Age is associated with asthma phenotypes.

BACKGROUND AND OBJECTIVE: The relationship between age and asthma phenotypes is important as population is ageing, asthma is becoming common in older ages and recently developed treatments for asthma are guided by phenotypes. The aim of this study is to evaluate whether age is associated with specific asthma phenotypes. METHODS: This is a cross-sectional study. We included subjects with asthma of varied degrees of severity. Subjects underwent spirometry, skin prick test to aeroallergens, answered the Asthma Control Questionnaire and had blood samples collected. We performed binary logistic regression analysis to evaluate whether age is associated with asthma phenotypes. RESULTS: We enrolled 868 subjects. In comparison with subjects ≤ 40 years, older subjects had high odds of irreversible airway obstruction (from 41 to 64 years, OR: 1.83 (95% CI: 1.32-2.54); ≥65 years, OR: 3.45 (2.12-5.60)) and severe asthma phenotypes (from 41 to 64 years, OR: 3.23 (2.26-4.62); ≥65 years, OR: 4.55 (2.39-8.67)). Older subjects had low odds of atopic (from 41 to 64 years, OR: 0.56 (0.39-0.79); ≥65 years, OR: 0.47 (0.27-0.84)) and eosinophilic phenotypes (from 41 to 64 years, OR: 0.63 (0.46-0.84); ≥65 years, OR: 0.39 (0.24-0.64)). CONCLUSION: Older subjects with asthma have low odds of atopic and eosinophilic phenotypes, whereas they present high odds of irreversible airway obstruction and severe asthma.

Relationship between symptoms and results on spirometry in adults seen in non-tertiary public health facilities presenting with preserved ratio impaired spirometry.

Preserved ratio impaired spirometry (PRISm), defined by reduced forced expiratory volume in 1 second (FEV1) without meeting criteria for airway obstruction, is often encountered in clinical practice. The management of this heterogeneous condition in individuals with chronic respiratory symptoms is challenging, especially under limited diagnostic resources. Since 2020, all consecutive patients referred for spirometry at our institution have been invited to participate in our registry. Other than spirometry, no other physiological lung function testing is available in this public health service. Therefore, we reviewed our databank with the aim of assessing: i) the proportion of symptomatic patients aged 18 years or older referred for spirometry presenting with PRISm; ii) the rate of inhaled medication used in this group, suggesting a referral diagnosis of obstructive airway disease (OAD); and iii) the relationship between symptoms and results on spirometry in PRISM compared to a group with obstruction matched by FEV1. To this end, the COPD Assessment Test (CAT) and the Asthma Control Test (ACT) were conjointly responded to by 1032 participants, irrespective of the clinical suspicion. We found that 22% had PRISM, of whom 200 were paired with obstruction by FEV1 (68±10% of predicted). The CAT and ACT results were well-correlated in both groups (r=-0.727 and -0,698, respectively; p<0.001) and used to measure symptoms. Participants in the final sample (n=400) were aged 62±13 years; 70% were ever smokers; and 55% reported household exposure to biomass smoke (at least 5 years). The CAT responses were in the range of moderate symptoms (17±9) and ACT borderline for uncontrolled symptoms (19±5). The main differences were higher body mass index (33±7 versus 29±7 kg/m2; p<0.001) and proportion of females (72 versus 49%; p<0.001) in PRISm compared to obstruction. This group had lower exposure to tobacco (65 versus 76% of ever-smokers) but greater exposure to biomass smoke (61 versus 49%) (p<0.05 for all). The rate of inhaled medication use was as high in PRISm as in obstruction (80%). Notwithstanding matched FEV1, we found less prominent signs of airway disease in PRISM: marginally reduced FEV1/forced vital capacity (FVC) ratio (94±8% of predicted); higher expiratory flow between 25% and 75% of vital capacity, despite presumed lower lung volumes (lower FVC); and lower rate of bronchial hyperresponsiveness. In an identical multivariate model, FEV1 predicted symptoms of obstruction only. In conclusion, these data raise suspicion of a substantial rate of misclassification of individuals with PRISM as having OAD in healthcare facilities with constraints on diagnostic resources.

Comparing hospital admissions, comorbidities, and biomarkers between severe asthma and Gold III-IV chronic obstructive pulmonary disease.

INTRODUCTION: In spite of difficulties in differentiating asthma from chronic obstructive pulmonary disease (COPD), physicians should strive for accurate diagnosis because outcomes may be different. OBJECTIVES: Our aims were to compare the frequency of hospital admissions (HA) between severe asthmatic (SA) and Gold III-IV COPD subjects receiving disease-specific guideline recommended therapy and to depict the frequency of prevalent chronic disorders and the laboratorial profile suggesting allergic and eosinophilic phenotypes. METHODS: This cross-sectional study comprises one group of SA subjects and another group of Gold III-IV COPD subjects. Subjects answered standard questionnaires, underwent spirometry, and provided a peripheral blood sample. We validated the HA that have occurred during the preceding year by review of the report emitted by the hospital. We detected comorbidities by review of current pharmacological therapies. RESULTS: We enrolled 160 SA and 41 Gold III-IV COPD subjects. As compared with Gold III-IV COPD subjects, SA subjects had lower odds of HA (odds ratio [OR] 0.19, 95% confidence interval [CI] 0.05-0.74) and higher odds of obesity (OR 9.17, 95%CI 2.68-31.37), hypertension (OR 2.54, 95%CI 1.16-5.57), and diabetes mellitus (OR 5.71, 95%CI 1.56-20.85). The frequency of atopic and eosinophilic phenotypes was similar between study groups. CONCLUSIONS: Our results demonstrated that Gold III-IV COPD subjects had worse outcomes as compared with SA subjects. We also observed that the frequency of atopy and high peripheral blood eosinophil count were similar between study groups. Finally, we exposed aspects of comorbidities related to asthma and COPD that indicate the need of close monitoring the cardiovascular risk in SA subjects above 40 years of age.

Asthma similarities across ProAR (Brazil) and U-BIOPRED (Europe) adult cohorts of contrasting locations, ethnicity and socioeconomic status.

BACKGROUND: Asthma prevalence is 339 million globally. 'Severe asthma' (SA) comprises subjects with uncontrolled asthma despite proper management. OBJECTIVES: To compare asthma from diverse ethnicities and environments. METHODS: A cross-sectional analysis of two adult cohorts, a Brazilian (ProAR) and a European (U-BIOPRED). U-BIOPRED comprised of 311 non-smoking with Severe Asthma (SAn), 110 smokers or ex-smokers with SA (SAs) and 88 mild to moderate asthmatics (MMA) while ProAR included 544 SA and 452 MMA. Although these projects were independent, there were similarities in objectives and methodology, with ProAR adopting operating procedures of U-BIOPRED. RESULTS: Among SA subjects, age, weight, proportion of former smokers and FEV1 pre-bronchodilator were similar. The proportion of SA with a positive skin prick tests (SPT) to aeroallergens, the scores of sino-nasal symptoms and quality of life were comparable. In addition, blood eosinophil counts (EOS) and the % of subjects with EOS > 300 cells/µl were not different. The Europeans with SA however, were more severe with a greater proportion of continuous oral corticosteroids (OCS), worse symptoms and more frequent exacerbations. FEV1/FVC pre- and post-bronchodilator were lower among the Europeans. The MMA cohorts were less comparable in control and treatment, but similar in the proportion of allergic rhinitis, gastroesophageal reflux disease and EOS >3%. CONCLUSIONS: ProAR and U-BIOPRED cohorts, with varying severity, ethnicity and environment have similarities, which provide the basis for global external validation of asthma phenotypes. This should stimulate collaboration between asthma consortia with the aim of understanding SA, which will lead to better management.

Gene encoding Duffy antigen/receptor for chemokines is associated with asthma and IgE in three populations.

RATIONALE: Asthma prevalence and severity are high among underserved minorities, including those of African descent. The Duffy antigen/receptor for chemokines is the receptor for Plasmodium vivax on erythrocytes and functions as a chemokine-clearing receptor. Unlike European populations, decreased expression of the receptor on erythrocytes is common among populations of African descent, and results from a functional T-46C polymorphism (rs2814778) in the promoter. This variant provides an evolutionary advantage in malaria-endemic regions, because Duffy antigen/receptor for chemokines-negative erythrocytes are more resistant to infection by P. vivax. OBJECTIVES: To determine the role of the rs2814778 polymorphism in asthma and atopy as measured by total serum IgE levels among four populations of African descent (African Caribbean, African American, Brazilian, and Colombian) and a European American population. METHODS: Family-based association tests were performed in each of the five populations to test for association between the rs2814778 polymorphism and asthma or total IgE concentration. MEASUREMENTS AND MAIN RESULTS: Asthma was significantly associated with the rs2814778 polymorphism in the African Caribbean, Colombian, and Brazilian families (P < 0.05). High total IgE levels were associated with this variant in African Caribbean and Colombian families (P < 0.05). The variant allele was not polymorphic among European Americans. CONCLUSIONS: Susceptibility to asthma and atopy among certain populations of African descent is influenced by a functional polymorphism in the gene encoding Duffy antigen/receptor for chemokines. This genetic variant, which confers resistance to malarial parasitic infection, may also partially explain ethnic differences in morbidity of asthma.

[Controversies in the association between type 1 diabetes and asthma]. / Controvérsias na associação entre diabetes mellitus tipo 1 e asma.

OBJECTIVE: Critical review of the literature to investigate the relationship between asthma and type 1 diabetes mellitus (DM1). SOURCE OF DATA: Bibliography search in MEDLINE and LILACS databases in the last twenty years. SUMMARY OF DATA: Several studies demonstrate an inverse relationship between asthma, atopic diseases and the risk to develop DM1. According to the "Hygiene Hypothesis", the risk of allergic diseases decreases with infections early in childhood, towards distance of Th2 profile, common at birth, to the Th1 phenotype. Other articles described lack of association or positive association between DM1 and allergies. There is a possibility of environmental factors interfering in the development of disorders mediated by Th1 and Th2 cells, in the same individual, due to the absence of immunomodulatory mechanisms mediated by interleukin-10 and regulatory cells. CONCLUSION: The existing information about the inverse association between Th1-mediated diseases (e.g., DM1), and those that are Th2-mediated (e.g., allergies) are conflicting requiring more investigation to explain this question.

Asthma prevalence and severity in low-resource communities.

PURPOSE OF REVIEW: The prevalence of asthma was thought to be low in most low-income countries, but several reports have indicated this is not always true. This is a narrative review of recent publications on the burden of asthma in low and middle-income countries (LMIC) and underprivileged communities from developed countries. RECENT FINDINGS: Several studies have reported a low prevalence of asthma is LMIC, but indicate it is increasing. In the last few years, however, many surveys demonstrated this may not always be true. An analysis of the International Study for Asthma and Allergy in Childhood phase III database indicated although the prevalence of asthma among children and adolescents is higher in the developed countries, symptoms of asthma are often more severe in less affluent nations. The rate of uncontrolled asthma is also higher among underprivileged communities of developed countries. Secondary analysis of data generated by the WHO's world health survey performed among adults of 70 countries indicate symptoms of asthma are less frequent in middle-income countries and more frequent in the extremes, low income and high income. This sort of U shaped distribution suggests the disease (or syndrome) comprise more than one major phenotype related to diverse underlying mechanisms. In fact, recent reports show symptoms of asthma among the poor are associated with unhygienic living conditions, which may reduce the risk of atopy but increase the risk of nonatopic wheezing. Urbanization and exposure to air pollution also seem to contribute to an increasing prevalence severity of asthma in LMIC. Access to proper diagnosis and treatment with controller medications for asthma, specially with inhaled corticosteroids is feasible and cost-effective, reduce symptoms, health resource utilization, improves quality of life, and reduce mortality in low-resource settings. SUMMARY: Prevalence of asthma was thought to be low in low-income countries, but several reports have indicated this is not always true. Under diagnosis, under treatment, exposure to air pollution, and unhygienic living conditions may contribute to a higher frequency and severity of symptoms of asthma among the poor. Proper diagnosis and treatment with controller medications for asthma is feasible and cost-effective in low-resource settings.

The impact of a program for control of asthma in a low-income setting.

The prevalence of asthma is increasing in developing countries and the burden of uncontrolled asthma affects patients, families, and the health system. This is to summarize, evaluate, and discuss previous reports on the impact of a targeted and comprehensive approach to the most severe cases of asthma in a low-income setting. A Program for Control of Asthma (ProAR) was developed in Salvador, Bahia, Brazil, prioritizing the control of severe asthma. By facilitating referrals from the public health system and providing proper multidisciplinary but simple management including education and medication, for free, the Program enrolled 2385 patients in 4 reference clinics. They are offered regular follow up and discharged back to primary health care only when asthma control can be maintained without requirement of a combination of an inhaled corticosteroid and a long-acting ß2 agonist. ProAR has markedly reduced health resource utilization and decreased the rate of hospital admissions because of asthma in the entire City (2.8 million inhabitants) by 74%. Moderate to severe rhinitis was associated with lack of control of asthma. The average income of the families in the ProAR was US$2955 a year, and they spent 29% of all their income attempting to control the severe asthma of one member, a unbearable expenditure for a low-income family. The ProAR was shown to be cost-effective, reducing costs to the public health system (US$387 patient/year) and the families (US$789 patient/year). In a low-income setting of Brazil, an intervention prioritizing the control of severe asthma was feasible, effective, and reduced costs.

Polymorphisms in the sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) gene are associated with susceptibility to asthma.

Sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) promotes the apoptosis of eosinophils and inhibits FcvarepsilonRI-dependent mediator release from mast cells. We investigated the genetic association between sequence variants in Siglec-8 and diagnosis of asthma, total levels of serum IgE (tIgE), and diagnosis of eosinophilic esophagitis (EE) in diverse populations. The effect of sequence variants on Siglec-8 glycan ligand-binding activity was also examined. Significant association with asthma was observed for SNP rs36498 (odds ratios (OR), 0.69, P=8.8 x 10(-5)) among African Americans and for SNP rs10409962 (Ser/Pro) in the Japanese population (OR, 0.69, P=0.019). Supporting this finding, we observed association between SNP rs36498 and current asthma among Brazilian families (P=0.013). Significant association with tIgE was observed for SNP rs6509541 among African Americans (P=0.016), and replicated among the Brazilian families (P=0.02). In contrast, no association was observed with EE in Caucasians. By using a synthetic polymer decorated with 6'-sulfo-sLe(x), a known Siglec-8 glycan ligand, we did not find any differences between the ligand-binding activity of HEK293 cells stably transfected with the rs10409962 risk allele or the WT allele. However, our association results suggest that the Siglec8 gene may be a susceptibility locus for asthma.

Controvérsias na associação entre diabetes mellitus tipo 1 e asma / Controversies in the association between type 1 diabetes and asthma

OBJETIVO: Revisão crítica da literatura sobre a associação entre asma e diabetes mellitus tipo 1 (DM1). FONTE DOS DADOS: Pesquisa bibliográfica na base de dados MEDLINE e LILACS nos últimos vinte anos. SíNTESE DOS DADOS: Muitos estudos mostram associação inversa entre asma, atopia e o risco de desenvolver DM1. De acordo com a "Hipótese da Higiene", o risco de doenças alérgicas diminui com infecções precoces na infância no sentido de afastar-se do perfil Th2, predominante ao nascimento, em direção ao fenótipo Th1. No entanto, outros trabalhos demonstram associação positiva ou ausência de associação entre DM1 e alergias. Existe a possibilidade de fatores ambientais contribuírem para ocorrência de doenças mediadas por células Th1 e Th2 no mesmo indivíduo, por provável deficiência de mecanismos imunomodulatórios mediados pela interleucina-10 e células regulatórias. CONCLUSÃO: As informações sobre a associação inversa entre doenças mediadas por resposta Th1 (por exemplo, DM1), e aquelas mediadas por resposta Th2 (por exemplo, alergias) são conflitantes, requerendo mais estudos para esclarecer esta questão.

OBJECTIVE: Critical review of the literature to investigate the relationship between asthma and type 1 diabetes mellitus (DM1). SOURCE OF DATA: Bibliography search in MEDLINE and LILACS databases in the last twenty years. SUMMARY OF DATA: Several studies demonstrate an inverse relationship between asthma, atopic diseases and the risk to develop DM1. According to the "Hygiene Hypothesis", the risk of allergic diseases decreases with infections early in childhood, towards distance of Th2 profile, common at birth, to the Th1 phenotype. Other articles described lack of association or positive association between DM1 and allergies. There is a possibility of environmental factors interfering in the development of disorders mediated by Th1 and Th2 cells, in the same individual, due to the absence of immunomodulatory mechanisms mediated by interleukin-10 and regulatory cells. CONCLUSION: The existing information about the inverse association between Th1-mediated diseases (e.g., DM1), and those that are Th2-mediated (e.g., allergies) are conflicting requiring more investigation to explain this question.

Asma grave e progressão rápida para morte: relato de caso e revisão da literatura / Severe asthma and rapid evolution to death: caso report and literature review

Objetivo: Relatar um caso de asma grave súbita fatal e revisar os fatores de risco e prognóstico associados à morte por asma. Métodos: Relato de caso e revisão narrativa sobre asma grave e fatal. Foram selecionados artigos publicados em português e inglês, a partir dos bancos de dados MEDLINE, Scielo e Lilacs, nos últimos 20 anos. Fontes complementares de pesquisa foram os sítios do Ministério da Saúde do Brasil (DATASUS) e Organização Mundial de Saúde. Resultados: Os autores relataram a progressão súbita e rápida para morte de uma paciente asmática aparentemente bem controlada com tratamento adequado e que apresentara melhora da função pulmonar. A asma é doença inflamatória crônica que causa substancial morbidade e mortalidade. A inflamação das vias aéreas e parênquima pulmonar contribui para as alterações mecânicas e funcionais da asma. A perda da função pulmonar ocorre precocemente e, agrava-se com a idade e progressão da doença. Apesar do tratamento antiasmático adequado um grupo de asmáticos cursa sem controle dos sintomas e apresenta exacerbações graves e freqüentes. Má percepção da gravidade da obstrução brônquica pode ser a causa mais relevante de exacerbações quase fatais e fatais nesses pacientes. Um ano depois de um episódio de asma quase fatal 10 dos asmáticos evoluem desfavoravelmente para morte. A identificação dos fatores prognósticos desta doença pode contribuir para prevenção de alguns eventos fatais, porém a caracterização fenotípica isoladamente ainda constitui método impreciso para o entendimento da síndrome da asma. Marcadores prognósticos individuais para asma com risco de asfixia devem ser procurados para melhorar o manejo da asma grave. Conclusões: Parâmetros e mercadores prognósticos devem ser identificados para melhorar o manejo da asma grave.

Inflamação nas pequenas vias aéreas em asmáticos / Small airway inflamation in asthmatics

Objetivo: Rever de forma sistemática as evidências de envolvimento das pequenas vias aéreas na fisiopatologia da asma, a importância deste novo conhecimento na avaliação do paciente e as implicações terapêuticas. Método: Foi realizada uma revisão sistemática da literatura publicada na Medline e Lilacs a partir do ano de 1972. Foram selecionados artigos originais que abordassem o tema inflamação das pequenas vias aéreas na asma nos seguintes aspectos: anatomia patológica, imunopatologia, estudo de imagem, função pulmonar e tratamento da inflamação de pequenas vias aéreas. Resultado: Foram selecionados 36 artigos originais abordando o tema. Pudemos observar que o envolvimento inflamatório das unidades pulmonares distais, bronquíolos e alvéolos, na asma, vêm sendo demonstrado mais recentemente com técnicas variadas. Entre elas temos a medida direta da resistência de vias aéreas periféricas, o estudo anátomo-patológico das vias aéreas de menos de 2 milímetros de perímetro interno, a demonstração da expressão aumentada de citocinas e quimiocinas nesta região do pulmão, o uso da tomografia computadorizada de alta resolução com cortes finos e de técnicas de medida de função pulmonar com inalação de gás de baixa densidade. Este novo conhecimento é importante na medida que explica a dissociação da intensidade de sintomas assim como dos distúrbio das trocas gasosas de asmáticos, das alterações funcionais ventilatórias medidas pelo VEF1, que avalia as vias aéreas de maior calibre. Existem também implicações terapêuticas, como o crescente interesse pelo propelente de spray dosimetrado hidro-fluoroalcano, que gera partículas de menor diâmetro que se depositam nas vias aéreas mais distais. Ademais a inflamação das pequenas vias aéreas pode resultar em remodelamento e obstrução irreversível. Conclusão: O processo inflamatório da asma envolve as vias aéreas de maior calibre, bronquíolos e alvéolos. A inflamação de pequenas vias aéreas pode trazer conseqüências clínicas importantes como o remodelamento e obstrução irreversível, sendo necessá-rio a de buscar estratégias para tratamento da inflamação nesta região do pulmão.