytopenia, and a reduced CD4/CD8 ratio (0.2). Two subpopulations of gamma delta T lymphocytes were found (CD3+/CD4-/CD8+, 47%; CD3+/CD4-/CD8-, 53%), the vast majority of which expressed V-delta 1. An infectious cause for the patient's gamma delta T lymphocytosis could not be found. The sputum was chronically colonized with Staphylococcus aureus, and the organism produced TSST-1 in vitro. A bronchoalveolar lavage (BAL) revealed marked lymphocytosis, but gamma delta T lymphocytes were not overrepresented in the BAL. Lymphocyte functional studies revealed poor proliferative responses to mitogens and staphylococcal superantigens and diminished cytokine production. V-delta 1 T lymphocytes from the patient's blood were not expanded in vitro in response to staphylococcal superantigens. TCR gene rearrangement studies confirmed the presence of J gamma and J beta 1 clonal rearrangements accounting for only a small subpopulation of the gamma delta T lymphocytes. These studies were repeated 5 months later and were unchanged. A bone marrow biopsy was negative for leukemia. Hence, the cause of the patient's gamma delta T lymphocytosis could not be determined despite evaluation for underlying malignancy, occult infection, or superantigen-driven stimulation. The patient ultimately died of progressive respiratory insufficiency. The state of current knowledge regarding gamma delta T lymphocytosis, decreased production of alpha beta T lymphocytes, and a low CD4/ CD8 ratio in association with CVID is discussed.

Eosinophil infiltration in nonallergic chronic hyperplastic sinusitis with nasal polyposis (CHS/NP) is associated with endothelial VCAM-1 upregulation and expression of TNF-alpha.

We studied potential mechanisms of eosinophil accumulation in nonallergic chronic hyperplastic sinusitis with nasal polyposis (CHS/NP). We measured expression of endothelial vascular cell adhesion molecule-1 (VCAM-1), which mediates selective eosinophil transendothelial migration, the cytokines interleukin (IL)-1 beta, TNF-alpha and IL-13 which upregulate VCAM-1 expression, and the chemokine RANTES which mediates lymphocyte, monocyte, and eosinophil chemotaxis in chronic hyperplastic sinusitis with nasal polyposis (CHS/NP) nasal polyps (nonallergic versus allergic) and middle turbinate biopsies from normal controls. By immunohistochemical staining, the density of EG2+ eosinophils was increased in both the nonallergic and allergic CHS/NP subgroups compared to normal controls. VCAM-1 expression was significantly increased in CHS/NP subjects compared to normal controls (P = 0.0005), with the highest intensity seen in nonallergic CHS/NP. By in situ hybridization, the densities of IL-1 beta, TNF-alpha, IL-13, and RANTES mRNA+ cells were all increased in nonallergic CHS/NP compared to normal controls (P = 0.009, 0.0005, 0.0005, and 0.001, respectively). In comparison to allergic CHS/NP, nonallergic CHS/NP had a significantly higher tissue density of TNF-alpha (P = 0.04) and a lower density of IL-13 (P = 0.005) mRNA+ cells. In general, VCAM-1 expression correlated strongly in CHS/NP with the density of TNF-alpha (R = .91, P = 0.0005) but not the density of IL-1 beta, IL-13, or RANTES mRNA+ cells. We conclude that upregulation of VCAM-1 and elaboration of RANTES may contribute to the marked accumulation of eosinophils in nonallergic CHS/NP. TNF-alpha may play a critical role in VCAM-1 upregulation in this nonallergic eosinophilic disorder.

GM-CSF, IL-5 and RANTES immunoreactivity and mRNA expression in chronic hyperplastic sinusitis with nasal polyposis (NP).

BACKGROUND: Eosinophils are a prominent feature of chronic hyperplastic sinusitis with nasal polyposis (CHS/NP). Our previous studies showed that their presence was associated with the expression of GM-CSF and RANTES mRNA. In allergic NP, increased expression of IL-5 was also found. OBJECTIVE: We wished to examine cytokine immunoreactivity for IL-5, GM-CSF and RANTES mRNA in allergic and non-allergic NP and compare immunoreactivity with expression of cytokine mRNA by in situ hybridization. Methods NP were obtained from five allergic and eight non-allergic subjects with CHS/ NP. Middle turbinate tissue from eight normal subjects were used as controls. Cell-associated cytokine mRNA was detected by in situ hybridization (ISH). Cytokine immunoreactive cells were enumerated by immunostaining. Colocalization immunostaining was also performed to identify specific cell types producing IL-5. RESULTS: Immunostaining for GM-CSF, IL-5 and RANTES protein was increased in both allergic and non-allergic NP compared with control middle turbinates. Allergic polyps contained greater numbers of IL-5 immunoreactive cells (P = 0.01), whereas non-allergic polyps contained greater numbers of GM-CSF immunoreactive cells (P = 0.04). Immunostaining was primarily associated with inflammatory cells, but immunostaining for RANTES and, to a lesser extent GM-CSF, was also seen in the epithelium. The density of immunoreactive cells was variably correlated with cytokine mRNA+ cells (GM-CSF: R=0.56, P=0.05; IL-5: R=0.76, P=0.003; and RANTES: R=0.89, P=0.0005). Colocalization immunostaining revealed that the majority of IL-5 immunoreactive cells in both allergic and non-allergic NP were T lymphocytes. However, allergic NP contained greater numbers of IL-5+/CD3+ T lymphocytes and IL-5+ mast cells, whereas non-allergic NP contained greater numbers of IL-5+ eosinophils. CONCLUSION: We conclude that GM-CSF, IL-5 and RANTES are produced in increased amounts in both allergic and non-allergic NP. Distinguishing features of non-allergic NP include fewer numbers of CD3 T lymphocytes, fewer IL-5+/CD3+ T lymphocytes and greater numbers of IL-5+ eosinophils. These differences may suggest different mechanisms of eosinophil accumulation and activation in allergic vs non-allergic NP.

A double-blind study of troleandomycin and methylprednisolone in asthmatic subjects who require daily corticosteroids.

A group of 75 subjects with asthma requiring daily corticosteroids for control were enrolled in a 2-yr, double-blind, placebo-controlled study of the use of troleandomycin combined with methylprednisolone, compared with methylprednisolone alone, for the management of their asthma. The primary outcome variables were determination of the lowest stable methylprednisolone dose and assessment of corticosteroid side effects. Methylprednisolone dose was adjusted to maintain optimal control of asthma symptoms. A total of 30 patients receiving TAO and 27 patients receiving placebo completed 1 yr; 17 on TAO and 8 on placebo completed 2 yr of double-blind participation. Control of asthma was equivalent in both groups. The vast majority of patients in both groups achieved alternate-day dosing (29 of 30 on TAO and 23 of 27 on placebo in the first year). The lowest stable doses of methylprednisolone achieved were 10.4 mg/day (placebo) versus 6.3 mg/day (TAO) in the 1-yr group (p = 0.03). However, the baseline dose was also significantly higher in the placebo group (22.8 versus 17.6 mg/day in the TAO group). Therefore, the reductions in methylprednisolone dose were not significantly different between treatment groups. Differences were observed between the two treatment groups in serum IgG, fasting blood sugar, serum cholesterol, and progression of osteoporosis. In each instance the more unfavorable response occurred in those subjects receiving TAO. We conclude that the addition of TAO to methylprednisolone was not accompanied by a reduction in corticosteroid side effects compared with treatment with methylprednisolone alone. Furthermore, no evidence was found for a subset of "TAO responders."(ABSTRACT TRUNCATED AT 250 WORDS)