Alida Benfante

Lung penetration and patient adherence considerations in the management of asthma: role of extra-fine formulations

The mainstay of management in asthma is inhalation therapy at the target site, with direct delivery of the aerosolized drug into the airways to treat inflammation and relieve obstruction. Abundant evidence is available to support the concept that inflammatory and functional changes at the level of the most peripheral airways strongly contribute to the complexity and heterogeneous manifestations of asthma. It is now largely accepted that there is a wide range of clinical phenotypes of the disease, characterized primarily by small airways involvement. Thus, an appropriate diagnostic algorithm cannot exclude biological and functional assessment of the peripheral airways. Similarly, achievement of optimal control of the disease and appropriate management of specific phenotypes of asthma should be based on drugs (and delivery options) able to distribute uniformly along the bronchial tree and to reach the most peripheral airways. Products developed with the Modulite® technology platform have been demonstrated to meet these aims. Recent real-life studies have shown clearly that extra-fine fixed-combination inhaled therapy provides better asthma control than non-extra-fine formulations, thus translating the activity of the drugs into greater effectiveness in clinical practice. We suggest that in patients with incomplete asthma control despite good lung function, involvement of the peripheral airways should always be suspected. When this is the case, treatments targeting both the large and small airways should be used to improve asthma control. Above all, it is emphasized that patient adherence with prescribed medications can contribute to clinical success, and clinicians should always be aware of the role played by patients themselves in determining the success or failure of treatment.

Which factors affect the choice of the inhaler in chronic obstructive respiratory diseases

Inhalation is the preferred route of drug administration in chronic respiratory diseases because it optimises delivery of the active compounds to the targeted site and minimises side effects from systemic distribution. The choice of a device should be made after careful evaluation of the patients clinical condition (degree of airway obstruction, comorbidities), as well as their ability to coordinate the inhalation manoeuvre and to generate sufficient inspiratory flow. These patient factors must be aligned with the specific advantages and limitations of each inhaler when making this important choice. Finally, adherence to treatment is not the responsibility of the patient alone, but should be shared also by clinicians. Clinicians have access to a wide selection of pressurised metered dose inhalers (pMDIs) and dry powder inhalers (DPIs) that can be used effectively when matched to the needs of individual patients; this should be perceived as an opportunity rather than a limitation.

Serum low density lipoprotein subclasses in asthma

BACKGROUND The levels of serum low-density lipoproteins (LDL) have been implicated in the inflammatory cascade in a murine model of asthma. Recent findings suggest that LDL may modulate the inflammatory state of the asthmatic airways in humans. OBJECTIVE We explored whether LDL subclasses are associated with the occurrence and severity of asthma. METHODS 24 asthmatics (M/F: 11/13) and 24 healthy individuals, with normal BMI and absence of metabolic syndrome, matched for age and gender. Serum concentrations of LDL subclasses were distributed as seven bands (LDL-1 and -2 defined as large, least pro-inflammatory LDL, and LDL-3 to -7 defined as small, most pro-inflammatory LDL), using the LipoPrint(©) System (Quantimetrix Corporation, Redondo Beach, CA, USA). RESULTS LDL-1 was similar in the two groups (56 ± 16% vs. 53 ± 11, p = NS), while LDL-2 was significantly lower in asthmatics as compared to controls (35 ± 8% vs. 43 ± 10%, p = 0.0074). LDL-3 levels were two-fold higher in the asthmatics, but the difference did not reach the statistical significance (8 ± 7.3% vs. 4 ± 3%, p = NS). Smaller subclasses LDL-4 to LDL-7 were undetectable in controls. In asthmatics, LDL-1 was positively associated with VC% predicted (r = +0.572, p = 0.0035) and FEV1% predicted (r = +0.492, p = 0.0146). LDL-3 was inversely correlated with both VC% predicted (r = -0.535, p = 0.0071) and FEV1% predicted (r = -0.465, p = 0.0222). CONCLUSIONS The findings of this pilot study suggest a role of LDL in asthma, and advocate for larger studies to confirm the association between asthma and dyslipidemia.

Impact of extrafine formulations of inhaled corticosteroids/long-acting beta-2 agonist combinations on patient-related outcomes in asthma and COPD

Asthma and chronic obstructive pulmonary disease (COPD) are among the most common chronic diseases worldwide, characterized by a condition of variable degree of airway obstruction and chronic airway inflammation. A large body of evidence has demonstrated the importance of small airways as a pharmacological target in these clinical conditions. Despite a deeper understanding of the pathophysiological mechanisms, the epidemiological observations show that a significant proportion of asthmatic and COPD patients have a suboptimal (or lack of) control of their diseases. Different factors could influence the effectiveness of inhaled treatment in chronic respiratory diseases: patient-related (eg, aging); disease-related (eg, comorbid conditions); and drug-related/formulation-related factors. The presence of multiple illnesses is common in the elderly patient as a result of two processes: the association between age and incidence of degenerative diseases; and the development over time of complications of the existing diseases. In addition, specific comorbidities may contribute to impair the ability to use inhalers, such as devices for efficient drug delivery in the respiratory system. The inability to reach and treat the peripheral airways may contribute to the lack of efficacy of inhaled treatments. The recent development of inhaled extrafine formulations allows a more uniform distribution of the inhaled treatment throughout the respiratory tree to include the peripheral airways. The beclomethasone/formoterol extrafine formulation is available for the treatment of asthma and COPD. Different biomarkers of peripheral airways are improved by beclomethasone/formoterol extrafine treatment in comparison with equivalent nonextrafine inhaled corticosteroids/long-acting beta-2 agonist (ICS/LABA) combinations. These improvements are associated with improved lung function and clinical outcomes, along with reduced systemic exposure to inhaled corticosteroids. The increased knowledge in the pathophysiology of the peripheral airways may lead to identify specific phenotypes of obstructive lung diseases that would mostly benefit from the treatments specifically targeting the peripheral airways.

Safety and efficacy of montelukast as adjunctive therapy for treatment of asthma in elderly patients.

Asthma is a disease of all ages. This assumption has been challenged in the past, because of several cultural and scientific biases. A large body of evidence has accumulated in recent years to confirm that the prevalence of asthma in the most advanced ages is similar to that in younger ages. Asthma in the elderly may show similar functional and clinical characteristics to that occurring in young adults, although the frequent coexistence of comorbid conditions in older patients, together with age-associated changes in the human lung, may lead to more severe forms of the disease. Management of asthma in the elderly follows specific guidelines that apply to all ages, although most behaviors are pure extrapolation of what has been tested in young ages. In fact, age has always represented an exclusion criterion for eligibility to clinical trials. This review focuses specifically on the safety and efficacy of leukotriene modifiers, which represent a valid option in the treatment of allergic asthma, both as an alternative to first-line drugs and as add-on treatment to inhaled corticosteroids. Available studies specifically addressing the role of montelukast in the elderly are scarce; however, leukotriene modifiers have been demonstrated to be safe in this age group, even though cases of acute hepatitis and occurrence of Churg-Strauss syndrome have been described in elderly patients; whether this is associated with age is to be confirmed. Furthermore, leukotriene modifiers provide additional benefit when added to regular maintenance therapy, not differently from young asthmatics. In elderly patients, the simpler route of administration of leukotriene modifiers, compared with the inhaled agents, could represent a more effective strategy in improving the outcomes of asthma therapy, given that unintentional nonadherence with inhalation therapy represents a complex problem that may lead to significant impairment of asthma symptom control.

Asthma in the elderly: a different disease?

Key points Asthma in the elderly can be difficult to identify due to modifications of its clinical features and functional characteristics. Several comorbidities are associated with asthma in the elderly, and this association differs from that observed in younger patients. In clinical practice, physicians should treat comorbidities that are correlated with asthma (i.e. rhinitis or gastro-oesophageal reflux), assess comorbidities that may influence asthma outcomes (i.e. depression or cognitive impairment) and try to prevent comorbidities related to ‘drug-associated side-effects (i.e. cataracts, arrhythmias or osteoporosis). “Geriatric asthma” should be the preferred term because it implies the comprehensive and multidimensional approach to the disease in the older populations, whereas “asthma in the elderly” is only descriptive of the occurrence of the disease in this age range. Educational aims To present critical issues in performing differential diagnosis of asthma in the elderly. To offer the instrument to implement the management of asthma in the most advanced ages. Asthma is a chronic airway disease that affects all ages, but does this definition also include the elderly? Traditionally, asthma has been considered a disease of younger age, but epidemiological studies and clinical experience support the concept that asthma is as prevalent in older age as it is in the young. With the ever-increasing elderly population worldwide, the detection and proper management of the disease in old age may have a great impact from the public health perspective. Whether asthma in the elderly maintains the same characteristics as in young populations is an interesting matter. The diagnostic process in older individuals with suspected asthma follows the same steps, namely a detailed history supported by clinical examination and laboratory investigations; however, it should be recognised that elderly patients may partially lose reversibility of airway obstruction. The correct interpretation of spirometric curves in the elderly should take into account the physiological changes in the respiratory system. Several factors contribute to delaying the diagnosis of asthma in the elderly, including the age-related impairment in perception of breathlessness. The management of asthma in advanced age is complicated by the comorbidities and polypharmacotherapy, which advocate for a comprehensive approach with a multidimensional assessment. It should be emphasised that older age frequently represents an exclusion criterion for eligibility in clinical trials, and current asthma medications have rarely been tested in elderly asthmatics. Ageing is associated with pharmacokinetic changes of the medications. As a consequence, absorption, distribution, metabolism and excretion of antiasthmatic medications can be variably affected. Similarly, drug-to-drug interactions may reduce the effectiveness of inhaled medications and increase the risk of side-effects. For this reason, we propose the term “geriatric asthma” be preferred to the more generic “asthma in the elderly”. Asthma in the elderly: is it time think differently? http://ow.ly/Y71zN

Asthma in the older adult: presentation, considerations and clinical management

Asthma affects older adults to the same extent as children and adolescents. However, one is led to imagine that asthma prevalence decreases with aging and becomes a rare entity in the elderly. From a clinical perspective, this misconception has nontrivial consequences in that the recognition of the disease is delayed and the treatment postponed. The overall management of asthma in the elderly population is also complicated by specific features that the disease develops in the most advanced ages, and by the difficulties that the physician encounters when approaching the older asthmatic subjects. The current review article aims at describing the specific clinical presentations of asthma in the elderly and highlights the gaps and pitfalls in the diagnostic and therapeutic approaches. Relevant issues with regard to the clinical management of asthma in the elderly are also discussed.

Exhaled nitric oxide is associated with cyclic changes in sexual hormones

BACKGROUND We hypothesized that changes in the levels of sexual hormones during the menstrual cycle influence the concentration of nitric oxide in the exhaled air (FeNO) and alveolar exhaled nitric oxide (CANO). METHODS Twelve healthy, non allergic women in their reproductive age (age range 25-37 years) were recruited. Subjects were studied, on alternate days, over the course of their menstrual cycle. At each visit, measurements of FeNO and CANO were performed. Progesterone and 17-β-estradiol concentrations were measured in salivary samples. RESULTS Eight subjects completed the study. The levels of FeNO and CANO were 13 ± 4.7 pbb and 3.5 ± 1.9 pbb, respectively (mean ± SD). The mean salivary concentration of progesterone was 65.1 ± 16.2 pg/ml (mean ± SD), with a range of 32.4-107.7 pg/ml, and the concentration of 17 β-estradiol was 6.0 ± 1.6 pg/ml, with a range of 3.1-12.9 pg/ml. The Generalized Estimating Equations procedure demonstrated that levels of progesterone influenced both FeNO and CANO (Wald χ2 = 11.60, p = 0.001; and Wald χ2 = 87.55, p = 0.001, respectively). On the contrary, the salivary levels of 17 β-estradiol were not significantly associated with FeNO (Wald χ2 = 0.087, p = 0.768) or CANO (Wald χ2 = 0.58, p = 0.448). CONCLUSION In healthy women, the menstrual cycle-associated hormonal fluctuations selectively influence the levels of bronchial and alveolar NO. The current findings may have important clinical implications for the interpretation of eNO levels, by identifying a patient-related factor that influences the eNO measurements.

Airway Distensibility by HRCT in Asthmatics and COPD with Comparable Airway Obstruction

Abstract Introduction: Decreased airway distensibility (AD) in response to deep inspirations, as assessed by HRCT, has been associated with the severity of asthma and COPD. Aims: The current study was designed to compare the magnitude of AD by HRCT in individuals with asthma and COPD with comparable degrees of bronchial obstruction, and to explore factors that may influence it. Results: We enrolled a total of 12 asthmatics (M/F:7/5) and 8 COPD (7/1) with comparable degree of bronchial obstruction (FEV1% predicted mean±SEM: 69.1 ± 5.2% and 61.2 ± 5.0%, respectively; p = 0.31). Each subject underwent chest HRCT at FRC and at TLC. A total of 701 airways (range 20 to 38 airway per subject; 2.0 to 23.1 mm in diameter) were analyzed. AD did not differ between asthmatics and COPD (mean ± SEM: 14 ± 3.5% and 17 ± 4.3%, respectively; p = 0.58). In asthmatics, AD was significantly associated with FEV1% predicted (r2 = 0.45, p = 0.018). We found a significant correlation between the change in lung volume and the change in AD by HRCT (r2 = 0.64, p = 0.002). In COPD, we found significant correlations between AD and the RV% predicted (r2 = 0.51, p = 0.046) and the RV/TLC (r2 = 0.68, p = 0.01). Conclusions: AD was primarily affected by the dynamic ability to change lung volumes in asthmatics, and by static lung volumes in COPD.

Asthmatics with high levels of serum surfactant protein D have more severe disease

Pulmonary surfactant is a mixture of lipids and surfactant-specific proteins that covers the alveolar surface, as well as the terminal conducting airways, lowering the surface tension at the air–liquid interface during breathing. The involvement of pulmonary surfactant in the pathophysiology of asthma has been suggested [1–4]. An interesting working hypothesis is that the surface tension of the peripheral airways is altered in asthma, because the inflammatory process affects the structure and function of surfactant, leading to excessive airway narrowing and features of air trapping. We explored whether serum levels of surfactant protein D (SP-D) in asthmatics are related to the severity of the disease. In addition, we aimed to assess whether serum SP-D correlated with functional abnormalities of peripheral airways. Serum surfactant protein D could serve as a biomarker of small airways damage and severity of asthma http://ow.ly/YdeG9