Ronina A. Covar, MD
David M. Fleischer, MD
Christine Cho, MD
Mark Boguniewicz, MD
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 2009–2011 of 5% and 12.5%, respectively. While the prevalence of respiratory allergies has been stable, it is still the highest among children (17% in 2009–2011). 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.
Asthma is the most common chronic disease of childhood, affecting over 7 million children in the United States. While current prevalence rates for asthma have increased in the past decade (most recent estimate of 10%), the rate of asthma attack in the past year has been stable. 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 healthcare utilization for asthma among children compared to adults affected by this disease. Asthma health care encounters in primary care settings have increased over time; death rates and emergency department (ED) visits related to asthma have declined, and hospitalizations due to asthma have been steady. Hospitalizations and emergency department or urgent ambulatory or office visits, all indicators of asthma severity, impose significant costs to the healthcare system and to families, caretakers, schools, and parents’ employers. Indirect costs primarily from loss of productivity due to school/work absences are harder to measure, yet considerable. Asthma remains a potentially life-threatening disease for children; the rate of asthma deaths was 28 per 1 million children with current asthma. 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. Furthermore, RSV and parainfluenza have been associated with more severe respiratory illnesses, but in general, rhinovirus is the most commonly identified respiratory virus with wheezing episodes. 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. Furthermore, 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 which 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. Stronger pieces of evidence such as prospectively designed studies primarily addressing the questions of whether acetaminophen exposure truly increases the risk of the development of chronic asthma or even triggers acute asthma are needed.
Exposure to tobacco smoke, especially from the mother, is also a risk factor for asthma. Other triggers include exercise, cold air, cigarette smoke, pollutants, strong chemical odors, and rapid changes in barometric pressure. Aspirin sensitivity is uncommon in children. 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 airway hyperresponsiveness, airflow limitation, and disease chronicity. Persistent airway inflammation can lead to airway wall remodeling and irreversible changes.
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. In the National Asthma Education and Prevention Program (NAEPP) clinical guidelines, asthma control is introduced as an approach to assess the adequacy of current treatment, and to improve care and outcomes for children with asthma. For children with asthma, 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.
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
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 nonspecific 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 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 age 5 years is greater than in older children. The level of airway hyperresponsiveness usually correlates with the severity of asthma. Bronchoprovocation challenges may help to establish a diagnosis of asthma when the history, examination, and pulmonary function tests are not definitive.
Recent asthma clinical guidelines reinforce 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 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).
Figure 38–1. Representative flow-volume loops in persons with normal lung function, asthma, and vocal cord dysfunction.
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.
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.
Infant pulmonary function can be measured in sedated children with compression techniques. The forced oscillation technique can be used to measure 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 frequent findings. Their presence tends to reflect disease activity 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, and induced sputum. Each test has its strengths and weaknesses.
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, or immune deficiencies, can be better appreciated with high-resolution, thin-section chest 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.
Allergy testing is discussed in the section on General Measures under Treatment, Chronic Asthma.
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.
Table 38–1. Differential diagnosis of asthma in infants and children.
Airway stenosis or web
Enlarged lymph nodes
Vocal cord dysfunction
Vocal cord dysfunction is an important masquerader of asthma, although the two can coexist. It is characterized by the paradoxic closure of the vocal cords that can result in dyspnea and wheezing. Diagnosis is made by direct visualization of the vocal cords. 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 vocal cord dysfunction 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 using exercise or methacholine can precipitate symptoms of vocal cord dysfunction. The flow-volume loop may provide additional clues to the diagnosis of vocal cord dysfunction. 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 vocal cord dysfunction, 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 vocal cord dysfunction includes education regarding the condition and appropriate breathing exercises. Hypnosis, biofeedback, and psychotherapy 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 sociological 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.
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.
A. Chronic Asthma
1. General measures—Optimal asthma management includes 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.
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 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.
Table 38–2. Assessing severity and initiating treatment for patients who are not currently taking long-term control medications.
Table 38–3. Assessing asthma control and adjusting therapy in children.
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 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. On the other hand, 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.
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. 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 (URL: http://www.thechildrenshospital.org/conditions/lung/asthmavideos.aspx).
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; use in vitro testing (either by skin or blood test) to assess sensitivity to perennial indoor allergens; assess the significance of positive tests in the context of the patient’s history; and 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.
2. 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.
Table 38–4. Stepwise approach for managing asthma in children.
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. Inhaled corticosteroids, either as monotherapy or in combination with adjunctive therapy, are preferred treatment for all levels of persistent asthma.
4. Along with medium-dose inhaled corticosteroids, combination therapy with inhaled corticosteroids 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 inhaled corticosteroids 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.
Asthma medications are classified as long-term controller medications and quick-relief medications. The former includes anti-inflammatory agents, leukotriene modifiers, and long-acting bronchodilators. Although LABAs (salmeterol, formoterol) 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.
Inhaled corticosteroids are the most potent inhaled anti-inflammatory agents currently available. Different inhaled corticosteroids are not equivalent on a per puff or microgram basis (Table 38–5). Early intervention with inhaled corticosteroids 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 inhaled corticosteroids 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 inhaled corticosteroids need to be weighed against the risks from undertreated asthma. The adverse effects from inhaled corticosteroids are generally dose and duration dependent, so that greater risks for systemic adverse effects are expected with high doses. The various inhaled corticosteroids are delivered in different devices such as MDI (beclomethasone, ciclesonide, fluticasone, flunisolide, and triamcinolone), dry powder inhaler (DPI) (fluticasone [Diskus], 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.
Table 38–5. Estimated comparative inhaled corticosteroid doses.
Only inhaled corticosteroids have been shown to be effective in long-term clinical studies with 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 inhaled corticosteroids may be effective even in very young children when delivered by MDI with a spacer and mask.
Fewer data are available with nedocromil, although data from the Childhood Asthma Management Program study showed that an inhaled corticosteroid was superior to nedocromil with respect to several efficacy parameters, including rate of hospitalization, symptom-free days, need for albuterol rescue, and longer time to treatment with prednisone, when each was compared to a placebo.
Theophylline is rarely used. 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.
For school aged children whose asthma is uncontrolled on low dose inhaled corticosteroid (ie, requiring step 3 guidelines therapy), majority are likely to respond to a step up combination therapy with a long-acting β2-agonist bronchodilator (eg, salmeterol and formoterol), although some respond best either to an increased dose of inhaled corticosteroid or to an addition of a leukotriene receptor antagonist. LABAs should not be used for treatment of acute symptoms, nor should they be used without any inhaled corticosteroid therapy, even if the patient feels better. Salmeterol is available as an inhalation powder (one inhalation twice daily for patients aged 4 years and older). It is also available combined with fluticasone (50 mcg salmeterol with 100, 250, or 500 mcg fluticasone in a DPI or 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 as a DPI (Aerolizer, 12 mcg) or combined with an inhaled corticosteroid (formoterol fumarate, either 4.5 mcg with budesonide [80 or 160 mcg] or 5 mcg with mometasone [100 or 200 mcg], in an MDI). Formoterol DPI is approved for use in children 5 years and older, one inhalation (12 mcg) twice daily, while the combination product is approved for children 12 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). Of note, the U.S. Food and Drug Administration (FDA) has 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 chronic obstructive pulmonary disease) to update their product information warning sections regarding an increase in severe asthma episodes associated with these agents. This action is 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 is 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.
Montelukast and zafirlukast are leukotriene-receptor antagonists 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, 2 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 leukotriene-receptor antagonists (as well as inhaled corticosteroids), 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 inhaled corticosteroid and a leukotriene-receptor antagonist are concordant for individuals or whether asthmatic patients who do not respond to one medication respond to the other, response 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 inhaled corticosteroid.
Children with persistent asthma who remain uncontrolled on inhaled corticosteroid monotherapy are more likely to respond to a combination treatment of an inhaled corticosteroid and a LABA; however, there are children who can respond best to a higher dose of inhaled corticosteroid, or even a low dose inhaled corticosteroid plus montelukast. It has not been definitely determined what clinical features would be helpful in selecting the most appropriate medication for any one patient. Recent studies in adults have also shown the efficacy of a long-acting antimuscarinic agent, tiotropium (Spiriva), as an add-on therapy to inhaled corticosteroids.
Quick-relief medications include short-acting inhaled β2-agonists (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). 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, 1–3 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/d in single or divided doses for 3–10 days. There is no evidence that tapering the dose following a “burst” prevents relapse.
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 indicated for patients 12 years of age and older 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 30–700 IU/mL, and whose symptoms are inadequately controlled with medium to high dose inhaled corticosteroids. Omalizumab has been shown to decrease the incidence of asthma exacerbations and improve asthma control in these patients. 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 reports from approximately 39,500 patients, anaphylaxis following omalizumab treatment occurred in at least 0.1% of treated people. 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. The small risks of malignant neoplasms (a variety of types, e.g., breast, nonmelanoma skin, prostate, melanoma, and parotid) in clinical studies of adults and adolescents (≥ 12 years of age) with asthma and other allergic disorders were reported in 20 of 4127 (0.5%) omalizumab-treated patients compared to 5 of 2236 (0.2%) controls.
Immunotherapy (discussed in more detail in a subsequent section) can be considered for children 5 years and older with allergic asthma who require steps 2, 3, and 4 therapy.
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 age 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 anti-IgE therapy is being considered.
3. 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, leukotriene receptor antagonists, 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 cut-off values are conventionally set as > 80% (green), 50%–80% (yellow), and < 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; 2–6 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/d for > 24 hours). Doubling the dose of inhaled corticosteroids is not proven sufficient to prevent worsening of exacerbations; however, recent evidence indicates that quadrupling the inhaled corticosteroid dose at the early sign of deterioration might be effective. 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 emergency department 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. Flow-volume loops should be obtained to differentiate upper and lower airway obstruction, especially in patients with atypical presentation. Other tests may include oxygen saturation and 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, 4–8 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/d in divided doses; maximum of 60 mg/d for children aged ≤ 12 years and 80 mg/d 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 3 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/hour for small and 10–15 mg/hour 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. 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 emergency department 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 emergency department 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 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, typically within 1 week. 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 emergency department visits or hospitalizations.
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 healthcare providers, patients, and families include:
Asthma and Allergy Foundation of America
1233 20th St NW, Suite 402
Washington, DC 20036; (800) 7-ASTHMA
Asthma and Allergy Network/Mothers of Asthmatics
2751 Prosperity Avenue, Suite 150
Fairfax, VA 22031; (800) 878-4403
Asthma Device Training: http://www.thechildrenshospital.org/conditions/lung/asthmavideos.aspx
Agency for Healthcare Research and Quality. 2006 Hospital
Discharges by age groups.
http://hcupnet.ahrq.gov/. Accessed May 15, 2009.
Akinbami LJ et al: Trends in asthma prevalence, health care use, and mortality in the United States, 2001–2010. NCHS Data Brief. 2012 May;(94):1–8.
Akinbami LJ, Moorman JE, Liu X: Asthma prevalence, health care use, and mortality: United States, 2005–2009. Natl Health Stat Report 2011 Jan 12;(32):1–14 [PMID: 21355352].
Busse WW et al: Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med 2011 Mar 17; 364(11):1005–1015 [PMID: 21410369].
Center for Disease Control and Prevention. National Center for Health Statistics. Health Data Interactive. Summary Health Statistics for U.S. Children: National Health Interview Survey, 2011. Available at: http://www.cdc.gov/nchs/nhis/new_nhis.htm. Accessed March 31, 2013.
Covar RA et al: Childhood Asthma Management Program Research Group. Predictors of remitting, periodic, and persistent childhood asthma. J Allergy Clin Immunol 2010 Feb;125(2):359–366 [PMID: 20159245].
Guilbert T et al: Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006;354:1985 [PMID: 16687711].
Kelly HW et al; CAMP Research Group: Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med 2012 Sep 6; 367(10):904–912 [PMID: 22938716].
Jackson KD, Howie LD, Akinbami LJ: Trends in allergic conditions among children, US, 1997–2011. NCHS Data Brief 2013;121:1–7.
Lemanske RF Jr et al: Childhood Asthma Research and Education (CARE) Network of the National Heart, Lung, and Blood Institute. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med 2010 Mar 18;362(11):975–985 [PMID: 20197425].
National Asthma Education and Prevention Program: Expert Panel Report 3 (EPR 3): Guidelines for the Diagnosis and Management of Asthma—Summary Report 2007. J Allergy Clin Immunol 2007;120(5 Suppl):S94 [PMID: 17983880]. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.
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 postadolescent 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, seasonal (hay fever), 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.
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.
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 which 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 which 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.
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.
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) which 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.
For allergic rhinoconjunctivitis, topical nasal corticosteroids also reduce ocular symptoms, presumably through a naso-ocular reflex. For ocular allergies which 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 which 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/d or 2.5 mg twice a day), and 6 years or older (5–10 mg/d). It is now available without a prescription. Loratadine is approved for use in children aged 2–5 years (5 mg/d) and 6 years or older (10 mg/d), 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/d), 1–5 years (1.25 mg/d), and for 12 years and older (5 mg/d). 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/d) 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/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 (see also Chapter 16). 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.
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/d for ages 6–23 months) and seasonal allergic rhinitis in children 2 years and older in doses as discussed in the preceding section on 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 age 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.
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 and recommended in Europe, Argentina, Brazil, the Gulf States, and South Africa, for treatment of allergic rhinitis caused by pollens in both adults and children, and for allergic rhinitis caused by dust mites only in adults. Although local adverse effects are common (in about 35%), this form of immunotherapy allows for a less stringent administration as this can be given at home. This is still considered experimental in the United States, as extracts have not been FDA-approved.
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.
Bousquet J, Khaltaev N, Cruz AA: Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy 2008 Apr;63(Suppl 86):8–160 [PMID: 18331513].
Brozek JL et al: Global Allergy and Asthma European Network; Grading of Recommendations Assessment, Development, and Evaluation Working Group. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol 2010 Sep;126(3):466–476 [PMID: 20816182].
Cox L et al: Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol 2011;127:S1 [PMID: 21122901].
Atopic dermatitis is a chronically relapsing inflammatory skin disease typically associated with respiratory allergy. Over half of patients with atopic dermatitis will develop asthma and 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 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. The disease presents in early childhood, with onset prior to age 5 years in approximately 90% of patients.
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. Patients usually have dry, “lackluster” skin. During infancy, atopic dermatitis involves primarily the face, scalp, and extensor surfaces of the extremities. The diaper area is usually spared. When involved, it may be secondarily infected with Candida. In older patients with longstanding disease, the flexural folds of the extremities are the predominant location of lesions.
B. Laboratory Findings
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 double-blind, placebo-controlled food challenges unless there is a coincidental history of anaphylaxis to the suspected food. Alternatively, specific IgE levels to milk, egg, peanut, and fish proteins have been established with the Phadia ImmunoCAP assay correlating with a greater than 95% chance of a clinical reaction.
Elevated serum IgE levels can be demonstrated in 80%–85% of patients with atopic dermatitis, and a similar number have positive immediate skin tests or in vitro tests with food and inhalant allergens. Several well-controlled studies suggest that specific allergens can influence the course of this disease. However, triggers for clinical disease cannot be predicted simply by performing allergy testing. Double-blind, placebo-controlled food challenges show that food allergens can cause exacerbations in a subset of patients with atopic dermatitis. Although lesions induced by single positive challenges are usually transient, repeated challenges, more typical of real-life exposure, can result in eczematous lesions. Furthermore, elimination of food allergens results in amelioration of skin disease and a decrease in spontaneous basophil histamine release. 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 Staphylococcus aureus toxins secreted on the skin, and this correlates with clinical severity better than total serum IgE levels. Eosinophilia may occur. 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 using DNA from buccal swabs or blood are available. Testing 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.
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. Occasionally, 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.
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. Patients with atopic dermatitis often have toxin-secreting S aureus cultured from their skin and can make specific IgE antibodies against the toxins found on their skin. S aureus toxins can act as superantigens, contributing to persistent inflammation or exacerbations of atopic dermatitis. Patients without obvious superinfection may show a better response to combined antistaphylococcal and topical corticosteroid therapy than to corticosteroids alone. 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 such as hyper-IgE syndrome. Patients with atopic dermatitis may be predisposed to colonization and infections by microbial organisms due to decreased synthesis of antimicrobial peptides in the skin, which may be mediated by increased levels of TH2-type cytokines.
Patients with atopic dermatitis often have a nonspecific hand dermatitis. This is frequently irritant in nature and aggravated by repeated wetting.
Nutritional disturbances may result from unwarranted and unnecessarily vigorous dietary restrictions imposed by physicians and parents.
Poor academic performance and behavioral disturbances may be a result of uncontrolled intense or frequent itching, sleep loss, and poor self-image. Severe disease may lead to problems with social interactions and self-esteem.
A. General Measures
Patients with atopic dermatitis have a lowered threshold of irritant responsiveness. Avoidance of irritants such as detergents, chemicals, and abrasive materials as well as extremes of temperature and humidity is important in managing this disease. 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 is beneficial. Occlusive clothing should be avoided in favor of cotton or cotton blends. Temperature in the home and work environments should be controlled to minimize sweating. Swimming is usually well tolerated; however, because swimming pools are treated with chlorine or bromine, patients should shower and use a mild cleanser to remove these chemicals, then apply a moisturizer or occlusive agent. Sunlight may be beneficial to some patients with atopic dermatitis, but nonsensitizing sunscreens should be used to avoid sunburn. Prolonged sun exposure can cause evaporative losses, overheating, and sweating, all of which can be irritating.
In children who have undergone controlled food challenges, eggs, milk, peanuts, soy, wheat, and fish account for approximately 90% of the food allergens that exacerbate atopic dermatitis. Avoidance of foods implicated in controlled challenges can lead to clinical improvement. Extensive elimination diets, which can be nutritionally unsound and burdensome, are almost never warranted because even patients with multiple positive skin tests rarely react to more than three foods on blinded challenges.
In patients who demonstrate specific IgE to dust mite allergen, environmental control measures aimed at reducing the dust mite load improve atopic dermatitis. These include use of dust mite–proof covers on pillows and mattresses, washing linens weekly in hot water, decreasing indoor humidity levels, and in some cases removing bedroom carpeting.
Counseling may be of benefit when dealing with the frustrations associated with atopic dermatitis. 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: (800) 818-7546; http://www.nationaleczema.org.
Patients with atopic dermatitis have evaporative losses due to a defective skin barrier, so soaking the affected area or bathing for 10–15 minutes in warm 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. 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 use an occlusive preparation within a few minutes after soaking the skin to prevent evaporation, which is both drying and irritating.
C. Moisturizers and Occlusives
An effective emollient combined with hydration therapy will help skin healing and can reduce the need for topical corticosteroids. Moisturizers are available as lotions, creams, and ointments. Because lotions contain more water than creams, they are more drying because of their evaporative effect. 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. Topical nonsteroidal creams approved as medical devices (thus, currently requiring prescriptions) for relief and management of signs and symptoms of dermatoses include Atopiclair, MimyX, EpiCeram, and Eletone.
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. The dramatic improvement observed with systemic corticosteroids may be associated with an equally dramatic flaring of atopic dermatitis following their discontinuation. Topical corticosteroids are available in a wide variety of formulations, ranging from extremely high-potency to low-potency preparations (see Table 15–3). 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 significant atrophic changes as well as 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. Because topical corticosteroids are commercially available in a variety of bases, including ointments, creams, lotions, solutions, gels, and sprays, 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. Creams and 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 be irritating, especially to open lesions. 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. Several topical steroids including fluticasone 0.05% cream and desonide 0.05% hydrogel have been approved in infants as young as 3 months of age for up to 28 days.
E. Topical Calcineurin Inhibitors
Tacrolimus and pimecrolimus are immunomodulatory agents that inhibit the transcription of proinflammatory cytokines as well as other allergic mediators and target key cells in allergic inflammation. They are available in topical formulations, and long-term studies have confirmed both efficacy and safety. 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. 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. As a precaution, patients should wear sunscreen with both 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 cancer and the use of topical calcineurin inhibitors, the FDA has issued a boxed warning for pimecrolimus cream and tacrolimus ointment because of a lack of long-term safety data (see U.S. package inserts for Elidel [Novartis] and Protopic [Astellas]). The new 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 the age of 2 years is currently not recommended.
F. Tar Preparations
Tar preparations are used primarily in shampoos and rarely as bath additives. Side effects associated with tar products include skin dryness or irritation, especially if applied to inflamed skin, and, less commonly, photosensitivity reactions and folliculitis.
G. Wet Dressings
Wet dressings are used together with hydration and topical corticosteroids for the treatment of severe atopic dermatitis. They can serve as an effective barrier against the persistent scratching that often undermines therapy. Total body dressings can be applied by using wet pajamas or long underwear with dry pajamas or a sweat suit on top. Hands and feet can be covered by wet tube socks with dry tube socks on top. Alternatively, wet gauze with a layer of dry gauze over it can be used and secured in place with an elastic bandage. Dressings can be removed when they dry out, usually after several hours, and are often best tolerated at bedtime. Incorrect use of wet dressings can result in chilling, maceration of the skin, or secondary infection.
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 methicillin-resistant S aureus. Bleach baths (6% sodium hypochlorite, ½ cup in a full tub of water) two times per week in combination with nasal mupirocin (twice daily for 5 consecutive days per month) may be helpful for patients with recurrent methicillin-resistant S aureus, although some patients find this treatment irritating.
Disseminated eczema herpeticum usually requires treatment with systemic acyclovir. Patients with recurrent cutaneous herpetic lesions can be given prophylactic oral acyclovir. 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 mostly in the evening to avoid daytime somnolence. Nonsedating antihistamines may be less effective in treating pruritus, although beneficial effects have been reported in blinded studies. Use of topical antihistamines and local anesthetics should be avoided because of potential sensitization.
J. Recalcitrant Disease
Patients who are erythrodermic or who appear toxic may need to be hospitalized. Hospitalization may also be appropriate for those with severe disease who fail outpatient management. Marked clinical improvement often occurs when the patient is removed from environmental allergens or stressors. In the hospital, compliance with therapy can be monitored, the patient and family can receive intense education, and controlled provocative challenges can be conducted to help identify triggering factors.
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. Mycophenolate mofetil has also been shown to be safe and effective in children with severe atopic dermatitis although this was a retrospective case series.
Ultraviolet light therapy can be useful for chronic recalcitrant atopic dermatitis in a subset of patients under the supervision of a dermatologist. Photochemotherapy with oral methoxypsoralen therapy followed by UVA (ultraviolet A) has been used in a limited number of children with severe atopic dermatitis unresponsive to other therapy, and significant improvement has been noted. However, the increased long-term risk of cutaneous malignancies from this therapy prevents its widespread use.
K. Experimental and Unproved Therapies
Subcutaneous desensitization to dust mite allergen has been shown to improve atopic dermatitis in adult patients and one blinded, placebo-controlled study of sublingual desensitization in dust mite allergic children showed benefit in mild-moderate atopic dermatitis (currently not FDA approved); however, further controlled trials are needed before this form of therapy can be recommended for atopic dermatitis in children. Treatment of atopic dermatitis with high-dose intravenous immunoglobulin and omalizumab is currently investigational. 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.
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.
Boguniewicz M et al: A multidisciplinary approach to evaluation and treatment of atopic dermatitis. Semin Cutan Med Surg 2008;27:115 [PMID: 18620133].
Boguniewicz M et al: Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev 2011;242:233 [PMID: 21682749].
Schneider L et al: Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol 2013;131:295 [PMID: 23374261].
URTICARIA & ANGIOEDEMA
Urticaria and angioedema are common dermatologic conditions, occurring at some time in up to 25% of the population. About half of patients will have concomitant urticaria and angioedema, whereas 40% will have only urticaria and 10% only angioedema. Urticarial lesions are arbitrarily designated as acute, lasting less than 6 weeks, or chronic, lasting more than 6 weeks. Acute versus chronic urticaria can also be distinguished by differences in histologic features. A history of atopy is common with acute urticaria or angioedema. In contrast, atopy does not appear to be a factor in chronic urticaria. Note that bradykinin-mediated hereditary angioedema is discussed in the immunodeficiency chapter (Chapter 33).
Mast cell degranulation, dilated venules, and dermal edema are present in most forms of urticaria or angioedema. The dermal inflammatory cells may be sparse or dense depending on the chronicity of the lesions. 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. Chronic urticarial lesions have greater numbers of perivascular mononuclear cells, consisting primarily of T cells. There is also a marked increase in cutaneous mast cells.
The cause of acute disease can be identified in about half of patients and includes allergens such as foods, aeroallergens, latex, drugs, and insect venoms. Infectious agents, including streptococci, mycoplasmas, hepatitis B virus, and Epstein-Barr virus, can cause acute urticaria. Urticaria or angioedema can occur after the administration of blood products or immunoglobulin. This results from immune complex formation with complement activation, vascular alterations, and triggering of mast cells by anaphylatoxins. Opiate analgesics, polymyxin B, tubocurarine, and radiocontrast media can induce acute urticaria by direct mast cell activation. These disorders can also occur following ingestion of aspirin or nonsteroidal anti-inflammatory agents (see later section on Adverse Reactions to Drugs & Biologicals).
Physical urticarias represent a heterogeneous group of disorders in which urticaria or angioedema is triggered by physical stimuli, including pressure, cold, heat, water, or vibrations. Dermographism is the most common form of physical urticaria, affecting up to 4% of the population and occurring at skin sites subjected to mechanical stimuli. Many physical urticarias are considered to be acute because the lesions are usually rapid in onset, with resolution within hours. However, symptoms can recur for months to years.
The cause of chronic 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.
A. Symptoms and Signs
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. Two forms of dominantly inherited cold urticaria have been described. The immediate form is known as familial cold urticaria, in which erythematous macules appear rather than wheals, along with fever, arthralgias, and leukocytosis. The delayed form consists of erythematous, deep swellings that develop 9–18 hours after local cold challenge without immediate lesions.
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. Occasional episodes are triggered by stress or the ingestion of certain foods. 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 one or more of 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 dermographism. 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 may be helpful in implicating a potential cause. Specific tests for physical 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. A throat culture for streptococcal infection may be warranted with acute urticaria. In chronic urticaria, selected screening studies to look for an underlying disease may be indicated, including a complete blood count, erythrocyte sedimentation rate, biochemistry panel, and urinalysis. Antithyroid antibodies may be considered. 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. Other tests should be done based on suspicion of a specific underlying disease. If the history or appearance of the urticarial lesions suggests vasculitis, a skin biopsy for immunofluorescence is indicated. Patient diaries occasionally may be helpful to determine the cause of recurrent hives. A trial of food or drug elimination may be considered.
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). Life-threatening laryngeal angioedema may occur. Rare autoinflammatory disorders with urticaria or urticaria-vasculitic-like lesions include cold-induced autoinflammatory syndrome, Muckle-Wells syndrome, and Schnitzler syndrome.
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.
A. General Measures
The most effective treatment is identification and avoidance of the triggering agent. Underlying infection should be treated appropriately. Patients with physical 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.
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 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 treatment for treating urticaria. The addition of H2 antihistamines may benefit some patients who fail to respond to H1-receptor antagonists alone. In school-aged children, but especially adolescents who are of driving age or who operate machinery, nonsedating antihistamines should be used during the day and sedating antihistamines can be added at bedtime, if needed. Patients with urticaria may require treatment with higher than usual doses of antihistamines if they have breakthrough symptoms.
Although corticosteroids are usually not indicated in the treatment of acute or chronic urticaria, severe recalcitrant cases may require alternate-day or low dose therapy in an attempt to diminish disease activity or short-term use to facilitate control with antihistamines. However, high-dose chronic steroid use should be avoided. Systemic corticosteroids may also be needed in the treatment of urticaria or angioedema secondary to necrotizing vasculitis, an uncommon occurrence in patients with serum sickness or collagen-vascular disease.
D. Other Pharmacologic Agents
Limited studies suggest that some patients may benefit from treatment with a leukotriene-receptor antagonist. The tricyclic antidepressant doxepin blocks both H1 and H2 histamine receptors and may be particularly useful in chronic urticaria, although its use may be limited by the sedating side effect. Cyclosporine has been shown to be effective in multiple trials of severe chronic urticaria, but it does require blood pressure and renal function monitoring. Omalizumab trials for refractory chronic urticaria have shown promising results, but it is not currently FDA-approved for this condition. A limited number of patients—including euthyroid patients—with chronic urticaria and antithyroid antibodies have improved when given thyroid hormone, although this treatment remains controversial. Treatment of chronic urticaria with hydroxychloroquine, sulfasalazine, dapsone, colchicine, and intravenous immune globulin should be considered investigational.
Spontaneous remission of urticaria and angioedema is frequent, but some patients have a prolonged course, especially those with physical urticaria. In one natural history study, approximately 58% of children with chronic urticaria became symptom free after 6 months. Reassurance is important, because this disorder can cause significant frustration. Periodic follow-up is indicated, particularly for patients with laryngeal edema, to monitor for possible underlying cause.
Maurer M et al: Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. New Engl J Med 2013:368:924 [PMID: 23432142].
Zuberbier T et al: EAACI/GA2LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria. Allergy 2009:64:1417 [PMID: 19772512].
Zuberbier T et al: EAACI/GA2LEN/EDF/WAO guideline: management of urticaria. Allergy 2009;64:1427 [PMID: 19772513].
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 38–6. Idiopathic anaphylaxis by definition has no recognized external cause. The clinical history is the most important tool in making the diagnosis of anaphylaxis.
Table 38–6. Common causes of systemic allergic and pseudoallergic reactions.
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:
a. Respiratory compromise (eg, dyspnea, wheeze, bronchospasm, stridor, reduced peak expiratory flow, hypoxemia)
b. 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):
a. Involvement of the skin-mucosal tissue (eg, generalized urticaria, itch-flush, swollen lips-tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze, bronchospasm, stridor, reduced PEFR, hypoxemia)
c. Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. 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)
a. Infants and children: low systolic blood pressure (age specific) or greater than 30% decrease in systolic pressure
b. 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 and may be helpful when the diagnosis of anaphylaxis is in question. The blood sample should be obtained within 3 hours of onset of the reaction, although tryptase levels are often normal, particularly in individuals with food-induced anaphylaxis. The complete blood count may show an elevated hematocrit due to hemoconcentration. Elevation of serum creatine kinase, aspartate aminotransferase, and lactic dehydrogenase may be seen with myocardial involvement. 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.
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 poisoning, vasovagal reactions, vocal cord dysfunction, and anxiety attacks may cause symptoms mistaken for anaphylaxis.
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 ingestion of medications such as β-blockers.
Strict avoidance of the causative agent is extremely important. An 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. Testing for specific IgE to allergens with either in vitro or skin testing may be indicated. 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. When epinephrine autoinjectors are unavailable or unaffordable, patients in some communities have been provided with unsealed syringes containing premeasured epinephrine doses, but this is not the recommended form since it needs to be replaced every few months on a regular basis due to lack of stability and the use of a syringe is more unwieldy in an emergent situation. They should also carry an oral antihistamine such as diphenhydramine, preferably in liquid or fast-melt preparation to hasten absorption, and consider wearing a medical alert bracelet. 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.
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.
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. If the precipitating allergen has been injected intradermally or subcutaneously, absorption may be delayed by giving 0.1 mL of epinephrine subcutaneously at the injection site unless the site is a digit. 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 has been suggested.
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.
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.
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.
Although corticosteroids do not provide immediate benefit, when given early they may prevent protracted or biphasic anaphylaxis. 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.
Hypotension refractory to epinephrine and fluids should be treated with intravenous vasopressors such as noradrenaline, vasopressin, or dopamine (see Chapter 14).
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.
Anaphylaxis can be fatal. In two reports describing children, adolescents, and adults who died from food-induced anaphylaxis (eg, from peanuts, tree nuts, fish, shellfish, and milk) over the past 12 years, treatment with epinephrine was delayed for more than 1 hour after onset as it was not readily accessible in the majority of subjects. 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 (emergency action plan).
Lieberman P et al. The diagnosis and management of anaphylaxis practice parameter: 2010 Update. J Allergy Clin Immunol 2010;126(3):477–480; e1–e42 [PMID: 20692689].
Simons FE et al: World Allergy Organization. World Allergy Organization anaphylaxis guidelines: summary. J Allergy Clin Immunol 2011;127(3):587–593; e1–e22 [PMID: 21377030].
Simons FE et al: 2012 Update: World Allergy Organization Guidelines for the assessment and management of anaphylaxis. Curr Opin Allergy Clin Immunol 2012;12:389–399 [PMID: 22744267].
ADVERSE REACTIONS TO DRUGS & BIOLOGICALS
The majority of adverse drug reactions are not immunologically mediated and may be due to idiosyncratic reactions, overdosage, pharmacologic side effects, nonspecific release of pharmacologic effector molecules, or drug interactions.
Patients or caregivers often label any adverse drug reaction as an “allergy.” 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. Clinicians can report adverse drug reactions and get updated information on drugs, vaccines, and biologics at the FDA’s MedWatch website.
Antibiotics constitute the most frequent cause of allergic drug reactions. Amoxicillin, trimethoprim–sulfamethoxazole, and ampicillin are the most common causes of cutaneous drug reactions.
Most antibiotics and their metabolites are low-molecular-weight compounds that do not stimulate immunity until they have become covalently bound to a carrier protein. 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 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. 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 resulting from a drug or metabolite interaction with preformed specific IgE bound to the surfaces of tissue mast cells or circulating basophils. Release of mediators such as histamine and leukotrienes contributes to the clinical development of angioedema, urticaria, bronchospasm, or anaphylaxis immediately after the dose. Type II (cytotoxic) reactions involve IgG or IgM antibodies that recognize drug bound to cell membranes. In the presence of serum complement, the antibody-coated cell is either cleared or destroyed, causing drug-induced hemolytic anemia or thrombocytopenia. Type III (immune complex) reactions are caused by soluble complexes of drug or metabolite with IgG or IgM antibody. If the immune complex is deposited on blood vessel walls and activates the complement cascade, serum sickness may result. Type IV (T-cell–mediated) reactions require activated T lymphocytes that recognize a drug or its metabolite as seen in allergic contact dermatitis. Sensitization usually occurs via the topical route of administration. Immunopathologic reactions not fitting into the types I–IV classification include Stevens-Johnson syndrome, exfoliative dermatitis, and the maculopapular rash associated with penicillin or ampicillin. The prevalence of morbilliform rashes in patients given ampicillin is between 5.2% and 9.5% of treatment courses. However, patients given ampicillin during Epstein-Barr virus and cytomegalovirus infections or with acute lymphoblastic anemia have a 69%–100% incidence of non–IgE-mediated rash. 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. They may result from an inherited propensity for hepatic biotransformation of drug into toxic or immunogenic metabolites. 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.
A. Symptoms and Signs
Allergic reactions can result in pruritus, urticaria, angioedema, or anaphylaxis. 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.
B. Laboratory Findings
Skin testing is the most rapid, useful, and sensitive method of demonstrating the presence of IgE antibody to a specific allergen. Skin testing to nonpenicillin antibiotics may be difficult, however, because many immunologic reactions are due to metabolites rather than to the parent drug and because the relevant metabolites for most drugs other than penicillin have not been identified. Because metabolites are usually low-molecular-weight haptens, they must combine with carrier proteins to be useful for diagnosis. Skin testing for immediate hypersensitivity is helpful only in predicting reactions caused by IgE antibodies. Most nonpruritic maculopapular rashes will not be predicted by skin testing. In the case of contact sensitivity reactions to topical antibiotics, a 48-hour patch test can be useful.
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. Assays for specific IgG and IgM have been shown to correlate with a drug reaction in immune cytopenias, but in most other instances such assays are not clinically useful. Approximately 80% of patients with a history of penicillin allergy will have negative skin tests. Penicillin therapy in patients with a history of an immediate hypersensitivity reaction to penicillin, but with negative skin tests to both penicilloyl and the minor determinant mixture, is accompanied by a 1%–3% chance of urticaria or other mild allergic reactions at some time during therapy, with anaphylaxis occurring in less than 0.1% of patients. In contrast, the predictive value of a positive skin test is approximately 60%. Testing with penicilloyl linked to polylysine (PPL) alone has a sensitivity of about 76%; use of both PPL and penicillin G (used as a minor determinant) increases sensitivity to about 95%. Not using the minor determinant mixture in skin testing can result in failure to predict potential anaphylactic reactions. Unfortunately, the minor determinant mixture is still not commercially available, although some academic allergy centers make their own. Approximately 4% of subjects tested who have no history of penicillin allergy have positive skin tests. Rarely, patients may have skin test reactivity only to a specific semisynthetic penicillin. Resensitization in skin test–negative children occurs infrequently (< 1%) after a course of oral antibiotic. Of note, the manufacturing of the major determinant of penicillin testing reagent Pre-Pen (penicilloyl-polylysine) in the United States was discontinued for several years. AllerQuest received approval from the FDA in January 2008 to manufacture Pre-Pen and the product is once again available (distributed by ALK-Abello, Inc).
The degree of cross-reactivity of determinants formed from cephalosporins with IgE to other β-lactam drugs remains unresolved, especially because haptens that may be unique to cephalosporin metabolism remain unknown. The degree of clinical cross-reactivity is much lower than the in vitro cross-reactivity. A clinical adverse reaction rate of 3%–7% for cephalosporins may be expected in patients with a history of immediate reaction to penicillins with positive skin tests to penicillin. Antibodies to the second, third, and fourth generation cephalosporins appear to be directed at the unique side chains rather than at the common ring structure. The present literature suggests that a positive skin test to a cephalosporin used at a concentration of 1 mg/mL would place the patient at increased risk for an allergic reaction to that antibiotic. However, a negative skin test would not exclude sensitivity to a potentially relevant metabolite. One review concluded that there is no increased incidence of allergy to second- and third-generation cephalosporins in patients with penicillin allergy and that penicillin skin testing does not identify patients who develop cephalosporin allergy. However, another study suggested that although only 2% of penicillin-allergic patients would react to a cephalosporin, they would be at risk for anaphylaxis.
Carbacephems (loracarbef) are similar to cephalosporins, although the degree of cross-reactivity is undetermined. Carbapenems (imipenem) represent another class of β-lactam antibiotics with a bicyclic nucleus and a high degree of cross-reactivity with penicillin although recent prospective studies suggest an incidence of cross-reactivity on skin testing of approximately 1%. Monobactams (aztreonam) contain a monocyclic rather than bicyclic ring structure, and limited data suggest that aztreonam can be safely administered to most penicillin-allergic subjects. In contrast, administration of aztreonam to a patient with ceftazidime allergy may be associated with increased risk of allergic reaction due to similarity of side chains.
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.
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 (see previous sections). 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.
Administering gradually increasing doses of an antibiotic 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 should not be desensitized because of the high mortality rate.
The prognosis is good when drug allergens are identified early and avoided. Stevens-Johnson syndrome and toxic epidermal necrolysis may be associated with a high mortality rate.
2. Latex Allergy
Allergic reactions to latex and rubber products have become increasingly common since the institution of universal precautions for exposure to bodily fluids. Children with spina bifida appear to have a unique sensitivity to latex, perhaps because of early and frequent latex exposure as well as altered neuroimmune interactions. Atopy—especially symptomatic latex allergy—appears to be significantly increased in patients with spina bifida experiencing anaphylaxis during general anesthesia. Other conditions requiring chronic or recurrent exposure to latex such as urogenital anomalies and ventriculoperitoneal shunt have also been associated with latex hypersensitivity. The combination of atopy and frequent exposure seems to synergistically increase the risk of latex hypersensitivity.
Latex is the milky fluid obtained by tapping the cultivated rubber tree, Hevea brasiliensis. During manufacture of latex products, various antioxidants and accelerators such as thiurams, carbamates, and mercaptobenzothiazoles are added. IgE from latex-sensitized individuals reacts with different protein components, supporting the notion that more than one clinically important latex antigen exists. New allergenic epitopes are generated during the manufacturing process. Thus, polypeptides from latex glove extracts vary both quantitatively and qualitatively with different brands and lots of gloves. Identification of the causative antigens is important because it may be possible to alter the manufacturing process to reduce the final allergen content.
Latex is ubiquitous in medical settings, and many sources may be inconspicuous. Synthetic alternatives to some latex products—including gloves, dressings, and tape—are available. Avoidance of contact with latex-containing items, however, may be insufficient to prevent allergic reactions, because lubricating powders may serve as vehicles for aerosolized latex antigens. The use of powder-free latex gloves is an important control measure for airborne latex allergen.
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. Latex-allergic patients and their caregivers must be continuously vigilant for hidden sources of exposure.
A. Symptoms and Signs
The clinical manifestations of IgE-mediated reactions to latex can involve the full spectrum of symptoms associated with mast cell degranulation. Localized pruritus and urticaria occur after cutaneous contact; conjunctivitis and rhinitis can result from aerosol exposure or direct facial contact. Systemic reactions, including bronchospasm, laryngospasm, and hypotension, may occur with more substantial exposure or in extremely sensitive individuals. Finally, vascular collapse and shock leading to fatal cardiovascular events may occur. Intraoperative anaphylaxis represents a common and serious manifestation of latex allergy.
Allergic contact dermatitis to rubber products typically appears 24–48 hours after contact. The primary allergens include accelerators and antioxidants used in the manufacturing process. The diagnosis is established by patch testing. Shoe soles are an important source of exposure. The skin lesions appear primarily as a patchy eczema on exposed surfaces, although reactions can become generalized.
B. Laboratory Findings
Epicutaneous prick testing is a rapid, inexpensive, and sensitive test that detects the presence of latex-specific IgE on skin mast cells although a standardized antigen is not yet commercially available. Reports of life-threatening anaphylactic events have been associated with skin testing to latex, and intradermal testing may be especially dangerous.
Immunoassay testing involves the in vitro measurement of specific IgE, which binds latex antigens. Antigen sources used for testing have included native plant extracts, raw latex, and finished products. When compared with a history of latex-induced symptoms or positive skin tests, the sensitivity of immunoassays testing for latex antigens ranges from 50% to 100% with specificity between 63% and 100%. These broad ranges may reflect the patient population studied and the source of latex antigen as well as the assay employed. A positive immunoassay test to latex in the presence of a highly suggestive latex allergy history is useful and may circumvent the potential concerns associated with prick skin testing in certain patients. Patch testing with standardized T.R.U.E. Test or other sources of antigens can identify antigens used in the manufacturing of latex products that can cause allergic contact dermatitis.
Cross-reactivity has been demonstrated between latex and a number of other antigens such as foods. Banana, avocado, and chestnut have been found to be antigenically similar to latex both immunologically and clinically.
Complications may be similar to those caused by other allergens. Prolonged exposure to aerosolized latex may lead to persistent asthma. Chronic allergic contact dermatitis, especially on the hands, can lead to functional disability.
Avoidance remains the cornerstone of treatment for latex allergy. Prevention and supportive therapy are the most common methods for managing this problem. Patients identified as being allergic to latex may need to have a personal supply of vinyl or latex-free gloves for use when visiting a physician or dentist. “Hypoallergenic gloves” are poorly classified with respect to their ability to induce IgE-mediated reactions; the FDA currently uses this term to designate products that have a reduced capacity to induce contact dermatitis. Nonlatex gloves include nitrile and vinyl ones. A glove made from guayule latex has been approved by the FDA. Autoinjectable epinephrine and medical identification bracelets may be prescribed for latex-allergic patients along with avoidance counseling.
Prophylactic premedication of latex-allergic individuals has been used in some surgical patients at high risk for latex allergy. The rationale for this therapy is derived from the pretreatment protocols developed for iodinated radiocontrast media and anesthetic reactions. Although there has been some success using this regimen, anaphylaxis has occurred despite pretreatment. This approach should not substitute for careful avoidance measures.
Owing to the ubiquitous nature of natural rubber, the prognosis is guarded for patients with severe latex allergy. Chronic exposure to airborne latex particles may lead to chronic asthma. Chronic dermatitis can lead to functional disability.
Mumps-measles-rubella (MMR) vaccine has been shown to be safe in egg-allergic patients (although rare reactions to gelatin or neomycin can occur). Although the amount of ovalbumin in influenza vaccine is variable, content does not appear to predict risk of reaction and several studies suggest that egg allergic children can safely receive influenza vaccine injection as a single full dose. Skin prick testing and graded dosing is no longer recommended for egg-allergic patients who have not reacted to the influenza vaccine. Egg allergic patients should be observed for 30 minutes after receiving influenza vaccine and if there are concerns about administration, they should be referred to an allergist. In addition, the live intranasal influenza vaccine has not been studied in egg-allergic children so its safety is unknown.
4. 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.
Approximately 50% of patients receiving insulin have positive skin tests, but IgE-mediated reactions occur rarely. 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.
6. 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. To rule out paraben sensitivity, skin testing can be done with 1% lidocaine from a multidose vial.
7. Aspirin & Other Nonsteroidal Anti-Inflammatory Drugs
Adverse reactions to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) include urticaria and angioedema; rhinosinusitis, nasal polyps, and asthma (Aspirin-exacerbated respiratory disease AERD); anaphylactoid reactions; and NSAID-related hypersensitivity pneumonitis. After a systemic reaction, a refractory period of 2–7 days occurs. Most aspirin-sensitive patients tolerate sodium salicylate. All NSAIDs inhibiting cyclooxygenase (COX) cross-react with aspirin. 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. Oral challenge can induce severe bronchospasm in AERD patients. Aspirin desensitization can be performed to ameliorate the symptoms of AERD. Desensitization and cross-desensitization to NSAIDs can be achieved in most patients and maintained for a long term. Leukotriene-receptor antagonists or 5-lipoxygenase inhibitors attenuate the reaction to aspirin challenge and may be beneficial adjunct treatment in aspirin-sensitive asthmatic patients. COX-2 inhibitors are tolerated by patients with AERD.
8. 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 hypersensitivity reactions. The FDA issued a boxed warning regarding risk of anaphylaxis and need for patient monitoring with use of omalizumab (see section on Pharmacologic Therapy under Treatment, Chronic Asthma, earlier). Updated information can be found at the FDA’s MedWatch website under Vaccines, Blood, and Biologics.
9. 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. Rechallenge can be accompanied by significant hypotension and given a mortality rate of 0.03%; hypersensitivity to abacavir is an absolute contraindication for subsequent use. Prophylaxis with prednisolone does not appear to prevent hypersensitivity reactions to abacavir. Importantly, genetic susceptibility appears to be conferred by the HLA-B*5701 allele with a positive predictive value of > 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 < 1%.
10. Adverse Reactions to Chemotherapeutic Agents
A number of chemotherapeutic agents, including monoclonal antibodies, have been implicated in hypersensitivity reactions. 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.
Centers for Disease Control and Prevention, National Immunization Program. Available at: http://www.cdc.gov/nip
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Romano A et al: Diagnosis and management of drug hypersensitivity reactions. J Allergy Clin Immunol 2011;127:S67 [PMID: 21354502].
Vultaggio A et al: Immediate adverse reactions to biologicals: from pathogenic mechanisms to prophylactic management. Curr Opin Allergy Clin Immunol 2011;11:262 [PMID: 21460715].
The Guidelines for the Diagnosis and Management of Food Allergy in the United States: Report of the NIAID-Sponsored Expert Panel (henceforth referred to as the Food Allergy Guidelines) defines a food allergy 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 may be lifelong allergies. The highest prevalence of food allergy is found in children with moderate to severe atopic dermatitis, with approximately 35% affected, whereas chronic conditions such as urticaria and asthma are much less likely due solely to food allergy. Of note, food allergy can be caused by non–IgE-mediated mechanisms, in conditions such as food protein–induced enterocolitis or proctocolitis. It can also be caused by mixed IgE- and non–IgE-mediated mechanisms, as in eosinophilic esophagitis and gastroenteritis (Table 38–7).
Table 38–7. Food allergy disorders.
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.
A. Symptoms and Signs
A thorough medical history is crucial in 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. For the non–IgE-mediated and mixed disorders, reactions can be delayed in onset for more than several hours, such as in food protein–induced enterocolitis, to possibly days later with onset of vomiting or an eczema flare after food exposure due to eosinophilic esophagitis or atopic dermatitis, respectively. At times, acute symptoms may occur, but the cause may not be obvious because of hidden food allergens. A symptom diary kept for 7–14 days may be helpful in establishing an association between ingestion of foods and symptoms and also provides a baseline observation for the pattern of symptom expression. It is important to record both the form in which the food was ingested and the foods ingested concurrently.
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. Contact urticaria can occur without systemic symptoms in some children. 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.
B. Laboratory Findings
Typically, fewer than 50% of histories of food allergy will be confirmed 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 test is approximately 50%. Serum food-specific IgE tests have lower specificity and positive predictive values. In contrast, food-specific IgE levels to milk, egg, peanut, and fish proteins have been established with the ImmunoCAP assay correlating with a greater than 95% chance of a clinical reaction, but values have not been established for other foods. A list of nonstandardized and unproven procedures for the diagnosis of food allergy, including the measurement of allergen-specific-IgG to foods, is provided in the Food Allergy Guidelines.
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 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 without controlled challenge is a less desirable but at times more practical approach for suspected food allergy. Elimination diets and food challenges may also be the only tools for evaluation of suspected non–IgE-mediated food reactions.
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 consists of eliminating and avoiding foods that have been documented to cause allergic reactions. This involves educating the patient, parent, and caregivers regarding hidden food allergens, the necessity for reading labels, and the signs and symptoms of food allergy and its appropriate management (emergency action plan; a copy of this plan is provided in the Food Allergy Guidelines). New food labeling laws went into effect in January 2006 requiring simple terms to indicate the presence of the major food allergens listed previously (eg, milk instead of casein). 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 (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 sublingual immunotherapy are currently under investigation as potential future treatments of food allergy. 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 food allergy.
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 their 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 at: (800) 929-4040; www.foodallergy.org; and the Consortium of Food Allergy Research: www.cofargroup.org.
Boyce JA et al: Guidelines for the Diagnosis and Management of Food Allergy in the United States: report of the NIAID-Sponsored Expert Panel. J Allergy Clin Immunol 2010; 126(Suppl 1):1–58 [PMID: 21134576].
Burks AW et al. Oral immunotherapy for treatment of egg allergy in children. N Engl J Med. 2012; 367:233–243 [PMID: 22808958].
Fleischer DM et al. Sublingual immunotherapy for peanut allergy: a randomized, double-blind, placebo-controlled multicenter trial. J Allergy Clin Immunol 2013;131:119–127 [PMID: 23265698].
Kim JS et al: Dietary baked milk accelerates the resolution of cow’s milk allergy in children. J Allergy Clin Immunol 2011;128(1):125–131 [PMID: 21601913].
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 are almost exclusively caused by Hymenoptera and result in approximately 40 deaths each year in the United States. The order 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.
A. Symptoms and Signs
Insect bites or stings can cause local or systemic reactions ranging from mild to fatal responses in susceptible persons. The frequency increases in the summer months and with outdoor exposure. 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. 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. Of note, venom skin test results 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 venom RAST, there is a 15%–20% incidence of both false-positive and false-negative results. Tests for mosquito saliva antigens or other insect allergy are not commercially available.
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.
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 and 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, in which swelling extends beyond two joints or an extremity, may require a short course of oral corticosteroids. Anaphylactic reactions following Hymenoptera stings should be managed essentially the same as anaphylaxis (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 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. Immunotherapy is not indicated for children with only urticarial or local reactions.
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.
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