asthma is a chronic lower airway disease that affects approximately 300 million people worldwide - children accounting for 60% of all cases - resulting in more than 250,000 deaths per year.1 in some developing countries , particularly in latin america , the prevalence of asthma in children is high.2 currently , one of the most important aspects of asthma is how it affects the quality of life of patients . this occurs specifically in individuals with uncontrolled asthma and is more closely related to cases that are more severe , resulting in substantial costs to society.3 
  in children , difficult - to - control asthma is the greatest clinical challenge , its estimated prevalence being 0.5% in school - age children and approximately 5% among children with asthma.4 children with difficult - to - control asthma have frequent exacerbations , daily symptoms , and impaired quality of life , all of which have a major impact on medical care . in addition , difficult - to - control asthma results in school absenteeism , hospitalizations , and financial costs to families and society . children with difficult - to - control asthma are defined as those in whom the disease remains uncontrolled despite the use of high - dose inhaled corticosteroids and other control drugs.5 
  in such patients , the most complex and difficult - to - treat clinical presentation is severe therapy - resistant asthma ( stra ) , which requires a thorough approach . children with stra require systematic evaluation to rule out other chronic lung diseases , correct the inhalation technique , evaluate adherence to treatment , and manage comorbidities and important environmental factors . the only treatment options for such patients are omalizumab ( an anti - ige antibody ) and continuous oral corticosteroid use.6 unfortunately , stra in children has yet to be fully understood , and it appears to be different from stra in adults.7 few studies have specifically described the clinical characteristics of children with stra and analyzed in detail the mechanisms responsible for this severe presentation of asthma . in addition , no studies have described stra in children from developing countries , and it should be taken into account that the prevalence of severe asthma is high in continent - sized countries , such as brazil.13 therefore , the objective of the present retrospective study was to describe patient clinical characteristics , lung function , radiological findings , and airway inflammation in children and adolescents with stra treated at a referral center in southern brazil . we retrospectively analyzed children and adolescents followed for at least 6 months at monthly visits to a referral center in a tertiary care hospital in southern brazil ; all of the patients had been diagnosed with stra.7 the inclusion criteria were as follows : 1 ) children and adolescents 3 - 18 years of age diagnosed with asthma ; 2 ) use of at least 800 g of budesonide or equivalent in combination with a long - acting 2 agonist ; 3 ) appropriate management of treatable comorbidities ( particularly chronic rhinosinusitis and gastroesophageal reflux ) ; 4 ) correct inhalation technique , as determined at each visit during the initial 6 months of follow - up ; 5 ) good adherence to treatment , as determined by the treatment team ; and , finally , 6 ) meeting at least one of the following criteria for uncontrolled asthma : a ) chronic symptoms ( cough , wheezing , and dyspnea ) ; b ) three or more exacerbations in recent months ; c ) frequent need for short - acting 2 agonist use ; d ) reduced lung function that can not be reversed with treatment ; and e ) need for continuous oral corticosteroid use . children and adolescents diagnosed with other diseases ( cystic fibrosis , post - infectious bronchiolitis obliterans , immunodeficiency , and congenital heart disease , among others ) and those with significant cognitive impairment were excluded . sweat tests were performed , and blood samples were collected for blood workup , platelet counts , determination of immunoglobulin levels , and hiv testing . patients with a body mass index above the 95th percentile on the us centers for disease control and prevention clinical growth charts were considered obese.14 
  spirometry was performed at all visits , provided that the patients had no symptoms of exacerbation or viral respiratory infection . the first spirometry performed at the referral center and another , performed 6 months after treatment optimization , were chosen , provided that the patients had no symptoms of viral respiratory infection . all tests were performed in accordance with the american thoracic society / european respiratory society technical standards and acceptability / reproducibility criteria for children.15 a koko spirometer ( ferraris respiratory , louisville , co , usa ) was used . fvc , fev1 , fev1/fvc , and fef25 - 75% were presented as z scores , the reference values being those proposed by the global lung initiative.16 bronchodilator response was defined as an increase in fev1 of at least 10% .   at baseline , all patients underwent skin prick tests for sensitivity to aeroallergens ( ipi asac brasil , so paulo , brazil ) . the tests were performed on the forearm , with single drops of saline and histamine , as well as of dilutions of dermatophagoides pteronyssinus , d. farinae , blomia tropicalis , cockroach allergens , dog dander , cat dander , fungi , and grass , all of which were placed 2 cm apart . aspergillus fumigatus extract was included in cases of total ige > 2,000 iu / ml or total ige = 1,000 - 2,000 iu / ml and bronchiectasis on chest ct scans . subsequently , for each allergen , a skin prick test was performed with a device that limits skin penetration . the absence of papules indicated that the test was negative ; the presence of papules  3 mm in diameter indicated that the test was positive . atopic patients were defined as those with a positive response to at least one allergen . sputum induction was performed at baseline and at 3 - 6 months of follow - up . nebulization with hypertonic saline ( 4.5% ) was performed four times , each lasting 5 min . the procedure was terminated at 20 min or if fev1 fell by 20% or more . patients were instructed to cough and expectorate the sputum into a container after each nebulization . clumps of sputum were immediately separated and diluted in dulbecco 's pbs and dtt and filtered with a 60-m filter . after centrifugation at 2,000 rpm for 2 min , the supernatant was removed and the precipitate was resuspended in 1 ml of dulbecco 's pbs . differential cell counts were performed on slides stained with may - grnwald - giemsa after cytocentrifugation of the suspension ( at 500 rpm for 5 min ) . a total of 400 cells were counted , and the results were expressed as percentages . samples in which the proportion of squamous epithelial cells was > 20% were considered to have originated from the upper airways and were discarded . sputum samples in which the proportion of squamous epithelial cells was  20% were classified as paucigranulocytic ( < 2% of eosinophils and < 54% of neutrophils ) , eosinophilic ( > 2% of eosinophils and < 54% of neutrophils ) , neutrophilic ( < 2% of eosinophils and > 54% of neutrophils ) , or mixed ( > 2% of eosinophils and > 54% of neutrophils).17 
  during clinical follow - up , all patients underwent chest ct ( as recommended by the medical treatment team ) and were evaluated by a radiologist . esophageal ph monitoring was requested by the treatment team , and all results were interpreted by the same pediatric gastroenterologist . gastroesophageal reflux disease ( gerd ) was defined as the presence of at least one of the following : 1 ) at least one reflux episode lasting > 20 min ; 2 ) temporal association of more than 50% of signs and symptoms with episodes of acid reflux ; 3 ) reflux index > 10% ; and 4 ) mean duration of reflux episodes during sleep ( zmd index ) > 3.8 min / episode .   at the monthly visits , the asthma control test ( act ) was applied for the patients who were over 12 years of age . the act is a five - item questionnaire addressing symptoms , rescue medication use , and the effect of asthma on activities of daily living ; an act score of < 20 indicates uncontrolled asthma.18 the only act scores that were included in the present study were those of the patients to whom the act was administered more than five consecutive times ( once at each clinical visit ) . continuous variables were presented as mean and standard deviation or as median and interquartile range , depending on the distribution of the variable of interest . a student 's t - test for dependent samples was used in order to compare lung function variables , according to the distribution of the variable of interest . the objectives of the study were explained to the patients and their parents or legal guardians , and written informed consent was obtained from all participants . a total of 21 children and adolescents with stra were selected . of those , 10 ( 47.6% ) were male . of the 21 patients , 2 ( 9.5% ) were using continuous oral corticosteroids . all participants had asthma symptoms nearly every day ( including nocturnal symptoms and symptoms during exercise ) , as well as frequent exacerbations . half of the participants had a history of more than one hospitalization for asthma , their quality of life and that of their family members being severely impaired . total serum ige levels varied widely ; 12 ( 63.2% ) of 19 participants had values > 500 iu / ml .   omalizumab was used in 8 patients ( 38.1% ) and was discontinued more than 12 months later in only 1 , who had no clinical response to the drug . the remaining patients showed significant clinical improvement , with no further hospitalizations or frequent exacerbations . of the 8 patients who received omalizumab , 3 ( 37.5% ) became asymptomatic . there were no reports of adverse events in those patients . because they were not atopic , because they were under 6 years of age , or because their total serum ige levels were outside the recommended range , 13 of the 21 participants did not receive omalizumab . nevertheless , despite being atopic , the participant showed clinical improvement with the use of continuous azithromycin ( three times a week ) . variablespatients(n = 21)male gender , n ( % ) 10 ( 47.6)age , years9.20 2.98family history of asthma21 ( 100.0)household smoking8 ( 38.0)allergic rhinitis21 ( 100.0)atopic dermatitis4 ( 19.0)obesity5 ( 23.8)age at symptom onset , years1.14 0.95gerd symptoms3 ( 14.3)continuous oral corticosteroid use5 ( 23.8)montelukast use6 ( 25.6)history of hospitalization11 ( 52.4)serum ige , iu / ml 
 < 300 ( 0.0)30 - 5007 ( 36.8 ) > 50012 ( 63.2)bronchodilator response6 ( 25.6)abnormal ph monitoring results 
 6 ( 60.0)gerd : gastroesophageal reflux disease . n = 10 .   in 17 ( 85% ) of 20 participants , skin prick test results were positive . the skin prick test for sensitivity to a. fumigatus was performed in 5 patients , and all had negative results ( figure 1 ) .   with regard to lung function , all patients had flow - volume curves within normal limits or mild obstructive lung disease . this variation was found in the same patients in the second spirometry , performed approximately 6 months after the first , when pre - bronchodilator curves were evaluated . among lung function variables , there was no significant difference between the two measurements regarding the variables most closely related to bronchial obstructive disease ( figure 2 ) . esophageal ph monitoring revealed gerd , but only 1 patient appeared to show clinical improvement of asthma after the initiation of treatment with omeprazole , which was preceded by the optimization of inhaled asthma therapy . figure 1proportion of severe therapy - resistant asthma patients ( n = 20 ) with positive skin prick test results ( first black column ) and proportions of specific allergens in those patients ( n = 17 ) . sputum induction was performed in 18 patients but was successful in only 13 ( 73% ) . in the remaining patients , of the 13 patients in whom sputum induction was successful , 2 had a paucigranulocytic inflammatory phenotype , 4 had an eosinophilic inflammatory phenotype , and 7 had a neutrophilic inflammatory phenotype ( figure 3 ) . the inflammatory cell profile changed in 4 ( 67% ) of the 6 patients in whom sputum examination was successfully repeated , having changed from an eosinophilic profile to a neutrophilic profile in 1 , from a neutrophilic profile to a paucigranulocytic profile in 1 , from a paucigranulocytic profile to a neutrophilic profile in 1 , and from an eosinophilic profile to a mixed profile in 1 . sputum induction did not result in significant adverse events in any of the patients . ground - glass opacities were found in 2 patients , and hiatal hernia was an incidental finding in 1 patient . chest ct scans were normal in 3 ( 18.8% ) of the 16 patients .   with regard to the act , 6 patients were over 12 years of age and were administered the questionnaire more than five consecutive times . figure 4 shows that uncontrolled asthma ( an act score of < 20 ) predominated despite treatment optimization during follow - up . figure 2lung function in children and adolescents with severe therapy - resistant asthma ( n = 21 ) at baseline and at 6 months after treatment optimization . the variables are from pre - bronchodilator curves and are expressed as z scores for the global lung initiative reference values . in the last decade , many studies have focused on severe asthma in adults , describing multiple phenotypes / endotypes and complex , difficult - to - treat clinical presentations . few studies have described the clinical characteristics of children with stra , and none have involved populations of children in developing countries . chief among the few mechanisms of stra investigated in children are reduced th2 response , increased il-33 expression , and reduced il-10 expression . it is of note that , although stra accounts for only a small proportion of all cases of asthma in children , the fact that the quality of life of children with stra is significantly impaired results in high ( direct and indirect ) costs to society and warrants future investment in research into stra in children . ours is the first study to describe the clinical phenotype of stra in children and adolescents in urban areas of a large city in southern brazil .   in the present study , most ( 85% ) of the children had atopic asthma , with early disease onset , and a significant proportion ( nearly 25% ) was obese , findings that are similar to those in children with stra in developed countries . the number of phenotypes appears to be greater in adults with severe asthma than in children with severe asthma , as does the complexity of phenotype combinations .   in our study , cat , dog , and fungal allergens were uncommon , a finding that was reported by our research group in a previous study of children with asthma in the same region . 21 the chest ct findings were consistent with chronic inflammatory bronchial obstructive disease , consistent with severe asthma , and did not greatly contribute to the diagnosis . although chest ct is formally recommended for all asthma patients , this recommendation has been questioned in children with stra.7 
 
 figure 3success rate in the 18 patients who underwent sputum induction and proportions of inflammatory cell profiles in the patients in whom sputum induction was successful ( n = 13 ) . the most interesting findings of our study were those related to the lung function of the patients and the airway inflammatory profile . the spirometry tests performed when the patients had no exacerbations showed mild obstructive changes in most cases . in adults , severe asthma is closely associated with major lung function changes , which are not observed in children , as previously described . with regard to the natural history of the disease this does not mean that histopathological changes , such as bronchial remodeling , do not appear early in life , particularly in preschool - age children , and are already present in school - age children and adolescents , as demonstrated in previous studies involving transbronchial biopsies . given the near - normal baseline lung function and the lack of disease control in such patients , it is necessary to gain a better understanding of the obstructive mechanisms in order to use new therapies . one hypothesis to explain this finding is that children with stra have excessively labile bronchomotor tone , which might explain the lack of significant spirometric changes in patients with frequent symptoms . figure 4 in a , median asthma control test ( act ) scores ( solid horizontal bars ) for the patients to whom the act was administered at consecutive medical visits . in b , frequency of events in which patients were considered to have controlled asthma ( an act score  20 ) or uncontrolled asthma ( an act score of < 20 ) at consecutive visits during which the act was administered ( n = 6 ) . induced sputum allows noninvasive evaluation of lower airway inflammation in asthma patients and has been used in studies of children with asthma . we obtained samples that were adequate for analysis in 72% of the cases ; the inflammatory cell profile varied widely , with neutrophilic airway inflammation predominating . in addition , unlike what is commonly observed in adults , our results , together with the findings of another study,17 suggest that the inflammatory cell profile of children with severe asthma varies over time . this can be explained by the neutrophil component , which is possibly secondary to frequent ( often subclinical ) viral respiratory infections in this age group . given that the characteristics of induced sputum are more stable in adults than in children , sputum induction is rarely indicated in the management of severe asthma in children.7 however , it can be a useful clinical tool in specific patients , particularly those with a nonatopic neutrophilic phenotype . however , esophageal ph monitoring revealed that a larger number of patients appeared to have gerd . the results of esophageal ph monitoring should always be interpreted with caution , and clinical correlations should be established . however , in children with severe asthma , the treatment of gerd does not appear to result in clinical improvement in respiratory symptoms and is not commonly indicated.6 at our referral center , esophageal ph monitoring in children with severe asthma is currently reserved for those with high clinical suspicion and symptoms suggestive of gerd . children with stra are a major clinical challenge because the proportion of patients with uncontrolled disease is high despite the use of high - dose corticosteroids . in such individuals , the goal is to achieve the best possible degree of asthma control and to minimize the potential adverse effects of corticosteroids ; however , it should be borne in mind that , given the heterogeneous characteristics of the disease , treatment success rates generally vary.1 children with stra frequently do not respond well to corticosteroid therapy and therefore require high - dose corticosteroids . one alternative that has emerged in the last decade is omalizumab , a humanized monoclonal anti - ige antibody that blocks one of the domains of the heavy chain of the fc portion of free ige . this high affinity for the fc portion of ige competes with mast cell and basophil receptors , inhibiting the inflammatory response . in children with stra , including inner - city residents in the usa , omalizumab reduces corticosteroid doses , exacerbations , and hospitalizations . in our study , 7 ( 88% ) of 8 children responded clinically to omalizumab , as determined by the medical team , with omalizumab treatment reducing the number of exacerbations and preventing further hospitalizations . there were no adverse events related to the use of omalizumab in those patients during the study period . a recent multicenter real - life study conducted in france showed a 72% reduction in exacerbations in children with severe asthma treated with omalizumab.31 
  in our study , the patients in whom omalizumab was contraindicated ( because of their age , ige levels , or lack of allergen sensitization ) were started on empirical treatment with continuous macrolide antibiotic therapy ( azithromycin ) , and only 1 patient had a clinical response . no other therapeutic alternatives , such as antifungal agents , immunomodulators , and cytotoxic drugs , were used at our referral center . the most recent international guidelines for severe asthma in adults and children do not recommend the use of macrolides or other alternative drugs.7 
  the major limitation of our study is its descriptive and retrospective nature . however , given that our objective was to describe for the first time a sample of children with stra from a developing country , we believe that this limitation is of minor concern , particularly because all data and variables were prospectively collected in a database by the authors during medical visits .   in conclusion , the present study is the first to describe a sample of children and adolescents with stra from an urban area of a developing country . although the clinical characteristics of these children and adolescents are similar to the characteristics of those from developed countries , the mechanisms of and risk factors for severe asthma , particularly lung function , bronchial inflammation , and the immune response , should be further investigated in larger multicenter longitudinal studies . descrever as principais caractersticas clnicas , a funo pulmonar , as caractersticas radiolgicas e o perfil inflamatrio do escarro induzido de crianas e adolescentes com asma grave resistente a terapia ( agrt ) tratados em um centro de referncia do sul do brasil . foram analisadas retrospectivamente crianas e adolescentes de 3 - 18 anos com diagnstico de agrt no controlada acompanhados durante pelo menos 6 meses e tratados com doses elevadas de corticoide inalatrio associado a um 2-agonista de longa durao . foram coletados prospectivamente dados relativos ao controle da doena , funo pulmonar , teste cutneo para alrgenos , perfil inflamatrio do escarro induzido , tc de trax e phmetria esofgica . foram analisados 21 pacientes ( mdia de idade : 9,2 2,98 anos ) . dos 21 , 18 ( 86% ) eram atpicos . a maioria apresentava asma no controlada e funo pulmonar basal prxima em 4 e 7 pacientes , o escarro induzido revelou - se eosinoflico e neutroflico , respectivamente , e 67% dos pacientes que repetiram o exame apresentaram mudana no perfil inflamatrio . dos 8 pacientes que receberam omalizumabe ( um anticorpo anti - ige ) , 7 ( 87,5% ) apresentaram melhora importante da qualidade de vida , com reduo importante das exacerbaes e hospitalizaes . crianas com agrt apresentam funo pulmonar prxima do normal e padro inflamatrio das vias areas varivel durante o seguimento clnico , com importante resposta clnica ao omalizumabe . a agrt em crianas difere da agrt em adultos , e so necessrios mais estudos para esclarecer os mecanismos da doena . foram analisados retrospectivamente crianas e adolescentes acompanhados durante pelo menos 6 meses , em visitas mensais , em um centro de referncia de um hospital tercirio no sul do brasil , todas elas com diagnstico de agrt.7 os critrios de incluso dos pacientes foram os seguintes : 1 ) crianas e adolescentes de 3 - 18 anos com diagnstico de asma ; 2 ) uso de , no mnimo , 800 g de budesonida ou equivalente associada a 2-agonista de longa durao ; 3 ) manejo adequado das comorbidades tratveis ( particularmente rinossinusite crnica e refluxo gastroesofgico ) ; 4 ) tcnica de inalao adequada , verificada em cada consulta realizada durante o perodo inicial de 6 meses ; 5 ) boa adeso ao tratamento , avaliada pela equipe assistencial ; e , finalmente , 6 ) preenchimento de pelo menos um dos seguintes critrios de ausncia de controle da doena : a ) sintomas crnicos ( tosse , sibilos ou dispneia ) ; b ) trs ou mais exacerbaes nos ltimos meses ; c ) necessidade frequente de 2-agonista de curta durao ; d ) funo pulmonar reduzida e no reversvel com tratamento ; ou e ) necessidade de uso de corticoide oral contnuo . foram excludos crianas e adolescentes com diagnstico de outras doenas ( fibrose cstica , bronquiolite obliterante ps - infecciosa , imunodeficincias , cardiopatias congnitas etc . ) ou alterao cognitiva importante . foram realizados teste do suor e coleta de sangue para hemograma , plaquetas , imunoglobulinas e anti - hiv . foram considerados obesos os pacientes com ndice de massa corprea acima do percentil 95 das curvas dos centers for disease control and prevention dos eua.14 
  espirometrias foram realizadas em todas as consultas , sempre com os pacientes sem sintomas de exacerbao ou infeco respiratria viral . foram escolhidas a primeira espirometria feita no centro de referncia e outra , realizada 6 meses aps a otimizao do tratamento , sempre com os procedimentos tcnicos e os critrios de aceitabilidade e reprodutibilidade dos exames seguiram as recomendaes da american thoracic society e da european respiratory society para crianas.15 foi usado um espirmetro koko ( ferraris respiratory , louisville , co , eua ) . a cvf , o vef1 , a relao vef1/cvf e o fef25 - 75% foram apresentados na forma de escore z , com os valores de referncia da global lung initiative.16 considerou - se que houve resposta ao broncodilatador quando houve pelo menos 10% de aumento do vef1 .   os pacientes foram submetidos a teste cutneo para aeroalrgenos ( ipi asac brasil , so paulo , brasil ) no incio da avaliao clnica . o teste cutneo foi realizado no antebrao , com gotas nicas ( a cada 2 cm ) de soro fisiolgico , histamina , e os diluentes do extrato de dermatophagoides pteronyssinus , d. farinae , blomia tropicalis , alrgenos de barata , epitlio de co , epitlio de gato , fungos e gramneas . o extrato de aspergillus fumigatus era includo em casos de ige total > 2.000 ui / ml ou de ige total = 1.000 - 2.000 ui / ml e presena de bronquiectasias na tc de trax . posteriormente , realizava - se um teste cutneo de puntura para cada alrgeno com um dispositivo que limita o grau de penetrao na pele . na ausncia de ppula , o teste era considerado negativo ; a presena de ppulas com dimetro  3 mm indicava teste positivo . o paciente era considerado atpico se apresentasse resposta positiva a pelo menos um alrgeno .   realizou - se induo de escarro no incio do acompanhamento e 3 - 6 meses depois . eram realizadas quatro nebulizaes de 5 min de durao com soluo salina hipertnica ( 4,5% ) . o paciente era instrudo a tossir e a depositar o escarro em um recipiente ao final de cada nebulizao . grumos de escarro eram ento imediatamente separados e diludos em pbs de dulbecco e dtt e filtrados com um filtro de 60 m . aps centrifugao a 2.000 rpm durante 2 min , o sobrenadante era removido e o precipitado ressuspendido em 1 ml de pbs de dulbecco . o exame citolgico diferencial era realizado em lminas coradas com may - grnwald - giemsa aps a citocentrifugao da suspenso ( a 500 rpm durante 5 min ) . eram contadas 400 clulas , e os resultados eram expressos em porcentagem . amostras com > 20% de clulas epiteliais escamosas foram consideradas provenientes de vias areas superiores e descartadas . as amostras de escarro com  20% de clulas epiteliais escamosas foram classificadas em paucigranulocticas ( < 2% de eosinfilos e < 54% de neutrfilos ) , eosinoflicas ( > 2% de eosinfilos e < 54% de neutrfilos ) , neutroflicas ( < 2% de eosinfilos e > 54% de neutrfilos ) ou mistas ( > 2% eosinfilos e > 54% de neutrfilos).17 
  durante o acompanhamento clnico , todos os pacientes foram submetidos a tc de trax ( por indicao da equipe mdica assistencial ) e avaliados por um mdico radiologista . a phmetria esofgica foi solicitada pela equipe assistencial , e todos os exames foram interpretados pelo mesmo gastroenterologista peditrico . foram considerados portadores de doena do refluxo gastroesofgico ( drge ) os pacientes que apresentaram pelo menos uma das caractersticas a seguir : 1 ) pelo menos um episdio de refluxo com durao > 20 min ; 2 ) associao temporal de mais de 50% de sinais e sintomas e episdios de refluxo cido ; 3 ) ndice de refluxo > 10% ; ou 4 ) mdia de durao dos episdios de refluxo durante o sono ( ndice zmd ) nas consultas mdicas , o asthma control test ( act ) era aplicado nos pacientes com mais de 12 anos de idade . o act possui cinco itens que dizem respeito aos sintomas , uso de medicao de alvio e efeito da asma nas atividades dirias ; uma pontuao < 20 no act significa asma no controlada.18 s foram includos os resultados do act dos pacientes com mais de cinco avaliaes consecutivas em visitas clnicas . as variveis contnuas foram apresentadas em forma de mdia e desvio - padro ou mediana e intervalo interquartil , conforme a distribuio da varivel . para a comparao das variveis da funo pulmonar , foi utilizado o teste t de student para variveis dependentes , conforme a distribuio da varivel . para a incluso dos pacientes , foram explicados os objetivos da pesquisa e foi solicitada a assinatura do termo de consentimento livre e esclarecido pela criana e pelos pais ou responsveis . foram selecionados 21 crianas e adolescentes com agrt , 10 ( 47,6% ) das quais eram do sexo masculino . a mdia de idade foi de 9,2 2,98 anos . as caractersticas todos os pacientes includos apresentavam sintomas de asma quase todos os dias ( incluindo sintomas noturnos e sintomas durante o exerccio ) e exacerbaes frequentes . metade dos pacientes apresentava histria de mais de uma hospitalizao por causa da doena , com grande comprometimento da qualidade de vida ( a prpria e a dos familiares ) . os nveis sricos de ige total variaram bastante ; 12 ( 63,2% ) de 19 pacientes apresentaram valores > 500 ui / ml .   o omalizumabe foi utilizado em 8 pacientes ( 38,1% ) e foi suspenso mais de 12 meses depois em apenas 1 deles , pois no apresentou resposta clnica ao medicamento . todos os outros pacientes apresentaram melhora clnica importante , sem apresentar mais hospitalizaes ou exacerbaes frequentes . por no serem atpicos , por terem menos de 6 anos de idade ou por apresentarem ige total srica fora dos limites indicados , 13 dos 21 pacientes no receberam omalizumabe . por ter menos de 6 anos de idade , o paciente em questo no recebeu omalizumabe e , mesmo atpico , apresentou melhora clnica com azitromicina contnua ( trs vezes por semana ) . variveispacientes(n = 21)sexo masculino , n ( % ) 10 ( 47,6)idade , anos9,20 2,98histria familiar de asma21 ( 100,0)tabagismo domiciliar8 ( 38,0)rinite alrgica21 ( 100,0)dermatite atpica4 ( 19,0)obesidade5 ( 23,8)incio dos sintomas , anos1,14 0,95sintomas de drge3 ( 14,3)uso de corticoide oral contnuo5 ( 23,8)uso de montelucaste6 ( 25,6)histria de hospitalizao11 ( 52,4)ige srica , ui / ml 
 < 300 ( 0,0)30 - 5007 ( 36,8 ) > 50012 ( 63,2)resposta ao broncodilatador6 ( 25,6)phmetria alterada 
 6 ( 60,0)drge : doena do refluxo gastroesofgico . em 17 ( 85% ) de 20 pacientes , o teste cutneo mostrou - se positivo . os alrgenos mais frequentes foram os caros da poeira domstica e os alrgenos de barata . o teste de a. fumigatus foi realizado em 5 pacientes , e todos apresentaram resultados negativos ( figura 1 ) . no tocante  funo pulmonar , todos os pacientes apresentavam curva fluxo - volume dentro dos limites da normalidade ou distrbio ventilatrio obstrutivo leve . essa variao foi encontrada nos mesmos pacientes na segunda avaliao de espirometria , aproximadamente 6 meses depois da primeira , quando foram avaliadas as curvas pr - broncodilatador . das variveis de funo pulmonar , a cvf mostrou - se menor aps a otimizao do tratamento . no houve diferena significativa entre as duas medidas no tocante s variveis mais relacionadas  doena obstrutiva brnquica ( figura 2 ) . figura 1proporo de pacientes com asma grave resistente a terapia ( n = 20 ) com resultado positivo no teste cutneo ( primeira coluna preta ) e de alrgenos especficos nesses pacientes ( n = 17 ) . seis ( 60% ) revelaram drge , mas apenas 1 paciente pareceu apresentar melhora clnica da asma aps o incio do tratamento com omeprazol , j com terapia inalatria otimizada para a asma .   a induo de escarro foi realizada em 18 pacientes , porm s foi bem - sucedida em 13 ( 73% ) . dos 13 pacientes nos quais a induo de escarro foi bem - sucedida , 2 apresentaram fentipo inflamatrio paucigranuloctico , 4 apresentaram fentipo inflamatrio eosinoflico e 7 apresentaram fentipo inflamatrio neutroflico ( figura 3 ) . dos 6 pacientes nos quais o exame de escarro foi repetido com sucesso , 4 ( 67% ) apresentaram alterao do perfil inflamatrio ( de eosinoflico para neutroflico , de neutroflico para paucigranuloctico , de paucigranuloctico para neutroflico e de eosinoflico para misto ) . a induo de escarro no resultou em eventos adversos relevantes em nenhum dos pacientes . opacidades em vidro fosco foram observadas em 2 pacientes , e hrnia de hiato foi um achado ocasional em 1 paciente . figura 2funo pulmonar das crianas e adolescentes com asma grave resistente a terapia ( n = 21 ) no incio da avaliao clnica e 6 meses aps a otimizao do tratamento . as variveis so de curvas pr - broncodilatador e esto expressas em escore z dos valores de referncia da global lung initiative . * p = 0,015 
  no tocante ao act , 6 pacientes eram maiores de 12 anos e foram avaliados com o instrumento mais de cinco vezes consecutivas . a figura 4 mostra o predomnio de asma no controlada ( pontuao < 20 no act ) nas visitas mdicas , mesmo com a otimizao do tratamento no perodo . a asma grave tem sido amplamente estudada em adultos na ltima dcada , com mltiplos fentipos / endtipos descritos e com apresentao clnica complexa e de difcil manejo . h poucos estudos descrevendo as caractersticas clnicas de crianas com agrt , nenhum deles envolvendo populaes de crianas em pases em desenvolvimento . dos poucos mecanismos da agrt estudados em crianas , destacam - se reduzida resposta linfocitria do tipo th2 , expresso aumentada de il-33 e expresso reduzida de il-10 . importante destacar que , embora a agrt afete uma proporo pequena da populao de crianas com asma , esse grupo de pacientes apresenta um importante comprometimento da qualidade de vida , com elevados custos ( diretos e indiretos ) para a sociedade , o que justifica futuros investimentos em pesquisa nesses pacientes . nosso estudo descreve , pela primeira vez , o fentipo clnico de agrt em crianas e adolescentes provenientes de zonas urbanas de uma grande metrpole do sul do brasil . no presente estudo , a maioria das crianas apresentava asma atpica ( 85% dos casos ) , com incio precoce da doena , e uma proporo no desprezvel ( quase 25% ) era obesa , achados semelhantes queles em crianas com agrt em pases desenvolvidos . adultos com asma grave parecem apresentar um nmero maior e combinaes mais complexas de fentipos do que crianas com asma grave . em nosso estudo , os alrgenos mais comuns foram os caros da poeira domstica e os alrgenos de barata . alrgenos de ces , gatos e fungos mostraram - se pouco frequentes nessa populao , o que j foi demonstrado por nosso grupo em um estudo anterior de crianas com asma provenientes da mesma regio.21 as alteraes observadas na tc de trax foram compatveis com doena obstrutiva brnquica inflamatria crnica , compatveis com asma grave , e no contriburam muito para o diagnstico . a indicao formal de tc de trax para todos os pacientes com asma tem sido questionada em crianas com agrt.7 
 
 figura 3taxa de sucesso nos 18 pacientes submetidos a induo de escarro e proporo dos perfis inflamatrios nos pacientes nos quais a induo foi bem - sucedida ( n = 13 ) . figura 4em a , mediana ( barras horizontais cheias ) da pontuao no asthma control test ( act ) em pacientes avaliados consecutivamente pelo instrumento em visitas medicas . em b , frequncia de eventos em que os pacientes foram considerados portadores de asma controlada ( pontuao  20 no act ) ou no controlada ( pontuao < 20 no act ) em visitas consecutivas nas quais o instrumento foi aplicado ( n = 6 ) . os achados mais interessantes do nosso estudo foram em relao s caractersticas da funo pulmonar desses pacientes e ao perfil inflamatrio das vias areas . as espirometrias realizadas quando os pacientes no apresentavam exacerbaes mostraram discretas alteraes obstrutivas na maioria dos casos . a asma grave em adultos est muito associada a alteraes importantes da funo pulmonar , que no so observadas em crianas , como j se descreveu anteriormente . do ponto de vista da histria natural da doena , parece que o comprometimento funcional pulmonar comea a ser mais relevante no incio da idade adulta . isso no significa que alteraes histopatolgicas , tais como o remodelamento brnquico , no surjam cedo na vida , particularmente na idade pr - escolar , e que j no estejam presentes , portanto , na idade escolar e adolescncia , como demonstrado em estudos prvios com bipsias transbrnquicas . com funo pulmonar basal prxima do normal e ausncia de controle da doena nesses pacientes ,  necessrio compreender melhor os mecanismos obstrutivos a fim de utilizar novas terapias . uma hiptese para explicar esse achado  que crianas com agrt apresentam excessiva labilidade de tnus broncomotor , o que explicaria as poucas alteraes espiromtricas , no obstante os sintomas frequentes . o escarro induzido permite a avaliao no invasiva da inflamao das vias areas inferiores na asma , tendo sido explorado em estudos sobre crianas com asma . obtivemos amostras adequadas para anlise em 72% dos casos , com um perfil inflamatrio bastante varivel , com predomnio de escarro neutroflico . alm disso , ao contrrio do que se costuma observar em adultos , nossos resultados , junto com achados de outro estudo,17 parecem mostrar que o perfil inflamatrio de crianas com asma grave pode variar com o tempo . isso pode ser explicado pelo componente neutroflico , possivelmente secundrio s frequentes infeces respiratrias virais ( muitas vezes subclnicas ) nessa faixa etria . como o escarro induzido em adultos apresenta caractersticas mais estveis do que o escarro induzido em crianas , a induo de escarro no  comumente indicada no manejo de crianas com asma grave.7 porm , pode ser uma ferramenta clnica til em pacientes especficos , particularmente naqueles com um fentipo no atpico neutroflico . os resultados da phmetria esofgica devem ser sempre interpretados com cuidado , e correlaes clnicas devem ser estabelecidas . ainda no est claro se esses pacientes devem ou no ser tratados com medicamentos para drge . no entanto , o tratamento da drge em crianas com asma grave parece no resultar em melhora clnica respiratria e no  comumente indicado.6 atualmente , em nosso centro de referncia , a phmetria esofgica nesse grupo de pacientes  solicitada apenas para aqueles com elevada suspeita clnica e sintomas que sugerem a presena de drge . crianas com agrt so um grande desafio clnico , pois a proporo de pacientes com doena no controlada  alta , no obstante o uso de doses elevadas de corticoide . nesses indivduos , deve - se alcanar o melhor nvel de controle possvel e minimizar os potenciais efeitos adversos do corticoide , sem se esquecer de que , devido s caractersticas heterogneas da doena , o sucesso teraputico varia.1 crianas com agrt costumam apresentar resposta ruim aos corticoides e , por isso , necessitam de doses elevadas . uma alternativa que surgiu na ltima dcada para esse grupo de pacientes  o omalizumabe , um anticorpo anti - ige monoclonal humanizado que bloqueia um dos domnios da cadeia pesada da poro fc da ige livre . essa alta afinidade com a poro fc da ige compete com os receptores celulares de mastcitos e basfilos , inibindo a resposta inflamatria . em crianas com agrt , o omalizumabe reduz as doses de corticoide , exacerbaes e hospitalizaes , inclusive em populaes urbanas norte - americanas mais carentes . em nosso estudo , 7 ( 88% ) de 8 crianas apresentaram resposta clnica ao omalizumabe ( segundo critrio da equipe mdica ) , com reduo das exacerbaes e sem hospitalizaes aps o incio do tratamento . um recente estudo de vida real , multicntrico , realizado na frana , mostrou que crianas com asma grave que receberam omalizumabe apresentaram reduo de 72% das exacerbaes.31 
  os pacientes de nosso estudo sem indicao de omalizumabe ( em virtude da faixa etria , do nvel de ige ou da ausncia de sensibilizao a alrgenos ) foram submetidos a teste teraputico com macroldeo ( azitromicina ) contnuo , e somente 1 paciente apresentou resposta clnica . em nosso centro de referncia , no se usa nenhuma outra terapia alternativa , como antifngicos , imunomoduladores ou medicamentos citotxicos . as diretrizes internacionais mais recentes de asma grave em adultos e crianas no recomendam o uso de macroldeos ou outros frmacos alternativos.7 
  a maior limitao de nosso estudo  seu carter descritivo e retrospectivo . no entanto , como o objetivo era descrever pela primeira vez uma amostra de crianas com agrt de um pas em desenvolvimento , acreditamos que no seja uma limitao to relevante , particularmente porque todos os dados e variveis foram coletados prospectivamente em um banco de dados pelos autores durante as visitas mdicas . concluindo , nosso estudo  o primeiro a descrever uma amostra de crianas e adolescentes com agrt provenientes de uma rea urbana de um pas em desenvolvimento . embora as caractersticas clnicas dessas crianas e adolescentes so semelhantes s de crianas e adolescentes de pases desenvolvidos , os mecanismos e fatores de risco das formas mais graves devem ser mais bem estudados , particularmente a funo pulmonar , a inflamao brnquica e a resposta imune , em estudos longitudinais e multicntricos maiores .
abstractobjective : to describe the clinical characteristics , lung function , radiological findings , and the inflammatory cell profile in induced sputum in children and adolescents with severe therapy - resistant asthma ( stra ) treated at a referral center in southern brazil . 
 methods : we retrospectively analyzed children and adolescents ( 3 - 18 years of age ) with uncontrolled stra treated with high - dose inhaled corticosteroids and long - acting 2 agonists . 
 we prospectively collected data on disease control , lung function , skin test reactivity to allergens , the inflammatory cell profile in induced sputum , chest ct findings , and esophageal ph monitoring results . 
 results : we analyzed 21 patients ( mean age , 9.2  2.98 years ) . 
 of those , 18 ( 86% ) were atopic . 
 most had uncontrolled asthma and near - normal baseline lung function . in 4 and 7 , 
 induced sputum was found to be eosinophilic and neutrophilic , respectively ; the inflammatory cell profile in induced sputum having changed in 67% of those in whom induced sputum analysis was repeated . of the 8 patients receiving treatment with omalizumab ( an anti - ige antibody ) , 
 7 ( 87.5% ) showed significant improvement in quality of life , as well as significant reductions in the numbers of exacerbations and hospitalizations . 
 conclusions : children with stra present with near - normal lung function and a variable airway inflammatory pattern during clinical follow - up , showing a significant clinical response to omalizumab . in children 
 , stra differs from that seen in adults , further studies being required in order to gain a better understanding of the disease mechanisms .