Biomarker-guided withdrawal of inhaled corticosteroids in asthma patients with a non-T2 inflammatory phenotype - a randomized controlled trial study protocol.

BACKGROUND: Non-T2 asthma is characterized by the absence of elevated type 2 inflammatory biomarkers such as blood-eosinophils, total and allergen-specific Immunoglobulin E and Fractional exhaled Nitric Oxide (FeNO). According to guidelines, inhaled corticosteroids (ICS) are the cornerstone of asthma management. However, ICS treatment is associated with a risk of local side effects, including hoarseness and thrush, and long-term high-dose therapy may cause systemic adverse effects. Furthermore, whereas treatment with ICS is highly effective in T2 asthma, studies have shown a markedly reduced ICS efficacy in patients with a lower degree of T2 inflammation, thus posing a clinical challenge in this subgroup of patients. Hence, owing to the ICS dosage step-up approach in current clinical guidelines, patients with low T2 biomarkers are at risk of being exposed to high doses of ICS, and by that at risk of side effects. Thus, an ICS-treatment regime guided by biomarkers that reflects the inflammatory phenotype is warranted in order to reduce the corticosteroid burden in patients with non-T2 asthma. This study combines a panel of non-T2 inflammatory markers (low periostin, low blood-eosinophils, and low FeNO), to determine if this group of patients can maintain asthma control during ICS withdrawal. METHODS: This is an ongoing prospective multicenter open-label randomized, controlled trial aiming to assess if ICS can be safely tapered in patients with non-T2 asthma. The patients are randomized 1:1 to either standard of care or an ICS tapering regimen (n = 55 in each group) where the initial ICS dose is reduced by 50% for 8 weeks followed by total ICS removal. The primary endpoint is change in asthma control questionnaire (ACQ) from baseline to post-tapered ICS. The secondary endpoints are time from baseline to drop-out caused by loss of asthma control, changes in serum-periostin, blood-eosinophils, FeNO, Forced Expiratory Volume in 1 s (FEV1) and in sputum-eosinophils. DISCUSSION: This study aims to provide data on ICS tapering in non-T2 asthma patients and to contribute to a more individualized and corticosteroid-sparing treatment regime in this group of patients. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03141424. Registration date: May 5th, 2017.

Stability of FeNO and airway hyperresponsiveness to mannitol in untreated asthmatics.

OBJECTIVE: Airway hyperresponsiveness and airway inflammation are important hallmarks of asthma and are useful in asthma diagnosing, monitoring and treatment. The aim of the study was to assess whether two commonly used clinical tests, the mannitol challenge and Fraction of exhaled NO (FeNO), were stable clinical indicators over time in stable untreated asthmatics. METHODS: 54 non-smoking, asthma patients not treated with steroids were enrolled in the study and assessed at baseline and a median of 6 months later. At baseline and follow-up, FeNO and airway hyperesponsiveness to mannitol were measured, and asthma control was assessed with the Asthma Control Questionnaire (ACQ). RESULTS: A total of 41 subjects completed both visits. Mean (SD) FEV1% at baseline was 94.1% (17.7) and at re-examination 94.6% (19.7) (ns). The ACQ score was unchanged from baseline (Mean (SD): 0.90 (± 0.73)) to follow-up 0.90 (± 0.74) (ns), as was the FEV1% (94.1% (±17.1%) vs 94.6% (19.7%)(ns) indicating that patients were clinically stable during follow-up. The response to mannitol was unchanged at follow-up (Geometric mean (CI) of Response Dose Ratio (RDR) to mannitol: 0.026(0.013-0.046) vs 0.026(0.012-0.050) (ns). There was a slight decrease in FeNO at follow-up (25.5 ppb (19.7-32.9) to 21.9 ppb (17.1-28.2) (p < 0.001). CONCLUSIONS: In steroid-free non-smoking asthmatics with constant symptom scores and lung function, airway responsiveness to mannitol remained at the same level over a period of months, while a minor change in exhaled FeNO was reported. These results suggest that mannitol is a stable, reliable marker of clinical disease activity.

Predictors of neutrophilic airway inflammation in young smokers with asthma.

INTRODUCTION: Asthma is one of the most widespread chronic diseases worldwide. In spite of numerous detrimental effects on asthma, smoking is common among asthma patients. These smoking-induced aggravations of asthma may be attributed to changes in airway inflammation, which is characterized by a higher degree of neutrophilic inflammation than in non-smokers. A state of neutrophilic inflammation may lead to increased steroid resistance and an accelerated loss of lung function owing to tissue destruction. The aim of this study was to elucidate predictors of neutrophilic inflammation in young asthmatic smokers not on steroid treatment, including analysis of tobacco history and bacterial colonization. METHODS: In a cross-sectional study, 52 steroid-free, current smokers with asthma were examined with induced sputum, fractional exhaled nitric oxide (FeNO), lung function, ACQ6 score, mannitol and methacholine challenge. A sample from the sputum induction was taken for bacterial analysis using 16S gene PCR technique and sequencing. RESULTS: Using one-way analysis of variance and binary and linear regression models, only age and ACQ6 score were found to be significant predictors for airway neutrophilia. The investigation also included analysis for effect of pack years, current tobacco consumption, body mass index, lung function, FeNO; methacholine and mannitol responsiveness, atopy, gender, asthma history and presence of bacteria. The most common potentially pathogenic bacteria found were Streptococcus spp., Haemophilus spp. and Mycoplasma spp. CONCLUSION: In this study, no tobacco-related predictors of airway neutrophilia were found, indicating that in the younger years of asthma patients who smoke, the amount of tobacco smoked in life does not influence the degree of neutrophilia. Conversely, for asthmatic smokers, neutrophilia may be induced when a certain threshold of tobacco consumption is reached.

A review of mometasone furoate / formoterol in the treatment of asthma.

INTRODUCTION: Asthma is a common chronic respiratory disease affecting the airways causing inflammation, airway hyperreactivity (AHR), and respiratory symptoms. Frequently, asthma can be effectively treated with inhaled corticosteroids (ICS) but in more severe cases additional drugs are required, such as long-acting ß2-agonists (LABA). Mometasone furoate (MF) is a synthetic steroid exhibiting a strong affinity for the glucocorticoid receptor as well as a low bioavailability and a high plasma protein binding. In most cases, MF only requires once daily administration. Formoterol fumarate (F) is a full ß2-agonist with a rapid onset and 12 h of duration. AREAS COVERED: The present paper reviews the current knowledge of the novel combination of MF and F for the treatment of asthma. Furthermore, a description of the individual components is included. EXPERT OPINION: At present, only few clinical studies of MF/F are available for review and more studies of MF/F efficacy are needed, especially comparative studies on other ICS/LABA drugs. However, it does not appear from the reviewed literature that MF/F or its individual components are inferior to other equivalent treatments.

[Primary Epstein-Barr virus infections with neurological complications in two middle-aged men]. / Primær Epstein-Barr-virus-infektion med neurologiske komplikationer hos to midaldrende mænd.

Primary infections with Epstein-Barr virus (EBV) often lead to infectious mononucleosis with sore throat, lymphadenopathy and hepatitis, especially in youngsters. However, neurological complications can occur even in immunocompetent individuals. We report two case stories of two middle-aged men with primary EBV infections who presented severe neurological manifestations of the disease, but both fully recovered. Hepatitis was present in both cases, but not the classical mononucleosis. The cases stress that clinicians should be aware of these rare courses of primary EBV infections.

Morphometric characteristics of the primordial to primary follicle transition in the human ovary in relation to age.

BACKGROUND: The growth pattern of the smallest ovarian follicles in humans is still incompletely documented. Using follicle hemispheres in thick histological sections, morphometric changes of primordial to primary follicles and possible age-related effects were evaluated. METHODS: In ovarian sections from 25 females aged 4-39 years a total of 1122 primordial, transitory or primary follicles were assessed for the diameters of follicles, oocytes and oocyte nuclei and for number of granulosa cells (GCs). RESULTS: The number of GCs in primordial, transitory and primary follicles were approximately 30, 50 and 100, respectively. The diameters of primordial follicles and oocytes increased with the woman's age until the mid-30's, after which time they decreased in size. The number of GCs in primordial follicles showed a moderate increase with age, whereas the number of GCs in transitory follicles showed a clear increase with age . The oocyte nucleus diameter (14-23 microm) showed significant linear correlations with the oocyte and follicular diameters and number of GCs in the follicle, while the number of GCs in the whole follicle and in the largest cross-section were closely related to the oocyte diameter. CONCLUSIONS: The number of GCs in small follicles is accurately estimated and shows an increase with age, indicating that the starting point of follicular development alters with female age. The age-related changes observed may be linked to the poorer reproductive performance of older women.