MADRID — It is estimated that between 5% and 10% of Spanish people suffer from asthma. Of these patients, up to 10% may have severe asthma, which requires a multidisciplinary approach involving treatment with multiple drugs at high doses. It is estimated that among half of people living with asthma, their asthma is poorly controlled. This generates an annual cost per patient of more than €11,700. For this reason, a group of 92 pulmonologists belonging to the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) has updated the consensus document on severe asthma in adults, which is published in the Open Respiratory Archives. The objectives of the document are to improve treatment and quality of life and to decrease the mortality rate of these patients.
Francisco Javier Álvarez-Gutiérrez, PhD, coordinator for the document, indicated in a press release from the scientific society that “it is necessary to analyze the factors that may contribute to the poor control of these patients, such as the misuse of inhalers or certain environmental factors.”
For his part, Gregorio Soto, MD, PhD, coordinator of SEPAR’s Asthma Division and head of the Pulmonology and Allergy Clinical Management Unit at Jerez University Hospital, spoke to Medscape Spanish Edition about the factors relating to the fact that for 50% of patients, severe asthma is poorly controlled. “Some [cases] are due to intrinsic factors of the disease itself, others are due to the presence of aggravating factors and uncontrolled comorbidities, others to the patient, and others can be attributed to deficiencies in healthcare.
“Some authors point out that the presence of psychomorbidity (anxiety, depression), recurrent respiratory infections, gastroesophageal reflux, obstructive sleep apnea, and chronic rhinosinusitis are significantly associated with frequent flare-ups,” the specialist stressed.
It is known that treatment compliance for patients with asthma is low and is one of the most frequently cited causes of poor asthma control. Poor control is almost always multifactorial, “and tools aimed at detecting and improving asthma should be included as part of the asthma educational strategy if it is deficient. Poor inhalation technique seen in many patients must also be considered,” said Soto.
Among the factors underlying poor control is the presence of aggravating factors or comorbidities, such as exposure to perennial allergens and occupational agents, smoking, and psychomorbidity. “These are factors that condition poor asthma control in this group of patients. Patients with severe asthma have a high prevalence of functional disorders, such as functional dyspnea and dysthymic anxiety-depressive disorders, that are the cause of poor control,” said Soto.
“There is also controversy on the relationship between obesity and refractory asthma. Although there are studies that show an improvement in asthma control after weight reduction, it is not a consistent finding,” added Soto.
Phenotypes: Key Information
Another of the key factors pointed out by Álvarez-Gutiérrez “is the identification of the phenotypes of this disease, which can also vary over time.”
Phenotypes and subtypes of severe asthma are based on the underlying pathogenic mechanism. In distinguishing T2-high (allergic or eosinophilic) and T2-low asthma, consideration is given to the presence or absence of certain inflammatory markers, the natural history, and certain clinical characteristics.
Soto explained that on the basis of these concepts, “we consider three major phenotypes in severe asthma. Severe allergic asthma, which accounts for 40% to 50% and has a clear atopic basis, is characterized by early onset, having positive allergic tests with clinical concordance.”
Late-onset eosinophilic asthma accounts for slightly more than 25% of cases. High production of interleukin 5 (IL-5) is a causal factor. In general, “it appears after the age of 20 or a little later, and it is not uncommon for it to be preceded by upper or lower respiratory tract infection and even chronic sinusitis and nasal polyposis,” said Soto. “A subgroup of those with late-onset eosinophilic asthma further develops respiratory disease exacerbated by aspirin and nonsteroidal anti-inflammatory drugs.”
The T2-low phenotype, present in more than a third of patients with severe asthma, presents without eosinophilia and shows a paucigranulocytic or neutrophilic profile, with low concentration levels of fractional exhaled nitric oxide (FeNO) and poor response to glucocorticoids. “It tends to be accompanied by chronic airflow limitation with significant entrapment, and often has a history of smoking,” said Soto.
Severe Asthma Treatment
Systemic glucocorticoids should be reserved for patients with uncontrolled asthma in whom all other treatments, including drugs, have failed. They are used as the last therapeutic step at the lowest effective dose and for the shortest possible time. Frequent cycles of oral corticosteroids are associated with side effects.
Although there is no robust evidence to recommend triamcinolone, its use could be considered in well-selected steroid-dependent patients. It is advisable to determine plasmatic cortisol for patients with a cumulative dose ≥1 g/year and maintenance with any dose for more than 6 months per year.
For patients being managed with monoclonal antibodies, the results obtained with omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab are similar to those for patients with severe uncontrolled asthma, although the populations studied do not exactly overlap.
For patients sensitized to a seasonal allergen, omalizumab could be an alternative, and for those who do not respond adequately to a first antibody, switching to another should be considered. Consideration should be given on an individual basis to the evidence regarding effectiveness and safety. For patients with eosinophil counts >300 cells/µL for whom omalizumab has failed, anti-IL-5 and dupilumab are valid alternatives.
For patients with allergic phenotype and eosinophil count <150 cells/µL who have not received maintenance treatment with glucocorticoids, omalizumab is the first option. For those with 150–300 eosinophils, omalizumab as well as mepolizumab and dupilumab are valid alternatives.
For patients with eosinophilic phenotype, anti-IL5/anti-eosinophils and dupilumab are indicated. In case of incomplete response after sequential treatment with two monoclonal antibodies with different mechanisms of action (anti-IgE and anti-IL5/anti-eosinophil), dupilumab should be proposed as the first option. For patients for whom anti-IL-5 and dupilumab have failed, if IgE levels are >30 IU/µL, compassionate use omalizumab could be an alternative. In some cases, an FeNO concentration value ≥25 ppb may be relevant for the choice of antibody.
In the context of the SARS-CoV-2 pandemic, it is recommended that the usual maintenance treatment of asthma or rhinitis be continued so as not to lose control of the disease. It is advisable to maintain the biological treatments indicated for severe asthma for patients not infected with SARS-CoV-2, if possible via self-administration to avoid risk of transmission of the virus. In the case of SARS-CoV-2 infection, the administration of the biological agent should be delayed until clinical resolution, since its effect on the immune response to the virus is unknown.
In cases of coronavirus infection and exacerbated asthma, the administration of the biological agent should be tailored to the individual, since no adverse reactions have been observed in the few cases in which it was administered during the infection.
In the consensus document, the definition of uncontrolled severe asthma is different from the definitions in previous versions. The current definition involves, in addition to treatment with long-acting adrenergic agonists and high-dose inhaled steroids, the use of long-acting anticholinergics or a cumulative dose of corticosteroids (prednisone) >1 g.
Another change is the inclusion of scales, such as “the assessment of the response to treatment through the multidimensional scale called the Exact Index, with two scores ranging from 0–10 or from 0–7 for patients with and without continuous systemic steroid treatment, respectively,” Soto explained. In addition, “in cases that also present rhinosinusitis with nasal polyposis, a scale that includes the SNOT 22 and a visual analogue scale” should be utilized, as well as “an index of patient satisfaction with biological treatment, with a simple scale from 0–10 that includes important aspects, such as efficacy, adverse effects, comfort of use, impact on daily activities, and general opinion,”
The document recommends monitoring of all patients with severe asthma. In general, it advises monitoring every 3 months, although monitoring must be tailored to each patient. The effects of inhaled treatment on symptoms and forced expiratory volume in the first second (FEV1) are assessed, and it is recommended that one wait a minimum of 4 months for a first assessment of clinical response by patients treated with monoclonal antibodies. In addition, the reduction of exacerbations at 12 months should be assessed.
Overall, the recommended markers for monitoring the majority of patients with severe asthma at each visit are validated questionnaires (ACT/ACQ), number and severity of exacerbations since the last visit, FEV1, inhaler adherence test, FeNO, blood eosinophilia, and consumption of systemic steroids. Peripheral eosinophilia is a biomarker that helps indicate monoclonal antibodies, and its persistence in sputum may reflect insufficient response to treatment with a monoclonal agent.
Significant Health Cost
Adult patients with severe asthma represent more than half of the total asthma expenditure. The direct costs for patients without asthma was €11,703.
In Spain, 2% of public health resources are allocated to asthma, or what equates to €1,480,000. According to the ASMACOST study carried out by the Asthma Division of the Spanish Society of Pulmonology and Thoracic Surgery, it is estimated that the average cost per patient per year is €1726. This amount varies, depending on the severity of the asthma; cost can range from €959 for mild asthma to €2635 for severe asthma.
“Expenditures due to asthma are directly related to the degree of control of the disease and to the severity, in such a way that the worse the control and the greater the severity, the costs increase. Therefore, in our environment, a good strategy and planning of the diagnosis and treatment of asthma would substantially reduce costs,” explained Soto.
The previous study also showed that 16.1% of the expenditure corresponded to nonhealthcare resources, such as absenteeism from work and school, disabilities, early retirement, and premature deaths, while 83.9% corresponded to health costs.
The study also pointed out that the health resources that generate higher economic cost are medications (27.9%), examinations (24%), and hospital admissions (17%). Furthermore, “the data confirm that the costs of asthma depend on the level of individual patient control and the degree to which exacerbations are avoided. Poor asthma control represents 70% of the total cost of this respiratory disease,” said Soto.
Integrating New Technologies
The evolution of imaging techniques, new ways of measuring biological processes (omics), and the use of big data will be helpful in the near future in assessing more objectively the phenotypes and endotypes of these patients and their response to treatments so as to achieve truly personalized medicine, said Álvarez-Gutiérrez.
Soto pointed out, “We have mobile applications that allow us to monitor the symptoms and the use of medications, this being a key aspect in learning to control the disease.” These devices are of great help for the transmission of information and for patient education, which may include an action plan in case of decompensation of the underlying pathology. “They can also help to improve treatment compliance, as they allow issuing reminders to take the medication or making an appointment with a professional.
“SEPAR has been conscious of the need to incorporate new technologies into our professional activity, and with this objective, the ForoAsma application has been developed,” Soto added. To date, existing asthma-related applications have focused either on providing information about the disease or on providing electronic peak expiratory flow measurement calculators or records.
Few applications have combined both functions, and in many of those that have, the quality of the information provided was very low. For this reason, the SEPAR Asthma Forum founded an initiative to develop an application that would adequately cover these needs. This app has been developed entirely by members of the Asthma Division. Its purpose is to disseminate basic knowledge of asthma to the general population, help them manage inhalation devices, and provide them with a tool to monitor their symptoms and lung function.
“This information may be presented to the visiting doctor, also being an aid to them when seeing the evolution of the disease and the potential triggers responsible for the loss of control of the disease. The ForoAsma application is available in the Play Store (Android) and App Store (iOS), and it is free to download,” said Soto.
Another key recommendation is for the creation of units that specialize in the treatment of this pathology. Already in 2013, from the Asthma Work Division and following the guidelines of the SEPAR Quality Committee, the task of defining different levels of these asthma units was addressed so as to accredit them and define the minimum service portfolio in each of the categories. “Then a process began that sought to officially accredit the specialized asthma activity in centers that requested this hallmark using the benchmarks defined by our scientific society. Due to this, we were able to share this quality hallmark with official organizations such as the Ministry of Health and autonomous communities,” said Soto.
The aims of the accreditation were to improve the level of care for patients, thus ensuring a quality care framework; to establish resources and facilitate their management; to promote the development of training plans in asthma; to promote collaboration with professionals from other clinical disciplines; and to promote research in asthma.
An Asthma Unit accreditation tool was thus designed on the SEPAR web platform. Three levels of certification were established: high-complexity asthma specialized unit, asthma specialized unit, and asthma basic unit.
“To date, 73 units spread across Spain have requested accreditation, and this system has been the subject of interest, analysis, and subsequent scientific publications,” said Soto. The pandemic brought the asthma unit accreditation process to a standstill. “In 2023, it will start up again with a change to the evaluable criteria that is more in line with the current situation, with the search for health results within the pathology.”
Soto receives fees for participating as a speaker in meetings sponsored by AstraZeneca, Boehringer-Ingelheim, Novartis, and GlaxoSmithKline. He also receives fees as a consultant to AstraZeneca, Sanofi, GlaxoSmithKline, Chiesi, Novartis, Rovi, and Bial. He receives financial aid for attendance at congresses from Boehringer-Ingelheim, Bial, FAES, Boehringer-Ingelheim, and Novartis and aid for research projects from GlaxoSmithKline, Sanofi, and Boehringer-Ingelheim.
Follow Javier Cotelo, MD, of Medscape Spanish Edition on Twitter @Drjavico.
This article was translated from the Medscape Spanish edition.
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