Severe asthma in adults

Severe asthma remains poorly understood and frustrating to care for, partly because it is a heterogeneous disease. Patients with severe asthma disproportionately consume health care resources related to asthma. Severe asthma may develop over time, or shortly after onset of the disease. The genetic and environmental elements that may be most important in the development of severe disease are poorly understood, but likely include both allergic and nonallergic elements. Physiologically, these patients often have air trapping, airway collapsibility, and a high degree of methacholine hyperresponsiveness. Specific phenotypes of severe asthma are only beginning to be defined. However, describing severe asthma by age at onset (early- vs. late-onset) appears to describe two phenotypes that differ at immunologic, physiologic, epidemiologic, and pathologic levels. In particular, early-onset severe asthma is a more allergic-associated disease than late-onset severe asthma. In addition, patients with severe asthma can be defined on the basis of presence and type of inflammation. Severe asthma with persistent eosinophilia (of either early or late onset) is more symptomatic and has more near-fatal events. However, at least 50% of patients with severe asthma have very little identifiable inflammation. Thus, "steroid resistance" may occur at numerous levels, not all of which are caused by a lack of effect of steroids on inflammation. Treatment remains problematic, with corticosteroids remaining the most effective therapy. However, 5-lipoxygenase inhibitors, anti-IgE, and immunomodulatory drugs are also likely to have a place in treatment. Improving therapy in this disease will require a better understanding of the phenotypes involved.     

Asthma phenotyping: a necessity for improved therapeutic precision and new targeted therapies

Asthma is a common heterogeneous disease with a complex pathophysiology that carries a significant mortality rate and high morbidity. Current therapies based on inhaled corticosteroids and long‐acting β‐agonists remain effective in a large proportion of patients with asthma, but ~10% (considered to have ‘severe asthma’) do not respond to these treatments even at high doses or with the use of oral corticosteroids. Analytical clustering methods have revealed phenotypes that include dependence on high‐dose corticosteroid treatment, severe airflow obstruction and recurrent exacerbations associated with an allergic background and late onset of disease. One severe phenotype is eosinophilic inflammation‐predominant asthma, with late‐onset disease, rhinosinusitis, aspirin sensitivity and exacerbations. Blood and sputum eosinophilia have been used to distinguish patients with high Th2 inflammation and to predict therapeutic response to treatments targeted towards Th2‐associated cytokines. New therapies in the form of humanized antibodies against Th2 targets, such as anti‐IgE, anti‐IL4Rα, anti‐IL‐5 and anti‐IL‐13 antibodies, have shown encouraging results in terms of reduction in exacerbations and improvement in airflow in patients with a ‘Th2‐high’ expression profile and blood eosinophilia. Research efforts are now focusing on elucidating the phenotypes underlying the non‐Th2‐high (or Th2‐low) group, which constitutes ~50% of severe asthma cases. There is an increasing need to use biomarkers to indicate the group of patients who will respond to a specifically targeted treatment. The use of improved tools to measure activity of disease, a better definition of severe asthma and the delineation of inflammatory pathways with omics analyses using computational tools, will lead to better‐defined phenotypes for specific therapies.     

Exacerbations of severe asthma

Exacerbations occur frequently in severe asthma. They result in significant morbidity and can lead to hospitalization and death. Severe exacerbations can also lead to an accelerated decline in lung function. Phenotyping severe asthma can aid with both prognostication of exacerbation risk and maintenance treatment selection to minimize future risks of exacerbations in severe asthma. The rate of exacerbations differs by phenotype, and is most frequent in refractory eosinophilic asthma and early onset allergic asthma. Phenotype specific therapy can reduce exacerbations in both these forms of severe asthma. Exacerbations are multi-component events. Each exacerbation represents an opportunity to assess and target treatment to the domains of airway pharmacotherapy, self-management behaviour, risk factors, and relevant co-morbidities.     

Eosinophilic inflammation in sputum of poorly controlled asthmatics.

Despite full effective treatment, asthmatic patients often present with poorly controlled asthma. Airway eosinophilia is associated with asthma, but its relationship with asthma control is still undetermined. To investigate the relationship between airway eosinophilia and asthma control, cellular and biochemical markers of airway inflammation were measured in 19 subjects with poorly controlled asthma, 16 subjects with asthma under control and eight normal volunteers. The severity of asthma was mild-to-moderate persistent in 23 patients (14 poorly controlled) and severe prednisone-dependent in 12 subjects (five poorly controlled). Induced sputum was analysed for total and differential cell counts, leukotriene E4 (LTE4), eosinophil cationic protein (ECP), regulated on activation, normal T-cell expressed and secreted (RANTES), and interleukin (IL)-8. Sputum eosinophils, LTE4, ECP and RANTES levels (but not IL-8) were significantly higher in patients with poorly controlled asthma as compared to patients with controlled asthma. By contrast, sputum cells and sputum inflammatory markers were not different among groups of patients with different severity of asthma. These results suggest that sputum eosinophilia is associated with poorly controlled asthma rather than with the severity of asthma.     

Physiologic and pathologic abnormalities in severe asthma

Severe asthma remains poorly understood and frustrating to treat, partly because it is a heterogeneous disease. Recent improvements in the definition of severe asthma have allowed better characterization of the phenotypes of severe asthma and the related physiologic and pathologic abnormalities. Early-onset severe asthma is a more allergy-associated disease than late-onset asthma. Persistent eosinophilia is more commonly seen in patients who have late-onset disease but is associated with a more symptomatic disease in both early- and late-onset disease. Recent studies suggest that response to therapy in severe asthma may depend on the phenotype.     

Interleukin-5 Antagonists Usher in a New Generation of Asthma Therapy

Asthma is the most common chronic respiratory disease in the USA. A subset of patients with asthma have refractory symptoms, persistent eosinophilic inflammation, and recurrent exacerbations despite maximal medical therapy. The monoclonal antibodies targeting the IL-5 pathway are a new class of medications designed to target severe eosinophilic asthma. There are two medications clinically available: mepolizumab and reslizumab, both of which target IL-5. A third medication, benralizumab, is currently under development and targets the IL-5 receptor. Clinical data suggest these medications can reduce asthma exacerbations and improve lung function in patients with peripheral eosinophilia and poorly controlled asthma despite maximal medical therapy. The anti-IL-5 medications are among the first targeted molecular therapies for asthma and will usher in an exciting new era in the treatment of severe asthma.     

Quel est le profil d’un asthme sévère chez l’enfant ?

Severe asthma is estimated to occur in 9.6% of asthmatics. Even though severe asthma does not occur frequently in asthmatic children, still it accounts for 80% of health expenditures in this group of patients. International guidelines grade the severity of asthma in four stages (intermittent, mild persistent, moderate, severe) according to daytime and night time symptoms, the frequency of exacerbations that affect the patient's activities, and the forced expiratory volume in the first second (FEV₁) before starting treatment. This classification appears insufficient for an evaluation of the severity of asthma in children because it does not take into account their current treatment, namely, inhaled corticoids, as well as previous acute severe exacerbations, the condition of the lower airways, the existence of an atopic terrain, and the importance of the patient's age and sex on the severity of the asthma. Finally, it must be remembered that in the clinical workup of a child with severe asthma, it is first of all necessary to rule out “false asthma” (by systematic etiologic investigation), to distinguish between severe asthma and poorly controlled asthma related to co-existing conditions not otherwise considered, an inadequate environment, and poor adherence to prescribed therapy.     

Lymphocytes T CD8+ : implications dans l’asthme

CD8⁺ T lymphocytes include several T cell populations with various functional properties: CD8⁺αβ T cells that produce cytokines (Tc1, Tc2), cytotoxic T cells, CD8⁺ NKT cells, and CD8⁺γδ. Their role in asthma has been assessed in a limited number of studies which are reviewed here. Evidence from animal models indicates that conventional CD8⁺αβ T cells are protective or enhance the immunoallergic immune response. While Tc2 is always an amplifier in immune reactions, the role of Tc1 is still controversial. Cytotoxic T cells, producing perforin and expressing CX3CR1⁺, are found in excess in asthma, notably during exacerbations. Bronchial infiltration by CD8⁺ T cells is associated with reduced FEV₁ in both asthma and COPD; it is also correlated with asthma mortality. During exacerbations, viruses, allergens, and/or pollutants induce CD8⁺ lymphocytes that are able to increase asthmatic inflammation, probably non-specifically, via the involvement of these bystander CD8⁺ cells. The role of the nonconventional CD8⁺γδ T cells, intermediate between innate and adaptive immunity, is likewise controversial and depends on the models studied. They recognize nonpeptidic antigens and are said to be involved in occupational asthma caused by low molecular weight agents. In conclusion, all the CD8⁺ T cell populations are implicated in asthmatic inflammation. They are involved in exacerbations of asthma and its severity. As their activation is less sensitive to corticosteroids than CD4⁺ T cells, targeting CD8⁺ T cells appears to be an important therapeutic target in severe corticosteroid-dependent asthma.     

Severe asthma in children: Evaluation and management

Severe asthma in children is associated with significant morbidity. Children with severe asthma are at increased risk for adverse outcomes including medication-related side effects, life-threatening exacerbations, and impaired quality of life. It is important to differentiate between severe therapy resistant asthma and difficult-to-treat asthma due to comorbidities. The most common problems that need to be excluded before a diagnosis of severe asthma can be made are poor medication adherence, poor medication technique or incorrect diagnosis of asthma. Difficult to treat asthma is a much more common reason for persistent symptoms and exacerbations and can be managed if comorbidities are clearly addressed. Children with persistent symptoms and exacerbations despite correct inhaler technique and good medical adherence to standard Step 4 asthma therapies according to the guidelines^1,2, should be referred to an asthma specialist with expertise in severe asthma.     

Drug‐induced liver injury with skin reactions: Drugs and host risk factors,clinical phenotypes and prognosis

While dermatologic manifestations of adverse drug reactions are frequent, drug‐induced liver injury is rare. Numerous drugs are implicated in either Drug‐Induced Liver Injury or Drug‐Induced Skin Injury. However, concomitant Drug‐Induced Liver Injury and Drug‐Induced Skin Injury are uncommon, not well characterized and appear to be caused by a limited number of drugs. These are often associated with immuno‐allergic or hypersensitivity features such as fever, skin rash, blisters or peeling of skin, eosinophilia, lymphadenopathy and mucositis. Liver injury can range from asymptomatic elevation of liver biochemical tests to severe hepatitis and acute liver failure needing liver transplantation. Severe cutaneous adverse reaction, particularly drug reaction with eosinophilia and systemic symptoms is commonly associated with internal organ involvement, the liver being the most frequently involved in approximately 90% of the cases. In Stevens‐Johnson Syndrome/Toxic Epidermal Necrolysis, abnormalities in liver biochemistry tests are common but severe liver disease is rare. There is a strong association of Human Leukocyte Antigen genotype with both drug reaction with eosinophilia and systemic symptoms and Stevens‐Johnson Syndrome/Toxic Epidermal Necrolysis. It is likely that the delayed immune‐mediated reaction triggering skin reaction is also responsible for hepatitis. Drug‐specific lymphocytes are found in the organs involved and also in circulating blood, which along with the cytokines and chemokines play a role in pathogenesis. Anti‐epileptic drugs, allopurinol, sulfonamides, antibiotics and nevirapine are the top five causes of concomitant liver and skin injury. This review will focus on drug and host factors causing concomitant Drug‐Induced Skin Injury and Drug‐Induced Liver Injury and discuss the characteristics of liver involvement in patients with severe cutaneous adverse reaction.     

Current treatment of severe asthma

Severe asthma is considered a heterogeneous disease in which a variety of clinical, physiological and inflammatory markers determine disease severity. Pivotal studies in the last 5 years have led to substantial progress in many areas, ranging from a more accurate definition of truly severe, refractory asthma, to classification of the disease into distinct clinical phenotypes, and introduction of new therapies. This review focuses on three common clinical phenotypes of severe asthma in adults (early onset severe allergic asthma, late onset non-atopic eosinophilic asthma, late onset non-eosinophilic asthma with obesity), and provides an overview of recent developments regarding treatment options that are best suited for each of these phenotypes.     

A perspective on point-of-care tests to detect eosinophilic bronchitis

Approximately 50% of asthma exacerbations and a third of COPD exacerbations are associated with an eosinophilic bronchitis. Quantitative cell counts reliably identify the number of eosinophils in sputum and treatment strategies that are guided by sputum eosinophil counts lead to significantly better outcomes than strategies guided by conventional assessments of symptoms and airflow. However, cell counts are not widely available and the results are not available in real time. Similarly, more sophisticated detection methods using immunoassays or genetic analysis via polymerase chain reaction are too costly and thus not amenable to rapid point-of-care diagnosis. Blood eosinophil counts and fraction of exhaled nitric oxide correlate poorly with airway eosinophilia, particularly in patients with severe airway diseases who are on corticosteroid therapy. Point of care assessments of eosinophil-specific activity may be provided by breathomics that employ metabolomics profiling of volatile compounds in breath. However, it is too early to decide if this would provide quantitative data to monitor therapy and disease activities longitudinally. Herein we provide a perspective on the potential for developing simple point-of-care tests with special emphasis on the potential for a bio-active paper diagnostic test to quantitatively assay the amount of eosinophil peroxidase in sputum samples by employing different types of detection systems.     

Challenges in managing difficult‐to‐treat asthma in children: Stop,look, and listen

It is recognized that asthma places a significant economic burden on the United States, with a total cost of $81.9 billion total costs including costs incurred by absenteeism and mortality. Severe asthma places a large burden of morbidity on children and their caregivers, including severe exacerbations, medication side effects, increased missed school days leading to impaired school performance, and lower caregiver quality of life. Therefore, we need to take a careful look at how we can make asthma care more efficient and cost effective, especially for those children with severe asthma. The 2019 American Thoracic Society symposium reported in this theme issue presented four aspects of managing severe asthma in children that merit attention including patient variables that affect severe asthma, understanding patient behaviors around medications, the appropriate use of bronchoscopy in diagnosis and management of severe asthma, and also the rational use of biologic therapy. This editorial will summarize key points in each of these reviews and prompt a more careful reading of each contribution.     

IL4R alpha mutations are associated with asthma exacerbations and mast cell/IgE expression

BACKGROUND: Severe asthma has been associated with severe exacerbations, lower lung function and greater tissue inflammation. Previous studies have suggested that mutations in interleukin-4 receptor alpha (IL4Ralpha) are associated with lower lung function, higher IgE, and a gain in receptor function. However, an effect on exacerbations and tissue inflammation has not been shown. HYPOTHESIS: Allelic substitutions in IL4Ralpha are associated with asthma exacerbations, lower lung function, and tissue inflammation, in particular to mast cells and IgE. METHODS: Two well-characterized cohorts of subjects with severe asthma were analyzed for five single nucleotide polymorphisms (SNPs) in IL4Ralpha. These polymorphisms were compared with the history of severe asthma exacerbations and lung function. In the primary (National Jewish) cohort, these polymorphisms were also compared with endobronchial tissue inflammatory cells and local IgE. RESULTS: In both cohorts, the presence of the minor alleles at E375A and Q551R, which were more common in African Americans, was associated with a history of severe exacerbations and lower lung function. In the National Jewish cohort, the C allele at E375A was associated with higher tissue mast cells and higher levels of IgE bound to mast cells. The significance for most of these associations remained when whites (the larger racial subgroup) were analyzed separately. CONCLUSIONS: SNPs in IL4Ralpha, which are more common in African Americans, are associated with severe asthma exacerbations, lower lung function, and increased mast cell-related tissue inflammation. Further studies of the impact of these mutations in African Americans and on receptor function are indicated.     

IFN-γ Attenuates Eosinophilic Inflammation but Is Not Essential for Protection against RSV-Enhanced Asthmatic Comorbidity in Adult Mice

The susceptibility to respiratory syncytial virus (RSV) infection in early life has been associated with a deficient T-helper cell type 1 (Th1) response. Conversely, healthy adults generally do not exhibit severe illness from RSV infection. In the current study, we investigated whether Th1 cytokine IFN-γ is essential for protection against RSV and RSV-associated comorbidities in adult mice. We found that, distinct from influenza virus, prior RSV infection does not induce significant IFN-γ production and susceptibility to secondary Streptococcus pneumoniae infection in adult wild-type (WT) mice. In ovalbumin (OVA)-induced asthmatic mice, RSV super-infection increases airway neutrophil recruitment and inflammatory lung damage but has no significant effect on OVA-induced eosinophilia. Compared with WT controls, RSV infection of asthmatic Ifng^−/− mice results in increased airway eosinophil accumulation. However, a comparable increase in eosinophilia was detected in house dust mite (HDM)-induced asthmatic Ifng^−/− mice in the absence of RSV infection. Furthermore, neither WT nor Ifng^−/− mice exhibit apparent eosinophil infiltration during RSV infection alone. Together, these findings indicate that, despite its critical role in limiting eosinophilic inflammation during asthma, IFN-γ is not essential for protection against RSV-induced exacerbation of asthmatic inflammation in adult mice.     

Risk factors of frequent exacerbations in difficult-to-treat asthma.

Recurrent exacerbations are a major cause of morbidity and medical expenditure in patients with asthma. Various exogenous and endogenous factors are thought to influence the level of asthma control, but systematical data on the involvement of these factors in the recurrence of asthma exacerbations are scarce. In this study, 13 clinical and environmental factors potentially associated with recurrent exacerbations were investigated in 136 patients with difficult-to-treat asthma. Patients with more than three severe exacerbations (n = 39) in the previous year were compared with those with only one exacerbation per year (n = 24). A systematic diagnostic protocol was used to assess 13 potential risk factors. Factors significantly associated with frequent exacerbations included: severe nasal sinus disease (adjusted odds ratio (OR) 3.7); gastro-oesophageal reflux (OR 4.9); recurrent respiratory infections (OR 6.9); psychological dysfunctioning (OR 10.8); and obstructive sleep apnoea (OR 3.4). Severe chronic sinus disease and psychological dysfunctioning were the only independently associated factors (adjusted OR 5.5 and 11.7, respectively). All patients with frequent exacerbations exhibited at least one of these five factors, whilst 52% showed three or more factors. In conclusion, the results show that recurrent exacerbations in asthma are associated with specific co-morbid factors that are easy to detect and that are treatable. Therapeutic interventions aimed at correcting these factors are likely to reduce morbidity and medical expenditure in these patients.     

A case of bronchial asthma and PIE Syndrome induced by disodium cromoglycate

A 54-year-old female with bronchial asthma and PIE syndrome induced by disodium cromoglycate (DSCG) was reported. She was referred to our hospital for further examination of the abnormal chest shadows and eosinophilia. She had been treated with DSCG, Cefaclor. Bromhexine and bronchodilator for bronchial asthma and bronchitis. Withdrawal of the drugs except for the bronchodilators alleviated her symptoms. Therefore, drug induced lymphocytes stimulation tests (DLST) were performed for those three drugs. Only DLST for DSCG showed a positive result. She had been asthmatic for ten years and treated by the drug for 18 months prior to admission. The skin test for the drug was negative and a precipitating antibody for the drug could not be found. To obtain a definite diagnosis, bronchial challenge by DSCG was performed, after her symptoms were under control. Severe asthmatic responses were provoked in 6 and 24 hours after the inhalation of DSCG. Bronchoalveolar lavage, performed 8 days after the provocation, revealed increased eosinophils and lymphocytes in BAL fluid. Although several cases of PIE syndrome induced by DSCG have been reported, this seems to be the first report of late and delayed type bronchial response and pulmonary infiltration with eosinophilia provoked by DSCG. The bronchial response to the drug was a late and delayed type reaction and sustained for a long period. This might indicate that PIE syndrome induced by the drug may be caused by a same mechanism as the provoked asthmatic response.     

Severe Asthma in Primary Care: Identification and Management

Most patients with asthma are managed by primary care providers. Severe asthma is associated with substantial morbidity and health care resource use, and long-term sequelae of severe asthma include airway remodeling and a greater risk of developing chronic obstructive pulmonary disease. These consequences highlight the importance of early identification and improved management of patients with severe asthma. Although treatment guidelines can be confusing and it can be difficult to keep abreast of updates, routine assessments of lung function, frequency and severity of exacerbations, symptom control, and medication adherence in the primary care setting provide the necessary information for identifying severe asthma and determining appropriate management strategies. An increased understanding of asthma pathophysiology and its relationship to disease activity has identified therapeutic targets and associated biomarkers. Biologic therapies directed at these targets offer individualized targeted treatment of severe asthma. We review evidence-based guidelines for identification and management of severe asthma, clarify the relationship of asthma control and asthma severity, and provide an overview of new biologic therapies offering additional treatment options for patients with severe asthma.     

Inhaled corticosteroids and leukotriene modifiers in the acute treatment of asthma exacerbations

Asthma exacerbation has a considerable impact on patients' quality of life and constitutes a challenging condition for primary health-care providers. Severe exacerbations are also an important cause of hospital admissions and require high costs. Despite this, a widely accepted definition is still lacking; etiologic and pathogenetic mechanisms are still incompletely defined. Although the efficacy of inhaled corticosteroids (ICS) and leukotriene modifiers in preventing mild to moderate asthma exacerbation is well recognized, their role within the context of an asthma action plan in general practice and in home-based early intervention for acute exacerbations is still controversial. Although systemic corticosteroids (CS) are standard care for severe exacerbation in the emergency department's (ED) management of asthma, published evidence suggests that high doses of ICS may be beneficial in the ED. The additive benefit of ICS when used with systemic CS is still debated. Data on leukotriene modifiers in the management of asthma exacerbation are limited. However, therapeutic strategies of this emergency including ICS and leukotriene modifiers seem logical and may be suitable, at least in certain patient groups. The availability of different drugs, active on different targets, can potentially contribute to a better management of asthma exacerbations.     

Pattern of airway inflammation and its determinants in children with acute severe asthma.

The aim of this study was to examine the relationship between sputum cell counts and clinical variables in children with an acute exacerbation of asthma. Sputum was successfully obtained from 37 of 42 children presenting to the Emergency Department with acute asthma, using ultrasonically nebulized normal saline (n = 19) or spontaneous expectoration (n = 18). Sputum portions were selected and dispersed, and total and differential cell counts were performed. Sputum supernatant was assessed for eosinophil cationic protein (ECP), interleukin (IL)-5, and IL-8. The exacerbations were of 3 inflammatory cell patterns: eosinophilic (n = 16 or 43% of total), combined eosinophilic/neutrophilic (E/N; n = 13.3 or 35% of total), or noneosinophilic (n = 8 or 22% of total). IL-5 was highest in eosinophilic exacerbations. Combined E/N exacerbations had increased mast cells (77%) and higher sputum ECP levels than eosinophilic exacerbations: 2,146 ng/mL vs. 666 ng/mL (P = 0.04). The speed of onset of the exacerbation was not related to the inflammatory cell profile. Logistic regression identified maintenance asthma treatment (odds ratio (OR), 5.9; 95% confidence interval (CI), 1.3-26.8) and lung function during the acute episode (OR, 4.0; 95% CI, 1.7-93) as significantly associated with the intensity of sputum eosinophilia. Eosinophils were lowest in children who received maintenance treatment with oral corticosteroids compared to those with no background asthma preventer therapy (P = 0.001). In conclusion, we identified three distinct patterns of airway inflammation in children with acute asthma; they included increased eosinophils, combined eosinophilic-neutrophilic infiltration, and a noneosinophilic pattern. Eosinophil degranulation was greatest with the combined eosinophilic/neutrophilic pattern of airway inflammation. Sputum eosinophils were associated with clinical severity, and background asthma therapy, but not with outcome, nor with speed of onset of exacerbations. These different inflammatory cell profiles imply different etiological agents and may require differing treatment strategies.