Bronchodilator test in extreme old age: Adverse effects of short-acting beta-2 adrenergic agonists with clinical repercussion and bronchodilator response

SUMMARY OBJECTIVE: To evaluate chronological age as a limiting factor to perform the bronchodilator test, determine significant adverse effects of short-acting beta 2 agonists with clinical repercussions, and assess bronchodilator response in extreme-old-age patients who undergo the spirometry test. METHODS: This is a cross-sectional and retrospective study. The sample was extracted from the database (spirometer and respiratory questionnaire) of a pulmonary function service. Patients over 90 years old were included in the research, and we evaluated their bronchodilator response and its significant adverse effects that may have clinical repercussions related to the bronchodilator. RESULTS: A sample of 25 patients aged 92.12 ± 2.22 years (95% CI, 91.20 - 93.04), with a minimum age of 90 years and a maximum of 97 years and a predominance of females with 72% (18/25). The bronchodilator test was performed in 84% (21/25) of the patients. The bronchodilator response was evaluated in 19 of the 21 patients (90.47%) who underwent the bronchodilator test. Two tests did not meet the criteria of acceptability and reproducibility. No clinical adverse effects were observed with the bronchodilator medication (salbutamol) during or after the exam. CONCLUSIONS: Chronological age is not a limiting factor for the bronchodilator test, short-acting beta-2 agonists did not present adverse effects with significant clinical repercussion and were useful in the diagnosis and therapeutic guidance of extreme-old-age patients.

RESUMO OBJETIVOS: Avaliar se idade cronológica é um fator limitante para realizar prova broncodilatadora, determinar efeitos adversos significativos com repercussão clínica dos beta-2 agonistas de curta ação e avaliar a resposta broncodilatadora na espirometria, na velhice extrema. MÉTODOS: Estudo transversal, retrospectivo. Amostra extraída do banco de dados (espirômetro e questionário respiratório) de um serviço de função pulmonar. Incluídos na pesquisa pacientes com ≥90 anos, sendo avaliados a resposta broncodilatadora e efeitos adversos significativos com repercussão clínica ao broncodilatador. RESULTADOS: Amostra de 25 pacientes com idade de 92,12 ± 2,22 anos (IC 95%; 91,20 - 93,04), idade mínima de 90 anos e máxima de 97 anos, predominando o sexo feminino, com 72% (18/25). A prova broncodilatadora foi realizada em 84% (21/25) dos pacientes. A avaliação da resposta ao broncodilatador foi feita em 19 dos 21 pacientes (90,47%) que realizaram a prova broncodilatadora, uma vez que dois desses exames não preencheram os critérios de aceitabilidade e reprodutibilidade. A resposta broncodilatadora foi significativa em 10,52% (2/19) dos pacientes, ambos portadores de pneumopatia obstrutiva. Não foram observados efeitos adversos com repercussão clínica da medicação broncodilatadora (salbutamol) durante ou após sua realização. CONCLUSÕES: A idade cronológica não é um fator limitante para a realização da prova broncodilatadora, os beta-2 agonistas de curta ação não apresentaram efeitos adversos com repercussão clínica significativa e foram bastante úteis para auxiliar no diagnóstico e orientação terapêutica na velhice extrema.

Safety of and cellular response to segmental bronchoprovocation in allergic asthma.

RATIONALE: Despite its incorporation into research studies, the safety aspects of segmental allergen bronchoprovocation and differences in cellular response among different allergens have received limited consideration. METHODS: We performed 87 segmental challenges in 77 allergic asthma subjects. Allergen dose was based on each subject's response to whole lung allergen challenge. Bronchoalveolar lavage was performed at 0 and 48 hours. Safety indicators included spirometry, oxygen saturation, heart rate, and symptoms. RESULTS: Among subjects challenged with ragweed, cat dander, or house dust mite, there were no differences in safety indicators. Subjects demonstrated a modest oxygen desaturation and tachycardia during the procedure that returned to normal prior to discharge. We observed a modest reduction in forced vital capacity and forced expiratory volume in one second following bronchoscopy. The most common symptoms following the procedure were cough, sore throat and fatigue. Total bronchoalveolar lavage fluid cell numbers increased from 13±4 to 106±108×10(4) per milliliter and eosinophils increased from 1±2 to 44±20 percent, with no significant differences among the three allergens. CONCLUSIONS: In mild allergic asthma, segmental allergen bronchoprovocation, using individualized doses of aeroallergens, was safe and yielded similar cellular responses.

Provoked models of asthma: what have we learnt?

Asthma is a chronic inflammatory disease of the airways characterized by physiological abnormalities of variable airflow obstruction and airway hyperresponsiveness (AHR) to a wide variety of physical and inhaled chemical stimuli and the presence of symptoms. AHR is measured by challenging the airways with a variety of agonists and naturally occurring stimuli, which results in constriction of the airway smooth muscle, leading to airway narrowing and airflow limitation. There are two distinct mechanisms by which the airways can narrow to a constrictor stimulus and these are defined by the pathways they take to induce AHR. Direct stimuli are pharmacological agents administered exogenously (such as histamine or methacholine) that act 'directly' on specific receptors on the bronchial smooth muscle to cause constriction. The other mechanism by which the airway can narrow is via the inhalation of indirect stimuli, which include natural stimuli, such as allergen or exercise, and pharmacological agents such as adenosine monophosphate and hyper-osmotic agents (e.g. hypertonic saline or dry powder mannitol). These stimuli induce airway narrowing 'indirectly' by causing the endogenous release of mediators of bronchoconstriction from airway inflammatory cells. Provoked models of asthma have been extremely valuable in understanding the pathobiology of asthma, in aiding diagnosis, in helping to clarify the mechanisms of actions of effective drugs and in the development of new entities to treat asthma. Some provoked models are valuable clinically, particularly those that measure direct AHR, while others, particularly allergen challenge, have been used in animal models and in humans to study the mechanisms of allergen-induced airway inflammation and the associated physiological changes, as well in the development of new drugs for asthma. An emerging role for measurements of AHR is in the evaluation of the optimal treatment for patients with asthma.

Safety of segmental allergen challenge in human allergic asthma.

BACKGROUND: Segmental allergen challenge is widely used to study mechanisms of human allergic asthma. Despite the relatively large dissemination, limited information is available about the safety of this method. OBJECTIVE: Observational, retrospective study to report the adverse events of segmental allergen challenge in a large group of volunteers with asthma. METHODS: In total, 78 cases from several studies performed between 1994 and 2007 were pooled for this analysis. Volunteers underwent allergen challenge using either a fixed dose of allergen (7 cases) or an individually standardized allergen dose defined by an inhaled allergen test before the challenge (71 cases). A subgroup of 13 volunteers underwent repeated challenges, with more than 6 months between the challenges. RESULTS: With a fixed dose instilled during bronchoscopy, 43% of the participants developed wheezing and coughing, requiring 2-6 puffs of a ss(2)-agonist after segmental allergen challenge. In volunteers with individually standardized doses, a ss(2)-agonist was required in only 19% of the cases. No severe adverse events occurred in all cases studied. Volunteers who underwent repeated challenges did not develop more adverse events than those who underwent 1 challenge. CONCLUSIONS: Segmental allergen challenge is a safe tool to study the mechanisms of human allergic asthma, even when repeated challenges are performed in the same patient. It is associated with only a few, tolerable adverse events, especially when the dose of allergen is standardized individually.

Escarro induzido em crianças e adolescentes com asma: segurança, aplicabilidade clínica e perfil de células inflamatórias em pacientes estáveis e durante exacerbação / Induced sputum in children and adolescents with asthma: safety, clinical applicability and inflammatory cells aspects in stable patients and during exacerbation

OBJETIVOS: Verificar a segurança da indução de escarro em crianças e adolescentes asmáticos. Caracterizar a citologia do escarro durante a estabilidade clínica e exacerbação. Correlacionar a citologia do escarro com os eosinófilos no sangue periférico, IgE sérica e grau de obstrução brônquica. MÉTODOS: Foram recrutados 96 pacientes asmáticos, de 6 a 18 anos, para um estudo transversal. Foi realizada espirometria antes e, após, broncodilatador. A seguir, foi coletado o escarro, espontaneamente ou após indução com inalação de solução salina em concentrações crescentes. Foi coletada amostra de sangue para quantificar a IgE sérica e os eosinófilos. RESULTADOS: Obtiveram-se amostras adequadas de escarro para análise em 68 (70,8 por cento) dos pacientes recrutados. Não houve broncoconstrição relevante durante a indução. A presença de maior número de eosinófilos no escarro de acordo com a maior gravidade clínica da asma não foi estatisticamente significante. Não houve correlação entre o grau de obstrução brônquica medido pelo VEF1 e as células inflamatórias do escarro. O mesmo foi observado em relação aos eosinófilos no sangue periférico e à IgE sérica. No grupo com exacerbação da asma, observou-se uma quantidade maior de neutrófilos (p < 0,05). CONCLUSÕES: A indução de escarro mostrou-se segura para obtenção de amostras clínicas em crianças e adolescentes, mesmo durante exacerbações, respeitando-se limitações clínicas e funcionais. O índice de sucesso da indução de 67 por cento foi considerado satisfatório. A quantificação dos eosinófilos não discriminou a gravidade clínica e funcional da asma e mostrou-se independente do grau de obstrução das vias aéreas neste grupo de pacientes em tratamento com corticosteróides inalatórios. No escarro de pacientes em exacerbação da asma, houve um predomínio proporcional de neutrófilos.

Indirect airway challenges.

Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract. This is in contrast to the direct challenges where agonists such as methacholine or histamine cause airflow limitation predominantly via a direct effect on airway smooth muscle. Direct airway challenges have been used widely and are well standardised. They are highly sensitive, but not specific to asthma and can be used to exclude current asthma in a clinic population. Indirect bronchial stimuli, in particular exercise, hyperventilation, hypertonic aerosols, as well as adenosine, may reflect more directly the ongoing airway inflammation and are therefore more specific to identify active asthma. They are increasingly used to evaluate the prevalence of bronchial hyperresponsiveness and to assess specific problems in patients with known asthma, e.g. exercise-induced bronchoconstriction, evaluation before scuba diving. Direct bronchial responsiveness is only slowly and to a modest extent, influenced by repeated administration of inhaled steroids. Indirect challenges may reflect more closely acute changes in airway inflammation and a change in responsiveness to an indirect stimulus may be a clinically relevant marker to assess the clinical course of asthma. Moreover, some of the indirect challenges, e.g. hypertonic saline and mannitol, can be combined with the assessment of inflammatory cells by induction of sputum.

Alterations in exhaled gas profile during allergen-induced asthmatic response.

The source of exhaled carbon monoxide (CO) and the relationship to airway inflammation are not clear. If CO is produced by the inflamed airway, we hypothesized that inflammation induced by allergen challenge would increase exhaled CO of atopic asthmatics. Eight atopic asthmatics underwent whole lung allergen challenge. CO, nitric oxide (NO), oxygen, and carbon dioxide (CO(2)) were measured simultaneously in exhaled breath which was collected into Mylar balloons before (baseline), immediately after, and at subsequent times after allergen. NO was higher in asthmatics than control subjects at baseline, increased further in seven of the eight asthmatics after allergen, and was inversely correlated to specific conductance. In contrast, exhaled CO of asthmatics was not higher than that of control individuals at baseline, decreased immediately after allergen, and returned to baseline levels during the late asthmatic response. Thus, allergen-induced airway inflammation did not lead to increased exhaled CO in asthma.

Chronic cough: eosinophilic bronchitis without asthma.

Sputum cell-counts were studied in 7 non-smokers with corticosteroid-responsive chronic cough productive of sputum and 8 smokers with a clinical diagnosis of chronic bronchitis, all of whom had normal lung function tests and methacholine airway responsiveness, and in 10 non-smokers with asthma, examined during an exacerbation. Sputum from asthmatic patients and subjects with corticosteroid-responsive cough contained eosinophils and metachromatic cells. Macrophages were by far the dominant cell type in sputum from subjects with chronic bronchitis. Airway inflammation with eosinophils and metachromatic cells is not always accompanied by increased airway responsiveness, and current definitions of obstructive airways disease may need to be revised.

Inflammatory response in bronchoalveolar lavage fluid after inhaling histamine.

To examine the influence of the histamine chloride challenge test on the bronchoalveolar lavage cell population, lavage fluid from 15 subjects was collected 24 h after the histamine test, and was compared with the lavage fluid from a reference group of 25 subjects. Inhaled histamine is commonly used to quantitate non-specific bronchial responsiveness. Increase in airway responsiveness after exposure to ozone or allergen is associated with airway inflammation. Bronchoalveolar lavage, has therefore become a valuable tool in the study of bronchoalveolar cells and mediators in subjects with asthma and bronchial hyperresponsiveness. The total cell number and differential cell counts in bronchoalveolar lavage fluid 24 h after inhalation challenge test with histamine-chloride were studied. There was a significant increase in lymphocytes, mast cells and neutrophils after histamine test. The conclusion was that inhaled histamine-chloride can induce an inflammatory cell response in the lung. Thus the histamine-chloride test should not be performed before bronchoalveolar lavage.