Background
Severe uncontrolled asthma comprises three categories [
1]: untreated severe asthma; difficult-to-treat severe asthma; and treatment-resistant severe asthma. Those categories differ in terms of their connotation in the context of public health, as well as in terms of the challenges they pose. Failure to achieve and maintain asthma control can increase the risk and frequency of exacerbations, as well as increasing the risk of asthma-related death. Individuals with uncontrolled asthma are also more likely to have adverse reactions to asthma medications and to develop chronic morbidity, such as impaired pulmonary function. In children with uncontrolled asthma, lung growth can also be impaired [
1].
Patients with severe uncontrolled asthma should be evaluated carefully. The evaluation of such patients should include the differential diagnosis of their symptoms, the determination of their access to medications, and the identification of potentially reversible risk factors (comorbidities, inefficient inhaler technique, poor adherence to the treatment regimen, and asthma triggers in the environment). In addition, attempts should be made to determine whether the use of maintenance medications is optimal [
1-
3]. The objective of such evaluations is to distinguish patients with treatment-resistant severe asthma, in whom the symptoms remain uncontrolled despite the highest level of recommended treatment or control can be maintained only with the highest level of recommended treatment, from those with difficult-to-treat severe asthma, in whom control can be achieved after the removal of reversible risk factors [
1]. It is important to make the distinction between treatment-resistant severe asthma and difficult-to-treat severe asthma, in order to avoid unnecessary invasive procedures, minimize adverse effects of asthma medications, and hold down health care costs, given that asthma control is possible in patients with difficult-to-treat severe asthma, whereas those with treatment-resistant severe asthma are candidates for clinical trials of other treatment strategies [
1,
3].
There have been few studies aimed at distinguishing between difficult-to-treat severe asthma and treatment-resistant severe asthma in children and adolescents. Studies conducted in high-income countries have reported inconsistent findings [
4,
5]. Some authors have suggested that patients with difficult-to-treat severe asthma show better baseline pulmonary function and lower fractional exhaled nitric oxide (FeNO) than do those with treatment-resistant severe asthma [
4]. In contrast, others have found that neither FeNO nor forced expiratory volume in one second (FEV
1) discriminate between those two phenotypes of severe uncontrolled asthma [
5].
According to data from the International Study of Asthma and Allergies in Childhood [
6], the prevalence of asthma among 13- to 14-year-olds in Brazil is approximately 20%. The morbidity associated with severe uncontrolled asthma is disproportionately higher in low- and middle-income countries (LMICs) than in high-income countries [
1,
7], which calls attention to the need for studies aimed at identifying strategies for reducing asthma-related morbidity in LMICs. A group of experts assembled by the World Health Organization (WHO) has proposed a protocol for severe asthma follow-up and intervention, which defines three categories of severe uncontrolled asthma [
1]. The objective of the present study was to describe the phenotypes of severe uncontrolled asthma in a sample of children and adolescents in Brazil.
Results
We found that 10 (16.4%) of the 61 patients evaluated had been misdiagnosed (i.e., they did not have asthma), 15 (24.6%) had moderate asthma, and 36 (59.0%) had severe uncontrolled asthma. The alternative diagnoses included bronchiolitis obliterans following an infection (in six patients), cystic fibrosis (in one), primary ciliary dyskinesia (in one), pulmonary tuberculosis (in one), and a sequela of bronchopulmonary dysplasia (in one). Those 36 patients comprised our study sample. Table
1 shows the baseline demographic, anthropometric, and clinical characteristics of the patients.
Table 1
Baseline characteristics of pediatric patients with severe uncontrolled asthma (N = 36) treated at a referral center for asthma in Brazil
Female gender | 23 (63.9) | |
Age (years) | | 11.6 (6.2 to 17.8) |
Height (Z score) | | 0.05 (−2.66 to 1.00) |
BMI (Z score) | | −0.48 (−2.90 to 1.84) |
Well-controlled home environment | 9 (25.0) | |
Severe persistent allergic rhinitis | 35 (97.2) | |
Severe exacerbations in the last 12 months | | 5 (1 to 20) |
Allergic rhinitis score | | 8 (0 to 18) |
Gastroesophageal reflux disease | 7 (19.4) | |
Psychiatric disorder | 3 (8.3) | |
Smoking in the home (reported by the residents) | 12 (33.3) | |
Fully adherent to treatment | 2 (5.6) | |
Previous pulmonary function testing | 16 (44.4) | |
Incorrect inhaler technique | 13 (36) | |
Previous ICU admission | 7 (19.5) | |
Uncontrolled asthma (GINA criteria) | 36 (100) | |
Posology and medications in use | | |
Equivalent dose of budesonide (μg) | | 800 (800 to 1200) |
ICS alone | 9 (25.0) | |
ICS + LABA | 27 (75.0) | |
Leukotriene receptor antagonists | 4 (11.1) | |
Continuous oral ICS | 3 (8.3) | |
Omalizumab | 0 (0.0) | |
In the sample as a whole, asthma-related morbidity was high, with a median of five exacerbations in the last 12 months. All of the patients had uncontrolled asthma and were taking high doses of ICS, which is characteristic of severe uncontrolled asthma. Despite the lack of control, 25% of the patients were being treated with regimens that did not include a LABA and were therefore classified as receiving treatment that was not appropriate to the level of control. The majority of the patients had severe persistent allergic rhinitis and were exposed to dust mite allergens and tobacco smoke in their environment. In addition, 36% used incorrect inhaler techniques, the most common errors being not exhaling completely before inhaling the medication and not inhaling deeply enough. Table
2 shows the characteristics of the patients before and after the interventions recommended by the WHO consultants [
1]. After the interventions, there was an increase in the proportion of patients showing correct inhaler technique, together with better rhinitis scores, better ACT scores, and an increase in the use of leukotriene receptor antagonists. In addition, there were post-intervention reductions in the number of exacerbations, in the FeNO levels, and in the post-bronchodilator variations in FEV
1 and FEF
25–75%, as well as an increase in the absolute values for FEV
1.
Table 2
Characteristics of pediatric patients with severe uncontrolled asthma (N = 36) before and after application of the WHO protocol
a,b
Correct inhaler technique | 23 (63.9) | 31 (86.1) | 0.008 |
Fully adherent to treatment | 2 (5.6) | 34 (94.4) | N/A |
Rhinitis score | 8 (0–18) | 5 (0–15) | 0.001 |
Asthma Control Test score | 16.5 (6–25) | 22.5 (8–25) | 0.002 |
Posology and medications in use | | | |
Leukotriene receptor antagonists | 4 (11.1) | 12 (33.3) | 0.008 |
Omalizumab | 0 (0) | 1 (2.7) | N/A |
Continuous oral ICS | 3 (8.3) | 8 (22.2) | 0.063 |
Equivalent dose of budesonide (μg) | 800 (800–1200) | 800 (800–1600) | 0.059 |
Well-controlled home environment | 9 (25) | 15 (41.7) | 0.109 |
Psychiatric disorder | 3 (8.3) | 8 (22.2) | 0.125 |
Number of exacerbations | 4 (0–20) | 2 (0–11) | 0.006 |
Sputum cytology
c
| | | |
Eosinophils (%) | 2.0 (0–37) | 1.1 (0–49) | 0.948 |
Eosinophils ≥ 2.5% | 9 (25.0) | 9 (25.0) | 0.362 |
Neutrophils > 54% | 4 (17.4) | 6 (18.8) | 0.114 |
Pre-BD FEV1 (%) | 77.0 (36–113) | 78.7 (31–113) | 0.038 |
Pre-BD FEV1/FVC ratio (%) | 78.0 (53–100) | 80.0 (43–95) | 0.417 |
Pre-BD FE 25–75% (%) | 61.0 (16–131) | 66.5 (15–110) | 0.156 |
Post-BD variation in FEV1 (%) | 11.0 (0–70) | 5.0 (0–45) | 0.004 |
Post-BD variation in FEF25–75% (%) | 31.0 (0.0–166.0) | 14.0 (0.0–96.0) | 0.013 |
FeNO (ppb) | 31 (5–125) | 14 (0–112) | 0.016 |
Table
3 shows the comparative analysis between the patients with treatment-resistant severe asthma and those with difficult-to-treat severe asthma. At baseline, FEV
1 was 61% and 87% of the predicted value in the patients with treatment-resistant severe asthma and difficult-to-treat severe asthma, respectively, and the pre-bronchodilator values of FEV
1, FEV
1/FVC ratio, and FEF
25–75% were lower in the patients with treatment-resistant severe asthma than in those with difficult-to-treat severe asthma, as were the post-bronchodilator variations in FEV
1 and FEF
25–75%. After the interventions, 20 (55.6%) of the 36 patients were classified as having treatment-resistant severe asthma and 16 (44.4%) were classified as having difficult-to-treat severe asthma. We found that the two phenotypes were indistinguishable on the basis of baseline clinical characteristics or atopy, although a distinction between the two was suggested on the basis of the baseline spirometry results and level of FeNO. In the sample as a whole, the median time to achieving ≥ 80% adherence to treatment was six months, and there was no statistical difference between the two groups in terms of that parameter.
Table 3
Baseline characteristics of pediatric patients with severe uncontrolled asthma (N = 36) treated at a referral center for asthma in Brazil, by phenotype
a
Female gender | 13 (65.0) | 10 (62.5) | 0.846 |
Age (years) | 12.0 (6.4–17.8) | 11.0 (6.2–17.7) | 0.514 |
Pattern of sputum cellularity
b
| | | |
Eosinophilic | 5 (31.3) | 1 (14.3) | 0.52 |
Neutrophilic | 3 (18.8) | 1 (14.3) | |
Paucicellular
a
| 6 (37.5) | 4 (57.1) | |
Mixed | 2 (12.5) | 1 (14.3) | |
Number of ICU admissions | 0.0 (0.0–6.0) | 0.0 (0.0–4.0) | 0.621 |
Courses of oral corticosteroids in the last 12 months (n) | 0.5 (0.0–7.0) | 1.00 (0.0–12.0) | 0.143 |
Exacerbations in the last 12 months | 6 (1–12.0) | 4 (1–20.0) | 0.311 |
Time to achieve ≥ 80% adherence and complete the protocol (months) | 6.2 (0.7–24.2) | 5.8 (1.4–17.3) | 0.987 |
Asthma Control Test score | 14 (6–24) | 18 (10–24) | 0.091 |
Rhinitis score | 7.5 (4–15) | 9 (0–15) | 0.886 |
FVC (% of predicted) | 74.9 (59.6–106.7) | 93.6 (81.3–117) | <0.001 |
FEV1 (% of predicted) | 61.0 (36.0–98.6) | 87.0 (72.1–113) | <0.001 |
FEV1/FVC ratio | 78.3 (43.1–86.1) | 84.3 (72.1–98.9) | 0.009 |
FEF25–75% (%of predicted) | 39.8 (16.0–83.1) | 74.6 (29.1–131.3) | 0.002 |
Post-BD variation in FEV1 (%) | 17.0 (1.7–70.0) | 6.2 (0.0–38.3) | 0.012 |
Post-BD variation in FEF25–75% (%) | 38.9 (1.4–166.0) | 24.6 (0.0–59.2) | 0.031 |
Equivalent dose of budesonide (μg) | 800 (800–1200) | 800 (800–800) | 0.975 |
FeNO (ppb) | 40 (7–125) | 12 (5–53) | 0.037 |
Total IgE total (mg/dl) | 1040 (65–3000) | 454 (11–2500) | 0.098 |
Sensitization to dust mite allergens | 20 (100) | 12 (80) | 0.069 |
Sensitization to fungi | 7 (35) | 5 (33.3) | 0.603 |
Sensitization to pet dander | 5 (25) | 4 (26.7) | 0.605 |
Sensitization to cockroach allergens | 4 (20) | 3 (20) | 0.659 |
Discussion
We found that 16.4% of the patients referred with a diagnosis of severe uncontrolled asthma did not have asthma at all. This finding is in agreement with those of other studies, in which 12–50% of such patients were found to have been misdiagnosed [
25]. This underscores the importance of re-evaluating the diagnosis of asthma in patients who do not achieve control [
1,
9].
At baseline, the majority of our patients were under treatment with high doses of ICS and LABA, which is a reflection of the fact that those medications are made readily available by the health care system in the area served by our referral center. A consensus statement recently published jointly by the European Respiratory Society and the American Thoracic Society provided age-specific guidelines for the appropriate doses of inhaled corticosteroid in cases of “severe therapy-resistant asthma” [
26]. The median age of our patients was 11.6 years (range, 6.2–17.8 years). our patients who were ≤ 12 years of age were treated with a daily dose of 800 μg of inhaled budesonide or equivalent, which the aforementioned guidelines classify as a high dose for patients in this age group [
26]. The patients who were referred from health care systems in which LABAs are not made available accounted for the fact that 25% of the patients were not receiving treatment appropriate to the severity of their asthma. In addition, other asthma medications, such as leukotriene receptor antagonists and omalizumab, were unavailable to those patients. It is important that all effective asthma medications are made available and accessible to asthma patients, which is not always the case in LMICs [
1,
2]. In Brazil, a study designed to estimate the direct and indirect costs of severe asthma, as well as the overall economic impact of asthma, conducted under the auspices of the Bahia State Program for the Control of Asthma and Allergic Rhinitis, showed that the costs of asthma treatment consume, on average, 24% of the total family income in the city of Salvador (capital of the state of Bahia) [
27]. When the indirect costs were included, that figure rose to 29%. The participants in the present study had free access to appropriate medications via the public health care system.
It is of note that, at baseline, asthma was uncontrolled in all of the patients, even those for whom high doses of ICS and LABA had been prescribed. In the majority of cases, there was no documentation of the medication having been dispensed and the patients did not have their inhalers with them, which precluded the counting of the doses. Therefore, prescribing a given medication does not guarantee that it will be administered.
One of the major factors associated with a lack of asthma control is poor adherence to treatment. Despite the fact that there are no fully reliable methods of verifying such adherence, it is recommended that it be quantified with one of the methods available, given that the definition of severe uncontrolled asthma is based on of the dosage required to effectively achieve and maintain control of the symptoms [
1,
20]. Within the health care systems that provide asthma medications, dispensing records could play an important role by allowing patients who do not refill their prescriptions to be identified. Thus, pharmacists could be on the front lines of the battle to improve treatment adherence, which is particularly important in patients with severe asthma. Because poor adherence to treatment is one of the major determinants of severe uncontrolled asthma, we opted to evaluate the patients in our sample only after they had reached a rate of adherence ≥ 80%.
At baseline, it was not possible to determine the rate of adherence to treatment. In our sample, the median time required to reach ≥ 80% adherence was six months. We found it surprising that it took so long for our patients to achieve a satisfactory rate of adherence, especially because they were already receiving appropriate treatment, which made it impossible to increase the dosages or add other recommended medications during that period.
Sharples et al. reported that 41% of patients with treatment-resistant severe asthma were ≥ 80% adherent to treatment, compared with only 24% of those with difficult-to-treat severe asthma [
4]. In the present study, we distinguished between the two phenotypes only after ≥ 80% adherence had been achieved. The authors of an earlier study of asthma treatment in children and adolescents concluded that the rate of adherence reported by parents or guardians is higher than is the true (measured) rate [
28]. In a study of children with treatment-resistant severe asthma [
5], another group of authors used the reported rates of adherence but questioned the reliability of those data, suggesting that some method of quantifying adherence should be employed, which would allow poorly adherent individuals to be identified.
Despite the prerequisite of a documented ≥ 80% rate of adherence, 55.6% of our patients did not achieve clinical or functional asthma control. This finding is consistent with those of Sharples et al., who reported that, among the patients with uncontrolled asthma, the rate of adherence was 60.3% in those with treatment-resistant severe asthma, compared with 39.7% in those with difficult-to-treat severe asthma [
4].
By applying the interventions suggested by the WHO panel of experts, we were able to increase the rate of adherence, improve ACT scores, increase the proportion of patients using correct inhaler techniques, improve rhinitis scores, optimize the treatment regimens, and maximize the environmental control, which is considered essential. Although it is not always easy or simple to achieve, it is important that these essential measures are taken. In the present study, we found that the interventions applied resulted in a satisfactory level of environmental control, despite the fact that we were able to eliminate smoking from the home environment (as determined on the basis of self-reported smoking cessation on the part of the residents) in only six of the cases, in which family members who reported smoking in the home had been referred to the smoking cessation outpatient clinic of a university hospital for treatment. It is possible that the environment could have been controlled more efficiently had home visits occurred [
21].
Differentiating between treatment-resistant severe asthma and difficult-to-treat severe asthma has important implications for clinical practice. Patients with treatment-resistant severe asthma cannot achieve a satisfactory level of control even when potential risk factors are removed, such patients being candidates for clinical trials of new treatment strategies. In patients with treatment-resistant severe asthma, evaluations that are more invasive can be justified [
29]. In patients with difficult-to-treat severe asthma, however, control can be achieved when the essential measures are taken, resulting in fewer exacerbations, social reintegration of the patients, and a reduction in health care costs.
In the present study, it was not possible to distinguish between the patients with treatment-resistant severe asthma and those with difficult-to-treat severe asthma on the basis of their baseline clinical characteristics (including ACT and rhinitis scores) or clinical history (number of exacerbations and number of admissions to the intensive care unit). That might explain, in part, the high morbidity that both groups of patients exhibited at baseline. It is possible to distinguish between the two phenotypes only after the essential measures have been taken, which is difficult to achieve outside of a specialized treatment facility. However, we identified markers that are suggestive of a distinction between treatment-resistant and difficult-to-treat severe asthma prior to any intervention, such markers including spirometry values and the FeNO level.
We found statistically significant baseline differences between the patients with treatment-resistant severe asthma and those with difficult-to-treat severe asthma in terms of the pre-bronchodilator FEV
1, FEV
1/FVC ratio, and FEF
25–75%, as well as the post-bronchodilator variations in FEV
1 and FEF
25–75%. Sharples et al. observed such a difference, although only for post-bronchodilator variations in FEV
1, whereas Konradsen et al. found no difference in FEV
1 values between the two phenotypes [
5]. The latter group of authors reported that the parental level of education and family income were both lower among the patients with treatment-resistant severe asthma [
5]. In the present study, all of the patients belonged to families with monthly incomes below US$ 600.00 and only one patient had a parent with more than a high school education.
In our sample, the median FeNO values at baseline were higher in the patients with treatment-resistant severe asthma than in those with difficult-to-treat severe asthma (40 ppb vs. 12 ppb). Sharples et al. also showed that FeNO discriminates between the two phenotypes [
4], although Konradsen et al. found no such distinction [
5]. Despite the statistical significance observed in the present study, the viability of monitoring FeNO in LMICs has to be questioned. Although the determination of FeNO is a non-invasive procedure that is easily performed, it is too costly to be incorporated into the routine evaluation of all patients suspected of having severe asthma.
In another study evaluating induced sputum samples collected from children and adolescents, Bossley et al. reported that the median proportion of eosinophils was 7.5% in the atopic patients with treatment-resistant severe asthma, among whom the median age was 11.8 years of age [
30]. In a study comparing controlled severe asthma with mild asthma in children and adolescents, no significant differences were found between the two types in terms of the proportion of eosinophils in induced sputum [
31]. In the present study, we also found no significant difference between treatment-resistant severe asthma and difficult-to-treat severe asthma in terms of the pattern of cellularity in sputum. Nevertheless, it is notable that sputum eosinophilia persisted in 25% of our patients even after the treatment regimen had been optimized.
In a study of sputum induction in children with difficult asthma, Lex et al. found that 11% had sputum neutrophilia [
23]. The authors pointed out that, although all of the children evaluated were chronically symptomatic, only a minority had sputum neutrophilia or eosinophilia. One possible explanation proposed by the authors is that the high doses of corticosteroids used in treating those children might have altered the sputum cytology [
23]. In the present study, we identified sputum neutrophilia in 18.8% of the treatment-resistant severe asthma group patients who were able to produce usable sputum samples in the post-protocol evaluation, none of whom had shown any clinical signs or symptoms of respiratory tract infection. It is possible that this was also a side effect of treatment, given that our patients were using high doses of inhaled corticosteroids, which have been shown to inhibit neutrophil apoptosis [
32].
The measurement of pulmonary function variables is important to the evaluation of asthma control [
1,
9]. In our sample as a whole, 44.4% of the patients had never undergone pulmonary function testing. They presented with baseline values of 77% and 78% for FEV
1 and the FEV
1/FVC ratio, respectively, which are indicative of mild obstructive lung disease, as would be expected. In some studies, FEV
1 has been reported to be only slightly altered in children with severe uncontrolled asthma [
3]. In the present study, baseline FEV
1 was comparable between the patients with treatment-resistant severe asthma and those with difficult-to-treat severe asthma. Therefore, it was possible to distinguish between the two phenotypes only by evaluating pulmonary function in detail. Even at the end of the follow-up period (after the WHO protocol had been applied and a high rate of adherence to treatment had been achieved), pulmonary function was still abnormal in 55.6% of our patients. That might be attributable to airway remodeling. It is possible that this population of patients could benefit from treatment with medications that have yet to be standardized for use in pediatric patients. It is also possible that, in LMICs, there is a large contingent of individuals with severe asthma featuring persistent airway limitation. Studies investigating this issue are warranted. There is also a need for studies evaluating the medium- and long-term risks of persistent airway limitation in children and adolescents in LMICs. A study conducted in high-income countries showed that children with severe asthma are at increased risk of developing adult COPD in adulthood, even if they never become smokers. The fixed abnormalities in lung function in adult life are established in early childhood and track at lower values progressing to persistent airway limitation in adulthood [
33].
Evaluating 45 atopic pediatric patients with treatment-resistant severe asthma, Bossley et al. observed thickening of the basement membrane and of the smooth muscle layer, indicating airway remodeling [
30]. In those same patients, the authors found that the mean baseline FEV
1 was 66% of the predicted value, comparable to the 61% observed in our sample. The authors suggested that there is a real need for new therapeutic strategies targeting children and adolescents with asthma that cannot be controlled even with high doses of inhaled or oral corticosteroids [
34], having also noted that the strategies employed in adult asthma patients cannot necessarily be extrapolated to children and adolescents [
30]. Konradsen et al. reported mean baseline FEV
1 values of 86% and 76% in their patients with treatment-resistant and difficult-to-treat severe asthma, respectively [
5].
Some authors have identified a statistically significant difference between treatment-resistant and difficult-to-treat severe asthma in terms of allergic sensitization to aeroallergens, which was found to be more common in pediatric patients with the treatment-resistant form [
4]. In the present study, we found no such distinction. In our sample as a whole, all but two of the patients tested positive for allergic sensitization. One of the patients in our treatment-resistant severe asthma group tested positive for sensitivity to
Aspergillus fumigatus. Twelve patients (five in our difficult-to-treat severe asthma group and seven in our treatment-resistant severe asthma group) tested positive for sensitivity to
Alternaria alternata, although computed scans of the chest revealed no bronchiectasis in any of those patients. Fungal sensitization has been associated with greater asthma severity [
35].
One of the limitations of our study is that the sample was highly selected, given that it comprised patients seen at a referral center for severe asthma. However, the patients had been referred from secondary health care facilities and required an approach that involved asthma treatment at all levels of health care.
Authors’ contributions
LMLBFL and WCCA designed the study and drafted the manuscript; LMLBFL and WCCA performed the statistical analysis; LMLBFL, WCCA and CATR participated in the enrollment and follow-up of the children and in drafting the manuscript; LMLBFL, WCCA and CATR participated in the enrollment and follow-up of the children; LMLBFL and WCCA supervised the data entry and management; PAMC and AAC assisted with data interpretation and manuscript development; LMLBFL, WCCA, PAMC and AAC critically revised the study design and manuscript. All of the authors read and approved the final version of the manuscript.