Objective Assessment of Cough: An Early Marker of Response to Biological Therapies in Asthma?

Cough is an important symptom of asthma. The objective assessment of chronic cough has been enhanced by the development of ambulatory cough monitoring systems. Mepolizumab has been demonstrated to reduce exacerbations in eosinophilic asthmatics long-term. We evaluate the utility of objective cough count as an outcome measure in severe eosinophilic asthma treated with mepolizumab. Consecutive, consenting patients initiated on treatment with mepolizumab had a 24-h cough count recorded at baseline; this was repeated at 1, 3 and 6 months. Asthma control questionnaire (ACQ) scores and exacerbation frequency were also recorded. The mean 24-h cough count in 11 subjects (8 females, mean age 53.6 years) was 172.4 at baseline; at 1, 3 and 6 months following initiation of treatment this decreased to 101.4, 92 and 70.8, respectively (p < 0.02). Significant improvements were also observed in mean ACQ score (3-1.6, p < 0.01) and exacerbation frequency (5.5 per year - 1.3, p < 0.01). Objective cough measurement could be used as an early, precise and clinically relevant endpoint in assessing response to asthma therapy.

Comparative effectiveness of LABA-ICS versus LAMA as initial treatment in COPD targeted by blood eosinophils: a population-based cohort study.

BACKGROUND: Long-acting ß2 agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are the recommended initial maintenance treatment for chronic obstructive pulmonary disease (COPD), with almost all LABAs dispensed in fixed combination with inhaled corticosteroids (LABA-ICS). We compared the effectiveness and safety of LABA-ICS versus LAMA treatment initiation as a function of blood eosinophilia, a potential biomarker of ICS effectiveness, in a real-world setting. METHODS: In this population-based cohort study, we identified a cohort of patients with COPD initiating treatment with a LAMA or LABA-ICS during 2002-15, age 55 years or older, from the UK's Clinical Practice Research Datalink. We excluded patients who initiated treatment with both bronchodilators on the same date. All patients required at least 1 year of medical history and a measure of blood eosinophil concentration before cohort entry, defined by the date of the first cohort-defining bronchodilator prescription. Patients initiating a LAMA were matched on high-dimensional propensity scores with patients initiating a LABA-ICS. They were followed up for 1 year for the occurrence of a moderate or severe COPD exacerbation and for severe pneumonia. Sensitivity analyses included, among others, repeating the analysis among patients with two blood eosinophil concentration measures and stratification by concurrent asthma and previous exacerbations. FINDINGS: The base cohort included 539 643 patients with a prescription for LABAs or LAMAs from Jan 1, 2002, to Dec 31, 2015, of whom 18 500 were initiated on LABA-ICS and 13 870 on LAMAs. Propensity score analysis resulted in 12 366 initiators of LAMAs (mainly tiotropium) matched to 12 366 initiators of LABA-ICS. The hazard ratio (HR) of COPD exacerbation associated with LABA-ICS initiation, relative to LAMA initiation, was 0·95 (95% CI 0·90-1·01). In patients with blood eosinophil concentrations of less than 2% of white blood cell count, the HR was 1·03 (95% CI 0·93-1·13) and for those with eosinophil concentrations of 2-4%, the HR was 1·00 (0·91-1·10). For patients with eosinophil concentrations of more than 4%, the HR was 0·79 (0·70-0·88). The incidence of pneumonia increased with LABA-ICS initiation (HR 1·37 [95% CI 1·17-1·60]) and was similar across all eosinophil concentrations. Sensitivity analyses were consistent with these findings, but the incidence of exacerbation with LABA-ICS among the 2766 (11%) of all 24 732 patients with two or more COPD exacerbations during the baseline year was marginally lower (HR 0·87 [95% CI 0·79-0·97]). INTERPRETATION: In this real-world, clinical practice, observational study, initial COPD treatment with LABA-ICS inhalers was only more effective than with LAMAs in patients with high blood eosinophil concentrations (>4%) or counts (>300 cells per µL) and possibly in frequent exacerbators. Because of the increased risk of pneumonia associated with the ICS component, initiation with a LAMA should be preferred in patients with blood eosinophil concentrations of less than 4%. FUNDING: Canadian Institutes of Health Research, Canadian Foundation for Innovation.

Blood Eosinophils as Biomarkers to Drive Treatment Choices in Asthma and COPD.

BACKGROUND: Asthma and COPD are complex, heterogeneous conditions comprising a wide range of phenotypes, some of which are refractory to currently available treatments. Elucidation of these phenotypes and identification of biomarkers with which to recognize them and guide appropriate treatment remain a priority. OBJECTIVE: This review describes the utility of blood eosinophils as a surrogate biomarker of eosinophilic airway inflammation, a common feature of specific asthma and COPD phenotypes. The role of blood eosinophils in airway disease is described, as is their relevance in reflecting airway eosinophilia. Each disease is discussed separately as the manner in which blood eosinophils might be used as biomarkers differs. Focusing on patients with severe disease (persistent eosinophilic asthma and exacerbating COPD), we evaluate evidence examining eosinophils as biomarkers. RESULTS: In asthma, the rationale for using blood eosinophils to guide treatment is clearly defined, backed by prospective, well-controlled studies. Higher eosinophil counts identify patients with more severe disease and poorer outcomes, patients for whom biologic therapies targeting allergic and/or eosinophilic pathways are recommended. In COPD, the evidence is less robust. High blood eosinophil counts are a modest predictor of future exacerbations, and may predict a favourable response to ICS on top of LABA/LAMA, especially in patients with a history of frequent exacerbations. CONCLUSION: Before extensive application in clinical practice, further evaluation of these findings in prospective clinical studies, and standardization of the appropriate thresholds of clinically relevant eosinophilia are needed, together with establishing whether single or multiple measurements are required in different clinical settings.

Diagnostic criteria, severity classification and guidelines of eosinophilic fasciitis.

We established diagnostic criteria and severity classification of eosinophilic fasciitis because there is no established diagnostic criteria or widely accepted severity classification of the disease. Also, there has been no clinical guideline for eosinophilic fasciitis, so we established its clinical guideline ahead of all over the world. In particular, the clinical guideline was established by clinical questions based on evidence-based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guideline easy to use and reliable based on the newest evidence, and to present guidance as specific as possible for various clinical problems in treatment of eosinophilic fasciitis.

Effects of Xingbi gel on leukotriene E4 and immunoglobulin E production and nasal eosinophilia in a guinea pig model for allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal airways.Many therapies do not have immediate effects,even which have side-effects.However,the effects of Xingbi gel for the treatment of AR was investigated. OBJECTIVE: We investigated the effects of Xingbi gel on serum levels of leukotriene E4 (LTE4) and immunoglobulin E (IgE), as well as eosinophil counts in the nasal mucosa using a guinea pig model of allergic rhinitis (AR). METHODS: In addition to a healthy control group without AR, guinea pigs with AR were randomly divided into untreated AR control group, low-dose Xingbi gel (0.2483 g/mL) group, high-dose Xingbi gel (0.4966 g/mL) group, and budesonide group. RESULTS: Compared to the healthy controls, untreated AR guinea pigs had significantly higher ethology scores, serum LTE4 and IgE levels, and nasal mucosa eosinophil counts (p <0.01). Treatments with low-dose Xingbi gel, high-dose Xingbi gel, and budesonide significantly reduced the ethology scores, serum LTE4 and IgE levels, and nasal mucosa eosinophil counts as compared to untreated AR model guinea pigs (p <0.01). CONCLUSION: Xingbi gel alleviates AR in part through inhibiting LTE4 and IgE production and reducing eosinophilia in the nasal mucosa.

Drug reaction with eosinophilia and systemic symptoms syndrome probably induced by a lamotrigine-ginseng drug interaction.

The likelihood of a drug reaction with lamotrigine is increased by dose escalation that is too rapid or drug interactions that increase the concentration of lamotrigine. There is a well-documented interaction between valproic acid and lamotrigine in which lamotrigine levels are increased, subsequently increasing the risk of a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. This syndrome is characterized by fever, lymphadenopathy, diffuse maculopapular rash, multivisceral involvement, eosinophilia, and atypical lymphocytes and has a mortality rate of 10-40%. We describe the first case, to our knowledge, of DRESS syndrome that was probably induced by a drug interaction between lamotrigine and ginseng. A 44-year-old white man presented to the emergency department after experiencing a possible seizure. His medical history included two other lifetime events concerning for seizures at ages 14 and 29 years old. After referral to the neurology clinic, he was diagnosed with generalized tonic-clonic seizure disorder, and lamotrigine was started with up-titration according to the drug's package insert to a goal dosage of 150 mg twice/day. The patient had also been taking deer antler velvet and ginseng that he continued during his lamotrigine therapy. On day 43 of therapy, the patient presented to the emergency department with a pruritic rash that had started on his extremities and spread to his torso. He was thought to have experienced a drug reaction to lamotrigine, and the drug was discontinued. Thirteen days later, the patient was admitted from the acute care clinic for inpatient observation due to laboratory abnormalities in the setting of continued rash, headache, and myalgias. His admission laboratory results on that day were remarkable for leukocytosis, with a white blood cell count up to 17.6 × 10(3) /mm(3) , with a prominent eosinophilia of 3.04 × 10(3) /mm(3) ; his liver enzyme levels were also elevated, with an aspartate aminotransferase level of 191 U/L, alanine aminotransferase level 473 U/L, alkaline phosphatase level 465 U/L, and total bilirubin level 1.4 mg/dl. Use of the Drug Interaction Probability Scale indicated that a drug interaction between lamotrigine and ginseng was the probable cause (score of 5). The proposed mechanism of the interaction is ginseng inhibition of the uridine diphosphate glucuronosyltransferase 2B7 enzyme, similar to the mechanism of the interaction with valproic acid. Clinicians should be aware of this probable drug interaction and avoid coadministration of ginseng and lamotrigine or use a more conservative dose titration of lamotrigine for patients who are also taking ginseng.

Tirapazamine-doxorubicin interaction referring to heart oxidative stress and Ca²âº balance protein levels.

Doxorubicin (DOX) causes long-term cardiomyopathy that is dependent on oxidative stress and contractility disorders. Tirapazamine (TP), an experimental adjuvant drug, passes the same red-ox transformation as DOX. The aim of the study was to evaluate an effect of tirapazamine on oxidative stress, contractile protein level, and cardiomyocyte necrosis in rats administered doxorubicin. Rats were intraperitoneally injected six times once a week with tirapazamine in two doses, 5 (5TP) and 10 mg/kg (10TP), while doxorubicin was administered in dose 1.8 mg/kg (DOX). Subsequent two groups received both drugs simultaneously (5TP+DOX and 10TP+DOX). Tirapazamine reduced heart lipid peroxidation and normalised RyR2 protein level altered by doxorubicin. There were no significant changes in GSH/GSSG ratio, total glutathione, cTnI, AST, and SERCA2 level between DOX and TP+DOX groups. Cardiomyocyte necrosis was observed in groups 10TP and 10TP+DOX.

Docosahexaenoic acid exerts anti-inflammatory action on human eosinophils through peroxisome proliferator-activated receptor-independent mechanisms.

BACKGROUND: Despite the fact that previous studies have indicated the significant roles of polyunsaturated fatty acids (PUFAs) in the immune system through peroxisome proliferator-activated receptor alpha (PPARα) and PPARγ, the biological functions and the mechanisms of action in eosinophils are poorly understood. METHODS: We investigated the functional effects of docosahexaenoic acid (DHA, n-3 PUFA) on human peripheral blood eosinophils, using in vitro systems to test the hypothesis that DHA negatively regulates eosinophil mechanisms through PPARα and PPARγ. RESULTS: Eosinophil apoptosis that spontaneously occurs under normal culture conditions was accelerated in the presence of DHA. In addition, eotaxin-directed eosinophil chemotactic responses were inhibited by pretreatment with DHA, disturbing both the velocity and the directionality of the cell movement. Pharmacological manipulations with specific antagonists indicated that the effects of DHA were not mediated through PPARα and PPARγ, despite the presence of these nuclear receptors. DHA also induced Fas receptor expression and caspase-3 activation that appears to be associated with a proapoptotic effect of DHA. Further, DHA rapidly inhibited the expression of eotaxin receptor C-C chemokine receptor 3 and eotaxin-induced calcium influx and phosphorylation of extracellular signal-regulated kinase. Interestingly, these inhibitory effects were not observed with linoleic acid (n-6 PUFA). CONCLUSIONS: The data might explain one of the mechanisms found in previous research showing the favorable effects of n-3 PUFA supplementation on allergic diseases, and provide novel therapeutic strategies to treat eosinophilic disorders.

Iron administration reduces airway hyperreactivity and eosinophilia in a mouse model of allergic asthma.

The prevalence of allergic diseases has increased dramatically during the last four decades and is paralleled by a striking increase in iron intake by infants in affluent societies. Several studies have suggested a link between increased iron intake and the marked increase in prevalence of allergic diseases. We hypothesized that the increased iron intake by infants offers an explanation for the increased prevalence of allergic disease in industrialized societies during the past four decades. A well-established mouse model of ovalbumin (OVA)-driven allergic asthma was used to test the effects of differences in iron intake and systemic iron levels on the manifestations of allergic asthma. Surprisingly, iron supplementation resulted in a significant decrease in airway eosinophilia, while systemic iron injections lead to a significant suppression of both allergen-induced airway eosinophilia and hyperreactivity compared to placebo. In contrast, mice fed on an iron-deprived diet did not show any difference in developing experimentally induced allergic asthma when compared to those fed on an iron-sufficient control diet. In contrast to our hypothesis, airway manifestations of allergic asthma are suppressed by both increased levels of iron intake and systemic iron administrations in the mouse model.

Eosinophilic gastrointestinal disorders in infants: a Japanese case series.

BACKGROUND: Eosinophilic gastrointestinal disorders (EGIDs) are disorders characterized by primary eosinophil inflammation in the gastrointestinal tract. There are a small number of reports of eosinophil infiltration in gastrointestinal tracts presenting as EGIDs in infants. In this study, we present Japanese cases of EGIDs in infants. METHODS: Five patients diagnosed with or strongly suspected to have EGIDs in our hospital from 2008 to 2010 were reviewed. Radiographic contrast enema examinations and/or endoscopies were performed in 4 and 3 patients, respectively. RESULTS: There were patients with eosinophilic colitis (1 suspected and 2 biopsy-proven), a patient who was suspected of having allergic eosinophilic enterocolitis, and a patient with eosinophilic gastroenteritis associated with pediatric hypereosinophilic syndrome. CONCLUSIONS: The causes and clinical findings of patients with intestinal eosinophil inflammation vary. Therefore, deliberate examination and observation are important for patients with infantile EGID.

[Magnesium in skin allergy]. / Wplyw magnezu na reakcje alergiczne skóry.

Magnesium is involved in many biological processes within the body. Magnesium deficiency causes many disorders, including impairment of immunity. This review summarizes present knowledge on the relationship between magnesium and skin allergy reactions. Special focus is on allergy types I and IV. At present the best knowledge is on allergy I. Magnesium deficiency in experimental animals, mainly rats, leads to characteristic hyperemia, an increase in IgE, neutrophilia and eosinophilia, an increase in the level of proinflammatory cytokines, mastocyte degranulation, histaminemia, and splenomegaly. These symptoms observed in hypomagnesemic rats are similar to those in atopic patients. Data on the relationship between magnesium and other types of allergy are scarce. Clinical observations show the beneficial effect of topical and oral administration of magnesium salts in patients with skin allergy. All the presented data point to an important role of magnesium in allergy reactions. Other studies are needed to better understand the mechanism of magnesium's action. Well-controlled clinical protocols should also be conducted to assess the efficiency of magnesium supplementation in patients with skin allergy.

Eosinophil infiltration in post-transurethral resection prostatitis and cystitis with special reference to sequential changes of eosinophilia.

Post-transurethral resection (TUR) status in the prostate and urinary bladder has been infrequently documented. Furthermore, sequential changes in eosinophil count in peripheral blood (PB) after TUR have not been investigated in detail. In the present study, eosinophil counts and changes in eosinophils in PB were examined before to after TUR of the prostate (P) in 20 patients with benign prostatic hyperplasia. Among them, 14 patients exhibited increased numbers of eosinophils, the greatest increase being 17%. After TUR to treat bladder tumor (BT), massive infiltration of eosinophils into the resected areas, peaking 1 month later, was also detected in 8 of 15 cases of post-TUR cystitis. The PB eosinophil counts increased by more than 5% in two of five cases of post-TUR cystitis in which eosinophil counts were obtained before and after surgery. Most infiltrating eosinophils reacted positively to antibodies to eosinophil cationic proteins. These results indicated that, in patients with post-TUR prostatitis, the number of eosinophils in PB increased, and peaked 1 month later, with infiltration by eosinophils observed. Pathologists and urologists should be aware of the potential for increase in eosinophils not only in regions of TUR but also in PB.

Pneumonitis and eosinophilia after in vitro fertilization treatment.

A 33-year-old woman presented to the emergency department (ED) with tachypnea, tachycardia, and hypoxia, complaining of dyspnea and paroxysms of dry cough for 2 days. The patient had undergone an unsuccessful in vitro fertilization procedure 1 month earlier and had had another embryo implantation 6 days earlier. She had been receiving intramuscular injections of estradiol and progesterone in sesame oil to support implantation. A chest radiograph demonstrated extensive bilateral pulmonary consolidation; a leukocytosis count of 19.7 x 10(9) with 20% eosinophils was noted on a CBC count. A MEDLINE search yielded a case report in infertility literature describing an eosinophilic pneumonitis with similar clinical features after injections of progesterone in sesame oil. Treatment with intravenous corticosteroids was initiated in the ED, resulting in symptom and chest radiograph result improvement within 2 days and sparing the patient further imaging and antibiotic therapy.

[Variation in eosinophilia and measures of pollen counts of grasses (Poaceae) and ragweed (Ambrosia) in the Rhone valley]. / Variation de l'éosinophilie et mesures des taux polliniques des graminées (Poaceae) et ambroisies (Ambrosia) dans la vallée du Rhône.

Sensitivity to ragweed pollen, along with grasses pollen, is the leading cause of pollen-induced allergy in our region. Our study focuses on the variation of eosinophilia levels in the blood taken from a sample of the general population during both ragweed and grasses pollination periods. The pollen trap located in the central Rhône River Valley region has provided weekly counts since 1995. The Etablissement Français du Sang Rhône-Alpes-Valence routinely checks hypereosinophilia in the blood through systematic analysis after a blood donation. Average cumulative pollen counts for grasses and ragweed present an interesting correlation with the levels of hypereosinophilia measured at the end of the summer.

Evaluation of laboratory tests in childhood allergy. Total serum IgE, blood eosinophilia and eosinophil and mast cells in nasal mucosa of 178 children aged 3 years.

The diagnosis of atopic disease is often difficult in small children because of differences in symptoms and lack of specific and reliable laboratory tests. We evaluated the significance of four commonly used laboratory tests--blood eosinophil count, total serum IgE, and eosinophil and mast cells in the nasal smear--as indicators of atopy in 178 children aged 3 years. The children were followed from birth and examined at the age of 3 years. Symptoms of immediate hypersensitivity including atopic dermatitis, food allergy and pollen or animal allergy were recorded. Severe or obvious atopy correlated with the highest levels of serum IgE. A total serum IgE level higher than 150 U/ml was found to be strongly suggestive of atopic disease. A blood eosinophil count higher than 600 X 10(9)/l as well as an increased number of eosinophil and mast cells in the nasal smear were associated with atopy. On the other hand, normal levels of these laboratory tests did not exclude atopic disease. In other words, all of the tests were high in specificity, but low in sensitivity. Consequently, when small children's atopic disease is being diagnosed, emphasis can be laid on the elevated levels of serum total IgE, blood eosinophil count and eosinophil and mast cells in the nasal smear, all of which separately, but especially together, give valuable information on atopy.

Eosinophils and the integrity of the hypothalamic-pituitary-adrenal axis.

The level of blood eosinophils was studied in patients with adrenalectomy and/or hypophysectomy and in patients with asthma and eosinophilia. In the latter group was a patient who had asthma associated with hypopituitarism, which is cited in detail. It is concluded that blood eosinophils are independent from the integrity of the hypothalamic-pituitary-adrenal axis.