Chapter 38: Allergic Disorders

Allergic disorders are among the most common problems seen by pediatricians and primary care physicians, affecting over 25% of the population in developed countries. In the most recent National Health and Nutrition Examination Survey, 54% of the population had positive test responses to one or more allergens. According to a recent National Center for Health Statistics survey, the prevalence of food and skin allergies has increased over the past decade; with prevalence in 2015 of 5.7% and 12%, respectively. While the prevalence of respiratory allergies has been stable, it is still the highest among children (10.1%). In children, asthma, allergic rhinitis, and atopic dermatitis have been accompanied by significant morbidity and school absenteeism, with adverse consequences for school performance and quality of life, as well as economic burden measured in billions of dollars. In this chapter, atopy refers to a genetically determined predisposition to develop IgE antibodies found in patients with asthma, allergic rhinitis, and atopic dermatitis.

The Global Strategy for Asthma Management and Prevention (www.ginasthma.org) report gives a definition of asthma as “a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity, together with variable expiratory limitation.”

Asthma is the most common chronic disease of childhood, affecting 6.2 million children in the United States. While current prevalence rates for asthma had increased in the past decade, there has been an indication of a decrease in prevalence since 2011 (most recent estimate in children < 18 years is 8.4%). At least one-half of persons with current asthma reported having had an asthma attack in the past year. Gender, race, and socioeconomic disparities in the prevalence of asthma exist: (1) More boys than girls are affected in childhood; (2) higher percentage affected among black children compared to Hispanic and non-Hispanic white children; (3) children belonging to poor families are more likely to be affected.

There is still a disproportionately higher health care utilization for asthma among children compared to adults affected by this disease. Asthma accounts for almost 50% of the emergency department (ED) visits and one-third of the hospitalizations in children younger than 18 years. The ED visit rate due to asthma was the highest for children aged 0–4 years (20.8 visits per 100 persons with asthma). Children aged 0–17 years had a higher ED visit rate compared with adults (10.7 compared with 7.0 per 100 persons with asthma). Annual asthma hospitalizations rates were similar between children and adults. Still almost 140,000 children were hospitalized for asthma in 1 year. Hospitalizations and ED or urgent ambulatory or office visits, all indicators of asthma severity, impose significant costs to the health care system and to families, caretakers, schools, and parents’ employers. About one-half of children with asthma report one or more asthma-related missed school days. Indirect costs primarily from loss of productivity due to school/work absences are harder to measure, yet considerable, and are estimated to be three times the direct costs. Asthma remains a potentially life-threatening disease for children; among children, the population-based rate of asthma deaths per million was 2.8 in 2009, and the at-risk based rate of asthma deaths per 10,000 children with asthma was 0.3. Similar to disparities in prevalence, morbidity and mortality rates for asthma are higher among minority and inner city populations. The reasons for this are unclear but may be related to a combination of more severe disease, poor access to health care, lack of asthma education, delay in use of appropriate controller therapy, and environmental factors (eg, irritants including smoke and air pollutants, and perennial allergen exposure).

Up to 80% of children with asthma develop symptoms before their fifth birthday. Atopy (personal or familial) is the strongest identifiable predisposing factor. Sensitization to inhalant allergens increases over time and is found in the majority of children with asthma. The principal allergens associated with asthma are perennial aeroallergens such as dust mite, animal dander, cockroach, and Alternaria (a soil mold). Rarely, foods may provoke isolated asthma symptoms.

About 40% of infants and young children who have wheezing with viral infections in the first few years of life will have continuing asthma through childhood. Viral infections (eg, respiratory syncytial virus [RSV], rhinovirus, parainfluenza and influenza viruses, metapneumovirus) are associated with wheezing episodes in young children. RSV may be the predominant pathogen of wheezing infants in the emergency room setting, but rhinovirus can be detected in the majority of older wheezing children. It is uncertain if these viruses contribute to the development of chronic asthma, independent of atopy. Severe RSV bronchiolitis in infancy has been linked to asthma and allergy in childhood. Although speculative, individuals with lower airways vulnerability to common respiratory viral pathogens may be at risk for persistent asthma.

In addition to atopy and infections being associated with the development of asthma, observational studies have also demonstrated an increased risk of asthma attributed to acetaminophen exposure during prenatal periods, infancy, childhood, and even adulthood. Acetaminophen is the most commonly used antipyretic medication for children in the United States. There is evidence from secondary analyses suggesting that acetaminophen exposure increases the risk for subsequent asthma exacerbations or wheeze compared to ibuprofen; and that a dose-dependent elevated risk of asthma symptoms could be found.

There are several mechanisms that have been proposed: acetaminophen interfering with glutathione (a tripeptide antioxidant that is involved in free radical scavenging and xenobiotic detoxification) pathway and impairing respiratory antioxidant defenses; presence of genetic polymorphisms in the glutathione pathway that are associated with increased susceptibility to asthma; and acetaminophen causing a switch to a TH2 from a TH1 response. However, a recent double-blind placebo-controlled trial study comparing acetaminophen and ibuprofen used for fever or pain in preschool-aged children with persistent asthma did not show increased asthma worsening with use of either drug.

Exposure to tobacco smoke is also a risk factor and a trigger for asthma. Other triggers include exercise, cold air, pollutants, strong chemical odors, and rapid changes in barometric pressure. Aspirin sensitivity is uncommon in children. There are data suggesting that microbiome may also play a role in the development of asthma and allergy. Psychological factors may precipitate asthma exacerbations and place the patient at high risk from the disease.

Pathologic features of asthma include shedding of airway epithelium, edema, mucus plug formation, mast cell activation, and collagen deposition beneath the basement membrane. The inflammatory cell infiltrate includes eosinophils, lymphocytes, and neutrophils, especially in fatal asthma exacerbations. Airway inflammation contributes to bronchial hyperresponsiveness, airflow limitation, and disease chronicity. Persistent airway inflammation can lead to airway wall remodeling and irreversible changes.

Clinical Findings

A. Symptoms and Signs

The diagnosis of asthma in children, especially among preschool aged, is based largely on clinical judgment and an assessment of symptoms, activity limitation, and quality of life. For example, if a child with asthma refrains from participating in physical activities so as not to trigger asthma symptoms, their asthma would be inadequately controlled but not detected by the standard questions.

Wheezing is the most characteristic sign of asthma, although some children may have recurrent cough and shortness of breath. Complaints may include “chest congestion,” prolonged cough, exercise intolerance, dyspnea, and recurrent bronchitis or pneumonia. Chest auscultation during forced expiration may reveal prolongation of the expiratory phase and wheezing. As the obstruction becomes more severe, wheezes become more high-pitched and breath sounds diminished. With severe obstruction, wheezes may not be heard because of poor air movement. Flaring of nostrils, intercostal and suprasternal retractions, and use of accessory muscles of respiration are signs of severe obstruction. Cyanosis of the lips and nail beds may be seen with underlying hypoxia. Tachycardia and pulsus paradoxus also occur. Agitation and lethargy may be signs of impending respiratory failure.

B. Laboratory Findings

The importance of confirming the diagnosis of asthma cannot be overemphasized, as there can be as many as 30% of people in whom the diagnosis cannot be confirmed. Bronchial hyperresponsiveness, reversible airflow limitation, and airway inflammation are key features of asthma. Documentation of all these components is not always necessary, unless the presentation is rather atypical.

Bronchial hyperresponsiveness to various stimuli is a hallmark of asthma. These stimuli include inhaled pharmacologic agents such as histamine, methacholine, and mannitol, as well as physical stimuli such as exercise and cold air. Mannitol (Aridol) bronchoprovocation has been approved by the US Food and Drug Administration (FDA) and is simpler and easier to administer in the office. It is available as a dry powder inhalation kit and takes less time to complete. Unlike methacholine and histamine challenges and similar to exercise challenge, it is considered an indirect challenge; that is, it simulates airway responses to specific physiologic situations, by creating an osmotic effect within the airway that subsequently leads to an inflammatory response. Airways may exhibit hyperresponsiveness or twitchiness even when baseline pulmonary function tests are normal. Giving increasing concentrations of a bronchoconstrictive agent to induce a decrease in lung function (usually a 20% drop in forced expiratory volume in 1 second [FEV₁] for histamine and methacholine and a 15% reduction for mannitol) and doing an exercise challenge are ways to determine airway responsiveness. Hyperresponsiveness in normal children younger than 5 years is greater than in older children. Bronchoprovocation challenges are not always available in a clinical setting, but they help to establish a diagnosis of asthma when the history, examination, and pulmonary function tests are not definitive.

The National Asthma Education and Prevention Program Expert Panel Report 3 (NAEPP3) reinforces the use of spirometry over peak expiratory flow rate (PEFR) measurements in the evaluation of airflow limitation in asthma. This can be measured by reduction in FEV₁ and FEV₁/FVC (forced vital capacity) values compared to reference or predicted values. By itself, it is not adequate in establishing a diagnosis, but it can be an important parameter to monitor asthma activity and treatment response. In children, FEV₁ may be normal, despite frequent symptoms. Spirometric measures of airflow limitation can be associated with symptom severity, likelihood of exacerbation, hospitalization, or respiratory compromise. Regular monitoring of prebronchodilator (and ideally postbronchodilator) FEV₁ can be used to track lung growth patterns over time. During acute asthma exacerbations, FEV₁ is diminished and the flow-volume curve shows a “scooping out” of the distal portion of the expiratory portion of the loop (Figure 38–1).

In addition to the importance placed on documentation of airflow limitation at any time during the diagnostic process, the GINA global strategy puts an emphasis on documenting excessive variability in lung function. This can be gleaned from any of the following:

• Bronchodilator reversibility: increase in FEV₁ greater than 12% predicted

• Excessive variability in twice-daily peak flow readings over 2 weeks: average daily diurnal PEF variability greater than 13% ([day’s highest PEF minus day’s lowest PEF]/mean of day’s highest and lowest), averaged over 1 week

• Significant increase in lung function after 4 weeks of anti-inflammatory treatment (FEV₁ > 12% and 200 mL (or PEF > 20%)

• (+) Exercise challenge test: fall in FEV₁ greater than 12% predicted or PEF greater than 15%

• (+) Bronchoprovocation challenge test

• Excessive variation in lung function between visits: variation in FEV₁ of 12% or PEF greater than 15%

PEFR monitoring can be a simple and reproducible tool to assess asthma activity in children with moderate or severe asthma, a history of severe exacerbations, or poor perception of airflow limitation or worsening condition. Significant changes in PEFR may occur before symptoms become evident. In more severe cases, PEFR monitoring enables earlier recognition of suboptimal asthma control.

Lung function assessment using body box plethysmography to determine lung volume measurements can also be informative. The residual volume, functional residual capacity, and total lung capacity are usually increased, while the vital capacity is decreased. Reversal or significant improvement of these abnormalities in response to inhaled bronchodilator therapy or with anti-inflammatory therapy can be observed.

Infant pulmonary function can be measured in sedated children with compression techniques. The forced oscillation technique can be used to measure peripheral airway resistance even in younger children.

Hypoxemia is present early with a normal or low PCO₂ level and respiratory alkalosis. Hypoxemia may be aggravated during treatment with a β₂-agonist due to ventilation-perfusion mismatch. Oxygen saturation less than 91% is indicative of significant obstruction. Respiratory acidosis and increasing CO₂ tension may ensue with further airflow obstruction and signal impending respiratory failure. Hypercapnia is usually not seen until the FEV₁ falls below 20% of predicted value. Metabolic acidosis has also been noted in combination with respiratory acidosis in children with severe asthma and indicates imminent respiratory failure. PaO₂ less than 60 mm Hg despite oxygen therapy and PaCO₂ over 60 mm Hg and rising more than 5 mm Hg/h are relative indications for mechanical ventilation in a child in status asthmaticus.

Pulsus paradoxus may be present with moderate or severe asthma exacerbation. In moderate asthma exacerbation in a child, this may be between 10 and 25 mm Hg, and in severe asthma exacerbation between 20 and 40 mm Hg. Absence of pulsus paradoxus in a child with severe asthma exacerbation may signal respiratory muscle fatigue.

Clumps of eosinophils on sputum smear and blood eosinophilia are findings in a subset of children with asthma. Their presence tends to reflect a specific phenotype and does not necessarily mean that allergic factors are involved. Leukocytosis is common in acute severe asthma without evidence of bacterial infection and may be more pronounced after epinephrine administration. Hematocrit can be elevated with dehydration during prolonged exacerbations or in severe chronic disease. Noninvasive measures of airway inflammation include exhaled nitric oxide concentrations, serum eosinophil cationic protein levels, serum total (and specific) IgE, and induced sputum. Some of these biomarkers can identify children who can benefit from certain interventions, and some, like exhaled nitric oxide, can be used to adjust treatment and reduce exacerbations of asthma.

C. Imaging

Evaluation of asthma usually does not need chest radiographs (posteroanterior and lateral views) since they often appear normal, although subtle and nonspecific findings of hyperinflation (flattening of the diaphragms), peribronchial thickening, prominence of the pulmonary arteries, and areas of patchy atelectasis may be present. Atelectasis may be misinterpreted as the infiltrates of pneumonia. Some lung abnormalities, such as bronchiectasis, which may point to a different diagnosis implicating an asthma masquerader, such as cystic fibrosis, allergic bronchopulmonary mycoses (aspergillosis), ciliary dyskinesias, immune deficiencies, or even aspiration, can be better appreciated with high-resolution, thin-section chest computed tomography (high-resolution computed tomography [HRCT]) scans. It is primarily useful clinically in ruling out certain diagnoses in patients with difficult to manage asthma but radiation exposure should be considered when ordering HRCT, especially done serially. However, algorithms used in newer scanners allow for much reduced radiation exposure.

Allergy testing is discussed in the section General Measures under Treatment, Chronic Asthma.

Differential Diagnosis

Diseases that may be mistaken for asthma are often related to the patient’s age (Table 38–1). Congenital abnormalities must be excluded in infants and young children. Asthma can be confused with croup, acute bronchiolitis, pneumonia, and pertussis. Immunodeficiency may be associated with cough and wheezing. Foreign bodies in the airway may cause dyspnea or wheezing of sudden onset, and on auscultation, wheezing may be unilateral. Asymmetry of the lungs secondary to air trapping may be seen on a chest radiograph, especially with forced expiration. Cystic fibrosis can be associated with or mistaken for asthma.

Inducible laryngeal obstruction (previously recognized as vocal cord dysfunction) is an important masquerader of asthma, although the two can coexist. It is characterized by the paradoxical closure of the vocal cords that can result in difficulty breathing commonly on inspiration, throat tightness, and even wheezing. In normal individuals, the vocal cords abduct during inspiration and may adduct slightly during expiration. Asthmatic patients may have narrowing of the glottis during expiration as a physiologic adaptation to airway obstruction. In contrast, patients with isolated inducible laryngeal obstruction typically show adduction of the anterior two-thirds of their vocal cords during inspiration, with a small diamond-shaped aperture posteriorly. Because this abnormal vocal cord pattern may be intermittently present, a normal examination does not exclude the diagnosis. Bronchial challenges preferably exercise can precipitate symptoms of inducible laryngeal obstruction. The flow-volume loop may provide additional clues to the diagnosis of inducible laryngeal obstruction. Truncation of the inspiratory portion can be demonstrated in most patients during an acute episode, and some patients continue to show this pattern even when they are asymptomatic (see Figure 38–1). Children with inducible laryngeal obstruction, especially adolescents, tend to be overly competitive, primarily in athletics and scholastics. A psychiatric consultation may help define underlying psychological issues and provide appropriate therapy. Treatment of isolated inducible laryngeal obstruction includes education regarding the condition, appropriate breathing exercises, and therapeutic continuous laryngoscopy. Biofeedback, psychotherapy, and even hypnosis have been effective for some patients.

Conditions That May Increase Asthma Severity

Chronic hyperplastic sinusitis is frequently found in association with asthma. Upper airway inflammation has been shown to contribute to the pathogenesis of asthma, and asthma may improve after treatment of sinusitis. However, sinus surgery is usually not indicated for initial treatment of chronic mucosal disease associated with allergy. In older children, rarely, hyperplastic sinusitis and polyposis and severe refractory asthma can be associated with aspirin sensitivity, known as aspirin-exacerbated respiratory disease (AERD).

A significant correlation has been observed between nocturnal asthma and gastroesophageal reflux. Patients may not complain of burning epigastric pain or have other reflux symptoms—cough may be the only sign. For patients with poorly controlled asthma, particularly with a nocturnal component, investigation for gastroesophageal reflux may be warranted even in the absence of suggestive symptoms.

Population studies have demonstrated associations between obesity and asthma. Obesity has been linked not only to the development of asthma but also with asthma control and severity. What contributes to these associations or to what extent inflammation or physiologic impairment relates to both obesity and asthma is less established. It becomes difficult to determine if a child’s trouble breathing is a result of obesity itself, its comorbidities (eg, gastroesophageal reflux or obstructive sleep apnea), and/or asthma. A management approach targeting weight reduction in obese children is encouraged to improve asthma control or its assessment.

The risk factors for death from asthma include psychological and sociologic factors. They are probably related to the consequences of illness denial, poor coping or self-management skills, as well as to nonadherence with prescribed therapy. Recent studies have shown that less than 50% of inhaled asthma medications are taken as prescribed and that compliance does not improve with increasing severity of illness. Moreover, children requiring hospitalization for asthma, or their caregivers, have often failed to institute appropriate home treatment.

Complications

With acute asthma, complications are primarily related to hypoxemia and acidosis and can include generalized seizures. Pneumomediastinum or pneumothorax can be a complication in status asthmaticus. With chronic asthma, recent studies point to airway wall remodeling and loss of pulmonary function with persistent airway inflammation. Childhood asthma independent of any corticosteroid therapy has been shown to be associated with delayed maturation and slowing of prepubertal growth velocity.

Treatment

A. Chronic Asthma

1. General measures

The NAEPP EPR3 and the GINA global strategy offer slightly different management approaches. The NAEPP EPR 3 was last published over 10 years ago, while GINA is updated about every 1–2 years based on new studies, with the most recent one from 2019 Both guideline approaches include an assessment and regular monitoring of disease activity, education and partnership to improve the child’s and his/her family’s knowledge and skills for self-management, identification, and management of triggers and conditions that may worsen asthma, and appropriate medications selected to address the patient’s needs. The objective of asthma management is the attainment of the best possible asthma control.

2. Assessment of severity and control

The NAEPP EPR3 stepwise approach is based on an assessment of severity and control. An assessment of asthma severity (ie, the intrinsic intensity of disease) is generally most accurate in patients not receiving controller therapy. Hence, assessing asthma severity directs the level of initial therapy. For those already on treatment, asthma severity can be classified according to the level of medication requirement to maintain adequate asthma control. The two general categories are intermittent and persistent asthma; the latter is further subdivided into mild, moderate, and severe (Table 38–2). In contrast, asthma control refers to the degree to which symptoms, ongoing functional impairments, and risk of adverse events are minimized and goals of therapy are met. Assessment of asthma control should be done at every visit as this is important in adjusting therapy. It is categorized as “well controlled,” “not well controlled,” and “very poorly controlled” (Table 38–3). Responsiveness to therapy is the ease with which asthma control is attained by treatment. It can also encompass monitoring for adverse effects related to medication use.

The NAEPP EPR3 classification of either asthma severity or control is based on the domains of current impairment and risk, recognizing that these domains may respond differently to treatment. The level of asthma severity or control is established upon the most severe component of impairment or risk. Generally, the assessment of impairment is symptom based, except for the use of lung function for school-aged children and youths. Impairment includes an assessment of the patient’s recent symptom frequency and intensity and functional limitations (ie, daytime symptoms, nighttime awakenings, need for short-acting β₂-agonists [SABA] for quick relief, work or school days missed, ability to engage in normal or desired activities, and quality-of-life assessments) and airflow compromise preferably using spirometry. Numerous validated instruments and questionnaires for assessing health-related quality of life and asthma control have been developed. The Asthma Control Test (ACT, www.asthmacontrol.com), the Asthma Control Questionnaire (ACQ, www.qoltech.co.uk/Asthma1.htm), and the Asthma Therapy Assessment Questionnaire (ATAQ, www.ataqinstrument.com) for children 12 years of age and older and the Childhood ACT for children 4–11 years of age are examples of self-administered questionnaires that have been developed with the objective of addressing multiple aspects of asthma control such as frequency of daytime and nocturnal symptoms, use of reliever medications, functional status, missed school or work, and so on. A five-item caregiver-administered instrument, the Test for Respiratory and Asthma Control in Kids (TRACK), has been validated as a tool to assess both impairment and risk presented in the NAEPP Expert Panel Report 3 (EPR3) guidelines in young children with recurrent wheezing or respiratory symptoms consistent with asthma.

3. Risk assessment

“Risk” refers to an evaluation of the patient’s likelihood of developing asthma exacerbations, reduced lung growth in children (or progressive decline in lung function in adults), or risk of untoward effects from medications. The GINA 2019 strategy also cites risk factors for poor asthma outcomes (ie, exacerbations, persistent airflow limitation, and medication side effects). Having uncontrolled asthma symptoms is a risk factor for exacerbations. In those with infrequent symptoms, the following are considered modifiable risk factors for flare-ups: excessive SABA use (> 1 200-dose canister/month); inadequate inhaled corticosteroid (ICS) (from lack of prescription, poor adherence, or incorrect inhaler technique); low FEV₁, especially if less than 60% predicted; major psychological or socioeconomic problems; presence of smoking or allergen exposure (if sensitized); having comorbidities (obesity, rhinosinusitis, confirmed food allergy); sputum or blood eosinophilia; elevated exhaled nitric oxide (in allergic asthmatics on an ICS), and pregnancy. Considered major independent risk factors for flare-ups are history of intubation or ICU admission for asthma and one or more severe exacerbations in past 12 months. Risk factors for developing persistent airflow limitation are preterm birth (or low birth weight and greater infant weight gain), lack of ICS treatment; exposures to tobacco smoke, noxious chemicals, occupational exposures; low initial FEV₁; and chronic mucus hypersecretion, sputum or blood eosinophilia. Frequent oral corticosteroid use, long-term high-dose and/or potent ICS, and intake of P450 inhibitors are risk factors for systemic medication side effects, while high-dose or potent ICS and poor inhaler technique are also risk factors for local side effects.

4. Education

Education is important and partnership with the child’s family is a key component in the management to improve adherence and outcomes. The patient and family must understand the role of asthma triggers, the importance of disease activity even without obvious symptoms, how to use objective measures to gauge disease activity, and the importance of airway inflammation—and they must learn to recognize the warning signs of worsening asthma, allowing for early intervention. A stepwise care plan should be developed for all patients with asthma. Providing asthma action plans is currently a requirement that is tracked by many hospitals and others to document that educational instruction for chronic disease management has been given. Asthma action plans should be provided to school personnel and all those who care for children with asthma.

Because the degree of airflow limitation is poorly perceived by many patients, peak flow meters can aid in the assessment of airflow obstruction and day-to-day disease activity if used correctly and regularly, peak flow rates may provide early warning of worsening asthma. They are also helpful in monitoring the effects of medication changes. Spacer devices optimize delivery of medication from metered-dose inhalers (MDIs) to the lungs and, with inhaled steroids, minimize side effects. Large-volume spacers are preferred. Poor understanding by patients and families of proper device use can lead to inadequate delivery and treatment with inhaled medications, especially inhaled controllers. Short instructive videos for device use can be provided to educate families and other caregivers (http://www.thechildrenshospital.org/conditions/lung/asthmavideos.aspx).

5. Exposures

Patients should avoid exposure to tobacco smoke and allergens to which they are sensitized, exertion outdoors when levels of air pollution are high, β-blockers, and sulfite-containing foods. Patients with persistent asthma should be given the inactivated influenza vaccine yearly unless they have a contraindication.

For patients with persistent asthma, the clinician should use the patient’s history to assess sensitivity to seasonal allergens and Alternaria mold and in vitro testing (either by skin or blood test) to assess sensitivity to perennial indoor allergens, to assess the significance of positive tests in the context of the patient’s history, and to identify relevant allergen exposures. For dust mite–allergic children, important environmental control measures include encasing the pillow and mattress in an allergen-impermeable cover and washing the sheets and blankets on the patient’s bed weekly in hot water. Other measures include keeping indoor humidity below 50%, minimizing the number of stuffed toys, and washing such toys weekly in hot water. Children allergic to furred animals or feathers should avoid indoor exposure to pets, especially for prolonged periods of time. If removal of the pet is not possible, the animal should be kept out of the bedroom with the door closed. Carpeting and upholstered furniture should be removed. While a high-efficiency particle-arresting filter unit in the bedroom may reduce allergen levels, symptoms may persist if the pet remains indoors. For cockroach-allergic children, control measures need to be instituted when infestation is present in the home. Poison baits, boric acid, and traps are preferred to chemical agents, which can be irritating if inhaled by asthmatic individuals. Indoor molds are especially prominent in humid or damp environments. Measures to control dampness or fungal growth in the home may be of benefit. Patients can reduce exposure to outdoor allergens by staying in an air-conditioned environment. Allergen immunotherapy may be useful for implicated aeroallergens that cannot be avoided. However, it should be administered only in facilities staffed and equipped to treat life-threatening reactions.

Patients should be treated for rhinitis, sinusitis, or gastroesophageal reflux, if present. Treatment of upper respiratory tract symptoms is an integral part of asthma management. Intranasal corticosteroids are recommended to treat chronic rhinosinusitis in patients with persistent asthma because they reduce lower airway hyperresponsiveness and asthma symptoms. Intranasal cromolyn reduces asthma symptoms during the ragweed season but less so than intranasal corticosteroids. Treatment of rhinosinusitis includes medical measures to promote drainage and the use of antibiotics for acute bacterial infections (see Chapter 18). Medical management of gastroesophageal reflux includes avoiding eating or drinking 2 hours before bedtime, elevating the head of the bed with 6- to 8-in blocks, and using appropriate pharmacologic therapy.

6. Pharmacologic therapy

A revised stepwise approach to pharmacologic therapy, broken down by age categories, is recommended in the NAEPP EPR3 (http://www.nhlbi.nih.gov) (Table 38–4). This approach is based on the concepts of asthma severity and asthma control. A separate set of recommendations for younger children is provided given the lack of tools which can be used to assess lung function and quality of life otherwise available for older children. Treatment recommendations for older children and adults are better supported by stronger evidence from available clinical trials, whereas those for younger children have been extrapolated from studies in older children and adults.

The choice of initial therapy is based on assessment of asthma severity. For patients who are already on controller therapy, treatment can be adjusted based on assessment of asthma control and responsiveness to therapy. The goals of therapy are to reduce the components of both impairment (eg, preventing chronic and troublesome symptoms, allowing infrequent need of quick-relief medications, maintaining “normal” lung function, maintaining normal activity levels including physical activity and school attendance, meeting families’ expectations and satisfaction with asthma care) and risk (eg, preventing recurrent exacerbations, reduced lung growth, and medication adverse effects).

1. The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs.

2. In the absence of persistent symptoms, the new clinical guidelines recommend considering initiation of long-term controller therapy for infants and younger children who have risk factors for asthma (ie, modified asthma predictive index: parental history of asthma, physician-diagnosed atopic dermatitis, or sensitization to aeroallergens or two of the following: wheezing apart from colds, sensitization to foods, or peripheral eosinophilia) and four or more episodes of wheezing over the past year that lasted longer than 1 day and affected sleep or two or more exacerbations in 6 months requiring systemic corticosteroids.

3. ICS, either as monotherapy or in combination with adjunctive therapy, are preferred treatment for all levels of persistent asthma.

4. Along with medium-dose ICS, combination therapy with ICS plus any of the following adjunctive therapies—long-acting inhaled β₂-agonists (LABAs), leukotriene modifying agents, cromones, and theophylline—is recommended as step 3 treatment for moderate persistent asthma, or as step-up therapy for uncontrolled persistent asthma for school-aged children and youths. In children aged 0–4 years, medium-dose ICS as monotherapy remain the step 3 therapy, and combination therapy to be initiated only as a step 4 treatment. A rescue course of systemic corticosteroids may be necessary at any step.

The revised GINA global strategy has a very different set of recommending options for initiation of controller therapy (Table 38–5). In their stepwise approach (Table 38–6), emphasis on maximizing benefit from available medications, inhaler technique, and adherence, and treatment of risk factors and comorbidities before step-up treatment are pursued.

Asthma medications are classified as long-term controller medications and quick-relief medications. The former includes anti-inflammatory agents (ICS and leukotriene modifiers), long-acting bronchodilators (LABAs and long-acting antimuscarinic agents [LAMAs]), and biologics (omalizumab, mepolizumab, benralizumab, reslizumab, and dupilumab). Although LABAs (salmeterol, formoterol, and vilanterol) are β-agonists, they are considered to be daily controller medications, but unlike the other asthma controller medications with primarily anti-inflammatory properties, LABAs cannot be administered as monotherapy. In contrast, conventionally, ICS-LABAs are considered long-term controller medications, and GINA strategy now recommends them as as-needed, relief medications. Bronchial thermoplasty is also an option that can be considered for some adult patients with severe asthma.

1. Inhaled corticosteroids (ICS)

ICS are the most potent inhaled anti-inflammatory agents currently available. Although recommended as daily controller therapy, studies have shown their efficacy even for intermittent use for rescue or at the onset of acute respiratory illnesses. GINA strategy recommends inhaled steroids for all steps of asthma care. Different ICS are not equivalent on a per puff or microgram basis (Table 38–7). For most patients, low-dose ICS can provide adequate control, although some patients may need higher doses due to variable ICS responsiveness. High doses are associated with increased risk of local and systemic adverse effects. Early intervention with ICS can improve asthma control and prevent exacerbations during treatment, but they do not prevent the development of persistent asthma nor do they alter its natural history. Long-term ICS may be associated with early slowing of growth velocity in children, and although this can impact the final adult height by a minimum degree, it is not a cumulative effect. Possible risks from ICS need to be weighed against the risks from undertreated asthma. The adverse effects from ICS are generally dose and duration dependent, so that greater risks for systemic adverse effects are expected with high doses. The various ICS are delivered in different devices such as MDI (beclomethasone, ciclesonide, fluticasone propionate, flunisolide, mometasone, and triamcinolone), dry powder inhaler (DPI) (fluticasone propionate [Diskus], fluticasone furoate [Ellipta], budesonide [Flexhaler], and mometasone [Twisthaler]), and nebulized aerosol suspensions (budesonide respules). Inhaled medications delivered in MDI now use the more ozone-friendly hydrofluoroalkane (HFA) propellant, which has replaced chlorofluorocarbons (CFC). See instructions for different device use at the following URL: http://www.thechildrenshospital.org/conditions/lung/-asthmavideos.aspx.

Only ICS have been shown to be effective in long-term clinical studies for infants. Nebulized budesonide is approved for children as young as 12 months. The suspension (available in quantities of 0.25 mg/2 mL, 0.5 mg/2 mL, and 1.0 mg/2 mL) is usually administered either once or twice daily in divided doses. For effective drug delivery, it is critical that the child has a mask secured on the face for the entire treatment, as blowing it in the face is not effective and yet a common practice by parents. Notably, this drug should not be given by ultrasonic nebulizer. Limited data suggest that ICS may be effective even in very young children when delivered by MDI with a spacer and mask. Low daily dose in mcg (defined as a dose that has not been associated with adverse effects in trials that evaluated safety measures) for various ICS for children 5 years and younger is as follows: beclomethasone dipropionate (HFA) 100 mcg; budesonide pMDI + spacer 200 mcg; budesonide nebulized 500 mcg; fluticasone propionate (HFA) 100 mcg; and ciclesonide 160 mcg.

2. Combination of inhaled steroid and long-acting bronchodilator

For school-aged children whose asthma is uncontrolled on low-dose ICS (ie, requiring step 3 guidelines therapy), majority are likely to respond to a step-up combination therapy with a LABA bronchodilator (eg, salmeterol and formoterol), although some respond best either to an increased dose of ICS or to an addition of a leukotriene-receptor antagonist (LTRA). Salmeterol is available as an inhalation powder (one inhalation twice daily). It is also available combined with fluticasone (50 mcg salmeterol with 100, 250, or 500 mcg fluticasone or 14 mcg salmeterol with 55, 113, and 232 mcg fluticasone in a DPI and 21 mcg salmeterol with 45, 115, or 230 mcg fluticasone in an MDI). For children 12 years and older, one inhalation DPI or two inhalations MDI can be taken twice daily. (Note: The 100/50 fluticasone/salmeterol combination is approved in children aged 4 and older.) Salmeterol can also be used 30 minutes before exercise (but not in addition to regularly used LABAs). Formoterol has a more rapid onset of action and is available singly either as a DPI (Aerolizer, 12 mcg) or a nebulized solution approved only for chronic obstructive pulmonary disease (COPD, Perforomist); or combined with an inhaled steroid (formoterol fumarate, either 4.5 mcg with budesonide [80 or 160 mcg] or 5 mcg with mometasone [100 or 200 mcg], in an MDI). The combination product is approved for children 6 years and older, two inhalations twice daily. For long-term control, formoterol should be used in combination with an anti-inflammatory agent. It can be used for exercise-induced bronchospasm in patients 5 years and older, one inhalation at least 15 minutes before exercise (but not in addition to regularly used LABAs). An even longer-acting LABA, vilanterol, with a 24-hour activity, combined with fluticasone furoate (Breo) is approved for asthma in patients 18 years and older. Of note, FDA had requested the manufacturers of Advair Diskus and HFA (salmeterol and fluticasone), Serevent Diskus (salmeterol xinafoate), Foradil Aerolizer (formoterol fumarate), Symbicort HFA, and Brovana (arformoterol tartrate inhalation solution, a LABA approved for COPD) to update their product information warning sections regarding an increase in severe asthma episodes associated with these agents. This action was in response to data showing an increased number of asthma-related deaths in patients receiving LABA therapy in addition to their usual asthma care as compared with patients not receiving LABAs. This notice was also intended to reinforce the appropriate use of LABAs in the management of asthma. Specifically, LABA products should not be initiated as first-line asthma therapy, used with worsening wheezing, or used for acute control of bronchospasm. No data are available regarding safety concerns in patients using these products for exercise-induced bronchoconstriction. Additional information, including copies of the Patient and Healthcare Professional information sheets, can be found at: http://www.fda.gov/cder/drug/infopage/LABA/default.htm. In 2010, the FDA requested the four manufacturers of LABAs to conduct a prospective trial to evaluate whether a LABA added to an ICS would be noninferior to an ICS alone with regard to the risk of serious asthma related event (hospitalization, endotracheal intubation, or death). One study, focused on the safety of LABAs in children 4–11 years of age, found that there was no excess risk of serious asthma related event associated with fluticasone propionate-salmeterol combination compared to fluticasone alone. Similar findings were found in two other trials that enrolled adults and adolescents, that LABAs in fixed-dose combination with an ICS was associated with the risk of serious asthma-related event comparable to the risk with the ICS alone. Although not recommended in the United States and is still an off-label indication in other countries, GINA offers ICS-LABA (specifically low-dose beclomethasone/formoterol or budesonide/formoterol) as both maintenance and reliever treatment at steps 3–5 for adults and adolescents. In addition, for mild asthma as preferred controller for steps 1 and 2, GINA also now recommends symptom driven (as needed) or before exercise use of low-dose ICS-formoterol for adults and adolescents, instead of SABA alone. This option using ICS-LABA as reliever has been found to significantly reduce exacerbations and provide control at relatively low-maintenance ICS dose requirement. Patients prescribed as needed ICS-formoterol should seek medical attention if they consume 72 mcg formoterol in a day.

3. Leukotriene antagonists

Montelukast and zafirlukast are LTRAs available in oral formulations. Montelukast is given once daily and has been approved for treatment of chronic asthma in children aged 1 year and older, as an alternative step 2 monotherapy and add-on therapy for steps 3–6. It is also indicated for seasonal allergic rhinitis in patients 2 years and older, and for perennial allergic rhinitis in patients 6 months and older. To date, no drug interactions have been noted. The dosage is 4 mg for children 1–5 years (oral granules are available for children aged 12–23 months), 5 mg for children aged 6–14 years, and 10 mg for those aged 15 years and older. The drug is given without regard to mealtimes, preferably in the evening. Zafirlukast is approved for patients aged 5 years and older. The dose is 10 mg twice daily for those 5–11 years and 20 mg twice daily for those 12 years and older. It should be taken 1 hour before or 2 hours after meals. Zileuton is a 5-lipoxygenase inhibitor indicated for chronic treatment in children 12 years of age and older, available in regular 600 mg dose tablet four times a day or extended-release 600 mg dose tablet, two tablets twice a day. Patients need to have hepatic transaminase levels evaluated at initiation of therapy, then once a month for the first 3 months, every 2–3 months for the remainder of the first year, and periodically thereafter if receiving long-term zileuton therapy. Rare cases of Churg-Strauss syndrome have been reported in adult patients with severe asthma whose steroid dosage was being tapered during concomitant treatment with LTRAs (as well as ICS), but no causal link has been established. Both zafirlukast and zileuton are microsomal P-450 enzyme inhibitors that can inhibit the metabolism of drugs such as warfarin and theophylline. The FDA has requested that manufacturers include a precaution in the drug prescribing information (drug labeling) regarding neuropsychiatric events (agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior, and tremor) based on postmarket reports of patients taking leukotriene-modifying agents. Of note, in a study of children with mild to moderate persistent asthma that looked at whether responses to an ICS and a LTRA were concordant for individuals or whether asthmatic patients who did not respond to one medication responded to the other, responses to fluticasone and montelukast were found to vary considerably. Children with low pulmonary function or high levels of markers associated with allergic inflammation responded better to the ICS.

Children with persistent asthma who remain uncontrolled on ICS monotherapy are more likely to respond to a combination treatment of an ICS and a LABA; however, there are children who can respond best to a higher dose of ICS, or even a low-dose ICS plus montelukast. It has not been definitely determined what clinical features would be helpful in selecting the most appropriate medication for any one patient.

4. Long-acting antimuscarinics

The LAMA, tiotropium (Spiriva Respimat [1.25 mcg] has now been approved as once-daily maintenance treatment for asthma in patients 6 years and older, as an add-on therapy to ICS. GINA 2019 recommends tiotropium by mist inhaler as an add-on “other” controller option for step 4 and “preferred” controller option for step 5 treatment for with a history of exacerbations. Tiotropium by mist inhaler (particularly at 5 mcg daily dose) improves lung function and time to severe exacerbation.

5. Other treatment options

Biologics: Anti-IgE (omalizumab) is a recombinant DNA-derived humanized IgG₁ monoclonal antibody that selectively binds to human IgE. It inhibits the binding of IgE to the high-affinity IgE receptor (FcεRI) on the surface of mast cells and basophils. Reduction in surface-bound IgE on FcεRI-bearing cells limits the degree of release of mediators of the allergic response. Treatment with omalizumab also reduces the number of FcεRI receptors on basophils in atopic patients. Omalizumab is now indicated for children as young as 6 years with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen with total serum IgE of 30–1300 IU/mL for children 6–11 years (30–700 IU/mL for adolescents), and whose symptoms are inadequately controlled with medium- to high-dose ICS. Omalizumab has been shown to decrease the incidence of asthma exacerbations and improve asthma control. Dosing is based on the patient’s weight and serum IgE level and is given subcutaneously every 2–4 weeks. The FDA has ordered a black box warning to the label because of new reports of serious and life-threatening anaphylactic reactions (bronchospasm, hypotension, syncope, urticaria, and angioedema of the throat or tongue) in patients after treatment with omalizumab (Xolair^®). Based on premarketing clinical trials in patients with asthma, anaphylaxis occurred with 0.1% of patients; in postmarketing spontaneous reports based on an estimated exposure of about 57,300 patients from June 2003 through December 2006, the frequency of anaphylaxis attributed to Xolair^® use was estimated to be at least 0.2% of patients. From a case-control study, patients with a history of anaphylaxis from whatever cause considered at increased risk of anaphylaxis with Xolair^®, compared to those with no prior history of anaphylaxis. Although these reactions occurred within 2 hours of receiving a omalizumab subcutaneous injection, they also included reports of serious delayed reactions 2–24 hours or even longer after receiving the injections. Anaphylaxis occurred after any dose of omalizumab (including the first dose), even in patients with no allergic reaction to previous doses. Omalizumab-treated patients should be observed in the facility for an extended period after the drug is given, and medical providers who administer the injection should be prepared to manage life-threatening anaphylactic reactions. Patients who receive omalizumab should be fully informed about the signs and symptoms of anaphylaxis, their chance of developing delayed anaphylaxis following each injection, and how to treat it, including the use of autoinjectable epinephrine. Malignancy (eg, breast, non-melanoma skin, prostate, melanoma, and parotid, etc) was observed in 20 of 4127 (0.5%) Xolair-treated patients compared with 5 of 2236 (0.2%) control patients in clinical studies of adults and adolescents with asthma and other allergies. A more recent observational study of 5007 Xolair^®-treated and 2829 non-Xolair^®-treated patients with moderate to severe persistent allergic asthma followed for up to 5 years showed similar incidence rates (per/1000 patient years) of primary malignancies among Xolair^®-treated (12.3) and non-Xolair^®-treated patients (13.0).

In addition to omalizumab, new biologics or immunomodulators directed against specific T2 airway inflammation have been studied to target the inflammatory component of asthma. The US FDA has recommended approval of mepolizumab (Nucala, monoclonal antibody IgG1K, administered 100 mg subcutaneously every 4 weeks) for patients 12 years and older; reslizumab (Cinqair™, monoclonal antibody IgG4K, given 3 mg/kg intravenously monthly) for adult patients aged 18 years and older; and benralizumab (Fasenra™, humanized monoclonal antibody directed against the alpha subunit of the IL-5 receptor, subcutaneous injection 30 mg every 4 weeks for the first 3 doses, then 30 mg every 8 weeks thereafter), for aged 12 years and older, as add-on maintenance treatment of patients with severe asthma and with an eosinophilic phenotype. Dupilumab, (Dupixent^®) a monoclonal antibody directed against the IL4 receptor alpha, is the first FDA approved biologic for asthma which can be self-administered subcutaneously every 2 weeks, for patients aged 12 years and older with eosinophilic moderate to severe asthma or oral-corticosteroid dependent asthma. These drugs have been shown to be effective at reducing exacerbations, improving lung function and symptom control, and decreasing oral corticosteroid use. A simple algorithm to direct specialists to biological therapy using available biomarkers is proposed, as shown in Figure 38–2.

Immunotherapy (discussed in more detail in section Immunotherapy) can be considered for children 5 years and older with allergic asthma. GINA recommends adding house dust mite sublingual immunotherapy for adults and adolescents on steps 3 or 4 who are sensitized with allergic rhinitis and FEV₁ more than 70% predicted.

Chronic azithromycin therapy is another off-label add-on option for patients with symptomatic asthma despite moderate to high-dose ICS/LABA combination.

Theophylline is rarely used and is no longer mentioned in the GINA guidelines. Sustained-release theophylline, an alternative long-term control medication for older children, may have particular risks of adverse effects in infants, who frequently have febrile illnesses that increase theophylline concentrations. Hence, if theophylline is used, it requires monitoring of serum concentration to prevent numerous dose-related acute toxicities.

Oral corticosteroids (low dose) are only recommended as “other” controller option for step 5 therapy in the GINA guidelines, because of adverse effects. They are recommended in NAEPP EPR step 6 therapy.

6. Monitoring and management

Continual monitoring is necessary to ensure that control of asthma is achieved and sustained. Once control is established, gradual reduction in therapy is appropriate and may help determine the minimum amount of medication necessary to maintain control. Regular follow-up visits with the clinician are important to assess the degree of control and consider appropriate adjustments in therapy. At each step, patients should be instructed to avoid or control exposure to allergens, irritants, or other factors that contribute to asthma severity.

Referral to an asthma specialist for consultation or co-management is recommended if there are difficulties in achieving or maintaining control. For children younger than 5 years, referral is recommended for moderate persistent asthma or if the patient requires step 3 or 4 care and should be considered if the patient requires step 2 care. For children 5 years and older, consultation with a specialist is recommended if the patient requires step 4 care or higher and should be considered at step 3. Referral is also recommended if allergen immunotherapy or a biologic is being considered.

Quick-relief medications include inhaled SABAs such as albuterol, levalbuterol, pirbuterol, or terbutaline. Albuterol can be given by nebulizer, 0.05 mg/kg (with a minimal dose of 0.63 mg and a maximum of 5 mg) in 2–3 mL saline (although it is also available in a 2.5 mg/3 mL single vial or 5 mg/mL concentrated solution) or by MDI (90 mcg/actuation) or by breath-actuated DPI (Respiclick). It is better to use SABAs as needed rather than on a regular basis. Increasing use, including more than one canister per month, may signify inadequate asthma control and the need to step up or revise controller therapy. Levalbuterol, the (R)-enantiomer of racemic albuterol, is available in solution for nebulization in patients aged 6–11 years, 0.31 mg every 8 hours, and in patients 12 years and older, 0.63–1.25 mg every 8 hours. It has recently become available in an HFA formulation for children 4 years and older, two inhalations (90 mcg) every 4–6 hours as needed. Anticholinergic agents such as ipratropium, one to three puffs or 0.25–0.5 mg by nebulizer every 6 hours may provide additive benefit when used together with an inhaled SABA. Systemic corticosteroids such as prednisone, prednisolone, and methylprednisolone can be given in a dosage of 1–2 mg/kg, usually up to 60 mg/day in single or divided doses for 3–10 days. There is no evidence that tapering the dose following a “burst” prevents relapse.

7. Exercise-induced bronchospasm

Exercise-induced bronchospasm should be anticipated in all asthma patients. It typically occurs during or minutes after vigorous activity, reaches its peak 5–10 minutes after stopping the activity, and usually resolves over the next 20–30 minutes. Participation in physical activity should be encouraged in children with asthma, although the choice of activity may need to be modified based on the severity of illness, presence of other triggers such as cold air, and, rarely, confounding factors such as osteoporosis. Poor endurance or exercise-induced bronchospasm can be an indication of poorly controlled persistent asthma. If symptoms occur during usual play activities, either initiation of or a step-up in long-term therapy is warranted. However, for those with exercise-induced bronchospasm as the only manifestation of asthma despite otherwise being “well-controlled,” treatment immediately prior to vigorous activity or exercise is usually effective. SABAs, LTRAs, cromolyn, or nedocromil can be used before exercise. The combination of a SABA with either cromolyn or nedocromil is more effective than either drug alone. Salmeterol and formoterol may block exercise-induced bronchospasm for up to 12 hours (as discussed earlier). However, decreased duration of protection against exercise-induced bronchospasm can be expected with regular use. Montelukast may be effective up to 24 hours. An extended warm-up period may induce a refractory state, allowing patients to exercise without a need for repeat medications.

B. Acute Asthma

1. General measures

The most effective strategy in managing asthma exacerbations involves early recognition of warning signs and early treatment. For patients with moderate or severe persistent asthma or a history of severe exacerbations, this should include a written action plan. The latter usually defines the patient’s green, yellow, and red zones based on symptoms (and PEFR for patients with poor symptom perception) with corresponding measures to take according to the state the patient is in. PEFR cutoff values are conventionally set as more than 80% (green), 50%–80% (yellow), and less than 50% (red) of the child’s personal best. Prompt communication with the clinician is indicated with severe symptoms or a drop in peak flow or with decreased response to SABAs. At such times, intensification of therapy may include a short course of oral corticosteroids. The child should be removed from exposure to any irritants or allergens that could be contributing to the exacerbation.

2. Management at home

Early treatment of asthma exacerbations may prevent hospitalization and a life-threatening event. Initial treatment should be with a SABA such as albuterol or levalbuterol; two to six puffs from an MDI can be given every 20 minutes up to three times, or a single treatment can be given by nebulizer (0.05 mg/kg [minimum dose, 1.25 mg; maximum, 2.5 mg] of 0.5% solution of albuterol in 2–3 mL saline; or 0.075 mg/kg [minimum dose, 1.25 mg; maximum, 5 mg] of levalbuterol). If the response is good as assessed by sustained symptom relief or improvement in PEFR to over 80% of the patient’s best, the SABA can be continued every 3–4 hours for 24–48 hours. Patients should be advised to seek medical care once excessive doses of bronchodilator therapy are used or for prolonged periods (eg, > 12 puffs/day for > 24 hours). Doubling the dose of ICS is not proven sufficient to prevent worsening of exacerbations; and a recent study in children with mild persistent asthma also demonstrated lack of benefit of quintupling low-dose ICS as a yellow zone action plan. If the patient does not completely improve from the initial therapy or PEFR falls between 50% and 80% predicted or personal best, the SABA should be continued, an oral corticosteroid should be added, and the patient should contact the physician urgently. If the child experiences marked distress or if PEFR persists at 50% or less, the patient should repeat the SABA immediately and go to the ED or call 911 or another emergency number for assistance.

3. Management in the office or emergency department

Functional assessment of the patient includes obtaining objective measures of airflow limitation with PEFR or FEV₁ and monitoring the patient’s response to treatment; however, very severe exacerbations and respiratory distress may prevent the execution of lung function measurements using maximal expiratory maneuver. When possible flow-volume loops should be obtained to differentiate upper and lower airway obstruction, especially in patients with atypical presentation. Other tests should include oxygen saturation and if concerning then blood gases. Chest radiographs are not recommended routinely but should be considered to rule out pneumothorax, pneumomediastinum, pneumonia, or lobar atelectasis. If the initial FEV₁ or PEFR is over 40%, initial treatment can be with a SABA by inhaler (albuterol, four to eight puffs) or nebulizer (0.15 mg/kg of albuterol 0.5% solution; minimum dose, 2.5 mg), up to three doses in the first hour. Oxygen should be given to maintain oxygen saturation at greater than 90%. Oral corticosteroids (1–2 mg/kg/day in divided doses; maximum of 60 mg/day for children aged ≤ 12 years and 80 mg/day for those > 12 years) should be instituted if the patient responds poorly to therapy or if the patient has recently been on oral corticosteroids. Sensitivity to adrenergic drugs may improve after initiation of corticosteroids. For severe exacerbations or if the initial FEV₁ or PEFR is under 40%, initial treatment should be with a high-dose SABA plus ipratropium bromide, 1.5–3 mL every 20 minutes for three doses (each 3 mL vial contains 0.5 mg ipratropium bromide and 2.5 mg albuterol), then as needed by nebulizer. Continuous albuterol nebulized treatments (0.5 mg/kg/h for small and 10–15 mg/h for older children) can be administered for evidence of persistent obstruction. Oxygen should be given to maintain oxygen saturation at greater than 90%, and systemic corticosteroids should be administered. For patients with severe exacerbation having no response to initial aerosolized therapy, or for those who cannot cooperate with or who resist inhalation therapy, adjunctive therapies such as intravenous magnesium sulfate (25–75 mg/kg up to 2 g in children) and heliox-driven albuterol nebulization should be considered. There is an ongoing trial evaluating the efficacy of magnesium nebulization in the emergency room in preventing a hospital admission for asthma in children. Epinephrine 1:1000 or terbutaline 1 mg/mL (both 0.01 mg/kg up to 0.3–0.5 mg) may be administered subcutaneously every 20 minutes for three doses, although the use of intravenous β₂-agonists is still unproven. For impending or ongoing respiratory arrest, patients should be intubated and ventilated with 100% oxygen, given intravenous corticosteroids, and admitted to an intensive care unit (ICU). Potential indications for ICU admission also include any FEV₁ or PEFR less than 25% of predicted that improves less than 10% after treatment or values that fluctuate widely. (See asthma [life-threatening] in Chapter 14.) Further treatment is based on clinical response and objective laboratory findings. Hospitalization should be considered strongly for any patient with a history of respiratory failure.

4. Hospital management

For patients who do not respond to outpatient and ED treatment, admission to the hospital becomes necessary for more aggressive care and support. The decision to hospitalize should also be based on presence of risk factors for mortality from asthma, duration and severity of symptoms, severity of airflow limitation, course and severity of previous exacerbations, medication use at the time of the exacerbation, access to medical care, and home and psychosocial conditions. Fluids should be given at maintenance requirements unless the patient has poor oral intake secondary to respiratory distress or vomiting, because overhydration may contribute to pulmonary edema associated with high intrapleural pressures generated in severe asthma. Potassium requirements should be kept in mind because both corticosteroids and β₂-agonists can cause potassium loss. Moisturized oxygen should be titrated by oximetry to maintain oxygen saturation above 90%. Inhaled β₂-agonist should be continued by nebulization in single doses as needed or by continuous therapy, along with systemic corticosteroids (as discussed earlier). Ipratropium is no longer recommended during hospitalization. In addition, the role of methylxanthines in hospitalized children remains controversial. Antibiotics may be necessary to treat coexisting bacterial infection. Sedatives and anxiolytic agents are contraindicated in severely ill patients owing to their depressant effects on respiration. Chest physiotherapy is usually not recommended for acute exacerbations.

5. Patient discharge

Criteria for discharging patients home from the office or ED should include a sustained response of at least 1 hour to bronchodilator therapy with FEV₁ or PEFR greater than 70% of predicted or personal best and oxygen saturation greater than 90% in room air. Prior to discharge, the patient’s or caregiver’s ability to continue therapy and assess symptoms appropriately needs to be considered. Patients should be given an action plan for management of recurrent symptoms or exacerbations, and instructions about medications should be reviewed. The inhaled SABA as needed and oral corticosteroids should be continued, the latter for 3–10 days. Finally, the patient or caregiver should be instructed about the follow-up visit, recommended to happen within 2 days after an ED visit or hospitalization. Hospitalized patients should receive more intensive education prior to discharge. Referral to an asthma specialist should be considered for all children with severe exacerbations or multiple ED visits or hospitalizations.

Prognosis

Since the 1970s, morbidity rates for asthma have increased, but mortality rates may have stabilized. Mortality statistics indicate that a high percentage of deaths have resulted from underrecognition of asthma severity and undertreatment, particularly in labile asthmatic patients and in asthmatic patients whose perception of pulmonary obstruction is poor. Long-term outcome studies suggest that children with mild symptoms generally outgrow their asthma, while patients with more severe symptoms, marked airway hyperresponsiveness, and a greater degree of atopy tend to have persistent disease. Data from an unselected birth cohort from New Zealand showed more than one in four children had wheezing that persisted from childhood to adulthood or that relapsed after remission. Recent evidence suggests that early intervention with anti-inflammatory therapy does not alter the development of persistent asthma, and it is also unclear if such intervention or environmental control measures influence the natural history of childhood asthma. Nonetheless, the pediatrician or primary care provider together with the asthma specialist has the responsibility to optimize control and, it is hoped, reduce the severity of asthma in children. Interventions that can have long-term effects such as halting progression or inducing remission are necessary to decrease the public health burden of this common condition.

Resources for health care providers, patients, and families include the following:

• Asthma and Allergy Foundation of America

• 1233 20th St NW, Suite 402

• Washington, DC 20036; (800) 7-ASTHMA

• http://www.aafa.org/

• Asthma and Allergy Network/Mothers of Asthmatics

• 2751 Prosperity Avenue, Suite 150

• Fairfax, VA 22031; (800) 878-4403

• http://www.aanma.org/

• Asthma Device Training: http://www.thechildrenshospital.org/conditions/lung/asthmavideos.aspx

• Global Initiative for Asthma 2019 (www.ginasthma.org)

Allergic rhinoconjunctivitis is the most common allergic disease and significantly affects quality of life as well as school performance and attendance. It frequently coexists with asthma, can impact asthma control, and is a risk factor for subsequent development of asthma. Over 80% of patients with asthma have rhinitis and 10%–14% of patients with rhinitis have asthma. About 80% of individuals with allergic rhinitis develop their symptoms before age 20 years. It is estimated that 13% of children have a physician diagnosis of allergic rhinitis. Prevalence of this disease increases during childhood, peaking at 15% in the post adolescent years. Although allergic rhinoconjunctivitis is more common in boys during early childhood, there is little difference in incidence between the sexes after adolescence. Race and socioeconomic status are not considered to be important factors.

The pathologic changes in allergic rhinoconjunctivitis are chiefly hyperemia, edema, and increased serous and mucoid secretions caused by mediator release, all of which lead to variable degrees of nasal obstruction and conjunctival injection, nasal and ocular pruritus, or nasal and ocular discharge. Ocular allergies can occur in isolation, but more commonly, they are in conjunction with nasal symptoms. This process may involve other structures, including the sinuses and possibly the middle ear. Inhalant allergens are primarily responsible for symptoms, but food allergens can cause symptoms as well. Children with allergic rhinitis seem to be more susceptible to—or at least may experience more symptoms from—upper respiratory infections, which, in turn, may aggravate the allergic rhinitis.

Allergic rhinoconjunctivitis has been classified as perennial (usually caused by indoor allergens such as house dust mites, molds, cockroaches, and animal dander), seasonal (hay fever most frequently caused by outdoor allergens such as pollens and molds)), or episodic; however, there are areas where pollens and soil molds may be present year round while exposure to typical perennial allergens such as indoor furred animals may be intermittent. For this reason, the preferred terms are intermittent (ie, symptoms present < 4 days a week or for < 4 weeks) and persistent (ie, symptoms present > 4 days a week and for > 4 weeks). In addition, severity should be noted as mild (ie, without impairment or disturbance of sleep, daily activities, leisure, sport, school, or work, or without troublesome symptoms) or moderate-severe (ie, presence of one or more of the aforementioned). The major pollen groups in the temperate zones include trees (late winter to early spring), grasses (late spring to early summer), and weeds (late summer to early fall), but seasons can vary significantly in different parts of the country. Mold spores also cause seasonal allergic rhinitis, principally in the summer and fall. Seasonal allergy symptoms may be aggravated by coincident exposure to perennial allergens.

Clinical Findings

A. Symptoms and Signs

Patients may complain of itching of the nose, eyes, palate, or pharynx and loss of smell or taste. Nasal itching can cause paroxysmal sneezing and epistaxis. Repeated rubbing of the nose (so-called allergic salute) may lead to a horizontal crease across the lower third of the nose. Nasal obstruction is associated with mouth breathing, nasal speech, allergic salute, and snoring. Nasal turbinates may appear pale blue and swollen with dimpling or injected with minimal edema. Typically, clear and thin nasal secretions are increased, with anterior rhinorrhea, sniffling, postnasal drip, and congested cough. Nasal secretions often cause poor appetite, fatigue, and pharyngeal irritation. Conjunctival injection, tearing, periorbital edema, and infraorbital cyanosis (so-called allergic shiners) are frequently observed. Increased pharyngeal lymphoid tissue (“cobblestoning”) from chronic drainage and enlarged tonsillar and adenoidal tissue may be present.

B. Laboratory Findings

Eosinophilia often can be demonstrated on smears of nasal secretions or blood. This is a frequent but nonspecific finding and may occur in nonallergic conditions. Although serum IgE may be elevated, measurement of total IgE is a poor screening tool owing to the wide overlap between atopic and nonatopic subjects. Skin testing to identify allergen-specific IgE is the most sensitive and specific test for inhalant allergies; alternatively, the Phadia ImmunoCAP assay, radioallergosorbent test (RAST), or other in vitro tests can be done for suspected allergens.

Differential Diagnosis

Disorders that need to be differentiated from allergic rhinitis include infectious rhinosinusitis. Foreign bodies and structural abnormalities such as choanal atresia, marked septal deviation, nasal polyps, and adenoidal hypertrophy may cause chronic symptoms. Overuse of topical nasal decongestants may result in rhinitis medicamentosa (rebound congestion). Use of medications such as propranolol, clonidine, and some psychoactive drugs may cause nasal congestion. Illicit drugs such as cocaine can cause rhinorrhea. Spicy or hot foods may cause gustatory rhinitis. Nonallergic rhinitis with eosinophilia syndrome is usually not seen in young children. Vasomotor rhinitis is associated with persistent symptoms but without allergen exposure. Less common causes of symptoms that may be confused with allergic rhinitis include pregnancy, congenital syphilis, hypothyroidism, tumors, and cerebrospinal fluid rhinorrhea.

As in the differential diagnoses for allergic rhinitis, infectious conjunctivitis (secondary to viral, bacterial, or chlamydial etiology) can mimic allergic eye disorders. In this case, it typically develops in one eye first, and symptoms include stinging or burning sensation (rather than pruritus) with a foreign-body sensation and eye discharge (watery, mucoid, or purulent). Nasolacrimal duct obstruction, foreign body, blepharoconjunctivitis, dry eye, uveitis, and trauma are other masqueraders of ocular allergy.

The other conditions that comprise allergic eye diseases, presenting with bilateral conjunctivitis, include atopic keratoconjunctivitis, vernal conjunctivitis, and giant papillary conjunctivitis. Except for giant papillary conjunctivitis, the three (allergic conjunctivitis, atopic keratoconjunctivitis, and vernal conjunctivitis) are associated with allergic sensitization. Atopic keratoconjunctivitis and vernal conjunctivitis are both vision threatening. Atopic keratoconjunctivitis is rarely seen before late adolescence, and it most commonly involves the lower tarsal conjunctiva. Ocular symptoms (itching, burning, and tearing) are more severe than in allergic conjunctivitis and persist all year round, with accompanying eyelid eczema with erythema and thick, dry scaling skin, which can extend to the periorbital skin and cheeks. Vernal conjunctivitis is characterized by giant papillae, described as cobblestoning, seen in the upper tarsal conjunctiva. It affects boys more often than girls, and patients of Asian and African descent are more predisposed. It affects individuals in temperate areas, with exacerbations in the spring and summer months. In addition to severe pruritus that can be exacerbated by exposure to irritants, light, or perspiration, other accompanying signs and symptoms include photophobia, foreign body sensation, lacrimation, and presence of stringy or thick, ropey discharge, transient yellow-white points in the limbus (Trantas dots) and conjunctiva (Horner points), corneal “shield” ulcers, Dennie lines (prominent skin folds that extend in an arc form from the inner canthus beneath and parallel to the lower lid margin), and prominently long eyelashes. Giant papillary conjunctivitis is associated with exposure to foreign bodies such as contact lenses, ocular prostheses, and sutures. It is characterized by mild ocular itching, tearing, and mucoid discharge especially on awakening. Trantas dots, limbal infiltration, bulbar injection, and edema may also be found. One eye condition, contact allergy, which can also involve the conjunctivae especially when associated with use of topical medications, contact lens solutions, and preservatives, typically affects the eyelids.

Complications

Sinusitis may accompany allergic rhinitis. Allergic mucosal swelling of the sinus ostia can obstruct sinus drainage, interfering with normal sinus function, and predisposing to chronic mucosal disease. Nasal polyps due to allergy are unusual in children, and cystic fibrosis should be considered if they are present. Unlike vision-threatening complications associated with atopic keratoconjunctivitis and vernal conjunctivitis, allergic conjunctivitis manifests primarily with significant pruritus and discomfort affecting the patients’ quality of life.

Treatment

A. General Measures

The value of identification and avoidance of causative allergens cannot be overstated. Reducing indoor allergens through environmental control measures as discussed in the section on asthma can be very effective. Nasal saline irrigation may be useful. For ocular allergies, cold compresses and lubrication are also important.

B. Pharmacologic Therapy

Evidence-based clinical practice guidelines such as the Allergic Rhinitis and its Impact on Asthma (ARIA) that include the pharmacologic management of allergic rhinitis have been developed based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. While ARIA recommends the use of intranasal corticosteroids for adults with allergic rhinitis, the use of the topical corticosteroids over oral antihistamines for children is suggested.

The treatment of mild intermittent rhinitis includes oral or intranasal H₁-antihistamines and intranasal decongestants (for < 10 days and not to be repeated more than twice a month). Oral decongestants are not usually recommended in children. Options for moderate-severe intermittent rhinitis are oral or intranasal antihistamines, oral H₁-antihistamines and decongestants, intranasal corticosteroids, and cromones. The same medication options are available for persistent rhinitis, but a stepwise approach is proposed both for treatment of mild and moderate-severe persistent rhinitis. For mild persistent rhinitis, reassessment after 2–4 weeks is recommended and treatment should be continued, with a possible reduction in intranasal corticosteroids, even if the symptoms have abated. If, however, the patient has persistent mild symptoms while on H₁-antihistamines or cromones, an intranasal corticosteroid is appropriate. For moderate-severe persistent disease, use of intranasal corticosteroids as first-line therapy is recommended. For severe nasal congestion, either a short 1- to 2-week course of an oral corticosteroid or an intranasal decongestant for less than 10 days may be added. If the patient improves, the treatment should last for at least 3 months or until the pollen season is over. If the patient does not improve within 2–4 weeks despite adequate compliance and use of medications, comorbidities such as nasal polyps, sinusitis, and significant allergen exposure should be considered, as well as the possibility of misdiagnosis. Once these are ruled out, options include increasing the dose of the intranasal corticosteroid, combination therapy with an H₁-antihistamine (particularly if major symptoms are sneezing, itching, or rhinorrhea), ipratropium bromide (if major symptom is rhinorrhea), or an oral H₁-antihistamine and decongestant. Referral to a specialist may be considered if the treatment is not sufficient.

The recent ARIA update addressed several questions about comparative treatments for allergic rhinitis, based on a review of new pieces of evidence, albeit obtained mostly from adult patients. The recommendations on these questions are mostly considered conditional, based on low to at best moderate certainty of evidence. One question is whether to use combination antihistamine and nasal steroid spray compared to nasal steroid spray alone for the treatment of allergic rhinitis. Either option is appropriate for seasonal allergic rhinitis, while nasal steroid spray alone may be adequate for perennial allergic rhinitis. With regard to the use of nasal steroid with or without an intranasal antihistamine, either option for seasonal and perennial allergic rhinitis is also recommended. However, the combination of nasal steroid spray and intranasal antihistamine compared to intranasal antihistamine alone for seasonal rhinitis is favored. The use of a nasal steroid spray is favored over an intranasal antihistamine for both seasonal and perennial allergic rhinitis.

The preference of a LTRA versus an oral antihistamine was also evaluated. Either option is recommended for seasonal allergic rhinitis, while an oral antihistamine is suggested for perennial allergic rhinitis. Last, either intranasal or oral antihistamine for patients with seasonal or perennial allergic rhinitis can be used.

With most of these, patient preferences, cost, and local availability are determinants of choice of medications.

For allergic rhinoconjunctivitis, topical nasal corticosteroids also reduce ocular symptoms, presumably through a naso-ocular reflex. For ocular allergies that persist or occur independent of rhinitis, pharmacologic treatment includes use of oral or topical antihistamines, topical decongestants, mast cell stabilizers, and anti-inflammatory agents. In general, topical ophthalmic drops should not be used with contact lenses. Topical decongestants relieve erythema, congestion, and edema but do not affect the allergic response. Combined therapy with an antihistamine and a vasoconstrictive agent is more effective than either agent alone. Topical medications with both antihistamine and mast cell blocking properties provide the most benefits that incorporate fast-acting symptom relief and anti-inflammatory action. Refrigerating ophthalmic drops before use can provide soothing relief as well. However, children can get wary of eye drops and prefer oral preparations. Avoiding contamination by preventing the applicator tip from touching the eye or eyelid is important. Severe ocular allergy can be treated with topical, or rarely, oral corticosteroids. In such a case, a referral to an ophthalmologist is warranted, as these treatments can be associated with elevation of the intraocular pressure, viral infections, and cataract formation.

Allergen immunotherapy can be very effective in allergic rhinoconjunctivitis and may decrease the requirement for medications to control the symptoms in the long term.

1. Antihistamines

Antihistamines help control itching, sneezing, and rhinorrhea. Sedating antihistamines include diphenhydramine, chlorpheniramine, hydroxyzine, and clemastine. Sedating antihistamines may cause daytime somnolence and negatively affect school performance and other activities, especially driving. Second-generation antihistamines include loratadine, desloratadine, cetirizine, and fexofenadine. Cetirizine is approved for use in children aged 6–23 months (2.5 mg daily), 2–5 years (2.5–5.0 mg/day or 2.5 mg twice a day), and 6 years or older (5–10 mg/day). It is now available without a prescription. Loratadine is approved for use in children aged 2–5 years (5 mg/day) and 6 years or older (10 mg/day), and is available without prescription in tablet, rapidly disintegrating tablet, and liquid formulations. Desloratadine is approved for use in children aged 6–11 months (1 mg/day), 1–5 years (1.25 mg/day), and for 12 years and older (5 mg/day). Fexofenadine is approved for children aged 6–23 months (15 mg twice a day), 2–11 years (30 mg twice a day), and 12 years or older (60 mg twice a day or 180 mg once daily), and is also now available without a prescription. Levocetirizine (5 mg/day) is approved for children aged 6 years and older. Loratadine, fexofenadine, and cetirizine are available in combination with pseudoephedrine for patients aged 12 years or older, although regular use of these combination products is not recommended. Azelastine is available in nasal and ophthalmic formulations. Levocabastine and emedastine are available as ophthalmic preparations. They should not be used for treatment of contact lens–related irritation, and caution should be implemented with concomitant use of soft contact lenses.

2. Mast cell stabilizers

Intranasal ipratropium can be used as adjunctive therapy for rhinorrhea. Intranasal cromolyn may be used alone or in conjunction with oral antihistamines and decongestants. It is most effective when used prophylactically, one to two sprays per nostril, four times a day. This dose may be tapered if symptom control is achieved. Rarely, patients complain of nasal irritation or burning. Most patients find complying with four times–daily dosing difficult. Cromolyn is also available in an ophthalmic solution. It can be used to treat giant papillary and vernal conjunctivitis. Other ophthalmic mast cell stabilizers include lodoxamide 0.1% solution (can be used for vernal keratoconjunctivitis as well), one to two drops four times a day; nedocromil sodium 2%, one to two drops two times a day; and pemirolast potassium 0.1%, one to two drops four times a day.

3. Decongestants and vasoconstrictor agents

Nasal α-adrenergic agents help to relieve nasal congestion, and ophthalmic vasoconstrictors relieve ocular erythema, edema, and congestion. Topical nasal decongestants such as phenylephrine and oxymetazoline should not be used for more than 4 days for severe episodes because prolonged use may be associated with rhinitis medicamentosa. As with nasal decongestants, a rebound phenomenon (ie, conjunctivitis medicamentosa with hyperemia and stinging/burning) can occur with chronic use of ophthalmic vasoconstrictive agents such as naphazoline and tetrahydrozoline. Oral decongestants, including pseudoephedrine, phenylephrine, and phenylpropanolamine, are often combined with antihistamines or expectorants and cough suppressants in over-the-counter (OTC) cold medications, but there are no convincing data to support the use of oral decongestants for upper respiratory illnesses in children nor for regular use in patients with allergic rhinitis. They may cause insomnia, agitation, tachycardia, and, rarely, cardiac arrhythmias. Of note, the FDA has recommended the removal of phenylpropanolamine from all drug products due to a public health advisory concerning the risk of hemorrhagic stroke associated with its use.

4. Corticosteroids

Intranasal corticosteroid sprays are effective in controlling allergic rhinitis if used chronically. They are minimally absorbed in usual doses and are available in pressurized nasal inhalers and aqueous sprays. Mometasone and fluticasone furoate nasal sprays have been approved for use in children as young as age 2 years (one spray in each nostril once daily) and in children 12 years or older (two sprays/nostril once daily). Fluticasone propionate nasal spray is approved for children 4 years or older, and budesonide and triamcinolone nasal sprays are approved for those 6 years or older (one to two sprays/nostril once daily). Flunisolide is approved for ages 6–14 years (one spray/nostril three times a day or two sprays/nostril twice a day). Ciclesonide is approved for seasonal allergic rhinitis in children 6 years and older and those with perennial allergic rhinitis for children 12 years and older, two sprays in each nostril once daily. Side effects include nasal irritation, soreness, and bleeding, although epistaxis occurs commonly in patients with allergic rhinitis if corticosteroids are used chronically. Rarely, these drugs can cause septal perforation. Excessive doses may produce systemic effects, especially if used together with orally inhaled steroids for asthma. Onset of action is within hours, although clinical benefit is usually not observed for a week or more. They may be effective alone or together with antihistamines. A combination nasal corticosteroid-antihistamine formulation spray has been found to be better than either agent alone in alleviating symptoms for moderate to severe seasonal allergic rhinitis.

Use of oral or topical (eg, loteprednol etabonate) corticosteroids for the treatment of ocular allergy should be worked out in conjunction with an ophthalmologist due to potential complications mentioned in the preceding section.

5. Other pharmacologic agents

Montelukast is approved for perennial allergic rhinitis in children aged 6 months and older (4 mg/day for ages 6–23 months) and seasonal allergic rhinitis in children 2 years and older in doses as discussed in section Pharmacologic Therapy under Treatment, Chronic Asthma. Oral antihistamines are also available in combination with a decongestant. Ketorolac, a nonsteroidal anti-inflammatory drug (NSAID), is available as an ophthalmic solution but should be avoided in patients with aspirin or NSAID sensitivity and should be used with caution in those with complicated eye surgeries, corneal denervation or epithelial defects, ocular surface diseases, diabetes mellitus, or rheumatoid arthritis. Combination ophthalmic preparations are available. Both antazoline and pheniramine are antihistamine/vasoconstrictor formulations. Olopatadine 0.1%, epinastine 0.05%, and ketotifen 0.025% ophthalmic solutions have antihistamine and mast cell–stabilizing actions and can be given to children older than 3 years as one drop twice a day (8 hours apart) for olopatadine and every 8–12 hours for ketotifen, respectively. Ketotifen fumarate 0.025% is now available as an OTC ophthalmic medication. Olopatadine 0.2% is the first once-daily ophthalmic medication available for the treatment of ocular pruritus associated with allergic conjunctivitis.

C. Surgical Therapy

Surgical procedures, including turbinectomy, polypectomy, and functional endoscopic sinus surgery, are rarely indicated in allergic rhinitis or chronic hyperplastic sinusitis.

D. Immunotherapy

Allergen immunotherapy should be considered when symptoms are severe and due to unavoidable exposure to inhalant allergens, especially if symptomatic measures have failed. Immunotherapy is the only form of therapy that may alter the course of the disease. It should not be prescribed by sending the patient’s serum to a laboratory where extracts based on in vitro tests are prepared for the patient (ie, the remote practice of allergy). Subcutaneous immunotherapy should be done in a facility where a physician prepared to treat anaphylaxis is present. Patients with concomitant asthma should not receive an injection if their asthma is not under good control (ie, peak flows preinjection are below 80% of personal best), and the patient should wait for 25–30 minutes after an injection before leaving the facility. Outcomes with single allergen immunotherapy show success rates of approximately 80%. The optimal duration of therapy is unknown, but data suggest that immunotherapy for 3–5 years may have lasting benefit.

Sublingual immunotherapy has been developed for treatment of allergic rhinitis caused by pollens in both adults and children and for allergic rhinitis caused by dust mites only in adults (in other countries). A recent specific SLIT practice parameter emphasized that this mode of immunotherapy may not be appropriate for patients with certain medical conditions, such as eosinophilic esophagitis and those that may hamper the patient’s ability to deal with a systemic reaction or the treatment of the severe reaction.

There are no FDA-approved study indications for SLIT for oral allergy syndrome, food allergy, latex allergy, atopic dermatitis, or venom allergy. This mode of immunotherapy is attractive for pediatric patients because of convenience and ease. While there are off label SLIT preparations (eg, liquid SCIT extract delivered sublingually, sublingual drops), there are only three FDA approved sublingual immunotherapy tablets, all using a single allergen SLIT, as there are still no studies showing efficacy of multiple allergens in a mixture: Grastek, Ragwitek, and Oralair. Grastek may be prescribed for children (as young as 5 years) and adults who are allergic to timothy grass and cross-reactive pollens, while Ragwitek may be prescribed for persons 18 through 65 years of age who are allergic to ragweed pollen. Oralair is indicated for the treatment of grass pollen-induced allergic rhinitis with or without conjunctivitis, for any of five grass species: sweet vernal, orchard, perennial rye, timothy, and Kentucky blue grass, in patients 10–65 years old. They are recommended to be taken daily for about 12 weeks before and throughout the grass or ragweed pollens season, respectively, over a period of at least 3 years for sustained effects. Both timothy grass SLIT and 5-grass tablets have shown benefits beginning in the first year of treatment.

The first dose of SLIT should be in a supervised medical setting with much experience in the diagnosis and management of anaphylaxis, where patients can be observed closely for 30 minutes after taking the dose. Most systemic allergic reactions have been found to be with the first dose. Nevertheless, epinephrine should still be prescribed to patients receiving SLIT, and they should be trained when and how to use the device. Patients on SLIT should see an allergy specialist regularly for monitoring.

Prognosis

Allergic rhinoconjunctivitis associated with sensitization to indoor allergens tends to be protracted unless specific allergens can be identified and eliminated from the environment. In seasonal allergic rhinoconjunctivitis, symptoms are usually most severe from adolescence through mid-adult life. After moving to a region devoid of problem allergens, patients may be symptom free for several years, but they can develop new sensitivities to local aeroallergens.

Atopic dermatitis is a chronically relapsing inflammatory skin disease that typically presents in early childhood. Over one-third of patients with atopic dermatitis will develop asthma and/or allergic rhinitis. A subset of patients with atopic dermatitis has been shown to have mutations in the gene encoding filaggrin, a protein essential for normal epidermal barrier function. These patients have early-onset, more severe, and persistent disease. Mutations in filaggrin have also been associated with allergic sensitization as well as increased risk for asthma, but only in patients with atopic dermatitis. Atopic dermatitis may result in significant morbidity, leading to school absenteeism, occupational disability, and emotional stress.

Clinical Findings

A. Symptoms and Signs

Atopic dermatitis has no pathognomonic skin lesions or laboratory parameters. Diagnosis is based on the clinical features, including severe pruritus, a chronically relapsing course, and typical morphology and distribution of the skin lesions. Acute atopic dermatitis is characterized by intensely pruritic, erythematous papules associated with excoriations, vesiculations, and serous exudate; subacute atopic dermatitis by erythematous, excoriated, scaling papules; and chronic atopic dermatitis by thickened skin with accentuated markings (lichenification) and fibrotic papules. Patients with chronic atopic dermatitis may have all three types of lesions present concurrently. In skin of color, it may be difficult to appreciate erythema and associated inflammation. Patients usually have dry, xerotic skin. During infancy, atopic dermatitis involves primarily the face, scalp, and extensor surfaces of the extremities. The diaper area is usually spared. In older patients with long-standing disease, the flexural folds of the extremities are the predominant location of lesions, although this distribution can be seen even in infants.

B. Laboratory Findings

In patients with persistent disease despite appropriate treatment, consideration should be given for irritant, allergic, or infectious triggers. Elevated serum IgE levels can be demonstrated in 80%–85% of patients with atopic dermatitis but have little clinical utility, although they may be helpful in interpreting specific IgE tests. Identification of allergens involves taking a careful history and performing selective immediate hypersensitivity skin tests or in vitro tests when appropriate. Negative skin tests with proper controls have a high predictive value for ruling out a suspected allergen. Positive skin tests have a lower correlation with clinical symptoms in suspected food allergen–induced atopic dermatitis and should be confirmed with food challenges unless there is a coincidental history of anaphylaxis to the suspected food. Specific IgE levels determine probability of reaction, but not type of reaction or severity. Clinicians should avoid extensive testing, as results may reflect elevated total serum IgE with no clinical significance.

Exacerbation of atopic dermatitis can occur with exposure to aeroallergens such as house dust mites, and environmental control measures have been shown to result in clinical improvement. Patients can make specific IgE directed at S aureus toxins secreted on the skin. Peripheral blood eosinophilia is a common finding. Routine skin biopsy does not differentiate atopic dermatitis from other eczematous processes but may be helpful in atypical cases. Tests for the most common filaggrin gene mutations may identify patients who would be at increased risk for more severe, persistent atopic dermatitis and be more likely to develop allergic sensitizations and asthma. However, filaggrin gene mutations occur in individuals without atopic dermatitis.

Differential Diagnosis

Scabies can present as a pruritic skin disease. However, distribution in the genital and axillary areas and the presence of linear lesions as well as skin scrapings may help to distinguish it from atopic dermatitis. Seborrheic dermatitis may be distinguished by a lack of significant pruritus, its predilection for the scalp (so-called cradle cap), and its coarse, yellowish scales. Allergic contact dermatitis may be suggested by the distribution of lesions with a greater demarcation of dermatitis than in atopic dermatitis. Allergic contact dermatitis superimposed on atopic dermatitis may appear as an acute flare of the underlying disease. Nummular eczema is characterized by coin-shaped plaques. Although unusual in children, mycosis fungoides or cutaneous T-cell lymphoma has been described and is diagnosed by skin biopsy. Eczematous rash has been reported in patients with human immunodeficiency virus (HIV) infection. Other disorders that may resemble atopic dermatitis include Wiskott-Aldrich syndrome, severe combined immunodeficiency disease, hyper-IgE syndrome, immunodeficiency with DOCK8 mutations, IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome, zinc deficiency, phenylketonuria, and Letterer-Siwe disease (see Chapter 33).

Complications

Ocular complications associated with atopic dermatitis can lead to significant morbidity. Atopic keratoconjunctivitis is always bilateral, and symptoms include itching, burning, tearing, and copious mucoid discharge. It is frequently associated with eyelid dermatitis and chronic blepharitis and may result in visual impairment from corneal scarring (see Chapter 16). Keratoconus in atopic dermatitis is believed to result from persistent rubbing of the eyes in patients with atopic dermatitis and allergic rhinitis. Anterior subcapsular cataracts may develop during adolescence or early adult life.

Patients with atopic dermatitis have increased susceptibility to infection or colonization with a variety of organisms. These include viral infections with herpes simplex, molluscum contagiosum, and human papillomavirus. Of note, even a past history of atopic dermatitis is considered a contraindication for receiving the current smallpox (vaccinia) vaccine. Superimposed dermatophytosis may cause atopic dermatitis to flare. S aureus can be cultured from the skin of more than 90% of patients with atopic dermatitis, compared with only 5% of normal subjects. S aureus toxins can act as superantigens, contributing to persistent inflammation or exacerbations of atopic dermatitis. Community-acquired methicillin-resistant S aureus (MRSA) has become an increasing problem, especially in patients treated with frequent antibiotics. Although recurrent staphylococcal pustulosis can be a significant problem in atopic dermatitis, invasive S aureus infections occur rarely and should raise the possibility of an immunodeficiency.

Patients with atopic dermatitis often have nonspecific hand dermatitis. This is frequently irritant in nature and aggravated by repeated wetting.

Nutritional disturbances may result from unwarranted and extensive dietary restrictions imposed by providers or parents.

Poor academic performance and behavioral disturbances may be associated with uncontrolled itching, sleep loss, and poor self-image. Severe disease may lead to problems with social interactions and self-esteem.

Treatment

A. General Measures

Avoidance of irritants such as detergents, chemicals, and abrasive materials as well as extremes of temperature and humidity is important. New clothing should be washed to reduce the content of formaldehyde and other chemicals. Because residual laundry detergent in clothing may be irritating, using a liquid rather than a powder detergent and adding an extra rinse cycle can be beneficial. Occlusive clothing should be avoided in favor of cotton or cotton blends. Temperature in the home should be controlled to minimize sweating. Swimming is usually well tolerated; however, patients should shower and use a mild cleanser to remove chemicals such as chlorine, and then apply a moisturizer. Sunlight may be beneficial in moderation, but nonsensitizing sunscreens should be used to avoid sunburn.

Avoidance of foods implicated in controlled challenges can lead to clinical improvement. Extensive elimination diets are almost never warranted. In addition, elimination of foods that a child is tolerating may result in immediate-type allergic reactions with future reintroduction. Environmental control measures (eg, dust mite–proof covers) in sensitized patients may improve atopic dermatitis.

Evaluation by a behavioral health clinician may be of benefit when dealing with a pruritic, relapsing disease. Relaxation, behavioral modification, or biofeedback training may help patients with habitual scratching. Patients with severe or disfiguring disease may require psychotherapy.

Clinicians should provide the patient and family with both general information and specific written skin care recommendations. The patient or parent should demonstrate an appropriate level of understanding to help ensure a good outcome. Educational pamphlets and a video about atopic dermatitis can be obtained from the National Eczema Association, a national nonprofit, patient-oriented organization, at: http://www.nationaleczema.org.

B. Hydration

Patients with atopic dermatitis have evaporative losses due to a defective skin barrier, so soaking the affected area or bathing for approximately 10 minutes in warm (not lukewarm) water, then applying an occlusive agent to retain the absorbed water, is an essential component of therapy. Oatmeal or baking soda added to the bath may feel soothing to certain patients but does not improve water absorption. Atopic dermatitis of the face or neck can be treated by applying a wet facecloth or towel to the involved area. The washcloth may be more readily accepted by a child if it is turned into a mask and also allows the older patient to remain functional (eg, reading during bath). Lesions limited to the hands or feet can be treated by soaking in a basin. Daily baths may be needed and increased to several times daily during flares of atopic dermatitis, while showers may be adequate for patients with mild disease. It is important to apply a topical moisturizer or medication within a few minutes after soaking the skin to prevent evaporation, which is both drying and irritating.

C. Moisturizers and Occlusives

An effective moisturizer combined with hydration therapy will help skin healing and can reduce the need for topical medications. Moisturizers are available as lotions, creams, and ointments. Lotions can be drying because of their evaporative effect, especially in a nonhumid climate. Preservatives and fragrances in lotions and creams may cause skin irritation. Moisturizers often need to be applied several times daily on a long-term basis and should be obtained in the largest size available. Crisco shortening can be substituted as an inexpensive alternative. Petroleum jelly (Vaseline) is an effective occlusive agent when used to seal in water after bathing. There are several topical nonsteroidal creams (eg, EpiCeram) approved as medical devices (thus, currently requiring prescriptions) for relief and management of signs and symptoms of dermatoses. Their potential benefits need to be weighed against their cost.

D. Corticosteroids

Corticosteroids reduce the inflammation and pruritus in atopic dermatitis. Topical corticosteroids can decrease S aureus colonization. Systemic corticosteroids, including oral prednisone, should be avoided in the management of this chronic relapsing disease as the rapid clinical improvement may be associated with an equally dramatic disease flaring following discontinuation. Topical corticosteroids are available in a variety of formulations and range in potency, ranging from extremely high- to low-potency preparations (see Table 15–2). Choice of a particular product depends on the severity and distribution of skin lesions. Patients need to be counseled regarding the potency of their corticosteroid preparation and its potential side effects. In general, the least potent agent that is effective should be used. However, choosing a preparation that is too weak may result in persistence or worsening of the atopic dermatitis. Side effects include thinning of the skin, telangiectasias, bruising, hypopigmentation, acne, and striae, although these occur infrequently when low- to medium-potency topical corticosteroids are used appropriately. In contrast, use of potent topical corticosteroids for prolonged periods—especially under occlusion—may result in atrophic changes or rarely systemic side effects. The face (especially the eyelids) and intertriginous areas are especially sensitive to corticosteroid side effects, and only low-potency preparations should be used routinely on these areas. Perioral dermatitis may occasionally be worsened by use of topical steroids. Because topical corticosteroids are commercially available in a variety of bases, including ointments, creams, lotions, oil, solutions, gels, foams, and even tape, there is no need to compound them. Ointments are most occlusive and, in general, provide better delivery of the medication while preventing evaporative losses. However, in a humid environment, creams may be better tolerated than ointments because the increased occlusion may cause itching or even folliculitis. Lotions, while easier to spread, can contribute to skin dryness and irritation. Solutions can be used on the scalp and hirsute areas, although they can sting or be irritating, especially to open lesions so an oil or foam base may be preferred. With clinical improvement, a less potent corticosteroid should be prescribed and the frequency of use decreased. Topical corticosteroids can be discontinued when inflammation resolves, but hydration and moisturizers need to be continued. In patients with a relapsing course, twice-weekly treatment to previously involved, clear or almost clear skin can be done as proactive therapy (off-label). Several topical steroids including alclometasone 0.05%, desonide 0.05% hydrogel, and fluticasone 0.05% cream have been approved in infants as young as 3 months of age for up to 28 days. Undertreatment remains a common problem due to caregiver concerns about potential side effects of topical corticosteroids along with inadequate prescription size.

E. Topical Calcineurin Inhibitors

Tacrolimus and pimecrolimus are nonsteroidal immunomodulatory agents that are available in topical formulations. Tacrolimus ointment—0.03% for children 2–15 years of age and 0.1% for older patients—is approved for twice-daily short-term and intermittent long-term use in moderate to severe atopic dermatitis. Pimecrolimus 1% cream is approved for patients 2 years of age or older who have mild to moderate atopic dermatitis. Local burning at the site of application, which occurs more frequently with tacrolimus ointment, has been the most common side effect, although this is usually a transient problem. As a precaution, patients should wear sunscreen with these medications drugs. In Europe, tacrolimus ointment is approved as twice-weekly maintenance therapy for patients 2 years and older with a relapsing course after clearing up eczema with reevaluation of need for continued therapy after 12 months.

Although there is no evidence of a causal link between the use of topical calcineurin inhibitors and malignancy, in 2006, the FDA issued a boxed warning for these medications because of a lack of long-term safety data (see US package inserts for Elidel [Valeant] and Protopic [Leo]). The labeling states that these drugs are recommended as second-line treatment for short-term and noncontinuous chronic treatment and that their use in children younger than 2 years is currently not recommended. Long-term surveillance registries have been established for pediatric patients who had been treated with both topical tacrolimus and pimecrolimus.

F. PDE4 Inhibitors

Crisaborole 2% ointment has been approved in patients 2 years or older for mild-moderate atopic dermatitis.

G. Systemic Biologic

Dupilumab is a fully human monoclonal antibody that blocks interleukin 4 receptor alpha through which both IL-4 and IL-13, two key type 2 cytokines, signal. It is approved for patients 12 years and older with moderate to severe atopic dermatitis not adequately controlled with topical medications or when those are not appropriate. In patients 12–17 years, dosing is weight based with patients less than 60 kg receiving an initial dose of 400 mg, then 200 mg every 2 weeks by subcutaneous injection and patients 60 kg or more, 600 mg initial dose, then 300 mg every 2 weeks. Injections can be self-administered at home and currently, and there is no requirement for any laboratory monitoring. Injection site reactions and conjunctivitis have been the most commonly reported adverse events.

H. Anti-Infective Therapy

Systemic antibiotic therapy may be important when treating atopic dermatitis secondarily infected with S aureus. For limited areas of involvement, a topical antibiotic such as mupirocin or retapamulin ointment may be effective. A first- or second-generation cephalosporin or semisynthetic penicillin is usually the first choice for oral therapy, as erythromycin-resistant organisms are fairly common. Overuse may result in colonization by MRSA. Dilute bleach baths (6% sodium hypochlorite, ½ cup in a full tub of water) two times per week may be helpful for patients with atopic dermatitis, especially those with recurrent skin infections, although some patients find this treatment irritating.

Disseminated eczema herpeticum usually requires treatment with systemic antiviral. Patients with recurrent cutaneous herpetic lesions can be given prophylactic oral acyclovir or valacyclovir. Superficial dermatophytosis and Malassezia sympodialis infection can be treated with topical or (rarely) systemic antifungal agents.

I. Antipruritic Agents

Pruritus is usually the least well-tolerated symptom of atopic dermatitis. Oral antihistamines and anxiolytics may be effective owing to their tranquilizing and sedating effects and can be taken primarily at bedtime to avoid daytime somnolence. Nonsedating antihistamines may be helpful for associated allergic symptoms but are not usually effective in treating pruritus. Use of topical antihistamines and local anesthetics should be avoided because of potential sensitization.

J. Recalcitrant Disease

Patients who are erythrodermic may need to be hospitalized. Hospitalization may also be appropriate for those with severe disease failing outpatient management. Marked clinical improvement often occurs when the patient is removed from environmental allergens or stressors. In the hospital, adherence to therapy can be monitored, the patient and family can receive in-depth hands-on education, and controlled challenges can be conducted to help identify triggering factors.

Wet wrap therapy has been shown to be beneficial in severe atopic dermatitis. It can serve as an effective barrier against the persistent scratching that often undermines therapy. A layer of wet clothing (eg, pajamas, long underwear, tube socks) with dry layer on top (pajamas or a sweat suit, tube socks) over topical corticosteroid can be used for severely involved areas. Alternatively, wet gauze with a layer of dry gauze over it can be used and secured in place with an elastic bandage. Wet wraps can be removed when they dry out, usually after several hours, and are often best tolerated at bedtime. They should be considered an acute, not chronic intervention as overuse can result in chilling, skin maceration, or secondary infection.

Systemic immunosuppressive drugs including cyclosporine, methotrexate, mycophenolate, and azathioprine have been used in recalcitrant disease but are not approved for treatment of children with atopic dermatitis. Limited published data are available on use of cyclosporine in children treated with both continuous and intermittent therapy (5 mg/kg daily) for up to 1 year. Patients treated with this agent should have their dose titrated to the lowest effective dose after the disease is brought under control with appropriate monitoring, under the care of a specialist familiar with the drug. Ultraviolet light therapy approved for patients 12 years or older can be useful in a subset of patients under the supervision of a dermatologist.

K. Experimental and Unproved Therapies

Subcutaneous desensitization to dust mite allergen has been shown to improve atopic dermatitis in adult patients and sublingual desensitization in dust mite allergic children showed benefit in mild-moderate atopic dermatitis; however, further controlled trials are needed before this form of therapy can be recommended for atopic dermatitis in children. Treatment of atopic dermatitis with omalizumab and high-dose intravenous immunoglobulin has not shown consistent benefit. Although disturbances in the metabolism of essential fatty acids have been reported in patients with atopic dermatitis, controlled trials with fish oil and evening primrose have shown no clinical benefit.

L. Prevention

Studies of different hydrolyzed formulas, probiotics and prebiotics have yielded inconsistent results. While preliminary studies suggested a beneficial effect with application of a moisturizer in high-risk infants from birth, recent large-scale studies did not show this benefit.

Prognosis

While many children, especially those with mild disease will outgrow their atopic dermatitis, patients with filaggrin gene mutations are more likely to have more persistent and severe disease. In addition, these patients appear to be the ones at greater risk for developing asthma and allergic sensitizations.

Urticaria and angioedema are common dermatologic conditions, with an incidence of 3%–6% in children. Urticarial lesions are arbitrarily designated as acute, lasting less than 6 weeks, or chronic, lasting more than 6 weeks. It is also classified by trigger: allergic, physical/inducible, infectious, autoimmune, or spontaneous/idiopathic. Note that bradykinin-mediated hereditary angioedema is discussed in the immunodeficiency chapter (see Chapter 33).

Mast cells are thought to play a critical role in the pathogenesis of urticaria or angioedema through release of a variety of vasoactive mediators. Mast cell activation and degranulation can be triggered by different stimuli, including cross-linking of Fc receptor–bound IgE by allergens or anti-FcεRI antibodies. Non–IgE-mediated mechanisms have also been identified, including complement anaphylatoxins (C3a, C5a), radiocontrast dyes, and physical stimuli.

Viral infections are identified as the cause of acute urticaria in over one-half of pediatric patients, while in chronic urticaria, infections are considered an exacerbating factor. Infectious organisms associated with urticaria include streptococci, mycoplasmas, hepatitis B virus, Helicobacter pylori, and Epstein-Barr virus. Allergies to foods, latex, drugs, or insect venoms, immune complex formation with complement activation from blood products, and triggering of mast cells by anaphylatoxins can cause acute urticaria or angioedema. Opiate analgesics, polymyxin B, tubocurarine, and radiocontrast media can induce acute urticaria by direct mast cell activation. Urticaria and angioedema can also occur following ingestion of aspirin or nonsteroidal anti-inflammatory agents (see section Adverse Reactions to Drugs & Biologicals).

Inducible (physical) urticarias represent a heterogeneous group of disorders in which urticaria or angioedema is triggered by physical stimuli, including friction, radiation (solar), pressure, cold, heat, sweat, water, or vibrations. Dermatographism is the most common form of physical urticaria, affecting up to 4% of the population and occurring at skin sites subjected to mechanical stimuli. Physical urticarias are usually rapid in onset, with resolution within hours. However, symptoms can recur for months to years.

The cause of chronic spontaneous urticaria is usually not due to allergies and typically cannot be determined. It can be associated with autoimmunity, such as autoimmune thyroid disease, or the presence of basophil-activating IgG autoantibodies directed at the high-affinity receptor for IgE or at IgE.

Clinical Findings

A. Symptoms and Signs

Urticaria manifests as wheals with reflex erythema that are pruritic and transient. They resolve after hours without any change to the skin. Angioedema is rapid erythematous or skin-colored swelling that is associated with burning or pain more than pruritus. Cold-induced urticaria or angioedema can occur within minutes of exposure to a decreased ambient temperature or as the skin is warmed following direct cold contact. Systemic features include headache, wheezing, and syncope. If the entire body is cooled, as may occur during swimming, hypotension and collapse can occur. In solar urticaria, which occurs within minutes after exposure to light of appropriate wavelength, pruritus is followed by morbilliform erythema and urticaria. Cholinergic urticaria occurs after increases in core body and skin temperatures, and typically develops after a warm bath or shower, exercise, or episodes of fever. The eruption appears as small punctate wheals surrounded by extensive areas of erythema. Rarely, the urticarial lesions become confluent and angioedema develops. Associated features can include the following: headache, syncope, bronchospasm, abdominal pain, vomiting, and diarrhea. In severe cases, systemic anaphylaxis may develop. In pressure urticaria or angioedema, red, deep, painful swelling occurs immediately or 4–6 hours after the skin has been exposed to pressure. The immediate form is often associated with dermatographism. The delayed form, which may be associated with fever, chills, and arthralgias, may be accompanied by elevated erythrocyte sedimentation rate and leukocytosis. Lesions are frequently diffuse, tender, and painful rather than pruritic. They typically resolve within 48 hours.

B. Laboratory Findings

Laboratory tests are selected on the basis of the history and physical findings. Testing for specific IgE antibody to food or inhalant allergens or infections may be helpful in implicating a potential cause in acute urticaria particularly if the history is suggestive. Specific tests for inducible urticarias, such as an ice cube test or a pressure test, may be indicated. Intradermal injection of methacholine reproduces clinical symptoms locally in about one-third of patients with cholinergic urticaria. In chronic spontaneous urticaria, evaluation has rarely been helpful in management; therefore, diagnostic tests should be limited and guided by the history. Evaluation for underlying disease may be indicated, including a complete blood count, erythrocyte sedimentation rate, biochemistry panel, or antithyroid antibodies. Intradermal testing with the patient’s serum has been suggested as a method of detecting histamine-releasing activity, including autoantibodies (autologous serum skin test). In patients with well-characterized autoimmune urticaria, donor basophil and mast cell activation markers including CD63 and CD203c have been shown to be upregulated in patient serum. If the history or appearance of the urticarial lesions suggests vasculitis, a skin biopsy for immunofluorescence is indicated.

Differential Diagnosis

Urticarial lesions are usually easily recognized—the major dilemma is the etiologic diagnosis. Lesions of urticarial vasculitis typically last for more than 24 hours. “Papular urticaria” is a term used to characterize multiple papules from insect bites, found especially on the extremities, and is not true urticaria. Angioedema can be distinguished from other forms of edema because it is transient, asymmetrical, and nonpitting and does not occur predominantly in dependent areas. Hereditary angioedema is a rare autosomal dominant disorder caused by a quantitative or functional deficiency of C1-esterase inhibitor and characterized by episodic, frequently severe, nonpruritic angioedema of the skin, gastrointestinal tract, or upper respiratory tract (discussed in Chapter 33). Rare autoinflammatory disorders with urticaria or urticaria-vasculitic-like lesions include cold-induced autoinflammatory syndrome, Muckle-Wells syndrome, and Schnitzler syndrome.

Complications

In severe cases of cholinergic urticaria, systemic anaphylaxis may develop. In cold-induced disease, sudden cooling of the entire body as can occur with swimming can result in hypotension and collapse.

Treatment

A. General Measures

The most effective treatment is identification and avoidance of the triggering agent. Underlying infection should be treated appropriately. Patients with inducible urticarias should avoid the relevant physical stimulus. Patients with cold urticaria should be counseled not to swim alone and prescribed autoinjectable epinephrine in case of generalized mast cell degranulation with immersion in cold water or other widespread cold exposures. Epinephrine autoinjectors should also be considered for those with severe cholinergic urticaria because of the risk of anaphylaxis.

B. Antihistamines

For the majority of patients, H₁-antihistamines given orally or systemically are the mainstay of therapy. Antihistamines are more effective when given on an ongoing basis rather than after lesions appear. Second-generation H₁-antihistamines (discussed previously under Allergic Rhinoconjunctivitis) are long acting, show good tissue levels, are non- or minimally sedating at usual dosing levels, and lack anticholinergic effects. They are the preferred first-line treatment for urticaria. If refractory at the recommended dose, second-line treatment is increasing the dose up to fourfold.

C. Other Pharmacologic Agents

Third-line treatment for chronic spontaneous urticaria is the addition of omalizumab. Omalizumab has been demonstrated to be effective in antihistamine resistant urticaria in a double-blind placebo-controlled trial and in case series in patients younger than 12 years. It obtained FDA approval for chronic urticaria in patients 12 years old or older in 2014. Dosing is 150 mg or 300 mg subcutaneously every 4 weeks. Oral steroid courses tapered for up to 10 days can be considered for acute urticaria or acute exacerbations of chronic spontaneous urticaria but should not be given chronically. Addition of a LTRA and/or H₂-antihistamines has not been shown to be as effective as omalizumab, but the cost and safety profiles of these medications may be favorable to trial. In the case of omalizumab failure, treatment of chronic spontaneous urticaria with cyclosporine, hydroxychloroquine, azathioprine, tacrolimus, sulfasalazine, dapsone, and vitamin D can be considered.

Prognosis

Spontaneous remission of urticaria and angioedema is typical, but some patients have a prolonged course, especially those with inducible urticaria. Reassurance is important, because this disorder can cause significant frustration. Periodic follow-up is indicated, particularly for patients with development of noncutaneous symptoms, to monitor for possible underlying cause.

Considerations

Anaphylaxis is an acute life-threatening clinical syndrome that occurs when large quantities of inflammatory mediators are rapidly released from mast cells and basophils after exposure to an allergen in a previously sensitized patient. Anaphylactoid reactions mimic anaphylaxis but are not mediated by IgE antibodies. They may be mediated by anaphylatoxins such as C3a or C5a or through nonimmune mast cell degranulating agents. Some of the common causes of anaphylaxis or anaphylactoid reactions are listed in Table 38–8. Idiopathic anaphylaxis by definition has no recognized external cause. The clinical history is the most important tool in making the diagnosis of anaphylaxis.

Clinical Findings

A. Symptoms and Signs

The history is the most important tool to determine whether a patient has had anaphylaxis. The symptoms and signs of anaphylaxis depend on the organs affected. Onset typically occurs within minutes after exposure to the offending agent and can be short-lived, protracted, or biphasic, with recurrence after several hours despite treatment.

Anaphylaxis is highly likely when any one of the following three criteria is fulfilled:

1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) and at least one of the following:

   1. Respiratory compromise (eg, dyspnea, wheeze, bronchospasm, stridor, reduced peak expiratory flow, hypoxemia)

   2. Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], syncope, incontinence)

2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):

   1. Involvement of the skin-mucosal tissue (eg, generalized urticaria, itch-flush, swollen lips-tongue-uvula)

   2. Respiratory compromise (eg, dyspnea, wheeze, bronchospasm, stridor, reduced PEFR, hypoxemia)

   3. Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)

   4. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)

3. Reduced blood pressure after exposure to a known allergen for that patient (minutes to several hours):

   1. Infants and children: low systolic blood pressure (age specific) or greater than 30% decrease in systolic pressure

   2. Low systolic blood pressure in children, defined as less than 70 mm Hg in those aged from 1 month to 1 year, less than (70 mm Hg + [2 × age]) in those 1–10 years of age, and less than 90 mm Hg in those 11–17 years

B. Laboratory Findings

An absence of laboratory findings does not rule out anaphylaxis. Tryptase released by mast cells can be measured in the serum within 3 hours of onset of the reaction and may be helpful when the diagnosis of anaphylaxis is in question. However, tryptase levels are often normal, particularly in individuals with food-induced anaphylaxis. Electrocardiographic abnormalities may include ST-wave depression, bundle branch block, and various arrhythmias. Arterial blood gases may show hypoxemia, hypercapnia, and acidosis. The chest radiograph may show hyperinflation.

Differential Diagnosis

Although shock may be the only sign of anaphylaxis, other diagnoses should be considered, especially in the setting of sudden collapse without typical allergic findings. Other causes of shock along with cardiac arrhythmias must be ruled out (see Chapters 12 and 14). Respiratory failure associated with asthma may be confused with anaphylaxis. Mastocytosis, hereditary angioedema, scombroid fish poisoning, vasovagal reactions, inducible laryngeal obstruction, and anxiety attacks may cause symptoms mistaken for anaphylaxis.

Complications

Depending on the organs involved and the severity of the reaction, complications may vary from none to aspiration pneumonitis, acute tubular necrosis, bleeding diathesis, or sloughing of the intestinal mucosa. With irreversible shock, heart and brain damage can be terminal. Risk factors for fatal or near-fatal anaphylaxis include age (adolescents and young adults), reactions to peanut or tree nuts, associated asthma, strenuous exercise, and use of medications such as β-blockers.

Prevention

Strict avoidance of the causative agent is extremely important, and effort to determine its cause should be made, beginning with a thorough history. Typically, there is a strong temporal relationship between exposure and onset of symptoms. With exercise-induced anaphylaxis, patients should be instructed to exercise with another person and to stop exercising at the first sign of symptoms. If prior ingestion of food has been implicated, eating within 4 hours—perhaps up to 12 hours—before exercise should be avoided. Patients with a history of anaphylaxis should carry epinephrine for self-administration, preferably in the form of an autoinjector (eg, Auvi-Q or EpiPen in 0.15- and 0.3-mg doses), and they and all caregivers should be instructed on its use. They should also carry an oral antihistamine such as diphenhydramine or cetirizine, preferably in liquid or chewable preparation to hasten absorption, but epinephrine should be considered as the first-line treatment of anaphylaxis. Patients with idiopathic anaphylaxis may require prolonged treatment with oral corticosteroids. Specific measures for dealing with food, drug, latex, and insect venom allergies as well as radiocontrast media reactions are discussed in the next sections.

Treatment

A. General Measures

Anaphylaxis is a medical emergency that requires rapid assessment and treatment. Exposure to the triggering agent should be discontinued. Airway patency should be maintained and blood pressure and pulse monitored. Simultaneously and promptly, emergency medical services or a call for help to a resuscitation team should be made. The patient should be placed in a supine position with the legs elevated unless precluded by shortness of breath or emesis. Oxygen should be delivered by mask or nasal cannula with pulse oximetry monitoring. If the reaction is secondary to a sting or injection into an extremity, a tourniquet may be applied proximal to the site, briefly releasing it every 10–15 minutes.

B. Epinephrine

Epinephrine is the treatment of choice for anaphylaxis. Epinephrine 1:1000, 0.01 mg/kg to a maximum of 0.5 mg in adults and 0.3 mg in children, should be injected intramuscularly in the midanterolateral thigh without delay. This dose may be repeated at intervals of 5–15 minutes as necessary for controlling symptoms and maintaining blood pressure. There is no precisely established dosing regimen for intravenous epinephrine in anaphylaxis, but a 5–10 mcg intravenous bolus for hypotension and 0.1–0.5 mg intravenously for cardiovascular collapse have been suggested.

C. Antihistamines

Diphenhydramine, an H₁-blocker, 1–2 mg/kg up to 50 mg, can be given orally, intramuscularly or intravenously. Intravenous antihistamines should be infused over a period of 5–10 minutes to avoid inducing hypotension. Alternatively in young patients, cetirizine 0.25 mg/kg to a maximum dose of 10 mg could be given orally, as it was shown to have a longer duration of action and reduced sedation profile. Addition of ranitidine, an H₂-blocker, 1 mg/kg up to 50 mg intravenously, may be more effective than an H₁-blocker alone, especially for hypotension, but histamine blockers should be considered second-line treatment for anaphylaxis.

D. Fluids

Treatment of persistent hypotension despite epinephrine requires restoration of intravascular volume by fluid replacement, initially with a crystalloid solution, 20–30 mL/kg in the first hour.

E. Bronchodilators

Nebulized β₂-agonists such as albuterol 0.5% solution, 2.5 mg (0.5 mL) diluted in 2–3 mL saline, or levalbuterol, 0.63 mg or 1.25 mg, may be useful for reversing bronchospasm. Intravenous methylxanthines are generally not recommended because they provide little benefit over inhaled β₂-agonists and may contribute to toxicity.

F. Corticosteroids

Although corticosteroids do not provide immediate benefit, when given early they may prevent protracted or biphasic anaphylaxis, although data are limited regarding this. Intravenous methylprednisolone, 50–100 mg (adult) or 1 mg/kg, maximum 50 mg (child), can be given every 4–6 hours. Oral prednisone, 1 mg/kg up to 50 mg, might be sufficient for less severe episodes.

G. Vasopressors

Hypotension refractory to epinephrine and fluids should be treated with intravenous vasopressors such as noradrenaline, vasopressin, or dopamine (see Chapter 14).

H. Observation

The patient should be monitored after the initial symptoms have subsided, because biphasic or protracted anaphylaxis can occur despite ongoing therapy. Biphasic reactions occur in 1%–20% of anaphylactic reactions, but no reliable clinical predictors have been identified. Observation periods should be individualized based on the severity of the initial reaction, but a reasonable time for observation is 4–6 hours in most patients, with prolonged observation or admission for severe or refractory symptoms.

Prognosis

Anaphylaxis can be fatal. The prognosis, however, is good when signs and symptoms are recognized promptly and treated aggressively, and the offending agent is subsequently avoided. Exercise-induced and idiopathic anaphylaxis may be recurrent. Because accidental exposure to the causative agent may occur, patients, parents, and caregivers must be prepared to recognize and treat anaphylaxis (have an anaphylaxis action plan and epinephrine readily available). Resources for anaphylaxis can be found by entering the term anaphylaxis in the search boxes at the websites for the national allergy and immunology academic societies: https://www.aaaai.org and https://acaai.org.

Special Considerations: Infant Anaphylaxis

The recognition, diagnosis and management of anaphylaxis in infants/toddlers are associated with unique challenges given their nonverbal nature. Food allergy is the most common cause of anaphylaxis in this group. Guidance for the diagnosis and management of anaphylaxis in infants was recently published (see reference below). The FDA also approved an epinephrine autoinjector for infants and toddlers weighing between 7.5 and 15 kg (Auvi-Q 0.1 mg).

Adverse drug reactions are any undesirable and unintended response elicited by a drug. Allergic or hypersensitivity drug reactions are adverse reactions involving immune mechanisms. Although hypersensitivity reactions account for only 5%–10% of all adverse drug reactions, they are the most serious, with 1:10,000 resulting in death. Other causes of adverse drug reactions include idiosyncratic reactions, overdosage, pharmacologic side effects, nonspecific release of pharmacologic effector molecules, or drug interactions. Clinicians can report adverse drug reactions and get updated information on drugs, vaccines, and biologics at the FDA’s MedWatch website.

1. Antibiotics

Antibiotics constitute the most frequent cause of allergic drug reactions. Amoxicillin, trimethoprim-sulfamethoxazole, and ampicillin are the most common causes of cutaneous drug reactions. It is important but challenging to help families understand that some antibiotics can cause a rash in the setting of infections, but this is not necessarily a true allergy to the medication.

The penicillins and other β-lactam antibiotics, including cephalosporins, carbacephems, carbapenems, and monobactams, share a common β-lactam ring structure and a marked propensity to couple to carrier proteins. Penicilloyl is the predominant allergenic metabolite of penicillin and is called the major determinant. The other penicillin metabolites are present in low concentrations and are referred to as minor determinants. Regarding cross-reactivity between penicillins and cephalosporins, the R-side chains of the penicillins and cephalosporins have been implicated in most allergic reactions to both of these medications.

Sulfonamide reactions are mediated presumably by a reactive metabolite (hydroxylamine) produced by cytochrome P-450 oxidative metabolism. Slow acetylators appear to be at increased risk. Other risk factors for drug reactions include previous exposure, previous reaction, age (20–49 years), route (parenteral), and dose of administration (high, intermittent). Atopy does not predispose to development of a reaction, but atopic individuals have more severe reactions.

Immunopathologic reactions to antibiotics include type I (IgE-mediated) reactions, type II (cytotoxic) reactions such as drug-induced hemolytic anemia or thrombocytopenia, type III (immune complex) reactions such as serum sickness, and type IV (T-cell–mediated) reactions such as allergic contact dermatitis. Immunopathologic reactions not fitting into the types I–IV classification include interstitial nephritis, pneumonitis, hepatitis, eosinophilia, fixed-drug eruption, acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome, exfoliative dermatitis, and maculopapular exanthemas. The prevalence of morbilliform rashes in patients given ampicillin increases significantly during Epstein-Barr virus and cytomegalovirus infections or with acute lymphoblastic anemia, 69%–100% compared to 5%–9%. Serum sickness–like reactions resemble type III reactions, although immune complexes are not documented; β-lactams, especially cefaclor, and sulfonamides have been implicated most often. The incidence of “allergic” cutaneous reactions to trimethoprim-sulfamethoxazole in patients with AIDS has been reported to be as high as 70%. The mechanism is thought to relate to severe immune dysregulation, although it may be due to glutathione deficiency resulting in toxic metabolites.

2. Latex Allergy

Allergy to latex and rubber products was common among health care workers and children with spina bifida, but less so with the decreased use of latex equipment and gloves. The combination of atopy and frequent exposure seems to synergistically increase the risk of latex hypersensitivity. Nonmedical sources of latex are also common and include balloons, toys, rubber bands, erasers, condoms, and shoe soles. Pacifiers and bottle nipples have also been implicated as sources of latex allergen, although these products are molded rather than dipped, and allergic reactions to molded products are less common.

3. Vaccines

Mumps-measles-rubella (MMR) and the influenza vaccines have been shown to be safe in egg-allergic patients (although rare reactions to gelatin or neomycin can occur). Post-vaccination observation periods are no longer recommended. Local reactions are not associated with a higher rate of systemic allergic reactions. Skin testing can be performed if an IgE-mediated allergy to the vaccine is suspected.

4. Antiepileptic Drugs

Aromatic antiepileptic drugs (AEDs) have been most commonly implicated in drug hypersensitivity reactions to AEDs, which can be severe. This class of medications is one of the most common causes of drug rash with eosinophilia and systemic symptoms (DRESS) syndrome in children. This causes high fever, facial edema, morbilliform/confluent rash, eosinophilia, lymphadenopathy, and, most commonly, hepatic involvement 2–8 weeks after drug initiation. It can progress even with withdrawal of the offending medication and can last for months.

5. Radiocontrast Media

Non–IgE-mediated anaphylactoid reactions may occur with radiocontrast media with up to a 30% reaction rate on reexposure. Management involves using a low-molarity agent and premedication with prednisone, diphenhydramine, and, possibly, an H₂-blocker.

6. Insulin

Approximately 50% of patients receiving insulin have positive skin tests, but IgE-mediated reactions are rare. Insulin resistance is mediated by IgG. If less than 24 hours has elapsed after an allergic reaction to insulin, do not discontinue insulin but rather reduce the dose by one-third, then increase by 2–5 units per injection. Skin testing and desensitization are necessary if the interval between the allergic reaction and subsequent dose is greater than 24 hours.

7. Local Anesthetics

Less than 1% of reactions to local anesthetics are IgE-mediated. Management involves selecting a local anesthetic from another class. Esters of benzoic acid include benzocaine and procaine; amides include lidocaine and mepivacaine. Alternatively, the patient can be skin-tested with the suspected agent, followed by a provocative challenge.

8. Aspirin & Other Nonsteroidal Anti-Inflammatory Drugs

Adverse reactions to aspirin and NSAIDs include urticaria and angioedema; rhinosinusitis, nasal polyps, and asthma (AERD); anaphylactoid reactions; and NSAID-related hypersensitivity pneumonitis. All NSAIDs inhibiting cyclooxygenase (COX) cross-react with aspirin; patients with AERD and urticaria/angioedema will react to all. Fewer patients will react to only one NSAID. Cross-reactivity between aspirin and tartrazine (yellow dye No. 5) has not been substantiated in controlled trials. No skin test or in vitro test is available to diagnose aspirin sensitivity; the gold standard is a drug challenge. Aspirin desensitization can be performed to ameliorate the symptoms of AERD. LTRAs or 5-lipoxygenase inhibitors attenuate the reaction to aspirin challenge and may be beneficial adjunct treatment in AERD patients. COX-2 inhibitors are tolerated by patients with AERD.

9. Biological Agents

In recent years, a growing number of biological agents have become available for the treatment of autoimmune, neoplastic, cardiovascular, infectious, and allergic diseases, among others. Their use may be associated with a variety of adverse reactions, including increased risk of infections, neurologic defects, autoimmune syndromes, cardiovascular effects, and hypersensitivity reactions. Desensitization may be possible if there is no other good alternative in those patients who have developed an allergy to these medications.

10. Hypersensitivity to Retroviral Agents

Adverse drug reactions are being reported with increasing frequency to antiretroviral agents, including reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. Hypersensitivity to abacavir is a well-described, multiorgan, potentially life-threatening reaction that occurs in HIV-infected children. The reaction is independent of dose with onset generally within 9–11 days of initiation of drug therapy. Susceptibility appears to be conferred by the HLA-B*5701 allele with a positive predictive value of more than 70% and negative predictive value of 95%–98%. Genetic screening would be cost-effective in Caucasians, but not in African or Asian populations as their HLA-B*5701 allele frequency is less than 1%.

11. Adverse Reactions to Chemotherapeutic Agents

A number of chemotherapeutic agents, including monoclonal antibodies, have been implicated in hypersensitivity reactions. Skin testing can be performed to platinum agents. Rapid desensitization to unrelated agents, including carboplatin, paclitaxel, and rituximab, has been reported. This 12-step protocol appeared to be successful in both IgE- and non–IgE-mediated reactions.

Clinical Findings

A. Symptoms and Signs

Rash is the most common symptom of a hypersensitivity drug reaction in children. IgE-mediated reactions can cause pruritus, erythema, urticaria, angioedema, bronchospasm, or anaphylaxis within 1 hour of the dose. Delayed reactions can occur hours to weeks after the onset of a medication. Serum sickness is characterized by fever, rash, lymphadenopathy, myalgias, and arthralgias. Cytotoxic drug reactions can result in symptoms and signs associated with the underlying anemia or thrombocytopenia. Delayed-type hypersensitivity may cause contact dermatitis that appears 24–72 hours after contact.

B. Laboratory Findings

Skin testing is useful for evaluation of IgE-mediated drug allergies, particularly of β-lactam antibiotics where it has been most validated. Approximately 80% of patients with a history of penicillin allergy will have negative skin tests. Use of both the major determinants, Pre-Pen (penicilloyl-polylysine) and penicillin G or suspect penicillin, increases sensitivity to about 95%. Not using the minor determinant mixture, which is not commercially available, in skin testing can result in failure to predict potential anaphylactic reactions in up to 20% of those who test negative to both. Solid-phase in vitro immunoassays for IgE to penicillins are available for identification of IgE to penicilloyl but are considerably less sensitive than skin testing and the predictive values are not known. If skin testing is negative, drug provocation test should be performed for the final diagnosis.

Skin testing for non–β-lactam antibiotics is less reliable, because the relevant degradation products are for the most part unknown or multivalent reagents are unavailable.

For nonimmediate reactions, skin testing can be performed, but this is not validated and is controversial.

Patch testing with standardized Thin-Layer Rapid Use Epicutaneous Patch Test (T.R.U.E.) Test® or other sources of antigens can be performed when allergic contact dermatitis is suspected.

Differential Diagnosis

Differential diagnosis for drug allergy includes other types of adverse drug reactions related to drug toxicity, drug interactions, idiosyncratic reactions, or pseudoallergic reactions. As infections commonly cause exanthems or urticaria, these are often confused with drug reactions when the patient is placed on antibiotics.

Treatment

A. General Measures

Withdrawal of the implicated drug is usually a central component of management. Acute IgE-mediated reactions such as anaphylaxis, urticaria, and angioedema are treated according to established therapeutic guidelines that include the use of epinephrine, H₁- and H₂-receptor blocking agents, volume replacement, and systemic corticosteroids. Antibiotic-induced immune cytopenias can be managed by withdrawal of the offending agent or reduction in dose. Drug-induced serum sickness can be suppressed by drug withdrawal, antihistamines, and corticosteroids. Contact allergy can be managed by avoidance and treatment with antihistamines and topical corticosteroids. Reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome require immediate drug withdrawal and supportive care.

B. Alternative Therapy

If possible, subsequent therapy should be with an alternative drug that has therapeutic actions similar to the drug in question but with no immunologic cross-reactivity.

C. Desensitization

Administering gradually increasing doses of the drug either orally or parentally over a period of hours to days may be considered if alternative therapy is not acceptable. This should be done only by a physician familiar with desensitization, typically in an intensive care setting. Of note, desensitization is only effective for the course of therapy for which the patient was desensitized, unless maintained on a chronic prophylactic dose of the medication as patients revert from a desensitized to allergic state after the drug is discontinued. In addition, desensitization does not reduce or prevent non–IgE-mediated reactions. Patients with Stevens-Johnson syndrome, DRESS, or serum sickness should not be desensitized because of the high morbidity and mortality rate.

Prognosis

The prognosis is good when drug allergens are identified early and avoided. Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome may be associated with a high mortality rate.

General Considerations

Food allergy is defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food. Food allergy affects approximately 8% of young children and 3%–4% of adults. The most common IgE-associated food allergens in children are milk egg, peanut, soy, wheat, tree nuts, fish, and shellfish. In older patients, fish, shellfish, peanut, and tree nuts are most often involved in allergic reactions and are usually lifelong allergies. Food allergy can be caused by non–IgE-mediated mechanisms, in conditions such as food protein–induced enterocolitis (FPIES) or proctocolitis. It can also be caused by mixed IgE- and non–IgE-mediated mechanisms, as in eosinophilic esophagitis and gastroenteritis (Table 38–9).

Some adverse reactions diagnosed by patients or physicians as food allergy involve non–immune-mediated mechanisms, such as pharmacologic and metabolic mechanisms, reactions to food toxins, or intolerances (eg, lactose intolerance). These will not be covered in this chapter.

Clinical Findings

A. Symptoms and Signs

A thorough medical history is crucial to identifying symptoms associated with potential food allergy; a history of a temporal relationship between the ingestion of a suspected food and onset of a reaction—as well as the nature and duration of symptoms observed—is important in establishing the diagnosis. For all IgE-mediated reactions, reactions to foods occur within minutes and up to 2 hours after ingestion. Hives, flushing, facial angioedema, and mouth or throat itching are common. In severe cases, angioedema of the tongue, uvula, pharynx, or upper airway can occur. Gastrointestinal symptoms include abdominal discomfort or pain, nausea, vomiting, and diarrhea. Children with food allergy may occasionally have isolated rhinoconjunctivitis or wheezing. Rarely, anaphylaxis to food may involve only cardiovascular collapse.

In patients with IgE antibodies to galactose-a-1,3-galactose (a-Gal), delayed anaphylaxis, urticaria, and angioedema can occur up to 4–6 hours after ingestion of mammalian meats. For non–IgE-mediated and mixed disorders, reactions can be delayed in onset for more than several hours, such as in FPIES, to possibly days later with onset of vomiting or an eczema flare after food exposure due to eosinophilic esophagitis or atopic dermatitis, respectively.

B. Laboratory Findings

Typically, fewer than 50% of histories of adverse reactions to foods will be confirmed as food allergy by blinded food challenge (although this percentage is much higher in food-induced anaphylaxis). Prick skin testing is useful to rule out a suspected food allergen because the predictive value is high for a properly performed negative test with an extract of good quality (negative predictive accuracy of > 95%). In contrast, the predictive value for a positive skin test is approximately 50%. Serum food-specific IgE tests have lower specificity and positive predictive values; therefore, doing serum IgE food panels is not recommended, with referral to an allergist preferred to obtain a detailed clinical history and selective testing, if necessary. A list of nonstandardized and unproven procedures for the diagnosis of food allergy includes the measurement of allergen-specific IgG, lymphocyte stimulation, cytotoxic assays, applied kinesiology, and provocation neutralization, to name a few.

The double-blind, placebo-controlled food challenge is considered the gold standard for diagnosing food allergy, except in severe reactions. If there is high suspicion of possible allergic reactivity to a food with a negative skin test or an undetectable serum IgE level (or both), a food challenge may be necessary to confirm the presence or absence of allergy. Even when multiple food allergies are suspected, most patients will test positive to only three or fewer foods on blinded challenge. Therefore, extensive elimination diets are almost never indicated, and an evaluation by an allergist is preferred before multiple foods are eliminated from the diet unnecessarily. Elimination diets and food challenges may be the only tools for evaluation of suspected non–IgE-mediated food reactions.

Differential Diagnosis

Repeated vomiting in infancy may be due to pyloric stenosis or gastroesophageal reflux. With chronic gastrointestinal symptoms, enzyme deficiency (eg, lactase), cystic fibrosis, celiac disease, chronic intestinal infections, gastrointestinal malformations, and irritable bowel syndrome should be considered.

Treatment

Treatment consists of eliminating and avoiding foods that have been documented to cause allergic reactions. This involves educating the patient, parent/caregivers and systems such as child care and schools regarding hidden food allergens, the necessity for reading labels, and the signs and symptoms of food allergy and its appropriate management (anaphylaxis action plan; a copy of this plan can be obtained from the references). Consultation with a dietitian familiar with food allergy may be helpful, especially when common foods such as milk, egg, peanut, soy, or wheat are involved. All patients with a history of IgE-mediated food allergy should carry self-injectable epinephrine (eg, Auvi-Q or Epipen) and a fast-acting antihistamine, have an anaphylaxis action plan, and consider wearing medical identification jewelry. Clinical trials of oral and epicutaneous immunotherapy are under investigation as potential future treatments of food allergy, currently in phase III for peanut and with possible FDA approval by 2020. However, diets containing extensively heated (baked) milk and egg are potential alternative approaches to food oral immunotherapy and are changing the previous standard of strict avoidance diets for patients with allergy to these foods.

Prognosis

The prognosis is good if the offending food can be identified and avoided. Unfortunately, accidental exposure to food allergens in severely allergic patients can result in death. Most children outgrow food allergies to milk, egg, wheat, and soy but not to peanut or tree nuts (only 20% and 10% of children may outgrow peanut and tree nut allergy, respectively). The natural history of food allergy can be followed by measuring food-specific IgE levels and performing food challenges when indicated. Approximately 3%–4% of children will have food allergy as adults. Resources for food-allergic patients include the Food Allergy Research & Education: www.foodallergy.org; the Food Allergy & Anaphylaxis Connection Team: www.foodallergyawareness.org; and the Consortium of Food Allergy Research: www.cofargroup.org.

Prevention

Recently, multiple randomized controlled trials (RCTs) and a meta-analysis have shown that there appears to be no benefit with respect to food allergy prevention in delaying the introduction of any major food allergen into an infant’s diet. Specific guidelines for the prevention of peanut allergy have been published that provide recommendations and instructions on how and when to introduce peanut into an infant’s diet (https://www.niaid.nih.gov/diseases-conditions/guidelines-clinicians-and-patients-food-allergy).

Allergic reactions to insects include symptoms of respiratory allergy as a result of inhalation of particulate matter of insect origin, local cutaneous reactions to insect bites, and anaphylactic reactions to stings. The latter almost exclusively caused by Hymenoptera includes honeybees, yellow jackets, yellow hornets, white-faced hornets, wasps, and fire ants. Africanized honeybees, also known as killer bees, are a concern because of their aggressive behavior and excessive swarming, not because their venom is more toxic. Rarely, patients sensitized to reduviid bugs (also known as kissing bugs) may have episodes of nocturnal anaphylaxis. Lepidopterism refers to adverse effects secondary to contact with larval or adult butterflies and moths. Salivary gland antigens are responsible for immediate and delayed skin reactions in mosquito-sensitive patients.

Clinical Findings

A. Symptoms and Signs

Insect bites or stings can cause local or systemic reactions ranging from mild to fatal responses in susceptible persons. Local cutaneous reactions include urticaria as well as papulovesicular eruptions and lesions that resemble delayed hypersensitivity reactions. Papular urticaria is almost always the result of insect bites, especially of mosquitoes, fleas, and bedbugs. Toxic systemic reactions consisting of gastrointestinal symptoms, headache, vertigo, syncope, convulsions, or fever can occur following multiple stings. These reactions result from histamine-like substances in the venom. In children with hypersensitivity to fire ant venom, sterile pustules occur at sting sites on a nonimmunologic basis due to the inherent toxicity of piperidine alkaloids in the venom. Mild systemic reactions include itching, flushing, and urticaria. Severe systemic reactions may include dyspnea, wheezing, chest tightness, hoarseness, fullness in the throat, hypotension, loss of consciousness, incontinence, nausea, vomiting, and abdominal pain. Delayed systemic reactions occur from 2 hours to 3 weeks following the sting and include serum sickness, peripheral neuritis, allergic vasculitis, and coagulation defects.

B. Laboratory Findings

Skin testing is indicated for children with systemic reactions to insect stings. Venoms of honeybee, yellow jacket, yellow hornet, white-faced hornet, and wasp are available for skin testing and treatment. Fire ant venom is not yet commercially available, but an extract made from fire ant bodies appears adequate to establish the presence of IgE antibodies to fire ant venom. Importantly, venom skin tests can be negative in patients with systemic allergic reactions, especially in the first few weeks after a sting, and the tests may need to be repeated. The presence of a positive skin test denotes prior sensitization but does not predict whether a reaction will occur with the patient’s next sting, nor does it differentiate between local and systemic reactions. It is common for children who have had an allergic reaction to have positive skin tests to more than one venom. This might reflect sensitization from prior stings that did not result in an allergic reaction or cross-reactivity between closely related venoms. In vitro testing (compared with skin testing) has not substantially improved the ability to predict anaphylaxis. With in vitro testing, there is a 15%–20% incidence of both false-positive and false-negative results. IgE to mosquito saliva antigen can be measured by in vitro assay.

Complications

Secondary infection can complicate allergic reactions to insect bites or stings. Serum sickness, nephrotic syndrome, vasculitis, neuritis, and encephalopathy may be seen as late sequelae of reactions to stinging insects.

Treatment

For cutaneous reactions caused by biting insects, symptomatic therapy includes cold compresses, antipruritics (including antihistamines), and, occasionally, potent topical corticosteroids. Treatment of stings includes careful removal of the stinger, if present, by flicking it away from the wound, not by grasping in order to prevent further envenomation. Topical application of monosodium glutamate, baking soda, or vinegar compresses is of questionable efficacy. Local reactions can be treated with ice, elevation of the affected extremity, oral antihistamines, and NSAIDs as well as potent topical corticosteroids. Large local reactions may require a short course of oral corticosteroids. Anaphylactic reactions following Hymenoptera stings should be managed as discussed above (see section on Anaphylaxis). Children who have had severe or anaphylactic reactions to Hymenoptera stings—or their parents and caregivers—should be instructed in the use of autoinjectable epinephrine. Patients at risk for anaphylaxis from an insect sting should also wear a medical alert bracelet indicating their allergy. Children at risk from insect stings should avoid wearing bright-colored clothing and perfumes when outdoors and should wear long pants and shoes when walking in the grass. Patients who experience severe systemic reactions and have a positive skin test should receive venom immunotherapy. Venom immunotherapy is not indicated for children with only urticarial or local reactions.

Prognosis

Children generally have milder reactions than adults after insect stings, and fatal reactions are extremely rare. Patients aged 3–16 years with reactions limited to the skin, such as urticaria and angioedema, appear to be at low risk for more severe reactions with subsequent stings.