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6,601 | (e.g., well, not well, or very poorly controlled), especially for asthma management purposes. Because most children with asthma can be well controlled with conven tional management guidelines, children with asthma can also be charac terized according to treatment response and medication requirements as (1) easy to control (well controlled with low levels of controller therapy); (2) difficult to control (not as well controlled with multiple andor high levels of controller therapies); (3) exacerbators (despite being controlled, continue to have severe exacerbations); and (4) refractory asthma (con tinue to have poorly controlled asthma despite multiple and high levels of controller therapies; see Table 185.2). Different airways pathologic processes, causing airways inflammation, AHR, and airways congestion and blockage, are believed to underlie these different types of asthma. PATHOGENESIS Airflow obstruction in asthma is the result of numerous pathologic processes. In the small airways, airflow is regulated by smooth muscle encircling the airway lumen; bronchoconstriction of these bronchiolar muscular bands restricts or blocks airflow. A cellular inflammatory infil trate and exudates distinguished by eosinophils, but also including other inflammatory cell types (neutrophils, monocytes, lymphocytes, mast cells, basophils), can fill and obstruct the airways and induce epithelial damage and desquamation into the airways lumen. T lymphocytes and other immune cells that produce proallergic, proinflammatory cytokines (interleukin IL 4, IL 5, IL 13), and chemokines (eotaxins) mediate this inflammatory process. Hypersensitivity or susceptibility to a variety of provocative exposures or triggers (Table 185.3) can lead to airways inflammation, AHR, edema, basement membrane thickening, subepi thelial collagen deposition, smooth muscle and mucous gland hypertro phy, and mucus hypersecretion, which are all processes that contribute to the clinical manifestations of asthma. Although most children with asthma manifest this proallergic type 2 immunity and inflammation, other pathologic pathways can underlie asthma. CLINICAL MANIFESTATIONS AND DIAGNOSIS Asthma is characterized by repeated episodes of intermittent dry coughing and expiratory wheezing. Older children and adults report Table 185.1 Early Childhood Risk Factors for Persistent Asthma Parental asthma Allergy Atopic dermatitis (eczema) Allergic rhinitis Food allergy Inhalant allergen sensitization Food allergen sensitization Severe lower respiratory tract infection Pneumonia Bronchiolitis requiring hospitalization Wheezing apart from colds Male sex Low birthweight Environmental tobacco smoke exposure Reduced lung function at birth Formula feeding rather than breastfeeding Major risk factors. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1388 Part XIII u Allergic Disorders associated shortness of breath and chest congestion and tightness; younger children may report intermittent, nonfocal chest pain. Respiratory symptoms can be worse at night, associated with sleep, especially during prolonged exacerbations triggered by respiratory infections or inhalant allergens. Daytime symptoms, often linked with physical activities (exercise induced) or play, are reported with great est frequency in children. Other asthma symptoms in children can be subtle and nonspecific, including self imposed limitation of physical activities, general fatigue (possibly resulting from sleep disturbance), and difficulty keeping up with |
6,602 | peers in physical activities. Asking about previous experience with asthma medications (bronchodilators andor corticosteroids) may provide a history of symptomatic improvement with treatment that supports the diagnosis of asthma. Lack of improve ment with bronchodilator and corticosteroid therapy is inconsistent with underlying asthma and should prompt more vigorous consider ation of asthma masquerading conditions. Asthma symptoms can be triggered by numerous common events or exposures: physical exertion and hyperventilation (laughing), cold or dry air, and airways irritants (see Table 185.3). Exposures that induce airways inflammation, such as infections with common respiratory pathogens (rhinovirus, RSV, enterovirus, coronavirus, metapneumo virus, parainfluenza virus, influenza virus, adenovirus, Mycoplasma pneumoniae, Chlamydia pneumoniae), and inhaled allergens in sensi tized children, also increase AHR to dry, cold air and irritant exposures. An environmental history is essential for optimal asthma management. The presence of risk factors, such as a history of other allergic condi tions (allergic rhinitis, allergic conjunctivitis, atopic dermatitis, food allergies), parental asthma, andor symptoms apart from colds, sup ports the diagnosis of asthma. During routine clinic visits, children with asthma typically present without abnormal signs, emphasizing the importance of the medical history in diagnosing asthma. Some may exhibit a dry, persistent cough. The chest findings are often normal. Table 185.2 Asthma Patterns in Childhood, Based on Natural History and Asthma Management TRANSIENT NONATOPIC WHEEZING Common in early preschool years Recurrent coughwheeze, primarily triggered by common respiratory viral infections Usually resolves during the preschool and lower school years, without increased risk for asthma in later life Reduced airflow at birth, suggestive of relatively narrow airways; AHR near birth; improves by school age PERSISTENT ATOPY ASSOCIATED ASTHMA Begins in early preschool years Associated with atopy in early preschool years Clinical (e.g., atopic dermatitis in infancy, allergic rhinitis, food allergy) Biologic (e.g., early inhalant allergen sensitization, increased serum IgE, increased blood eosinophils) Highest risk for persistence into later childhood and adulthood Lung function abnormalities Those with onset before 3 yr of age acquire reduced airflow by school age Those with later onset of symptoms, or with later onset of allergen sensitization, are less likely to experience airflow limitation in childhood ASTHMA WITH DECLINING LUNG FUNCTION Children with asthma with progressive increase in airflow limitation Associated with hyperinflation in childhood, male gender ASTHMA MANAGEMENT TYPES (From national and international asthma management guidelines) Severity Classification Intrinsic disease severity while not taking asthma medications Intermittent Persistent Mild Moderate Severe Control Classification Clinical assessment while asthma being managed and treated Well controlled Not well controlled Very poorly controlled Management Patterns Easy to control: well controlled with low levels of daily controller therapy Difficult to control: inadequately controlled with multiple andor high levels of controller therapies Frequent exacerbators: have severe exacerbations Refractory: continue to have poorly controlled asthma despite multiple and high levels of controller therapies From National Asthma Education and Prevention Program Expert Panel Report 3 (EPR3): Guideline for the Diagnosis and Management of Asthma, NIH Pub No 07 4051, Bethesda, MD, 2007, US Department of Health and Human Services; National Institutes |
6,603 | of Health; National Heart, Lung, and Blood Institute Health; National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program. https:www.nhlbi.nih.govhealth proguidelinescurrentasthma guidelinesfull report. AHR, Airways hyperresponsiveness. Table 185.3 Asthma Triggers COMMON VIRAL INFECTIONS OF THE RESPIRATORY TRACT AEROALLERGENS IN SENSITIZED ASTHMATIC PATIENTS Indoor Allergens Animal dander Dust mites Cockroaches Molds Seasonal Aeroallergens Pollens (trees, grasses, weeds) Seasonal molds AIR POLLUTANTS Environmental tobacco smoke Ozone Nitrogen dioxide Sulfur dioxide Particulate matter Wood or coal burning smoke Mycotoxins Endotoxin Dust STRONG OR NOXIOUS ODORS OR FUMES Perfumes, hairsprays Cleaning agents OCCUPATIONAL EXPOSURES Farm and barn exposures Formaldehydes, cedar, paint fumes Rhinitis Sinusitis Gastroesophageal reflux DRUGS Aspirin and other nonsteroidal antiinflammatory drugs Blocking agents OTHER Cold dry air Exercise Crying, laughter, hyperventilation Comorbid conditions Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 185 u Childhood Asthma 1389 Deeper breaths with forced exhalation can sometimes elicit otherwise undetectable wheezing. In clinic, quick resolution (within 10 minutes) or convincing improvement in symptoms and signs of asthma with administration of an inhaled short acting agonist (SABA; e.g., alb uterol) is supportive of the diagnosis of asthma. Asthma exacerbations can be classified by their severity based on symp toms, signs, and functional impairment (Table 185.4). Coughing and shortness of breath are common. Expiratory wheezing and a prolonged exhalation phase can usually be appreciated by auscultation. Decreased breath sounds in some of the lung fields, commonly the right lower pos terior lung field, are consistent with regional hypoventilation caused by airways obstruction. Rhonchi and crackles (or rales) can sometimes be heard, resulting from excess mucus production and inflammatory exudate in the airways. The combination of segmental crackles and poor breath sounds can indicate lung segmental atelectasis that is difficult to distin guish from bronchial pneumonia and can complicate acute asthma man agement. In severe exacerbations the greater extent of airways obstruction causes labored breathing and respiratory distress, which manifests as inspi ratory and expiratory wheezing, increased prolongation of exhalation, poor air entry, suprasternal and intercostal retractions, nasal flaring, and accessory respiratory muscle use. In extremis, airflow may be so limited that wheezing cannot be heard (silent chest). DIFFERENTIAL DIAGNOSIS Many childhood respiratory conditions can present with symptoms and signs like those of asthma (Table 185.5). Along with asthma, other common causes of chronic, intermittent coughing include gastroesophageal reflux (GER) and rhinosinusitis. Both GER and chronic sinusitis can be challeng ing to diagnose in children. Often, GER is clinically silent in children, and children with chronic sinusitis do not report sinusitis specific symptoms, such as localized sinus pressure and tenderness. In addition, both GER and rhinosinusitis are often comorbid with childhood asthma and, if not spe cifically treated, may make asthma difficult to manage. In early life, consideration of congenital and anatomic conditions is essential. Chronic coughing and wheezing can indicate recurrent aspi ration, tracheobronchomalacia (congenital anatomic abnormality of airways), |
6,604 | vascular ringsling, foreign body aspiration, cystic fibrosis, or bronchopulmonary dysplasia. In older children and adolescents, vocal cord dysfunction (VCD) can manifest as intermittent daytime wheezing, most often in the setting of exercise (Table 185.6). The vocal cords involuntarily close inappropriately during inspiration and sometimes exhalation, produc ing shortness of breath, coughing, throat tightness, and often audible laryngeal wheezing andor stridor. In most cases of VCD, spiromet ric lung function testing reveals truncated and inconsistent inspira tory and expiratory flow volume loops, a pattern that differs from the reproducible pattern of airflow limitation in asthma that improves with bronchodilators. VCD can coexist with asthma. Hypercarbia and severe hypoxia are uncommon in uncomplicated VCD. Flexible rhinolaryn goscopy in the patient with symptomatic VCD can reveal paradoxical vocal cord movements with anatomically normal vocal cords. Before the diagnosis, patients with VCD are often treated unsuccessfully Table 185.4 Formal Evaluation of Asthma Exacerbation Severity in the Urgent or Emergency Care Setting MILD MODERATE SEVERE SUBSET: RESPIRATORY ARREST IMMINENT SYMPTOMS Breathlessness While walking While at rest (infant: softer, shorter cry, difficulty feeding) While at rest (infant: stops feeding) Extreme dyspnea Anxiety Can lie down Prefers sitting Sits upright Upright, leaning forward Talks in Sentences Phrases Words Unable to talk Alertness May be agitated Usually agitated Usually agitated Drowsy or confused SIGNS Respiratory rate Increased Increased Often 30 breathsmin Use of accessory muscles; suprasternal retractions Usually not Commonly Usually Paradoxical thoracoabdominal movement Wheeze Moderate; often only end expiratory Loud; throughout exhalation Usually loud; throughout inhalation and exhalation Absence of wheeze Pulse rate (beatsmin) 100 100 120 120 Bradycardia Pulsus paradoxus Absent 10 mm Hg May be present 10 25 mm Hg Often present 25 mm Hg (adult) 20 40 mm Hg (child) Absence suggests respiratory muscle fatigue FUNCTIONAL ASSESSMENT Peak expiratory flow (value predicted or personal best) 70 Approx. 4069 or response lasts 2 hr 40 25 Pao2 (breathing air) Normal (test not usually necessary) 60 mm Hg (test not usually necessary) 60 mm Hg; possible cyanosis andor Pco2 42 mm Hg (test not usually necessary) 42 mm Hg (test not usually necessary) 42 mm Hg; possible respiratory failure Sao2 (breathing air) at sea level 95 (test not usually necessary) 9095 (test not usually necessary) 90 Hypoxia despite oxygen therapy Hypercapnia (hypoventilation) develops more readily in young children than in adults and adolescents. Notes: The presence of several parameters, but not necessarily all, indicates the general classification of the exacerbation. Many of these parameters have not been systematically studied, especially as they correlate with each other; thus they serve only as general guides. The emotional impact of asthma symptoms on the patient and family is variable but must be recognized and addressed and can affect approaches to treatment and follow up. Normal breathing rates in awake children by age: 2 mo, 60 breathsmin; 2 12 mo, 50 breathsmin; 1 5 yr, 40 breathsmin; 6 8 yr, 30 breathsmin. Normal pulse rates in children by age: 2 12 mo, 160 beatsmin; 1 2 yr, 120 beatsmin; 2 |
6,605 | 8 yr, 110 beatsmin. Peak expiratory flow testing may not be needed in very severe attacks. Adapted from National Asthma Education and Prevention Program Expert Panel Report 3 (EPR3). Guideline for the Diagnosis and Management of Asthma, NIH Pub No 07 4051, Bethesda, MD: U.S. Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program: 2007. https:www.nhlbi.nih.govhealth proguidelinescurrentasthma guidelinesfull report. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1390 Part XIII u Allergic Disorders with multiple different classes of asthma medications. This condition can be well managed with specialized speech therapy training in the relaxation and control of vocal cord movement. Furthermore, treat ment of underlying causes of vocal cord irritability (e.g., high GER aspiration, allergic rhinitis, rhinosinusitis, asthma) can improve VCD. During acute VCD exacerbations, relaxation breathing techniques in conjunction with inhalation of heliox (a mixture of 70 helium and 30 oxygen) can relieve vocal cord spasm and VCD symptoms. In some locales, hypersensitivity pneumonitis (farming communities, homes of bird owners), pulmonary parasitic infestations (rural areas of devel oping countries), or tuberculosis may be causes of chronic coughing and or wheezing. Rare mimics of asthma in childhood are noted in Table 185.5. Table 185.5 Differential Diagnosis of Childhood Asthma UPPER RESPIRATORY TRACT CONDITIONS Allergic rhinitis Chronic rhinitis Sinusitis Adenoidal or tonsillar hypertrophy Nasal foreign body LARGECENTRAL AIRWAYS CONDITIONS Laryngotracheobronchomalacia Laryngotracheobronchitis (e.g., pertussis) Laryngeal web, cyst, or stenosis Exercise induced laryngeal obstruction Vocal cord dysfunction Vocal cord paralysis Tracheoesophageal fistula Vascular ring, sling, or external mass compressing on the airway (e.g., tumor) Endobronchial or mediastinal tumor Foreign body aspiration Chronic bronchitis from environmental tobacco smoke exposure Repaired tracheoesophageal fistula Toxic inhalations PERIPHERAL AIRWAYS CONDITIONS Bronchopulmonary dysplasia (chronic lung disease of preterm infants) Viral bronchiolitis Gastroesophageal reflux Causes of bronchiectasis Cystic fibrosis Immunodeficiency Allergic bronchopulmonary mycoses (e.g., aspergillosis) Chronic aspiration Primary ciliary dyskinesia Bronchiolitis obliterans Interstitial lung diseases Hypersensitivity pneumonitis (acute or chronic) Loeffler syndrome Eosinophilic granulomatosis with angiitis Eosinophilic pneumonia Tropical pulmonary eosinophilia Pulmonary hemosiderosis Tuberculosis Pneumonia Pulmonary edema (e.g., congestive heart failure) Pulmonary vascular congestions (congenital or acquired heart disease) Vasculitis Sarcoidosis Visceral larva migrans Medications associated with chronic cough Acetylcholinesterase inhibitors Adrenergic antagonists Angiotensin converting enzyme inhibitors Daptomycin More common asthma masqueraders. Table 185.6 Features Distinguishing Paradoxical Vocal Cord Motion Disorder from Asthma FEATURE PVCM ASTHMA Incidence Less common More common Age and sex Young, female Any Triggers Usually exercise or emotional stress Many triggers History of allergy Usually absent May be present Family history Usually absent May be present Sensation of tightness Throat Chest Inspiratory stridor More common, heard loudly over larynx Rare Sputum production Rare Common Nocturnal awakening with symptoms Rare Common Response to bronchodilators and steroids No response Good response Hypoxemia Rare Common Eosinophilia Rare Common in allergic asthma Chest radiograph Usually normal May show hyperinflation and |
6,606 | peribronchial thickening Residual volume and total lung capacity Normal May be increased Flow volume loop Flattening of inspiratory loop Obstructive pattern Bronchial provocation test May be positive Usually positive Laryngoscopy Inspiratory adduction of the anterior two thirds of vocal folds with posterior chink Usually normal PVCM, Paradoxical vocal cord motion. Modified from Ibrahim WH, Gheriani HA, Almohamed AA, Raza T. Paradoxical vocal cord motion disorder: Past present and future. Post Grad Med J. 2007;83:164172. Table 2, p 168. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 185 u Childhood Asthma 1391 Chronic pulmonary diseases often produce clubbing (e.g., in cystic fibro sis), but clubbing is a very unusual finding in childhood asthma. LABORATORY FINDINGS Laboratory tests such as blood eosinophil counts and allergen specific IgE testing may be useful for ascertaining allergy, but are not diagnostic for asthma itself. Lung function tests can help to confirm the diagnosis of asthma and to determine disease severity. Pulmonary Function Testing Forced expiratory airflow measures are helpful in diagnosing and monitoring asthma and in assessing efficacy of therapy. Lung function testing is particularly helpful in children with asthma who are poor perceivers of airflow obstruction, or when physical signs of asthma do not occur until airflow obstruction is severe. Many asthma guidelines promote spirometric measures of airflow and lung volumes during forced expiratory maneuvers as standard for asthma assessment. Spirometry is a helpful objective measure of airflow limitation (Fig. 185.2). It is an essential assessment tool in children who are at risk for severe asthma exacerbations and those who have poor perception of asthma symptoms. Valid spirometric measures depend on a patients abil ity to properly perform a full, forceful, and prolonged expiratory maneuver, usually feasible in children 4 5 years old (with some younger exceptions). In asthma, airways blockage results in reduced airflow with forced exha lation (see Fig. 185.2). Because asthmatic patients typically have hyperin flated lungs, forced expiratory volume in 1 second (FEV1) can be simply adjusted for full expiratory lung volume (the forced vital capacity FVC) with an FEV1FVC ratio, which is generally an FEV1FVC ratio below the lower limit of normal (Table 185.7). Normative values for these measures of lung function have been determined for children by height, gender, and age. Abnormally low FEV1 as a percentage of predicted norms is one of six criteria used to determine asthma severity and control in asthma manage ment guidelines sponsored by the U.S. National Institutes of Health (NIH) and the Global Initiative for Asthma (GINA). Such measures of airflow alone are not diagnostic of asthma, because numerous other conditions can cause airflow limitation. In addi tion, approximately 50 of children with mild to moderate persistent asthma will have normal spirometric values when well. Bronchodilator Table 185.7 Lung Function Abnormalities in Asthma Spirometry (in clinic): Airflow limitation Low FEV1 (relative to percentage of predicted |
6,607 | norms), although many children with asthma have normal FEV1 FEV1FVC ratio below the lower limit of normal for age Bronchodilator response (to inhaled agonist) assesses reversibility of airflow limitation Reversibility is determined by an increase in either FEV1 912 or predicted FEV1 10 after inhalation of a short acting agonist (SABA) Exercise challenge Worsening in FEV1 15 Daily peak expiratory flow (PEF) or FEV1 monitoring: day to day andor am to pm variation 20 PEF variability is insensitive, while being highly specific for asthma. Of note, 50 of children with mild to moderate asthma will have a normal FEV1 and will not have a significant bronchodilator response. Main criteria consistent with asthma. FEV1, Forced expiratory volume in 1 sec; FVC, forced vital capacity; ICS, inhaled corticosteroid; ppb, parts per billion. 6 2 ?2 ?4 ?6 4 0 100 50 E D C B A Peak flow FEV1 FVC F lo w ( L s ec ) 2 1 1 2 3 4 Time (sec) 5 6 7 4 3 V ol um e (L ) Expiratory flow volume loop Subject 1 Subject 2 Inspiratory flow volume loop A B 0 Vital capacity () Subject 1: A nonasthmatic child FEV1 ? 3.4 (100 of predicted) FVC ? 3.8 (100 of predicted) FEV1FVC ? 0.86 Subject 2: An asthmatic child FEV1 ? 2.1 (62 of predicted) FVC ? 3.7 (97 of predicted) FEV1FVC ? 0.57 Fig. 185.2 Spirometry. A, Spirometric flow volume loops. Loop A is an expiratory flow volume loop of a nonasthmatic person without airflow limi tation. Loops B through E are expiratory flow volume loops in asthmatic patients with increasing degrees of airflow limitation (B is mild; E is severe). Note the scooped or concave appearance of the asthmatic expiratory flow volume loops; with increasing obstruction, there is greater scooping. B, Spirometric volume time curves. Subject 1 is a nonasthmatic person; subject 2 is an asthmatic patient. Note how the FEV1 and FVC lung volumes are obtained. The FEV1 is the volume of air exhaled in the first second of a forced expiratory effort. The FVC is the total volume of air exhaled during a forced expiratory effort, or forced vital capacity. Note that subject 2s FEV1 and FEV1:FVC ratio are smaller than subject 1s ratio, demonstrating airflow limitation. Also, subject 2s FVC is very close to what is expected. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1392 Part XIII u Allergic Disorders response to an inhaled agonist (e.g., albuterol) is greater in asthmatic patients than nonasthmatic persons; an improvement in FEV1 12 is consistent with asthma. However, many children will not demonstrate an improvement with bronchodilator when well. Bronchoprovocation challenges can be helpful in diagnosing asthma. Asthmatic airways are hyperresponsive and therefore more sensitive to inhaled methacholine, mannitol, and cold or dry air. The degree of AHR to these exposures cor |
6,608 | relates to some extent with asthma severity and airways inflammation. Although bronchoprovocation challenges are carefully dosed and moni tored in an investigational setting, their use is rarely practical in general practice. Exercise challenges (aerobic exertion or running for 6 8 min utes) can help to identify children with exercise induced bronchospasm (EIB). Although the airflow response of nonasthmatic persons to exer cise is to increase functional lung volumes and improve FEV1 slightly (510), exercise often provokes airflow obstruction in persons with inadequately treated asthma. Accordingly, in asthmatic patients, FEV1 typically decreases during or after exercise by 15 (see Table 185.7). The onset of EIB usually begins within 5 minutes, reaching a peak at 15 minutes after vigorous exercise, and often spontaneously resolves within 30 60 minutes. Studies of exercise challenges in school age children typically identify an additional 510 with EIB and previously unrec ognized asthma. There are two caveats regarding exercise challenges: (1) treadmill challenges in the clinic are not completely reliable and can miss exertional asthma that can be demonstrated on the playing field and (2) exercise challenges can induce severe exacerbations in at risk patients. Careful patient selection for both bronchoprovocation and exercise chal lenges and preparedness for severe asthma exacerbations are required. Peak expiratory flow (PEF) monitoring devices provide simple and inexpensive home use tools to measure airflow and can be help ful in some circumstances. Like spirometry in clinics, poor perceivers of asthma may benefit by monitoring PEFs at home to assess their airflow as an indicator of asthma control or problems. PEF devices vary in the ability to detect airflow obstruction; they are less sensitive and reliable than spirometry to detect airflow obstruction, such that, in some patients, PEF values decline only when airflow obstruction is severe. Therefore PEF monitoring should be started by measuring morning and evening PEFs (best of three attempts) for several weeks for patients to practice the technique, to determine diurnal variation and a personal best, and to correlate PEF values with symptoms (and ideally spirometry). Diurnal variation in PEF 20 is consistent with asthma (see Table 185.7). If PEF monitoring is employed, morn ing measurements are preferable when peak flows are typically lower. Exhaled Nitric Oxide Fractional exhaled nitric oxide (FeNO) is a noninvasive measure of allergiceosinophilic airways inflammation measured in exhaled breath (Table 185.8). FeNO can be used in children as young as 5 years to help distinguish asthma from other airways diseases that are mediated by nonallergicnoneosinophilic inflammation, such as GER, VCD, and cys tic fibrosis. FeNO can substantiate the diagnosis of asthma in untreated patients, complement the assessment of asthma control, predict response to ICS and biologic therapy, assess adherence with ICS therapy, predict loss of control with ICS tapering, and predict future asthma exacerba tions. However, an elevated FeNO level alone is not diagnostic of asthma and can be seen in children with allergic rhinitis without asthma. Additional Tests to Consider Other tests, such as allergy testing to assess sensitization to inhalant allergens (skin testing |
6,609 | or allergen specific IgE levels) and peripheral blood total eosinophil counts, are markers of allergic type 2 immu nity and inflammation and can help with the management and progno sis of asthma. In a comprehensive U.S. study of 512 year old asthmatic children, the Childhood Asthma Management Program (CAMP), 88 of patients had inhalant allergen sensitization according to results of allergy skin prick testing. Radiology The findings of chest radiographs (posteroanterior and lateral views) in children with asthma often appear to be normal, aside from subtle and nonspecific findings of hyperinflation (e.g., flattening of the diaphragms) and peribronchial thickening (Fig. 185.3). Chest radiographs can help identify abnormalities that are hallmarks of asthma mimics (retained foreign body, vascular rings, aspiration pneumonitis, hyperlucent lung fields in bronchiolitis obliterans) and complications during asthma exacerbations (atelectasis, pneumomediastinum, pneumothorax). Some lung abnormalities can be better appreciated with high resolution, thin section chest CT scans. Bronchiectasis, which is sometimes difficult to appreciate on chest radiograph but is clearly seen on CT scan, implicates an asthma mimic such as cystic fibrosis, allergic bronchopulmonary mycoses (aspergillosis), ciliary dyskinesias, or immune deficiencies. TREATMENT National and international guidelines have been published to help promote evidence based asthma management. These include the NIH sponsored National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 4 (EPR4), Guidelines for the Diagnosis and Management of Asthma, and The Global Strategy for Asthma Man agement and Prevention (GINA), 2022. NAEPP and GINA guidelines are generally consistent in their management recommendations for children with asthma, with some key differences that are noted in this chapter. The key components to optimal asthma management are speci fied (Fig. 185.4). Management of asthma should have the following https:www.nhlbi.nih.govhealthtopicsasthmamanagementguidelines2020updates https:ginasthma.orgginareports Table 185.8 Interpretations of FeNO Test Results for Asthma Diagnosis in Nonsmoking Individuals Not Taking Corticosteroids FeNO LEVEL 25 PPB (20 IN CHILDREN AGE 5 12 YR) 25 50 PPB (20 35 IN CHILDREN AGE 5 12 YR) 50 PPB (35 IN CHILDREN AGE 5 12 YR) Recent or current corticosteroid use Alternative diagnoses Phenotype less likely to benefit from ICS Noneosinophilic asthma COPD Bronchiectasis CF Vocal cord dysfunction Rhinosinusitis Smoking Obesity Evaluate in clinical context Consider other diagnoses Consider other factors influencing result Eosinophilic asthma less likely Eosinophilic airways inflammation likely Phenotype more likely to respond to ICS Allergic asthma Eosinophilic bronchitis CF, Cystic fibrosis; COPD, chronic obstructive pulmonary disease; FeNO, fractional exhaled nitric oxide; ICS, inhaled corticosteroid; ppb, parts per billion. From NAEPPCC Expert Panel Working Group: 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020;146(6):12171269. Table II. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 185 u Childhood Asthma 1393 components: (1) assessment and monitoring of disease activity, (2) education to enhance patient and family knowledge and skills for |
6,610 | self management, (3) identification and management of precipitating fac tors and comorbid conditions that worsen asthma, and (4) appropriate selection of medications to address the patients needs. The long term goals of asthma management are to attain and maintain asthma con trol, to reduce risk of severe exacerbations, and to minimize impair ment of daily activities. Component 1: Regular Assessment and Monitoring Regular assessment and monitoring are based on the concepts of asthma severity, asthma control, and responsiveness to therapy. Asthma severity is the intrinsic intensity of disease, and assess ment is generally most accurate in patients not receiving controller therapy. Therefore assessing asthma severity directs the initial level of therapy. The two general categories are intermittent asthma and persistent asthma, the latter being further subdivided into mild, moderate, and severe. In contrast, asthma control is dynamic and refers to the day to day variability of an asthmatic patient. In chil dren receiving controller therapy, assessment of asthma control is important in adjusting therapy and is categorized into three lev els: well controlled, not well controlled, and very poorly controlled. Responsiveness to therapy is the ease or difficulty with which asthma control is attained by treatment. Fig. 185.3 Frontal (A) and lateral (B) radiographs of a 4 year old with asthma show pulmonary hyperinflation, flattening of the diaphragms, and minimal peribronchial thickening. No asthmatic complication is apparent. BA Fig. 185.4 The key elements to optimal asthma management. SABA, Short acting agonist. Recurrentchronic cough, wheeze, chest tightness andor shortness of breath Asthma Diagnosis Symptoms Exacerbations Risk factors Triggers Lung function Differential diagnosis Management Assess severity Monitor control Med adverse effects Key elements Environmental controls Comorbidities Longterm controllers Quick relievers Assessment Management Highrisk features Home asthma action plan Assessment and monitoring Education Control environmental factors and comorbid conditions Medications Exacerbations Optimal goal: Well controlled asthma Prevent chronic symptoms Prevent sleep disturbance Infrequent SABA need Maintain (near) normal lung function Maintain normal activity Prevent exacerbations Reduce exacerbation severityduration Prevent reduced lung growth No (minimal) adverse effects of therapy Reduce impairment Reduce risk Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1394 Part XIII u Allergic Disorders Classification of asthma severity and control is based on the domains of impairment and risk. These domains do not necessarily correlate with each other and may respond differently to treatment. Childhood asthma is often characterized by minimal day to day impairment, with the potential for frequent, severe exacerbations most often triggered by viral infections. The NIH and GINA guide lines have distinct criteria for three childhood age groups, 0 4 years (GINA 0 5 years), 5 11 years (GINA 6 11 years), and 12 years, for the evaluation of both severity (Table 185.9) and control (Table 185.10). The level of asthma severity or control is based on the most severe impairment or risk category. In assessing asthma severity, impairment consists of |
6,611 | an assessment of the patients recent symp tom frequency (daytime and nighttime, with subtle differences in numeric cutoffs between the three age groups), SABA use for quick relief, ability to engage in normal or desired activities, and airflow compromise evaluated by spirometry in children 5 years. Risk refers to the likelihood of developing severe asthma exacerbations. Of note, even in the absence of frequent symptoms, persistent asthma can be diagnosed and long term controller therapy initiated. For children 5 years, two exacerbations requiring oral corticosteroids (OCSs) in 1 year, and for infants and preschool age children who have risk fac tors for asthma (see earlier) 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 corticoste roids, qualifies them as having persistent asthma. Asthma management can be optimized through regular clinic visits every 2 6 weeks until good asthma control is achieved. For children on controller medication therapy, management is tailored to the childs level of control. The NIH guidelines provide tables for evaluating asthma control for the three age groups (see Table 185.10). In evaluation of asthma control, as in severity assessment, impairment includes an assessment of the patients symptom fre quency (daytime and nighttime), SABA use for quick relief, ability to engage in normal or desired activities, and for older children, airflow measurements. Validated asthma control questionnaires such as the Asthma Control Test (ACT, for adults and children 12 years), the Childhood ACT (C ACT, for children 4 11 years), and the Test for Respiratory and Asthma Control in Kids (TRACK, for children 4 years) can also be used to assess level of control. An ACT score of 20 indicates a child with well controlled asthma, a value of 16 19 indicates not well controlled asthma, and 15 indi cates very poorly controlled asthma. For the C ACT, a score 20 indicates well controlled, 13 19 indicates not well controlled, and 12 indicates very poorly controlled. For the TRACK, a score of less than 80 points suggests that a childs breathing problems might not be controlled. Assessment of risk, in addition to considering severity and frequency of exacerbations requiring systemic corticosteroids, includes tracking the lung growth of older children to identify those with reduced and or progressive loss of lung function, and monitoring adverse effects of Table 185.9 Assessing Asthma Severity CLASSIFICATION OF ASTHMA SEVERITY INTERMITTENT PERSISTENT MILD MODERATE SEVERE COMPONENTS OF SEVERITY Impairment Daytime symptoms 2 dayswk 2 dayswk but not daily Daily Throughout the day Nighttime awakenings Age 0 4 yr 0 1 2mo 3 4mo 1wk Age 5 yr 2mo 3 4mo 1wk but not nightly Often 7wk Short acting 2 agonist use for symptoms (not for EIB prevention) 2 dayswk 2 dayswk but not daily, and not more than 1 on any day Daily Several times per day Interference with normal activity None Minor limitation Some limitation Extreme limitation Lung function FEV1 predicted, age |
6,612 | 5 yr Normal FEV1 between exacerbations 80 predicted 80 predicted 6080 predicted 60 predicted FEV1FVC ratio: Age 5 11 yr 85 80 7580 75 Age 12 yr Normal Normal Reduced 5 Reduced 5 Risk Exacerbations requiring systemic corticosteroids Age 0 4 yr 0 1yr (see notes) 2 exacerbations in 6 mo requiring systemic CS or 4 wheezing episodesyr lasting 1 day and risk factors for persistent asthma Age 5 yr 0 1yr (see notes) 2yr (see notes) 2yr (see notes) 2yr (see notes) Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time for patients in any severity category. Relative annual risk of exacerbations may be related to FEV1. Notes: Level of severity is determined by both impairment and risk. Assess impairment domain by patientscaregivers recall of previous 2 4 wk. Symptom assessment for longer periods should reflect a global assessment, such as inquiring whether a patients asthma is better or worse since the last visit. Assign severity to the most severe category in which any feature occurs. At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma severity. For treatment purposes, patients who had 2 exacerbations requiring oral systemic corticosteroids in the past 6 mo, or 4 wheezing episodes in the past year, and who have risk factors for persistent asthma, may be considered the same as patients who have persistent asthma, even in the absence of impairment levels consistent with persistent asthma. Normal FEV1FVC: 8 19 yr, 85; 20 39 yr, 80. FEV1, Forced expiratory volume in 1 sec; FVC, forced vital capacity; CS, corticosteroid; EIB, exercise induced bronchospasm. Adapted from the National Asthma Education and Prevention Program Expert Panel Report 3 (EPR3). Guidelines for the Diagnosis and Management of AsthmaSummary Report 2007. J Allergy Clin Immunol. 2007;120(Suppl):S94S138. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 185 u Childhood Asthma 1395 Table 185.10 Assessing Asthma Control and Adjusting Therapy in Children CLASSIFICATION OF ASTHMA CONTROL WELL CONTROLLED NOT WELL CONTROLLED VERY POORLY CONTROLLED COMPONENTS OF CONTROL Impairment Symptoms 2 dayswk but not more than once on each day 2 dayswk or multiple times on 2 dayswk Throughout the day Nighttime awakenings: Age 0 4 yr 1mo 1mo 1wk Age 5 11 yr 1mo 2mo 2wk Age 12 yr 2mo 1 3wk 4wk Short acting 2 agonist use for symptoms (not for EIB pretreatment) 2 dayswk 2 dayswk Several times per day Interference with normal activity None Some limitation Extremely limited Lung function: Age 5 11 yr: FEV1 ( predicted or peak flow) 80 predicted or personal best 6080 predicted or personal best 60 predicted or personal best FEV1FVC: 80 7580 75 Age 12 yr: FEV1 ( predicted or peak flow) 80 predicted or personal best 6080 predicted or personal best 60 predicted or personal best Validated questionnaires: Age 12 yr: ATAQ |
6,613 | 0 1 2 3 4 ACQ 0.75 1.5 NA ACT 20 16 19 15 Risk Exacerbations requiring systemic corticosteroids: Age 0 4 yr 0 1yr 2 3yr 3yr Age 5 yr 0 1yr 2yr (see notes) Consider severity and interval since last exacerbation. Treatment related adverse effects Medication side effects can vary in intensity from none to very troublesome and worrisome; the level of intensity does not correlate to specific levels of control but should be considered in the overall assessment of risk Reduction in lung growth or progressive loss of lung function Evaluation requires long term follow up care RECOMMENDED ACTION FOR TREATMENT Maintain current step Regular follow up every 1 6 mo to maintain control Consider step down if well controlled for at least 3 mo Step up (1 step) and reevaluate in 2 6 wk If no clear benefit in 4 6 wk, consider alternative diagnoses or adjusting therapy For side effects, consider alterna tive options Consider short course of oral corticosteroids Step up (1 2 steps) and reevaluate in 2 wk If no clear benefit in 4 6 wk, consider alternative diagnoses or adjusting therapy For side effects, consider alternative options Notes: The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs. The level of control is based on the most severe impairment or risk category. Assess impairment domain by caregivers recall of previous 2 4 wk. Symptom assessment for longer periods should reflect a global assessment, such as inquiring whether the patients asthma is better or worse since the last visit. At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma control. In general, more frequent and intense exacerbations (e.g., requiring urgent, unscheduled care, hospitalization, or intensive care unit admission) indicate poorer disease control. For treatment purposes, patients who had 2 exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as patients who have not well controlled asthma, even in the absence of impairment levels consistent with not well controlled asthma. Validated questionnaires for the impairment domain (the questionnaires do not assess lung function or the risk domain) and definition of minimal important difference (MID) for each: ATAQ, Asthma Therapy Assessment Questionnaire; MID 1.0. ACQ, Asthma Control Questionnaire; MID 0.5. ACT, Asthma Control Test; MID not determined. ACQ values of 0.76 1.40 are indeterminate regarding well controlled asthma. Before step up therapy: (1) review adherence to medications, inhaler technique, and environmental control and (2) if alternative treatment option was used in a step, discontinue it and use preferred treatment for that step. FEV1, Forced expiratory volume in 1 sec; FVC, forced vital capacity; EIB, exercise induced bronchospasm; NA, not available. Adapted from the National Asthma Education and Prevention Program Expert Panel Report 3 (EPR 3). Guidelines for the Diagnosis and Management of AsthmaSummary Report 2007. J Allergy Clin Immunol. 2007;120(Suppl):S94S138. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on |
6,614 | April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1396 Part XIII u Allergic Disorders medications. The degree of impairment and presence of risk are used to determine the patients level of asthma control as well controlled, not well controlled, or very poorly controlled. Children with well controlled asthma have daytime symptoms 2 daysweek and need a rescue bron chodilator 2 daysweek, an FEV1 of 80 of predicted (and FEV1 FVC ratio 80 for children 5 11 years), no interference with normal activity, and 2 exacerbations in the past year and an ACT score of 20. The impairment criteria vary slightly depending on age group. Children whose status does not meet all the criteria of well controlled asthma are determined to have either not well controlled or very poorly controlled asthma, which is determined by the single criterion with the poorest rating. Two to four asthma checkups per year are recommended for reas sessing and maintaining good asthma control. Lung function test ing (spirometry) is recommended at least annually and more often if asthma is poorly perceived, is inadequately controlled, andor lung function is abnormally low. Component 2: Patient Education Asthma education that focuses on home management and medica tion adherence is critical for optimal clinical care of children with asthma (Table 185.11). Asthma education should consider socio cultural and ethnic factors and provide an open forum for concerns about asthma and its treatment. Families should be active participants in the development of treatment goals and selection of medications. Self management skills should be reevaluated regularly (e.g., inhaler medication technique). During initial patient visits, a basic understanding of the patho genesis of asthma (chronic inflammation and AHR underlying a clinically intermittent presentation) can help children with asthma and their parents understand the importance of recommendations aimed at reducing airways inflammation to achieve and maintain good asthma control. It is helpful to specify the expectations of good asthma control resulting from optimal asthma management (see Fig. 184.4). Addressing concerns about potential adverse effects of asthma pharmacotherapeutic agents, especially their risks relative to their benefits, is essential in achieving long term adherence with asthma pharmacotherapy and environmental control measures. All children with asthma should benefit from a written Asthma Action Plan (Fig. 185.5). This plan has two main components: (1) a daily rou tine management plan describing regular asthma medication use and other measures to keep asthma under good control and (2) an action plan to manage worsening asthma, describing indicators of impend ing exacerbations, identifying what medications to take, and specifying when and how to contact the regular physician andor obtain urgent emergency medical care. Regular follow up visits are recommended to help to maintain optimal asthma control. Follow up visits provide the opportunity to reassess asthma medication perceptions and delivery techniques. The Asthma Action Plan can be revised as needed. Adherence Asthma is a chronic condition that is usually best managed with daily controller medication. However, symptoms wax and wane |
6,615 | and exac erbations may be infrequent. A natural tendency is to reduce or dis continue daily controller therapies once asthma symptoms improve. As such, adherence to a daily controller regimen is frequently subop timal; ICSs are underused 60 of the time. In one study, children with asthma who required an OCS course for an asthma exacerbation had used their daily controller ICS 15 of the time. Misconceptions about controller medication time to onset, efficacy, and safety often underlie poor adherence and can be addressed by asking about such concerns at each visit. Component 3: Control of Factors Contributing to Poor Asthma Control Controllable factors that can worsen asthma can be generally grouped as (1) environmental exposures and (2) comorbid conditions (Table 185.12). Eliminating and Reducing Problematic Environmental Exposures Steps should be taken to investigate and minimize exposures in asth matic patients. These exposures include allergens as well as irritants (e.g., smoke, pollutants, and other chemicals such as perfumes), in the patients home or school. However, patients often cannot identify poten tial triggers. Allergy testing should be considered for all patients with persistent asthma to identify allergens that may contribute to airway inflammation, asthma symptoms, and exacerbations. For asthmatic patients who are allergic to allergens in their homes andor schools or daycare centers, reducing or eliminating these indoor allergen expo sures can reduce asthma symptoms, medication requirements, AHR, severe exacerbations, and disease persistence. Common home, school, and daycare allergen exposures include furred or feathered animals as pets (cats, dogs, rodents, birds) or as pests (mice, rats, cockroaches), and occult indoor allergens such as dust mites and molds. Allergen mitigation strategies can be used in patients with allergy of all ages and asthma severities, but these strategies should be tailored to the individual. Multicomponent interventions are recommended to control indoor allergens, because single component interventions are often not effective. Examples of single component interventions for dust mite allergy include (1) encasing bedding and pillows in allergen impermeable covers, (2) washing bedding weekly in hot water (130F), (3) removing wall to wall carpeting and upholstered furni ture, or (4) reducing and maintaining indoor humidity 50. In con trast, a multicomponent strategy for dust mite allergy might include all of these measures. Integrated pest management strategies are also recommended for patients exposed to cockroaches, mice, or rats in the home who have sensitization to these allergens. Integrated pest man agement can also be used with other interventions to reduce exposures to pest related allergens. Families should be educated that it can take 6 months for the levels of these indoor allergens to drop significantly and for asthma control to improve after intervention. Allergen miti gation strategies are not recommended for patients with no allergy to indoor allergens. Tobacco, wood and coal smoke, dusts, strong odors, and noxious air pollutants (e.g., nitrogen dioxide from inadequately vented gas stoves and furnaces) can also aggravate asthma. These airway irritants should be eliminated from or reduced in the homes, schoolsdaycare centers, and automobilesschool transportation used by children with |
6,616 | asthma. Care providers can be strong influencers of smoking cessation by parents, caregivers, and adolescent patients (see also Chapters 157.2 and 759.1). Secondhand marijuana smoke contains many of the same chemicals and Table 185.11 Key Elements of Productive Clinic Visits for Asthma Standardize assessment of asthma control (e.g., Asthma Control Test, exacerbations in past 12 mo) Specify goals of asthma management Explain basic facts about asthma Contrast normal vs asthmatic airways Link airways inflammation, twitchiness, and bronchoconstriction Long term control and quick relief medications Address concerns about potential adverse effects of asthma pharmacotherapy Teach, demonstrate, and have patient show proper technique Inhaled medication use (spacer use with metered dose inhaler) Investigate and manage factors that contribute to asthma severity Environmental exposures Comorbid conditions Create written two part Asthma Action Plan (see Fig. 185.5) Daily management Action plan for asthma exacerbations Regular follow up visits Twice yearly (more often if asthma not well controlled) Monitor lung function at least annually Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 185 u Childhood Asthma 1397 Fig. 185.5 Asthma action plan for home use. This plan has two main components: (1) a daily management plan to keep asthma in good control and (2) an action plan to recognize and manage worsening asthma. (From U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute, NIH Pub No 07 5251, April 2007. https:www.nhlbi.nih.govhealthasthmatreatment action plan.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1398 Part XIII u Allergic Disorders particulates as tobacco smoke, and should also be avoided (see Chapter 759.2). Exposure to electronic cigarette aerosol may also aggravate asthma. Annual influenza vaccination (both inactivated and live attenuated) is safe in children with asthma and continues to be recommended for all children with asthma to reduce the risk of severe complications, although influenza is not responsible for the large majority of virus induced asthma exacerbations experienced by children. Identifying and Treating Comorbid Conditions Rhinitis, sinusitis, GER, and obesity often accompany asthma and may make the asthma difficult to treat. These conditions can also mimic asthma symptoms and lead to misclassification of asthma severity and control. Indeed, these conditions, along with asthma, are the most common causes of chronic cough. Poor conditioning from obesity may also be confused with asthma related dyspnea. Effective management of these comorbid conditions may improve asthma symptoms, such that less asthma medication is needed to achieve good asthma control. Component 4: Principles of Asthma Pharmacotherapy The current version of NIH asthma guidelines (2020) provides treatment recommendations that vary by level of asthma severity and age groups (Table 185.13). There are six treatment steps. Patients at Treatment Step 1 have intermittent asthma. Children |
6,617 | with mild persistent asthma are at Treatment Step 2. Children with moderate persistent asthma can be at Treatment Step 3 or 4. Children with severe persistent asthma are at Treatment Steps 5 and 6. The goals of therapy are to achieve a well controlled state by reducing the components of both impairment (e.g., preventing or minimizing symptoms, infrequently needing quick reliever medications, maintaining normal lung function and normal activity levels) and risk (e.g., preventing recurrent exacerbations, reduced lung growth, and medication adverse effects). The recommendations for initial therapy are based on assessment of asthma severity, whereas level of control determines any modifications of treatment in children who are already using controller therapy. A major objective of this approach is to identify and treat all persistent and inadequately controlled asthma with anti inflammatory controller medication. Treatment Step 1 (intermittent asthma) management is simply the use of a SABA as needed for symptoms and for pretreatment in those with EIB. For chil dren 5 years with recurrent episodic wheeze in the setting of viral ill ness, a short course of daily high dose ICS may also be considered. The preferred treatment for all patients with persistent asthma includes an ICS containing therapy, as monotherapy or in combination with adjunctive therapy. The type(s) and amount(s) of daily control ler medications to be used are determined by the asthma severity and control rating. At Treatment Step 2 (mild persistent asthma), low dose daily ICS therapy is the treatment of choice for all children. Common alternative medications include a leukotriene receptor antagonist (LTRA) such as montelukast. At Treatment Step 3 (moderate persistent asthma), for school age children, the preferred treatment has recently been modified to the daily and as needed use of a low dose ICSformoterol (a rapid onset, long acting 2 agonist LABA) combination inhaler, used twice daily as both maintenance therapy and as needed reliever therapy (in place of a separate SABA inhaler). Single maintenance and reliever therapy (SMART) is a fundamen tal change from the conventional distinct daily controllers vs quick reliever medications. Although SMART has been determined to be effective in reducing asthma exacerbations relative to use of SABA as a reliever (i.e., favorable benefit harm ratio), some current challenges to implementation for providers and patients include ICSformoterol availabilityaffordability, FDA approval for use as a reliever therapy, and asthma management and action plan reeducation for home and school, including the appropriate use of SABA in asthma care (e.g., exercise pretreatment). A SABAICS combination inhaler (albuterol budesonide 90 mcg80 mcg per actuation) is FDA approved for as needed use as a quick reliever in adults ages 18 years and older (not in children). Common alternate choices for the treatment of school age children at Treatment Step 3 include (1) medium dose ICS or (2) low dose ICS used in combination with an inhaled LABA. In a study of chil dren with uncontrolled asthma receiving low dose ICS, the addition of LABA was more likely to provide improvement than either adding an LTRA |
6,618 | or increasing ICS dosage. However, some children had a good response to medium dose ICS or the addition of an LTRA, justifying them as step up controller therapy options. Thus if a child is not well controlled with a given step 3 treatment, trials of the alternate treat ment approaches should be considered before stepping up to step 4. In patients 12 years and older with uncontrolled persistent asthma for whom a LABA is not used, current guidelines recommend addition of a LABA or a long acting muscarinic antagonist (LAMA) to the ICS as a step up approach. Adding a LAMA is not more efficacious than adding a LABA, so LAMAs should not be selected over a LABA unless neces sary. LAMAs also have a less favorable benefit harm profile and should not be used in patients with a risk of urinary retention or glaucoma. LAMAs can also be added to ICSLABA combination therapy if the patient remains symptomatic. For young children (4 years) at Treatment Step 3, NAEPP guide lines recommend daily medium dose ICS, whereas GINA recommends three co equal preferred options: (1) daily low dose ICSLABA, (2) daily low dose ICS LTRA, or (3) daily medium dose ICS. At Treatment Step 4 (moderate persistent asthma), the preferred therapy for school age children is daily and as needed use of a medium dose ICSformoterol combination inhaler, used twice daily for maintenance and as needed for reliever therapy. Alterna tives include daily medium dose ICS with either a LABA, LTRA, or other controller (such as a LAMA in patients 12 years and older). For preschool age children at Treatment Step 4, daily medium dose ICS LABA is recommended. For children age 5 years with allergic asthma requiring Treatment Steps 2 4 care, subcutaneous allergen immunotherapy (SCIT) can be considered. Current guidelines recommend SCIT as an adjunct treat ment to standard pharmacotherapy in patients whose asthma can be adequately controlled and managed at the initiation, buildup, and maintenance phases of SCIT. Some requirements for effective and safe SCIT include (1) allergen sensitization evaluation using either immediate hypersensitivity skin testing or in vitro antigen specific IgE antibody testing, and by a trained healthcare professional skilled in proper testing and result interpretation; (2) before each SCIT injec tion, evaluation to ensure that asthma is well controlled because poorly controlled asthma is a major risk factor for life threatening and fatal Table 185.12 Control of Factors Contributing to Asthma Severity ELIMINATE OR REDUCE PROBLEMATIC ENVIRONMENTAL EXPOSURES Environmental tobacco smoke elimination or reduction in home and automobiles Allergen exposure elimination or reduction in sensitized asthmatic patients Pets (cats, dogs, rodents, birds) Pests (mice, rats) Dust mites Cockroaches Molds Other airway irritants Wood or coal burning smoke Strong chemical odors and perfumes (e.g., household cleaners) Dusts TREAT COMORBID CONDITIONS Rhinitis Sinusitis Gastroesophageal reflux Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All |
6,619 | rights reserved. Chapter 185 u Childhood Asthma 1399 Table 185.13 Stepwise Approach for Managing Asthma in Children Persistent AsthmaAge 04 years 511 years 12 years For children age 4 years only, see Step 3 and Step 4 for ages 511 years Steps 24: Conditionally recommend use of subcutaneous immunotherapy as an adjunct treatment to standard pharmacotherapy in individuals 5 years of age whose asthma is controlled at the initiation, build up, and maintenance phases of immunotherapy Steps 24: Conditionally recommend use of subcutaneous allergen immunotherapy as an adjunct treatment to standard pharmacotherapy in individuals 5 years of age whose asthma is controlled at the initiation, build up, and maintenance phases of immunotherapy First check adherence, inhaler technique, environmental factors, and comorbid conditions. Step up if needed, reassess in 46 weeks Step down if possible (if asthma is well controlled for at least 3 consecutive months) Consult with asthma specialist if Step 3 or higher is required for those 04 years of age (and consider consultation at Step 2) or if Step 4 is required for those 5 years of age (and consider consultation at Step 3). Control assessment is a key element of asthma care. This involves both impairment and risk. Use of objective measures, selfreported control, and health care utilization are complementary and should be employed on an ongoing basis, depending on the individuals clinical situation. Consider adding asthma biologics (e.g., antiIgE, antiIL5, antiIL5R, antiIL4IL13R, antiTSLP) Step 6 Intermittent Asthma Step 1 Consider omalizumab Step 5Step 4Step 3 Assess control Step 2 Treatment Daily highdose ICSLABA oral systemic corticosteroids and PRN SABA PRN SABA And At the start of RTI: Add short course daily ICS Daily highdose ICSLABA and PRN SABA Daily medium dose ICSLABA and PRN SABA Daily lowdose ICSLABA and PRN SABA Or Daily lowdose ICS montelukast or daily medium dose ICS and PRN SABA Daily lowdose ICS and PRN SABA Preferred Daily highdose ICSLABA montelukast oral systemic corticosteroids and PRN SABA Daily highdose ICS montelukast and PRN SABA Daily medium dose ICS montelukast and PRN SABA Daily montelukast or Cromolyn and PRN SABA Alternative Daily highdose ICSLABA oral systemic corticosteroids and PRN SABA PRN SABA Daily highdose ICSLABA and PRN SABA Daily and PRN combination mediumdose ICSformoterol Daily and PRN combination lowdose ICS formoterol Daily lowdose ICS and PRN SABA Preferred Daily highdose ICS LTRA oral systemic corticosteroid or daily highdose ICS Theophylline oral systemic corticosteroid, and PRN SABA Daily highdose ICS LTRA or daily highdose ICS Theophylline, and PRN SABA Daily medium dose ICSLABA and PRN SABA Or Daily medium dose ICS LTRA, or daily medium dose ICS theophylline, and PRN SABA Daily mediumdose ICS and PRN SABA Or Daily lowdose ICSLABA, or daily lowdose ICS LTRA, or daily lowdose ICS theophylline, and PRN SABA Daily LTRA, or Cromolyn, or Nedocromil, or Theophylline, and PRN SABA Alternative Daily highdose ICSLABA oral systemic corticosteroids and PRN SABA PRN SABA Daily mediumhigh dose ICSLABA LAMA and PRN SABA Daily and PRN combination mediumdose ICSformoterol Daily and PRN |
6,620 | combination lowdose ICSformoterol Daily lowdose ICS and PRN SABA Or PRN concomitant ICS and SABA Preferred Daily mediumhigh dose ICSLABA or daily highdose ICS LTRA, and PRN SABA Daily medium dose ICS or daily mediumdose ICS LAMA, and PRN SABA Or Daily medium dose ICS LTRA, or daily medium dose ICS theophylline, and PRN SABA Daily medium dose ICS and PRN SABA Or Daily lowdose ICSLABA, or Daily lowdose ICS LAMA, or daily lowdose ICS LTRA, or daily lowdose ICS theophylline, and PRN SABA Daily LTRA and PRN SABA Or Cromolyn, or Nedocromil, or Theophylline, and PRN SABA Alternative Continued Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1400 Part XIII u Allergic Disorders Notes: The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs. If alternative treatment is used and response is inadequate, discontinue it and use the preferred treatment before stepping up. If clear benefit is not observed within 4 6 wk and patientfamily medication technique and adherence are satisfactory, consider adjusting therapy or alternative diagnosis. Studies on children age 0 4 yr are limited. Clinicians who administer allergen immunotherapy or biologic therapy should be prepared and equipped to identify and treat anaphylaxis that may occur. Theophylline is a less desirable alternative because of the need to monitor serum concentration levels. The 2016 GINA guidelines do not recommend the use of theophylline as a controller medication and in IV forms to treat status asthmaticus due to its severe adverse effects profile. Alphabetical order is used when more than 1 treatment option is listed within either preferred or alternative therapy. ICS, Inhaled corticosteroid; LABA, inhaled longacting 2agonist; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid; prn, as needed; SABA, inhaled shortacting 2agonist. Adapted from the National Asthma Education and Prevention Program Expert Panel Report 3 (EPR3): Guidelines for the diagnosis and management of asthma summary report 2007, J Allergy Clin Immunol 120(Suppl):S94S138, 2007 and 2020 Focused Updates to Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. Table 185.13 Stepwise Approach for Managing Asthma in Childrencontd allergic reactions from SCIT; and (3) being well prepared to respond to systemic allergicanaphylactic reactions to SCIT injections. Patients with allergic asthma may also benefit from improvements in comorbid allergic rhinitis and conjunctivitis, which could additionally improve quality of life. SCIT efficacy with regard to asthma medication use and exacerbations is not clear. SCIT is not recommended in patients with severe asthma given the potential for systemic reactions of potentially great severity. Sublingual immunotherapy is not currently recom mended based on available data. At Treatment Steps 5 and 6 (severe persistent asthma), all chil dren should receive daily high dose ICS plus LABA as the preferred approach; alternative secondary controllers to LABA include LTRA or LAMA. Long term administration |
6,621 | of OCSs as controller therapy may be effective but is rarely required and should be avoided when ever possible due to potential for significant corticosteroid side effects. In addition, biologics should be considered in children with specific asthma phenotypes: (1) omalizumab can be used in children 6 years old with severe allergic asthma; (2) mepolizumab (6 years), dupilumab (6 years), and benralizumab (12 years) can be used in children with severe eosinophilic asthma; and (3) tezepelumab (12 years) can be used in children with severe asthma. A rescue course of systemic corticoste roids may be necessary at any step for very poorly controlled asthma. Adjusting Asthma Pharmacotherapy By determining the lowest number or dose of daily controller medi cations that can maintain good control, the potential for medication adverse effects is reduced. Asthma controller therapy can be stepped down after good asthma control has been achieved and maintained for at least 3 months. Stopping ICS controller therapy should be given careful consideration in children with a history of exacerbations. For example, in children with a history of fall seasonal asthma exacerba tions and whose asthma becomes well controlled in the summer, ICS may be reduced but not completely discontinued. Regular follow up is still emphasized because the variability of asthmas course is well rec ognized. When asthma is not well controlled, adherence, inhaler tech nique, and comorbidities should be considered first before increasing controller treatment. If increased treatment is required, the recom mendation is to step up by one level and closely monitor for clinical improvement. For a child with very poorly controlled asthma, the rec ommendations are to consider a short course of prednisone andor to increase therapy by two step levels, with reevaluation in 2 weeks. Referral to Asthma Specialist Referral to an asthma specialist for consultation or co management is recommended if there are difficulties in achieving or maintaining good asthma control. For children 4 years, referral is recommended if the patient requires at least Treatment Step 3 care, and should be consid ered if the patient requires Treatment Step 2 care. For children 5 years, consultation with a specialist is recommended if the patient requires Treatment Step 4 care or higher, and should be considered if Treatment Step 3 is required. Referral is also recommended if allergen immuno therapy (AIT) or biologic therapy is being considered. Long Term Controller Medications All levels of persistent asthma should be treated with an ICS containing therapy to reduce airway inflammation, improve long term control, and reduce exacerbation risk (see Table 185.13). Other long term control ler medications include LABAs, leukotriene modifiers, LAMAs, SCIT, cromolyn, sustained release theophylline, and tiotropium in adolescents. Omalizumab and mepolizumab are approved by the FDA for use as an add on therapy in children 6 years who have severe allergic asthma or eosinophilic asthma, respectively, that remains difficult to control. For adolescents 12 years and older, benralizumab is approved by the FDA for severe asthma with an eosinophilic phenotype. Dupilumab is approved by the FDA |
6,622 | for moderate to severe asthma with an eosinophilic pheno type for children 6 years and older. Tezepelumab is approved by the FDA for severe asthma in adolescents 12 years and older (see Tables 185.13 and 185.14). Inhaled Corticosteroids ICS therapy serves as the cornerstone of therapy in persistent asthma, as it improves lung function; reduces asthma symptoms, AHR, and use of rescue medications; improves quality of life; and most impor tantly reduces exacerbations, the need for systemic corticosteroids, urgent care visits, and hospitalizations. Epidemiologic studies have also shown that ICS therapy in adults substantially lowers the risk of death attributable to asthma if used regularly. Because ICS therapy frequently achieves all the goals of asthma management, it is viewed as first line treatment for persistent asthma. The selection of the initial ICS dose is based on the determination of disease severity. Seven ICSs are approved by the FDA for use in children. The NIH and GINA guidelines provide equivalence classifications (Table 185.15), although direct comparisons of efficacy and safety outcomes are lack ing. ICSs are available in metered dose inhalers (MDIs) using hydro fluoroalkane (HFA) as their propellant, in dry powder inhalers (DPIs), or in suspension for nebulization. Fluticasone propionate, flutica sone furoate, mometasone furoate, ciclesonide, and to a lesser extent budesonide are considered second generation ICSs, in that they have greater antiinflammatory potency and less systemic bioavailability. Even though ICSs are very effective in most patients, there has been some reluctance to treat children with ICSs due to parental and occa sionally physician concerns regarding their potential for adverse effects with chronic use. The most serious adverse effects that occur with long term systemic corticosteroid therapy have not been seen or have only rarely been reported in children receiving ICSs in recommended doses. The risk of adverse effects from ICS therapy is related to the dose and frequency of administration (Table 185.16). High doses (1,000 gday in children) and frequent administration (4 times per day) are more likely to have both local and systemic adverse effects. Children who receive maintenance therapy with higher ICS doses are also likely to require frequent systemic corticosteroid courses for asthma exacerba tions, further increasing their risk of corticosteroid adverse effects. The most common ICS adverse effects are local: oral candidiasis (thrush) and dysphonia (hoarse voice). Thrush results from propellant induced mucosal irritation and local immunosuppression, and dysphonia Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 185 u Childhood Asthma 1401 is the result of vocal cord myopathy. These effects are dose dependent and are most common in individuals receiving high dose ICS or OCS therapy. The incidence of these local effects can be greatly minimized by using a spacer with an MDI with the ICS, because spacers reduce oro pharyngeal deposition of the drug and propellant. Mouth rinsing using a swish and spit technique after ICS |
6,623 | use is also recommended. The potential for growth suppression and osteoporosis with long term ICS use had been an unanswered concern. A long term, pro spective NIH sponsored study (CAMP) followed the growth and bone mineral density (BMD) of 1,000 children (age 6 12 years at entry) with mild to moderate asthma until they reached adulthood and found slight growth suppression and osteopenia in some children who received long term ICS therapy. A small (1.1 cm), limited (1 year) growth suppressive effect was noted in children receiving budesonide, 200 g twice daily, after 5 years of therapy. Height was then followed until all children had reached adulthood (mean age 25 years). Those who received ICS therapy remained approximately 1 cm shorter than those who received placebo. Thus children treated with long term low dose ICS therapy may be about 1 cm shorter than expected as an adult, which is of little clinical significance. BMD was no different in those receiving budesonide vs placebo during the duration of the study, whereas a follow up study after a mean of 7 years found a slight dose dependent effect of ICS therapy on bone mineral accretion only among males. A much greater effect on BMD was observed with increasing numbers of OCS bursts for acute asthma, as well as an increase in risk for osteopenia, which was again limited to males. These findings were with use of low dose budesonide; higher ICS doses, especially of agents with increased potency, are likely to have a greater potential for adverse effects. Thus osteoporosis screening and prevention measures are recommended for patients receiving higher ICS doses, because these patients are also likely to require systemic courses for exacerbations (see Table 185.16). Systemic Corticosteroids The development of second generation ICSs, especially when used in combination with a LABA in a single device, along with the addition of biologics, have allowed almost all children with asthma to achieve and maintain good control without need for maintenance OCS therapy. Thus short courses of OCSs are used primarily to treat asthma exacerbations and, very rarely, as maintenance therapy in children with very severe dis ease. In these patients, every attempt should be made to exclude comorbid conditions and to keep the OCS dose at 20 mg every other day. Doses exceeding this amount are associated with numerous adverse effects (see Chapter 615). To determine the need for continued OCS therapy, taper ing of the OCS dose over several weeks should be attempted, with close monitoring of the patients symptoms and lung function. Prednisone, prednisolone, methylprednisolone, and dexameth asone are rapidly and completely absorbed, with peak plasma Table 185.14 Usual Dosages for Long Term Control Medications MEDICATION AGE 0 4 YR 5 11 YR 12 YR INHALED CORTICOSTEROID MONOTHERAPIES (SEE TABLE 185.13) Inhaled CorticosteroidLong Acting Agonist (ICSLABA) Combination Therapies: Fluticasonesalmeterol (Advair): NA DPI: 100, 250, or 500 g50 g 1 inhalation bid; dose depends on level of severity or control (the 10050 dosage is indicated in children 4 yr) 1 inhalation |
6,624 | bid; dose depends on level of severity or control HFA: 45 g21 g, 115 g21 g, 230 g21 g 2 inhalations bid; dose depends on level of severity or control Budesonideformoterol (Symbicort): HFA: 80 g4.5 g, 160 g4.5 g NA 2 inhalations bid; dose depends on level of severity or control Mometasoneformoterol (Dulera): HFA: 100 g5 g, 200 g5 g 2 inhalations bid; dose depends on level of severity or control Leukotriene Receptor Antagonists: Montelukast (Singulair): 4 or 5 mg chewable tablet 4 mg granule packets 10 mg tablet Black box warning (see text) 4 mg qhs (1 5 yr) 5 mg qhs (6 14 yr) 10 mg qhs (indicated in children 15 yr) Zafirlukast (Accolate): 10 mg or 20 mg tablet NA 10 mg bid (7 11 yr) 40 mg daily (20 mg tablet bid) Biologic Therapies: Omalizumab (anti IgE; Xolair): SC injection, 150 mg NA 75 375 mg SC q 2 4 wk (6 11 yr), depending on body weight and pretreatment serum IgE level 75 375 mg SC q 2 4 wk, depending on body weight and pretreatment serum IgE level Mepolizumab (antiIL 5; Nucala): SC injection, 100 mg NA 40 mg SC q 4 wk (6 11 yr) 100 mg SC q 4 wk Benralizumab (antiIL 5 R; Fasenra) SC injection, 30 mg NA NA 30 mg SC q 4 wk 3 doses, then 30 mg SC q 8 wk Dupilumab (antiIL 4 R; Dupixent) SC injection, 200 mg, 300 mg NA 15 to 30 kg:100 mg q 2 wk or 300 mg q 4 wk 30 kg: 200 mg q2 wk 400 mg or 600 mg SC starting dose, then 200 or 300 mg SC q 2 wk Tezepelumab (antiTSLP; Tezspire) SC injection, 210 mg NA NA 210 mg SC q 4 wk bid, Two times daily; DPI, dry powder inhaler; HFA, hydrofluoroalkane; IL, interleukin; q, every; qhs, every night; SC, subcutaneous(ly). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1402 Part XIII u Allergic Disorders concentrations occurring within 1 2 hours. Prednisone is an inac tive prodrug that requires biotransformation via first pass hepatic metabolism to prednisolone, its active form. For asthma exacerba tions in children, oral dexamethasone is also commonly used given its long half life of 36 54 hours and association with less vomiting when compared with oral prednisone. These corticosteroids are metabolized in the liver into inactive compounds, with the rate of metabolism influenced by drug interactions and disease states. Anti convulsants (phenytoin, phenobarbital, carbamazepine) increase the metabolism of prednisolone, methylprednisolone, and dexa methasone, with methylprednisolone most significantly affected. Rifampin also enhances the clearance of corticosteroids and can result in diminished therapeutic effect. Other medications (keto conazole, oral contraceptives) can significantly delay corticosteroid metabolism. Some macrolide antibiotics, such as erythromycin and clarithromycin, delay the clearance of only methylprednisolone. Long term OCS therapy can cause numerous |
6,625 | adverse effects over time (see Chapter 617). Some occur immediately (metabolic effects), whereas others can develop insidiously over several months to years (growth suppression, osteoporosis, cataracts). Most adverse effects occur in a cumulative dose and duration dependent manner. Children who require routine or frequent short courses of OCSs, especially with concurrent high dose ICSs and often intranasal corticosteroids, should receive corticosteroid adverse effects screening (see Table 185.16) and osteoporosis preventive measures (see Chapter 749). Long Acting Inhaled Agonists Although considered daily controller medications, LABAs (salmeterol, formoterol) are not intended for use as monotherapy for persistent asthma because they can increase the risk for serious asthma exacerbations (ICU admission, endotracheal intubation) and asthma related deaths when used without an ICS. The likely mechanism involves the ability of LABAs to mask worsening asthma inflammation and asthma severity, leading to a delay in seeking urgent care and increased risk of a life threatening exacerbation. Although both salmeterol and formoterol have a prolonged duration of effect (12 hours), salmeterol has a prolonged onset of effect (60 minutes), whereas formoterols onset of effect is rapid (5 10 minutes) after administration. Given their long duration of action, LABAs are well suited for patients with nocturnal asthma and for individuals who require frequent use of SABA inhalations during the day to prevent EIB, but only in combination with ICSs. The FDA recommends that once a patient is well controlled on combination ICSLABA therapy, the LABA component should be discontinued while continuing treatment with the ICS, although many patients experience disease worsening on LABA discontinuation. Combination ICSLABA Therapy Combination ICSLABA therapy is recommended for patients who are suboptimally controlled with ICS therapy alone and those with moderate or severe persistent asthma. In most patients who are inadequately controlled with ICS alone, combination ICSLABA therapy is superior to add on therapy with either an LTRA or LAMA or doubling the ICS dose. Benefits include improvement in baseline lung function, less need for rescue SABA therapy, improved quality of life, and fewer asthma exacerbations. A large study found that in chil dren inadequately controlled with low dose ICS therapy, combination low dose fluticasonesalmeterol (100 g21 g) twice daily was almost twice as likely to be effective as other step up regimens, including fluticasone (250 g) twice daily or low dose fluticasone (100 g twice daily) plus montelukast once daily, with the greatest improvement in reducing exacerbations requiring prednisone and study withdrawals due to poorly controlled asthma. In addition, combination fluticasone salmeterol was as likely to be effective as medium dose fluticasone and Table 185.15 Estimated Comparative Inhaled Corticosteroid Doses GLUCOCORTICOID LOW DAILY DOSE MEDIUM DAILY DOSE HIGH DAILY DOSE Beclomethasone (Qvar) MDI: 40 or 80 g (Approved for children 5 yr) 80 160 g 160 320 g 320 g Budesonide (Pulmicort Flexhaler) DPI: 90, 180 g (Approved for children 6 yr) 200 g 200 400 g 400 g Budesonide suspension for nebulization (Generic and Pulmicort Respules) 0.25 mg, 0.5 mg, 1 mg (Approved for children 1 8 yr) 0.5 mg |
6,626 | 1.0 mg 2.0 mg Ciclesonide (Alvesco) MDI: 80, 160 g (Approved for children 12 yr) 80 g 80 160 g 160 g Flunisolide (Aerospan) MDI: 80 gpuff (Approved for children 6 yr) 80 g 80 160 g 160 g Fluticasone propionate (Flovent, Flovent Diskus) MDI: 44, 110, 220 g DPI: 50, 100, 250 g (44 and 50 g approved for children 4 yr) 88 176 g 100 200 g 176 440 g 200 500 g 440 g 500 g Fluticasone furoate (Arnuity Ellipta) DPI: 100, 200 g (Approved for children 12 yr) 100 g 100 200 g 200 g Mometasone Furoate (Asmanex, Asmanex Twisthaler) MDI: 100, 200 g DPI: 110, 220 g (Approved for children 4 yr) 110 g 100 g 110 g 100 g 110 g 100 g DPI, Dry powder inhaler; MDI, metered dose inhaler. Adapted from National Asthma Education and Prevention Program Expert Panel Report 3 (EPR3). Guidelines for the Diagnosis and Management of AsthmaSummary Report 2007. J Allergy Clin Immunol. 2007;120(Suppl):S94S138. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 185 u Childhood Asthma 1403 was superior to combination fluticasonemontelukast therapy in Black children, arguing against the notion that Black children are more prone to serious asthma exacerbations than White children when treated with combination ICSLABA therapy. Despite their efficacy and widespread use, the long term safety of LABAs, even when used in combination with ICS in a single inhaler, has been questioned. To address this concern of rare, severe asthma related events with LABAICS use, large randomized controlled trials (RCTs) compared the safety of combination ICSLABA vs ICS mono therapy. Two studies of 23,000 adults and adolescents 12 years old with various levels of asthma severity were randomized to receive ICS (low or medium dose) monotherapy vs equivalent ICSLABA (flutica sone vs fluticasonesalmeterol; budesonide vs budesonideformoterol) over 26 weeks to determine whether small but significant differences might occur in asthma hospitalization, intubation, or death attribut able to ICSLABA. No intubations or asthma deaths occurred dur ing the study, and no differences in asthma hospitalizations between treatment groups were observed. The similar pediatric study enrolled 6,000 children age 4 11 years with various levels of asthma severity to receive either fluticasone (low or medium dose) or equivalent fluti casonesalmeterol dose over 26 weeks, with similar findings of no sig nificant differences in severe asthma related events between treatment groups. These results strongly suggest that the use of combination ICS LABA products in children and adults with moderate to severe persistent asthma is both effective and safe. Leukotriene Modifying Agents Leukotrienes are potent proinflammatory mediators that can induce bronchospasm, mucus secretion, and airways edema. LTRAs have bronchodilator and targeted antiinflammatory properties and reduce exercise , aspirin , and allergen induced bronchoconstriction. LTRAs may be an alternative treatment for mild persistent asthma and as an add on medication with ICS for moderate |
6,627 | persistent asthma. Two LTRAs with FDA approved use in children are montelukast and zafirlukast. Both medications improve asthma symptoms, decrease the need for rescue agonist use, and modestly improve lung func tion. Montelukast is approved for use in children 1 year of age and is administered once daily, whereas zafirlukast is approved in children 5 years and is given twice daily. LTRAs are less effective than ICSs in patients with mild persistent asthma (e.g., ICSs improve baseline lung function 515, whereas LTRAs improve lung function 2.57.5). The FDA has identified serious behavior and mood related changes in some patients treated with montelukast and suggests that the benefits of mon telukast may not outweigh the risks in some patients, particularly when the symptoms of disease may be mild and adequately treated with other medicines. When initially prescribing montelukast, a precaution is to inform the child and family that, if mood changes are noted after starting montelukast, they should discontinue its use and contact their physician. Long Acting Inhaled Anticholinergics Tiotropium is a LAMA (24 hour duration of action) that is approved by the FDA for use in children with asthma 6 years old. In studies in children and adolescents with moderate persistent asthma, tiotropium improved lung function as an add on therapy to ICS. Adding a LAMA is not more efficacious than adding a LABA, so LAMAs should not be selected over a LABA unless necessary. LAMAs can also be added to ICSLABA combination therapy if the patient remains symptomatic. Allergen Immunotherapy AIT involves administering gradually increasing doses of allergens to a person with allergic disease to reduce or eliminate the patients allergic response to those allergens, including allergic rhinoconjunctivitis and asthma. Conventional AIT is given subcutaneously (SCIT) under the direction of an experienced allergist. The goal of SCIT is to increase the dose of allergen extract administered to reach a therapeutic main tenance dose of each major allergen, in a manner that minimizes the likelihood of systemic allergic reactions. Allergen extracts are formu lated for each patient based on documented allergen sensitizations Table 185.16 Risk Assessment for Corticosteroid Adverse Effects CONDITIONS RECOMMENDATIONS Low risk (1 risk factor) Low to medium dose ICS (see Table 185.13) Monitor blood pressure and weight with each physician visit Measure height annually (stadiometry); monitor periodically for declining growth rate and pubertal developmental delay Encourage regular physical exercise Ensure adequate dietary calcium and vitamin D with additional supplements for daily calcium if needed. Avoid smoking and alcohol Ensure TSH status if patient has history of thyroid abnormality Medium risk (If 1 risk factor, consider evaluating as high risk) High dose ICS (see Table 185.13) At least four courses of OCS per year As above, plus: Yearly ophthalmologic evaluations to monitor for cataracts or glaucoma Baseline bone densitometry (DEXA scan) Consider patient at increased risk for adrenal insufficiency, especially with physiologic stressors (e.g., surgery, accident, significant illness) High risk Chronic systemic corticosteroids (7.5 mg daily or equivalent for 1 mo) 7 OCS burst treatments per year Very |
6,628 | high dose ICS (e.g., fluticasone propionate 800 gday) As above, plus: DEXA scan: if DEXA z score 1.0, recommend close monitoring (every 12 mo) Consider referral to a bone or endocrine specialist Bone age assessment Complete blood count Serum calcium, phosphorus, and alkaline phosphatase determinations Urine calcium and creatinine measurements Measurements of testosterone in males, estradiol in amenorrheic premenopausal women, vitamin D (25 OH and 1,25 OH vitamin D), parathyroid hormone, and osteocalcin Urine telopeptides for those receiving long term systemic or frequent OCS treatment Assume adrenal insufficiency for physiologic stressors (e.g., surgery, accident, significant illness) Risk factors for osteoporosis: presence of other chronic illness(es), medications (corticosteroids, anticonvulsants, heparin, diuretics), low body weight, family history of osteoporosis, significant fracture history disproportionate to trauma, recurrent falls, impaired vision, low dietary calcium and vitamin D intake, and lifestyle factors (decreased physical activity, smoking, alcohol intake). DEXA, Dual energy x ray absorptiometry; ICS, inhaled corticosteroid; OCS, oral corticosteroid; TSH, thyroid stimulating hormone. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1404 Part XIII u Allergic Disorders and problematic exposures. Maintenance doses are generally given monthly, to complete a 35 year course. A meta analysis of 20 trials examining the effects of SCIT on allergic asthma revealed significant improvement with fewer symptoms, improved lung function, less need for medication, and AHR reduction. Although AIT is regarded as safe, the potential for anaphylaxis always exists when patients receive extracts containing allergens to which they are sensitized. Local transient allergic reactions at the injection site are common. Systemic allergic reactions can also occur with SCIT, with fatal anaphylaxis occurring in approximately 1 per 2 million injections. Because of the risks of systemic allergic reac tions to SCIT, standard precautions include administering SCIT in medical settings where a physician with access to emergency equip ment and medications required for the treatment of anaphylaxis is available (see Chapter 190). Patients should be observed in the office for 30 minutes after each injection because most systemic reactions to SCIT begin within this time frame. SCIT should never be given at home or by untrained personnel. Because of the complexities and risks of administration, SCIT should only be administered by an experi enced allergist. SCIT is not recommended for patients with severe and uncontrolled asthma. AIT should be discontinued in patients who have not shown improvement after 1 year of receiving maintenance doses of an appro priate allergen extract(s), or who have a serious systemic allergic or adverse reaction. Biologic Therapies Biologic therapies are genetically engineered proteins derived from human genes and designed to inhibit specific immune mediators of disease. Several are approved by the FDA as add on controller thera pies (i.e., in addition to conventional controller therapies) for severe asthma in adults and children. Omalizumab (Anti IgE Antibody). Omalizumab is a human ized monoclonal antibody (mAb) that binds IgE and prevents its |
6,629 | binding to the high affinity IgE receptor on mast cells and baso phils, thereby blocking IgE mediated allergic responses and inflammation. It is approved by the FDA for patients 6 years old with severe allergic asthma who continue to have inadequate dis ease control despite treatment with high dose ICS andor OCS. Omalizumab is given every 2 4 weeks subcutaneously, with the dosage based on body weight and serum IgE levels. Omalizumab can improve asthma control while allowing ICS andor OCS dose reduction. Omalizumab has been studied in inner city children with exacerbation prone asthma. When added to guideline based controller management, omalizumab reduced exacerbations (50), particularly those that peak in the spring and fall seasons. A follow up prospective preseasonal treatment study confirmed the effect on fall seasonal exacerbations and demonstrated how omalizumab restores antiviral (interferon IFN ) immune responses to rhi novirus (the most common infectious trigger of exacerbations) that are impaired by IgE mediated mechanisms. Omalizumab is generally well tolerated, although local injection site reactions can occur. Hypersensitivity reactions (including anaphylaxis) have been reported following approximately 0.1 of injections. As a result, omalizumab has an FDA black box warning of potentially serious and life threatening anaphylactic adverse reactions, and an epi nephrine autoinjector should be available to all patients receiving omalizumab. Mepolizumab and Reslizumab (AntiIL 5 Antibodies). Mepo lizumab, an antiIL 5 mAb that blocks IL 5 mediated eosinophi lopoiesis, reduces severe asthma exacerbations and lowers sputum and blood eosinophils while allowing for a significant reduction in OCS dose in adults and adolescents with severe exacerbation prone eosinophilic asthma. It is administered subcutaneously every 4 weeks and is approved by the FDA for severe eosinophilic asthmatic children 6 years old. Reslizumab, another antiIL 5 mAb thera peutic, is administered intravenously and is approved by the FDA for severe asthmatics 18 years old (i.e., not currently approved for use in children). Benralizumab (AntiIL 5Ra Antibody). Benralizumab is also an mAb that binds to the IL 5 receptor subunit, resulting in apoptosis of eosinophils and basophils. Benralizumab is approved for patients 12 years old with severe eosinophilic asthma with a suggested abso lute blood eosinophil count of at least 300 cellsL. Benralizumab is administered subcutaneously every 4 weeks for three doses followed by every 8 week dosing. Dupilumab (AntiIL 4 Receptor Antibody). Dupilumab, an antiIL 4 receptor human mAb that inhibits both IL 4 and IL 13 production (both cytokines share the same IL 4 receptor chain) and atopic immune responses, reduces exacerbations and symp toms and improves lung function in moderate to severe asthmatic patients with an eosinophilic phenotype. Dupilumab is adminis tered subcutaneously every 2 weeks and is approved by the FDA for patients 6 years old with moderate to severe eosinophilic asthma. It is suggested that patients have an absolute eosinophil count of at least 150 cellsL or an exhaled nitric oxide level of at least 25 parts per billion (ppb). In meta analysis, dupilumab was associated with significant reductions of the annualized rate of severe |
6,630 | asthma exacerbations and OCS use and a statistical improvement in lung function. Tezepelumab (AntiThymic Stromal Lymphopoietin TSLP Antibody). Tezepelumab, an antiTSLP human mAb, binds and blocks TSLPs inflammatory actions, reduces asthma exacerbations and symptoms, and improves lung function. Tezepelumab is administered subcutaneously every 4 weeks and is approved by the FDA for patients 12 years old with severe asthma. Quick Reliever Medications Quick reliever or rescue medications (SABAs, inhaled anticholiner gics, and short course systemic corticosteroids) are used in the man agement of acute asthma symptoms (Table 185.17). Short Acting Inhaled Agonists Given their rapid onset of action, effectiveness, and 46 hour duration of action, SABAs (albuterol, levalbuterol, terbutaline, pirbuterol) are the drugs of choice for acute asthma symptoms (rescue medication) and for preventing EIB. Adrenergic ago nists cause bronchodilation by inducing airway smooth muscle relaxation, reducing vascular permeability and airways edema, and improving mucociliary clearance. Levalbuterol, the R isomer of alb uterol, is associated with less tachycardia and tremor, which can be bothersome to some asthmatic patients. Overuse of agonists is associated with an increased risk of death or near death episodes from asthma. This is a major concern for some patients with asthma who rely on the frequent use of SABAs as a quick fix for their asthma, rather than using controller medications in a preventive manner. It is helpful to monitor the frequency of SABA use, in that use of one or more MDIs per month or three or more MDIs per year (200 inhalations per MDI) indicates inadequate asthma con trol and necessitates improving other aspects of asthma therapy and management. Of note, a SABAICS combination inhaler (albuterol budesonide 90 mcg80 mcg per actuation) has recently been FDA approved for asneeded use as a quick reliever in adults ages 18 years and older (not in children). Anticholinergic Agents As bronchodilators, the anticholinergic agents (e.g., ipratropium bromide) are less potent than the agonists. Inhaled ipratropium is used primarily in the treatment of acute severe asthma. When used in combination with albuterol, ipratropium can improve lung function and reduce the rate of hospitalization in children who present to the ED with acute asthma. Ipratropium has few central nervous system adverse effects and is available in both MDI and nebulizer formula tions. Although widely used in all children with asthma exacerbations, it is approved by the FDA for use in children 12 years old. A combina tion ipratropiumalbuterol product is also available in both nebulized and mist formulations. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 185 u Childhood Asthma 1405 Table 185.17 Management of Asthma Exacerbation (Status Asthmaticus) RISK ASSESSMENT ON ADMISSION Focused history Onset of current exacerbation Frequency and severity of daytime and nighttime symptoms and activity limitation Frequency of rescue bronchodilator use Current medications and allergies Potential triggers History of systemic steroid courses, emergency department visits, hospitalization, intubation, or |
6,631 | life threatening episodes Clinical assessment Physical examination findings: vital signs, breathlessness, air movement, use of accessory muscles, retractions, anxiety level, alteration in mental status Pulse oximetry Lung function (defer in patients with moderate to severe distress or history of labile disease) Risk factors for asthma morbidity and death See Table 185.18 TREATMENT DRUG AND TRADE NAME MECHANISMS OF ACTION AND DOSING CAUTIONS AND ADVERSE EFFECTS Oxygen (mask or nasal cannula) Treats hypoxia Monitor pulse oximetry to maintain O2 saturation 92 Cardiorespiratory monitoring Inhaled short acting agonists Bronchodilator During exacerbations, frequent or continuous doses can cause pulmonary vasodilation, VQ mismatch, and hypoxemia Adverse effects: palpitations, tachycardia, arrhythmias, tremor, hypoxemia Albuterol nebulizer solution (5 mg mL concentrate; 2.5 mg3 mL, 1.25 mg3 mL, 0.63 mg3 mL) Nebulizer: 0.15 mgkg (minimum 2.5 mg) as often as every 20 min for 3 doses as needed, then 0.15 0.3 mgkg up to 10 mg every 1 4 hr as needed, or up to 0.5 mgkghr by continuous nebulization Nebulizer: when giving concentrated forms, dilute with saline to 3 mL total nebulized volume. Albuterol MDI (90 gpuff) 2 8 puffs up to every 20 min for 3 doses as needed, then every 1 4 hr as needed For MDI: use spacerholding chamber Levalbuterol (Xopenex) nebulizer solution (1.25 mg0.5 mL concentrate; 0.31 mg3 mL, 0.63 mg3 mL, 1.25 mg3 mL) 0.075 mgkg (minimum 1.25 mg) every 20 min for 3 doses, then 0.075 0.15 mgkg up to 5 mg every 1 4 hr as needed, or 0.25 mgkghr by continu ous nebulization Levalbuterol 0.63 mg is equivalent to 1.25 mg of standard albuterol for both efficacy and side effects Systemic corticosteroids Antiinflammatory If patient has been exposed to chickenpox or measles, consider passive immunoglobulin prophylaxis; also, risk of complications with herpes simplex and tuberculosis For daily dosing, 8 am administration minimizes adrenal suppression Children may benefit from dosage tapering if course exceeds 7 days Adverse effects monitoring: frequent therapy bursts risk numerous corticosteroid adverse effects (see Chapter 615); see Table 185.14 for adverse effects screening recommenda tions Prednisone: 1, 2.5, 5, 10, 20, 50 mg tablets Methylprednisolone (Medrol): 2, 4, 8, 16, 24, 32 mg tablets Prednisolone: 5 mg tablets; 5 mg5 mL and 15 mg5 mL solution Short course oral burst for exacerbation: 1 2 mgkgday divided qd or bid for 3 7 days (maximum 40 mgday) Depo Medrol (IM); Solu Medrol (IV) 0.5 1 mgkg every 6 12 hr for 48 hr, then 1 2 mgkg day qd or bid Dexamethasone: 0.5, 0.75, 1, 1.5, 2, 4, 6 mg tablets; 0.5 mg5 mL, 1 mgmL Intensol solution Short course oral burst for exacerbation: 0.6 mg kg, maximum 16 mg; can be repeated next day Anticholinergics Mucolyticbronchodilator Should not be used as first line therapy; added to 2 agonist therapy Ipratropium Atrovent (nebulizer solution 0.5 mg2.5 mL; MDI 18 ginhalation) Nebulizer: 0.5 mg q6 8h (tid qid) as needed MDI: 2 puffs qid Ipratropium with albuterol DuoNeb nebulizer solution (0.5 mg ipra tropium 2.5 mg albuterol3 |
6,632 | mL vial) 1 vial by nebulizer qid Nebulizer: may mix ipratropium with albuterol Injectable sympathomimetic epinephrine Bronchodilator For extreme circumstances (e.g., impending respiratory failure despite high dose inhaled SABA, respiratory failure) Continued Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1406 Part XIII u Allergic Disorders Delivery Devices and Inhalation Technique Inhaled medications are delivered in aerosolized form in an MDI, as a DPI formulation, or in a suspension form delivered via a nebu lizer. Spacer devices, recommended for the administration of all MDI medications, are simple and inexpensive tools that (1) decrease the coordination required to use MDIs, especially in young children; (2) improve the delivery of inhaled drug to the lower airways; and (3) minimize the risk of drug and propellant mediated oropharyngeal adverse effects (dysphonia and thrush). Optimal inhalation technique for each puff of MDI delivered medi cation is a slow (5 second) inhalation, then a 510 second breath hold. No waiting time is required between puffs of medication. Preschool age children cannot perform this inhalation technique. As a result, MDI medications in this age group are delivered with a spacer and mask, using a different technique: Each puff is adminis tered with regular breathing for about 30 seconds or 5 10 breaths; a tight seal must be maintained; and talking, coughing, or crying will blow the medication out of the spacer. This technique will not deliver as much medication per puff as the optimal MDI technique used by older children and adults. DPI devices (e.g., Diskus, Flexhaler, Autohaler, Twisthaler, Aerolizer, Ellipta) are popular because of their simplicity of use, although adequate inspiratory flow is needed. DPIs are breath actuated devices (the drug comes out only as it is breathed in), and spacers are not needed. Mouth rinsing is recommended after ICS use to remove ICS deposited on the oral mucosa and reduce the swallowed ICS and the risk of thrush. Nebulizers are the mainstay of aerosol treatment for infants and young children. An advantage of using nebulizers is the simple tech nique required of relaxed breathing. The preferential nasal breathing, small airways, low tidal volume, and high respiratory rate of infants greatly increase the difficulty of inhaled drug therapy targeting the lung airways. Disadvantages of nebulizers include the need for a power source, inconvenience in that treatments take a significantly longer time, are more expensive, and have the potential for bacterial contamination. Asthma Exacerbations and Their Management Asthma exacerbations are acute or subacute episodes of progressively worsening symptoms and airflow obstruction. Airflow obstruction dur ing exacerbations can become extensive, resulting in life threatening respiratory insufficiency. Often, asthma exacerbations worsen during sleep (between midnight and 8 am), when airways inflammation and hyperresponsiveness are at their peak. Importantly, SABAs, which are first line therapy for asthma symptoms and exacerbations, increase pulmonary blood flow through obstructed, unoxygenated areas of the lungs with increasing |
6,633 | dosage and frequency. When airways obstruc tion is not resolved with SABA use, ventilationperfusion mismatching can cause hypoxemia, which can perpetuate bronchoconstriction and further worsen the condition. Severe, progressive asthma exacerba tions need to be managed in a medical setting, with administration of supplemental oxygen as first line therapy and close monitoring for potential worsening. Complications that can occur during severe exacerbations include atelectasis (common) and air leaks in the chest (pneumomediastinum, pneumothorax; rare). A severe exacerbation of asthma that does not improve with stan dard therapy is termed status asthmaticus. Immediate management of an asthma exacerbation involves a rapid evaluation of the severity of obstruction and assessment of risk for further clinical deterioration (Fig. 185.6; see Tables 185.4 and 185.17). For most patients, exacerbations improve with frequent bronchodilator treatments and a course of sys temic (oral or intravenous) corticosteroid. However, the optimal man agement of a child with an asthma exacerbation should include a more comprehensive assessment of the events leading up to the exacerbation and the underlying disease severity. Indeed, the frequency and severity of asthma exacerbations help define the severity of a patients asthma. Whereas most children who experience life threatening asthma episodes have moderate to severe asthma by other criteria, some children with asthma appear to have mild disease except when they have severe, even near fatal exacerbations. The biologic, environmental, economic, and psychosocial risk factors associated with asthma morbidity and death can further guide this assessment (Table 185.18). Table 185.17 Management of Asthma Exacerbation (Status Asthmaticus)contd Adrenalin 1 mgmL (1:1000) EpiPen autoinjection device (0.3 mg; EpiPen Jr 0.15 mg) IM: 0.01 mgkg (max dose 0.5 mg); may repeat after 15 30 min Terbutaline Terbutaline is agonistselective relative to epinephrine Monitoring with continuous infusion: cardiorespiratory monitor, pulse oximetry, blood pressure, serum potassium Adverse effects: tremor, tachycardia, palpitations, arrhythmia, hypertension, headaches, nervousness, nausea, vomiting, hypoxemia Brethine 1 mgmL Continuous IV infusion (terbutaline only): 2 10 gkg loading dose, followed by 0.1 0.4 gkgmin Titrate in 0.1 0.2 gkgmin increments every 30 min, depending on clinical response. Other medications Magnesium sulfate 2575 mgkg over 20 min Max 2 gm Flushing, headache, hypotension (rare) RISK ASSESSMENT FOR DISCHARGE Medical stability Discharge home if there has been sustained improvement in symptoms and bronchodilator treatments are at least 3 hr apart, physical findings are normal, PEF 70 of predicted or personal best, and oxygen saturation 92 when breathing room air Home supervision Capability to administer intervention and to observe and respond appropriately to clinical deterioration Asthma education See Table 185.10 IM, Intramuscular; IV, intravenous; MDI, metered dose inhaler; PEF, peak expiratory flow; SABA, short acting agonist; VQ, ventilationperfusion; bid, 2 times daily; tid, 3 times daily; qid, 4 times daily; qd, every day. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 185 u Childhood Asthma 1407 Assess symptomspeak flow Follow this plan for After |
6,634 | Hours patients only. Nurse may decide not to follow this home management plan if: Parent does not seem comfortable with or capable of following plan Nurse is not comfortable with this plan, based on situation and judgment Nurses time does not allow for callbacks In all cases, tell parent to call 911 if signs of respiratory distress occur during the episode NOTE: If action plan has already been attempted without success, go to RED ZONE poor response or YELLOW ZONE incomplete response as symptoms indicate. YELLOW ZONE Mildtomoderate exacerbation PEF 5080 predicted or personal best or Signs and symptoms Coughing, shortness of breath or chest tightness (correlate imperfectly with severity of exacerbation), or Unable to sleep at night due to asthma, or Decreased ability to perform usual activities With or without wheezing RED ZONE Severe exacerbation PEF ? 50 predicted or personal best or Signs and symptoms Very hard time breathing; constant coughing Trouble walking or talking due to asthma (unable to complete sentences; only using 2 to 3word phrases) Nails blue Suprasternal or supraclavicular retractions Albuterol not relieving symptoms within 1015 minutes With or without wheezing Instructions to patient Inhaled shortacting 2agonist: 24 puffs of inhaler or nebulizer treatment every 20 minutes up to 3 times in 1 hour Assess asthma symptoms andor peak flow 1520 minutes after each treatment Nurse to call family after 1 hour If patient worsens during treatment, have parent call back immediately or call 911 GREEN ZONE Good response Mild exacerbation PEF ? 80 predicted or personal best or Signs and symptoms No wheezing, shortness of breath, cough or chest tightness, and Response to 2agonist sustained for 4 hours YELLOW ZONE Incomplete response Moderate exacerbation PEF 5080 predicted or personal best or Signs and symptoms Persistent wheezing, shortness of breath, cough or chest tightness RED ZONE Poor response Severe exacerbation PEF ? 50 predicted or personal best or Signs and symptoms Marked wheezing, shortness of breath, cough, or chest tightness Distress is severe and nonresponsive Response to 2agonist last ? 2 hours Instructions to patient Proceed to ED, or call ambulance or 911 and repeat treatment while waiting Instructions to patient May continue 24 puffs (or nebulizer) 2agonist every 34 hours for 2428 hours prn For patients on inhaled steroids, double dose for 710 days Contact PCP within 48 hours for instructions Instructions to patient Take 24 puffs (or nebulizer) 2 agonist every 24 hours for 2448 hours prn Add oral steroid (see contraindications below) Contact PCP urgently (within 24 hours) for instructions Instructions to patient IMMEDIATELY: Take 46 puffs (or nebulizer) 2 agonist Start oral steroids if available (see contraindications below) Instruct parent to call back in 5 minutes after treatment finished If still in RED ZONE proceed to ED, or call ambulance or 911 and repeat treatment while waiting If in YELLOW ZONE, move to YELLOW ZONE protocol (top left box) Documentation faxed or given to PCP within 24 hours; phone or verbal contact sooner as indicated. Ask patient about preexisting conditions |
6,635 | that may be contraindications to oral steroids (including type 1 diabetes, active chicken pox, chicken pox exposure or varicella vaccine within 21 days, MMR within 14 days). If so, nurse to contact PCP before initiating steroids. Oral steroid dosages: Child: 2 mgkgday, maximum 60 mgday, for 5 days. Date: Signature Fig. 185.6 Algorithm for treatment of acute asthma symptoms. ED, Emergency department; PCP, primary care physician; PEF, peak expiratory flow. (Courtesy BJC HealthcareWashington University School of Medicine, Community Asthma Program, January 2000.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1408 Part XIII u Allergic Disorders Asthma exacerbations characteristically vary among individuals but tend to be similar in the same patient. Severe asthma exacerbations, resulting in respiratory distress, hypoxia, hospitalization, and respira tory failure, are the best predictors of future life threatening exacer bations or a fatal asthma episode. In addition to distinguishing such high risk children, some experience exacerbations that develop over days, with airflow obstruction resulting from progressive inflamma tion, epithelial sloughing, and cast impaction of small airways. When such a process is extreme, respiratory failure because of fatigue can ensue, necessitating mechanical ventilation for numerous days. In con trast, some children experience abrupt onset exacerbations that may result from extreme AHR and physiologic susceptibility to airways clo sure. Such exacerbations, when extreme, are asphyxial in nature, often occur outside medical settings, are initially associated with very high arterial partial pressure of carbon dioxide (Pco2) levels, and tend to require only brief periods of supportive ventilation. Recognizing the characteristic differences in asthma exacerbations is important for optimizing their early management. Home Management of Asthma Exacerbations Families of all children with asthma should have a written Asthma Action Plan (see Fig. 185.5) to guide their recognition and manage ment of exacerbations, along with the necessary education, medications, and tools to manage them. Early recognition of asthma exacerbations to intensify treatment early can often prevent further worsening and keep exacerbations from becoming severe. The NIH guidelines recom mend immediate treatment with rescue medication (inhaled SABA, 2 4 puffs, up to 3 times every 20 minutes in 1 hour). A good response is characterized by resolution of symptoms within 1 hour and no further symptoms over the next 4 hours. The childs physician should be con tacted for follow up, especially if bronchodilators are required repeatedly over the next 24 48 hours. If the child has an incomplete response to initial treatment with rescue medication, a short course of OCS therapy (for example, prednisone, 1 2 mgkgday not to exceed 40 mgday for 4 days) should be instituted, in addition to inhaled agonist therapy. The physician should also be contacted for further instructions. Immedi ate medical attention should be sought for severe exacerbations, persis tent signs of respiratory distress, lack of expected response or sustained improvement after initial treatment, further deterioration, or high risk factors |
6,636 | for asthma morbidity or mortality (e.g., previous history of severe exacerbations). For patients with severe asthma andor a history of life threatening episodes, especially if abrupt in onset, an epinephrine auto injector and perhaps portable oxygen at home can be considered. Use of either of these extreme measures for home management of asthma exacer bations would be an indication to call 911 for emergency support services. Emergency Department Management of Asthma Exacerbations In the ED, the primary goals of asthma management include correction of hypoxemia, rapid improvement of airflow obstruction, and preven tion of progression or recurrence of symptoms. Interventions are based on clinical severity on arrival, response to initial therapy, and presence of risk factors associated with asthma morbidity and mortality (see Table 185.18). Indicators of a severe exacerbation include breathless ness, dyspnea, retractions, accessory muscle use, tachypnea or labored breathing, cyanosis, mental status changes, a silent chest with poor air exchange, and severe airflow limitation (PEF or FEV1 value 50 of personal best or predicted values). Initial treatment includes supple mental oxygen, inhaled agonist therapy every 20 minutes for 1 hour, and, if necessary, oral, injectable or IV systemic corticosteroids (see Tables 185.4 and 185.17, and Fig. 185.6). Inhaled ipratropium may be added to the agonist treatment, especially if no significant response is seen with the first inhaled agonist treatment. In the ED, single oral, IV, or intramuscular (IM) dose dexamethasone (0.6 mgkg, maximum 16 mg) is an effective alternative to prednisone and with a lower inci dence of emesis. A second dose of dexamethasone can be given the next day whether discharged or admitted to the hospital. An IM injec tion of epinephrine or other agonist may be administered in severe cases. Oxygen should be administered and continued for at least 20 minutes after SABA administration to compensate for possible ventila tionperfusion abnormalities caused by SABAs. Close monitoring of clinical status, hydration, and oxygenation are essential elements of immediate management. A poor response to inten sified treatment in the first hour suggests that the exacerbation will not remit quickly. The patient may be discharged home if there is sustained improvement in symptoms, normal physical findings, PEF 70 of pre dicted or personal best, and oxygen saturation 92 while the patient is breathing room air for 4 hours. Discharge medications include adminis tration of an inhaled agonist up to every 3 4 hours plus a short course of an OCS. Optimizing controller therapy before discharge is also rec ommended. The addition of ICS to a course of OCS in the ED setting reduces the risk of exacerbation recurrence over the subsequent month. Hospital Management of Asthma Exacerbations For patients with severe exacerbations that do not adequately improve within 1 2 hours of intensive treatment, observation andor admission to the hospital, at least overnight, is likely to be needed. Other indica tions for hospital admission include high risk features for asthma mor bidity or death (see Table 185.18). Admission to an ICU is indicated for patients with severe respiratory |
6,637 | distress, poor response to therapy, and concern for potential respiratory failure and arrest. Supplemental oxygen, frequent or continuous administration of an inhaled bronchodilator, and systemic corticosteroid therapy are the conventional interventions for children admitted to the hospital for status asthmaticus (see Table 185.17). Supplemental oxygen is admin istered because many children hospitalized with acute asthma have or will eventually have hypoxemia, especially at night and with increasing Table 185.18 Risk Factors for Asthma Morbidity and Mortality BIOLOGIC Previous severe asthma exacerbation (intensive care unit admission, intubation for asthma) Sudden asphyxia episodes (respiratory failure, arrest) Two or more hospitalizations for asthma in past year Three or more emergency department visits for asthma in past year Increasing and large diurnal variation in peak flows Use of 2 canisters of short acting agonists per month Poor response to systemic corticosteroid therapy Male sex Low birthweight NonWhite Sensitivity to Alternaria ENVIRONMENTAL Allergen exposure Environmental tobacco smoke exposure Air pollution exposure Urban environment ECONOMIC AND PSYCHOSOCIAL Poverty Crowding Mother 20 yr old Mother with less than high school education Inadequate medical care Inaccessible Unaffordable No regular medical care (only emergency) Lack of written Asthma Action Plan No care sought for chronic asthma symptoms Delay in care of asthma exacerbations Inadequate hospital care for asthma exacerbation Psychopathology in the parent or child Poor perception of asthma symptoms or severity Alcohol or substance abuse Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 185 u Childhood Asthma 1409 SABA administration. SABAs can be delivered frequently (every 20 minutes to 1 hour) or continuously (at 5 15 mghr). When adminis tered continuously, significant systemic absorption of agonist occurs, and thus continuous nebulization can obviate the need for IV agonist therapy. Adverse effects of frequently administered agonist therapy include tremor, irritability, tachycardia, and hypokalemia; lactic aci dosis is an uncommon complication. Patients requiring frequent or continuous nebulized agonist therapy should have ongoing cardiac monitoring. Because frequent agonist therapy can cause ventilation perfusion mismatch and hypoxemia, oximetry is also indicated. Inhaled ipratropium is often added to albuterol every 6 hours if patients do not show a remarkable improvement, although there is little evidence to support its use in hospitalized children receiving aggressive inhaled agonist therapy and systemic corticosteroids. In addition to its potential to provide a synergistic effect with a agonist agent in relieving severe bronchospasm, ipratropium may be beneficial in patients who have mucus hypersecretion or who are receiving blockers. Short course systemic corticosteroid therapy is recommended for use in moderate to severe asthma exacerbations to hasten recovery and prevent recurrence of symptoms. Studies in children hospitalized with acute asthma have found corticosteroids administered orally to be as effective as IV corticosteroids. Accordingly, OCS therapy can often be used, although children with sustained respiratory distress and those unable to tolerate oral preparations or liquids are obvious candidates for IV corticosteroid therapy. Patients with |
6,638 | persistent severe dyspnea and high flow oxygen requirements require additional evaluation, such as complete blood count, arterial blood gases, serum electrolytes, and chest radiograph, to monitor for respiratory insufficiency, comorbidities, infection, and dehydration. Hydration status monitoring is especially impor tant in infants and young children, whose increased respiratory rate (insensible losses) and decreased oral intake put them at higher risk for dehydration. Further complicating this situation is the association of increased antidiuretic hormone secretion with status asthmaticus. Administration of fluids at or slightly below maintenance fluid require ments is recommended. Chest physical therapy, incentive spirometry, and mucolytics are not recommended during asthma exacerbations because they can trigger severe bronchoconstriction. Despite intensive therapy, some asthmatic children remain critically ill and at risk for respiratory failure, intubation, and mechanical ventilation. Complications (e.g., air leaks) related to asthma exacerbations increase with intubation and assisted ventilation, so every effort should be made to relieve bronchospasm and prevent respiratory failure. Several therapies, including parenteral agonists, magnesium sulfate (25 75 mgkg, maxi mum dose 2.5 g, given intravenously over 20 minutes), and inhaled heliox (helium and oxygen mixture) have demonstrated some benefit as adjunc tive therapies in patients with severe status asthmaticus. Administration of magnesium sulfate requires monitoring of serum levels and cardiovascular status. Noninvasive positive pressure ventilation (e.g., continuous positive airway pressure CPAP or biphasic positive airway pressure BiPAP) might improve severe asthma exacerbations through a variety of mecha nisms. Their use in the care of children with severe persistent asthma exacerbations has increased in efforts to avert mechanical ventilation, even though evidence supporting the intervention has been considered weak, and current NAEPP and GINA guidelines do not recommend the intervention. Parenteral (SC, IM, or IV) epinephrine or terbutaline sulfate may be effective in patients with life threatening obstruction that is not responding to high doses of inhaled agonists, because inhaled medica tion may not reach the lower airway in such patients. Rarely, a severe asthma exacerbation in a child results in respiratory failure, and intubation and mechanical ventilation become necessary. Mechanical ventilation in severe asthma exacerbations requires the careful balance of enough pressure to overcome airways obstruction while reducing hyperinflation, air trapping, and the likelihood of baro trauma (pneumothorax, pneumomediastinum; see Chapter 461). To minimize the likelihood of such complications, mechanical ventilation should be anticipated, and asthmatic children at risk for the development of respiratory failure should be managed in a pediatric ICU. Elective tra cheal intubation with rapid induction sedatives and paralytic agents is safer than emergency intubation. Mechanical ventilation aims to achieve adequate oxygenation while tolerating mild to moderate hypercapnia (Pco2 50 70 mm Hg) to minimize barotrauma. As measures to relieve mucus plugs, chest percussion and airways lavage are not recommended because they can induce further bronchospasm. One must consider the nature of asthma exacerbations leading to respiratory failure; those of rapid or abrupt onset tend to resolve quickly (hours to 2 days), whereas those that progress gradually to respiratory failure can require days to weeks of mechanical ventilation. Such prolonged |
6,639 | cases are further com plicated by corticosteroid induced myopathy, which can lead to severe muscle weakness requiring prolonged rehabilitation. In children, management of severe exacerbations in medical centers is usually successful, even when extreme measures are required. Con sequently, asthma deaths in children rarely occur in medical centers; most occur at home or in community settings before lifesaving medi cal care can be administered. This point highlights the importance of home and community management of asthma exacerbations, early intervention measures to keep exacerbations from becoming severe, and steps to reduce asthma severity. A follow up appointment within 1 2 weeks of a childs discharge from the hospital after resolution of an asthma exacerbation should be used to monitor clinical improvement and to reinforce key educational elements, including action plans and controller medications. Special Management Circumstances Management of Infants and Young Children Recurrent wheezing episodes in preschool age children are common, occurring in as much as one third of this population. Of these, most improve and even become asymptomatic during the prepubescent school age years, whereas others have lifelong persistent asthma. All require management of their recurrent wheezing problems. The NIH guidelines recommend risk assessment to identify preschool age chil dren who are likely to have persistent asthma. One implication of this recommendation is that these at risk children may be candidates for conventional asthma management, including daily controller therapy and early intervention with exacerbations (see Tables 185.9, 185.10, 185.13, and 185.14). For young children with recurrent episodic wheeze in the setting of viral illness, a short course of daily high dose ICS may also be considered. For young children with a history of moderate to severe exacerbations, nebulized budesonide is approved by the FDA, and its use as a controller medication could prevent sub sequent exacerbations. Using aerosol therapy in infants and young children with asthma presents unique challenges. There are two delivery systems for inhaled medications for this age group: the nebulizer and the MDI with spacer holding chamber and face mask. Multiple studies demonstrate the effectiveness of both nebulized albuterol in acute episodes and nebu lized budesonide in the treatment of recurrent wheezing in infants and young children. In such young children, inhaled medications adminis tered via MDI with spacer and face mask may be acceptable, although perhaps not preferred because of limited published information and lack of FDA approval for children 4 years of age. Asthma Management During Surgery Patients with asthma are at risk from disease related complications from surgery, such as bronchoconstriction and asthma exacerbation, atelectasis, impaired coughing, respiratory infection, and latex expo sure, which may induce asthma complications in patients with latex allergy. All patients with asthma should be evaluated before surgery, and those who are inadequately controlled should allow time for inten sified treatment to improve asthma stability before surgery, if possible. A systemic corticosteroid course may be indicated for the patient who is having symptoms andor FEV1 or PEF values 80 of the patients personal best. In addition, patients who have received |
6,640 | 2 weeks of sys temic corticosteroid andor moderate to high dose ICS therapy may be at risk for intraoperative adrenal insufficiency. For these patients, anesthesia services should be alerted to provide stress replacement doses of systemic corticosteroid for the surgical procedure and possibly the postoperative period. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1410 Part XIII u Allergic Disorders PROGNOSIS Recurrent coughing and wheezing occur in 35 of preschool age children. Of these, approximately one third continue to have per sistent asthma into later childhood, and approximately two thirds improve on their own through their teen years. Concomitant atopic disorders (such as allergen sensitization or atopic dermatitis) are asso ciated with greater likelihood of disease persistence. Asthma severity by ages 7 10 years is predictive of asthma persistence in adulthood. Children with moderate to severe asthma and with lower lung func tion measures are likely to have persistent asthma as adults. Children with milder asthma and normal lung function are likely to improve over time, with some becoming periodically asthmatic (disease free for months to years). PREVENTION Although chronic airways inflammation may result in pathologic remodeling of lung airways, conventional antiinflammatory interven tionsthe cornerstone of asthma controldo not help children out grow their asthma. Although controller medications reduce asthma morbidities, most children with moderate to severe asthma continue to have symptoms into young adulthood. Investigations into the envi ronmental and lifestyle factors responsible for the lower prevalence of childhood asthma in rural areas and farming communities suggest that early immunomodulatory intervention might prevent asthma develop ment. A hygiene hypothesis purports that naturally occurring micro bial exposures in early life might drive early immune development away from allergic sensitization, persistent airways inflammation, and remodeling through early microbiome and innate immune develop ment. If these natural microbial exposures truly have an asthma protective effect, without significant adverse health consequences, these findings may foster new strategies for asthma prevention. Several nonpharmacologic measures with numerous positive health attributesavoidance of environmental tobacco smoke (beginning prenatally), prolonged breastfeeding (4 months), an active lifestyle, and a healthy dietmight reduce the likelihood of asthma develop ment. Care providers can be strong influencers of smoking cessation by parents, caregivers, and adolescent patients (see Chapters 157.2 and 759.1). Immunizations are not considered to increase the likelihood of development of asthma; therefore all standard childhood immuniza tions are recommended for children with asthma, including varicella, SARS CoV 2, and annual influenza vaccines. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Atopic dermatitis (AD), or eczema, is the most common chronic relapsing skin disease seen in infancy and childhood. It affects 1030 of children worldwide and frequently occurs in families with other atopic diseases. Infants with AD are predisposed to the development of food allergy, allergic rhinitis, and asthma later in childhood, a process called the atopic march. Chapter 186 Atopic Dermatitis (Atopic Eczema) Donald Y.M. |
6,641 | Leung and Scott H. Sicherer ETIOLOGY AD is a complex genetic disorder that results in a defective skin barrier, reduced skin innate immune responses, and primarily type 2 adaptive immune responses to environmental allergens and microbes that lead to chronic skin inflammation. PATHOLOGY Acute AD skin lesions are characterized by spongiosis, or marked intercellular edema, of the epidermis. In AD, dendritic antigen presenting cells (APCs) in the epidermis, such as Langerhans cells, exhibit surface bound IgE molecules with cell processes that reach into the upper epidermis to sense allergens and pathogens. These APCs play an important role in cutaneous responses to type 2 immune responses (see Chapter 182). There is marked perivascular T cell and inflammatory monocyte macrophage infiltration in acute AD lesions. Chronic, lichenified AD is characterized by a hyperplastic epidermis with hyperkeratosis and minimal spongiosis. There are predominantly IgE bearing Langerhans cells in the epidermis, and macrophages in the dermal mononuclear cell infiltrate. Mast cell and eosinophil numbers are increased, contributing to skin inflammation. PATHOGENESIS AD is associated with multiple phenotypes and endotypes that have overlapping clinical presentations. Atopic eczema is associated with IgE mediated sensitization (at onset or during the course of eczema) and occurs in 7080 of patients with AD. Nonatopic eczema is not associated with IgE mediated sensitization and is seen in 2030 of patients with AD. Both forms of AD are associated with eosinophilia. In atopic eczema, circulating T cells expressing the skin homing recep tor cutaneous lymphocyte associated antigen produce increased lev els of T helper type 2 (Th2) cytokines, including interleukin (IL) 4 and IL 13, which induce isotype switching to IgE synthesis. Another type 2 cytokine, IL 5, plays an important role in eosinophil development and IL 31 is a key itch cytokine (Fig. 186.1). Nonatopic eczema is associated with lower IL 4 and IL 13 but increased IL 17 and IL 23 production than in atopic eczema. Age has also been found to affect the immune profile in AD. Compared with the skin of healthy individuals, both unaffected skin and acute skin lesions of patients with AD have an increased number of cells expressing IL 4, IL 13, and IL 31. Chronic AD skin lesions, by contrast, have fewer cells that express IL 4 and IL 13, but they have more cells that express IL 5, granulocyte macrophage colony stimulating factor, IL 12, and interferon (IFN) than acute AD lesions. Despite increased type 1 and type 17 immune responses in chronic AD, IL 4 and IL 13 as well as other type 2 cytokines (e.g., thymic stromal lymphopoietin TSLP, IL 31, IL 33) predominate and reflect increased numbers of type 2 innate lymphoid cells and Th2 cells. The infiltration of IL 22expressing T cells correlates with severity of AD, blocks keratinocyte differentiation, and induces epidermal hyper plasia. The importance of IL 4 and IL 13 in driving severe persistent AD has been validated by multiple clinical trials now demonstrating that biologics blocking IL 4 and IL 13 action lead to |
6,642 | clinical improve ment in moderate to severe AD. In healthy people, the skin acts as a protective barrier against exter nal irritants, moisture loss, and infection. Proper function of the skin depends on adequate moisture and lipid content, functional immune responses, and structural integrity. Severely dry skin is a hallmark of AD. This results from compromise of the epidermal barrier, which leads to excess transepidermal water loss, allergen penetration, and microbial colonization. Filaggrin, a structural protein in the epidermis, and its breakdown products are critical to skin barrier function, including moisturization of the skin. Genetic pathogenic variants in the filaggrin gene (FLG) family have been identified in patients with ichthyosis vul garis (dry skin, palmar hyperlinearity) and in up to 50 of patients with severe AD. FLG pathogenic variant is strongly associated with the development of food allergy and eczema herpeticum. Nonetheless, up to 60 of carriers of an FLG pathogenic variant do not develop atopic diseases. Cytokines found in allergic inflammation, such as IL 4, IL 13, IL 22, and IL 25, and tumor necrosis factor, can also reduce filaggrin Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1410 Part XIII u Allergic Disorders PROGNOSIS Recurrent coughing and wheezing occur in 35 of preschool age children. Of these, approximately one third continue to have per sistent asthma into later childhood, and approximately two thirds improve on their own through their teen years. Concomitant atopic disorders (such as allergen sensitization or atopic dermatitis) are asso ciated with greater likelihood of disease persistence. Asthma severity by ages 7 10 years is predictive of asthma persistence in adulthood. Children with moderate to severe asthma and with lower lung func tion measures are likely to have persistent asthma as adults. Children with milder asthma and normal lung function are likely to improve over time, with some becoming periodically asthmatic (disease free for months to years). PREVENTION Although chronic airways inflammation may result in pathologic remodeling of lung airways, conventional antiinflammatory interven tionsthe cornerstone of asthma controldo not help children out grow their asthma. Although controller medications reduce asthma morbidities, most children with moderate to severe asthma continue to have symptoms into young adulthood. Investigations into the envi ronmental and lifestyle factors responsible for the lower prevalence of childhood asthma in rural areas and farming communities suggest that early immunomodulatory intervention might prevent asthma develop ment. A hygiene hypothesis purports that naturally occurring micro bial exposures in early life might drive early immune development away from allergic sensitization, persistent airways inflammation, and remodeling through early microbiome and innate immune develop ment. If these natural microbial exposures truly have an asthma protective effect, without significant adverse health consequences, these findings may foster new strategies for asthma prevention. Several nonpharmacologic measures with numerous positive health attributesavoidance of environmental tobacco smoke (beginning prenatally), prolonged breastfeeding (4 months), an active lifestyle, and |
6,643 | a healthy dietmight reduce the likelihood of asthma develop ment. Care providers can be strong influencers of smoking cessation by parents, caregivers, and adolescent patients (see Chapters 157.2 and 759.1). Immunizations are not considered to increase the likelihood of development of asthma; therefore all standard childhood immuniza tions are recommended for children with asthma, including varicella, SARS CoV 2, and annual influenza vaccines. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Atopic dermatitis (AD), or eczema, is the most common chronic relapsing skin disease seen in infancy and childhood. It affects 1030 of children worldwide and frequently occurs in families with other atopic diseases. Infants with AD are predisposed to the development of food allergy, allergic rhinitis, and asthma later in childhood, a process called the atopic march. Chapter 186 Atopic Dermatitis (Atopic Eczema) Donald Y.M. Leung and Scott H. Sicherer ETIOLOGY AD is a complex genetic disorder that results in a defective skin barrier, reduced skin innate immune responses, and primarily type 2 adaptive immune responses to environmental allergens and microbes that lead to chronic skin inflammation. PATHOLOGY Acute AD skin lesions are characterized by spongiosis, or marked intercellular edema, of the epidermis. In AD, dendritic antigen presenting cells (APCs) in the epidermis, such as Langerhans cells, exhibit surface bound IgE molecules with cell processes that reach into the upper epidermis to sense allergens and pathogens. These APCs play an important role in cutaneous responses to type 2 immune responses (see Chapter 182). There is marked perivascular T cell and inflammatory monocyte macrophage infiltration in acute AD lesions. Chronic, lichenified AD is characterized by a hyperplastic epidermis with hyperkeratosis and minimal spongiosis. There are predominantly IgE bearing Langerhans cells in the epidermis, and macrophages in the dermal mononuclear cell infiltrate. Mast cell and eosinophil numbers are increased, contributing to skin inflammation. PATHOGENESIS AD is associated with multiple phenotypes and endotypes that have overlapping clinical presentations. Atopic eczema is associated with IgE mediated sensitization (at onset or during the course of eczema) and occurs in 7080 of patients with AD. Nonatopic eczema is not associated with IgE mediated sensitization and is seen in 2030 of patients with AD. Both forms of AD are associated with eosinophilia. In atopic eczema, circulating T cells expressing the skin homing recep tor cutaneous lymphocyte associated antigen produce increased lev els of T helper type 2 (Th2) cytokines, including interleukin (IL) 4 and IL 13, which induce isotype switching to IgE synthesis. Another type 2 cytokine, IL 5, plays an important role in eosinophil development and IL 31 is a key itch cytokine (Fig. 186.1). Nonatopic eczema is associated with lower IL 4 and IL 13 but increased IL 17 and IL 23 production than in atopic eczema. Age has also been found to affect the immune profile in AD. Compared with the skin of healthy individuals, both unaffected skin and acute skin lesions of patients with AD have an increased number of cells expressing IL 4, IL 13, and IL 31. Chronic AD skin lesions, |
6,644 | by contrast, have fewer cells that express IL 4 and IL 13, but they have more cells that express IL 5, granulocyte macrophage colony stimulating factor, IL 12, and interferon (IFN) than acute AD lesions. Despite increased type 1 and type 17 immune responses in chronic AD, IL 4 and IL 13 as well as other type 2 cytokines (e.g., thymic stromal lymphopoietin TSLP, IL 31, IL 33) predominate and reflect increased numbers of type 2 innate lymphoid cells and Th2 cells. The infiltration of IL 22expressing T cells correlates with severity of AD, blocks keratinocyte differentiation, and induces epidermal hyper plasia. The importance of IL 4 and IL 13 in driving severe persistent AD has been validated by multiple clinical trials now demonstrating that biologics blocking IL 4 and IL 13 action lead to clinical improve ment in moderate to severe AD. In healthy people, the skin acts as a protective barrier against exter nal irritants, moisture loss, and infection. Proper function of the skin depends on adequate moisture and lipid content, functional immune responses, and structural integrity. Severely dry skin is a hallmark of AD. This results from compromise of the epidermal barrier, which leads to excess transepidermal water loss, allergen penetration, and microbial colonization. Filaggrin, a structural protein in the epidermis, and its breakdown products are critical to skin barrier function, including moisturization of the skin. Genetic pathogenic variants in the filaggrin gene (FLG) family have been identified in patients with ichthyosis vul garis (dry skin, palmar hyperlinearity) and in up to 50 of patients with severe AD. FLG pathogenic variant is strongly associated with the development of food allergy and eczema herpeticum. Nonetheless, up to 60 of carriers of an FLG pathogenic variant do not develop atopic diseases. Cytokines found in allergic inflammation, such as IL 4, IL 13, IL 22, and IL 25, and tumor necrosis factor, can also reduce filaggrin Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 186 u Atopic Dermatitis (Atopic Eczema) 1411 and other epidermal proteins and lipids. AD patients are at increased risk of bacterial, viral, and fungal infection related to impairment of innate immunity, disturbances in the microbiome, skin epithelial dys function, and overexpression of polarized immune pathways, which dampen host antimicrobial responses. Patients with the combination of AD and food allergy have significantly lower levels of filaggrin and increased type 2 immune activation than patients with AD only. CLINICAL MANIFESTATIONS AD typically begins in infancy. Approximately 50 of patients experi ence symptoms in the first year of life, and an additional 30 are diag nosed between 1 and 5 years of age. Intense pruritus, especially at night, and cutaneous reactivity are the cardinal features of AD. Scratching and excoriation cause increased skin inflammation that contributes to the development of more pronounced eczematous skin lesions. Foods (cows milk, egg, peanut, tree nuts, |
6,645 | soy, wheat, fish, shellfish), aeroal lergens (pollen, grass, animal dander, dust mites), infection (Staphy lococcus aureus, herpes simplex, coxsackievirus, molluscum), reduced humidity, excessive sweating, and irritants (wool, acrylic, soaps, toilet ries, fragrances, detergents) can trigger pruritus and scratching. Acute AD skin lesions are intensely pruritic with erythematous papules (Figs. 186.2 and 186.3). Subacute dermatitis manifests as ery thematous, excoriated, scaling papules. In contrast, chronic AD is char acterized by lichenification (Fig. 186.4), or thickening of the skin with accentuated surface markings, and fibrotic papules. In chronic AD, all three types of skin reactions may coexist in the same individual. Most patients with AD have dry, lackluster skin regardless of their stage of illness. Skin reaction pattern and distribution vary with the patients age and disease activity. AD is generally more acute in infancy and involves the face, scalp, and extensor surfaces of the extremities. The diaper area is usually spared. Older children and children with chronic AD have lichenification and localization of the rash to the flexural folds of the extremities. AD can go into remission as the patient grows older; however, many children with AD have persistent eczema as an adult (see Fig. 186.2C). LABORATORY FINDINGS There are no specific laboratory tests to diagnose AD. Many patients have peripheral blood eosinophilia, increased serum IgE levels, and T cells expressing type 2 cytokines. Serum IgE measurement or skin prick testing can identify the allergens (foods, inhalantmicrobial aller gens) to which patients are sensitized. The diagnosis of clinical allergy to these allergens requires confirmation by history and environmental challenges. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS AD is diagnosed on the basis of three major features: pruritus, an eczematous dermatitis that fits into a typical pattern of skin inflam mation, and a chronic or chronically relapsing course (Table 186.1). Associated features, such as a family history of asthma, hay fever, food Allergens Epidermis Dermis Sensory neuron Epidermal hyperplasia PDE4 activity in T cells leads to in cytokine mediators Barrier disruption Differentiation Filaggrin Loricrin Involucrin Barrier inhibitionCytokines Chemokines Itch LC DC IL4 IL4 IL4 IL4 Basophil Mast cell Eosinophil IL13 ADDC B cell IgE Lymph node ADDC Th0 ThO Th2 Th1 products Th2 Th22 Th0 Th1 Scratch LichenificationMicrobiome (S aureus) Nonlesional Blood vessel Acute Chronic Disrupted barrier Keratinocyte Fig. 186.1 Pathogenic pathways and immunologic targets in atopic dermatitis (AD). Skin barrier defects in nonlesional atopic dermatitis leads to penetration by allergens, which encounter antigen presenting Langerhans cells (LCs) in the epidermis and dendritic cells (DCs) in the dermis, resulting in immune activation and inflammatory cell recruitment. Elevated T helper type 2 (Th2) cell counts in the acute state leads to increased secretion of cytokines, especially interleukin (IL) 4 and IL 13, which disrupt the skin barrier by decreasing expression of barrier proteins (i.e., filaggrin, loricrin, and involucrin). In addition, Th2 cytokines recruit eosinophils and basophils to lesional sites, and increase B cell IgE production. Eosinophils, basophils, and activated IgE bound mast cells release proinflammatory mediators, further potentiating pathogenesis. Th2 cytokines also impair anti microbial peptide |
6,646 | responses to pathogens which, in combination with barrier disruption, increases the risk of colonization and barrier penetration by allergens and pathogens (i.e., Staphylococcus aureus). Chronic atopic dermatitis results in a skewed Th1 response, leading to further inflammation and immune activation. Processes mediated by Janus kinase (JAK) receptors are marked with a green asterisk. PDE4, phosphodiesterase 4. (From Vahharia PP, Silverberg JI. New and emerging therapies for paediatric atopic dermatitis. Lancet Child Adolesc. 2019;3:343352.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1412 Part XIII u Allergic Disorders allergy, elevated IgE, and immediate skin test reactivity, reinforce the diagnosis of AD. Many inflammatory skin diseases, immunodeficiencies, skin malignancies, genetic disorders, infectious diseases, and infes tations share symptoms with AD and should be considered and excluded before a diagnosis of AD is established (Tables 186.2 and 186.3). Severe combined immunodeficiency (see Chapter 165.1) should be considered for infants presenting in the first year of life with diarrhea, failure to thrive, generalized scaling rash, and recur rent cutaneous andor systemic infection. Histiocytosis should be excluded in any infant with AD and failure to thrive (see Chapter 556). Wiskott Aldrich syndrome, an X linked recessive disorder associated with thrombocytopenia, immune defects, and recurrent severe bacterial infections, is characterized by a rash almost indis tinguishable from that in AD (see Chapter 165.4). One of the hyper IgE syndromes is characterized by markedly elevated serum IgE values, recurrent deep seated bacterial infections, chronic derma titis, and refractory dermatophytosis. Many of these patients have disease as a result of autosomal dominant STAT3 pathogenic vari ants. In contrast, some patients with hyper IgE syndrome present with increased susceptibility to viral infections and an autosomal recessive pattern of disease inheritance. These patients may have a dedicator of cytokinesis 8 gene (DOCK8) pathogenic variants. This diagnosis should be considered in young children with severe eczema, food allergy, and disseminated skin viral infections. Adolescents who present with an eczematous dermatitis but no his tory of childhood eczema, respiratory allergy, or atopic family history may have allergic contact dermatitis. A contact allergen may be the problem in any patient whose AD does not respond to appropriate therapy. Sensitizing chemicals, such as parabens and lanolin, can be irritants for patients with AD and are commonly found as vehicles in therapeutic topical agents. Topical glucocorticoid contact allergy has been reported in patients with chronic dermatitis receiving topical cor ticosteroid therapy. Eczematous dermatitis has also been reported with HIV infection as well as with a variety of infestations such as scabies. Other conditions that can be confused with AD include psoriasis, ich thyosis, and seborrheic dermatitis. TREATMENT The treatment of AD requires a systematic, multifaceted approach that incorporates skin moisturization, topical antiinflammatory therapy, identification and elimination of flare factors (Table 186.4), and, if nec essary, systemic therapy (Fig. 186.5). Assessment of the severity also helps direct therapy (Table 186.5; |
6,647 | see Fig. 186.5). Cutaneous Hydration Because patients with AD have impaired skin barrier function from reduced filaggrin and skin lipid levels, they present with diffuse, abnor mally dry skin, or xerosis. Moisturizers are first line therapy. Luke warm soaking baths or showers for 15 20 minutes followed by the Fig. 186.2 Typical clinical appearance and locations of atopic dermatitis at different ages. A, In infants, atopic dermatitis is generally acute, with lesions mainly on the face and the extensor surfaces of the limbs. The trunk might be affected, but the napkin area is typically spared. B, From age 1 2 years onward, polymorphous manifestations with different types of skin lesions are seen, particularly in flexural folds. C, Adolescents and adults often present lichenified and excoriated plaques at flexures, wrists, ankles, and eyelids; in the head and neck type, the upper trunk, shoulders, and scalp are involved. Adults might have only chronic hand eczema or present with prurigo like lesions. (From Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387:1111.) A B C Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 186 u Atopic Dermatitis (Atopic Eczema) 1413 application of an occlusive emollient to retain moisture provide symp tomatic relief. Hydrophilic ointments of varying degrees of viscosity can be used according to the patients preference. Occlusive ointments are sometimes not well tolerated because of interference with the func tion of the eccrine sweat ducts and may induce the development of folliculitis. In these patients, less occlusive agents should be used. Sev eral prescription (classified as a medical device) therapeutic moistur izers or barrier creams are available, containing components such as ceramides and filaggrin acid metabolites intended to improve skin barrier function. There are minimal data demonstrating their efficacy over standard emollients. Hydration by baths or wet dressings promotes transepidermal pen etration of topical glucocorticoids. Dressings may also serve as effec tive barriers against persistent scratching, in turn promoting healing of excoriated lesions. Wet dressings are recommended for use on severely affected or chronically involved areas of dermatitis refractory to skin care. It is critical that wet dressing therapy be followed by topical emollient application to avoid potential drying and fissuring from the therapy. Wet dressing therapy can be complicated by maceration and secondary infection and should be closely monitored by a physician. Topical Corticosteroids Topical corticosteroids are the cornerstone of antiinflammatory treat ment for acute exacerbations of AD. Patients should be carefully instructed on their use of topical glucocorticoids to avoid potential adverse effects. There are seven classes of topical glucocorticoids, ranked according to their potency, as determined by vasoconstric tor assays (Table 186.6). Because of their potential adverse effects, the ultra high potency glucocorticoids should not be used on the face or intertriginous areas and should be used only for very short periods on the trunk and extremities. Mid potency glucocorticoids can be used |
6,648 | for longer periods to treat chronic AD involving the trunk and extrem ities. Long term control can be maintained with twice weekly applica tions of topical fluticasone or mometasone to areas that have healed but are prone to relapse, once control of AD is achieved after a daily regimen of topical corticosteroids. Compared with creams, ointments have a greater potential to occlude the epidermis, resulting in enhanced systemic absorption. Adverse effects of topical glucocorticoids can be divided into local adverse effects and systemic adverse effects, the latter resulting from suppression of the hypothalamic pituitary adrenal axis. Local adverse effects include the development of striae and skin atrophy. Systemic adverse effects are related to the potency of the topical corticosteroid, site of application, occlusiveness of the preparation, percentage of the body surface area covered, and length of use. The potential for adrenal suppression from potent topical corticosteroids is greatest in infants and young children with severe AD requiring intensive therapy. Topical Calcineurin Inhibitors The nonsteroidal topical calcineurin inhibitors are effective in reducing AD skin inflammation. Pimecrolimus cream 1 (Elidel) is indicated for mild to moderate AD. Tacrolimus ointment 0.1 and 0.03 (Pro topic) is indicated for moderate to severe AD. Both are approved for short term or intermittent long term treatment of AD in patients 2 years whose disease is unresponsive to or who are intolerant of other conventional therapies or for whom these therapies are inadvisable Fig. 186.4 Lichenification of the popliteal fossa from chronic rubbing of the skin in atopic dermatitis. (From Weston WL, Lane AT, Morelli JG. Color Textbook of Pediatric Dermatology. 2nd ed. St Louis: Mosby; 1996. p 33.) Table 186.1 Clinical Features of Atopic Dermatitis MAJOR FEATURES Pruritus Facial and extensor eczema in infants and children Flexural eczema in adolescents Chronic or relapsing dermatitis Personal or family history of atopic disease ASSOCIATED FEATURES Xerosis Cutaneous infections (Staphylococcus aureus, group A streptococcus, herpes simplex, coxsackievirus, vaccinia, molluscum, warts) Nonspecific dermatitis of the hands or feet Ichthyosis, palmar hyperlinearity, keratosis pilaris Nipple eczema White dermatographism and delayed blanch response Anterior subcapsular cataracts, keratoconus Elevated serum IgE levels Positive results of immediate type allergy skin tests Early age at onset Dennie lines (Dennie Morgan infraorbital folds) Facial erythema or pallor Course influenced by environmental andor emotional factors Lichenification Perioral, periauricular sites Prurigo Fig. 186.3 Crusted lesions of atopic dermatitis on the face. (From Eichenfield LF, Friedan IJ, Esterly NB. Textbook of Neonatal Dermatol ogy. Philadelphia: Saunders; 2001. p 242.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1414 Part XIII u Allergic Disorders because of potential risks. Topical calcineurin inhibitors may be better than topical corticosteroids in the treatment of patients whose AD is poorly responsive to topical steroids, patients with steroid phobia, and those with face and neck dermatitis, in whom ineffective, low potency topical corticosteroids are typically used because of fears |
6,649 | of steroid induced skin atrophy. Phosphodiesterase Inhibitor Crisaborole (Eucrisa) is an approved nonsteroidal topical antiinflam matory phosphodiesterase 4 (PDE 4) inhibitor indicated for the treatment of mild to moderate AD of children 3 months or older. It may be used as an alternative to topical corticosteroids or calcineurin inhibitors. Table 186.2 Differential Diagnosis of Atopic Dermatitis MAIN AGE GROUP AFFECTED FREQUENCY CHARACTERISTICS AND CLINICAL FEATURES OTHER TYPES OF DERMATITIS Seborrheic dermatitis Infants Common Salmon red greasy scaly lesions, often on the scalp (cradle cap) and napkin area; generally presents in the first 6 wk of life; typically clears within weeks Seborrheic dermatitis Adults Common Erythematous patches with yellow, white, or grayish scales in seborrheic areas, particularly the scalp, central face, and anterior chest Nummular dermatitis Children and adults Common Coin shaped scaly patches, mostly on legs and buttocks; usually no itch Irritant contact dermatitis Children and adults Common Acute to chronic eczematous lesions, mostly confined to the site of exposure; history of locally applied irritants is a risk factor; might coexist with AD Allergic contact dermatitis Children and adults Common Eczematous rash with maximum expression at sites of direct exposure but might spread; history of locally applied irritants is a risk factor; might coexist with AD Lichen simplex chronicus Adults Uncommon One or more localized, circumscribed, lichenified plaques that result from repetitive scratching or rubbing because of intense itch Asteatotic eczema Adults Common Scaly, fissured patches of dermatitis overlying dry skin, most often on lower legs INFECTIOUS SKIN DISEASES Dermatophyte infection Children and adults Common One or more demarcated scaly plaques with central clearing and slightly raised reddened edge; variable itch Impetigo Children Common Demarcated erythematous patches with blisters or honey yellow crusting Scabies Children Common Itchy superficial burrows and pustules on palms and soles, between fingers, and on genitalia; might produce secondary eczematous changes HIV Children and adults Uncommon Seborrhea like rash CONGENITAL IMMUNODEFICIENCIES (SEE TABLE 186.3) KERATINIZATION DISORDERS Ichthyosis vulgaris Infants and adults Uncommon Dry skin with fine scaling, particularly on the lower abdomen and extensor areas; perifollicular skin roughening; palmar hyperlinearity; full form (i.e., 2 FLG pathogenic variants) is uncommon; often coexists with AD NUTRITIONAL DEFICIENCYMETABOLIC DISORDERS Zinc deficiency (acrodermatitis enteropathica) Children Uncommon Erythematous scaly patches and plaques, most often around the mouth and anus; rare congenital form accompanied by diarrhea and alopecia Biotin deficiency (nutritional or biotinidase deficiency) Infants Uncommon Scaly periorofacial dermatitis, alopecia, conjunctivitis, lethargy, hypotonia Pellagra (niacin deficiency) All ages Uncommon Scaly crusted epidermis, desquamation, sun exposed areas, diarrhea Kwashiorkor Infants and children Geographic dependent Flaky scaly dermatitis, swollen limbs with cracked peeling patches Phenylketonuria Infants Uncommon Eczematous rash, hypopigmentation, blonde hair, developmental delay NEOPLASTIC DISEASE Cutaneous T cell lymphoma Adults Uncommon Erythematous pink brown macules and plaques with a fine scale; poorly responsive to topical corticosteroids; variable itch (in early stages) Langerhans cell histiocytosis Infants Uncommon Scaly and purpuric dermatosis, hepatosplenomegaly, cytopenias Common approximately 1 in 10 to 1 in 100; uncommon 1 in 100 to 1 in 1,000; rare 1 in 1,000 |
6,650 | to 1 in 10,000; very rare 1 in 10,000. Especially in developing countries. AD, Atopic dermatitis; FLG, filaggrin gene. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 186 u Atopic Dermatitis (Atopic Eczema) 1415 Tar Preparations Coal tar preparations have antipruritic and antiinflammatory effects on the skin; however, their antiinflammatory effects are usually not as pronounced as those of topical glucocorticoids or calcineurin inhibi tors. Therefore topical tar preparations are not a preferred approach for management of AD. Tar shampoos can be particularly beneficial for scalp dermatitis. Adverse effects associated with tar preparations include skin irritation, folliculitis, and photosensitivity. Antihistamines Systemic antihistamines act primarily by blocking the histamine H1 receptors in the dermis, thereby reducing histamine induced pruritus. Histamine is only one of many mediators that induce pruritus of the skin, so patients may derive minimal benefit from antihistaminic ther apy. Because pruritus is usually worse at night, sedating antihistamines (hydroxyzine, diphenhydramine) may offer an advantage with their soporific side effects when used at bedtime. Doxepin hydrochloride has both tricyclic antidepressant and H1 and H2 receptor blocking effects. Short term use of a sedative to allow adequate rest may be appropriate in cases of severe nocturnal pruritus. Studies of nonsedating antihista mines have shown variable effectiveness in controlling pruritus in AD, although they may be useful in the small subset of patients with AD and concomitant urticaria. For children, melatonin may be effective in promoting sleep because production is deficient in AD. Systemic Corticosteroids Systemic corticosteroids are rarely indicated in the treatment of chronic AD. The dramatic clinical improvement that may occur with systemic corticosteroids is frequently associated with a severe rebound flare of AD after therapy discontinuation. Short courses of oral corticosteroids may be appropriate for an acute exacerbation of AD while other treatment mea sures are being instituted in parallel. If a short course of oral corticoste roids is given, as during an asthma exacerbation, it is important to taper the dosage and begin intensified skin care, particularly with topical corti costeroids, and frequent bathing, followed by application of emollients or proactive topical corticosteroids, to prevent rebound flaring of AD. Table 186.3 Features of Primary Immunodeficiencies Associated with Eczematous Dermatitis DISEASE GENE INHERITANCE CLINICAL FEATURES LAB ABNORMALITIES AD HIES STAT3 AD, less commonly sporadic Cold abscesses Recurrent sinopulmonary infections Mucocutaneous candidiasis Coarse facies Minimal trauma fractures Scoliosis Joint hyperextensibility Retained primary teeth Coronary artery tortuosity or dilation Lymphoma High IgE (2,000 IUL) Eosinophilia DOCK8 deficiency DOCK8 AR Severe mucocutaneous viral infections Mucocutaneous candidiasis Atopic features (asthma, allergies) Squamous cell carcinoma Lymphoma High IgE Eosinophilia With or without decreased IgM PGM3 deficiency PGM3 AR Neurologic abnormalities Leukocytoclastic vasculitis Atopic features (asthma, allergies) Sinopulmonary infections Mucocutaneous viral infections High IgE Eosinophilia WAS WASP XLR Hepatosplenomegaly Lymphadenopathy Atopic diathesis Autoimmune conditions (especially hemolytic anemia) Lymphoreticular malignancies Thrombocytopenia (80,000L) Low mean platelet volume Eosinophilia is |
6,651 | common Lymphopenia Low IgM, variable IgG SCID Variable, depends on type XLR and AR most common Recurrent, severe infections Failure to thrive Persistent diarrhea Recalcitrant oral candidiasis Omenn syndrome: lymphadenopathy, hepatosplenomegaly, erythroderma Lymphopenia common Variable patterns of reduced lymphocyte subsets (T, B, natural killer cells) Omenn syndrome: high lymphocytes, eosinophilia, high IgE IPEX FOXP3 XLR Severe diarrhea (autoimmune enteropathy) Various autoimmune endocrinopathies (especially diabetes mellitus, thyroiditis) Food allergies High IgE Eosinophilia Various autoantibodies Netherton syndrome SPINK5 AR Hair shaft abnormalities Erythroderma Ichthyosis linearis circumflexa Food allergies Recurrent gastroenteritis Neonatal hypernatremic dehydration Upper and lower respiratory infections High IgE Eosinophilia AD, Autosomal dominant; AD HIES, autosomal dominant hyper IgE syndrome; AR, autosomal recessive; DOCK8, dedicator of cytokinesis 8 gene; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X linked syndrome; PGM3, phosphoglucomutase 3; SCID, severe combined immunodeficiency; WAS, Wiskott Aldrich syndrome; XLR, X linked recessive. From Kliegman RM, Bordini BJ, eds. Undiagnosed and rare diseases in children. Pediatr Clin N Amer. 2017;64(1):4142. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1416 Part XIII u Allergic Disorders Dupilumab A monoclonal antibody that binds to the IL 4 receptor subunit, dupi lumab (Dupixent) inhibits the signaling of IL 4 and IL 13, cytokines associated with AD. In children with moderate to severe AD not con trolled by standard topical therapy, dupilumab reduces pruritus and improves skin clearing. Dupilumab is approved for children 6 years or older. Lebrikizumab, an IgG4 monoclonal antibody that targets IL13, has shown efficacy in adolescents and adults with moderate to severe atopic dermatitis. Phototherapy Natural sunlight is often beneficial to patients with AD as long as sunburn and excessive sweating are avoided. Many phototherapy modalities are effective for AD, including ultraviolet A 1, ultra violet B, narrow band ultraviolet B, and psoralen plus ultraviolet A. Phototherapy is generally reserved for patients in whom standard treatments fail. Maintenance treatments are usually required for pho totherapy to be effective. Short term adverse effects with phototherapy include erythema, skin pain, pruritus, and pigmentation. Long term adverse effects include predisposition to cutaneous malignancies. Cyclosporine Cyclosporine is a potent immunosuppressive drug that acts primarily on T cells by suppressing cytokine gene transcription and has been shown to be effective in the control of severe AD. Cyclosporine forms a complex with an intracellular protein, cyclophilin, and this complex in turn inhib its calcineurin, a phosphatase required for activation of nuclear factor of activated T cells (NFAT), a transcription factor necessary for cytokine Table 186.4 Counseling and Aggravating Factors for Patients with Atopic Dermatitis Maintain cool temperature in bedroom, and avoid too many bed covers. Increase emollient use with cold weather. Avoid exposure to herpes sores; urgent visit if flare of unusual aspect. Clothing: Avoid skin contact with irritating fibers (wool, large fiber textiles). Do not use tight and too warm clothing to avoid excessive sweating. New, nonirritating clothing designed for AD children |
6,652 | is being evaluated. Tobacco: Avoid exposure. Vaccines: Normal schedule in noninvolved skin, including egg allergic patients (see text). Sun exposure: No specific restriction. Usually helpful because of improvement of epidermal barrier. Encourage summer holidays in altitude or at beach resorts. Physical exercise, sports: No restriction. If sweating induces flares of AD, progressive adaptation to exercise. Shower and emollients after swimming pool. Food allergens: Maintain breastfeeding exclusively to 4 6 mo if possible. Consider evaluation for early introduction of allergens (see Chapter 192). Otherwise normal diet, unless an allergy workup has proved the need to exclude a specific food. Indoor aeroallergens: House dust mites. Use adequate ventilation of housing; keep the rooms well aerated even in winter. Avoid wall to wall carpeting. Remove dust with a wet sponge. Vacuum floors and upholstery with an adequately filtered cleaner once a week. Avoid soft toys in bed (cradle), except washable ones. Wash bedsheets at a temperature higher than 55C (131F) every 10 days. Use bed and pillow encasings made of Gore Tex or similar material. Furred pets: Advise to avoid. If allergy is demonstrated, be firm on avoidance measures, such as pet removal. Pollen: Close windows during peak pollen season on warm and dry weather days and restrict, if possible, time outdoors. Windows may be open at night and early in the morning or during rainy weather. Avoid exposure to risk situations (lawn mowing). Use pollen filters in motor vehicles. Clothes and pets can vectorize aeroallergens, including pollen. Adapted from Darsow U, Wollenberg A, Simon D, et al. ETFADEADV Eczema Task Force 2009 position paper on diagnosis and treatment of atopic dermatitis. J Eur Acad Dermatol Venereol. 2010;24:321. Yes Yes No No Yes Yes No No Is AD severe? Management successful? Patient presents with an eczematous pruritic dermatitis Patient meets diagnostic criteria for AD? Identification and elimination of exacerbating factors (irritants, proven allergens) Addressing psychosocial aspectsqualityoflife issues Education Hydration Moisturizers Topical corticosteroids (low to mid potency) Topical calcineurin inhibitors Topical PDE4 inhibitor Antiinfective therapy Antipruritic therapy Written care plan Consider other conditions as per differential diagnosis? Periodic followup Review treatment plan Consider maintenance therapy with topical immunomodulators Reassess: Is diagnosis of AD correct? Consultation with AD specialist Intensification of treatment measures discussed above Consider Culture and sensitivity of skin lesion (Ro MRSA) Wet wrap therapy Dupilumab Hospitalization UV light therapy Systemic immunosuppressives Possibly oral or topical JAK inhibitors Fig. 186.5 Approach to the patient with atopic dermatitis (AD). Per boxed warning: second line, intermittent therapy for patients 2 years of age. Approved for patients 12 years of age with moderate to severe AD. JAK, Janus kinase; MRSA; methicillin resistant Staphylococ cus aureus; PDE, phosphodiesterase; UV, ultraviolet. (Modified from Boguniewicz M, Fonacier L, Leung DYM. Atopic dermatitis and allergic contact dermatitis. In Hershey GKK, Sheikh A, OHehir RE, Holgate ST, eds. Allergy Essentials. 2nd ed. Philadelphia: Elsevier; 2022. Fig 11.5.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other |
6,653 | uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 186 u Atopic Dermatitis (Atopic Eczema) 1417 gene transcription. Cyclosporine (5 mgkgday) for short term and long term (1 year) use has been beneficial for children with severe, refractory AD. Possible adverse effects include renal impairment and hypertension. Janus Kinase Inhibitors Oral and topical Janus kinase (JAK) inhibitors have demonstrated rapid improvement in adults and older children with severe AD. These inhibitors also have potential side effects including infec tions (tuberculosis), malignancy (cutaneous lymphoma), and headaches. Topical therapy is effective and has fewer side effects. Clinical trials are in progress to address the efficacy and safely of JAK inhibitors. Antimetabolites Mycophenolate mofetil is a purine biosynthesis inhibitor used as an immunosuppressant in organ transplantation that has been used for treatment of refractory AD. Aside from immunosuppression, herpes simplex retinitis and dose related bone marrow suppression have been reported with its use. Of note, not all patients benefit from treatment. Therefore mycophenolate mofetil should be discontinued if the disease does not respond within 4 8 weeks. Methotrexate is an antimetabolite with potent inhibitory effects on inflammatory cytokine synthesis and cell chemotaxis. Methotrexate has been used for patients with recalcitrant AD. In AD, dosing is more frequent than the weekly dosing used for psoriasis. Azathioprine is a purine analog with antiinflammatory and antip roliferative effects that has been used for severe AD. Myelosuppression is a significant adverse effect, and thiopurine methyltransferase levels may identify individuals at risk. Before any of these drugs are used, patients should be referred to an AD specialist who is familiar with treatment of severe AD to weigh relative benefits of alternative therapies. Unproven Therapies Other therapies may be considered in patients with refractory AD. Interferon IFN is known to suppress Th2 cell function. Several studies, includ ing a multicenter, double blind, placebo controlled trial and sev eral open trials, have demonstrated that treatment with recombinant human IFN results in clinical improvement of AD. Reduction in clinical severity of AD correlated with the ability of IFN to decrease total circulating eosinophil counts. Influenza like symptoms are com mon side effects during the treatment course. Omalizumab Treatment of patients who have severe AD and elevated serum IgE values with monoclonal anti IgE may be considered in those with allergen induced flares of AD. However, there have been no published double blind, placebo controlled trials supporting omalizumab as a preferred therapy for moderate to severe AD. Most reports show incon sistent responses to anti IgE. Allergen Immunotherapy In contrast to its acceptance for treatment of allergic rhinitis and extrinsic asthma, immunotherapy with aeroallergens in the treatment of AD is controversial. There are reports of both disease exacerbation and improvement. Studies suggest that specific immunotherapy in patients with AD sensitized to dust mite allergen showed improve ment in severity of skin disease, as well as reduction in topical corti costeroid use. Probiotics Perinatal administration of the probiotic Lactobacillus rhamnosus strain GG has been shown to reduce the incidence of AD |
6,654 | in at risk children during the first 2 years of life. The treatment response has been found to be more pronounced in patients with positive skin prick test results and elevated IgE values. Other studies have not demonstrated a benefit. Chinese Herbal Medications Several placebo controlled clinical trials have suggested that patients with severe AD may benefit from treatment with traditional Chinese herbal therapy. The patients had significantly reduced skin disease and decreased pruritus. The beneficial response of Chinese herbal therapy is often temporary, and effectiveness may wear off despite continued treatment. The possibility of hepatic toxicity, car diac side effects, or idiosyncratic reactions remains a concern. The specific ingredients of the herbs also remain to be elucidated, and some preparations have been found to be contaminated with corti costeroids. At present, Chinese herbal therapy for AD is considered investigational. Table 186.5 Categorization of Physical Severity of Atopic Eczema Clear: Normal skin, with no evidence of atopic eczema Mild: Areas of dry skin, infrequent itching (with or without small areas of redness) Moderate: Areas of dry skin, frequent itching, redness (with or without excoriation and localized skin thickening) Severe: Widespread areas of dry skin, incessant itching, redness (with or without excoriation, extensive skin thickening, bleeding, oozing, cracking, and alteration of pigmentation) From Lewis Jones S, Mugglestone MA, Guideline Development Group. Management of atopic eczema in children aged up to 12 years: summary of NICE guidance. BMJ. 2007;335:12631264. Table 186.6 Selected Topical Corticosteroid Preparations GROUP 1 Clobetasol propionate (Temovate) 0.05 ointmentcream Betamethasone dipropionate (Diprolene) 0.05 ointmentlotiongel Fluocinonide (Vanos) 0.1 cream GROUP 2 Mometasone furoate (Elocon) 0.1 ointment Halcinonide (Halog) 0.1 cream Fluocinonide (Lidex) 0.05 ointmentcream Desoximetasone (Topicort) 0.25 ointmentcream Betamethasone dipropionate (Diprolene) 0.05 cream GROUP 3 Fluticasone propionate (Cutivate) 0.005 ointment Halcinonide (Halog) 0.1 ointment Betamethasone valerate (Valisone) 0.1 ointment GROUP 4 Mometasone furoate (Elocon) 0.1 cream Triamcinolone acetonide (Kenalog) 0.1 ointmentcream Fluocinolone acetonide (Synalar) 0.025 ointment GROUP 5 Fluocinolone acetonide (Synalar) 0.025 cream Hydrocortisone valerate (Westcort) 0.2 ointment GROUP 6 Desonide (DesOwen) 05 ointmentcreamlotion Alclometasone dipropionate (Aclovate) 0.05 ointmentcream GROUP 7 Hydrocortisone (Hytone) 2.5, 1, 0.5 ointmentcreamlotion Representative corticosteroids are listed by group from 1 (superpotent) through 7 (least potent). Adapted from Stoughton RB. Vasoconstrictor assay specific applications. In: Malbach HI, Surber C, eds. Topical Corticosteroids. Basel, Switzerland: Karger; 1992. p 4253. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1418 Part XIII u Allergic Disorders Vitamin D Vitamin D deficiency often accompanies severe AD. Vitamin D enhances skin barrier function, reduces corticosteroid requirements to control inflammation, and augments skin antimicrobial function. Sev eral small clinical studies suggest vitamin D can enhance antimicro bial peptide expression in the skin and reduce severity of skin disease, especially in patients with low baseline vitamin D, as during winter, when exacerbation of AD often occurs. Patients with AD might benefit from supplementation with vitamin D, particularly if |
6,655 | they have a docu mented low level or low vitamin D intake. AVOIDING TRIGGERS It is essential to identify and eliminate triggering factors for AD, both during the period of acute symptoms and on a long term basis to pre vent recurrences (see Table 186.4). Irritants Patients with AD have a low threshold response to irritants that trigger their itch scratch cycle. Soaps or detergents, chemicals, smoke, abra sive clothing, and exposure to extremes of temperature and humidity are common triggers. Patients with AD should use soaps with minimal defatting properties and a neutral pH. New clothing should be laun dered before wearing to decrease levels of formaldehyde and other chemicals. Residual laundry detergent in clothing may trigger the itch scratch cycle; using a liquid rather than powder detergent and adding a second rinse cycle facilitates removal of the detergent. Every attempt should be made to allow children with AD to be as normally active as possible. A sport such as swimming may be better tolerated than others that involve intense perspiration, physi cal contact, or heavy clothing and equipment. Rinsing off chlorine immediately and lubricating the skin after swimming are impor tant. Although ultraviolet light may be beneficial to some patients with AD, high sun protection factor (SPF) sunscreens should be used to avoid sunburn. Foods Food allergy is comorbid in approximately 40 of infants and young children with moderate to severe AD (see Chapter 192). Undiagnosed food allergies in patients with AD may induce eczematous dermatitis in some patients and urticarial reactions, wheezing, or nasal conges tion in others. Increased severity of AD symptoms and younger age correlate directly with the presence of food allergy. Removal of food allergens from the diet may lead to clinical improvement but also car ries a risk of the patient developing immediate type allergic reactions to the food allergen removed. Potential allergens can be identified by a careful history and per forming selective skin prick tests or in vitro blood testing for allergen specific IgE. Negative skin and blood test results for allergen specific IgE have a high predictive value for excluding suspected aller gens. Positive results of skin or blood tests using foods often do not correlate with clinical symptoms and should be confirmed with con trolled food challenges and elimination diets. Extensive elimination diets, which can be nutritionally deficient, are rarely required. Even with multiple positive skin test results, the majority of patients react to fewer than three foods under controlled challenge conditions. Aeroallergens In older children, AD flares can occur after intranasal or epicutaneous exposure to aeroallergens such as fungi, animal dander, grass, and rag weed pollen. Avoiding aeroallergens, particularly dust mites, can result in clinical improvement of AD. Avoidance measures for dust mite allergic patients include using dust miteproof encasings on pillows, mattresses, and box springs; washing bedding in hot water weekly; removing bedroom carpeting; and decreasing indoor humidity levels with air conditioning. Infections Patients with AD have increased susceptibility to bacterial, viral, and fungal skin infections. Antistaphylococcal |
6,656 | antibiotics are very help ful for treating patients who are heavily colonized or infected with S. aureus. Erythromycin and azithromycin are usually beneficial for patients who are not colonized with a resistant S. aureus strain; a first generation cephalosporin (cephalexin) is recommended for macrolide resistant S. aureus. Topical mupirocin is useful in the treat ment of localized impetiginous lesions, with systemic clindamycin or trimethoprimsulfamethoxazole needed for methicillin resistant S. aureus (MRSA). Cytokine mediated skin inflammation contributes to skin colonization with S. aureus. This finding supports the importance of combining effective antiinflammatory therapy with antibiotics for treating moderate to severe AD to avoid the need for repeated courses of antibiotics, which can lead to the emergence of antibiotic resistant strains of S. aureus. Dilute bleach baths ( cup of bleach in 40 gallons of water) twice weekly may be also considered to reduce S. aureus colo nization. In one randomized trial, the group who received the bleach baths plus intranasal mupirocin (5 daysmonth) had significantly decreased severity of AD at 1 and 3 months compared with placebo. Patients rinse off after the soaking. Bleach baths may not only reduce S. aureus abundance on the skin but also have antiinflammatory effects. Herpes simplex virus (HSV) can provoke recurrent dermatitis and may be misdiagnosed as S. aureus infection (Fig. 186.6). The presence of punched out erosions, vesicles, and infected skin lesions that fail to respond to oral antibiotics suggests HSV infection, which can be diagnosed by a Giemsa stained Tzanck smear of cells scraped from the vesicle base or by viral polymerase chain reaction or culture. Topical Fig. 186.6 Eczema herpeticum infection in a patient with atopic dermatitis. Numerous punched out vesicles and erosions involving the face (A) and extremities (B). (From Papulosquamous eruptions. In Cohen BA, ed. Pediatric Dermatology. Philadelphia: Saunders; 2013. pp 68103.) BA Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 187 u Insect Allergy 1419 corticosteroids should be temporarily discontinued if HSV infection is suspected. Reports of life threatening dissemination of HSV infections in patients with AD who have widespread disease mandate antiviral treatment. Persons with AD are also susceptible to eczema vaccina tum, which is similar in appearance to eczema herpeticum and histori cally follows smallpox (vaccinia virus) vaccination. Cutaneous warts, coxsackievirus, and molluscum contagiosum are additional viral infections affecting children with AD. Dermatophyte infections can also contribute to exacerbation of AD. Patients with AD have been found to have a greater susceptibility to Trichophyton rubrum fungal infections than nonatopic controls. There has been particular interest in the role of Malassezia furfur (formerly known as Pityrosporum ovale) in AD because it is a lipophilic yeast commonly present in the seborrheic areas of the skin. IgE antibodies against M. furfur have been found in patients with head and neck der matitis. A reduction of AD severity has been observed in these patients |
6,657 | after treatment with antifungal agents. COMPLICATIONS Exfoliative dermatitis may develop in patients with extensive skin involve ment. It is associated with generalized redness, scaling, weeping, crusting, systemic toxicity, lymphadenopathy, and fever and is usually caused by superinfection (e.g., with toxin producing S. aureus or HSV infection) or inappropriate therapy. In some cases the withdrawal of systemic glucocor ticoids used to control severe AD precipitates exfoliative erythroderma. Eyelid dermatitis and chronic blepharitis may result in visual impair ment from corneal scarring. Atopic keratoconjunctivitis is usually bilateral and can have disabling symptoms that include itching, burning, tearing, and copious mucoid discharge. Vernal conjunctivitis is associated with papillary hypertrophy or cobblestoning of the upper eyelid conjunc tiva. It typically occurs in younger patients and has a marked seasonal inci dence with spring exacerbations. Keratoconus is a conical deformity of the cornea believed to result from chronic rubbing of the eyes in patients with AD. Cataracts may be a primary manifestation of AD or from extensive use of systemic and topical glucocorticoids, particularly around the eyes. PROGNOSIS AD generally tends to be more severe and persistent in young children, particularly if they have homozygous null pathogenic variants in their fil aggrin genes. Periods of remission occur more frequently as patients grow older. Spontaneous resolution of AD has been reported to occur after age 5 years in 4060 of patients affected during infancy, particularly for mild disease. Earlier studies suggested that approximately 84 of children out grow their AD by adolescence; however, later studies reported that AD resolves in approximately 20 of children monitored from infancy until adolescence and becomes less severe in 65. Of those adolescents treated for mild dermatitis, 50 may experience a relapse of disease as adults, which frequently manifests as hand dermatitis, especially if daily activities require repeated hand wetting. Predictive factors of a poor prognosis for AD include widespread AD in childhood, FLG null pathogenic variants, concomitant allergic rhinitis and asthma, family history of AD in parents or siblings, early age at onset of AD, being an only child, and very high serum IgE levels. PREVENTION Breastfeeding may be beneficial. Probiotics and prebiotics may also reduce the incidence or severity of AD, but this approach is unproven. If an infant with AD is diagnosed with food allergy, the breastfeeding mother may need to eliminate the implicated food allergen from her diet. For infants with severe eczema, introduction of infant safe forms of peanut as early as 4 6 months, after other solids are tolerated, is recommended after consul tation with the childs pediatrician andor allergist for allergy testing. This approach may prevent peanut allergy (see Chapter 192). Identification and elimination of triggering factors are the mainstay for prevention of flares as well as for the long term treatment of AD. Emollient therapy applied to the whole body for the first few months of life may enhance the cutaneous barrier and reduce the risk of eczema. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Allergic responses to stinging or, more rarely, biting |
6,658 | insects vary from localized cutaneous reactions to systemic anaphylaxis. Allergic reac tions caused by inhalation of airborne particles of insect origin result in acute and chronic respiratory symptoms of seasonal or perennial rhinitis, conjunctivitis, and asthma. ETIOLOGY Most reactions to stinging and biting insects, such as those induced by wasps, mosquitoes, flies, and fleas, are limited to a primary lesion isolated to the area of the sting or bite and do not represent an aller gic response. Occasionally, insect stings or bites induce pronounced localized reactions or systemic reactions that may be based on imme diate or delayed hypersensitivity reactions. Systemic allergic responses to insects are usually attributed to IgE antibodymediated responses, which are caused primarily by stings from venomous insects of the order Hymenoptera and more rarely from ticks, spiders, scorpions, and Triatoma (kissing bug). Members of the order Hymenoptera include apids (honeybee, bumblebee), vespids (yellow jacket, wasp, hornet), and formicids (fire and harvester ants) (Fig. 187.1). Among winged stinging insects, yellow jackets are the most notorious for sting ing because they are aggressive and ground dwelling, and they linger near activities involving food. Hornets nest in trees, whereas wasps build honeycomb nests in dark areas such as under porches; both are aggressive if disturbed. Honeybees are less aggressive and nest in tree hollows; unlike the stings of other flying Hymenoptera, honeybee stings almost always leave a barbed stinger with venom sac. In the United States, fire ants are found in the Southeast, living in large mounds of soil. When disturbed, the ants attack in large numbers, anchor themselves to the skin by their mandibles, and sting multiple times in a circular pattern. Sterile pseudopustules form at the sting sites. Systemic reactions to stinging insects occur in 0.40.8 of chil dren and 3 of adults and account for approximately 40 deaths each year in the United States. Although reactions to insect bites are common, IgE mediated reac tions are infrequently reported and anaphylaxis is rare. The Triatoma (kissing bug) bite causes an erythematous plaque that is painless. Mos quito bites generally result in local reactions that are pruritic. Large, Chapter 187 Insect Allergy Julie Wang and Scott H. Sicherer A D E F B C Fig. 187.1 Representative venomous Hymenoptera. A, Hornet (Vespula maculata). B, Wasp (Chlorion ichneumerea). C, Yellowjacket (Vespula maculiforma). D, Honeybee (Apis mellifera). E, Fire ant (So lenopsis invicta). F, Bumblebee (Bombus species). (From Erickson TB, Marquez A. Arthropod envenomation and parasitism. In: Auerbach PS, Cushing TA, Harris NS, eds. Auerbachs Wilderness Medicine. 7th ed. Philadelphia: Elsevier; 2017: Fig 41 1, p 937.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1420 Part XIII u Allergic Disorders local reactions to mosquito bites can occur in some young children; this is known as skeeter syndrome and is often misdiagnosed as cel lulitis. The tabanid species (horsefly, deerfly), typically found in rural |
6,659 | and suburban areas, are large flies that induce painful bites. IgE antibodymediated allergic responses to airborne particulate matter carrying insect emanations contribute to seasonal and peren nial symptoms affecting the upper and lower airways. Seasonal allergy is attributed to exposures to a variety of insects, particularly aquatic insects such as the caddis fly and midge, or lake fly, at a time when lar vae pupate and adult flies are airborne. Perennial allergy is attributed to sensitization to insects such as cockroaches and ladybugs, as well as house dust mite, which is phylogenetically related to spiders rather than insects and has eight rather than six legs. PATHOGENESIS Hymenoptera venoms contain numerous components with toxic and pharmacologic activity and with allergenic potential. These constitu ents include vasoactive substances such as histamine, acetylcholine, and kinins; enzymes such as phospholipase and hyaluronidase; apamin; melittin; and formic acid. The majority of patients who experience sys temic reactions after Hymenoptera stings have IgE mediated sensitivity to antigenic substances in the venom. Some venom allergens are homol ogous among members of the Hymenoptera order; others are family specific. There is substantial cross reactivity among vespid venoms, but these venom allergies are distinct from honeybee venom allergies. Localized skin responses to biting insects are caused primarily by vasoactive or irritant materials derived from insect saliva; they rarely occur from IgE associated responses. Systemic IgE mediated allergic reactions to salivary proteins of biting insects such as mosquitoes are reported but uncommon. A variety of proteins derived from insects can become airborne and induce IgE mediated respiratory responses, causing inhalant allergies. The primary allergen from the caddis fly is a hemocyanin like protein, and that from the midge fly is derived from hemoglobin. Allergens from the cockroach are the best studied and are derived from cock roach saliva, secretions, fecal material, and debris from skin casts. CLINICAL MANIFESTATIONS Clinical reactions to stinging venomous insects are categorized as local, large local, generalized cutaneous, systemic, toxic, and delayed late. Simple local reactions involve limited swelling and pain and gen erally last 24 hours. Large local reactions develop over hours and days, involve swelling of extensive areas (10 cm) that are contigu ous with the sting site, and may last for days. Generalized cutaneous reactions typically progress within minutes and include cutaneous symptoms of urticaria, angioedema, and pruritus beyond the site of the sting. Systemic reactions are identical to anaphylaxis from other triggers and may include symptoms of generalized urticaria, laryngeal edema, bronchospasm, and hypotension. A subset of patients with hypotension and persistently elevated (once recovered) tryptase lev els may have mast cell activation syndrome (see Chapter 190). Stings from numerous insects at once may result in toxic reactions of fever, malaise, emesis, and nausea because of the chemical properties of the venom in large doses. Serum sickness, nephrotic syndrome, vasculi tis, neuritis, or encephalopathy may occur as delayedlate reactions to stinging insects. Insect bites are usually urticarial but may be papular or vesicular. Papular urticaria affecting the lower extremities in children is |
6,660 | usu ally caused by multiple bites. Occasionally, individuals have large, local reactions. IgE antibodyassociated immediate and late phase allergic responses to mosquito bites sometimes mimic cellulitis. Inhalant allergy caused by insects results in clinical disease similar to that induced by other inhalant allergens such as pollens. Depending on individual sensitivity and exposure, reactions may result in seasonal or perennial rhinitis, conjunctivitis, or asthma. DIAGNOSIS The diagnosis of allergy from stinging and biting insects is generally evident from the history of exposure, typical symptoms, and physical findings. The diagnosis of Hymenoptera allergy rests in part on the identification of venom specific IgE by skin prick testing or in vitro testing. The primary reasons to pursue testing are to confirm reactivity when venom immunotherapy (VIT) is being considered or when it is clinically necessary to confirm venom hypersensitivity as a cause of a reaction. Venoms of five Hymenoptera (honeybee, yellow jacket, yel low hornet, white faced hornet, and wasp), as well as the jack jumper ant in Australia and whole body extract of fire ant, are available for skin testing. Although skin tests are considered to be the most sensitive modality for detection of venom specific IgE, additional evaluation with an in vitro serum assay for venom specific IgE is recommended if skin test results are negative in the presence of a convincing history of a severe systemic reaction. In vitro tests have a 20 incidence of both false positive and false negative results, so it is not appropriate to exclude venom hypersensitivity based on this test alone. If initial skin prick and in vitro test results are negative in the context of a con vincing history of a severe reaction, repeat testing is recommended before concluding that allergy is unlikely. Skin tests are usually accurate within 1 week of a sting reaction, but occasionally a refractory period is observed that warrants retesting after 4 6 weeks if the initial results are negative. An elevated basal tryptase level is associated with more severe reac tions to venom stings. Therefore basal tryptase should be measured if there is a history of severe reaction to a sting, hypotensive reaction, lack of urticaria in a systemic sting reaction, or negative venom IgE in a patient who has a history of systemic reaction to a sting. As many as 40 of skin testpositive patients may not experience anaphylaxis on sting challenge, so testing without an appropriate clinical history is potentially misleading. The diagnosis of inhalant insect allergy may be evident from a his tory of typical symptoms. A chronic respiratory symptom during long term exposure, as may occur with cockroach allergy, is less amenable to identification by history alone. Skin prick or in vitro immunoassay tests for specific IgE to the insect are used to confirm inhalant insect allergy. Allergy tests may be particularly warranted for potential cock roach allergy in patients with persistent asthma and known cockroach exposure. TREATMENT For local cutaneous reactions caused by insect stings and bites, treat ment with cold compresses, topical |
6,661 | medications to relieve itching, and occasionally a systemic antihistamine and oral analgesic are appropri ate. Stingers should be removed promptly by scraping, with caution not to squeeze the venom sac because doing so could inject more venom. Sting sites rarely become infected, possibly because of the antibacte rial actions of venom constituents. Vesicles left by fire ant stings that are scratched open should be cleansed to prevent secondary infection. Anaphylactic reactions after a Hymenoptera sting are treated the same as anaphylaxis from any cause; epinephrine is the drug of choice. Adjunctive treatment includes antihistamines, corticosteroids, intrave nous fluids, oxygen, and transport to the emergency department (see Chapter 190). Referral to an allergist immunologist should be consid ered for patients who have experienced a generalized cutaneous or sys temic reaction to an insect sting, who need education about avoidance and emergency treatment, who may be candidates for VIT, or who have a condition that may complicate management of anaphylaxis (e.g., use of blockers). Venom Immunotherapy Hymenoptera VIT is highly effective (9597) in decreasing the risk for severe anaphylaxis. The selection of patients for VIT depends on several factors (Table 187.1). Individuals with local reactions, Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 187 u Insect Allergy 1421 regardless of age, are not at increased risk for severe systemic reactions on a subsequent sting and are not candidates for VIT. The risk of a systemic reaction for those who experienced a large, local reaction is approximately 7; testing or VIT is usually not recommended, and prescription of self injectable epinephrine is considered optional but usually not necessary. There is growing evidence that VIT can reduce the size and duration of large, local reactions, and therefore VIT may be considered for those with frequent or unavoidable large, local reactions. Those who experience severe systemic reactions, such as airway involvement or hypotension, and who have specific IgE to venom allergens, should receive immunotherapy. Immunotherapy against winged Hymenoptera is generally not required when stings have caused only generalized urticaria or angioedema, because the risk for a systemic reaction after a subsequent sting is approximately 10 and the chance of a more severe reaction is 3. VIT may be consid ered if there are potential high risk cofactors such as comorbid car diovascular disease or use of specific cardiovascular medications (e.g., angiotensin converting enzyme ACE inhibitors, blockers), elevated basal tryptase level, or high likelihood of future stings. VIT is usually not indicated if there is no evidence of IgE to venom. The incidence of adverse effects in the course of treatment is not trivial in adults; 50 experience large, local reactions, and about 10 experience systemic reactions. The incidence of both local and sys temic reactions is much lower in children. Patients treated with honey bee venom are at higher risk for systemic reactions to VIT than those receiving |
6,662 | treatment with vespid venom. Individuals with mast cell dis orders are at increased risk for severe anaphylaxis and more frequent systemic reactions with VIT; thus some experts recommend basal tryptase level for risk assessment purposes. It is uncertain how long immunotherapy with Hymenoptera venom should continue. In general, treatment duration of 3 5 years is recom mended because 80 of adults who have received 5 years of therapy tolerate challenge stings without systemic reactions for 5 10 years after completion of treatment. Long term responses to treatment are even better for children. Follow up over a mean of 18 years of children with moderate to severe insect sting reactions who received VIT for a mean of 3 5 years and were stung again showed a reaction rate of only 5; untreated children experienced a reaction rate of 32. Whereas dura tion of therapy with VIT may be individualized, it is clear that a sig nificant number of untreated children retain their allergy. Extended or lifelong treatment may be considered for those who have had life threatening anaphylaxis with insect stings or severe reaction during VIT, those with honeybee allergy, and those with occupational expo sures to Hymenoptera. Lifelong VIT should also be considered for patients with mast cell disorders because they have a higher rate of failure of VIT and relapse when VIT is discontinued. Less is known about the natural history of fire ant hypersensitivity and efficacy of immunotherapy for this allergy. The criteria for start ing immunotherapy are similar to those for hypersensitivities to other Hymenoptera, but there is stronger consideration to treat patients who have only cutaneous systemic reactions with VIT. Only whole body fire ant extract is commercially available for diagnostic skin testing and immunotherapy. Inhalant Allergy The symptoms of inhalant allergy caused by insects are managed as for other causes of seasonal or perennial rhinitis (see Chapter 184), con junctivitis (see Chapter 188), and asthma (see Chapter 185). PREVENTION Avoidance of stings and bites is essential. To reduce the risk of stings, sensitized individuals should have known or suspected nests near the home removed by trained professionals, should wear gloves when gar dening, should wear long pants and shoes with socks when walking in the grass or through fields, and should avoid or be cautious about eat ing or drinking outdoors. Typical insect repellents do not guard against Hymenoptera. Individuals who are at high risk for future severe reactions to Hyme noptera stings should have immediate access to self injectable epi nephrine. High risk individuals include those who have a history of severe reactions or have elevated basal tryptase level. Adults respon sible for allergic children and older patients who can self treat must be carefully taught the indications and technique of administration for this medication. Particular attention is necessary for children in out of home daycare centers, at school, or attending camps, to ensure that an emergency action plan is in place. The individual at risk for ana phylaxis from an insect sting should |
6,663 | also wear medical identification jewelry indicating the allergy. Avoidance of the insect is the preferred management of inhalant allergy. This can prove difficult, particularly for those living in apart ments, where eradication of cockroaches may be problematic. Immu notherapy for dust mites is effective and should be considered in conjunction with avoidance measures. In contrast, there is limited data regarding the efficacy of cockroach immunotherapy. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 187.1 Risk of Systemic Reaction in Untreated Patients with History of Sting Anaphylaxis andor Positive Venom Skin Test Results ORIGINAL STING REACTION RISK OF SYSTEMIC REACTION SEVERITY AGE ANY SYSTEMIC () ANAPHYLAXIS () No reaction Adult 515 3 Large local All 410 Cutaneous systemic All 10 3 Anaphylaxis Child 40 30 Adult 60 40 From Golden DBK: Insect allergy. In Burks AW, Holgate ST, OHehir RE, et al., eds. Middletons Allergy Principles and Practice, ed 9, vol 2, Philadelphia: Elsevier, 2020, Table 76.2, p. 1253. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1422 Part XIII u Allergic Disorders The ocular surface of the eye, the conjunctiva, is the most immu nologically active tissue of the external eye. The conjunctiva is a common target of allergic disorders because of its marked vascu larity and direct contact with allergens in the environment. Ocular allergies can occur as isolated target organ disease or more often in conjunction with nasal allergies. Ocular symptoms can significantly affect quality of life. CLINICAL MANIFESTATIONS Allergic eye diseases represent a spectrum of conditions that require allergic sensitization and range from acute (seasonal) progressing to the perennial and then to the more chronic forms and potentially sight threatening forms, vernal and atopic keratoconjunctivitis (Table 188.1). Allergic Conjunctivitis Allergic conjunctivitis is the most common hypersensitivity response of the eye, affecting approximately 25 of the general population and 30 of children with atopy. It is caused by direct exposure of the muco sal surfaces of the eye to environmental allergens. Patients complain of variable ocular itching, rather than pain, with increased tearing. Clini cal signs include bilateral injected conjunctivae with vascular conges tion that may progress to chemosis, or conjunctival swelling, and a watery discharge (Fig. 188.1). Allergic conjunctivitis occurs in a seasonal or, less frequently, perennial form. Seasonal allergic conjunctivitis is typically asso ciated with allergic rhinitis (see Chapter 184) and is most com monly triggered by pollens. 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 sea sons vary significantly in different parts of the United States. Mold spores can also cause seasonal allergy symptoms, principally in the summer and fall. Seasonal allergy symptoms may be aggravated by coincident exposure to perennial allergens. Perennial allergic con junctivitis is triggered by allergens such as animal danders or dust mites that are |
6,664 | present throughout the year. Symptoms are usually less severe than with seasonal allergic conjunctivitis. Because pol lens and soil molds may be present intermittently by season, and exposure to allergens such as furred animals may be perennial, clas sification as intermittent (symptoms present 4 daysweek or for 4 weeks) and persistent (symptoms present 4 daysweek and for 4 weeks) has been proposed. Vernal Keratoconjunctivitis Vernal keratoconjunctivitis is a severe bilateral chronic inflamma tory process of the upper tarsal conjunctival surface that occurs in two forms, limbal or palpebral. It may threaten eyesight if there is corneal involvement. Vernal keratoconjunctivitis is only associated with positive cutaneous allergic reactivities in 50 of cases, although it occurs most frequently in children with seasonal allergies, asthma, or atopic derma titis. Vernal keratoconjunctivitis affects males twice as often as females Chapter 188 Ocular Allergies Leonard Bielory, Brett P. Bielory, and Scott H. Sicherer Table 188.1 Allergic Diseases of the Eye DISEASE CLINICAL PARAMETERS SIGNSSYMPTOMS DIFFERENTIAL DIAGNOSIS Seasonal allergic conjunctivitis (SAC) Sensitized individuals Both females and males Bilateral involvement Seasonal allergens Self limiting Ocular itching Tearing (watery discharge) Chemosis, redness Often associated with rhinitis Not sight threatening Infective conjunctivitis Preservative toxicity Medicamentosa Dry eye PACAKCVKC Perennial allergic conjunctivitis (PAC) Sensitized individuals Both females and males Bilateral involvement Year round allergens Self limiting Ocular itching Tearing (watery discharge) Chemosis, redness Often associated with rhinitis Not sight threatening Infective conjunctivitis Preservative toxicity Medicamentosa Dry eye SACAKCVKC Atopic keratoconjunctivitis (AKC) Sensitized individuals Peak incidence 20 50 years of age Both females and males Bilateral involvement Seasonalperennial allergens Atopic dermatitis Chronic symptoms Severe ocular itching Red flaking periocular skin Mucoid discharge, photophobia Corneal erosions Scarring of conjunctiva Cataract (anterior subcapsular) Sight threatening Contact dermatitis Infective conjunctivitis Blepharitis Pemphigoid VKCSACPACGPC Vernal keratoconjunctivitis (VKC) Some sensitized individuals Peak incidence 3 20 years of age Males predominate 3:1 Bilateral involvement Warm, dry climate Seasonalperennial allergens Chronic symptoms Severe ocular itching Severe photophobia Thick, ropy discharge Cobblestone papillae Corneal ulceration and scarring Sight threatening Infective conjunctivitis Blepharitis AKCSACPACGPC Giant papillary conjunctivitis (GPC) Sensitization not necessary Both females and males Bilateral involvement Prosthetic exposure Occurs anytime Chronic symptoms Mild ocular itching Mild mucoid discharge Giant papillae Contact lens intolerance Foreign body sensation Protein buildup on contact lens Not sight threatening Infective conjunctivitis Preservative toxicity SACPACAKCVKC From Barney NP. Allergic and immunologic diseases of the eye. In: Burks AW, Holgate ST, OHehir RE, et al., eds. Middletons Allergy: Principles and Practice. 9th ed. Philadelphia: Elsevier, 2020: Table 38.1, p. 607) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 188 u Ocular Allergies 1423 and is more common in the Mediterranean basin and in persons of Asian and African descent. It affects primarily children in temperate areas, with exacerbations in the spring and summer, but can occur throughout the year. Symptoms include intense ocular itching exacerbated by exposure to irritants, |
6,665 | light, or perspiration. In addition, patients may complain of severe photophobia due to corneal involvement, foreign body sensation, and lacrimation. Giant papillae occur predominantly on the upper tarsal plate and are typically described as cobblestoning (Fig. 188.2). Other signs include a stringy or thick, ropey discharge, cobblestone papillae, tran sient yellow white points at the corneal limbus (Trantas dots) (Fig. 188.3) and conjunctiva (Horner points), corneal shield ulcers (Fig. 188.4), and Dennie lines (Dennie Morgan folds), which are prominent symmetric skin folds that extend in an arc from the inner canthus beneath and par allel to the lower lid margin. Children with vernal keratoconjunctivitis have measurably longer eyelashes, which may represent a reaction to ocular inflammation. Atopic Keratoconjunctivitis Atopic keratoconjunctivitis is a chronic inflammatory ocular dis order most often involving the lower tarsal conjunctiva. It may threaten eyesight if there is corneal involvement. Almost all patients have atopic dermatitis, and a significant number have asthma. Atopic keratoconjunctivitis rarely presents before late adolescence. Symptoms include severe bilateral ocular itching, burning, photo phobia, and tearing with a mucoid discharge that are much more severe than in allergic conjunctivitis and persist throughout the year. The bulbar conjunctiva is injected and chemotic; cataracts may occur. Trantas dots at the corneal limbus or giant papillae typically found in inferior palpebral conjunctiva may also be present. Eyelid eczema can extend to the periorbital skin and cheeks with erythema and thick, dry scaling. Secondary staphylococcal blepharitis is com mon because of eyelid induration and maceration. Chronic eye rub bing associated with vernal and atopic keratoconjunctivitis can lead to keratoconus, a noninflammatory cone shaped corneal ectasia. This may lead to corneal thinning and perforation. Giant Papillary Conjunctivitis Giant papillary conjunctivitis is not associated with IgE sensitiza tion, but has been linked to chronic exposure to foreign bodies, such Fig. 188.2 Vernal keratoconjunctivitis. Cobblestone papillae and ropey discharge are seen on the underside (tarsal conjunctiva) of the upper eyelid. (From Adkinson NF Jr, Bochner BS, Burks AW, et al., eds. Middletons Allergy: Principles Practice. 8th ed. St Louis: Elsevier, 2014: p. 627.) Fig. 188.3 Horner Trantas dots. Classic appearance of small white yellow chalky concretions with collections of degenerated epithelial cells and eosinophils around the corneal limbus (arrows). (From Cheng J, Jiang L, Morrow NC, et al. Recognition of atopic keratoconjunctivitis during treatment with dupilumab for atopic dermatitis. J Am Acad Der matol. 2021;85(1):265267. Fig 1.) Fig. 188.4 Corneal shield ulcer classic depiction of sterile plaques containing fibrin and mucous that accumulate into macro erosions forming a shield ulcer. (From LaMattina K, Thompson L. Pediatric con junctivitis. Dis Mon. 2014;60(6):231238. Fig 6.) Fig. 188.1 Allergic conjunctivitis. Arrow indicates area of chemosis in the conjunctivitis. (From Adkinson NF Jr, Bochner BS, Burks AW, et al., eds. Middletons Allergy: Principles Practice. 8th ed. St Louis: Elsevier, 2014: p. 619.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All |
6,666 | rights reserved. 1424 Part XIII u Allergic Disorders as contact lenses (both hard and soft), ocular prostheses, and sutures. Symptoms and signs include mild bilateral ocular itching, tearing, a foreign body sensation, and excessive ocular discomfort with mild mucoid discharge with white or clear exudate on awakening, which may become thick and stringy. Trantas dots, limbal infiltration, bulbar conjunctival hyperemia, and edema may develop. Contact Allergy Contact allergy typically involves the eyelids but can also involve the conjunctivae. It is frequently associated with increased exposure to topical medications, contact lens solutions, and preservatives. DIAGNOSIS Nonallergic conjunctivitis can be viral, bacterial, or chlamydial in ori gin. It is typically unilateral, but can be bilateral with symptoms initially developing in one eye (see Chapter 666). Symptoms include stinging or burning rather than itching and often a foreign body sensation. Ocular discharge can be watery, mucoid, or purulent. Masqueraders of ocu lar allergy also include nasolacrimal duct obstruction, foreign body, blepharoconjunctivitis, dry eye, uveitis, and trauma. Dry Eye Dry eye conditions are being increasingly recognized as a concomitant and comorbid condition in children directly correlated with increased use of computers and gaming and mobile devices that are associated with decreased blinking time and increased evaporative tear film dysfunction. TREATMENT Primary treatment of ocular allergies includes avoidance of allergens, cold compresses, and lubrication. Secondary treatment regimens include the use of oral or topical antihistamines and, if necessary, topi cal decongestants, mast cell stabilizers, and antiinflammatory agents (Table 188.2). Drugs with dual antihistamine and mast cellblocking activities provide the most advantageous approach in treating allergic conjunctivitis, with both fast acting symptomatic relief and disease modifying action. Children often complain of stinging or burning with use of topical ophthalmic preparations and usually prefer oral antihis tamines for allergic conjunctivitis. It is important not to contaminate topical ocular medications by allowing the applicator tip to contact the eye or eyelid. Using refrigerated medications may decrease some of the discomfort associated with their use. Topical decongestants act as vasoconstrictors, reducing erythema, vascular congestion, and eye lid edema, but do not diminish the allergic response. Adverse effects of topical vasoconstrictors include burning or stinging and rebound hyperemia or conjunctivitis medicamentosa with chronic use. Com bined use of an antihistamine and a vasoconstrictor is more effective than use of either agent alone. Use of topical nasal corticosteroids for allergic rhinoconjunctivitis decreases ocular symptoms, presumably through a nasoocular reflex. Table 188.2 Topical Ophthalmic Medications for Allergic Conjunctivitis DRUG AND TRADE NAMES MECHANISM OF ACTION AND DOSING COMMENTS, CAUTIONS AND ADVERSE EVENTS Azelastine hydrochloride, 0.05 Optivar Antihistamine Children 3 yr: 1 gtt bid Not for treatment of contact lensrelated irritation; the preservative may be absorbed by soft contact lenses Wait at least 10 min after administration before inserting soft contact lenses Emedastine difumarate, 0.05 Emadine Antihistamine Children 3 yr: 1 gtt qid Soft contact lenses should not be worn if the eye is red Wait at least 10 min after administration before inserting soft contact lenses Levocabastine hydrochloride, 0.05 Livostin Antihistamine Children |
6,667 | 12 yr: 1 gtt bid qid up to 2 wk Not for use in patients wearing soft contact lenses during treatment Pheniramine maleate Antihistaminevasoconstrictor Avoid prolonged use (3 4 days) to avoid rebound symptoms Not for use with contact lenses Naphazoline hydrochloride, 0.3 Children 6 yr: 1 2 gtt qid Avoid prolonged use (3 4 days) to avoid rebound symptoms Not for use with contact lenses 0.025 Naphcon A, Opcon A Cromolyn sodium, 4 Crolom, Opticrom Mast cell stabilizer Children 4 yr: 1 2 gtt q4 6h Can be used to treat giant papillary conjunctivitis and vernal keratitis Not for use with contact lenses Lodoxamide tromethamine, 0.1 Alomide Mast cell stabilizer Children 2 yr: 1 2 gtt qid up to 3 mo Can be used to treat vernal keratoconjunctivitis Not for use in patients wearing soft contact lenses during treatment Nedocromil sodium, 2 Alocril Mast cell stabilizer Children 3 yr: 1 2 gtt bid Avoid wearing contact lenses while exhibiting the signs and symptoms of allergic conjunctivitis Pemirolast potassium, 0.1 Alamast Mast cell stabilizer Children 3 yr: 1 2 gtt qid Not for treatment of contact lensrelated irritation; the preservative may be absorbed by soft contact lenses Wait at least 10 min after administration before inserting soft contact lenses Epinastine hydrochloride, 0.05 Elestat Antihistaminemast cell stabilizer Children 3 yr: 1 gtt bid Contact lenses should be removed before use Wait at least 15 min after administration before inserting soft contact lenses Not for the treatment of contact lens irritation Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 188 u Ocular Allergies 1425 Table 188.2 Topical Ophthalmic Medications for Allergic Conjunctivitiscontd DRUG AND TRADE NAMES MECHANISM OF ACTION AND DOSING COMMENTS, CAUTIONS AND ADVERSE EVENTS Ketotifen fumarate, 0.025 Zaditor Antihistaminemast cell stabilizer Children 3 yr: 1 gtt bid q8 12h Not for treatment of contact lensrelated irritation; the preservative may be absorbed by soft contact lenses Wait at least 10 min after administration before inserting soft contact lenses Olopatadine hydrochloride, 0.1, 0.2, 0.7 Patanol, Pataday, Pazeo Antihistaminemast cell stabilizer Children 3 yr: 1 gtt bid (8 hr apart) Children 2 yr: 1 gtt qd Not for treatment of contact lensrelated irritation; the preservative may be absorbed by soft contact lenses Wait at least 10 min after administration before inserting soft contact lenses Alcaftadine, 0.25 Lastacaft Antihistaminemast cell stabilizer Children 2 yr: 1 gtt bid q8 12h Contact lenses should be removed before application; may be inserted after 10 min Not for the treatment of contact lens irritation Bepotastine besilate, 1.5 Bepreve Antihistaminemast cell stabilizer Children 2 yr: 1 gtt bid q8 12h Contact lenses should be removed before application; may be inserted after 10 min Not for the treatment of contact lens irritation Cetirizine, 0.24 Zerviate Antihistamine Children 2 yr: 1 gtt bid Contains lubricant hydrocellulose, preservative free unit doses Ketorolac tromethamine, 0.5 Acular |
6,668 | NSAID Children 3 yr: 1 gtt qid Avoid with aspirin or NSAID sensitivity Use ocular product with caution in patients with complicated ocular surgeries, corneal denervation or epithelial defects, ocular surface diseases (e.g., dry eye syndrome), repeated ocular surgeries within a short period, diabetes mellitus, or rheumatoid arthritis; these patients may be at risk for corneal adverse events that may be sight threatening Do not use while wearing contact lenses Fluorometholone, 0.1, 0.25 suspension and 0.1 ointment FML, FML Forte, Flarex Fluorinated corticosteroid Children 2 yr: 1 gtt into conjunctival sac of affected eye(s) bid qid During initial 24 48 hr, dosage may be increased to 1 gtt q4h Ointment (1.3 cm in length) into conjunctival sac of affected eye(s) 1 3 times daily May be applied q4h during initial 24 48 hr of therapy. If improvement does not occur after 2 days, patient should be reevaluated Patient should remove soft contact lenses before administering (contains benzalkonium chloride) and delay reinsertion of lenses for 15 min after administration Close monitoring for development of glaucoma and cataracts Cyclosporine ophthalmic solution, 01. Verkazia Immunomodulation Children 3 yr:1 gtt qid Unpreserved single dose units Approved for treatment of vernal keratoconjunctivitis loteprednol, 0.5 Lotemax, Alrex Steroid, antiinflammatory Children 2 yr:12 gtt qid Lowest steroid associated with cataract formation or increase in intraocular pressure Comes in suspension and gel formulations NSAID, Nonsteroidal antiinflammatory drug; bid, 2 times daily; gtt, drops; qid, 4 times daily; q4 6h, every 4 6 hr; qd, every day. Tertiary treatment of ocular allergy includes topical (or rarely oral) corticosteroids and should be conducted in conjunction with an ophthal mologist. Local administration of topical corticosteroids may be associated with increased intraocular pressure, viral infections, and cataract forma tion. Other immunomodulatory medications, such as topical tacrolimus or topical cyclosporine, are used as steroid sparing agents. Allergen immu notherapy is very effective in seasonal and perennial allergic conjunctivitis, especially when associated with rhinitis, and can decrease the need for oral or topical medications to control allergy symptoms. Because vernal and atopic keratoconjunctivitis can be associated with visual morbidity, if these diagnoses are suspected, the patient should be referred to an ophthalmologist. Symptoms that should prompt referral to an ophthalmologist include unilateral red eye with pain, photophobia, change in vision, refractory dry eyes, or corneal abnormality. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1426 Part XIII u Allergic Disorders Urticaria affects 20 of individuals at some point in their life. Episodes of hives that last for 6 weeks are considered acute, whereas those that occur on most days of the week for 6 weeks are designated chronic. The distinction is important, because the causes and mechanisms of urticaria formation and the therapeutic approaches are different in each instance. ETIOLOGY AND PATHOGENESIS Urticaria is defined as the presence of wheals (hives), |
6,669 | angioedema, or both. Acute urticaria is often caused by an allergic IgEmediated reaction (Table 189.1). This form of urticaria is a self limited process that occurs when an allergen activates mast cells in the skin. Common causes of acute generalized urticaria include foods, drugs (particularly antibiotics), and stinging insect venoms. If an allergen (latex, animal dander) penetrates the skin locally, hives often can develop at the site of exposure. Acute urticaria can also result from nonIgE mediated stimulation of mast cells, caused by viral infections, nonsteroidal anti inflammatory drugs (NSAIDs), and opiates. The diagnosis of chronic urticaria is established when lesions occur on most days of the week for 6 weeks (Tables 189.2 and 189.3). In about half the cases, chronic urticaria is accompanied by angioedema. In 20 of chronic urticaria patients, angioedema occurs without wheals. Acute angioedema with out wheals is often a result of allergy, but recurrent isolated angioedema raises the possibility of other diagnoses. A typical hive is an erythematous, pruritic, raised wheal that blanches with pressure, is transient, and resolves without residual lesions, unless the area was intensely scratched. In contrast, urticaria associated with systemic lupus erythematosus (SLE), or other vasculitides in which a skin biopsy reveals a small vessel vasculitis, often have distinguishing clinical features. Lesions that burn more than itch, last 24 hours, do not blanch, blister, heal with scarring, or that are associated with bleed ing into the skin (purpura) suggest urticarial vasculitis, which is a rare condition in children. Atypical aspects of the gross appearance of the hives or associated systemic symptoms should heighten concern that the urticaria or angioedema may be the manifestation of a systemic disease process (Table 189.4). INDUCIBLE URTICARIA Inducible urticaria and angioedema (previously referred to as physical urticaria) share the common property of being induced by an environ mental stimulus, such as a change in temperature or direct stimulation of the skin with pressure, stroking, vibration, or light (Table 189.5; see also Table 189.2). In contrast to chronic spontaneous urticaria (CSU), the wheals of inducible urticaria are more short lived, often lasting 1 hour. Cold Dependent Disorders Cold urticaria is characterized by the development of localized pru ritus, erythema, and urticariaangioedema after exposure to a cold stimulus. Total body exposure, as seen with swimming in cold water, can cause anaphylaxis, resulting in hypotension, loss of consciousness, and even death if not promptly treated. The diagnosis is most easily confirmed by challenge testing by holding an ice cube in place on the patients skin for 5 minutes. In patients with cold urticaria, a urticarial lesion develops about 10 minutes after removal of the ice cube and on rewarming of the chilled skin. Most cases of acquired cold urticaria are idiopathic. Cold urticaria is rarely associated with the presence of cryoproteins such as cold agglutinins, cryoglobulins, cryofibrino gen, and the Donath Landsteiner antibody seen in secondary syphilis (paroxysmal cold hemoglobinuria). Multiple subtypes of atypical cold urticaria with a negative ice cube test have also been reported. Cold Chapter 189 |
6,670 | Urticaria (Hives) and Angioedema David A. Khan, Aleena Banerji, and Scott H. Sicherer Table 189.1 Etiology of Acute Urticaria Foods Egg, milk, wheat, peanuts, tree nuts, soy, shellfish, fish, direct mast cell degranulation Medications Suspect all medications, even nonprescription or homeopathic Insect stings Hymenoptera (honeybee, yellow jacket, hornets, wasp, fire ants), biting insects (papular urticaria) Infections Bacterial (streptococcal pharyngitis, Mycoplasma, sinusitis); Viral (hepatitis, mononucleosis Epstein Barr virus, coxsackieviruses A and B); Parasitic (Ascaris, Ancylostoma, Echinococcus, Fasciola, Filaria, Schistosoma, Strongyloides, Toxocara, Trichinella); Fungal (dermatophytes, Candida) Contact allergy Latex, pollen, animal saliva, nettle plants, caterpillars Transfusion reactions Blood, blood products, or intravenous immune globulin administration From Lasley MV, Kennedy MS, Altman LC. Urticaria and angioedema. In: Altman LC, Becker JW, Williams PV, eds. Allergy in Primary Care. Philadelphia: Saunders; 2000: p. 232. Table 189.2 Etiology of Chronic Urticaria Spontaneousautoimmune Approximately 30 of chronic urticaria cases are inducible urticaria, and 6070 are spontaneous; of the spontaneous cases approximately 2060 have autoantibodies (see text) Inducible Dermographism Cholinergic urticaria Cold urticaria (see Table 189.6) Delayed pressure urticaria Solar urticaria Vibratory urticaria Aquagenic urticaria Autoimmune diseases Systemic lupus erythematosus Juvenile idiopathic arthritis Thyroid disease (Graves, Hashimoto) Celiac disease Inflammatory bowel disease Urticarial vasculitis Autoinflammatoryperiodic fever syndromes See Tables 189.3 and 189.6. Neoplastic Lymphoma Mastocytosis Leukemia Angioedema Hereditary angioedema Acquired angioedema Angiotensin converting enzyme inhibitors Modified from Lasley MV, Kennedy MS, Altman LC. Urticaria and angioedema. In: Altman LC, Becker JW, Williams PV, eds. Allergy in Primary Care. Philadelphia: Saunders; 2000: p. 234. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 189 u Urticaria (Hives) and Angioedema 1427 urticaria must be distinguished from the familial cold autoinflamma tory syndrome (see later, Diagnosis) (Table 189.6; see also Table 189.3 and Chapter 204). Because 20 of pediatric patients with cold urticaria may experience anaphylaxis, counseling on risks of anaphylaxis and prescribing epinephrine autoinjectors should be considered. Cholinergic Urticaria Cholinergic urticaria is characterized by the onset of small, punctate pruritic wheals surrounded by a prominent erythematous flare and associated with exercise, hot showers, emotional stress, and sweat ing. Once the patient cools down, the rash usually subsides in 30 60 minutes. Occasionally, symptoms of more generalized cholinergic stimulation, such as lacrimation, wheezing, salivation, and syncope, are observed. These symptoms are mediated by cholinergic nerve fibers that innervate the musculature via parasympathetic neurons and innervate the sweat glands by cholinergic fibers that travel with the sympathetic nerves. Elevated plasma histamine values parallel the onset of urticaria triggered by changes in body temperature. Table 189.3 Febrile Autoinflammatory Diseases Causing Urticaria in Children DISEASE GENE (PROTEIN) INHERITANCE ATTACK LENGTH TIMING OF ONSET CUTANEOUS FEATURES EXTRACUTANEOUS CLINICAL FEATURES FCAS NLRP3 (cryopyrin) AD Brief; minutes to 3 days Neonatal or infantile Cold induced pseudourticaria Arthralgia Conjunctivitis Headache Muckle Wells syndrome NLRP3 (cryopyrin) AD 1 3 days Neonatal, infantile, childhood (can be later) Widespread pseudourticaria Arthralgiaarthritis Sensorineural hearing loss |
6,671 | Conjunctivitisepiscleritis Headache Amyloidosis Neonatal onset multisystem inflammatory disease (aka chronic infantile neurologic cutaneous articular syndrome) NLRP3 (cryopyrin) AD Continuous flares Neonatal or infantile Widespread pseudourticaria Deforming osteoarthropathy, epiphyseal overgrowth Sensorineural hearing loss Dysmorphic facies Chronic aseptic meningitis, headaches, papilledema, seizures Conjunctivitisuveitis, optic atrophy Growth retardation Developmental delay Amyloidosis HIDS MVK (mevalonate kinase) AR 3 7 days Infancy (2 yr) Intermittent morbilliform or urticarial rash Aphthous mucosal ulcers Erythema nodosum Arthralgiaarthritis Cervical lymphadenopathy Severe abdominal pain Diarrheavomiting Headache Elevated IgD and IgA antibody levels Elevated urine mevalonic acid during attacks Tumor necrosis factor receptor associated periodic syndrome TNFRSF1A (TNFR1) AD 7 days Childhood Intermittent migratory erythematous macules and edematous plaques overlying areas of myalgia, often on limbs Periorbital edema Migratory myalgia Conjunctivitis Serositis Amyloidosis Systemic onset juvenile idiopathic arthritis (SoJIA) Polygenic Varies Daily (quotidian) Peak onset at 1 6 yr Nonfixed erythematous rash; may be urticarial With or without dermographism With or without periorbital edema Polyarthritis Myalgia Hepatosplenomegaly Lymphadenopathy Serositis PLAID PLCG2 AD NA Infancy Urticaria induced by evaporative cooling Ulcers in cold exposed areas Allergies Autoimmune disease Recurrent sinopulmonary infections Elevated IgE antibody levels Decreased IgA and IgM antibody levels Often elevated antinuclear antibody titers AD, Autosomal dominant; AR, autosomal recessive; HIDS, hyperimmunoglobulinemia D syndrome; FCAS, familial cold induced autoinflammatory syndrome; NA, not available; PLAID, PLCG2 associated antibody deficiency and immune dysregulation. From Youseff MJ, Chiu YE. Eczema and urticaria as manifestations of undiagnosed and rare diseases. Pediatr Clin North Am. 2017;64:3956. Table 2, pp. 4950. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1428 Part XIII u Allergic Disorders Symptomatic Dermographism Symptomatic dermographism (also called dermatographism or urti caria factitia) may occur as an isolated disorder or may accompany chronic urticaria or other inducible urticarias. It can be diagnosed by observing the skin after stroking it with a tongue depressor. In patients with dermographism, a linear response occurs secondary to reflex vasoconstriction, followed by pruritus, erythema, and a linear wheal caused by secondary dilation of the vessel and extravasation of plasma. Symptomatic dermographism is distinct from the more common sim ple dermographism, affecting 4 of the population, whereas whealing but no itch occurs with stroking the skin. Delayed Pressure Urticaria Delayed pressure urticaria differs from other inducible urticaria in that symptoms typically occur 4 6 hours after pressure has been applied. Some patients may complain of swelling, with or without pruritus, secondary to pressure, without hives. Other lesions are predominantly wheals and may or may not be associated with significant swelling. When wheals are present, an infiltrative skin lesion is seen, character ized by a perivascular mononuclear cell infiltrate and dermal edema similar to that seen in CSU. Symptoms occur at sites of tight cloth ing; foot swelling is common after walking; and buttock swelling may be prominent after sitting for a few hours. This condition can coexist with CSU or can occur |
6,672 | separately. The diagnosis is confirmed by chal lenge testing, most commonly via the sand bag test. This test can be performed by using 15 lb of weights attached to a strap applied to the shoulder, thigh, or forearm for 15 minutes and observing the site over the next 24 hours for evidence of hives or edema. Solar Urticaria Solar urticaria is a rare disorder in which urticaria develops within minutes of direct sun exposure. Typically, pruritus occurs first, in approximately 30 seconds, followed by edema confined to the light exposed area and surrounded by a prominent erythematous zone. The lesions usually disappear within 1 3 hours after cessation of sun expo sure. When large areas of the body are exposed, systemic symptoms may occur, including hypotension and wheezing. Solar urticaria has been classified into six types, depending on the wavelength of light that induces skin lesions and the ability or inability to transfer the disorder passively with serum IgE. Aquagenic Urticaria Patients with aquagenic urticaria demonstrate small wheals after con tact with water, regardless of its temperature, and are thereby distin guishable from patients with cold urticaria or cholinergic urticaria. Direct application of a compress of water to the skin is used to test for the presence of aquagenic urticaria. Rarely, chlorine or other trace contaminants may be responsible for the reaction. CHRONIC SPONTANEOUS URTICARIA CSU is the most common form of chronic urticaria and is associated with normal routine laboratory values and no evidence of systemic dis ease. CSU differs from allergen induced skin reactions and from physi cally induced urticaria in that histologic studies reveal cellular infiltrate predominantly around small venules. Skin examination reveals infil trative hives with palpably elevated borders, sometimes varying greatly in size and shape but generally rounded. Biopsy of a typical lesion reveals nonnecrotizing, perivascular, mononuclear cellular infiltration. Varying histopathologic processes can occur in the skin and manifest as urticaria. Patients with urticar ial vasculitis can have urticaria andor angioedema. Biopsy of these lesions in patients who may present with urticaria, arthralgias, myal gias, an elevated erythrocyte sedimentation rate (ESR), and in some cases hypocomplementemia as manifestations of urticarial vasculitis can reveal fibrinoid necrosis with a predominantly neutrophilic infil trate. Although urticarial vasculitis lesions are typically less blanchable, the lesions may be clinically indistinguishable from those seen in the more typical, nonvasculitic cases. The immunopathogenesis of CSU is not entirely clear; however, mast cell activation is thought to have a key role. A key activating receptor in mast cells is the high affinity IgE receptor (FcRI). Two theories sug gest that autoimmune factors may lead to FcRI activation. In type 1 autoimmunity (aka autoallergy), patients have IgE autoantibodies to self antigens such as thyroperoxidase or interleukin (IL) 24, which can cross link the IgE autoantibodies leading to mast cell activation and urticaria. In type II autoimmunity, patients have autoantibodies (IgG, IgM, IGA) directed against FcRI or IgE itself, which can similarly lead to mast cell activation. Direct measurement of these autoantibodies is limited to |
6,673 | research studies with no clear clinical utility at present. How ever, the autoallergy theory is an attractive explanation for the effec tiveness of anti IgE therapies like omalizumab. Diagnosis The diagnosis of both acute and chronic urticaria is primarily clinical and requires that the clinician be aware of the various forms of urticaria (wheals and angioedema). Hives are transient, pruritic, erythematous, raised wheals that may become tense and painful. The lesions may coalesce and form poly morphous, serpiginous, or annular lesions (Figs. 189.1 and 189.2). Individual lesions usually last minutes to several hours and rarely more than 24 hours. The lesions often disappear, only to reappear at another site. Angioedema involves the deeper subcutaneous tissues in loca tions such as the eyelids, lips, tongue, genitals, dorsum of the hands or feet, and in the case of hereditary angioedema (HAE), the wall of the gastrointestinal (GI) tract (see Chapter 189.1). Viral infections, drugs, and foods are the most common identifiable causes of acute urticaria in children. Allergy skin testing for foods can be helpful in identifying a cause of acute urticaria, but only when sup ported by historical evidence. The role of an offending food can then be proved by elimination and food challenge, when needed. In the absence of information implicating an ingestant cause, skin testing for foods and implementation of elimination diets are generally not use ful for either acute or chronic urticaria. Patients with delayed urticaria 3 6 hours after a meal consisting of mammalian meat should be evalu ated for IgE to galactose 1,3 galactose (alpha gal), a carbohydrate allergen. Alpha gal has been identified as a trigger in this circumstance, Table 189.4 Distinguishing Features Between Urticaria and Systemic Urticarial Syndromes COMMON URTICARIA URTICARIAL SYNDROMES (1 OF FOLLOWING) Only typical wheals: Atypical wheals: Erythematous edematous lesions Infiltrated plaques Transient (24 36 hr) Persistent (24 36 hr) Asymmetric distribution Symmetric distribution Resolution without signs Resolution with signs (hypo hyperpigmentation, bruising, or scarring) No associated different elementary lesions (papules, vesicles, purpura, crustae) Associated different elementary lesions (papules, vesicles, purpura, scaling, crustae) Pruritic (rarely stingingburning) Not pruritic; rather painful or burning Possibly associated with angioedema Usually no associated angioedema No associated systemic symptoms Often associated with systemic symptoms (fever, malaise, arthralgia, abdominal pain, weight loss, acral circulatory abnormalities, neurologic signs From Peroni A, Colato C, Zanoni G, Girolomoni G. Urticarial lesions: if not urticaria, what else? The differential diagnosis of urticaria. J Am Acad Dermatol. 2009;62(4):559. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. C hap ter 1 8 9 u U rticaria (H ives) and A ng io ed em a 1 4 2 9 Table 189.5 Comparison of the Physical Urticarias URTICARIA RELATIVE FREQUENCY PRECIPITANT TIME OF ONSET DURATION LOCAL SYMPTOMS SYSTEMIC SYMPTOMS TESTS MECHANISM TREATMENT Symptomatic dermographism Most frequent Stroking skin Minutes 2 3 hr Irregular pruritic attacks None Stroke skin |
6,674 | Passive transfer, IgE, histamine, possible role of adenosine triphosphate, substance P, possible direct pharmacologic mechanism Continual antihistamines Delayed dermographism Rare Stroking skin 30 min to 8 hr 48 hr Burning, deep swelling None Stroke skin, observe early and late Unknown Avoidance of precipitants Pressure urticaria Frequent Pressure 3 12 hr 8 24 hr Diffuse, tender swelling Flulike symptoms Apply weight Unknown Avoidance of precipitants; if severe, omalizumab Solar urticaria Frequent Various wavelengths of light 2 5 min 15 min to 3 hr Pruritic wheals Wheezing, dizziness, syncope Phototest Passive transfer, reverse passive transfer, IgE, possible histamine Avoidance of precipitants; antihistamines, sunscreens, antimalarials Familial cold urticaria Rare Change in skin temperature 30 min to 3 hr 48 hr Burning wheals Tremor; headache; arthralgia; fever Expose skin to cold air Unknown Avoidance of precipitants Essential acquired cold urticaria Frequent Cold contact 2 5 min 1 2 hr Pruritic wheals Wheezing, syncope, drowning Apply ice filled copper beaker to arm, immerse Passive transfer, reverse passive transfer, IgE (IgM), histamine; vasculitis can be induced Cyproheptadine hydrochloride, other antihistamines; desensitization; avoidance of precipitants Heat urticaria Rare Heat contact 2 5 min (rarely delayed) 1 hr Pruritic wheals None Apply hot waterfilled cylinder to arm Possibly histamine; possibly complement Antihistamines, desensitization; avoidance of precipitants Cholinergic urticaria Very frequent General overheating of body 2 20 min 30 min to 1 hr Papular, pruritic wheals Syncope; diarrhea; vomiting, salivation; headaches Bathe in hot water; exercise until perspiring, inject methacholine chloride Passive transfer; possible immunoglobulin; product of sweat gland stimulation; histamine, reduced protease Application of cold water or ice to skin; antihistamines; omalizumab Aquagenic urticaria Rare Water contact Several minutes 30 45 min Papular, pruritic wheals None reported Apply water compresses to skin Unknown Avoidance of precipitants; antihistamine; application of inert oil Vibratory angioedema Very rare Vibrating against skin 2 5 min 1 hr Angioedema None reported Apply vibration to forearm Unknown Avoidance of precipitants Ig, Immunoglobulin. From Lee AD, Jorizzo JL. Urticaria. In: Callen JP, Jorizzo JL, Bolognia JL, et al., eds. Dermatological Signs of Internal Disease. 4th ed. Philadelphia: Elsevier; 2009: p. 59, Table 6.4. D ow nloaded for m oham ed ahm ed (dr.m m s2020 gm ail.com ) at U niversity of Southern C alifornia from C linicalK ey.com by Elsevier on A pril 21, 2024. For personal use only. N o other uses w ithout perm ission. C opyright 2024. Elsevier Inc. A ll rights reserved. 1430 Part XIII u Allergic Disorders with sensitization linked to tick bites in specific geographic regions, such as the mid Atlantic area of the United States. Skin testing for aero allergens is not indicated unless there is a concern about contact urti caria (animal dander or grass pollen). Autoimmune diseases are very rare causes of chronic urticaria or angioedema. Clinically available tests marketed for chronic urticaria such as basophil activation tests (used as surrogates for detecting type 2 autoantibodies) are generally not recommended. The differential diagnosis of chronic urticaria includes atopic or contact dermati tis, cutaneous or systemic |
6,675 | mastocytosis, complement mediated mast cell degranulation as may occur with circulating immune complexes, malignancies, mixed connective tissue diseases, and cutaneous blis tering disorders (e.g., bullous pemphigoid; see Table 189.2). Rou tine laboratory testing in chronic urticaria in the absence of other history has not been found to be cost effective as it rarely changes management. Urticaria guidelines recommend either no testing or limited laboratory testing such as a complete blood cell count with differential and ESR or CRP. Further studies are warranted if the patient has fever, arthralgias, or elevated ESR (Table 189.7; see also Table 189.4). HAE is potentially life threatening, usually associated with deficient C1 inhibitor (C1 INH) activity, and the most impor tant familial form of angioedema (see Chapter 189.1), but it is not associated with typical urticaria. In patients with eosinophilia, stools should be obtained for ova and parasite testing, because infection with helminthic parasites has been associated with urticaria. A rare syndrome of episodic (approximately 3 to 4 week intervals) angio edema less often with urticaria, weight gain, and occasionally fever with associated hypereosinophilia has been described in both adults and children. Skin biopsy for diagnosis of possible urticarial vasculitis is rec ommended for urticarial lesions that persist at the same location for 24 hours, those with pigmented or purpuric components, and those that burn more than itch. Collagen vascular diseases such as SLE may manifest urticarial vasculitis as a presenting feature. The skin biopsy in urticarial vasculitis typically shows endothelial cell swelling of postcap illary venules with necrosis of the vessel wall, perivenular neutrophil infiltrate, diapedesis of red blood cells, and fibrin deposition associated with deposition of immune complexes. Mastocytosis is characterized by mast cell hyperplasia in the bone marrow, liver, spleen, lymph nodes, and skin. Clinical effects of mast cell activation are common, including pruritus, flushing, urtication, abdominal pain, nausea, and vomiting. The diagnosis is confirmed by a bone marrow biopsy showing increased numbers of spindle shaped mast cells that express CD2 and CD25. Maculo papular cutaneous mastocytosis (aka urticaria pigmentosa) is the most common skin manifestation of mastocytosis and may occur as an isolated skin finding. It appears as small, yellow tan to reddish brown macules or raised papules that urticate on scratching (Darier sign). This sign can be masked by antihistamines. The diagnosis is confirmed by a skin biopsy that shows increased numbers of dermal mast cells. Inducible urticaria should be considered in any patient with chronic urticaria and a suggestive history (see Tables 189.2 and 189.5). Papular urticaria often occurs in small children, generally on the extremities, but the lesions are more persistent than true urticaria. It manifests as grouped or linear, highly pruritic wheals or papules mainly on exposed skin at the sites of insect bites. Exercise induced anaphylaxis manifests as varying combina tions of pruritus, urticaria, angioedema, wheezing, or hypotension after exercise (see Chapter 190). Cholinergic urticaria is differenti ated by positive results of heat challenge tests and the rare occurrence Table 189.6 Hereditary Diseases with Cold Induced |
6,676 | Urticaria EPISODIC SYMPTOMS SUSTAINEDPROGRESSIVE SYMPTOMS CAPS FCAS Urticarial rash, arthralgia, myalgia, chills, fever, swelling of extremities Renal amyloidosis MWS Urticarial rash, arthralgia, chills, fever Sensorineural deafness, renal amyloidosis CINCA Fever Rash, arthritis, chronic meningitis, visual defect, deafness, growth retardation, renal amyloidosis NAPS12 (FCAS2) Fever, arthralgia, myalgia, urticaria, abdominal pain, aphthous ulcers, lymphadenopathy Sensorineural deafness PLAID (FCAS3) Urticaria induced by evaporative cooling, sinopulmonary infections Serum low IgM and IgA levels; high IgE levels; decreased B and NK cells; granulomata; antinuclear antibodies CAPS, Cryopyrin associated periodic syndromes; FCAS, familial cold induced autoinflammatory syndrome; MWS, Muckle Wells syndrome; CINCA, chronic infantile neurologic cutaneous articular syndrome; NAPS, NLRP 12associated periodic syndrome; PLAID, PLCG2 associated antibody deficiency and immune dysregulation; NK, natural killer; Ig, immunoglobulin. From Kanazawa N. Hereditary disorders presenting with urticaria. Immunol Allergy Clin N Amer. 2014;34:169179. Table 4, p. 176. Fig. 189.1 Polycyclic lesions of urticaria associated with prostaglan din E2 infusion. (From Eichenfield LF, Friedan IJ, Esterly NB. Textbook of Neonatal Dermatology. Philadelphia: Saunders; 2001: p. 300.) Fig. 189.2 Annular urticaria of unknown etiology. (From Eichenfield LF, Friedan IJ, Esterly NB. Textbook of Neonatal Dermatology. Philadel phia: Saunders; 2001: p. 301.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 189 u Urticaria (Hives) and Angioedema 1431 of anaphylactic shock. The combination of ingestion of various food allergens and postprandial exercise has been associated with urticaria angioedema and anaphylaxis. In patients with this combination disor der, the offending food or exercise alone does not produce the reaction. Muckle Wells syndrome and familial cold autoinflammatory syn drome are rare, autosomal dominantly inherited conditions associ ated with recurrent urticaria like lesions. Muckle Wells syndrome is characterized by arthritis and joint pain that usually appears in adoles cence. It is associated with progressive nerve deafness, recurrent fever, elevated ESR (see Tables 189.3 and 189.6), hypergammaglobulinemia, renal amyloidosis, and a poor prognosis. Familial cold autoinflamma tory syndrome is characterized by a cold induced rash that has urti carial features but is rarely pruritic. Cold exposure leads to additional symptoms such as conjunctivitis, sweating, headache, and nausea. Treatment Acute urticaria is a self limited illness requiring little treatment other than antihistamines and avoidance of any identified trigger. Hydroxyzine and diphenhydramine are sedating but are effective and frequently used for treatment of urticaria. Loratadine, fexofenadine, and cetirizine are also effective and are preferable because of reduced sedation (Table 189.8). Epinephrine 1:1,000, 0.01 mgkg (maximum 0.5 mg) intramuscularly, usually provides rapid relief of acute, severe urticariaangioedema but is seldom required. A short course of oral corticosteroids may be given for more severe episodes of urticaria and angioedema that are unresponsive to antihistamines. The best treatment of inducible urticaria is avoidance of the stimulus; however, for some conditions like cholinergic urticaria, this can be very difficult. Antihistamines with appropriate updosing, should be tried in all inducible urticarias but may not be effective in |
6,677 | many patients. Management of chronic urticaria through dietary manipulation is not recommended by U.S. guidelines. The mainstay of therapy for chronic urticaria is the use of nonsedating or low sedating H1 anti histamines. In those patients not showing response to standard doses, increasing the dose up to fourfold the recommended dose is recom mended; however, studies on the safety and efficacy of this approach in children are lacking. The addition of H2 antihistamines andor leukotriene receptor antagonists (e.g., montelukast) is controversial. These medications are generally benign but evidence supporting their efficacy is weak. For chronic urticaria patients that are not well con trolled, brief courses of oral corticosteroids may be considered, but long term corticosteroid use is not recommended. The monoclonal antibody omalizumab (anti IgE) is approved by the US Food and Drug Administration (FDA) for the treatment of chronic urticaria in children 12 years and older. Other agents that have been used for chronic urticaria but are not approved by the FDA include cyclo sporine, tacrolimus, mycophenolate, dapsone, hydroxychloroquine, sulfasalazine, and azathioprine. Ultraviolet light therapy may also be beneficial in refractory cases. Bruton tyrosine kinase (BTK) inhibitors have demonstrated efficacy in treating chronic spontaneous urticaria and have a rapid onset of action with few side effects. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 189.7 Diagnostic Testing for Urticaria and Angioedema DIAGNOSIS DIAGNOSTIC TESTING Chronic spontaneous urticaria No testing required for diagnosis Food and drug reactions Elimination of offending agent, skin testing, and challenge with suspected foods Autoimmune urticaria Autologous serum skin test; antithyroid antibodies Thyroiditis Thyroid stimulating hormone; antithyroid antibodies Infections Appropriate cultures or serology Collagen vascular diseases and cutaneous vasculitis Skin biopsy, CH50, C1q, C4, immunofluo rescence of tissues, antinuclear antibod ies, cryoglobulins Cold urticaria Ice cube test usually positive but may be negative in familial autoinflammatory disorders Solar urticaria Exposure to defined wavelengths of light, red blood cell protoporphyrin, fecal protoporphyrin, and coproporphyrin Dermographism Stroking with narrow object (e.g., tongue blade) Pressure urticaria Application of pressure for defined time and intensity Vibratory urticaria Vibration for 4 min Aquagenic urticaria Challenge with tap water at various temperatures Urticaria pigmentosa Skin biopsy, test for dermographism Hereditary angioedema C4, C1 INH testing by protein and function Familial cold autoinflammatory syndrome Genetic testing for NALP3 pathogenic variants Table 189.8 Treatment of Urticaria and Angioedema CLASSDRUG DOSE FREQUENCY ANTIHISTAMINES, TYPE H1 (SECOND GENERATION) Fexofenadine 6 11 yr: 30 mg Twice daily 12 yr: 60 mg Adult: 180 mg Once daily Loratadine 2 5 yr: 5 mg Once daily 6 yr: 10 mg Desloratadine 6 11 mo: 1 mg 12 mo 5 yr: 1.25 mg Once daily 6 11 yr: 2.5 mg 12 yr: 5 mg Cetirizine 6 23 mo: 2.5 mg Once daily 2 6 yr: 2.5 5 mg 6 yr: 5 10 mg Levocetirizine 12 yr: 10 mg Once daily 6 mo 5 yr: 1.25 mg Once daily 6 11 yr: 2.5 mg Once daily 12 yr: 5 mg Once daily ANTIHISTAMINES, TYPE H2 Cimetidine Infants: 10 20 mgkgday Divided |
6,678 | q6 12h Children: 20 40 mgkgday Ranitidine 1 mo 16 yr: 5 10 mgkgday Divided q12h Famotidine 3 12 mo: 1 mgkgday Divided q12h 1 16 yr: 1 2 mgkgday LEUKOTRIENE PATHWAY MODIFIERS Montelukast 12 mo 5 yr: 4 mg Once daily 6 14 yr: 5 mg 14 yr: 10 mg Zafirlukast 5 11 yr: 10 mg Twice daily IMMUNOMODULATORY DRUGS Omalizumab (anti IgE) 11 yr: 300 mg Every 28 days Cyclosporine 1 4 mgkgday Divided q12h Monitor blood pressure and serum creatinine, potassium, and magnesium levels monthly. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1432 Part XIII u Allergic Disorders 189.1 Hereditary Angioedema Aleena Banerji, David A. Khan, and Scott H. Sicherer ETIOLOGY, PATHOGENESIS, CLINICAL MANIFESTATIONS, AND DIAGNOSTIC APPROACH HAE (types 1 and 2) is an inherited autosomal dominant genetic dis ease caused by low functional levels of the plasma protein C1 INH. Patients typically report unpredictable episodic attacks of angioedema or deep localized swelling, most often on a hand or foot, that begin dur ing childhood or adolescence. Cutaneous nonpitting and nonpruritic edema not associated with urticaria is the most common symptom. The swelling usually becomes more severe over about several hours and then resolves over 2 5 days when left untreated. However, the dura tion of attacks can be quite variable. In some patients, attacks are pre ceded by the development of a rash, erythema marginatum, that is erythematous, not raised, and not pruritic. A second major symptom complex noted by patients is attacks of severe abdominal pain caused by edema of the mucosa of any portion of the GI tract. The intensity of the pain can approximate that of an acute abdomen, often resulting in unnecessary surgery, including appendectomy. Either constipation or diarrhea during these attacks can be noted. The GI edema generally follows the same time course to resolution as the cutaneous attacks. Patients may have a prodrome, a tightness or tingling in the area that will swell, usually lasting several hours, followed by the development of angioedema. Laryngeal edema, the most worrisome complication of HAE, can cause complete respiratory obstruction with a high risk of mortal ity when untreated. Although life threatening attacks are infrequent, more than half of patients with HAE experience laryngeal involvement at some time during their lives. Laryngeal edema can be triggered by local trauma but can also occur spontaneously without any identifi able trigger. The clinical condition may deteriorate rapidly, progressing through mild discomfort to complete airway obstruction over hours. Soft tissue edema can be readily seen when the disease involves the throat and uvula. If this edema progresses to difficulty swallowing secretions or a change in the tone of the voice, the patient may require emergency intubation or even tracheostomy to ensure an adequate airway. As symptoms are bradykinin mediated, patients with HAE typically do not respond well to treatment with |
6,679 | epinephrine, antihista mines, or glucocorticoids. In most cases the cause of the attack is unknown, but in some patients, trauma, infections or emotional stress clearly precipitates attacks. Drugs such as estrogen or angiotensin converting enzyme (ACE) inhibitors that inhibit the degradation of bradykinin make the disease strikingly worse. In some females, menstruation can be associ ated with an increase in attacks. The frequency of attacks varies greatly among affected individuals and at different times in the same individ ual. Some individuals experience weekly episodes, whereas others may go years between attacks. Episodes can start at any age. C1 INH is a member of the serpin family of proteases, similar to antitrypsin, antithrombin III, and angiotensinogen. These proteins stoichiometrically inactivate their target proteases by forming stable, 1:1 complexes with the protein to be inhibited. Synthesized primarily by hepatocytes, C1 INH is also synthesized by monocytes. The regu lation of the protein production is not completely understood, but it is believed that androgens may stimulate C1 INH synthesis, because patients with the disorder respond clinically to androgen therapy with elevated serum C1 INH levels. C1 INH deficiency is an autosomal dominant disease, with as many as 25 of patients giving no family history. Because all C1 INHdeficient patients are heterozygous for this gene variation, it is believed that half the normal level of C1 INH is not sufficient to prevent attacks. Figure 189.3 shows the diagnostic approach. Although named for its action on the first component of comple ment (C1 esterase), C1 INH also inhibits components of the fibrino lytic, clotting, and kinin pathways. Specifically, C1 INH inactivates plasmin activated Hageman factor (factor XII), activated factor XI, plasma thromboplastin antecedent, and kallikrein. Within the comple ment system, C1 INH blocks the activation of C1 and the rest of the classical complement pathway by binding to C1r and C1s. Without adequate C1 INH, unchecked activation of C1 causes cleavage of C4 and C2, the proteins following in the complement cascade. Levels of C3 are normal. C1 INH also inhibits serine proteases associated with activation of the lectin activation pathway. The major factor respon sible for the edema formation is bradykinin, an important nonapeptide mediator that can induce leakage of postcapillary venules. Bradyki nin is derived from cleavage of the circulating protein high molecular weight kininogen by the plasma enzyme kallikrein. A B THE DIAGNOSIS OF C1INH DEFICIENCY Asymptomatic pediatric patient with positive family history of C1INHHAE THE DIAGNOSIS OF PEDIATRIC C1INHHAE Pediatric patient with angioedema of unknown etiology Positivenegative family history C1INH functional and antigenic level, C4 Positive screen Perform initial testing on peripheral blood after 12 mo of age C1INHHAE excluded Consider DNA analysis Negative screen If a pathogenic variant has been detected in the family, and the test is available then Consider genetic testing before 12 mo of age Umbilical cord blood C1INH functional antigenic levels, C4 Repeat after 1 year of age Until C1INHHAE diagnosis is ruled out with testing performed after one year of age, the pediatric patient should |
6,680 | be considered to have inherited C1INH deficiency. Normal C1INH antigen but low C1INH activity confirms HAE2 Angioedema with acquired C1INH deficiency is also excluded, but HAE with normal C1INH function, which is very rare in pediatric patients, is not ruled out Complete after 12 mo of age Peripheral blood C1INH functional antigenic levels, C4 Neonate Infant Fig. 189.3 A, Diagnosis of C1 INH deficiency in families with known C1 INH hereditary angioedema (HAE). B, Diagnosis of C1 INH HAE in pediatric patients with angioedema of unknown etiology. (From Far kas H, Martinez Saguer I, Bork K, et al. International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency. Eur J Allergy Clin Immunol. 2017;72:300313. Fig. 1, p. 304.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 189 u Urticaria (Hives) and Angioedema 1433 Two major genetic types of C1 INH deficiency are described that result in essentially the same phenotypic expression. The C1 INH gene is located on chromosome 11 in the p11 q13 region. The inheritance is autosomal dominant with incomplete penetrance. Persons inherit ing the variant gene can have a clinical spectrum ranging from asymp tomatic to severely affected. Type 1 HAE is the most common form, accounting for approximately 8085 of cases. Synthesis of C1 INH is blocked at the site of the faulty allele, or the protein is not secreted normally because of faulty protein processing, but secretion occurs at the normal allele. The result is secretion of the normal protein, yielding quantitative serum concentrations of C1 INH approximately 2040 of normal. Type 2 HAE accounts for approximately 1520 of cases. Pathogenic variants of one of the amino acids near the active site of the inhibitor lead to synthesis of nonfunctional C1 INH protein and again less than half of the normal functioning protein. Patients with type 2 HAE have either normal or increased concentrations of the protein but low values in assays of C1 INH function. A clinical syndrome resembling HAE termed HAE with normal C1 INH has been described that more commonly affects females, with a tendency to cause fewer abdominal attacks and more upper airway attacks. In this condition, no abnormalities of complement or of C1 INH have been described. A small number of affected patients have been found to have a gain of function abnormality of clotting factor XII, but the fundamental cause of this syndrome is still unknown. Additional pathogenic variants including ANGPT1 (angiopoietin 1), PLG (plasminogen), KNG1 (kininogen), MYOF (myoferlin), and HS3ST6 (heparan sulfate glucosamine 3 O sulfotransferase 6) have been identified. Acquired C1 INH is associated with low levels of C4, C1 INH, and C1q (Table 189.9). TREATMENT Treatment of HAE is aimed at use of on demand treatment when an attack starts along with long term prophylaxis to prevent attacks. Short term prophylaxis is |
6,681 | used prior to a known trigger such as a surgical or dental procedure. The medical management of HAE has improved significantly in recent years with the availability of several new safe and effective therapies approved by the FDA in the United States. To provide optimal care and restore a normal quality of life, treatment of patients with HAE needs to be individualized based on patient specific factors including patient preference and access to emergency care. Options for long term prophylaxis in patients with HAE include an intravenous formulation of plasma derived C1 INH concentrate (Cinryze) given twice a week. Cinryze was FDA approved in 2008 for adolescents and adults. The half life of this plasma protein is relatively short, about 40 hours, and the approved regimen is 1,000 units twice a week. In 2017, a subcutaneous C1 INH concentrate formulation given twice a week was approved for long term prophylaxis in adolescents and adults. Lanadelumab, a monoclonal antibody that inhibits plasma kallikrein, given subcutaneously once every 2 4 weeks, along with berotralstat, an oral once a day pill, which inhibits plasma kallikrein, are the newest treatment options available for long term prophylaxis in patients with HAE (see Table 189.10). Garadacimab, a fully human recombinant monoclonal antibody targeting activated factor XII, has shown efficacy as a prophylactic agent. Androgens, like the gonadotropin inhibitor danazol, were pre viously used more frequently for long term prophylaxis to prevent attacks. Weak androgens have many side effects that preclude their use in some patients. Their use in children is problematic because of the possibility of premature closure of the epiphyses, and these agents are Table 189.9 Complement Evaluation of Patients with Recurrent Angioedema C4 C1 INH LEVEL C1 INH FUNCTION C1q Idiopathic angioedema Normal Normal Normal Normal Type 1 HAE Low Low Low Normal Type 2 HAE Low Normal Low Normal HAE nlC1 INH Normal Normal Normal Normal Acquired C1 INH deficiency Low Low Low Low Urticarial vasculitis Low or normal Normal Normal Low or normal C1 INH, C1 inhibitor; HAE nlC1 INH, hereditary angioedema with normal C1 INH; nl, normal. From Joshi SR, Khan DA. Urticaria and angioedema. In: Leung DYM, Akdis CA, Bacharier LB, et al., eds. Pediatric Allergy Principles and Practice. 4th ed. Philadelphia: Elsevier; 2021: Table 39.3, p. 338. Table 189.10 Long Term Prophylactic Treatment Options for Patients with Hereditary Angioedema in the United States DRUG DATE OF FDA APPROVAL IN US MECHANISM OF ACTION ROUTE OF ADMINISTRATION OTHER CONSIDERATIONS Intravenous plasma derived C1 INH 2008 Replacing missing protein Intravenous Dependent on plasma supply Extensive clinical experience Subcutaneous plasma derived C1 INH 2017 Replacing missing protein Subcutaneous Dependent on plasma supply Improved steady state C1 INH levels Lanadelumab 2018 Plasma kallikrein inhibitor Subcutaneous Unknown safety in pregnancy Infrequent dosing every 2 4 wk Berotralstat 2020 Plasma kallikrein inhibitor Oral Unknown safety in pregnancy Once a day pill Attenuated androgens 1976 Increases circulating levels of C1 INH protein Oral Significant adverse effects Contraindicated in pregnancy, lactation and children Antifibrinolytics 1986 Reduces complement |
6,682 | activation and C1 INH protein consumption Oral Significant adverse effects Inferior efficacy compared with other agents Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1434 Part XIII u Allergic Disorders not used in pregnant women. The fibrinolysis inhibitor aminocaproic acid (EACA) is also effective in preventing attacks and has been used in children, but its use is attenuated by the development of severe fatigue and muscle weakness over time. A cyclized analog of EACA, tranexamic acid, has been used extensively in Europe; because of side effects and increased availability of other novel treatment options, it has been used less extensively in the United States. Tranexamic acid is believed to be more effective than EACA and has lower toxicity, but there have been few direct studies. Its mechanism of action is not clearly defined, and not all patients respond to this agent. There are four on demand treatment options FDA approved in the United States for patients with HAE. The first, approved in 2009, is a purified C1 inhibitor product (Berinert) that is administered as 20 U kg intravenously. It was approved for the treatment of attacks. In 2009 the FDA approved a kallikrein inhibitor, ecallantide, given subcuta neously, for acute treatment in patients age 16 years and older. This 60amino acid peptide causes anaphylaxis rarely and is approved only for administration by medical personnel. In 2010 a bradykinin type 2 receptor antagonist, icatibant, was approved for acute treatment in patients age 18 years and older. An intravenous recombinant C1 INH product has been FDA approved in 2014 for treatment of acute attacks (and in Europe) in adolescents and adults (see Table 189.11). All treat ments are most effective when given early in an attack and begin to have a noticeable effect about 1 4 hours after treatment. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 189.11 On Demand Treatment Options for Patients with Hereditary Angioedema in the United States DRUG DATE OF FDA APPROVAL IN US MECHANISM OF ACTION ROUTE OF ADMINISTRATION OTHER CONSIDERATIONS Intravenous plasma derived C1 INH 2009 Replacing missing protein Intravenous Dependent on plasma supply Extensive clinical experience Recombinant C1 INH 2014 Replacing missing protein Intravenous No human virus risk Scalable supply Ecallantide 2009 Plasma kallikrein inhibitor Subcutaneous No infectious risk 34 risk of anaphylaxis Requires administration by a healthcare provider Icatibant 2011 B2 bradykinin receptor antagonist Subcutaneous No infectious risk Stable at room temperature Local injection reactions Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. Anaphylaxis in children, particularly infants, may be underdiagnosed. Anaphylaxis occurs when there is a sudden release of potent, biologically active mediators from mast cells and basophils, leading to cutaneous (urticaria, angioedema, flushing), respiratory (bronchospasm, laryngeal edema), cardiovascular (hypotension, dys rhythmias, myocardial ischemia), and gastrointestinal (GI; nausea, col icky abdominal pain, vomiting, diarrhea) symptoms (Table 190.1 and Fig. 190.1). |
6,683 | Chapter 190 Anaphylaxis Hugh A. Sampson, Julie Wang, and Scott H. Sicherer Table 190.1 Clinical Criteria for Diagnosing Anaphylaxis 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 (e.g., generalized urticaria, itching or flushing, swollen lips tongue uvula) And at least one of the following: A. Respiratory compromise (e.g., dyspnea, wheeze bronchospasm, stridor, hypoxemia) B. Reduced blood pressure or associated symptoms of end organ dysfunction (e.g., hypotonia collapse, syncope, incontinence) OR 2. Two or more of the following that occur rapidly after exposure to a likely allergen (or other trigger) for that patient (minutes to several hours) A. Involvement of the skinmucosal tissue (e.g., generalized urticaria, itch flush, swollen lips tongue uvula) B. Respiratory compromise (e.g., dyspnea, wheeze or bronchospasm, stridor, reduced peak expiratory flow, hypoxemia) C. Reduced blood pressure or associated symptoms (e.g., hypotonia collapse, syncope, incontinence) D. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) OR 3. Reduced blood pressure after exposure to a known allergen or other trigger for that patient (minutes to hours). A. Infants and children: low systolic blood pressure (age specific) or greater than 30 decrease in systolic blood pressure B. Adults: systolic blood pressure of less than 90 mm Hg or greater than 30 decrease from that persons baseline From Sampson HA, MuozFurlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary reportSecond National Institute of Allergy and Infectious DiseaseFood Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117(2):3917. ETIOLOGY The most common causes of anaphylaxis in children are different for hospital and community settings. Anaphylaxis occurring in the hospital results primarily from allergic reactions to medications and latex. Food allergy is the most common cause of anaphylaxis occurring outside the hospital, accounting for about half the anaphylactic reactions reported in pediatric surveys from the United States, Italy, and South Australia (Table 190.2). Peanut allergy is an important cause of food induced ana phylaxis, accounting for the majority of fatal and near fatal reactions. In the hospital, latex is a particular problem for children undergoing mul tiple operations, such as patients with spina bifida and urologic disor ders, and has prompted many hospitals to switch to latex free products. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 190 u Anaphylaxis 1435 Patients with latex allergy may also experience food allergic reactions from homologous proteins in foods such as bananas, kiwi, avocado, chestnut, and passion fruit. Anaphylaxis to galactose 1,3 galactose has been reported 3 6 hours after eating red meat (see Chapter 189). Anaphylaxis may be idiopathic and in some of these patients related to mast cell activation syndrome (Fig. 190.2; see Chapter 700.1) or familial hypertryptasemia. Exercise induced anaphylaxis has been associated with the |
6,684 | combination of certain foods and exercise. Ingestion of the food without exercise does not produce allergic symptoms or anaphylaxis. EPIDEMIOLOGY The overall annual incidence of anaphylaxis in the United States is estimated at 42 cases per 100,000 person years, totaling 150,000 cases per year. Food allergens are the most common trigger in chil dren, with an incidence rate of approximately 20 per 100,000 person years. An Australian parental survey found that 0.59 of children 3 17 years of age had experienced at least one anaphylactic event. Having asthma and the severity of asthma are important anaphy laxis risk factors (Table 190.3). In addition, patients with systemic Complement cascade activation Coagulation pathway activation Exercise Cold Medications (e.g. opioids) Other Skin Itching Flushing Hives Angioedema Respiratory Cough Dyspnea Hoarseness Stridor Wheeze GI Vomiting Diarrhea Abdominal pain CVS Dizziness Hypotension Shock Incontinence Angina Arrhythmia CNS Headache ANAPHYLAXIS PATHOGENESIS Immunologic other Immunologic IgEFc RI Direct mast cell activation Food Insect stingsbites Medications (e.g. lactam antibiotics) Other (e.g. latex) Histamine Tryptase Carboxypeptidase A Chymase PAF Prostaglandins Leukotrienes Other Mast cells Basophils Fig. 190.1 Summary of the pathogenesis of anaphylaxis. See text for details about mechanisms, triggers, key cells, and mediators. Two or more target organ systems are typically involved in anaphylaxis. CNS, Central nervous system; CVS, cardiovascular system; GI, gastrointestinal; PAF, platelet activating factor. (From Leung DYM, Szefler SJ, Bonilla FA Akdis CA, Sampson HA, eds. Pediatric Allergy Principles and Practice. 3rd ed. Philadelphia: Elsevier; 2016: p. 525.) Table 190.2 Anaphylaxis Triggers in the Community ALLERGEN TRIGGERS (IgE DEPENDENT IMMUNOLOGIC MECHANISM) Foods (e.g., peanut, tree nuts, shellfish, fish, milk, egg, wheat, soy, sesame, meat galactose 1,3 galactose) Food additives (e.g., spices, colorants, vegetable gums, contaminants) Stinging insects: Hymenoptera species (e.g., bees, yellow jackets, wasps, hornets, fire ants) Medications (e.g., lactam antibiotics, ibuprofen) Biologic agents (e.g., monoclonal antibodies infliximab, omalizumab and allergens challenge tests, specific immunotherapy) Natural rubber latex Vaccines Inhalants (rare) (e.g., horse or hamster dander, grass pollen) OTHER IMMUNE MECHANISMS (IgE INDEPENDENT) IgG mediated (infliximab, high molecular weight dextrans) Immune aggregates (IVIG) Drugs (aspirin, NSAID, opiates, contrast material, ethylene oxide dialysis tubing) Complement activation Physical factors (e.g., exercise, cold, heat, sunlightultraviolet radiation) Ethanol Idiopathic In the pediatric population, some anaphylaxis triggers, such as hormones (progesterone), seminal fluid, and occupational allergens, are uncommon, as is idiopathic anaphylaxis. Exercise with or without a co trigger, such as a food or medication, cold air, or cold water. IVIG, Intravenous immunoglobulin; NSAID, nonsteroidal antiinflammatory drug. Adapted from Leung DYM, Sampson HA, Geha RS, et al. Pediatric Allergy Principles and Practice. Philadelphia: Elsevier; 2010. p. 652. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1436 Part XIII u Allergic Disorders mastocytosis or monoclonal mast cellactivating syndrome are at increased risk for anaphylaxis, as are patients with an elevated base line serum tryptase level. PATHOGENESIS Principal pathologic features in fatal anaphylaxis include acute bron |
6,685 | chial obstruction with pulmonary hyperinflation, pulmonary edema, intraalveolar hemorrhaging, visceral congestion, laryngeal edema, and urticaria and angioedema. Acute hypotension is attributed to vasomo tor dilation and cardiac dysrhythmias. Most cases of anaphylaxis are believed to be the result of activation of mast cells and basophils via cell bound allergen specific IgE molecules (see Fig. 190.1). Patients initially must be exposed to the responsible allergen to generate allergen specific IgE antibodies. In many cases the child and the parent are unaware of the initial exposure, which may be from passage of food proteins in maternal breast milk or exposure to inflamed skin (e.g., eczematous lesions). When the child is reexposed to the sensitizing allergen, mast cells and basophils, and possibly other cells such as macrophages, release a variety of mediators (histamine, tryptase) and cytokines that can produce allergic symptoms in any or all target organs. Anaphylaxis may also be caused by mechanisms other than IgE mediated reactions, including direct release of mediators from mast cells by medications and physical factors (opiates, exercise, cold), disturbances of leukotriene metabolism (aspirin and nonste roidal antiinflammatory drugs), immune aggregates and complement activation (blood products), probable complement activation (radio contrast dyes, dialysis membranes), and IgG mediated reactions (high molecular weight dextran, chimeric or humanized monoclonal anti bodies) (see Table 190.2). Idiopathic anaphylaxis (IA) is a diagnosis of exclusion when no inciting agent is identified, and other disorders have been excluded (see Chapter 700.1). Symptoms are similar to IgE mediated causes of anaphylaxis; episodes often recur (see Fig. 190.2). IA may be secondary to mast cell activation syndrome with bone marrow expansion of mast cells exhibiting a D816V KIT pathologic variant or aberrant mast cell clonality on flow cytometry expressing CD117, CD2, or CD25 markers. Associated features of IA associated mast cell activation syndrome include insect (venom) sting anaphy laxis with hypotension and persistent (once recovered) elevations of tryptase at times associated with autosomal dominant familial hypertryptasemia. CLINICAL MANIFESTATIONS The onset of symptoms may vary depending on the cause of the reaction. Reactions from ingested allergens (foods, medications) are delayed in onset (minutes to 2 hours) compared with those from injected allergens (insect sting, medications) and tend to have more GI symptoms. Initial symptoms may include any of the following con stellation of symptoms: pruritus about the mouth and face; flushing, urticaria and angioedema, and oral or cutaneous pruritus; a sensation of warmth, weakness, and apprehension (sense of doom); tightness in the throat, dry staccato cough and hoarseness, periocular pruri tus, nasal congestion, sneezing, dyspnea, deep cough and wheezing; nausea, abdominal cramping, and vomiting, especially with ingested allergens; uterine contractions (manifesting as lower back pain); and faintness and loss of consciousness in severe cases. Some degree of obstructive laryngeal edema is typically encountered with severe reac tions. Cutaneous symptoms may be absent in up to 10 of cases, and the acute onset of severe bronchospasm in a previously well person with asthma should suggest the diagnosis of anaphylaxis. Sudden collapse in the absence of cutaneous symptoms should |
6,686 | also raise sus picion of vasovagal collapse, myocardial infarction, aspiration, pul monary embolism, or seizure disorder. Laryngeal edema, especially with abdominal pain, may also be a result of hereditary angioedema (see Chapter 189.1). Symptoms in infants may not be easy to iden tify. Infants may manifest nonspecific symptoms such as sudden cry ing, fussiness, flushing, dysphonia, drooling, vomiting, and becoming quiet or drowsy. Fig. 190.2 The criteria of idiopathic anaphylaxis versus mast cell activation syndrome. Note that when there is no likely cause of the reactions, if the onset of illness is acute, a diagnosis of idiopathic anaphylaxis can only be made when either reduced blood pressure (or its symptoms such as syncope) andor respiratory compromise are present accompanied by the involvement of the skin mucosal tissue symptoms. (From Gulen T, Akin C. Idiopathic anaphylaxis: A perplexing diagnostic challenge for allergists. Curr Allergy Asthma Rep. 2021;212:11. Fig. 1.) Idiopathic anaphylaxis Acute onset of symptoms with involvement of organs as below And either Or Acute onset of symptoms with concurrent involvement of minimum 2 of the 5 organ systems as below MCAS clinical criterion Skin andor mucosa Flushing Pruritus Hives Angioedema Respiratory Dyspnea Wheezing Stridor Hypoxia Cardiovascular Hypotonia Syncope Collapse Incontinence Skin andor mucosa Flushing Pruritus Hives Angioedema Gastrointestinal Vomiting Abdominal cramps Diarrhea Respiratory Dyspnea Wheezing Stridor Hypoxia Nasoocular Nasal congestion Nasal pruritus Sneezing Rhinorrhea Cardiovascular Hypotonia Syncope Collapse Incontinence Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 190 u Anaphylaxis 1437 Table 190.3 Patient Risk Factors for Anaphylaxis AGE RELATED FACTORS Infants: anaphylaxis can be difficult to recognize, especially if the first episode; patients cannot describe symptoms Adolescents and young adults: increased risk taking behaviors, such as failure to avoid known triggers and to carry an epinephrine autoinjector consistently Pregnancy: risk of iatrogenic anaphylaxis, as from lactam antibiotics to prevent neonatal group B streptococcal infection, agents used perioperatively during caesarean sections, and natural rubber latex Older people: increased risk of death because of concomitant disease and drugs CONCOMITANT DISEASES Asthma and other chronic respiratory diseases Cardiovascular diseases Systemic mastocytosis or monoclonal mast cellactivating syndrome Allergic rhinitis and eczema Depression, cognitive dysfunction, substance misuse DRUGS NSAIDs Adrenergic blockers Mast cell destabilizers ACE inhibitors Sedatives, antidepressants, narcotics, recreational drugs, and alcohol may decrease the patients ability to recognize triggers and symptoms. Caffeine FACTORS THAT MAY INCREASE RISK FOR ANAPHYLAXIS OR MAKE IT MORE DIFFICULT TO TREAT Age Asthma Eczema Drugs Alcohol Other cofactors such as exercise, infection, menses Atopic diseases are a risk factor for anaphylaxis triggered by food, latex, and exercise, but not for anaphylaxis triggered by most drugs or by insect stings. Those taking blockers may not respond optimally to epinephrine treatment and may need glucagon, a polypeptide with noncatecholamine dependent inotropic and chronotropic cardiac effects, atropine for persistent bradycardia, or ipratropium for persistent bronchospasm. ACE, Angiotensin converting enzyme; NSAID, nonsteroidal antiinflammatory drugs. |
6,687 | Adapted from Lieberman P, Nicklas RA, Randolph C, et al. Anaphylaxisa practice parameter update 2015. Ann Allergy Asthma Immunol. 2015;115(5):341384. Table I 9. Table 190.4 Differential Diagnosis of Anaphylaxis Anaphylaxis to exogenously administered agents Physical factors Exercise Cold, heat, sunlight Idiopathic VASODEPRESSOR (VASOVAGAL) RESPONSES Flushing syndromes Carcinoid, pheochromocytoma, medullary carcinoma of the thyroid Menopause Side effects of chlorpropamide, alcohol, calcium channel blockers Autonomic epilepsy FOOD ASSOCIATED SYNDROMES Scombroidosis Sulfites Monosodium glutamate (MSG) OTHER FORMS OF SHOCK Cardiogenic Septic Vascular EXCESS ENDOGENOUS PRODUCTION OF HISTAMINE SYNDROMES Mast cell activation syndrome Systemic mastocytosis Cutaneous mastocytosis Mast cell leukemia Acute promyelocytic leukemia NONORGANIC DISEASE Panic attacks Munchausen stridor Vocal cord dysfunction Undifferentiated somatoform anaphylaxis MISCELLANEOUS Acute urticaria with or without angioedema Hereditary angioedema Idiopathic angioedema Neurologic (seizure, stroke) Red man syndrome (vancomycin) Capillary leak syndrome From Dreskin SC, Stitt JM. Anaphylaxis. In: Burks AW, Holgate ST, OHehir RE, et al., eds. Middletons Allergy: Principles and Practice. 9th ed. Philadelphia: Elsevier; 2020: Box 75.6, p. 1237. LABORATORY FINDINGS Laboratory studies may indicate the presence of IgE antibodies to a suspected causative agent, but this result is not definitive. Plasma histamine is elevated for a brief period but is unstable and difficult to measure in a clinical setting. Plasma tryptase is more stable and remains elevated for several hours but often is not elevated, especially in food induced anaphylactic reactions. Plasma tryptase may also be elevated with chronic renal disease, eosinophilic GI disorders, parasitic infections, Gaucher disease, and mast cell activation syndrome or as a familial trait. DIAGNOSIS A National Institutes of Health (NIH)sponsored expert panel has recommended an approach to the diagnosis of anaphylaxis (see Table 190.1). The differential diagnosis includes other forms of shock (hem orrhagic, cardiogenic, septic), vasopressor reactions, including flush ing syndromes (e.g., carcinoid syndrome), ingestion of monosodium glutamate, scombroidosis, and hereditary angioedema (Table 190.4). In addition, panic attack, vocal cord dysfunction, pheochromocytoma, and vancomycin induced flushing should be considered. TREATMENT Anaphylaxis is a medical emergency requiring aggressive management with intramuscular (IM, first line) or intravenous (IV) epinephrine. Oral (PO), IM, or IV H1 and H2 antihistamine antagonists, oxy gen, IV fluids, inhaled agonists, and corticosteroids are adjunctive medications that may be used (Table 190.5 and Fig. 190.3). The initial assessment should ensure an adequate airway with effective respira tion, circulation, and perfusion. Epinephrine is the most important medication, and there should be no delay in its administration. Epi nephrine should be given by the IM route to the lateral thigh (1:1000 dilution, 0.01 mgkg; maximum 0.5 mg). Children weighing 25 kg or more should receive 0.3 mg IM, with many recommending 0.5 mg IM for older adolescents. The IM dose can be repeated at intervals of 5 15 minutes if symptoms persist or worsen. If there is no response to mul tiple doses of epinephrine, IV epinephrine using the 1:10,000 dilution Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. |
6,688 | Elsevier Inc. All rights reserved. 1438 Part XIII u Allergic Disorders Table 190.5 Management of a Patient with Anaphylaxis TREATMENT MECHANISM(S) OF EFFECT DOSAGE(S) COMMENTS; ADVERSE REACTIONS PATIENT EMERGENCY MANAGEMENT (DEPENDENT ON SEVERITY OF SYMPTOMS) Epinephrine (adrenaline) 1 , 1 , 2 Adrenergic effects 0.01 mgkg, up to 0.3 mg IM in lateral thigh (0.5 mg autoinjectors are not available in the United States) Epinephrine autoinjector: 0.1 mg for 7.5 13 kg 0.15 mg for 25 kg 0.3 mg for 25 kg or more A second dose may be given in 5 min if symptoms worsen or do not improve Tachycardia, hypertension, nervousness, headache, nausea, irritability, tremor Cetirizine (liquid) Antihistamine (competitive of H1 receptor) Cetirizine liquid: 5 mg5 mL 0.25 mgkg, up to 10 mg PO Hypotension, tachycardia, somnolence Alternative: Diphenhy dramine Antihistamine (competitive of H1 receptor) 1.25 mgkg up to 50 mg PO or IM Hypotension, tachycardia, somnolence, paradoxical excitement Transport to an emergency facility EMERGENCY PERSONNEL MANAGEMENT (DEPENDENT ON SEVERITY OF SYMPTOMS) Epinephrine (adrenaline) 1 , 1 , 2 Adrenergic effects 0.01 mgkg, up to 0.5 mg IM in lateral thigh Epinephrine autoinjector: 0.1 mg for 7.5 13 kg 0.15 mg for 25 kg 0.3 mg for 25 kg or more 0.01 mLkgdose of 1:1,000 (vial) solution, up to 0.5 mL IM May repeat every 10 15 min For severe hypotension: 0.01 mLkgdose of 1:10,000 slow IV push Tachycardia, hypertension, nervousness, headache, nausea, irritability, tremor Supplemental oxygen and airway management Volume Expanders Crystalloids (normal saline or Ringer lactate) 30 mLkg in first hour Rate titrated against BP response If tolerated, place patient supine with legs raised Colloids (hydroxyethyl starch) 10 mLkg rapidly followed by slow infusion Rate titrated against BP response If tolerated, place patient supine with legs raised Antihistamines Cetirizine (liquid) Antihistamine (competitive of H1 receptor) Cetirizine liquid: 5 mg5 mL 0.25 mgkg, up to 10 mg PO Hypotension, tachycardia, somnolence Alternative: Diphenhydramine Antihistamine (competitive of H1 receptor) 1.25 mgkg, up to 50 mg PO, IM, or IV Hypotension, tachycardia, somnolence, paradoxical excitement Ranitidine Antihistamine (competitive of H2 receptor) 1 mgkg, up to 50 mg IV Should be administered slowly Headache, mental confusion Alternative: Cimetidine Antihistamine (competitive of H2 receptor) 4 mgkg, up to 200 mg IV Should be administered slowly Headache, mental confusion Corticosteroids Methylprednisolone Antiinflammatory Solu Medrol (IV): 1 2 mgkg, up to 125 mg IV Depo Medrol (IM): 1 mgkg, up to 80 mg IM Hypertension, edema, nervousness, agitation Prednisone Antiinflammatory 1 mgkg up, to 75 mg PO Hypertension, edema, nervousness, agitation Nebulized albuterol Agonist 0.83 mgmL (3 mL) via mask with O2 Palpitations, nervousness, CNS stimulation, tachycardia; use to supplement epinephrine when bronchospasm appears unresponsive; may repeat Preventive Treatment Prescription for epinephrine autoinjector and antihistamine Provide written plan outlining patient emergency management (may download form from http:www.aap.org or http:www.foodallergy.org; English and Spanish versions available) Follow up evaluation to determineconfirm etiology Immunotherapy for insect sting allergy Patient Education Instruction on avoidance of causative agent Information on recognizing early signs of anaphylaxis Stress early treatment |
6,689 | of allergic symptoms to avoid systemic anaphylaxis Encourage wearing medical identification jewelry BP, Blood pressure; CNS, central nervous system; IM, Intramuscularly; IV, intravenously; PO, orally; qd, every day. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 190 u Anaphylaxis 1439 Immediate intervention Assess airway, breathing, circulation, mentation Inject epinephrine and reevaluate for repeat injection if necessary Supine position (if cardiovascular involvement suspected) Subsequent emergency care that may be necessary depending on response to epinephrine: Consider: Consider inhaled bronchodilators if wheezing Call 911 and request assistance Recumbent position with elevation of lower extremity Establish airway O2 Repeat epinephrine injection if indicated IV fluids if hypotensive; rapid volume expansion H1 and H2 antihistamines Corticosteroids Call 911 if not already done Consider: Epinephrine intravenous infusion Other intravenous vasopressors Consider glucagon Cardiopulmonary arrest during anaphylaxis: CPR and ACLS measures Prolonged resuscitation efforts encouraged (if necessary) Consider: Highdose epinephrine Rapid volume expansion Atropine for asystole or pulseless electrical activity Transport to emergency dept. or ICU Observation Length and setting of observation must be individualized Provide epinephrine autoinjector prescription Anaphylaxis preparedness Initial assessment supports potential anaphylaxis? e.g., nonlocalized urticaria after immunotherapy Patient presents with possibleprobable acute anaphylaxis Consider other diagnosis NO NO NO YES YES YES Good clinical response? Good clinical response? Consultation with allergist immunologist NO IMPROVEMENT Fig. 190.3 Algorithm for treatment of anaphylactic event in outpatient setting. ACLS, Advance cardiac life support; CPR, cardiopulmonary resusci tation; ICU, intensive care unit; IV, intravenous. (From Lieberman P, Nicklas RA, Oppenheimer J, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol. 2010;126:477480 e471 442.) may be needed. If IV access is not readily available, epinephrine can be administered via the endotracheal or intraosseous routes. For refractory hypotension, other vasopressors may be needed. Ana phylaxis refractory to repeated doses of epinephrine in a patient receiv ing adrenergic blockers has anecdotally been treated with glucagon. The patient should be placed in a supine position when there is concern for hemodynamic compromise. Fluids are also important in patients with shock. Other drugs (antihistamines, glucocorticosteroids) have a secondary role in the management of anaphylaxis. Patients may experience biphasic anaphylaxis, which occurs when anaphylactic symptoms recur after apparent resolution. The mecha nism of this phenomenon is unknown, but more severe initial pre sentation and the need for more than one dose of epinephrine to treat initial symptoms are risk factors for biphasic anaphylaxis. Treatment with antihistamines or corticosteroids do not provide clear ben efit for prevention of biphasic reactions. Extended observation after resolution of initial anaphylaxis symptoms should be considered for patients with risk factors for biphasic anaphylaxis. At discharge, Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1440 Part XIII u |
6,690 | Allergic Disorders Table 190.6 Considerations with Epinephrine Injection for Anaphylaxis WHY HEALTHCARE PROFESSIONALS FAIL TO INJECT EPINEPHRINE PROMPTLY Lack of recognition of anaphylaxis symptoms; failure to diagnose anaphylaxis Episode appears mild, or there is a history of previous mild episode(s) Inappropriate concern about transient mild pharmacologic effects of epinephrine (e.g., tremor) Lack of awareness that serious adverse effects are almost always attributable to epinephrine overdose or IV administration, especially IV bolus, rapid IV infusion, or IV infusion of a 1:1,000 epinephrine solution instead of an appropriately diluted solution (1:10,000 concentration) WHY PATIENTS AND CAREGIVERS FAIL TO INJECT EPINEPHRINE PROMPTLY Lack of recognition of anaphylaxis symptoms; failure to diagnose anaphylaxis Episode appears mild, or there is a history of previous mild episode(s) H1 antihistamine or asthma puffer is used initially instead, relieving early warning signs such as itch or cough, respectively Prescription for epinephrine autoinjectors (EAIs) is not provided by physician Prescription for EAIs is provided but not filled at pharmacy (e.g., not affordable) Patients do not carry EAIs consistently (due to size and bulk, or dont think theyll need it) Patients and caregivers are afraid to use EAIs (concern about making an error when giving the injection or about a bad outcome) Patients and caregivers are concerned about injury from EAIs Competence in using EAIs is associated with regular allergy clinic visits; it decreases as time elapses from first EAI instruction; regular retraining is needed Difficulty in understanding how to use EAIs (15 of mothers with no EAI experience could not fire an EAI immediately after a one on one demonstration) Errors in EAI use can occur despite education, possibly related to the design of some EAIs WHY PATIENTS OCCASIONALLY FAIL TO RESPOND TO EPINEPHRINE INJECTION Delayed recognition of anaphylaxis symptoms; delayed diagnosis Error in diagnosis: problem being treated (e.g., foreign body inhalation) is not anaphylaxis Rapid progression of anaphylaxis Epinephrine: Injected too late; dose too low on mgkg basis; dose too low because epinephrine solution has degraded (e.g., past the expiration date, stored in a hot place) Injection route or site not optimal; dose took too long to be absorbed Patient suddenly sits up or walks or runs, leading to the empty ventricle syndrome Concurrent use of certain medications (e.g., adrenergic blockers) Subsequent anaphylaxis episodes can be more severe, less severe, or similar in severity. Median times to respiratory or cardiac arrest are 5 min in iatrogenic anaphylaxis, 15 min in stinging insect venom anaphylaxis, and 30 min in food anaphylaxis; however, regardless of the trigger, respiratory or cardiac arrest can occur within 1 min in anaphylaxis. Adapted from Leung DYM, Szefler SJ, Bonilla FA Akdis CA, Sampson HA, eds. Pediatric Allergy Principles and Practice. Philadelphia: Elsevier; 2016: p. 531. referrals should be made to appropriate specialists for further evalu ation and follow up. PREVENTION For patients experiencing anaphylactic reactions, the triggering agent should be avoided, and education regarding early recognition of ana phylactic symptoms and administration of emergency medications should be provided. Patients with food allergies must be |
6,691 | educated in allergen avoidance, including active reading of food ingredient labels and knowledge of potential contamination and high risk situations. Any child with food allergy and a history of asthma and a peanut, tree nut, fish, or shellfish allergy or a previous systemic reaction should be given an epinephrine autoinjector. The expert panel also indicates that epinephrine autoinjectors should be considered for any patient with IgE mediated food allergy. In addition, liquid cetirizine (or alternatively, diphenhydramine) and a written emergency plan should also be pro vided in case of accidental ingestion or allergic reaction. A form can be downloaded from the American Academy of Pediatrics (www.aap.org) or Food Allergy Research Education (www.foodallergy.org). In cases of food associated exercise induced anaphylaxis, children must not exercise within 2 4 hours of ingesting the triggering food; children with exercise induced anaphylaxis should exercise with a friend, learn to recognize the early signs of anaphylaxis (sensation of warmth, facial pruritus), and stop exercising and seek help immedi ately if symptoms develop. Foods associated with exercise induced anaphylaxis include wheat, vegeas, nuts, fruits, and shellfish. Children experiencing a systemic anaphylactic reaction, includ ing respiratory symptoms, to an insect sting should be evaluated and treated with immunotherapy, which is 90 protective. Reactions to medications can be reduced and minimized by using oral medications instead of injected forms and avoiding cross reacting medications. Low osmolarity radiocontrast dyes and pretreatment can be used in patients with suspected reactions to previous radiocontrast dye. Non latex gloves and materials should be used in children undergoing mul tiple operations. Any child at risk for anaphylaxis should receive emergency medi cations (including epinephrine autoinjector), education on identifica tion of signs and symptoms of anaphylaxis and proper administration of medications (Table 190.6), and a written emergency plan in case of accidental exposure. They should be encouraged to wear medical iden tification jewelry. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 191 u Serum Sickness 1441 Serum sickness is a systemic, immune complexmediated hypersensi tivity vasculitis classically attributed to the therapeutic administration of foreign serum proteins or other medications (Table 191.1). ETIOLOGY Immune complexes involving heterologous (animal) serum proteins and complement activation are important pathogenic mechanisms in serum sickness. Antibody therapies derived from the horse, sheep, or rabbit are available for treatment of envenomation by the black widow spider and a variety of snakes, for treatment of botulism, and for immunosuppression (antithymocyte globulin ATG). The availability of alternative medical therapies, modified or bioengineered antibodies, and biologics of human origin have supplanted the use of nonhuman antisera, reducing the risk of serum sickness. However, rabbit generated ATGs, which target human T cells, continue to be widely used as immunosuppressive agents during treatment of kidney allograft recipients; serum sickness is associated with a late graft loss in kidney transplant recipients. A serum |
6,692 | sicknesslike reac tion may be attributed to drug allergy, triggered by antibiotics (particu larly cefaclor, trimethoprim sulfamethoxazole, anticonvulsants, prolonged high dose intravenous penicillin G), infections (streptococcal infections, hepatitis B), or rabies vaccine. In contrast to a true serum sickness, serum sicknesslike reactions do not exhibit the immune complexes, hypocom plementemia, vasculitis, and renal lesions that are seen in serum sickness reactions. PATHOGENESIS Serum sickness is a classic example of a type III hypersensitivity reaction caused by antigen antibody complexes. In the rabbit model using bovine serum albumin as the antigen, symptoms develop with the appearance of antibody against the injected antigen. As free antigen concentration falls and antibody production increases over days, antigen antibody complexes of various sizes develop in a manner analogous to a precipitin curve. Whereas small complexes usually circulate harmlessly and large com plexes are cleared by the reticuloendothelial system, intermediate sized complexes that develop at the point of slight antigen excess may deposit in blood vessel walls and tissues. There the immune microprecipitates induce vascular (leukocytoclastic vasculitis with immune complex deposition) and tissue damage through activation of complement and granulocytes. Complement activation (C3a, C5a) promotes chemotaxis and adher ence of neutrophils to the site of immune complex deposition. The pro cesses of immune complex deposition and of neutrophil accumulation may be facilitated by increased vascular permeability, because of the release of vasoactive amines from tissue mast cells. Mast cells may be activated by binding of antigen to IgE or through contact with anaphylatoxins (C3a). Tissue injury results from the liberation of proteolytic enzymes and oxygen radicals from the neutrophils. CLINICAL MANIFESTATIONS The symptoms of serum sickness generally begin 7 12 days after injection of the foreign material, but may appear as late as 3 weeks afterward. The onset of symptoms may be accelerated if there has been earlier exposure or previous allergic reaction to the same antigen. A few days before the onset of generalized symptoms, the site of injection may become edematous and erythematous. Symptoms usually include fever, malaise, and rashes. Urticaria and morbilliform rashes are the predominant types of skin erup tions (Fig. 191.1). In a prospective study of serum sickness induced by administration of equine ATG, an initial rash was noted in most patients. It began as a thin, serpiginous band of erythema along the sides of the hands, fingers, feet, and toes at the junction of the palmar or plantar skin with the skin of the dorsolateral surface. In most patients the band of ery thema was replaced by petechiae or purpura, presumably because of low platelet counts or local damage to small blood vessels. Additional symp toms include edema, myalgia, lymphadenopathy, symmetric arthralgia or arthritis involving multiple joints, and gastrointestinal complaints, includ ing pain, nausea, diarrhea, and melena. Symptoms typically resolve within 2 weeks of removal of the offending agent, although in unusual cases, symptoms can persist for as long as 2 3 months. Carditis, glomerulone phritis, Guillain Barr syndrome, and peripheral neuritis are rare com plications. Serum sicknesslike reactions from |
6,693 | drugs are characterized by fever, pruritus, urticaria, and arthralgias that usually begin 1 3 weeks after drug exposure. The urticarial skin eruption becomes increasingly Chapter 191 Serum Sickness Anna H. Nowak Wegrzyn and Scott H. Sicherer Table 191.1 Proteins and Medications That Cause Serum Sickness PROTEINS FROM OTHER SPECIES Antibotulinum globulin Antithymocyte globulin Antitetanus toxoid Antivenin (Crotalidae) polyvalent (horse serum based) Crotalidae polyvalent immune Fab (ovine serum based) Antirabies globulin Infliximab Rituximab Etanercept Omalizumab Adalimumab Natalizumab Anti HIV antibodies (PEHRG214) Hymenoptera stings Streptokinase H1N1 influenza vaccine Rabies vaccine DRUGS Antibiotics Cefaclor Penicillins Trimethoprim sulfamethoxazole Minocycline Meropenem Neurologic Bupropion Carbamazepine Phenytoin Sulfonamides Barbiturates Based on review of the most current literature. Other medications that are not listed might also cause serum sickness. Adapted from Aceves SS. Serum sickness. In: Burg FD, Ingelfinger JR, Polin RA, Gershon AA, eds. Current Pediatric Therapy. 18th ed. Philadelphia: Elsevier; 2006: p. 1138. Fig. 191.1 Serum sicknesslike reaction (SSLR). Note the swollen hand and large urticarial wheals in this girl with SSLR and arthralgias. (From Paller AS, Mancini AJ, eds. Hurwitz Clinical Pediatric Dermatol ogy. 5th ed. Philadelphia: Elsevier; 2016: p. 476.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1442 Part XIII u Allergic Disorders erythematous as the reaction progresses and can evolve into dusky centers with round plaques. Serum sickness and serum sicknesslike reactions are more likely to occur with higher doses and intermittent exposures of cul prit antigens. DIFFERENTIAL DIAGNOSIS The differential diagnosis of serum sickness and serum sicknesslike reac tions includes viral illnesses with exanthems, hypersensitivity vasculitis, Kawasaki disease, acute rheumatic fever, acute meningococcal or gono coccal infection, endocarditis, systemic onset juvenile idiopathic arthritis (Still disease), Lyme disease, hepatitis, autoinflammatory syndromes, acute annular urticaria (urticaria multiforme), Stevens Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), and ery thema multiforme (see Chapters 193 and 686.2). DIAGNOSIS In most patients the diagnosis of serum sickness is made clinically based on the characteristic pattern of acute or subacute onset of a rash, fever, and severe arthralgia and myalgia disproportionate to the degree of swell ing, occurring after exposure to a potential culprit. Patients who appear moderately or severely ill, or who are not taking a medication that can be readily identified as the culprit, should be evaluated with the following laboratory tests: Complete blood count and differential: Thrombocytopenia is often present. Erythrocyte sedimentation rate (ESR) and C reactive protein: ESR is usually elevated. Urinalysis: Mild proteinuria, hemoglobinuria, and microscopic he maturia may be seen. Serum chemistries: Including blood urea nitrogen, creatinine, and liver function tests. Complement studies, including CH50, C3, and C4: Serum comple ment levels (C3 and C4) are generally decreased and reach a nadir at about day 10. C3a anaphylatoxin may be increased. Testing for specific infectious diseases: If indicated by the history or physical examination. Appropriate viral or bacterial cultures: If an infection is |
6,694 | suspected. Skin biopsies are not usually necessary for confirming the diagno sis, because the findings are variable and not specific for serum sick ness. Direct immunofluorescence studies of skin lesions often reveal immune deposits of IgM, IgA, IgE, or C3. TREATMENT There are no evidence based guidelines or controlled trials on which to base therapy recommendations. Treatment is primarily supportive, con sisting of discontinuation of the offending agent, antihistamines for pruri tus, and nonsteroidal antiinflammatory drugs and analgesics for low grade fever and mild arthralgia. When the symptoms are especially severe, for example, fever 38.5C (101.3F), severe arthralgia or myalgia, or renal dysfunction, systemic corticosteroids can be used. Prednisone (1 2 mg kgday; maximum 60 mgday) for 1 2 weeks is usually sufficient. Once the offending agent is discontinued and depending on its half life, symp toms resolve spontaneously in 1 4 weeks. Symptoms lasting longer suggest another diagnosis. PREVENTION The primary mode of prevention of serum sickness is to seek alternative therapies. In some cases, nonanimal derived formulations may be avail able (human derived botulinum immune globulin). Other alternatives are partially digested antibodies of animal origin and engineered (humanized) antibodies. The potential of these therapies to elicit serum sicknesslike disease appears low. When only animal derived antitoxinantivenom is available, skin tests should be performed before administration of serum, but this procedure indicates the risk only of anaphylaxis, not of serum sick ness. For patients who have evidence of anaphylactic sensitivity to horse serum, a riskbenefit assessment must be made to determine the need to proceed with treatment. If needed, the serum can usually be success fully administered by a process of rapid desensitization using protocols of gradual administration outlined by the manufacturers. Serum sickness is not prevented by desensitization or by pretreatment with corticosteroids. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Adverse reactions to foods consist of any untoward reaction follow ing the ingestion of a food or food additive and are classically divided into food intolerances and food allergies. Food intolerances are non immunologic physiologic responses and can include metabolic, toxic, pharmacologic, or other mechanisms. Food allergies are adverse immunologic responses and can be IgE mediated, nonIgE medi ated, or mixed (Tables 192.1 and 192.2). Food allergies appear to have increased over the past 3 decades, primarily in westernizedindustrial ized countries. Worldwide, estimates of food allergy prevalence range from 111 with regional variations. The vast majority of food aller gies are due to peanut, tree nuts, seeds, milk, egg, soy, wheat, fish, and Chapter 192 Food Allergy and Adverse Reactions to Foods Anna H. Nowak Wegrzyn, Hugh A. Sampson, Amanda L. Cox, and Scott H. Sicherer Table 192.1 Adverse Food Reactions FOOD INTOLERANCE (NONIMMUNE SYSTEM MEDIATED, NONTOXIC, NONINFECTIOUS) Host Factors Enzyme deficiencieslactase (primary or secondary), sucrase isomaltase, hereditary fructose intolerance, galactosemia, alcohol dehydrogenase deficiency Gastrointestinal disordersinflammatory bowel disease, irritable bowel syndrome, pseudoobstruction, colic Idiosyncratic reactionscaffeine in soft drinks (hyperactivity) Psychologicfood phobias, obsessivecompulsive disorder Migraines (rare) Food Factors (Toxic or Infectious or Pharmacologic) Infectious organismsEscherichia coli, Staphylococcus aureus, Clostridium |
6,695 | perfringens, Shigella, botulism, Salmonella, Yersinia, Campylobacter Toxinshistamine (scombroid poisoning), saxitoxin (shellfish) Pharmacologic agentscaffeine, theobromine (chocolate, tea), tryptamine (tomatoes), tyramine (cheese), benzoic acid in citrus fruits (perioral flare) Contaminantsheavy metals, pesticides, antibiotics FOOD ALLERGY IgE Mediated Cutaneousurticaria, angioedema, morbilliform rashes, flushing, contact urticarial Gastrointestinaloral allergy syndrome, gastrointestinal anaphylaxis Respiratoryacute rhinoconjunctivitis, bronchospasm Generalizedanaphylactic shock, exercise induced anaphylaxis Mixed IgE Mediated and NonIgE Mediated Cutaneousatopic dermatitis, contact dermatitis Gastrointestinalallergic eosinophilic esophagitis and gastroenteritis Respiratoryasthma NonIgE Mediated Cutaneouscontact dermatitis, dermatitis herpetiformis (celiac disease) Gastrointestinalfood proteininduced enterocolitis, proctocolitis, and enteropathy syndromes, celiac disease Respiratoryfood induced pulmonary hemosiderosis (Heiner syndrome) Unclassified IgE, Immunoglobulin E. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 192 u Food Allergy and Adverse Reactions to Foods 1443 Table 192.2 Differential Diagnosis of Adverse Food Reactions GASTROINTESTINAL DISORDERS (WITH VOMITING ANDOR DIARRHEA) Structural abnormalities (pyloric stenosis, Hirschsprung disease, reflux) Enzyme deficiencies (primary or secondary) Disaccharidase deficiencylactase, fructase, sucrase isomaltase Galactosemia Malignancy with obstruction Other: pancreatic insufficiency (cystic fibrosis), peptic disease CONTAMINANTS AND ADDITIVES Flavorings and preservativesrarely cause symptoms Sodium metabisulfite, monosodium glutamate, nitrites Dyes and coloringsvery rarely cause symptoms (urticaria, eczema) Tartrazine Toxins Bacterial, fungal (aflatoxin), fish related (scombroid, ciguatera) Infectious organisms Bacteria (Salmonella, Escherichia coli, Shigella) Virus (rotavirus, enterovirus) Parasites (Giardia, Akis simplex in fish) Accidental contaminants Heavy metals, pesticides Pharmacologic agents Caffeine, glycosidal alkaloid solanine (potato spuds), histamine (fish), serotonin (banana, tomato), tryptamine (tomato), tyramine (cheese) PSYCHOLOGIC REACTIONS Food phobias Table 192.3 Natural History of Food Allergy FOOD USUAL AGE AT ONSET OF ALLERGY USUAL AGE AT RESOLUTION Hens egg white 0 1 yr 7 yr (75 of cases resolve) Cows milk 0 1 yr 5 yr (76 of cases resolve) Peanut 1 2 yr Persistent (20 of cases resolve) Tree nuts 1 2 yr; in adults, onset occurs after cross reactivity to birch pollen Persistent (9 of cases resolve) Fish Late childhood and adulthood Persistent Shellfish (crustacean) Adulthood (in 60 of patients with this allergy) Persistent Wheat 6 24 mo 5 yr (80 of cases resolve) Soybean 6 24 mo 2 yr (67 of cases resolve) Kiwi Any age Unknown Apple, carrot, and peach Late childhood and adulthood Unknown Studies suggest that resolution may occur at a later age, especially in children with multiple food allergies and lifetime peak food specific IgE 50 kUAL. Fish allergy that is acquired in childhood can resolve. Allergy to fresh apples, carrots, and peaches (oral allergy syndrome) is typically caused by heat labile proteins. Fresh fruit causes oral pruritus, but cooked fruit is tolerated. There is generally no risk of anaphylaxis, although in rare cases, allergies to cross reactive lipid transfer protein can cause anaphylaxis after ingestion of fruits (e.g., peach) and vegetables. Adapted from Lack G. Food allergy. N Engl J Med. 2008;359:12521260. shellfish, with regional variations in prevalence. It has been estimated that 811 of children have food allergy, with 2.4 having multiple food |
6,696 | allergies. Up to 6 of children experience food allergic reactions in the first 3 years of life, including approximately 2.5 with cows milk allergy, 2 with egg allergy, and 23 with peanut allergy. Most chil dren outgrow milk and egg allergies, with approximately 50 doing so by school age. In contrast, 8090 of children with peanut, tree nut, or seafood allergy retain their allergy for life (Table 192.3). GENETIC AND ENVIRONMENTAL RISK FACTORS Allergic sensitization and food allergy development is influenced by genetics, environment, and genome environment interactions (pos sible epigenetic effects). Family and twin studies show that family history confers a 2 to 10 fold increased risk, depending on the study setting, population, specific food, and diagnostic test. Can didate gene studies suggest that genetic variants in the HLA DQ locus (HLA DQB102 and DQB106:03P), filaggrin, interleukin (IL) 10, STAT6, and FOXP3 genes are associated with food allergy, although the results are inconsistent across different populations. In a genome wide association study, differential methylation at the HLA DR and DQ regions was associated with food allergy. Epigen etic studies implicate DNA methylation effects on IL 4, 5 and 10, and interferon (IFN) genes and in the mitogen activated protein kinase (MAPK) pathway. Many environmental factors have been observed to influence the development of food allergy. Skin exposure to foods in the set ting of infantile eczema, characterized by impaired skin barrier and inflammation, can lead to sensitization and allergy. Decreased microbial exposure (hygiene hypothesis), decreased microbiome diversity, and the specific makeup of microbial communities in the gastrointestinal (GI) tract, airway, and skin, influence allergic con ditions, including food allergy (see Chapter 182). Additional envi ronmental factors that may be associated with increased risk of food allergy include reduced diversity of the diet, delayed introduction of allergenic foods, vitamin D deficiency, and other factors. PATHOGENESIS Food intolerances are the result of a variety of nonimmunologic mechanisms, whereas food allergy is predominantly caused by IgE mediated and cell mediated immune mechanisms. In food allergy, normal physiologic oral tolerance of food, which is induced largely by regulatory T cells (Tregs) and the microbiome of the gut mucosa, breaks down. Susceptible individuals exposed to certain allergens generate food specific IgE antibodies that bind to Fc receptors on mast cells, basophils, macrophages, and dendritic cells, resulting in allergic sensitization. When food allergens penetrate mucosal bar riers and reach cell bound IgE antibodies, mediators are released that induce vasodilation, smooth muscle contraction, and mucus secretion, which result in symptoms of immediate hypersensitiv ity (allergy). Activated mast cells, basophils, and macrophages may release several cytokines that attract and activate other cells, such as eosinophils and lymphocytes, leading to prolonged inflamma tion. During acute IgE mediated reactions, mast cell and basophil Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1444 Part XIII u Allergic Disorders degranulation elicits symptoms that can affect |
6,697 | the skin (urticaria, angioedema, flushing, pruritus), GI tract (oral pruritus, angio edema, nausea, abdominal pain, vomiting, diarrhea), respira tory tract (nasal congestion, rhinorrhea, nasal pruritus, sneezing, laryngeal edema, dyspnea, wheezing), and cardiovascular system (dysrhythmias, hypotension, loss of consciousness). In non IgE food allergies, lymphocytes, primarily food allergenspecific T cells, secrete excessive amounts of various cytokines that lead to a delayed, more chronic inflammatory process affecting the skin (pruritus, erythematous rash), GI tract (failure to thrive, early satiety, abdominal pain, vomiting, diarrhea), and respiratory tract (food induced pulmonary hemosiderosis). Mixed IgE and cellular responses to food allergens can also lead to chronic disorders, such as atopic dermatitis, asthma, eosinophilic esophagitis (EoE), and eosinophilic gastroenteritis. Children who develop IgE mediated food allergies may be sensi tized by food allergens penetrating the inflamed skin barrier, e.g., eczema, or GI barrier (referred to as class 1 food allergens), or by food allergens that are partially homologous to plant pollens pen etrating the respiratory tract (referred to as class 2 food allergens). Any food may serve as a class 1 food allergen, but egg, milk, pea nuts, tree nuts, seeds, fish, soy, and wheat account for 90 of food allergies during childhood. Many of the major allergenic proteins of these foods have been characterized. There is variable but signifi cant cross reactivity with other proteins within an individual food group. Exposure and sensitization to these proteins often occur very early in life. Class 2 food allergens are typically vegetable, fruit, or nut proteins that are partially homologous to pollen proteins. With the development of seasonal allergic rhinitis from birchoak, grass, ragweed, or mugwort weed pollens, subsequent ingestion of certain nuts, uncooked fruits, or vegetables provokes the pollen food allergy syndrome (also called oral allergy syndrome). Inter mittent ingestion of allergenic foods may lead to acute symptoms such as urticaria or anaphylaxis, whereas prolonged exposure may lead to poor control of chronic disorders such as atopic dermatitis and asthma. Cell mediated sensitivity typically develops to class 1 allergens. The galactose 1,3 galactose (alpha gal) syndrome is an IgE mediated allergy to a carbohydrate allergen, and manifests as delayed allergic reactions 2 6 hours after ingestion of mammalian meats (pork, beef, lamb, venison) and rarely gelatin or milk. Sensitization occurs after multiple tick bites, in particular by the lone star tick (Amblyomma americanum). This unique form of food allergy is seen more often in teenagers and adults. CLINICAL MANIFESTATIONS From a clinical and diagnostic standpoint, it is most useful to subdivide food hypersensitivity disorders according to the pre dominant target organ (Table 192.4) and immune mechanism (see Table 192.1). Gastrointestinal Manifestations GI food allergies are often the first form of allergy to affect infants and young children and typically manifest as irritability, vomiting or spitting up, diarrhea, and poor weight gain. Cell mediated hypersensitivities without IgE involvement predominate, making standard allergy tests such as skin prick tests and in vitro tests for food specific IgE antibodies of little diagnostic value. The non IgE mediated GI food allergic |
6,698 | disorders food proteininduced enterocolitis syndrome (FPIES), food proteininduced allergic proctocolitis (FPIAP), and eosinophilic GI disorders are discussed in Chapter 192.1. Pollen food allergy syndrome (oral allergy syndrome) is an IgE mediated hypersensitivity to certain uncooked or unprocessed plant based foods that occurs in many older children who have pollen induced allergic rhinitis. Symptoms are usually confined to the oropharynx and consist of the rapid onset of oral pruritus; tin gling and angioedema of the lips, tongue, palate, and throat; and occasionally a sensation of pruritus in the ears and tightness in the throat. Symptoms are generally short lived and are caused by local mast cell activation following contact with fresh raw fruit and vegetable proteins that cross react with birch tree pollen (including but not limited to apple, carrot, potato, celery, hazelnuts, peanuts, kiwi, cherry, pear), grass pollen (potato, tomato, watermelon, kiwi), Table 192.4 Symptoms of Food Induced Allergic Reactions TARGET ORGAN IMMEDIATE SYMPTOMS DELAYED SYMPTOMS Cutaneous Erythema Pruritus Urticaria Morbilliform eruption Angioedema Erythema Flushing Pruritus Morbilliform eruption Angioedema Eczematous rash Ocular Pruritus Conjunctival erythema Tearing Periorbital edema Pruritus Conjunctival erythema Tearing Periorbital edema Upper respiratory Nasal congestion Pruritus Rhinorrhea Sneezing Laryngeal edema Hoarseness Dry staccato cough Lower respiratory Cough Chest tightness Dyspnea Wheezing Intercostal retractions Accessory muscle use Cough Dyspnea Wheezing Gastrointestinal (oral) Angioedema of the lips, tongue, or palate Oral pruritus Tongue swelling Gastrointestinal (lower) Nausea Colicky abdominal pain Reflux Vomiting Diarrhea Nausea Abdominal pain Reflux Vomiting Diarrhea Hematochezia Irritability and food refusal with weight loss (young children) Cardiovascular Tachycardia (occasionally bradycardia in anaphylaxis) Hypotension Dizziness Fainting Loss of consciousness Other Uterine contractions Sense of impending doom From Boyce JA, Assaad A, Burks AW, et al. Guideline 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(6):S1S58. Table IV, p. S19. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 192 u Food Allergy and Adverse Reactions to Foods 1445 mugwort weed pollen (celery, fennel, mustard, peach), and ragweed pollen (banana, melons such as watermelon and cantaloupe). Acute GI allergy generally manifests as acute abdominal pain, vom iting, or diarrhea that accompanies IgE mediated allergic symptoms in other target organs. Skin Manifestations Cutaneous food allergies are also common in infants and young children. Atopic dermatitis is a form of eczema that generally begins in early infancy and is characterized by pruritus, a chronic relapsing course, and association with asthma and allergic rhinitis (see Chapter 186). Although not often apparent from history, at least 30 of children with moderate to severe atopic dermatitis have IgE mediated food allergies. The younger the child and the more severe the eczema, the more likely food allergy is playing a pathogenic role in the disorder. Atopic derma titis is a risk factor for the development of food allergy rather than a result of |
6,699 | food allergy. Acute urticaria and angioedema are among the most common symptoms of food allergic reactions (see Chapter 189). The onset of symptoms may be very rapid, within minutes after ingestion of the responsible allergen. Symptoms result from activation of IgE bearing mast cells by food allergens that are absorbed and circulated rapidly throughout the body. Foods most commonly implicated in children include egg, milk, peanuts, and tree nuts, although reac tions to various seeds (sesame, sunflower, poppy) and fruits (kiwi) are becoming more common. Chronic urticaria and angioedema are very rarely caused by food allergies. Contact urticaria may occur in the perioral region of infants and young children, espe cially in those with eczema, when otherwise tolerated food causes small, self resolving hives on direct skin contact while eating. In the absence of any other symptoms, food exclusion is not generally needed and the rash could be avoided by wiping the face during feeding or using a barrier ointment (such as petroleum jelly) in the perioral area before feeding. Perioral dermatitis is a contact dermatitis often caused by sub stances in toothpaste, gums, lipstick, or medications. Perioral flushing is often noted in infants fed citrus fruits and may be caused by benzoic acid in the food. It may also occur in nursing infants. In both situations the effect is benign. Flushing may also be caused by auriculotempo ral nerve (Frey) syndrome (familial, forceps delivery), which resolves spontaneously. Respiratory Manifestations Respiratory food allergies are uncommon as isolated symptoms. Although many parents believe nasal congestion in infants to be caused by milk allergy, studies show this not to be the case. Food induced rhinoconjunctivitis symptoms typically accompany aller gic symptoms in other target organs, such as skin, and consist of typical allergic rhinitis symptoms (periocular pruritus and tearing, nasal congestion and pruritus, sneezing, rhinorrhea). Wheezing occurs in approximately 25 of IgE mediated food allergic reac tions, but only 10 of asthmatic patients have food induced respi ratory symptoms. Anaphylaxis Anaphylaxis (see Chapter 190) is defined as a serious, multisys tem allergic reaction that is rapid in onset and potentially fatal. Food allergic reactions are the most common cause of anaphylaxis seen in U.S. hospital emergency departments. Fatal food induced anaphylaxis is rare, with death affecting 0.03 0.3 per million per year. In addition to the rapid onset of cutaneous, respiratory, and GI symptoms, patients with anaphylaxis may demonstrate cardio vascular symptoms, including hypotension, vascular collapse, and cardiac dysrhythmias, which are presumably caused by massive mast cellmediator release. Food dependent exercise induced anaphylaxis is a special form of acute IgE mediated food allergy in which moderate intensity exercise performed within a few hours of ingestion of a particular food, most commonly wheat or shellfish, results in anaphylaxis but when ingested without exercise, there is no allergic reaction. DIAGNOSIS A thorough medical history is necessary to determine whether a patients symptomatology represents an adverse food reaction (see Table 192.2), whether it is an intolerance or food allergic reaction, and, if the latter, whether |
6,700 | it is likely to be an IgE mediated or a cell mediated response (Fig. 192.1). An understanding of the basic pathophysiology and clinical presentations of different adverse food reactions is essential and if allergy is suspected, referral to an allergist immunologist is recommended. The following facts should be established: (1) the food suspected of provoking the reac tion and the quantity ingested, (2) the interval between ingestion and the development of symptoms, because most reactions occur within minutes to 2 hours of ingestion, (3) the types of symptoms elicited by the ingestion, which may suggest the pathophysiology of the adverse reaction, (4) whether ingesting the suspected food produced similar symptoms on other occasions because reproduc ibility is expected, (5) whether other inciting factors, such as exer cise, are necessary, and (6) time interval since last reaction to the food because evaluation for potential resolution of the allergy may be warranted. Skin prick tests and in vitro laboratory tests are useful for dem onstrating IgE sensitization, defined as presence of food specific IgE antibodies. Sensitization alone is not diagnostic of a food allergy. In general, increasingly higher serum food specific IgE levels or increasingly large skin test wheal size (especially 8 mm diameter) indicate a higher chance of clinical allergy. A negative serum food specific IgE test or skin test result virtually excludes an IgE mediated form of food allergy. In limited studies, serum food specific IgE lev els 15 kUAL for milk (5 kUAL for children 1 year), 7 kUAL for egg (2 kUAL for children 2 years), and 14 kUAL for peanut are associated with a 95 likelihood of clinical reactivity to these foods in children with suspected allergy. Evaluation of IgE binding to specific digestion resistant allergens that trigger reactions or labile proteins unlikely to cause significant reactions in a food, termed molecular or component resolved diagnostic (CRD) test ing, can provide additional clinically relevant information. Identifi cation of sensitization to digestion resistant proteins (components) in the foods correlates with a greater chance of systemic allergic reactions. Examples of tests for digestion resistant proteins include Ara h 1, 2, 3, and 6 for peanut; Jug r 1 and Jug r 3 for walnut; Ana o 3 for cashew; Ber e 1 for Brazil nut; and Cor a 9 and Cor a 14 for hazelnut. Ara h 8 in peanut is a labile, birch pollenrelated protein generally not associated with significant allergic reactions, and iso lated sensitization to this component is typically associated with no or only mild oral reactions. Importantly, most children with positive serum food specific IgE or skin test responses do not react when the food is ingested. It is therefore crucial to avoid indiscriminate testing (i.e., sending pan els of food tests). In the absence of a clear history of reactivity to a food and evidence of food specific IgE antibodies, definitive studies must be performed before recommendations are made for avoidance or the use of highly restrictive diets that may be nutri tionally deficient, |
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