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Alkis Togias

Publications and source records attributed to Alkis Togias.

35 records · Page 2Linked to original sources
PubMed2004

Systemic effects of local allergic disease.

Allergic reactions are not confined to the area they originated, but assume a secondary systemic, nonanaphylactic element. This element has two consequences: it feeds back into the site of the original reaction and it leads to the development of distant local manifestations. The well-established interactions between the nasal and the lower airways in allergic disease could be viewed as an example of this model. Interactions between the nasal mucosa and the paranasal sinuses, as well as interactions between the respiratory system, the skin, and the gastrointestinal tract have been described and may also fall under the same category. Two conduits of the systemic element of allergic disease are proposed: the systemic circulation and the nervous system. The mechanisms that lead to the development of the systemic element, and particularly the mechanisms of distant manifestations after a local allergic reaction have not been elucidated, but they probably include intricate interactions between the classic mediators of the acute allergic reaction, locally- and systemically-produced cytokines and neurotrophins, the vascular epithelium and the adhesion molecule system, the chemokine network, antigen-presenting dendritic cells and their interactions with T-lymphocytes, as well as a strong bone marrow component. From this perspective, the systemic element presents an exciting area of current and future research in allergic disease.

Asthma↗
PubMed2004

Systemic effects of allergen exposure on blood basophil IL-13 secretion and FcepsilonRIbeta.

BACKGROUND: Airway allergen challenge studies have shown the upregulation of cytokines in local airway tissues and distal effects on bone marrow precursors for eosinophils and basophils. OBJECTIVE: We investigated whether local intranasal allergen challenge alters the phenotype of circulating basophils to a primed state. METHODS: Ten subjects with allergic rhinitis were challenged with allergen by means of intranasal spray on 3 sequential days. Basophils were isolated from subjects before challenge and 3, 24, and 96 hours after the third allergen challenge. Basophils were compared before challenge and after the last allergen challenge for levels of FcepsilonRIbeta protein by means of Western blotting and for FcepsilonRIbeta mRNA expression by means of real-time PCR. Basophils were also compared with regard to spontaneous secretion of IL-4 and IL-13. RESULTS: Basophil FcepsilonRIbeta protein levels increased in 5 of 6 subjects after allergen challenge relative to before challenge. Likewise, basophil FcepsilonRIbeta mRNA levels increased a median of 2-fold after the last challenge relative to before challenge ( P=.007, n=9). IL-13 protein was detected in supernatants of 7 of 9 subjects' basophil-enriched cultures after the last challenge compared with 3 of 9 basophil-enriched cultures before challenge (median, 6.2 vs 0 pg/mL; P=.058). IL-4 was not detected in any culture supernatant. CONCLUSION: Intranasal allergen challenge transiently activates circulating basophils by increasing expression of the FcepsilonRIbeta subunit and spontaneous IL-13 secretion. Because FcepsilonRIbeta is an amplifier of FcepsilonRI-mediated responses and IL-13 is proinflammatory, these findings support a primed basophil functional state and demonstrate a systemic effect of local allergen challenge that could contribute in exacerbating allergic reactions.

Administration, Intranasal↗
PubMed2004

Omalizumab-induced reductions in mast cell Fce psilon RI expression and function.

BACKGROUND: By design, omalizumab binds free IgE in the circulation and prevents its attachment to the surface of mast cells and basophils, thereby preventing them from responding to allergens. Previously, omalizumab rapidly reduced free IgE levels, as well as basophil high-affinity IgE receptors, leading to significant reductions in basophil mediator response to allergen. It is assumed that tissue mast cells are similarly altered in their Fc epsilon RI density and function. OBJECTIVE: We examined the phenotypic shift of skin mast cells in parallel to that of blood basophils in 3 subjects infused with omalizumab. METHODS: Three subjects with allergic rhinitis underwent intradermal skin test titration with house dust mite antigen at days 0, 7, 70, and 196 of omalizumab treatment. As control subjects, 5 untreated subjects with allergic rhinitis were evaluated at similar time points. All subjects underwent skin biopsy 18 to 24 hours later at the site of allergen injection. Biopsy specimens were characterized by means of immunohistochemisty for tryptase and Fc epsilon RI alpha immunoreactivity, as well other markers (CD3, CD45RO, CD68, cutaneous lymphocyte antigen, and major basic protein). RESULTS: Omalizumab recipients, but not control subjects, demonstrated reductions in Fc epsilon RI alpha immunoreactivity at days 70 and 196 in parallel with reductions in the acute wheal response to allergen. However, no reductions in tryptase-positive cells were noted at these time points. CONCLUSION: Reductions in free IgE levels by omalizumab leads to a rapid reduction in basophil Fc epsilon RI receptor expression. In contrast, the time course for the decrease of Fc epsilon RI expression in skin mast cells is slower and associated with decreased acute allergen wheal size.

Allergens↗
PubMed2004

The bronchodilatory effect of deep inspiration diminishes with aging.

Deep inspirations have the ability to dilate constricted airways. The impairment of this function has been associated with the occurrence of asthmatic symptoms. We evaluated whether the bronchodilatory effect of deep inspiration (DI) is affected by aging. We tested 25 healthy subjects (median age: 54 yrs, range: 25-83 yrs). Single dose methacholine (Mch) provocations were performed in the absence of DI, which induced at least 15% reduction in inspiratory vital capacity (IVC) from baseline. The post-Mch IVC measurement was followed by 4 DIs and by another IVC (post-DI IVC). The fractional difference between post-DI IVC and post-Mch IVC represented the % bronchodilation by DI. The % bronchodilation significantly diminished with aging (r=0.65, P=0.0005). The bronchodilatory ability of DI was also positively associated with the degree of Mch-induced reduction in IVC (r=0.84, P<0.0001). In multiple regression analysis, where % bronchodilation was the dependent variable, both % reduction in IVC (P<0.0001) and age (P=0.02) entered the model. Our data raise the hypothesis that aging is associated with reduction in DI-induced bronchodilation.

Adult↗
PubMed2004

Allergic rhinitis: a potential cause of increased asthma medication use, costs, and morbidity.

Allergic rhinitis and asthma each require costly medical resource utilization, and the impact of both conditions is believed to be even greater. This retrospective cost of illness study evaluated the impact of allergic rhinitis on asthma medical care resource utilization rates and costs for patients with asthma plus allergic rhinitis vs. patients with asthma alone. Patients with one or more claims for asthma (n=27,398) were identified from a medical claims database from a large, northeastern U.S. health insurance plan (1992-1994). A subset of 9226 patients also had at least one visit for allergic rhinitis. Inpatient, professional service, major medical, and pharmaceutical (prescription medications) claims were examined. Patients with asthma and allergic rhinitis had greater medical utilization and costs than individuals with asthma only. The presence of allergic rhinitis was associated with greater frequencies and costs of prescriptions for all asthma-related medications evaluated in the study. Patients with both conditions were also more likely to receive care from medical specialists and less likely to be in managed care. Controlling for these factors, allergic rhinitis was still associated with an increase (P<0.0001) in annual costs of more than dollars 350. Allergic rhinitis in patients with asthma nearly doubles annual medical resource utilization and costs and is associated with increased utilization of asthma-related medications. Based on use of asthma medications, patients with concomitant allergic rhinitis can be regarded as having more severe asthma than do those without allergic rhinitis. Physicians should assess asthma patients for symptoms of allergic rhinitis to improve asthma treatment.

Adolescent↗
PubMed2004

Bronchodilatory effect of deep inspiration is absent in subjects with mild COPD.

STUDY OBJECTIVES: To investigate whether the bronchodilatory effect of deep inspiration is impaired in subjects with COPD. METHODS: We measured deep inspiration-induced bronchodilation in 19 patients with COPD and 17 healthy subjects (mean age, 67.8 +/- 7.1 years vs 62.5 +/- 9.3 years, respectively [+/- SEM]). Each subject underwent a series of single-dose methacholine provocations to induce at least a 15% reduction in inspiratory vital capacity (IVC). When this was achieved, subjects were asked to perform four consecutive deep inspirations, after which the IVC measurement was repeated and the percentage of bronchodilation by deep inspiration was calculated. RESULTS: The percentage of reduction in IVC from baseline prior to the deep inspirations did not differ between the two groups (COPD, 20.1 +/- 1.6%; healthy, 22.7 +/- 2.4%; p = 0.38); median single methacholine doses employed were 20 mg/mL (range, 0.025 to 75 mg/mL) and 25 mg/mL (range, 10 to 75 mg/mL), respectively (p = 0.19). Deep inspirations were not able to reverse bronchoconstriction in patients with COPD (bronchodilation, 3.9 +/- 2.6%; p = 0.15 by one-sample t test). Bronchodilation by deep inspiration was present in healthy subjects (13.7 +/- 3.0%, p = 0.0003), and was significantly higher than that of patient with COPD (p = 0.02). In patients with COPD, deep inspiration-induced bronchodilation correlated with the percentage of predicted transfer factor of the lung for carbon monoxide (r = 0.53, p = 0.05), but not with airway obstruction, as assessed by FEV(1) or FEV(1)/FVC. CONCLUSIONS: The bronchodilatory ability of deep inspiration is lost in mild COPD. We speculate that the absence of deep inspiration-induced bronchodilation contributes to the development and severity of chronic respiratory symptoms in patients with COPD.

Aged↗
PubMed2003

Absence of deep inspiration-induced bronchoprotection against inhaled allergen.

Deep inspiration-induced bronchoprotection appears to be a major mechanism through which airway obstruction by spasmogens is avoided. Loss of bronchoprotection is associated with airway hyper-responsiveness. Individuals with allergic rhinitis and no airway hyperresponsiveness develop obstruction after allergen inhalation. To test the hypothesis that deep inspiration-induced bronchoprotection is not active against allergic reactions, we performed four single-dose bronchial challenges, two with methacholine and two with allergen, on 10 subjects with allergic rhinitis. Without deep inspirations, the methacholine-induced reduction in FEV1 from baseline was 36.9 +/- 3.6% (mean +/- SEM); this was attenuated to 15.0 +/- 2.0 when five deep inspirations preceded methacholine inhalation (p = 0.0001). When allergen was inhaled, the reduction in FEV1 was 24.7 +/- 2.9% and 28.8 +/- 6.4% without and with deep inspirations, respectively. We conclude that bronchoprotection by deep inspirations is absent against allergic reactions. Understanding the cause of this phenomenon may shed light into the pathogenesis of airway hyperresponsiveness in allergic asthma.

Adult↗
PubMed2003

Evidence for asthma susceptibility genes on chromosome 11 in an African-American population.

Initial genome-wide scan data provided suggestive evidence for linkage of the asthma phenotype in African-American (AA), but not Caucasian, families to chromosome 11q markers (peak at D11S1985; LOD=2). To refine this region, mapping analysis of 91 AA families (51 multiplex families and 40 asthmatic case-parent trios) was performed with an additional 17 markers flanking the initial peak linkage marker. Multipoint analyses of the 51 multiplex families yielded significant evidence of linkage with a peak non-parametric linkage score of 4.38 at marker D11S1337 (map position 68.6 cM). Furthermore, family-based association and transmission disequilibrium tests conducted on all 91 families showed significant evidence of linkage in the presence of disequilibrium for several individual markers in this region. A putative susceptibility locus was estimated to be at map position 70.8 cM with a confidence interval spanning the linkage peak. Evidence from both linkage and association analyses suggest that this region of chromosome 11 contains one or more susceptibility genes for asthma in these AA families.

Adolescent↗
PubMed2003

H1-receptors: localization and role in airway physiology and in immune functions.

Histamine H(1)-receptors are involved in the pathologic processes of allergy. Clinical trials of H(1)-receptor antagonists have demonstrated the efficacy of these agents in reducing the sneezing, pruritus, and rhinorrhea associated with allergic rhinitis. In the lung, H(1)-receptors mediate the bronchoconstrictive effects of histamine and increase vascular permeability, which lead to plasma exudation. H(1)-receptors are present on T cells, B cells, monocytes, and lymphocytes, and stimulation of these receptors induces pro-inflammatory effects. It has been suggested that a signal from the H(1)-receptor contributes to the antigen receptor-mediated signaling pathways that induce proliferative responses and lead to the production of cytokines and antibodies by T cells and B cells, respectively. It would appear, therefore, that the H(1)-receptor has a wider role in inflammatory processes than simply mediating the actions of histamine.

Anti-Allergic Agents↗
PubMed2003

Rhinitis and asthma: evidence for respiratory system integration.

The vast majority of patients with asthma have rhinitis, and rhinitis is a major independent risk factor for asthma in cross-sectional and longitudinal studies. The relationships between rhinitis and asthma can be viewed under the concept that the 2 conditions are manifestations of one syndrome, the chronic allergic respiratory syndrome, in 2 parts of the respiratory tract. At the low end of the syndrome's severity spectrum, rhinitis appears to be the sole manifestation, although pathologic abnormalities in the lower airways are already present. At the higher end, rhinitis is worse, and the lower airways disease becomes clinically evident. Once manifested, the 2 conditions track in parallel in terms of severity. This parallel relationship is influenced by many interactions between the nasal and the lower airways: some interactions stem from the fact that the nasal passages play a major homeostatic role by conditioning inhaled air, but perhaps even more important is the bidirectional interaction that results from the systemic inflammation that is produced after local allergic reactions. Successful management of the chronic allergic respiratory syndrome requires an integrated view of the airways and an understanding of their interactions.

Asthma↗
PubMed2003

Bronchodilation and bronchoprotection by deep inspiration and their relationship to bronchial hyperresponsiveness.

Bronchial hyperresponsiveness (BHR) is a cardinal feature of asthma. Airway inflammation and BHR are probably linked, but the mechanisms underlying this relationship remain elusive. BHR is closely associated with defects in the beneficial responses to lung inflation. These responses, which become apparent by the fact that healthy individuals can develop severe airway obstruction if they are exposed to methacholine in the absence of deep inspirations, include bronchodilation and bronchoprotection. Bronchodilation refers to the effect of lung inflation after the induction of airway smooth muscle tone, while bronchoprotection is used to indicate the effect prior to inhalation of a spasmogen. Mild asthmatics who manifest BHR lack bronchoprotection by lung inflation. In contrast, many of them are able to bronchodilate. In more severe disease, both functions are impaired. The lack of bronchoprotection is also found in individuals with rhinitis and BHR, but no asthma. These and other observations suggest that the mechanisms of bronchodilation and bronchoprotection may be distinct, although overlap is possible. We believe that the loss of bronchoprotection is pertinent to the phenomenon of hyperresponsiveness, but that both the bronchodilatory and bronchoprotective functions of deep inspiration interact to produce the asthmatic phenotype. In this review, we describe the phenomena of lung inflation-induced bronchodilation and bronchoprotection and detail potential mechanical and neurohumoral mechanisms accounting for these physiologic functions. In addition, possible mechanisms leading to the impairment of these functions in subjects with BHR are discussed.

Animals↗
PubMed2002

Health care costs of allergic rhinitis-associated conditions vary with allergy season.

BACKGROUND: Studies have documented how allergic respiratory symptoms vary with allergen levels, but the impact of allergen levels on health care expenditures for allergy-related conditions has never been shown using actual data on outdoor allergen levels. Evidence linking respiratory allergy to comorbid conditions has also been scanty. OBJECTIVE: To investigate the link between respiratory allergy and presumably associated conditions by documenting seasonal patterns in their severity and co-occurrence, and to suggest a plan for future research. METHODS: A retrospective, cross-sectional analysis of medical claims data from 1995 to 1996 were linked to monthly data from federal counting stations on outdoor allergen levels. Participants were employed persons and their dependents, living within 15 miles of an allergen-counting station, continuously enrolled in a health plan for 1995 and 1996, and identified through medical claims data as having asthma, allergic rhinitis (AR), migraines, sinusitis, tonsillitis, otitis media, depression, or anxiety disorder. RESULTS: All conditions studied were more likely to occur during allergy season than during nonallergy season. For persons with health care claims for a condition of interest in both seasons, total health care costs during allergy season were significantly higher than during nonallergy season. Predicted condition-related expenditures were higher in allergy season for every condition even after controlling for the effect of AR. CONCLUSION: Allergy effects appear to extend beyond AR symptoms. Other conditions may be affected by outdoor allergen levels even in the absence of AR symptoms, implying that these conditions may be etiologically related to allergy, irrespective of their co-existence with allergic rhinitis, further implying that allergic sensitization can independently affect different parts of the respiratory tract as well as the brain.

Anxiety Disorders↗
PubMed2002

Risk factors for recurrent asthma hospital visits and death among a population of indigent older adults with asthma.

BACKGROUND: Little is known about the morbidity and mortality among older adults with asthma requiring hospital care. OBJECTIVES: To determine whether an initial hospital visit for asthma was associated with an increase in use of inhaled corticosteroids (CCS) at discharge, and to identify risk factors for recurrent asthma hospital visits and death. METHODS: A retrospective cohort analysis identified 93,174 persons 65 years and older enrolled in the Tennessee Medicaid program for at least 1 year and free of asthma hospital visits during that year; 510 survived a single hospital visit for asthma in 1992 and comprised the study population. Main outcome measures included recurrent hospital visit for asthma and all-cause mortality during the year after an asthma hospital visit. RESULTS: Among the 510 study subjects, 10% were on inhaled CCS at admission compared with 11% at discharge. Twenty-three percent of the population had recurrent asthma hospital visits and 12% died during 1-year followup. Asthma severity was the strongest independent risk factor for both a recurrent hospital visit [relative risk for moderate to severe disease 1.92 (1.01 to 3.66), and for near-fatal disease 2.28 (1.01 to 5.13), respectively] and death [relative risk for moderate to severe disease 2.99 (1.07 to 8.32) and for near-fatal disease 4.44 (1.34 to 4.69), respectively]. CONCLUSIONS: In this population, older adults with an exacerbation of asthma requiring hospital care experienced significant morbidity and mortality. An acute hospital visit for an asthma exacerbation did not result in initiation of inhaled CCS therapy. Asthma severity predicted both recurrent hospital visits and all-cause mortality among older adults with asthma requiring hospital care.

Acute Disease↗
PubMedDate not supplied

Mechanisms of action of anti-immunoglobulin E therapy.

The currently approved anti-immunoglobulin E (IgE) agent omalizumab is a humanized monoclonal antibody that recognizes human IgE in the vicinity of its binding sites for high- and low-affinity IgE receptors. Omalizumab binds free IgE and the complexes that are formed are removed by the hepatic reticuloendothelial system. Over time, IgE comes off its receptors on various cells (primarily basophils and mast cells), rendering these cells "nonfunctional," in that they lose their ability to respond to allergen. This process is enhanced by the fact that, as IgE receptors are freed, their numbers on cell surfaces decline. The kinetics of cellular defunctionalization may differ depending on the cell type (basophils are believed to lose IgE earlier), the number of cell-surface-specific IgE molecules before initiation of treatment, and the cellular sensitivity of individual patients. Inability to respond to allergen reduces acute allergic reactions and their inflammatory and physiological consequences such as late reductions in lung function and tissue eosinophilia. Chronic airway inflammation is suppressed also, but the effect on airway hyperresponsiveness is modest. A potential role of anti-IgE therapy to act as an immunomodulator by affecting antigen presentation through the removal of IgE from the surface of dendritic cells has not been explored. Also unknown is whether anti-IgE can bind to membrane-bound IgE on B lymphocytes and influence IgE production by these cells. Anti-IgE therapy has provided a strong proof of concept for the central role of the IgE system in asthma and other allergic diseases. (Allergy Asthma

Antibodies, Anti-Idiotypic↗