Rudolph's Pediatrics, 22nd Ed.

CHAPTER 191. Clinical Aspects of Allergic Diseases

Maria Garcia-Lloret

Allergic rhinoconjunctivitis, asthma, and food allergy are some of the prototypical allergic diseases. While allergies may develop at any age, allergic sensitization (ie, development of IgE responses) occurs predominantly early in life. Food-specific IgE antibodies may appear in the very young to herald an early presentation of clinical food allergies. Environmental allergen-specific IgE antibodies develop mostly after the age of 2, often leading to allergic rhinitis and or allergic asthma in preschool or school-aged children. Although not all allergic diseases invariably develop in the same patient, in a sizeable number of children the progressive sensitization to multiple antigens will result in sequential and often cumulative manifestations of atopy, a continuum that is known as the allergic march or the allergic marathon. It follows that allergic sensitization in childhood can have long-lasting effects throughout the life of the individual and implies a considerable burden to society as a whole.

IMMUNOPATHOGENESIS

The fundamental role of the immune system is to protect the host against microbial pathogens while maintaining tolerance to “self” and to harmless exogenous antigens. This task is accomplished through a series of interactions between elements of the innate and the adaptive immune system and involves multiple pathways of recognition, activation, response, and memory. Deficient immune responses to pathogens can lead to increased susceptibility to infection, whereas a failure in the mechanisms of tolerance results in allergy or autoimmunity. On the other hand, an uncontrolled inflammatory response during the course of an infection can increase morbidity and mortality and augmented tolerance can hamper tumor rejection.

At the cellular level, dendritic cells and T lymphocytes are central to the regulation of immune homeostasis (Fig. 191-1). Specific interactions between these two key players lead to the differentiation of naïve T cells into one of three T helper (TH) subtypes (TH1, TH2, and TH17). These effector T cells are kept in check by another set of T cells: the regulatory T cells, of which there are several subtypes that presumably represent distinct lineages.1

TH1 cells express the transcription factor T-bet and produce interferon gamma as their distinctive cytokine. They play an essential role in host defense against intracellular bacterial and viral pathogens and also provide help, through the agency of interferon gamma, for IgG2 antibody production. TH2 cells, which play an essential role in host defenses against parasitic infections, are defined by the expression of the transcription factor GATA-3. They produce IL-4 and IL-13, which are essential for IgE production by B cells. Both cytokines also act to program cellular elements of the innate immune response, including macrophages and airway epithelial cells and others, to produce proallergic inflammatory products. TH2 cells also produce other cytokines such as IL-5, which is a key factor for eosinophil development and survival. The more recently discovered TH17 cells are defined by their expression of the transcription factor retinoic acid orphan receptor gamma-T. TH17 cells express signature cytokines such as IL-17, which plays a critical role in mobilizing neutrophilic inflammation, that are essential to successful host defenses against certain pathogens such as fungi (especially Candida species).

Since the 1980s, the allergic phenotype had been understood in terms of an imbalance between TH1 and TH2 responses. This concept provided an operational mechanism behind the “hygiene hypothesis,” which states that the lack of exposure to certain types of microbes early in life as a result of modern hygienic and medical practices fails to elicit robust TH1 responses and, by doing so, removes the restraint on TH2 responses that then become predominant.2As a result of the TH2 skewing, there is a functional enhancement of the cellular responses to the TH2 cytokines, which predominantly target the mechanisms involved in hypersensitivity reactions such as IgE production, mast cell maturation and survival, and eosinophil development and migration (Fig. 191-2). In addition to a TH2 skewing, in allergy there is a breakdown in the normal mechanisms of tolerance. This is well illustrated by the observation that patients with the immune dysregulation polyendocrinopathy enteropathy X-linked syndrome, who have defective expression of the Fox-P3 transcription factor and lack functional regulatory T cells, exhibit a phenotype characterized by severe allergies and autoimmunity. Conversely, subcutaneous allergen-specific immunotherapy induces the expansion of regulatory T cells in the periphery, and it has been shown that children that outgrow their milk allergy have more milk-specific regulatory T cells than those that remain clinically reactive.3

FIGURE 191-1. TH2 differentiation and allergen sensitization. Allergens are sampled directly by dendritic cells at the mucosal surfaces or access the submucosal dendritic cells through the epithelium. Activated dendritic cells mature and process the allergen and then present it to naïve T cells in the context of major histocompatibility complex (MHC) class II molecules. Differentiation of naïve T cells toward the TH2 phenotype is favored by the availability of interleukin 4 (IL-4) in the microenvironment. Cellular sources of this early IL-4 include basophils, mast cells, T cells, and eosinophils. TH2 cells produce IL-4 and IL-13 cytokines that promote immunoglobulin class-switch recombination and IgE production by B cells. IgE diffuses locally and then is distributed systemically, where it can bind to high-affinity receptors present on mast cells and basophils “sensitizing” them to respond when the host is reexposed to the allergen. While sensitization is the hallmark of allergy, it does not necessarily result in clinical symptoms. Other TH2-derived cytokines (ie, IL-3, IL-9, and IL-5) promote the development and function of mast cells, basophils, and eosinophils, cellular elements that play a fundamental role in allergic inflammation.

FIGURE 191-2. Clinical and molecular aspects of the allergic response. Upon reexposure to allergen, cross-linking of IgE molecules bound to the FcεRI expressed on tissue-resident mast cells (or on blood-borne basophils) activates these cells to secrete a host of preformed mediators that are responsible for much of the clinical manifestations of the early phase of the allergic response. This is followed by synthesis of a variety of cytokines and chemokines promoting the influx of inflammatory cells at the affected sites (eg, the airway), which in turn amplifies and perpetuates the allergic response and may result in chronic inflammatory changes and tissue remodeling.

CLINICAL ASPECTS

Allergen-specific IgE bound to the high-affinity FcεR1 on mast cells is crucial in the initiation of the cascade of events that characterizes allergic inflammation.4 IgE cross-linking by its cognate antigen results in mast cell degranulation and release of biologically active products, including autacoids, prostaglandins, leukotrienes, histamine, proteases, chemokines, and growth factors. The release of these mediators occurs within minutes of allergen exposure and contributes to the clinical manifestations associated with early-phase allergic reactions that in general depend on the target organ involved (eg, skin, gastrointestinal tract, or airway). Pruritus, sneezing, and coughing are triggered by the stimulation of sensory nerves in the airway or the skin. Some mediators promote erythema, vasodilation, and increased vascular permeability. In the skin, this results in the characteristic wheal and flare reaction, typical of the urticarial rash. Other mast cell products favor the contraction of the smooth muscles, which can lead to wheezing or to abdominal cramping and diarrhea, if the antigen encounter occurs in the gut. While most allergic reactions are primarily local, systemic release of these mediators into the circulation can lead to anaphylaxis.

In some patients, the early phase is followed by a late-phase reaction, also orchestrated by the mast cell products in conjunction with T-cell–derived cytokines and chemokines. Late-phase reactions occur within 6 to 8 hours of allergen exposure and result from the accumulation and activation of inflammatory cells at the affected sites. Chemokines promote the infiltration of the mucosa with eosinophils, neutrophils, basophils, T lymphocytes, and macrophages. These cells become activated and release inflammatory mediators, which in turn can reactivate many of the proinflammatory reactions of the early-phase response.

While the acute signs and symptoms of an allergic reaction usually subside with no sequelae, continuous or repetitive exposure to allergen can spawn a series of structural changes in the affected tissues that can have more permanent consequences for the individual. In the airway, chronic allergic inflammation can lead to epithelial injury and tissue remodeling, factors that play a central role in the pathogenesis of asthma. In the gut, continuous exposure results in mucosal damage and malabsorption, and in the skin dysregulated epithelial repair underlies the features of chronic eczema, such as hyperkeratosis and lichenification.

In addition to increasing the risk of infection, the disruption of the epithelial barrier is thought to lead to further sensitizations. About one third of infants with atopic eczema present high levels of IgE against food allergens even before any known oral exposure to these foods. While exposure through breast milk cannot be ruled out, an alternative hypothesis is that encounter of allergenic foodstuffs through nonoral routes (eg, through a broken skin) favors sensitization, whereas exposure through the natural oral route results in tolerance. In support of this hypothesis is a recent report linking the rise in the prevalence of peanut allergy in Great Britain to the use of peanut-containing emollients in infants with atopic dermatitis.5 In turn, allergic sensitization perpetuates TH2-type responses in the skin that lead to chronic allergic inflammation and worsening of the eczema following repeated exposures to the allergen, whether through the oral or the nonoral route. This could explain why, in some children, excluding the offending food from the diet results in improvement, if not complete resolution, of the symptoms of atopic dermatitis.

Successive sensitization to environmental allergens during childhood and early adolescence is a well-documented phenomenon and is directly linked to the progression of the atopic march. Atopic children (ie, those presumably genetically predisposed to mount IgE responses) first become sensitized to the predominant aeroallergens present in the home, such as dust mites, pet dander, and certain molds. Allergic inflammation with a local TH2 bias can alter the physiology of the nasal epithelium and favor further sensitization, this time to outdoor aeroallergens such as plant pollens. From a clinical standpoint, these children initially present the classical symptoms of allergic rhinoconjunctivitis. Because the lower airway responds to mediators similar to those in the nasal mucosa, in the context of chronic allergic inflammation, many of these children go on to develop symptoms of allergic asthma that persist well into adulthood.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Symptoms associated with respiratory allergies (nasal congestion, cough, wheezing) are among the most common complaints encountered by pediatricians. Accordingly, the clinical history is key in the correct diagnosis of allergies. Signs and symptoms will vary not only depending on the target organ and on the immunopathogenesis of the specific disorder but also on the age of the patient and the duration of the disease. The characteristic temporal association between allergen exposure and clinical symptoms is not always evident and only becomes apparent after a guided questionnaire is completed. In other cases, the type of exposure is completely unknown, but the symptoms are characteristic enough to warrant further investigations.

In respiratory allergies, the age of the patient is an important consideration. In the infant or the young toddler, nasal congestion or wheezing are rarely manifestations of allergy. In this age range, common respiratory infections are the main cause of these symptoms. After the age of 3, viral infections continue to be prevalent, but allergy to indoor allergens can also play a role, especially in the presence of chronic nasal symptoms or associated ocular manifestations. Seasonal allergies (eg, “hay fever”) usually present when the child is close to school age, since sensitization to pollen allergens in general occurs later in life.

Recurrent emesis and/or bloody diarrhea in a bottle-fed young infant is suggestive of a cow’s milk allergy. In the older child, the typical symptoms of an IgE-mediated food allergic reaction are flushing, urticaria, and angioedema, with or without gastrointestinal manifestations, whereas heartburn, recurrent emesis, and dysphagia, even in the absence of skin manifestations, hints at the presence of eosinophilic esophagitis, an increasingly common disorder in which food allergies may play a role (see Chapters 394 and 411).

Allergies have also been implicated in the pathogenesis of several conditions such as recurrent otitis media,6 chronic sinusitis, and nasal polyposis. The pathogenesis of these illnesses may involve chronic allergic inflammation of the upper airway. In contrast, there is no evidence to substantiate the belief that childhood allergies are a common cause of isolated constitutional symptoms such as poor appetite, fatigue, chronic pain, or behavioral problems such as learning difficulties. A notable exception may be the child with severe, perennial allergic rhinosinusitis leading to significant nasal obstruction with or without sleep apnea. These children do benefit from medical treatment and often display significant improvement in their school performance when their allergies are under control.7

When the clinical history and the presenting symptoms are suggestive of an IgE-mediated allergic condition, laboratory tests can be useful for determining the presence of specific IgE against the presumed allergen(s). Pediatricians can easily request a serum determination of allergen-specific IgE (formerly known as RAST, or radioallergoabsorbent test, but now mostly performed by other comparable technologies). To aid in the selection of tested allergens, many laboratories offer panels that include the most common allergens implicated in a particular condition (food allergy panel, animal dander, molds, etc) and, in the case of aeroallergens, a sampling of pollens relevant to the patient’s environment. One has to bear in mind that sensitization (ie, IgE production) does not always correlate with clinical allergy, and therefore these tests should be regarded as confirmatory only in the context of a documented or highly probable reaction following exposure. The same can be said of the skin-prick tests, in-office tests performed routinely by pediatric allergists. They are highly sensitive and specific, and results can be obtained within minutes. Yet, in a way, they are far more useful for ruling out a particular allergen as the trigger for an allergic reaction than ruling it in because the positive predictive value of these tests has been estimated to be about 40% and the negative predictive value approaches 90% or more.

MANAGEMENT OF ALLERGIC DISEASES

With the exception of subcutaneous immunotherapy, which has a proven record of success in the treatment of allergic rhinoconjunctivitis and bee sting allergy, presumably by inducing a long-lasting tolerance, most therapeutic modalities for allergic diseases are geared toward ameliorating the symptoms of the affected patients and, at the same time, to prevent possible complications or involvement of other organs. This is not to say that the available therapies are not effective, and compliance with these treatments can certainly improve the quality of life of these patients.

The proper management of the allergic child requires a multipronged approach that includes minimizing the exposure to the allergic trigger(s) as well as using a cohort of medications that can revert or control an established allergic reaction (eg, antihistaminics, epinephrine) or limit its development (eg, glucocorticoids, leukotriene inhibitors, and others).10

ALLERGEN AVOIDANCE

Exclusion of the allergenic food from a child’s diet clearly reduces the likelihood of developing an allergic reaction to this food and should always be recommended.8 Although there have been isolated reports of nondietary exposures to food allergens (eg, through the skin or inhalation) resulting in systemic reactions, these are rare occurrences. Minimizing the exposure to allergens that act primarily on the respiratory tract has been shown to decrease symptoms and improve control in children with respiratory allergies and asthma.9 Environmental control measures directed at decreasing the levels of indoor allergens such as dust mites, mold, and pet dander usually result in a tangible relief in allergic symptoms, particularly in children with perennial allergic rhinoconjunctivitis and/or asthma. Removal of the pet from the home should be recommended but is not always an acceptable option for the family. In those cases, limiting the access of the animal to the child’s bedroom and placing an air purifier (especially useful for cat allergens) can be helpful. Measures to prevent exposure to pollens are largely ineffective because the distribution of these allergens is widespread and they can travel airborne over large distances.

PHARMACOLOGICAL AGENTS

Corticosteroids

Corticosteroids are pleiotropic anti-inflammatory drugs with proven efficacy in the management of various aspects of the allergic inflammation. The development of highly effective topical preparations (intranasal, inhaled, or dermatological creams) with minimal systemic effects has revolutionized the therapy of common disorders such as allergic rhinitis, allergic asthma, and atopic dermatitis. Inhaled corticosteroids are the first line of treatment for patients with persistent asthma, and they provide relief in children even when used on an as-needed schedule (see Chapter 512). As monotherapy, intranasal corticosteroids are more efficacious than either leukotriene receptor antagonists or anti-histamines, or their combination, in the management of the both nasal and ocular symptoms of allergic rhinoconjunctivitis. When used at the recommended doses, most intranasal corticosteroid preparations are not generally associated with clinically significant effects on the hypothalamic-pituitary-adrenal axis, ocular pressure or cataract formation, or bone density.

Antihistamines

Histamine is a primary amine produced by mast cells and basophils that orchestrates many aspects of the allergic response by binding to specific receptors present on the surface of its target cells. So far, four types of histamine receptors belonging to the G protein–coupled receptor family have been identified: H1, H2, H3, and H4. Signals transduced via the H1 (and to a lesser extent H2) receptor mediate many of the acute symptoms and signs of allergic disease in the skin, airway, and gastrointestinal tract, whereas H1 and H4 appear to promote the accumulation of inflammatory cells at sites of allergic inflammation.

Histamine receptor antagonists are widely prescribed for the treatment of allergic disorders. Pretreatment with an oral H1 antihistamine reduces early responses to allergen in the conjunctiva, nose, lower airway, and skin, and administering the drug during the course of an allergic response curbs the symptoms triggered by acute allergic inflammation. Onset of action occurs within 1 to 3 hours. Newer H1-antihistamines have a prolonged half-life and need to be administered only once or twice daily, whereas others have to be administered several times a day to maintain efficacy. Tolerance to doses that achieve clinical efficacy does not develop, but symptom relief may be insufficient when other mediators (leukotrienes, neuropeptides, etc) are involved. This is often the case in the pruritus of atopic dermatitis, which, by and large, is resistant to antihistamines.

There are more than 40 H1 antagonists available worldwide. These agents, which have diverse chemical structures, are in general effective and safe to use in infants and children.11 However, they are not interchangeable, and the safety profile varies from agent to agent. First-generation H1 blockers (eg, brompheniramine, cyproheptadine, chlorpheniramine, hydroxyzine, and promethazine) are lipophilic and penetrate the CNS readily, causing sedation or, in some patients, paradoxical excitation. These drugs are excreted in breast milk and have been reported to induce drowsiness or respiratory depression in nursing infants. Thus, unless sedation is a primary goal, second-generation H1 antihistamines (eg, loratadine, cetirizine, and fexofenadine), which penetrate the CNS poorly, are preferable.

Leukotriene Receptor Antagonists

Leukotrienes are products of the 5-lipoxygenase pathway synthesized by white cells in response to a variety of inflammatory stimuli. Within this family, the cysteinyl leukotrienes (LTC4, LTD4, and LTE4) account for the biologic activity known as slow-reacting substance of anaphylaxis. Leukotriene receptors (BLT1 and 2, CysLT1 and 2) are expressed in several tissues, including hemopoietic cells, smooth muscle cells, and epithelia, where they mediate a myriad of biological functions. Pertinent to allergic disease, leukotrienes induce the migration and activation of virtually all white cells involved in allergic inflammation as well as smooth muscle and asthma.

Several studies have demonstrated the efficacy of leukotriene receptor antagonists (LTRA) in the treatment of asthma. The best studied in this group is montelukast, which is now approved for the treatment of asthma in children 12 months and older and for relief of symptoms of perennial allergic rhinitis in infants from 6 months on.12 As single drugs, LTRA are less effective than nasal or inhaled corticosteroids in the treatment of allergic rhinitis or asthma. Furthermore, the clinical response to LTRA is somewhat unpredictable, which may be due in part to genetic factors. Yet, the safety profile of leukotriene receptor antagonists makes them a suitable alternative for those patients who cannot receive steroids or who are wary of their side effects. The efficacy of LTRA in other allergic disorders such as atopic dermatitis and urticaria has been suggested but not demonstrated.

ALLERGEN-SPECIFIC IMMUNOTHERAPY

Allergen-specific subcutaneous immunotherapy (SCIT) has been practiced since the late 1950s and has proven to be clearly effective therapy for allergic airway diseases and insect venom allergy. Currently, SCIT is the only treatment that can potentially modify the course of allergic rhinoconjunctivitis by redirecting the immune response toward a tolerant state, and its clinical benefits may be sustained years after discontinuation of treatment.13 Allergen immunotherapy for allergic rhinitis diminishes the risk of new allergen sensitizations in monosensitized children and has reduced the risk of asthma in children with allergic rhinitis.

While the cost of SCIT is comparable to that of pharmacotherapy, it is a time- and resource-consuming therapy that requires long-term (minimum of 2 years) commitment on the part of the patient. In children, usually fearful of shots, there is the added drawback that it implies subcutaneous injections. Non-injection routes (sublingual immunotherapy) have been in use for years in Europe and are effective in the treatment of allergic rhinoconjunctivitis in adults, although the evidence in children is promising but still inconclusive.14