Allergy and Immunology

Insect Sting Allergy

Life-threatening reactions to Hymenoptera are rare in childhood. A typical local reaction from a bee sting involves erythema, induration, pain, and/or itching secondary to local effects of the insect venom. ( Fig 4.6 ) Hypersensitivity reactions may manifest as large local reactions (LLRs), generalized urticaria or anaphylaxis. LLRs involve extreme swelling (>10 cm) contiguous to the sting and may involve lymphangitic streaking towards nodes in the groin or axilla. They typically progress in size 12 to 24 hours after the sting and may take 5 to 10 days to resolve. While these reactions may look like an infection, LLRs occur more rapidly than cellulitis and respond to therapy such as cool compresses antihistamines and NSAIDs. Corticosteroids may rarely be required. Patients with LLRs have an excellent long-term prognosis. While LLRs may occur again, the risk for anaphylaxis with future stings is only 4% to 10%. Allergy testing does not predict risk for anaphylaxis with future stings and is therefore not recommended in the evaluation of patients with LLRs.

Children and adults who have a history of generalized urticaria without respiratory, cardiovascular, or GI symptoms after an insect sting also have a good long-term prognosis. The risk for severe anaphylaxis after experiencing a mild cutaneous-only systemic reaction is less than 3% which is not greater than that of the general population. Allergy testing or desensitization with immunotherapy is generally not recommended unless other risk factors are present such as frequent unavoidable exposure or underlying medical conditions such as mastocytosis. The decision about whether to prescribe an epinephrine autoinjector to children with a history of generalized reactions confined to the skin or LLRs from stinging insects is left to physician discretion.

Children with a history of systemic anaphylaxis involving extracutaneous systems after a hymenoptera sting have a 30% to 40% risk of a similar reaction with future stings and should undergo allergy testing for consideration of immunotherapy. Testing should be performed no sooner than 4 weeks after the reaction to decrease the potential for false-negative test results. Allergen immunotherapy for Hymenoptera sensitivity is the most effective form of allergen immunotherapy available. Venom immunotherapy for wasps, yellow jackets, and hornets reduces the risk for anaphylaxis by greater than 95%, whereas it is slightly less effective for honeybees, providing complete protection in 80% to 85% of patients on therapy. Most venom immunotherapy protocols start with weekly injections for about 10 to 16 weeks followed by maintenance injections every 1 to 2 months for a duration of 3 to 5 years in most cases.

The Hymenoptera that have been associated with anaphylaxis come from three subfamilies: Apidae (honeybees); Vespidae (yellow jackets, wasps, and white- and yellow-faced hornets); and Formicidae (fire ants). In the United States, yellow jackets are the most common cause of Hymenoptera-induced anaphylaxis. Yellow jackets typically nest in the ground, are scavengers for food, and, consequently, are frequently encountered at picnics and around garbage cans. The yellow jacket is small with tight yellow and black bands. The honeybee is the least aggressive of the Hymenoptera family. Stings from honeybees occur most commonly in beekeepers and after accidental contact. The honeybee’s stinger is barbed and is retained in the skin after stings ( Fig. 4.7 ). If the stinger is visible, it should be gently flicked away from the skin with a fingernail. The stinger and venom sac should not be removed by pinching between the thumb and forefinger, because this process can express additional venom. Wasps and hornets are very territorial and will sting to protect their nests. The fire ant is an increasingly important cause of Hymenoptera-induced anaphylaxis. Fire ants are found in the south and southeastern United States, but their natural habitat appears to be expanding.

Food Allergy

If tolerance, or lack of an immune or other reaction, to a food represents a normal host response to ingestion, an adverse food reaction can be broadly defined as any abnormal reaction. These adverse food reactions can be further subdivided into those that are immune-mediated and not. Within the immune-mediated reactions are IgE-mediated (those most commonly referred to as food allergy), non-IgE mediated, mixed IgE and non-IgE, and cell-mediated ( Fig. 4.8 ). Nonimmune-mediated reactions are commonly referred to as intolerances (e.g., lactose intolerance), and although these reactions can lead to significant symptoms, allergy testing is not helpful or indicated in the evaluation of these disorders. IgE-mediated food allergy reactions are highly reproducible (i.e., occur with every exposure to the food), and often are triggered by ingestions of very small quantities. Anaphylaxis is the best described and understood type I hypersensitivity to food. Although contact reactions (erythema, pruritus, hives) are common if an individual touches his or her food allergen, the most severe allergic reactions occur with ingestion. Milk, egg, wheat, soy, and peanut account for more than 90% of pediatric food allergic reactions. The onset of type I hypersensitivity to milk and egg is almost always in the first year of life. Fortunately, sensitivity to milk and egg is eventually outgrown in the vast majority of patients, frequently by school age.

Most allergic reactions to foods occur with the first few ingestions of a food. In contrast to type I hypersensitivity to milk and egg, less than 25% of patients will outgrow their peanut or tree nut sensitivity. Peanuts and tree nuts cause the majority of life-threatening reactions to foods. Other risk factors for life-threatening reactions from food-induced anaphylaxis include asthma, adolescence, and the delayed administration of epinephrine. A past history of mild reactions does not rule out the possibility of a future life-threatening episode of food-induced anaphylaxis. Some patients with type I hypersensitivity to peanut will develop type I hypersensitivity to one or more tree nuts. Nuts are also frequently processed together, increasing the risk of cross-contact exposures with nuts. A simplified approach includes avoiding all nuts if a patient is allergic to either peanuts or tree nuts, however recommendations should be individualized as many tree nut–allergic children can ingest peanut butter and many peanut-allergic children can ingest tree nuts as long as they avoid foods that may contain traces of the nut to which they are allergic.

Another common form of type I–mediated hypersensitivity to food is oral allergy syndrome (also known as pollen-food allergy syndrome ). Patients with this syndrome typically have underlying seasonal allergic rhinitis and develop pruritus and mild angioedema of the oropharynx when ingesting fresh fruits and vegetables. The reaction is due to cross-reactivity between heat-labile proteins in some fruits and vegetables and outdoor seasonal pollens. The reaction is often eliminated by heating the vegetable or fruit. The reaction does not generally extend beyond the oropharynx, and patients typically do not need to carry epinephrine. In a minority of cases, reactions may be severe, so taking a thorough history is essential before recommendations are made for avoidance and the need for epinephrine.

Type I hypersensitivity to foods can be an unrecognized trigger in up to one-third of younger children with severe atopic dermatitis although it is an uncommon trigger in older children and those with mild atopic dermatitis. It has rarely been described in adults with atopic dermatitis. The evaluation of type I hypersensitivity to foods in children with atopic dermatitis should be reserved for patients whose disease cannot be managed with good skin care and intermittent use of low- to moderate-potency topical antiinflammatory medications. When food hypersensitivity plays a role in poorly controlled atopic dermatitis, six foods account for the vast majority of reactions: milk, egg, wheat, soy, and peanut.

One of the challenges with diagnosing type I hypersensitivity to foods is the poor specificity of both the skin prick and in vitro tests. These tests have a 20% to 50% false positive rate. Therefore, the “gold standard” for the diagnosis of food allergy is a double-blind, placebo-controlled food challenge (DBPCFC). A distinction must be drawn between patients who are “sensitized,” based on skin or serum testing, and those who are clinically allergic, based on a history of reactions to ingestions. IgE-mediated reactions occur quickly and reproducibly with ingestion of the triggering food. Over the years, research using in vitro allergy tests has identified levels of specific IgE against certain foods that predict a reaction during a DBPCFC with 95% likelihood. In vitro food-specific IgE levels are most useful clinically when used in association with a patient’s ingestion history and (if indicated) skin test results. In a nationally representative survey study, approximately 17% of the overall population in the United States displayed serum sensitization to either cow’s milk, egg, peanut, or shrimp, and this prevalence rate was even higher (28%) among children from 1 to 5 years old. Yet, on the basis of these serum levels in the same study, only approximately 2.5% of the United States population was predicted to be clinically allergic to one of these foods. The data concerning positive predictive levels depend on the age of the patient and are not available for all foods ( Table 4.4 ). The in vitro allergy test may also be repeated over time to try to help with the identification of patients who may have outgrown their sensitivity. The sensitivity of both the skin prick and in vitro tests is excellent but not 100%. If there is a strong clinical history of a type I reaction to a food, it may be necessary to perform an oral challenge in a medically supervised setting before food hypersensitivity can be fully ruled out.

Current treatment for IgE-mediated food allergic reactions consists of avoidance of the trigger food, as well as tools to manage an accidental ingestion reaction. Many patients with this severe food allergy will require access to an epinephrine autoinjector, and patients/families should be instructed in its use. These patients and their families should be provided with an anaphylaxis action plan outlining appropriate symptom-based treatment. Although avoidance is the current standard of care, there are currently multiple potential “active” therapies being investigated for IgE-mediated food allergy. These interventions aim to raise the threshold of the amount of allergen that can lead to an allergic reaction if there is an accidental ingestion of that particular food. To date, the most well studied of these approaches involve exposing the allergic individual to very small amounts of the food allergen in question, either orally (oral immunotherapy [OIT]), sublingually (sublingual immunotherapy [SLIT]), or through the skin (epicutaneous immunotherapy [EPIT]). As of this writing, the only U.S. Food and Drug Administration (FDA)-approved immunotherapy treatment for food allergy is Palforzia, which involves the graded administration of pharmaceutical grade peanut powder for children 4 to 17 years. Phase III studies for EPIT for peanut have been completed and are under consideration for approval by the FDA.

Triggers of eosinophilic gastrointestinal disorders (EGIDs) are more challenging to evaluate as eosinophilic infiltration of the gut is thought to be caused by a mixed reaction involving type I (IgE-mediated) hypersensitivity and other immune pathways. Patients with EGIDS often have type I hypersensitivity to certain foods and sometimes inhaled aeroallergens that are inadvertently swallowed. The pathogenesis of EGIDs is thought, however, to also involve non–IgE-mediated pathways such that a negative skin prick or in vitro test does not eliminate the possibility that food may be causing or contributing to the disease. Similarly, a positive allergy test to a food does not definitely establish causation. Patch testing has also been studied to determine potential food triggers of EGIDs revealing equally concerning limitations in sensitivity and specificity. Patients with eosinophilic inflammation of the upper GI tract tend to have problems with dysphagia, food impaction, abdominal pain, and vomiting. Patients with eosinophilic inflammation of the lower GI tract tend to have diarrhea, failure to thrive, and abdominal pain. Treatments for EGIDs include elemental diets, selected dietary elimination, proton pump inhibitors, and swallowed steroids while biologic therapies targeting eosinophilic pathways and other mediators involved in the process are currently under evaluation. The long-term prognosis is not completely understood and the disease often follows a relapsing and remitting course.

The term food allergy also encompasses the food reactions elicited through non–IgE-mediated immune pathways. The classic example of a non–IgE-mediated hypersensitivity to food is seen in milk protein proctocolitis of infancy (also known as food-induced eosinophilic proctitis ). These children usually present with bloody diarrhea in the first few months of life and this improves within days of removing milk proteins from the diet. Many of these children are breastfed, and they react to either cow’s milk or another protein in the maternal diet. Approximately half of children with milk protein enterocolitis will also experience symptoms with soy protein–based formulas. Since milk protein proctocolitis is not IgE-mediated, allergy testing is not recommended in its evaluation. Almost all infants will outgrow this condition by 1 to 2 years old.

Food protein–induced enterocolitis syndrome (FPIES) is another non–IgE-mediated reaction with a more severe presentation. Infants typically present 1 to 4 hours after an ingestion of the triggering food, with profuse vomiting sometimes to the point of dehydration hypotension and lethargy. Fecal leukocytes, a rise in the peripheral absolute neutrophil count, acidosis, and methemoglobinemia may also be seen, whereas skin lesions are not present. Cow’s milk, soy, rice, and oat are the most common triggers of FPIES, although it has been described with a variety of other foods. Infants frequently are diagnosed with recurrent sepsis or infectious gastroenteritis before the condition of FPIES is realized. Since FPIES is not IgE-mediated, the gold standard for diagnosis is a food challenge. While skin prick testing and in vitro IgE testing are not helpful in determining causality or resolution, a positive test may have prognostic value in predicting a longer course to resolution and/or the risk for IgE-mediated potentially anaphylactic symptoms on reintroduction of the food. Many cases, however, resolve by 2 to 6 years and the triggering foods are tolerated without issue.

Asthma

Asthma is the most common chronic respiratory condition affecting children. The Centers for Disease Control and Prevention (CDC) reported more than 6 million children (1 in 12) have asthma (CDC National Center for Environmental Health, 2018). In 2016, more than half of children with asthma had one or more attacks, occurring more frequently in children younger than the age of 5. Each year, 1 in 6 children with asthma go to the emergency room and 1 in 20 children with asthma are hospitalized because of their disease. Of note, asthma hospitalizations of children did decline by 50% from 10% in 2003 to 5% in 2013. Data analyzed from the 2001 to 2016 National Health Interview Survey for children 0 to 17 demonstrated that there was a higher prevalence in boys, non-Hispanic black children and Puerto Rican children and children from low-income households. This survey also noted a decrease in asthma prevalence and asthma attacks ( Fig. 4.17 ).

Defining characteristics of asthma, as elucidated by the National Heart, Lung, and Blood Institute (NHLBI), include the following: (1) lower airway obstruction that is partially or fully reversible either spontaneously or with bronchodilator or antiinflammatory treatments, (2) the presence of lower airway inflammation, and (3) increased lower airway responsiveness (bronchial hyperreactivity) (NHLBI National Asthma Education and Prevention Program [NAEPP], 2016). The last is characterized by inherent hyperreactivity of the airways to stimuli, including allergens, infection, exercise, chemical agents (such as methacholine), cold or dry air, emotions, and weather changes ( Fig. 4.18 ).

Many cases of asthma, particularly in children, have an atopic basis. Specific allergens implicated in atopic patients are pollen, mold spores, house dust mites, and animal dander, whereas drugs, food, and insect venoms typically cause similar symptoms of wheezing and respiratory distress as part of anaphylaxis (see earlier discussion). On exposure, these allergens, via cross-linking specific IgE, produce the characteristic features of asthma: mucosal edema, increased mucus production, and smooth muscle contraction that result in airway inflammation, airway hyperreactivity, and bronchoconstriction. These responses combine to produce a state of reversible obstruction of the large and small airways that is the hallmark of asthma.

Patients with asthma should be evaluated to determine the important triggers for their disease. Affected individuals are often aware of the specific trigger for exacerbations of their asthma. Viruses are the most common precipitants of acute asthma in children, especially rhinoviruses, respiratory syncytial virus, and parainfluenza viruses. These infections usually affect the upper and lower airways, producing rhinorrhea, nasal congestion, and wheezing, which tends to develop insidiously. In contrast, allergen-triggered episodes typically lack fever and have a more abrupt onset of wheezing.

The diagnosis of asthma, especially in younger children who cannot do pulmonary function tests, is frequently based on historical findings alone, indicating the importance of taking a thorough history. Updated NHLBI and American Academy of Pediatrics (AAP) guidelines have stressed the importance of complementing good history taking with objective measurements of lung function. Important parts of the medical history include description and pattern of the symptoms, precipitating factors, development of disease and treatments tried, family history, social history, history of exacerbations, impact on the patient and family, and the patient’s perception of the disease ( Fig. 4.19 ). In-office pulmonary function testing can be attempted in children of 5 years old and older, but it is important to understand that normal results in an asymptomatic patient do not exclude asthma. Peak flow monitoring is not recommended for use in diagnosis but can sometimes be used for monitoring. The greatest shortcomings of peak flow monitoring are that it is effort dependent, requires compliance, and does not measure small-airway function. In addition, there is a wide variability in types of peak flow meters, along with different reference ranges. When peak flow monitoring is used, patients should be given a written plan with instructions on what to do as their peak flow falls along with increase in symptoms.

As with many common diseases, asthma incidence is influenced by both genes and environment (see Fig. 4.23 ). Family history often reveals affected siblings, parents, or other relatives. An environmental survey can determine possible provocative factors, especially allergens, infections, occupational exposures, smoking, exercise, stress, climate, and medication use (NSAIDs, beta-blockers). The history should emphasize the frequency, duration, and intensity of suspected episodes ( Box 4.1 ). Individuals with asthma commonly present with recurrent episodes of wheezing that, depending on the severity, may require emergency treatment. Episodes may be infrequent and/or seasonal or may occur daily. The spectrum of presenting complaints, however, is broad, and affected individuals may complain only of mild, occasional wheezing or shortness of breath with exercise and/or colds or a persistent dry, hacking cough (particularly at night or in the morning). Breathlessness and chest tightness are also commonly reported.

The frequency and severity of acute asthma episodes and the level of symptoms between episodes can be used to grade asthma severity and ultimately assess and monitor asthma control as shown in Table 4.5 and see Table 4.6 . Stepwise therapy recommendations were updated in the 2020 Focused Updates to the Asthma Management Guidelines by the Expert panel Working Group of the National Heart, Lung and Blood Institute as noted in Tables 4.6–4.10 .

The early stages of an asthma exacerbation in children are characterized by the onset of cough, chest tightness, and chest retractions or audible wheezing. The parents should be educated to observe their child for the warning signs and identify the onset of asthmatic exacerbation at home. A written asthma action plan that details use of rescue medicines (such as albuterol) can minimize emergency department visits for asthma ( Fig. 4.20 ).

Asthma should be considered part of the differential diagnosis in any child with recurrent or chronic lower respiratory symptoms or signs. Even though a high index of suspicion must be maintained, excessive or erroneous diagnoses may result if they are made hastily without appropriate supportive evidence; normal children or those with potentially more severe disorders may be mistakenly diagnosed with asthma and inappropriately treated. Box 4.2 provides a differential diagnosis for asthma. Parents must be instructed that physician assessment is essential during suspected episodes of asthma so that wheezing or other signs of lower airway obstruction and reversibility may be documented. Pulmonary function tests in asthmatic children older than 5 years may show airway obstruction at baseline or after appropriate challenge with methacholine, exercise, or cold air and document reversibility after administration of an aerosolized bronchodilator ( Fig. 4.21 ). For children younger than 5 years old or for those in whom testing is unreliable, the diagnosis must be made on the basis of historical and physical findings and clinical response to bronchodilator or antiinflammatory medications. Lack of an immediate response to a bronchodilator does not eliminate asthma as a consideration, however. In the instance of poor response to prescribed medications, appropriate inhaler technique should be addressed, as well as the importance of using a spacer device with any metered dose inhaler to ensure adequate medication delivery to the distal airways ( Fig. 4.22 ).

A thorough physical examination provides valuable information regarding the diagnosis of asthma and its severity and chronicity. The physical findings in asthma vary with the state of activity of the disease process at the time of examination. The findings of acute asthma are markedly different from those of chronic and latent or quiescent asthma. Between episodes, the examination is usually entirely normal, although prolongation of the expiratory phase is sometimes noted. Clubbing as a sign of chronic asthma is rare and suggests another chronic pulmonary disease.

During acute asthma, the following historical features should be noted: time of onset, possible triggers, present medications, comparison with previous episodes, and presence of complicating factors (e.g., vomiting, fever, or chest pain). Examination should document accessory muscle use, retractions, and color. Auscultation should be done to assess air exchange, wheezing, and inspiratory-to-expiratory ratio. The ability to speak (words, phrases, or complete sentences) is a useful measure of dyspnea. Lethargy, decreased air exchange, and increased work of breathing are the most worrisome signs indicating acute deterioration.

In addition, rales are often heard, and pulse, respiratory rate, and blood pressure are frequently elevated. Pulsus paradoxus, an exaggerated decrease in systolic blood pressure during inspiration ( Table 4.11 ), correlates highly with degree of airway obstruction, although it is rarely measured clinically. This phenomenon may result from physical forces on the pericardium that impede venous return and reduce cardiac output during forced inspiration. Normally, the inspiratory decrease in systolic blood pressure is less than 10 mm Hg and is not discernible during routine sphygmomanometry. In acute asthma, it is usually greater than 10 mm Hg (up to 30 and 40 mm Hg) and is easily detectable.

Individuals with asthma may be distinguished by their characteristic symptoms and signs during acute episodes, which typically change with the degree of airway obstruction. Symptoms usually consist of progressively increasing shortness of breath and difficulty breathing with or without rhinorrhea, low-grade fever, and vomiting. On examination, expiratory wheezing or a prolonged expiratory phase may be the only manifestation of mild asthma. However, as the obstructive process progresses, the expiratory phase becomes longer and the wheezing becomes louder and occurs on both inspiration and expiration. Eventually, airways collapse and signs of hyperinflation develop (low diaphragms, decreased lateral excursions of the chest wall with breathing, and hyperresonance to percussion). Visible sternocleidomastoid contractions; increased anteroposterior chest diameter; circumoral cyanosis; and suprasternal, intercostal, and substernal retractions occur. Subjectively, the patient experiences chest tightness and anxiety and works harder to breathe. Accessory muscle use and retractions can develop with or without marked wheezing on auscultation. To maximize air exchange, the child assumes a characteristic sitting posture, bending slightly forward. Frequent examinations are warranted, and any change in sensorium requires prompt evaluation. As respiratory muscles tire, the patient becomes lethargic and cyanotic, even with supplemental oxygen. A decrease in wheezing with increased air entry represents response to therapy. Decreased wheezing with decreased air entry is an ominous sign. With extreme fatigue, respiratory muscles fail, retractions decrease, and respiratory failure is imminent unless appropriate therapy is promptly initiated. After initial examination, serial assessment of the degree of respiratory distress, using the parameters outlined in Table 4.12 , assists determination of the response to therapy.

A particularly useful aspect of the physical examination is the respiratory rate, which increases as the degree of airway obstruction progresses. Respiratory rates of normal children are shown in Table 4.13 .

The underlying pathology of asthma is lung inflammation. Histopathologic features of acute asthma include airway infiltration with inflammatory cells, increased intraluminal mucus with plugging of small airways, edema, bronchoconstriction, and smooth muscle hypertrophy. Because asthma has bronchoconstrictive and inflammatory components, the ideal therapeutic regimen should incorporate a combination of bronchodilator and antiinflammatory agents. Characteristic features of asthmatic inflammation include mast cell activation, inflammatory cell infiltration, edema, denudation and disruption of the bronchial epithelium, collagen deposition beneath the basement membrane, goblet cell hyperplasia, and smooth muscle thickening. These morphologic changes may not be completely reversible and may contribute to airway remodeling ( Fig. 4.23 ).

Education is a key component of asthma therapy, incorporating information about disease pathogenesis; avoidance of environmental triggers (including second-hand tobacco smoke exposure); benefits and risks of medications; and a written, individualized therapeutic plan for chronic and acute management that outlines the goals of asthma therapy, as well as indications and correct use for prescribed medications.

The radiographic features of hyperinflation, peribronchial cuffing, and atelectasis, which are characteristic of uncomplicated acute asthma, are illustrated in Fig. 4.24 . Complications are diagnosed radiographically but may be suggested by symptoms and signs. Pneumothorax ( Fig. 4.25 ) should be suspected in any patient with asthma who develops chest pain associated with dyspnea, cyanosis, tachypnea, and occasionally cough. Examination reveals respiratory distress, marked hyperinflation and decreased chest wall excursion, and decreased or absent breath sounds on the affected side. With tension pneumothorax, the trachea, mediastinum, and cardiac landmarks may be shifted to the opposite side. Pneumomediastinum and subcutaneous emphysema ( Fig. 4.26 ), usually involving the neck and supraclavicular areas, are more common than pneumothorax. When mild, they may be asymptomatic and may be detected incidentally on radiographs. With more extensive air dissection, the patient may complain of neck and chest pain, and the subcutaneous emphysema may be visibly evident as a soft tissue swelling of the neck and chest that is crepitant on palpation. Pneumothorax and pneumomediastinum can produce characteristic auscultatory findings, including a crackling “mediastinal crunch” at the base of the heart and a systolic crunch or knock. The latter sound has been referred to as noisy pneumothorax and is frequently audible to the patient and physician without the aid of a stethoscope.

Other complications that may be observed on physical examination include those induced by chronic systemic steroid use, such as weight gain, “moon-type” facies, hirsutism, polycythemia (red, ruddy complexion) ( Fig. 4.27 ), and short stature (see Chapter 9 ). The introduction of effective antiinflammatory therapy, particularly inhaled corticosteroids, has made such sequelae rare.

In children with recent onset of wheezing, asthma must be differentiated from other disorders associated with wheezing. In infants, this differentiation includes bronchiolitis, the features of which are listed in Table 4.14 (see Chapter 17 ). This differentiation may be difficult, because up to 50% of children with recurrent bronchiolitis are later diagnosed with asthma, and asthma exacerbations are often triggered by viral infection. However, the distinction remains a clinically useful one for the following reasons: (1) the children with bronchiolitis who do not develop asthma may be inappropriately labeled as asthmatic; and (2) children younger than 2 years old frequently do not respond to inhaled bronchodilators. In infants and young children who wheeze with viral upper respiratory infections, different patterns of illness may emerge over time.

The Tucson Children’s Respiratory Study, a large, longitudinal assessment of respiratory illnesses in children, identified different patterns of wheezing illness in children. As summarized in Fig. 4.28 , 51% of children enrolled in this study never wheezed, 20% had transient infant wheezing (defined as wheezing during the first 3 years of life but no wheezing at 6 years old), 14% had persistent wheezing (defined as wheezing during the first 3 years of life with wheezing present at 6 years old), and 15% had late-onset wheezing (defined as no wheezing during the first 3 years of life but wheezing present at 6 years old). Children with transient wheezing had significantly lower lung function in infancy (before any wheezing illness) than all the other groups ( Table 4.15 ). At 6 years old, children with early transient wheezing had significantly lower lung function than those who had never wheezed, and children with persistent wheezing had the lowest levels of lung function of all the groups.

It is hypothesized that children with early transient wheezing have congenitally smaller airways, which predispose to wheezing with viral illnesses. As their airways grow in size with age, these children outgrow wheezing with viral infections. In contrast, children with persistent wheezing are born with normal airway function, which deteriorates over time, reflecting the effects of the chronic asthmatic disease process. Distinguishing transient versus persistent wheezing during infancy and early childhood remains problematic. Infant pulmonary function testing is still experimental and not widely available, there are currently no reliable genetic markers, and the use of any single biochemical marker is controversial. However, a combination of clinical and biochemical markers may be useful in predicting persistent wheezing ( Box 4.3 ). These include increased serum IgE level, atopic dermatitis and rhinitis (unrelated to upper respiratory infection) during the first year of life, severe lower respiratory infections requiring hospitalization, and diminished airway function as measured by spirometry at 6 years old. Other factors associated with persistent wheezing include a family history of asthma and/or allergy and perinatal exposure to passive tobacco smoke. A clinical index has been developed to predict which children with recurrent wheezing are at risk for persistent asthma ( Table 4.16 ).

Although children with pneumonia (particularly of viral origin) may wheeze, they are more likely to have rales or normal findings on auscultation, with the diagnosis suggested by tachypnea in association with retractions, nasal flaring, or expiratory grunting. Other causes of wheezing are listed in Table 4.17 . Airway compression by anomalous vessels (see Chapter 5 ) or mass lesions is often distinguishable from bronchiolitis by the absence of signs of infection and from asthma by failure to respond to bronchodilators. The history and presence of infiltrates help in the diagnosis of aspiration, which can mimic asthma closely, often responding to bronchodilator therapy. Radiographic studies (such as barium swallow with fluoroscopy) can be helpful in distinguishing among these entities ( Fig. 4.29 ). pH probe testing may be required to identify gastroesophageal reflux (see Chapter 17 ), although a trial of antireflux medicines is often attempted.

In older children who have sudden onset of wheezing and respiratory distress, the differential diagnosis includes respiratory infections, left ventricular failure, aspiration, and vocal cord dysfunction. Respiratory infections (such as croup) may be distinguished by their characteristic histories and tendencies to involve the upper airways (see Chapter 17 ). Lower respiratory infections (pneumonia) generally produce fever and more localized findings of rales, a decrease in the number of and change in the quality of breath sounds, and egophony. Left ventricular failure, especially with pulmonary edema, may present with acute respiratory distress and wheezing. A history of cardiac disease, diffuse crackles or basilar rales, and a third heart sound on auscultation help distinguish this condition from asthma. Aspiration of a foreign body that lodges in a mainstem bronchus may produce wheezing ( Fig. 4.30 ). A history of a choking episode and physical findings of unilateral wheezing and hyperresonance aid in distinguishing aspiration from asthma but do not confirm the diagnosis, because wheezing resulting from foreign body aspiration may respond at least in part to bronchodilator therapy. Vocal cord dysfunction is becoming more recognized in children and adolescents and is often confused with asthma by families, school nurses, as well as primary care and emergency room physicians. Symptoms include acute-onset dyspnea and often stridor, which can be mistaken for wheezing to the untrained observer, secondary to partial or complete adduction of the vocal cords during inspiration. Symptoms rarely awaken individuals from sleep, and there are many triggers that are similar to asthma, including exercise, inhalational irritants, psychosocial stressors, and rhinitis. Bronchodilators are not effective and objective measurements of pulmonary function, including pulse oximetry and chest radiographs, are unremarkable during acute episodes. Some episodes of vocal cord dysfunction can become severe enough to result in syncope from hyperventilation, which often successfully resolves the acute episode as the vocal cords relax.

In the older child with mild, infrequent episodes of wheezing that respond to bronchodilator therapy, asthma is readily diagnosed. However, with daily wheezing, frequent exacerbations, lack of response to bronchodilators, or poor growth, other diagnoses must be considered, including chronic obstructive pulmonary disease, cystic fibrosis, α ₁ -antitrypsin deficiency, and immunodeficiency. Chronic obstructive pulmonary diseases, which include chronic bronchitis, emphysema, bronchiectasis, and bronchopulmonary dysplasia, are distinguished by their lack of significant reversibility with bronchodilator therapy. Cystic fibrosis may present with chronic cough, wheezing, and recurrent infections. In addition, malabsorption with bulky, foul-smelling stools; failure to thrive; and clubbing of the nail beds are common. An inherited autosomal recessive disorder, α ₁ -antitrypsin deficiency, is characterized by the onset of progressive emphysema in a young adult and is one cause of neonatal hepatitis.

Hypersensitivity Pneumonitis

Although IgE-mediated allergic respiratory diseases (allergic rhinitis, asthma) are the most common manifestations of inhalant sensitivities in humans, other immunologic respiratory diseases, involving non-IgE immune mechanisms, may result from the inhalation of antigens from the susceptible individual’s environment. A wide variety of inhaled biologic dusts may induce an inflammatory lung disease involving the interstitium, alveoli, and airways. The most common form of hypersensitivity pneumonitis is caused by inhalation of thermophilic actinomycetes ( Saccharopolyspora rectivirgula, formerly Micropolyspora faeni ), antigens present in moldy vegetable compost, and is termed farmer’s lung. Other forms (and their causative dusts and antigens) include malt-worker’s lung (moldy malt, Aspergillus species) and bird-breeder’s lung (avian dust, avian proteins). The disorder is termed hypersensitivity pneumonitis or extrinsic allergic alveolitis and appears to be mediated by a complex immune response involving both immune complexes (type III) and T cells (type IV).

Hypersensitivity pneumonitis is a syndrome with a broad spectrum of presenting symptoms and signs that have been subdivided into acute, subacute, and chronic. The clinical features depend on the following factors: (1) the nature of the inhaled dust, (2) the intensity and frequency of inhalation exposure, and (3) the immunologic responsiveness of the exposed individual. A concomitant upper respiratory infection or another pulmonary insult may be an important factor in induction. Development of sensitization to the inhaled organic dust requires several months to years, although organic dust toxic syndrome can present similarly after a single exposure to a large dose of antigen. The acute form of hypersensitivity pneumonitis is usually readily differentiated from asthma by the lack of wheezing, prominence of rales, and presence of severe systemic symptoms, such as high fever and myalgia. Subacute and chronic forms generally present with insidious development of respiratory symptoms.

Allergic Bronchopulmonary Aspergillosis

Aspergillus species, in addition to being one cause of hypersensitivity pneumonitis and allergic asthma, cause a disorder termed allergic bronchopulmonary aspergillosis (ABPA). This entity is characterized by migrating pulmonary infiltrates and peripheral blood and sputum eosinophilia. Type I and type III hypersensitivity are thought to be involved in the pathogenesis. Affected individuals are usually atopic and have a history of asthma and/or cystic fibrosis. They often present with systemic symptoms and difficulty weaning off systemic corticosteroids. Sputum production is prominent. Physical findings include the general signs of lower airway obstruction (see the earlier section, Asthma).

Laboratory studies that assist in diagnosis include the following:

• • Peripheral blood examination reveals eosinophilia (generally >1000/mm ³ ).

  • The serum IgE level is markedly elevated, often greater than 1000 ng/mL, and specific IgE to Aspergillus fumigatus is elevated.

  • Skin testing for A. fumigatus is positive. Although mold- sensitive patients with asthma without ABPA may have a positive reaction, a negative reaction rules out ABPA.

  • Serum precipitating antibody (IgG) to A. fumigatus is found in most patients, but the titer has a poor correlation with disease activity.

  • Chest radiography commonly shows infiltrates in active ABPA. The upper lobes are commonly involved, and infiltrates characteristically shift rapidly from one site to the other. Remarkably, radiographic findings do not correlate well with clinical severity, and patients with extensive consolidation may be asymptomatic ( Fig. 4.31 ).

    

  • High-resolution computed tomography (CT) scanning may show bronchiectasis, especially late in the course of the disease.