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Criteri minori
I fenotipi dell’asma Maria Caruso Il riscontro di sibili è un sintomo frequente nei primi anni di vita nel bambino molto piccolo troviamo cause diverse dall’asma ( fibrosi cistica, inalazione di latte, discinesia ciliare primitiva, immunodeficienze primitive, cardiopatie congenite, malformazioni congenite, aspirazione di corpo estraneo, ecc) FENOTIPI DEL BAMBINO CON RESPIRO SIBILANTE PEDIATRICS Vol. 109 No. 2 February 2002, pp. 362-367 Development of Wheezing Disorders and Asthma in Preschool Children Fernando D. Martinez, MD From the University of Arizona, Tucson, Arizona TABLE 1. Distribution of Asthma in 401 Subjects Aged 35 According to Whether They Had Bronchitis or Asthma as Children Asthma at Age 35* N(%) At Age 7* No Recent Asthma Infrequent Frequent Persistent Total Mild wheezy bronchitis 42 (65) 8 (12) 10 (15) 5 (8) 65 Wheezy bronchitis 54 (63) 10 (12) 9 (10) 13 (15) 86 Asthma 29 (30) 20 (20) 18 (18) 31 (32) 98 7 (10) 10 (15) 8 (12) 42 (63) 67 132 48 45 91 401 Severe asthma Total * Values are numbers (percentages) of participants. Eighty-five controls are excluded. Patients entered study at age 10. Adapted from Oswald et al.7 Tucson children's respiratory study: 1980 to present*1 Lynn M. Taussig MDa, Anne L. Wright PhDb, Catharine J. Holberg PhDb, Marilyn Halonen PhDb, Wayne J. Morgan MDb and Fernando D. Martinez MDb Volume 111,number 4 APRIL 2003 Table I. Potential risk factors evaluated for possible relationships with acute LRI or chronic lung disease (asthma) Sex, ethnicity Birth weight Parents' education, income, age Respiratory symptoms and illnesses in other household members Genetic determinants Number and order of siblings Bottle/breast-feeding Day care Type of home heating, cooking, and cooling Number and type of pets Indoor air pollution Passive/active smoking Atopy Immune function Lung function Airway reactivity Tucson children's respiratory study: 1980 to present*1 Lynn M. Taussig MDa, Anne L. Wright PhDb, Catharine J. Holberg PhDb, Marilyn Halonen PhDb, Wayne J. Morgan MDb and Fernando D. Martinez MDb Volume 111,number 4 APRIL 2003 Table II. Data collection Enrollment (birth) Questionnaire (family) data Maternal pregnancy history Cord blood (IgE, immune studies) CBC/differential Periodic data Well-baby visit forms Periodic questionnaires on all household members 2 to 3 months of age Pulmonary function tests 9 to 15 months of age IgE, CBC and differential, immune studies LRIs in first 3 years of life Sign/symptom and history forms Cultures, serologies, CBC and differential, IgE Convalescence (3-5 wk post LRI) serologies, IgE, CBC and differential CBC, Complete blood count. Table III. Number of index subjects in the CRS with data at each evaluation Early years of In-depth life I In-depth II Age of index subjects In-depth III Birth to 3 y 6y 11 y 16 y 1055 (age 2 y) 1025 955 509† 888 — — — — 762 689 397† Serum IgE 1120 (at birth) 550 633 357† Peripheral blood eosinophils 880 (at 9 mo) 550 633 357† Pulmonary function studies 176 (at 4 mo) 676 595 376† Airway challenge studies — 368 396 303† Peak flow variability — — 600 383† Respiratory questionnaires* LRI evaluations through age 3 y Skin prick tests *Respiratory questionnaires were also obtained on the enrolled child at age 3 (n = 940), 8 (n = 841), and 13 (n = 714) years. Questionnaires are also being obtained at age 18, but this is still in progress. †Data collection is still in progress. Table IV. Evaluation of family members at in-depth I Mothers Fathers Siblings Questionnaire 1008 908 1150 Pulmonary function tests 840 671 625 Blood sample 806 635 540 Allergy skin tests 813 664 847 Methacholine studies 319 272 51 Hypothetical yearly peak prevalence of wheezing according to phenotype in childhood Martinez, F. D. Pediatrics 2002;109:362-367 Copyright ©2002 American Academy of Pediatrics Am. J. Respir. Crit. Care Med., Volume 162, Number 4, October 2000, 1403-1406 A Clinical Index to Define Risk of Asthma in Young Children with Recurrent Wheezing JOSÉ A. CASTRO-RODRÍGUEZ, CATHARINE J. HOLBERG, ANNE L. WRIGHT, and FERNANDO D. MARTINEZ Respiratory Sciences Center, University of Arizona, College of Medicine, TABLE 1 Tucson, Arizona A CLINICAL INDEX TO DEFINE ASTHMA RISK* Major Criteria 1. Parental MD asthma 2. MD eczema Minor Criteria 1. MD allergic rhinitis§ 2. Wheezing apart from colds 3. Eosinophilia ( 4%) * Loose index for the prediction of asthma: Early wheezer plus at least one of two major criteria or two of three minor criteria. Stringent index for the predication of asthma: Early frequent wheezer plus at least one of two major criteria or two of three minor criteria. History of a physician diagnosis of asthma. Physician diagnosis of atopic dermatitis as reported in questionnaires at ages 2 or 3. § Physician diagnosis of allergic rhinitis as reported in questionnaires at ages 2 or 3. Criteri di Rischio per Asma nell’Early Wheezing (Castro-Rodriguez, AJRCCM 2000;162:1403) Criteri Maggiori Criteri Mino 1. Asma nei genitori 1. Rinite allergica 2. Dermatite atopica 2. Wheezing anche senza raffreddore 3. Eosinofilia (> 4%) 1 criterio maggiore oppure 2 criteri minori + Wheezing precoce Asma nel 59% Wheezing precoce frequente Asma nel 76 % Criteri di Rischio per Asma nell’Early Wheezing (Castro-Rodriguez, AJRCCM 2000;162:1403) Criteri Maggiori Criteri Mino 1. Asma nei genitori 1. Rinite allergica 2. Dermatite atopica 2. Wheezing anche senza raffreddore 3. Eosinofilia (> 4%) 1 criterio maggiore oppure 2 criteri minori Wheezing precoce No asma nel 73 % Wheezing precoce frequente No asma nel 68 % December 2004 • Volume 114 • Number 6 Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma Theresa W. Guilbert, Wayne J. Morgan, Robert S. Zeiger, Leonard B. Bacharier, Susan J. Boehmer, Marzena Krawiec, Gary Larsen, Robert F. Lemanske, Andrew Liu, David T. Mauger, Chris Sorkness, Stanley J. Szefler, Robert C. Strunk, Lynn M. Taussig, Fernando D. Martinez 1 2 8 2 mAPI versus original API ( Castro-Rodriguez et al) Il bambino deve avere una storia di 4 o più episodi di wheezing con almeno una diagnosi da parte del medico Criteri maggiori: • Asma in un genitore • Dermatite atopica diagnosticata da un medico • Sensibilizzazione ad 1 o più aeroallergeni Criteri minori: • Sensibilizzazione ad allergeni alimentari ( latte, uova, arachidi) • Wheezing non correlato a raffreddamento • Eosinofilia ematica ≥ 4% Asma Predictive Index Castro-Rodriguez , Martinez. Am J respir Crit Care Med, 2000; 162: 1403-6 • L’individuazione precoce del fenotipo del bambino che “ fischia” nei primi anni di vita è importante per distinguere quei bambini che hanno broncospasmo ma non saranno destinati a presentare un quadro cronico, più persistente di asma. • Il 70-80%dei bambini con indice positivo continueranno ad avere asma fra i 6-13 anni, mentre il 68% di quelli con indice negativo non hanno più asma nel periodo scolastico Bambino con respiro sibilante transitorio •L’80%dei bambini che “fischia” nel primo anno di vita rientra in questa categoria; nel 2° anno rientrano in tale categoria il 60% e nel 3° anno il 30- 40% •Non hanno una maggiore prevalenza di familiarità per atopia, dermatite atopica, eosinofilia o IgE elevate o altri markers di diatesi allergica •Condizione transitoria, priva di conseguenze a lungo termine, soprattutto nel bambino non allergico, che si risolve abitualmente entro i 3 anni •Il fattore di rischio principale è una riduzione della funzione polmonare , che persiste diminuita anche all’età di 6 anni. …….Bambino con respiro sibilante transitorio •Non presenta una iperreattività bronchiale. •Altri fattori di rischio sono la prematurità e il contatto con altri bambini nei primi anni di vita ( frequenza di comunità o presenza di altri fratelli) •Nell’età adulta è possibile che abbiano un aumentato rischio di BPCO, soprattutto se fumatori,a causa della loro congenita ristrettezza delle vie respiratorie Bambini non atopici Rientrano nella categoria precedentemente classificata come “persistent wheezer” , con sintomi ancora presenti all’età di 3 anni, e della quale i non atopici rappresentano il 40% mentre il 60% diventano atopici all’età di 6 anni possono presentare sibili associati ad infezioni respiratorie virali acute, molto frequentemente determinate da infezione da RSV ( in tali casi è aumentato il rischio di wheezing nei primi 10 anni e poi decresce e non è più significativa a 13 anni. Non è descritta correlazione fra infezione da RSV e sensibilizzazione allergica). ……Bambini non atopici •I sintomi per lo più scompaiono nel corso degli anni prescolari; possono residuare alterazioni minori della funzionalità respiratoria e una iperresponsività delle vie aeree. •All’età di 11 anni il test di broncodilatazione con salbutamolo riporta a valori di normalità il FEV1, dimostrando una completa reversibilità delle alterazioni minori della funzionalità respiratoria •Questo indicherebbe che i “ non atopic wheezers” rispondono con broncoostruzione a stimoli virali per un alterato controllo del tono bronchiale. Non è conosciuto se questa alterazione sia primitiva a secondaria ad infezione virale. Bambini atopici, con storia familiare di asma verso i 2-3 anni possono sviluppare sintomi di asma che persistono nel corso degli anni futuri. La comparsa di asma nei primi 3 anni di vita è associata a maggiore gravità. L’asma precoce è frequentemente associata ad atopia Una sensibilizzazione precoce gioca un importante ruolo nella persistenza dell’asma In essi prevale l’infiammazione eosinofila dei bronchi Allergy Volume 63 Issue 1 Page 5-34, January 2008 Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report L. B. Bacharier11Department of Pediatrics, Washington University, St Louis, MO, USA, A. Boner22Department of Pediatrics, University of Verona, Verona, Italy, K.-H. Carlsen33Department of Pediatrics, University of Oslo, Oslo, Norway, P. A. Eigenmann44Pediatric Allergy, University Children’s Hospital of Geneva, Geneva, Switzerland, T. Frischer55University Children’s Hospital Vienna, Vienna, Austria, M. Götz66Department of Paediatrics & Adolescent Medicine, Medical University of Vienna, Vienna, Austria, P. J. Helms77Department of Child Health, University of Aberdeen, Aberdeen, Scotland, J. Hunt88Department of Pediatrics, University of Virginia, Charlottesville, VA, USA, A. Liu99Department of Pediatrics, National Jewish Medical and Research Center, University of Colorado School of Medicine, Denver, CO, USA, N The European Pediatric Asthma Group* (2008) Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report Allergy 63 (1), 5–34. Asthma in children can be described as ‘repeated attacks of airway obstruction and intermittent symptoms of increased airway responsiveness to triggering factors, such as exercise, allergen exposure and viral infections’ . However, the definition becomes more difficult to apply confidently in infants and preschool age children who present with recurrent episodes of coughing and/or wheezing. Although these symptoms are common in the preschool years, they are frequently transient, and 60% of children with infantile wheeze will be healthy at school age . Physicians should manage and exclude diagnoses other than asthma, and be aware of the variable natural history patterns of recurrent wheezing in early childhood. Bacharier, L. B., Boner, A., Carlsen, K.-H., Eigenmann, P. A., Frischer, T., Götz, M., Helms, P. J., Hunt, J., Liu, A., Papadopoulos, N., Platts-Mills, T., Pohunek, P., Simons, F. E. R., Valovirta, E., Wahn, U. & Wildhaber, J. The European Pediatric Asthma Group* (2008) Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy 63 (1), 5-34. Asthma phenotypes In asthma, age and triggers can be used to define different phenotypes of disease. These phenotypes are likely to be useful because they recognize the heterogeneity of childhood asthma. They do not represent separate diseases, but are part of the ‘asthma syndrome’. Guidelines that recognize different phenotypes should provide better direction for prognosis and therapeutic strategies. The European Pediatric Asthma Group* (2008) Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report Allergy 63 (1), 5–34. Three different patterns of recurrent wheeze in pediatric patients have been proposed , and a fourth was recently described . However, it should be noted that patterns 1 and 2 (listed below) can only be discriminated retrospectively and are not suitable for use when treating the child. 1.Transient wheezing: Children who wheeze during the first 2–3 years of life, but do not wheeze after the age of 3 years 2. Nonatopic wheezing: Mainly triggered by viral infection and tends to remit later in childhood 3. Persistent asthma: Wheezing associated with the following: • Clinical manifestations of atopy (eczema, allergic rhinitis and conjunctivitis, food allergy), blood eosinophilia, and/or elevated total immunoglobulin E (IgE) • Specific IgE-mediated sensitization to foods in infancy and early childhood, and subsequently to common inhaled allergens • Inhalant allergen sensitization prior to 3 years of age, especially with sensitization and high levels of exposure to specific perennial allergens in the home • A parental history of asthma 4. Severe intermittent wheezing : Infrequent acute wheezing episodes associated with the following: • Minimal morbidity outside of time of respiratory tract illness • Atopic characteristics, including eczema, allergic sensitization and peripheral blood eosinophilia The highest incidence of recurrent wheezing is found in the first year of life. According to long-term population-related prospective birth cohort studies, up to 50% of all infants and children below the age of 3 years will have at least one episode of wheezing . Infants with recurrent wheezing have a higher risk of developing persistent asthma by the time they reach adolescence, and atopic children in particular are more likely to continue wheezing (Fig. 1) . In addition, the severity of asthma symptoms during the first two years of life is strongly related to later prognosis . However, both the incidence and period prevalence of wheezing decrease significantly with increasing age . Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy 63 (1), 5-34. Prevalence of current wheeze from birth to age 13 years in children with any wheezing episode at school age (5– 7 years), stratified for atopy at school age (10). Age is one of the strongest determinants of asthma phenotype in childhood, and involves pathophysiological events, exposure and natural history determinants. Because of differences in disease presentation between the age groups, it is important to design diagnostic and management strategies based on age. Practical age groupings for these purposes are: • Infants (0–2 years old) • Preschool children (3–5 years old) •School children (6–12 years old) • Adolescents. Infants (0–2 years old). In infants, persistence of symptoms is a major indicator of severity. Therefore, it should be established whether the child has wheezed on most days of the week during the last 3 months. If so, these children should be diagnosed with persistent infantile wheeze, after careful exclusion of other causes. Children with intermittent disease (recurrent episodes) can be classified as having either severe or mild disease, depending upon the need for medical resources (systemic steroids, hospitalization). Preschool children (3–5 years old). In preschool children, the key differentiator of asthma phenotype is persistence during the last year (Fig. 2). If symptoms disappear completely between episodes, and usually follow a cold, viral-induced asthma is the most appropriate diagnosis. Viruses are the most common trigger in this age group. Exerciseinduced asthma can also be a unique phenotype in this age group. Skin prick tests or in vitro tests for the presence of specific IgE antibodies should be performed along with efforts to ascertain whether there is a clinically relevant association between exposure and symptom occurrence. If so, the phenotype is allergen-induced asthma. It should be emphasized that atopy is a risk factor for asthma persistence irrespective of whether or not allergens are obvious triggers of disease activity. If no specific allergic trigger can be identified, the phenotype can be characterized as nonallergic asthma with some caution. However, this may still mean that the specific allergic trigger was not detected. School-age children (6–12 years old). The differentiators in school-age children are the same as those in preschool children (Fig. 2). However, allergen-induced cases are more common and visible and seasonality may become evident. Virus-induced asthma is still common in this age group. Severity may become an important issue in the treatment of allergen-induced asthma. Adolescents. Atopic asthma can have its onset during adolescence and there are more new cases than remissions . Nonatopic asthma can also start during adolescence . There are additional problems associated with managing and classifying asthma in adolescent patients. Many adolescents are reluctant to use regular daily medications and do not like having any restrictions placed on their lives. Smoking may also become an issue. Also, there may be a difficult transition period when patients stop seeing a pediatrician and start seeing another physician. Pathologically, severe asthma in both adults (76) and children has particular characteristics suggesting that it could be considered as a unique phenotype. Severity is associated with persistence and unresponsiveness to therapy. Although it can be useful as an additional parameter in defining phenotypes, severity levels tend to be arbitrary. Severity also depends on age. In infants, persistent disease should be considered severe; in older children, severe exacerbations are those with respiratory distress who require oxygen and hospitalization; these may occur independently of the usual measures of severity, i.e. frequency of symptoms, or lung function. Figure 2. Asthma phenotypes in children aged >2 years of age. Note that phenotypes are a useful guide to the predominant problem and overlap between phenotypes is frequently present. Interactions between respiratory tract infections and atopy in the aetiology of asthma Holt. ERJ 2002; 19: 538 …il danno determinato dagli episodi di wheezing virus indotti sulle basse vie aeree interagisce con le manifestazione allergiche respiratorie, incrementando il rischio di sviluppo di asma persistente. Le infezioni virali sono implicate sia nella patogenesi che nelle riacutizzazioni dell’ asma Primi anni di vita: RSV, virus parainfluenzale, adenovirus Nelle età successive: rinovirus e virus influenzali Il trattamento solo sintomatico degli episodi di wheezing determina un quadro infiammatorio che interferisce con lo sviluppo e la differenziazione del polmone e progressione verso una forma di asma cronica “Progression of intermittent infant wheezing to persistent asthma in early childhood” Holt, Nature Immunology 2004;5:695 Gli episodi di wheezing del bambino in età prescolare sono associati ad una infiammazione neutrofila sistemica e si ritiene che i bambini che sviluppano wheezing in corso di infezione virale abbiamo la propensione a reclutare maggiore quantità di neutrofili nelle loro vie aeree e che mediatori di derivazione neutrofila possano attivare altre cellule infiammatorie, quali i mastociti. “Sistemic neutrophil activation in acute preschool viral wheeze”. Oommen A.et all. Arch Dis Child 2003; 88: 529-531 Molti meccanismi sono stati ipotizzati per spiegare come i rinovirus inducano asma, comprendendo l’infiammazione diretta del tratto respiratorio, riduzione della funzione polmonare, incremento della reattività bronchiale ed una up-regolazione delle molecole di adesione ( ICAM-1)sulla membrana cellulare dell’epitelio delle vie aeree. “Allergy and infection: understanding their relationship”. Custovic A.et all. Allergy 2005; 60 (suppl.79): 10-13 L’infanzia è caratterizzata da una maggiore suscettibilità ad infezioni virali e questo stadio è anche caratterizzato da una moltiplicazione degli alveoli polmonari e da un remodeling delle vie aeree per accompagnare la crescita. Queste coincidenze suggeriscono che le infezioni virali possono agire in modo negativo sullo sviluppo del polmone. “Effect of viral respiratory infections on lung development and childhood asthma” Gern Je et all. J Allergy Clin Immunol 2005 Apr; 115 (4): 668-74 GRAZIE PER L’ATTENZIONE