Abstract
Allergic diseases in children have increased significantly in recent years and now affect up to 35% of children. They are a major cause of morbidity in children. Although there is a genetic predisposition, it is the exposure to environmental allergens, irritants and infections that will determine the sensitization to different dietary and inhalant allergens. As the genetic and environmental factors that act on an immature cellular immune system are better elucidated and their roles established, the implementation of more enduring preventive efforts will be developed. However, at present, the best approach to the child at high risk for the development of allergies is to institute dietary and environmental control measures early to decrease sensitization, and to recognize and appropriately treat the evolving signs and symptoms of allergic disease.
Keywords: Allergic diseases, Allergies, Environmental factors
RÉSUMÉ :
Les maladies allergiques chez l’enfant ont augmenté de manière considérable ces dernières années, et elles touchent désormais jusqu’à 35 % des enfants. Elles représentent une cause importante de morbidité chez l’enfant. Bien qu’il existe une prédisposition génétique, c’est l’exposition aux allergènes environnementaux, aux irritants et aux infections qui détermine la sensibilisation aux divers allergènes diététiques et inhalés. À mesure que les facteurs génétiques et environnementaux agissant sur un système immunitaire de cellules immatures seront élucidés et que leurs rôles seront établis, des efforts de prévention plus permanents seront implantés. Cependant, pour l’instant, la meilleure démarche face à un enfant à haut risque de présenter des allergies demeure des mesures précoces de contrôle diététique et environnemental pour réduire la sensibilisation ainsi que le dépistage et le traitement pertinents des signes et symptômes évolutifs des maladies allergiques.
Allergic diseases affect about 30% to 35% of all children, and the frequency of these diseases has been increasing in recent years. Atopic children have a genetic predisposition to develop immunoglobulin E (IgE) antibodies to a variety of dietary and inhalant allergens to which they are exposed. Subsequent exposure to the IgE produced that has fixed on mast cells results in a discharge of chemical mediators that causes both an immediate reaction and then a late inflammatory response in the target end organ. Atopic dermatitis (AD), IgE-mediated food allergies, asthma and allergic rhinitis are often interrelated. They can coexist, or as one condition improves, another can evolve (‘the allergic march’). The capacity to prevent and treat allergic diseases depends on an understanding of the immunology that underlies the development and expression of allergic diseases, as well as an understanding of the environmental factors that promote their development.
The propensity to develop allergies to dietary and inhalant allergens is largely genetically determined. Twelve per cent of children with no family history of allergy, 30% to 50% of children with a single parental allergy and 60% to 80% of children with biparental allergies will develop allergic disease (1).
Atopic individuals have a tendency to produce more IgE when exposed to certain antigens. The T helper cell is a major target for the genetic factors that control the expression of the IgE responder phenotype. Two types of T lymphocyte helper cells have been identified. T helper 1 (TH1) cells produce interferon gamma (INF γ) and other cytokines that are necessary to mount an effective immune response against infection. T helper 2 (TH2) cells that produce interleukin (IL)-4 and IL-5 play a dominant role in IgE production (2,3) and eosinophil activation. IL-4, which is produced by TH2 cells, is critical in initiating a switch in production by plasma cells to IgE. IL-5 increases eosinophil activation. INF γ, which is produced by TH1 helper lymphocytes, is important in cell-mediated responses, but can also ‘down-modulate’ TH2 cells and, consequently, the production of IL-4. Reciprocally, IL-4 can also decrease the production of INF γ by TH1 cells. Both types of T helper cells are reactive to allergens, but at the clonal level, the atopic response is predominantly TH2 as opposed to TH1 cells in healthy individuals.
There appears to be a strong association between allergen exposure in infants and young children, and the expression of atopic disease in later life (4). During pregnancy, the developing fetus is exposed to the TH2 environment of the placenta (5). At birth, the immune system of a newborn continues to be skewed toward TH2 type immunity. The postnatal maturation of the immune system is characterized by the gradual development of TH1 immunity. While the persistence of a TH2 pattern is to some extent genetically determined, the deviation toward a TH1 pattern is also modified to a considerable degree by the environment. A slower maturation of the TH1 immune response that normally occurs during the first 12 to 18 months of life is what predisposes a child to the subsequent development of allergy and asthma (6). Thus, in addition to genetic factors, a failure of TH2 responses that are present at birth to deviate to TH1 responses with the normal maturation of the immune system is postulated to drive the development of allergy and asthma. Indeed, a diminished peripheral blood cell generation of INF γ (generated by TH1 helper cells) has been associated with a greater likelihood of wheezing with a respiratory syncytial virus (RSV) infection (7,8). Treatment with INF γ has resulted in a decrease in bronchial inflammation after virus inoculation in rats (9). Exposure to specific environmental allergens and irritants during this critical period may cause the formation of long-lived memory T cell responses that will become clinically manifest many years later.
The hygiene hypothesis was first introduced in 1989 and was based on the observation that there was an inverse correlation between household size and allergic rhinitis (10). The incidence of infection was higher in households with more family members, and this increase in infection was postulated to reduce the development of the allergy phenotype. Infection is believed to stimulate the deviation toward a normal TH1 response. Further epidemiological studies investigating the protective role of childhood infections on the subsequent development of allergy have produced conflicting results, with some studies supporting the hygiene hypothesis and other studies not showing any link. The nature of the infectious agents (bacteria versus viral, as well as which specific bacteria or virus), the route of infection, the timing of infections and the length of follow-up all contribute to the conflicting results in the literature. Nevertheless, it has been hypothesized that one of the reasons for the significant increase in allergic diseases in developed countries is better hygiene and a relative lack of ‘TH1-inducing’ infections during infancy. In addition, antibiotic use during infancy may be associated with an increased risk of the subsequent development of allergy. It is postulated that antibiotics deplete normal gastrointestinal bacterial flora that normally suppress TH2 responses (11,12).
Current approaches to the allergic child involve the identification of ‘at risk’ children, the avoidance of potentially sensitizing dietary and inhalant allergens in early life, and recognition of the evolving allergic diseases. During early life, immature mucosal defenses permit the increased absorption of allergens, which then act on an immature immune system. In infants, the main exposure is to food allergens, whereas in older children, it is to inhalant allergens. As a consequence, allergy prone children may first present with IgE-mediated food allergies and eczema. These manifestations may either improve or persist, but in older children, asthma and allergic rhinitis provoked by inhalant allergens become predominant.
FOOD ALLERGIES AND INTOLERANCE
Few subjects in paediatrics evoke as much controversy as food allergies. Allergic reactions to foods are an important clinical problem because of both their frequency during early life and the potential for life-threatening reactions. Adverse reactions to foods are divided into two general categories: nonimmunological reactions (food intolerance) and immunological reactions (food allergy).
Food intolerance (nonimmunological reactions)
The majority of adverse reactions to foods are mediated by nonimmunological mechanisms. The most important cause of food-related reactions is toxic or microbial contamination.
Metabolic reactions are mainly due to problems in digesting carbohydrates, especially lactose, and involve symptoms related to the gastrointestinal tract (diarrhea, abdominal bloating and cramping). Primary and acquired lactase deficiency may vary dramatically among population groups. North American Afro-Americans and Afro-Canadians, and most Asiatics have primary lactase deficiency in about 80% of the population. Most individuals with this condition develop low lactase levels between the third year of life and puberty. In contrast, the prevalence of lactase deficiency is very low in Scandinavians, and ranges from 5% to 20% in North American whites (13).
Certain foods contain vasoactive amines (either natural or added) that can cause symptoms similar to those of true food allergies, in which the interaction between IgE and the food antigen stimulates a release of the vasoactive amine histamine. In some cases, enough vasoactive chemicals are present in the food or food additive that the reaction induced is similar to anaphylaxis. This type of reaction is termed ‘anaphylactoid’.
Food allergies (immunological reactions)
IgE-mediated food allergies:
The prevalence of IgE-mediated food allergies is unknown and appears to be anywhere between 3% and 7.5%; the higher frequencies usually occurring in younger children. One and one-half per cent of infants will experience milk allergy during the first year of life. Of those children, 15% will retain their sensitivity into their second decade of life, and 35% will have allergies to other foods. Egg allergy is believed to affect about 1.3% of children, and peanut allergy about 0.5% of children.
Genetic predisposition, the allergenicity of food and the timing of exposure will determine the foods to which the atopic child develops allergy. Young infants are especially prone to the development of food allergies. In younger children, the most common foods implicated are milk and eggs. These allergies tend to be self-limited, and most will resolve within a few years with appropriate elimination diets. As in older children and adults, most allergies to the more allergenic foods (such as nuts, fish and seafood) tend to persist throughout life.
IgE-mediated reactions to foods can present with a spectrum of immediate reactions (usually occurring within 4 h) that are of increasing severity and involve different organ systems. Skin involvement includes perioral skin rashes, AD, urticaria and angioedema. Respiratory involvement includes cough, stridor and wheezing. Gastrointestinal symptoms include projectile vomiting, abdominal cramps, nausea and diarrhea, and systemic symptoms include anaphylaxis.
Anaphylaxis:
Anaphylaxis is an acute, severe allergic reaction that usually involves two or more organ systems, resulting from the rapid release of potently pharmacologically active mediators from tissue mast cells. After exposure to the provoking factor, the response can occur within minutes to hours, and the patient may present with a broad spectrum of signs and symptoms (14). Anaphylaxis may start with cutaneous flushing and hives, which can rapidly progress to cardiorespiratory compromise and death. Other manifestations can be intraoral or laryngeal edema, bronchospasm, abdominal cramping, vomiting or diarrhea. While most symptoms will resolve spontaneously or within hours with treatment, in some cases, symptoms are protracted or recur several hours later (15). The frequency of symptoms in patients with anaphylaxis seen in an emergency room have been reported to be urticaria in 79% of cases, wheezing and dyspnea in 70% of patients, and hypotension in 24% of patients (16). The true incidence and prevalence of anaphylaxis is unknown, but estimates are 1:2700 hospitalizations from all causes, with up to 500 cases of deaths/year in the United States (17). Recognition of anaphylaxis and prompt therapy (Table 1) are essential for a successful outcome. The most common causes of anaphylaxis are foods (18), drugs (19) and insect stings (20).
TABLE 1:
Identification of children at high risk |
|
Management |
Acute |
|
Continue observation until reaction is fully resolved |
Discharge patient with Epipen (Dey Laboratories, USA) or Anakit (Hollister-Stier, USA) and refer to an allergist |
Prevention |
|
A wide variety of foods have been reported to trigger anaphylaxis, with peanut, tree nuts, fish, seafood, egg and milk being the most frequently encountered food allergens. Food antigens may be hidden in foods and may not be readily identifiable. Patients at risk for lethal food allergy usually have a history of a previous reaction to the food, and most patients have had coexisting asthma. Sampson et al (21) reviewed six fatal anaphylactic reactions and seven near fatal reactions. All patients had asthma and were allergic to other allergens. In this report, four of the six fatal reactions occurred in school, and even though epinephrine had been prescribed for three of the patients, none of them had it available at the time of the onset of the reaction. The major difference in outcome between the fatal and nonfatal reactions appeared to be the speed at which epinephrine was administered. In some patients, the reaction began with abdominal pain and was not recognized as being allergic in origin. Some of the children had quite mild symptoms before the onset of respiratory symptoms, and none of them had received epinephrine before the onset of the respiratory symptoms. Thus, epinephrine should be given promptly in anaphylaxis treatment (22).
In patients who present with a significant reaction that is associated with the ingestion of food, a detailed history of the reaction, including the time of onset, all manifestations, the nature of the progression, the duration of the reaction and the response to treatment, is necessary. At the time of the reaction, once treament has begun, a list of the ingredients of all foods ingested, manufacturers’ names and, if possible, the lot numbers of the food items is necessary. This information is useful when the confirmation of the allergy to the suspected foods is made by a trained allergist.
Management of anaphylaxis involves making the parent and patient aware of the potential risks of subsequent exposure. The foods to which the patient is highly allergic must be strictly avoided. Patients and parents should be educated about how to read ingredients on labels and to ask to see the list of ingredients of foods in restaurants before ingesting food. If there is doubt as to what the food contains, it should not be ingested. Small children should be taught not to accept any foods if their parents have not given permission to do so.
Patients at risk for severe reactions should be equipped with appropriate rescue medication, including epinephrine (Epipen; Dey Laboratories, USA) or an Anakit (Hollister-Stier, USA). In young patients, serious adverse effects from epinephrine, such as cardiac arrhythmias or hypertensive crises, are extremely rare, and the life-saving benefit of epinephrine far outweighs any small risk of adverse effects.
Patients should be advised to have MedicAlert bracelets that advise of the potential for significant reactions. If the child is in daycare or school, or goes to camp, the parents should advise caregivers about the child’s allergy, educate them about avoidance, and instruct them in how and when to use rescue medications.
In a child at risk for a potentially life-threatening reaction, that is a child who has presented with reactions to nuts, fish and seafood or who has presented with a significant reaction to any food in the past, epinephrine should be injected immediately, as soon as symptoms occur after ingestion. Do not wait for significant symptoms to occur. Antihistamines can then be administered to help maintain control. Once epinephrine has been injected, the patient should be transported as quickly as possible to a medical facility where oxygen, apparatus to open and maintain airways, bronchodilators and intravenous fluids for volume replacement are available. The patient should be kept under observation for at least 4 h but preferably for 12 to 24 h because, in some cases, the reaction recurs hours later.
Delayed immunological reactions to foods (non-IgE dependent)
Allergic gastroenteropathy represents a spectrum of diseases in which the inflammation of the bowel is the major problem. Reactions may be of varying severity. Mild symptoms include abdominal cramps and regurgitation, but these reactions may progress to the more significant symptoms of chronic diarrhea (often with foul smelling stools with blood and mucous), protein loss, anemia and failure to thrive. The inflammation is believed to be stimulated by a cell-mediated reaction rather than IgE-mediated response. The manifestations are usually delayed in onset, and the skin and respiratory systems are rarely involved.
In the enterocolitic disorders of infancy, irritability, protracted vomiting and diarrhea may occur 1 to 3 h after feeding. Continued exposure may result in bloody diarrhea, anemia, abdominal distention and failure to thrive. Hypotension occurs in about 15% of cases, and it may be associated with a metabolic acidosis. Cow’s milk or soya-based formula is the main cause of enterocolitic disorders in young children, whereas in older children, eggs, wheat, rice, oats, peanuts, treenuts, chicken, turkey and fish have been found to be the main causes. In adults, shellfish appears to be the main cause.
Infantile colic can, at times, be severe and cause significant anxiety. There have been a number of reports of improvement in colic when the baby is taken off cow’s milk formula (23) and even improvement in breastfed babies when the lactating mother stops drinking cow’s milk. Usually, the response is quite dramatic, and the baby improves within a few days. If improvement does not occur, continued changes in formula should not be pursued. The exact etiology of colic is unknown, but in severe cases, infantile colic may be a part of the spectrum of infantile colitis. Colic, even if due to milk, is rarely, if ever, an IgE-mediated reaction.
Diagnosis of food allergies
Any attempt to diagnose food allergies should begin with a careful history. This should include all food or foods that could be implicated, time of onset of the reaction after ingestion, organ involved (ie, skin, gastrointestinal system, respiratory tract), progression of the reaction and the response to treatment. General guidelines are provided in Table 2. Important aspects from the past include the following details of early life: surgery or gastrointestinal infection; a diary of the introduction of foods into the diet; and the coexistence of other atopic manifestations such as atopic dermatitis and asthma. The predisposition of the patient to develop IgE-mediated food allergies should be assessed by a family history of atopy in first-degree relatives. The ‘gold standard’ for the confirmation of an adverse reaction to a food is a double-blind, placebo-controlled challenge.
TABLE 2:
Patient history is notoriously inaccurate |
Food allergies are most common in young children, especially children with atopic dermatitis |
Relatively few foods are responsible for the vast majority of allergic reactions |
True food allergies generally involve ‘classical’ signs and symptoms that affect the skin, gastrointestinal tract and/or respiratory systems |
Subjective or behavioural symptoms as a sole manifestation are very rare |
Adverse reactions to dyes and additives are rare |
Data from reference 96
Laboratory diagnostic testing should reflect the type of reaction that is suspected. Reactions that occur within 2 h, and that primarily involve the skin and respiratory tract should be evaluated by appropriate skin prick testing, or, if skin testing is not feasible or available, the CAP (Pharmacia and Upjohn Diagnostics AB, Sweden) or Radioallergosorbent (RAST) tests.
Positive skin prick tests, which are twice as large as positive histamine control, have been found to be predictive of a positive challenge (24,25). As well, CAP tests have also been correlated with the probability of positive challenges. It should be noted that both skin prick and in vitro tests can remain positive, even after clinical sensitivity has waned, and elimination diets should not be based solely on positive tests. Positive laboratory and/or skin tests help to confirm the diagnosis, but challenges that are preferably blind should be carried out to prove the clinical relevance. If the cause of the reaction is uncertain, a trial elimination of suspected foods, followed by the subsequent reintroduction of the foods to confirm the reaction, is warranted. If the reaction is life-threatening, the reintroduction of the food or challenges may be dangerous and should only be carried out if absolutely necessary, with appropriate precautions under medical supervision. Because the majority of food allergies tend to improve, periodic re-evaluation is necessary.
Skin tests are not helpful in cases in which the gastrointestinal tract is primarily involved, especially if the symptoms are delayed in onset. Tests, such as serum vitamin A and carotene tests, will measure absorption, whereas blood eosinophilia may indicate eosinophilic infiltration of the intestinal mucosa. Hypoalbulminemia secondary to a protein-losing enteropathy is sometimes found. Anemia due to occult gastrointestinal bleeding can also be found. Usually, in moderate to severe cases of intestinal involvement, an endoscopic evaluation and biopsy are necessary.
Treatment
Once the diagnosis is confirmed, the treatment of choice is the strict avoidance of the identified food until the sensitivity has waned. Most allergies presenting in early life to milk, eggs and soya tend to be outgrown, and the foods usually can be reintroduced into the diet. Most allergies to peanuts, tree nuts, fish and seafood persist. In cases of allergic gastroenteropathy that is associated with significant inflammation, corticosteroids are sometimes necessary. Most of the allergic gastroenteropathies that present in early life resolve.
ATOPIC DERMATITIS
AD usually begins during early infancy and affects about 10% of the paediatric population. It is a complex, chronic, inflammatory skin disorder that is characterized by severe pruritis, a chronically relapsing course, classic skin distribution and other diagnostic criteria (26). AD appears before one year of age in 60% and within five years in 85% of those who are destined to acquire it (27). It is associated with an abnormal vascular response, increased transepidermal water loss, a decreased itch threshold and inflammation. In younger infants, the scalp areas near the neck and behind the ears, and the extensor surfaces of the arms and legs are affected. As the child grows older, the flexural creases become more involved.
Recent studies have shown the complex interrelationship of genetic, environmental, psychological, immunological and infectious factors that contribute to the development and severity of AD. Immunologically, defects in cell-mediated immunity, decreased phagocytic function and increased production of IgE have been demonstrated (28). Children with AD have decreased INF γ and increased IL-4 production (29). Most children with AD develop other atopic disorders (30). While the role of food or inhalant allergens in the pathogenesis of AD is controversial, considerable evidence implicates food allergens in many patients (31). A number of studies have confirmed the role of foods in AD by using double-blind, placebo controlled food challenges (32). It is estimated that 30% to 40% of patients with moderate to severe AD have an allergy to food that contributes to their disease. Most patients with food sensitivies that have been confirmed by controlled challenges are allergic to only a few foods. Milk, soya, eggs, wheat, peanuts, tree nuts, fish and seafood account for almost 90% of the foods confirmed by a challenge. It has also been observed that, although up to 80% of patients had positive skin tests to foods, only about one-third of positive tests correlate with positive immediate challenges. Interestingly, if the skin test is negative for the food in question, challenges are almost always negative. Therefore, positive skin testing is useful to indicate foods that may be contributing to the problem. The suspected foods can then be confirmed by a trial elimination diet. Negative skin testing eliminates suspected foods and allows a more varied diet. Although positive skin tests are suggestive, prolonged exclusion of foods from the diet should not be based solely on positive tests, unless there is a good clinical correlation between the improvement of the AD and the elimination of the suspected foods. The role played by aeroallergens in AD is unclear, but exposure to house dust mites and other aeroallergens have been implicated in older children (33).
Staphylococcus aureus is found in over 90% of patients with chronic AD skin lesions as well as on the unaffected skin in AD patients. In contrast, only 5% of nonaffected individuals harbour this organism on their skin. The importance of S aureus is supported by a significant reduction in skin disease when it is treated with a combination of antistaphylococcal antibiotics and topical corticosteroids (34). The reason for increased binding of S aureus to atopic skin is not completely understood, but it is most likely driven by the atopic inflammation. It has been found that treatment with topical corticosteroids will reduce S aureus counts on atopic skin (35). S aureus can exacerbate or maintain skin inflammation by secreting toxins known to act as superantigens (36), which can cause a marked activation of T cells and macrophages. Most patients with AD make specific IgE that is directed against staphylococcal superantigens found in their skin (37).
Treatment of AD is directed at avoiding causal factors, decreasing water loss by the use of emollients, decreasing itching by the use of antihistamines and decreasing inflammation by the use of corticosteroid creams. As well, the combination of topical steroids with antibiotics has been shown to be more effective than either topical steroid or antibiotic therapy alone (38). Spicy or ‘acidy ’foods, such as citrus fruits, which contain vasoactive amines that can directly increase pruritis and vasodilation, should be limited.
The majority of children with infantile eczema improve (39) (although one study is cited, this has been shown in many other studies). Less favourable prognostic signs included late onset and the involvement of extensor surfaces instead of flexor surfaces. In another study (40), severe widespread dermatitis, family history of AD, associated respiratory allergies (such as asthma and allergic rhinitis), early onset (younger than one year of age) and female sex were unfavourable prognostic features.
ASTHMA
The increasing morbidity (41,42) and mortality of asthma has prompted the development of guidelines that encourage an organized approach to patient education, and to the diagnosis, evaluation and treatment of asthma (43). Fundamental to this approach has been the ‘rediscovery’ of the role of inflammation in asthma and the use of inflammatory medication on an ongoing basis. As well, environmental avoidance measures and education have become foundations of treatment.
The main causes of asthma appear to be early viral infections, exposure to cigarette smoke and atopy. Viral infections have also been shown to increase hyperresponsiveness and have also been associated with acute exacerbations of asthma in children (44–46). The level of IgE to RSV has been associated with an increasing severity of bronchospasm and hypoxia (47). Persistent wheezing after RSV infection in infancy is short lived in the absence of other factors such as atopic family history or exposure to cigarette smoke (48). Passive smoking has a significant influence on the number of episodes of asthma, as judged by hospital admissions during the first year of life (49,50). Most of this effect can be attributed to maternal smoking, with a less consistent effect for paternal smoking (51).
Studies have shown that atopy is the most important predictor of chronic asthma in childhood. Transient infant wheezing is not characterized with the usual hallmarks of asthma in older cildren, namely a family history of asthma and markers of atopic diathesis (52). The main risk factor for transient infant wheezing appears to be maternal smoking during pregnancy.
Atopy, defined as skin test sensitivity to common allergens, has a close association with asthma and bronchial hyperresponsiveness (53,54). Demonstrable IgE sensitization, via skin test or RAST test, to allergens in the environment, has emerged as one of the leading causes of inflammation, and has been directly associated with increased bronchial hyper-reactivity and current asthmatic symptoms (55,56). Chronic exposure to low dose allergens has been associated with increased bronchial hyper-reactivity, even in the absence of overt asthmatic symptoms (57). Sensitivity to house dust mites and cat dander have been found to be highly significant risk factors that are associated with the development of asthma (58). Early exposure to high concentrations of house dust mites during the first year of life is associated with a significantly higher risk for developing asthma (59). In school aged children, the significance of the bronchial hyper-reactivty and the risk of symptomatic disease correlates with the number of and size of positive allergy skin tests. Recent studies have shown that many adults with ‘new’ asthma had a history of asthmatic symptoms beginning during childhood, indicating that although symptoms may remit, the asthmatic predisposition remains (60).
Knowledge about a child’s home, daycare and school environment, and the implementation of appropriate environmental measures are the foundations of asthma management, and are discussed below in the section ‘Approach to the allergic child’. Pharmacological management of asthma (Table 3) is based on the patient’s previous symptom pattern and environmental exposure. This information may be used to predict when the asthma may get worse so that anti-inflammatory treatment can be instituted early to control and/or prevent these attacks.
TABLE 3:
|
In mild, intermittent asthma, beta-2 agonists can be given on an ‘as needed’ basis for wheezing and shortness of breath or can be taken before specific identified provoking factors such as exercise. Inhaled ipratropium bromide is less effective, but is occasionally used as a reliever medication in patients who are intolerant to short-acting beta-2 agonists. In patients who require the frequent use of reliever medications, controller/preventer medication is necessary. These medications include inhaled (and oral) glucocorticosteroids, antileukotriene agents and long-acting beta agonists. Inhaled glucocorticosteroids are the most effective agents in this group of drugs and are considered to be the first-line therapy. Inhaled steroids should be given at the appropriate doses necessary to maintain control, and the dose can be raised or lowered to achieve this result. If higher doses are necessary, additional medication, such as antileukotrienes and long-acting beta agonists can be added to reduce steroid need. It should be remembered that anti-inflammatory treatment is delayed in onset and is also preventive, and as such, should be continued for weeks to months after the acute attack is over.
Inter-relationship with other allergic disease
Because, for the most part, asthma is a part of the allergic disease spectrum, it can be predicted from family history of allergic disease in a first-degree relative and/or the appearance of other allergic diseases such as AD, IgE-mediated food allergies and allergic rhinitis. As a result, the signs and symptoms of asthma can be identified early, and treated appropriately. In babies with AD or IgE-mediated food allergies, a chronic or prolonged coarse cough with colds may be an indication of ongoing airway inflammation.
Allergic rhinitis and asthma are both a part of the same systemic disease. Under normal circumstances, irritants, microbial agents and allergens in the air enter the respiratory tract through the nose. Inspired air becomes turbulent over the turbinates, and interacts with the ciliary and secretory humoral immune defenses to remove the majority of the irritants and allergens. Inspired air is also humidified, and is presented to the lungs in a conditioned and purified fashion. If the nasal passages become obstructed due to inflammation or infection, the above processes do not take place, and the lungs are exposed to increased irritants, allergens and microbials. In predisposed individuals, this increased exposure will augment allergic inflammatory processes, resulting in asthma. Many patients with allergic rhinitis, but no history of asthma, have evidence of abnormal pulmonary function that occurs either spontaneously or after bronchoprovocation with metacholine, histamine or cold air (61,62). Seasonal variation of airway responsiveness has been demonstrated in patients with seasonal allergic rhinitis (63). It has been shown that the treatment of allergic rhinitis with intranasal corticosteroids improves rhinitis and asthma symptoms, and airway responsiveness, as measured by methacholine challenge (64). Direct anti-inflammatory action of the intranasal corticosteroid in the lung appears to be unlikely because less than 2% of the nasal medication is delivered to the chest. Nasal beclomethasone treatment has also been shown to prevent the increase in bronchial responsiveness that is associated with seasonal rhinitis and asthma (65).
The association of sinusitis and asthma has been noted since the 1920s and 1930s (66–68). It has been suggested that postnasal drainage can lead to bacterial seeding of the lower airway, resulting in infection and inflammation. Also, the stimulation of the parasympathetic system via the afferent trigeminal nerve input from the nose and sinuses, and through efferent vagal pathways can cause reflex bronchoconstriction (69). In studies showing an increase in lower respiratory resistance after the stimulation of the upper respiratory airway, this effect can be abolished by the administration of atropine (70). Slavin et al (71) reported that 70% of patients with asthma showed subjective improvement, and 65% could reduce oral steroid requirements following medical or surgical treatment of their sinusitis. Treatment of sinusitis in asthmatic children with a combination of antibiotics, antihistamines and corticosteroids has shown an associated improvement in metacholine airway responsiveness (72).
ALLERGIC RHINITIS
Allergic rhinitis is a major cause of morbidity in children. It is the cause, coexisting disorder or predisposing factor in many cases of serous otitis, chronic sinusitis, increased susceptibility to upper and lower respiratory infections and orthodontic disorders such as overbite and maldeveloped dental archs (73). Many children who suffer from allergic rhinitis present with a chronic congested nose or recurrent upper respiratory infections and are repeatedly treated with cold medications and/or antibiotics. Over time, there often is a change to a more seasonal pattern, and the problem is then recognized as being allergic in origin. The direct costs of medical care and medication, and the indirect costs of the time lost from school and work days are enormous. However, allergic rhinitis is often dismissed as being inconsequential, and patients are left to find remedies on their own. Other symptoms of allergic rhinitis are listed in Table 4. Allergic rhinitis can also be recognized by the signs listed in Table 5.
TABLE 4:
Clear, watery nasal discharge |
Snoring |
Mouth breathing |
Sniffling |
Sneezing |
Facial twitch or tic |
‘Allergic salute’ |
Recurrent otitis media or serous otitis |
Recurrent sinusitis |
TABLE 5:
Allergic ‘shiners’ that are bluish edematous areas beneath the eyes due to vasodilation and decreased drainage |
Dennie-Morgan fold line running laterally from the medial epicanthus |
Transverse nasal crease on the border of the nasal cartilage caused by persistent rubbing (‘the allergic salute’) |
Maxillary hypoplasia caused by decreased aeration of the maxillary sinuses due to a chronically inflamed nasal mucosa |
High arched palate, maxillary malocclusion due to chronic mouth breathing |
Pale, bluish-grey nasal turbinates |
The differential diagnosis of allergic rhinitis includes infectious rhinitis, chronic sinusitis, foreign body (especially if there is a history of chronic unilateral purulent nasal discharge), nasal polyp or mechanical nasal obstruction.
Treatment
Antihistamines are effective in decreasing the sneezing, itchiness and secretions of rhinitis, and in relieving itchy eyes. If there is significant nasal congestion, a combination oral decongestant-antihistamine may be more effective (74). Unfortunately, antihistamines cause a high percentage of side effects, with sedation being the most common. Newer, nonsedating antihistamines are potentially more useful because they allow the patient to have symptomatic relief without the sedation. However, in children, the older, first-generation antihistamines cause less sedation than in adults.
If symptoms are severe or if there is a need to reduce congestion quickly, a topical decongestant can be used for short periods of time. After a few days of regular use, there appears to be a ‘rebound’ effect in which the nasal mucosa becomes more congested (rhinitis medicamentosa), and the symptoms can actually increase while the patient is taking the topical decongestant.
If the rhinitis is seasonal, symptoms can be anticipated, and taking preventive therapy with topical corticosteroids before and during the season is useful. Nasal corticosteroids significantly reduce the symptoms of congestion and sneezing (75). The side effects of nasal steroids generally are nasal burning, irritation, sneezing and epistaxis. If symptoms are severe, a short course of oral steroids may be necessary to decrease the symptoms. With sinusitis, aggressive and prolonged antibiotic treatment, in addition to appropriate anti-inflammatory therapy, may be necessary.
In many controlled studies, immunotherapy reduced the symptoms of rhinitis (76). Immunotherapy should be considered only after environmental precautions and appropriate medical management have not resulted in an adequate improvement in symptoms. The selection of allergens to be used in immunotherapy is based on the patient’s clinical history and confirmatory positive skin tests. Positive skin tests should not be the sole determinants of the allergens to be included in the immunotherapy vaccine preparation because there may be poor correlation between IgE titres and symptom severity during the pollen seasons (77). Patients should be advised that significant improvement may take a few years to occur; that they should not stop taking their medication until symptoms improve; that treatment is specific and will not prevent symptoms that are caused by other allergens; and that environmental precautions should continue to decrease the chance of a relapse.
Approach to the allergic child
Identification of patients at risk:
There is a genetic predisposition to develop allergic disease; however, environmental exposure determines to what a patient will become sensitized and also the severity of the disease (78). To decrease the frequency and severity of the sensitization, one can identify patients at risk by taking a good family history. If there is no close relative with allergies, the incidence is about 12%, but if one parent suffers from allergies, the incidence rises to 30% to 50%. If both parents have allergies, the chances of having an allergic child are 50% to 80%. Babies of allergic mothers are more likely to develop allergies than babies of allergic fathers (79). Measurement of cord blood IgE has been used to further predict whether a child would develop allergies. Initially, it was believed that this would have great predictive value (80,81), but recent studies have shown that family history is more important (82).
Although the tendency to develop allergic disease is inherited, disease manifests itself after sensitization to dietary and environmental allergens. Conditions that decrease mucosal immunity and/or allow the increased absorption of allergens increase the likelihood of sensitization (Table 6).
TABLE 6:
Immediate family atopy |
Maternal smoking |
Decreased humoral and cellular immune defenses in early life |
|
Surgical intervention or infection that disrupts mucosal integrity |
Early exposure to ingested or inhaled allergens |
|
Exposure to irritants (cigarettes, wood burning stoves, etc) |
Dietary control measures:
If an infant is believed to be at high risk for the development of allergic disease, the infant may benefit from decreased exposure to food allergens to decrease the incidence of food allergies in the first few years of life. A dietary avoidance regimen that involves breastfeeding (or if necessary, supplementation with hypoallergenic milk) for at least four months and the delayed introduction of allergenic solids should be considered (83). It has been suggested that mothers who breastfeed avoid ingesting highly allergenic foods such as nuts, fish and seafood in order to decrease exposure of babies to these foods. High risk infants who have followed this dietary regimen have been found to have significantly decreased food allergies and AD during the first year of life, but experience no decrease in the incidence of asthma or rhinitis later on. If these dietary control measures are undertaken, it is important that the mother’s diet be reviewed by a dietician. To decrease the possibility of potentially life-long sensitization, the introduction of highly allergenic foods, such as fish, nuts and seafood, should be delayed until age three years or later. However, it has been shown that the fetus has probably been exposed to these antigens and can mount an immunological response from about 22 weeks’ gestation (84). Because many children with food allergies will develop respiratory allergies, such as asthma and rhinitis, environmental counselling about allergen and irritant avoidance should be undertaken to minimize this evolution.
Environmental control measures:
Environmental control measures are the cornerstones in the treatment of respiratory allergies. If instituted early in the homes of high risk children, they decrease exposure to inhalant allergen and, hopefully, decrease the risk of sensitization (85).
A careful history, including an assessment of the home, school and/or daycare environments’ is needed to identify potential irritants and allergens (Table 7). Irritants in the environment, such as cigarette smoke, should be avoided. Sensitization to the suspected allergens should be confirmed by appropriate skin testing or in vitro tests such as RAST or CAP. If this is not feasible, corrective measures should be advised.
TABLE 7:
Indoor allergens |
House dust mites |
Animal dander (dogs, cats) |
Cockroaches |
Moulds |
Outdoor allergens |
Pollens |
Trees (early to late spring) |
Grass (late spring to early summer) |
Ragweed (late summer) |
Moulds |
Irritants |
Cigarette smoke |
Wood burning stoves |
Emissions from paints, lacquers, glues |
Dust mites:
Dust mites feed on human skin scales and thrive if humidity is greater than 50%. Mite avoidance measures consist of eliminating dust mite reservoirs and decreasing humidity (86). Bedrooms are the most important source of mite allergen exposure and are the first site on which control measures should be focused. Mattresses and pillows should be encased in impermeable, zippered covers. Bedding should be washed with hot water (above 55ºC).
Carpets, especially those layed on concrete slabs, are excellent mite reservoirs and should be removed if possible. If they cannot be removed, acaracides, such as benzyl benzoate (a fine powder that is sprinkled on carpets), can reduce mite counts. Because tightly insulated houses tend to be more humid, proper ventilation should be ensured. If it is difficult to reduce humidity to less than 50%, a dehumidifier or air exchanger may be necessary. Although air purifiers may help to reduce the level of the larger diameter allergens, most of them will not reduce the levels of house dust mites. In forced air heating systems, filters should be cleaned or washed often. Duct openings in the patient’s bedroom should be sealed or covered with filters, and if necessary, electric baseboard heaters should be installed. Central humidifiers should be either disconnected or cleaned often.
In mite-sensitive asthmatics, the most effective treatment is environmental control, and the above allergic precautions have been found to significantly decrease the severity of the illness and the need for symptomatic medication (87).
Dust mite precautions:
Dust mites thrive in humid, dusty environments. Therefore, the following environmental measures should be undertaken.
Humidity in the home should be kept well below 50%.
Mattresses and pillows should be encased in impermeable, zippered covers.
Bedding should be washed in hot (55ºC) water frequently.
In homes that are heated with forced air system, filters should be changed or washed frequently, and the duct opening in the bedroom should be sealed or covered with a cotton filter.
If possible, carpeting should be removed. If not, steam cleaning and drying, and vacuuming with a high efficiency particulate air or central vacuum reduces the amount of dust mites that recirculate in the air.
Dust trappers in the bedroom, such as stuffed animals or books, should be removed or put in covered bookshelves.
Cockroach allergens:
Cockroach allergens have been found to be a major allergen in inner city dwellings and other contaminated settings (88,89). Control depends primarily on good housekeeping and insecticides. Even so, because cockroaches seem to infest whole buildings, exposure is hard to avoid, unless the patient moves.
Animal dander:
Ideally, in patients found to be sensitized to animals, the animal should be removed from the home. For young children at high risk for developing allergy or children who have already demonstrated evidence of allergic disease, even though skin testing to the animal in question may be negative, the same counselling should apply. Cat allergen produced by the sebaceous glands in the skin are airborne particles of 2 to 4 μm that remain airborne for long periods (90). Once the cat has been removed from the environment, dander may remain in the carpets and in upholstered furniture for prolonged periods of time. Families who elect to keep their cats should wash the animal weekly in warm water to decrease the source of the allergen (91). Animals should be kept out of the patient’s bedroom, and reservoirs, such as carpets and upholstered furniture, should be removed. Mattresses should be covered with impermeable, zippered covers.
Mould:
Major indoor moulds are Aspergillus and Penicillium, but outdoor moulds (such as Alternaria and Cladosporium) permeate the indoor environment (92). Common to the growth of all moulds is the need for humidity, and the major reservoirs are damp, poorly ventilated basements, bathrooms and kitchens. Central humidifiers installed in forced air heating systems can harbour major amounts of mould if proper care is not taken.
If mould sensitization is confirmed, humidity should be kept low, to 35% if possible, but certainly not over 50%. Precautions include increasing ventilation throughout the house, especially in basements and bathrooms; venting dryers to the outside; removing carpeting from basements or other areas that have been flooded; checking walls for seepage; and removing wallpaper. A dehumidifier, air exchanger or air conditioner can also decrease humidity. Exposing the house to sunlight by cutting back trees and branches around the perimeter may also decrease humidity.
Pollens:
It is important to be aware of the timing of the appearance and disappearance of the major allergenic pollens in the area. In general, tree pollens appear in the early to late spring, grass pollen in late spring to early summer and ragweed in late summer. It is important to make the diagnosis not only by clinical history, but also by confirmation with appropriate skin testing. Occasionally, patients suffering from classic symptoms of pollen allergy may also be allergic to moulds that are also prominent during that time of year. Dust mites also tend to thrive in the humidity of spring, late summer and fall, and patients suffering from a dust mite allergy can become more symptomatic. Pollens are more abundant in the air in the early morning hours. Windows in the bedroom should be kept closed during that time to prevent the pollen from entering the house. Air conditioning in the house and in the car may help by allowing the patient to keep his or her windows closed. Outdoor activities should be planned to avoid being outside during peak pollen hours. For patients who suffer from severe symptoms, planning vacations to locations where the pollen in question is not as abundant may be warranted.
Irritants:
It has been clear for many years that exposure to cigarette smoke has a major impact on the frequency and severity of respiratory allergies (93,94). Patients should be counselled to stop smoking, and parents of patients with respiratory allergies should smoke outside of the house and not in the car. As energy costs have increased, there has been a tendency to tightly insulate houses and, in many cases, to add wood burning stoves. Children living in houses with wood burning stoves appear to suffer from more respiratory infections (95). Hobbies, such as woodworking or painting, may increase exposure to toxic irritants. In such cases, air exchangers may help to remove the irritants from the house.
CONCLUSIONS
Allergies in children are the result of the interaction between genetic and environmental factors on disease expression. Although there is a genetic predisposition, exposure to environmental allergens, irritants and infection determines a patient’s sensitization to different dietary and inhalant allergens. As the genetic and environmental factors that act on an immature cellular immune system are elucidated and their roles established, the implementation of more enduring preventive efforts will be developed. However, at present, the best approach to the child at high risk for the development of allergies is to institute dietary and environmental control measures early to decrease sensitization and to recognize, and appropriately treat, the evolving signs and symptoms of allergic disease. Inflammation is central to all of the allergic diseases, and anti-inflammatory treatment should be instituted early if there are ongoing symptoms.
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