Asthma : critical debates

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Nevertheless, Barnes and colleagues compared the similarities and differences between COPD, asthma and severe asthma.

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Both COPD and severe asthma response poorly to steroids 2. These datasets suggest ACOS and severe asthma express high clinical similarities, and further attracted our curiosity that whether ACOS represents a special phenotype of severe asthma? ICS based therapy combined with bronchodilators are generally recommended for both ACOS and severe asthma in the guidelines listed on Table 1. Therefore, it is rather interesting to explore the role of cytokine-targeted biologics on ACOS therapy.

We raised the concerns that certain portion of participants eligible for this severe asthma study might be ACOS patients Treatment with dupilumab explicitly resulted in improvement of FEV 1 and severe exacerbations in airflow limitation group and furthermore, the subgroup combining with smoking history in line exhibited identical observations. Hence, they concluded dupilumab might function in ACOS patients, including those with smoking history Similar to dupilumab, a portion of participants enrolled into the clinical trials of these two reagents also represented persistent airflow limitations, who might be ACOS patients 42 - These patients are probable to benefit from this treatment.

Of note, newly released data unraveled that omalizumab dramatically improved symptom control and quality of life in patients with ACOS In concert, some recent observational studies from independent groups reported that ACOS patients experienced lower rates of exacerbation and hospitalization, and fewer symptoms after omalizumab treatment 46 - 48 , although some drawbacks of the study design existed However, this conclusion is warranted to be validated by large-scale, double-blind, randomized clinical trials.

BT reduced exacerbations, dose of steroids, emergency department visits, hospitalizations and improved the symptoms of severe asthma As the therapeutic target, airway over-thickness was also found in ACOS subjects For this, selection of appropriate patients is the most crucial step.

It will supply important information showing whether ASM over-thickness is present and which lobe exhibits predominant airway remodeling. It has been applied in both asthma and COPD subjects, showing some beneficial effects 56 , 57 , especially in those with local neutrophilic inflammation Notably, increased airway neutrophils counts were also found in ACOS It is worth to perform a therapeutic trial of macrolide antibiotics in patients with ACOS.

It has been shown that viral-induced wheezing is uncommon before two months of age, and that the frequency decreases after the two years of age, not only due to immunological factors, but also due to the increased bronchial diameter. Immunological mechanisms may act in an antagonistic way, contributing to the genesis of viral-induced wheezing. For example, although cellular immunodeficiency has an important protective effect, it may lead to permanent alterations. Although an intensified cellular response is necessary to eradicate the virus, it may also cause airway damage, which may persist even after the eradication of the pathogenic agent.

It has been well established in the literature that there is a correlation between a pronounced cellular response and severe pulmonary disease accompanied by wheezing. However, breast milk may provide a certain degree of protection against wheezing, especially wheezing induced by the respiratory syncytial virus RSV. Neutralization of the lymphoproliferation response to the RSV seems to be correlated with the secretory IgA and the interferon-y present in it Among the viruses that induce wheezing, RSV is the most commonly found Currently, there is well-established evidence that toddlers with bronchiolitis caused by RSV are at increased risk for the continuation of respiratory symptoms until reaching school age.

The determining factor of this situation is poorly understood. Genetic and environmental factors seem to define the type as well as the intensity of the immune response to acute RSV infection, and this response affects the mechanisms that control muscle tonus. Among such responses is the cell-mediated defense mechanism. This mechanism is stimulated when the RSV infects respiratory epithelial cells such as macrophages and monocytes that produce cytokines and interleukins Stein et al. However, this correlation was less than significant among children of thirteen years of age and was not observed in children with a history of allergy.

Whereas RSV-induced wheezing tended to decrease with age, early allergic sensitization tended to increase rather than regress. The authors emphasized that the increase in the airway diameter may reduce the probability of wheezing unrelated to airway allergic inflammation. However, the alterations in airway tonus observed in children with a history of RSV infection tended to decrease with age. These children presented decreased bronchial responsiveness to methacholine at school age.

In summary, wheezing in nonatopic children is often induced by viral infection, especially by RSV, whereas wheezing in atopic children is mediated by IgE. The same view is shared by Ribeiro 27 , who stated that most episodes of bronchial obstruction in wheezing toddlers are viral in origin, and that, when there is no concomitant atopy, such children remain asymptomatic between crises.

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It is possible that the development of the persistent form of wheezing is dependent on genes and the action of certain environmental factors in early life. The identification of these factors would make it possible to devise a primary prevention strategy. Otherwise, we would contribute to the increased prevalence.

However, it has been observed that early exposure to certain factors, including interaction with other children in day care centers or interaction with animals, decreases the risk of persistent asthma For years, the correlation between persistent asthma and the development of IgE antibodies in response to certain airborne allergens, such as dust mites, favored the hypothesis that the risk of asthma would be correlated with the degree of exposure to those allergens in early life Nevertheless, studies determining the concentration of dust mites in the home have failed to establish a causal relationship between this factor and the development of asthma by school age Similarly, no correlation has been found between low dust mite concentrations and a lower incidence of asthma.

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  • Paradoxically, increased exposure to cat and dog allergens in the first years of life has been correlated with a marked decrease in the subsequent risk of developing asthma In fact, high microbial burdens have been found in the dust of houses where there are pets.

    This burden elicits immune responses that do not involve Th2 cells, which is a characteristic of persistent asthma. The infection would thus protect against the subsequent development of atopy 26, The role played by exposure to animals in the development of allergic diseases needs to be further investigated. In summary, genetic and environmental factors influence the expression and progression of asthma or atopy, or both.

    Among these factors are early sensitization to airborne allergens, premature birth, maternal smoking during pregnancy, exposure to smokers after birth, maternal asthma, growth and development of the respiratory system, and viral infections, such as RSV infection Therefore, a significant percentage of asthmatics will have presented wheezing and required therapeutic care while still toddlers.

    In addition, there are no methods available that are both easy to use and present high sensitivity and specificity for making a certain diagnosis of asthma in children under five years of age. However, the fact that diagnosis is made almost exclusively through evaluation of simple clinical parameters, as proposed, among others, by Castro-Rodriguez in his study 23 , makes it possible to diagnose such children in health centers presenting any level of complexity since no advanced technology is required.

    In addition, the fact that wheezing is triggered by numerous agents makes it possible to consider asthma to be, in terms of symptoms, a clinical syndrome that needs to be approached therapeutically, according to the severity of the manifestations In view of the difficulty in making a definitive diagnosis of asthma in children under five years of age, the British Guidelines on Asthma Management 40 recommend using the term wheezing disease as a substitute for the word asthma.

    The controversy regarding diagnosis of toddlers is equaled by that surrounding the timing of ICT introduction in such patients. Oswald et al. The authors stated that the acquired PF deficit could be explained by the chronic airway inflammation caused by the allergy. Sears 33 observed PF deficit in patients with persistent asthma. This deficit increased after the development of the first symptoms.

    Asthma : Critical Debates

    The author argued that it is plausible to suspect that the rapid growth of the lungs during the preschool period may be particularly susceptible to the effects of the more intense inflammation that accompanies persistent asthma. In summary, chronic inflammation may cause bronchial remodeling, stunt airway growth and reduce PF.

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    Therefore, delayed initiation of ICT would have a lesser effect on PF and bronchial hyperresponsiveness than would early initiation. Various authors have shown the response to ICT to correlate with time of treatment initiation, suggesting that initiation at the first clinical manifestations leads to better results since the inflammatory process occurs early in asthma Early initiation of ICT could reduce bronchial inflammation, thereby preventing the more severe form of the disease as well as protecting against the establishment of irreversible obstruction years later.

    Agertoft et al. The Childhood Asthma Management Program Research Group 46 monitored children from five and twelve years of age over a period of four to six years. Patients were given three types of maintenance treatment: placebo, budesonide and nedocromil. The authors observed that clinical control and improvement in bronchial hyperresponsiveness, measured using the methacholine provocation test, were significantly greater in patients treated with budesonide; an advantage that was not maintained after the discontinuation of treatment. The results of the responsiveness to methacholine seen in the group receiving budesonide suggest that the beneficial effect of this treatment was due to alterations in the muscle tonus and in bronchial inflammation rather than in the prevention or in the resolution of the bronchial remodeling.

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    After two months of budesonide use, there was an improvement in postbronchodilator forced expiratory volume in one second. However, the mean values for this parameter at the end of the treatment were similar to those obtained at the beginning of the treatment and to those found in the placebo group. The authors concluded that continuous treatment with budesonide in children five years of age or older with mild to moderate asthma did not present any therapeutic benefit in terms of PF, raising the hypothesis that, since the mean duration of the disease was five years at the beginning of the treatment, there is irreversible deterioration in PF prior to the initiation of treatment.

    Further studies are needed in order to determine the effect of ICT on the normalization of PF and to assess the capacity of such treatment to prevent alterations in the structure of the bronchial tree in asthmatic patients The positive effect of ICT on the control of clinical manifestations has been well established. In the Belo Horizonte Asthma Program 47 , the frequency of hospitalizations and emergency room visits was evaluated prior to and after ICT in children with asthma or wheezing syndrome.

    The occurrences of such episodes in the twelve months prior to ICT were the parameters of comparison. The study sample consisted of children under fifteen years of age. Mean age was 3. All were monitored in a clinical setting for at least twelve months after the initiation of ICT beclomethasone dipropionate. Hospitalizations and emergency room visits were reduced by Sano et al. Until the middle s, ICT was not recommended for toddlers or preschoolers However, its efficacy in this age group has now been documented.

    Making a certain diagnosis of persistent asthma in children under three years of age remains the greatest difficulty. Evidence suggests that ICT outcomes are better when asthma is diagnosed early, allowing the initiation of treatment within the first two years of illness According to Landau 50 , ICT should be introduced when the symptoms occur more than once or twice a week, or when there are more than two attacks a month. Ribeiro 28 enumerated possible situations and doses for use of ICT in toddlers and preschoolers.

    Based on the severity of symptoms, the author listed the following situations: continuous symptoms or symptoms manifesting themselves more than twice a week, attacks occurring more than twice a month, life-threatening acute respiratory insufficiency in a toddler and abnormal PF between attacks something that is difficult to evaluate in our milieu in a toddler.

    Based on evidence of atopy, the author included toddlers with moderate and severe atopic wheezing. Based on evidence of recurrent wheezing after an episode of acute viral bronchiolitis, the author included patients admitted to intensive care units because of acute respiratory insufficiency, and who, after discharge, continue having persistent wheezing.

    In cases of severe wheezing, the author suggests starting with high doses and decreasing the dosage as soon as possible. In toddlers with moderate wheezing, he recommends starting with low doses and discontinuing the medication within three months. However, clinical evaluation is the principal parameter and, depending on the response obtained, the dose level should be maintained or increased.

    Viral infections constitute an aspect that deserves special attention. The benefits of ICT or oral corticosteroid treatment in toddlers presenting recurrent wheezing episodes are still unclear and seem to be dependent on age and on symptom severity According to Taussig 8 , patients with recurrent viral-induced wheezing, even those without a certain diagnosis of asthma, may benefit from inhaled anti-inflammatory drugs.

    Intermittent use of high-dose ICT in preschoolers with episodic viral-induced wheezing has been correlated with modest improvement 52,53 , whereas continuous use has proven ineffective Svedmyr et al. Connett et al.

    The findings of the study carried out by Kajosaari et al. Another relevant aspect is hospitalization in children under five years of age. In studying patients with a possible diagnosis of asthma, Wever-Hess et al. In the revision of the Global Initiative for Asthma 10 it is stated that "the clinical benefits of the use of inhaled or systemic corticosteroids in the treatment of viral-induced bronchospasm remain controversial. Some studies did not find, in the acute phase of the viral-induced bronchospasm, short or long-term clinical benefits of the use of this treatment in previously healthy toddlers, although there are studies that reported improvement.

    The ideal timing of ICT initiation is still under debate. Therefore, the use of ICT in toddlers and preschoolers should be preceded by a critical evaluation in which its risks and benefits are carefully evaluated. In summary, ICT should be prescribed to children who present severe exacerbations, hospitalizations, frequent use of -agonists, persistent symptoms that lead to impaired growth and development or to pulmonary hyperinflation between attacks 2,3,17, The use of ICT in the treatment of bronchiolitis and exacerbation seems to bring positive results.

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