Review Article
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Recent Advances in the Understanding of Childhood Asthma SHIH-WEN H U A N G
The worldwide increase in diagnosed cases of asthma in the last 15 years, in spite of the better understanding of the pathogenesis of the disease and the availability of more potent bronchodilators and anti-inflammatory agents, has been the concern of clinicians worldwide. For pediatricians, it is most disturbing to learn that asthma is the most common chronic disease in childhood. In addition, asthma hospitalization rates are highest among children, and death rates from asthma are among the highest irrespective of ethnic background in U.S.. This article will review recent advances in the link between respiratory syncytial virus and asthma and discuss modified national guidelines for the diagnosis and management of asthma pertinent to care for childhood asthma, as well as current thought on allergen immunotherapy in children with asthma. A brief perspective is added on the future trend of asthma research. It is hoped that these issues will provide incentives for further efforts in childhood asthma research. (Acta Paediatr Sin 1999; 40:145-51)
Key words: asthma, childhood, RSV, bronchiolitis, steroid, immunotherapy The worldwide increase in the number of patients with asthma in recent years has resulted in many studies on its pathogenesis and management of asthma in children, and there are several areas that deserve our special attention. In regard to the pathogenesis of asthma, the association between infectious wheezing at a young age and the subsequent development of asthma has been supported by more clinical epidemiological data, especially on respiratory syncytial virus (RSV) infection. The National Guidelines on the Management of Asthma which was first published in 1995 in U.S., has now been revised to address specific questions about the management of asthma in children. It is noteworthy that in spite of many encouraging results regarding the effect of immunotherapy, the publication of a multiyear clinical outcome study from Johns Hopkins researchers has intensified the debate about the value of allergen immunotherapy in children. In this review, I examine the current understanding on these issues and outline the future direction of clinical research in the area of childhood asthma.
Although many respiratory viruses have been implicated as the cause of infection-related wheezing in children, RSV is the one that has been most studied. Likewise, the link between RSV bronchiolitis during infancy and the development of asthma later in childhood was first suggested at least 25 years ago.' The evidence relating to such a link has accumulated ever since as results of more epidemiological studies become available. RSV has been identified as the most common cause of bronchiolitis, as well as the most common respiratory tract pathogen in infants and children, with up to 80% of the U.S. pediatric population infected during the first year of life.^ In the majority of infants, RSV infection is limited to the upper respiratory tract. Lower respiratory tract infections (LRTls) are usually mild to moderate and can be treated at home. However, it is estimated that nearly 1% of infants with RSV, about 90,000 infants per year in the U.S. develop a severe LTRI that requires hospitalization. Such severe RSV-caused LRTls appear to be an independent risk factor for subsequent asthma. A number of studies have identified respiratory abnormalities up to 10 years after hospitalization for severe RSV-caused LRTls in infancy and early childhood. These abnormalities include asthma symptoms such as THE LINK BETWEEN RSV BRONCHIOLITIS wheezing, airway hyperreactivity or bronchial lability, AND ASTHMA Department of Pediatrics, University of Rorida College of Medicine Gainesville, Rorida 32610 U.S.A. Received: March 25, 1999. Revised: May 18, 1999. Accepted: June 7, 1999. Address reprint requests to: Dr. Shih-Wen HUANG, Division of Immunology & Infectious Diseases, Department of Pediatrics, University of Rorida College of Medicine Gainesville, Rorida 32610, U.S.A. TEL: 352-392-4037 FAX: 352-846-0619 E-mail:
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abnormality on various lung-function tests, low arterial oxygen tension, and recurrent respiratory illnesses. Some of these studies had a retrospective case control design.''^ The patients had been hospitalized with RSV LRTI as infants. The controls were matched socioeconomically, as well as by age and sex. In one study,' none of the controls had been hospitalized with bronchiolitis; in another study,'' less than 2% of control patients had been hospitalized with an LTRI; and in a third study,* the control group excluded any children with a medical history of wheezing or chronic respiratory problems. In the first study of 35 patients, a follow-up after 8 years revealed that 51% of patients who had been hospitalized as infants with RSV LRTI had wheezing while only 3% of controls developed wheezing.' In the second study 130 of patients, after a 10 year followup, the outcome of wheezing and bronchial lability between the co-host and control was 42% to 19%, and 25% to 7%, respectively." In the third study of 29 patients, a follow-up after 49 weeks revealed that 55% of patients with hospitalization for RSV LRTI as infants had wheezing, while none of the controls developed wheezing.* At least eight studies with prospective designs have used various outcome measures to examine the relationship between severe bronchiolitis in infancy and respiratory sequelae during childhood.^" Children have been followed as little as 12 months and for as long as 8 years. In some of these studies, not all of the measures showed abnormalities. However, wheezing, asthma, and/or recurrent LRT illnesses occurred in 23% to 92% of children following bronchiolitis,*"" and hyperreactive airways occurred in 23% to 67%.*'- One study found lung-function abnormalities in 75% of children 12 months after hospitalization for the initial infection.^ One study that followed children for up to 8 years after hospitalization found that the forced midexpiratory flow rate (FEF25. and the maximal expiratory flow when 25% of forced vital capacity has been expired (Vmax25) were significantly less than predicted values (68% and 71%, respectively).' These abnormalities generally reflect early or peripheral airway obstructions. In another study, which included a control cohort, 23% of children hospitalized with RSV LRTI during their first year of life developed asthma within 3 years, compared with only 1% of the controls." Overall, these studies suggest that the prevalence of respiratory symptoms following severe RSV LRTI is highest during the first few years after hospitalization and may diminish over time. In short, hospitalization for RSV bronchiolitis in infancy appears to be an important risk factor for the development of recurrent wheezing later in childhood. Other factors leading to wheezing later in childhood nave also been explored. The lipid envelope of RSV contains two glycoproteins: the G protein, which
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attaches the virus to cells, and the F (fusion) protein, which facilitates virus entry into the cell. RSV infects and replicates in lung epithelial cells, causing the fusion of adjacent epithelial cells and forming giant multinucleated cells (synechia). Clinical features of RSV bronchiolitis include tachypnea, chest wall retractions, cough, nasal flaring, expiratory wheezing, rales^ rhonchi, arterial oxygen desaturation, and apneic episodes. Severe RSV bronchiolitis causes necrosis of the bronchiolar epithelium, loss of cilia, and sloughing of dead cells. These effects, added to peribronchiolar infiltration of mononuclear cells airway wall edema, and mucus plugging, may result in partial airway obstruction, increased airway resistance, hypoxemia, and cyanosis. RSV-induced changes in the bronchial architecture can also last beyond the acute infection; regeneration of bronchiolar epithelium may take several days to weeks. One explanation for the airway hyperreactivity observed in some patients after RSV bronchiolitis is disruption of neural control mechanisms. Airway patency reflects a balance of neurotransmitter activity among several neural pathways influencing airway smooth muscle. RSV damage to epithelium can increase sensory nerve stimulation or trigger reflex bronchoconstriction.In airvvayssmooth muscle, RSV increases contractile responses and decreases relaxation.'* In animal models of RSV infection, acute increases in neurally mediated contractile responses persisted for several months.'* Several immunologic mechanisms have also been proposed to explain how severe RSV LRTI may result in pulmonary abnormalities later in life. Depending on the genetic background of the host, RSV may activate components of the immune response that are associated with allergen sensitization and subsequent asthma. Among those components, the role of IL-11 and IgE appear to be the most influential. RSV induces lung epithelial cells to produce IL-11, which activates T and B cells, stimulates the production of tachykinins (peptides that cause smooth muscle contraction and vasodilation), and may also directly induce bronchospasm and airway hyperresponsiveness.'* Overproduction of IL-11 in transgenic mice resulted in biologic changes similar to those seen in asthma." Another study found that the levels of IL-11 in nasal secretions were highest in infants with RSV upper respiratory tract infections accompanied by clinical bronchospasm, and that symptoms persisted in children whose IL-11 levels remained elevated.'* IgE antibodies are involved in allergic responses and may directly induce mast cell degranulation, with the subsequent release of inflammatory mediators such as leukotiienes, histamine, and eosinophilic cationic protein. Recurrent wheezing has been documented in 20% of children with no detectable RSV IgE in nasopharyngeal secretions at the time of bronchiolitis and in 70% of
Acta Paediatr Sin
S.W. HUANG
children with the highest titers of RSV IgE." It was concluded that the magnitude of the RSV IgE response at the time of RSV bronchiolitis is a useful prognostic indicator of recurrent wheezing. NATIONAL ASTHMA EDUCATION AND PREVENTION PROGRAM - EXPERT PANEL REPORT 2 FOCUS ON THE MANAGEMENT OF ASTHMA IN CHILDREN In 1991, under the auspices of the National Asthma Education and Prevention Program (NAEPP), the first Expert Panel on the Management of Asthma published Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma. In 1997, the Expert Panel Report 2 was published-" after three years of revision and refinement. The guidelines are an important resource for primary care providers and for specialists who care for children with asthma. Several important focal points particularly pertinent to childhood asthma are listed below. Childhood asthma It is now recognized that asthma often begins in childhood, and is frequently found in association with atopy, the genetic susceptibility to produce IgE against common environmental allergens such as house-dust mites, animal proteins, and fungi.-' With the production of IgE antibodies, mast cells and possibly other airway cells (e.g., lymphocytes) are sensitized to become activated when they encounter specific antigens. Although atopy has been found in 30% to 50% of the general population, it is frequently found in the absence of asthma. Nevertheless, atopy is one of the strongest predisposing factors in the development of asthma.-Furthermore, among infants and young children who have wheezing with viral infections, allergy or a family history of allergy is the factor that is most strongly associated with continuing asthma through childhood." Differential diagnostic possibilities for asthma Several other possibilities should be ruled out before the correct diagnosis of asthma in infants and children can be made. For upper airway diseases, allergic rhinitis and sinusitis could be to blame. For obstructions involving large airways, the presence of a foreign body in the trachea or bronchus, vocal cord dysfunction, vascular rings or laryngeal webs, laryngotracheomalecia, tracheal stenosis, bronchostenosis, enlarged lymph nodes, and tumor should be ruled out. Small airways may be affected by viral or obliterative bronchiolitis, cystic fibrosis, bronchopulmonary dysplasia and heart disease. Other alternatives to asthma include recurrent
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cough due to other causes, aspiration from a swallowing mechanism dysfunction, and gastroesophageal reflux. Assessment of pulmonary function The expert panel recommends ongoing monitoring with a peak-flow meter at home for patients with moderate to severe persistent asthma. Patients age 5 and older are usually able to use a peak-flow meter; nevertheless, parents should be instructed on how to use them correctly. The personal best-peak flow number for each patient should be determined, as the treatment plan for asthma is based on his number. A popular method for encouraging patients to follow the reading of peak flow meter is to put the peak flow numbers into zones that are set like a traffic light: green signals good control, yellow signals caution, and red signals a medical alert. Patients (and their parents) are encouraged to keep a diary to keep track of peak flow, and to take action when peak-flow numbers change. The strong association between sensitization to allergens and asthma: A summary of evidence The association between asthma and allergy has long been recognized. Recent studies confirm that sensitization among genetically susceptible pediatric populations to certain indoor allergens such as house dust mites, animal dander, and cockroaches, or to the outdoor fungus Altemaria is a risk for developing asthma.^^ Sensitization to outdoor pollen carries less risk for asthma,-' although grass'" and ragweed" pollen have been associated with seasonal asthma. It is widely accepted that the importance of inhalant sensitivity as a cause of asthma declines with advancing age.'- The important allergens for children and adults appear to be those that are inhaled; food allergens are not a common cause of asthma symptoms. Food allergy are an important cause of anaphylaxis in children," but significant lower respiratory tract symptoms are uncommon, even with positive double-blind challenges.'" For these reasons, home environmental control should be an important part of asthma management for children, because they spend more time in the home environment. Inhaled corticosteroids and linear growth in children Inhaled corticosteroids are the most effective longterm therapy available for mild, moderate, or severe persistent asthma. However, when they are used in children, growth should be monitored carefully. The following key points on linear growth in children and inhaled corticosteroids need to be emphasized: (1) The potential risks of inhaled corticosteroids are well balanced by their benefits. (2) Growth rates are highly variable in children. Shortterm evaluation may not be predictive of attaining
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final adult height. (3) Poorly controlled asthma may also delay growth in children. (4) In general, children with asthma tend to have longer periods of reduced growth rates prior to puberty (males > females). (5) The adverse effects on linear growth appear to be dose dependent High doses of inhaled corticosteroids have greater potential for growth suppression. (6) High doses of inhaled corticosteroids in children with severe persistent asthma have significantly less potential for causing adverse effects on linear growth than oral systemic corticosteroids. (7) The majority of studies on the use of inhaled corticoseroids by children have not demonstrated an effect on growth: only a few have identified growth delay. Some caution (e.g., monitoring growth, stepping down therapy when possible) is suggested while this issue is studied further. Key recommendations for managing asthma in infants and young children (1) Diagnosing asthma in infants is often difficult, so underdiagnosis and undertreatment are key problems in this age group. A diagnostic trial of inhaled bronchodilators and anti-inflammatory medications is recommended. (2) In general, infants and young children consistently requiring symptomatic treatment more than two times per week should be given daily anti-inflammatory therapy. (3) When initiating daily anti-inflammatory therapy, a cromolyn or nedocromil is often tried first due to the safety profile of these medications. (4) Response to therapy should be carefully monitored. Once control of asthma symptoms is established and sustained, a careful step down in therapy should by attempted. If clear benefit is not observed, alternative therapies or diagnoses should be considered. Key recommendations for managing asthma in schoolage children and adolescents (1) Pulmonary function testing should use appropriate reference populations; adolescents compare better to childhood than to adult predicted norms. (2) When initiating daily anti-inflammatory therapy for mild-to-moderate persistent asthma, a trial of cromolyn or nedocromil is often given. (3) Adolescents (and younger children as appropriate) should be directly involved in establishing goals for therapy and developing their asthma-management plan. (4) Active participation in physical activities, exercise, and sports should be encouraged.
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(5) A written asthma-management plan should be prepared for the student's school, including plans to ensure reliable, prompt access to medications. Special consideration in managing exacerbation of asthma in infants (1) Assessment depends on physical examination rather than on objective measurements. Use of accessory muscles, paradoxical breathing, cyanosis, and a respiratory rate >60 are key signs of serious distress. (2) Objective measurements such as oxygen saturation
