24 Atopic and Rheumatic Disorders
Atopic disorders and rheumatic diseases (collagen vascular or connective tissue diseases) of childhood share certain characteristics that lend to their combined discussion in this chapter. Inflammation, chronicity, and genetic predisposition are common to both groups of disorders. The triad of atopic disorders that may or may not coexist consists of atopic dermatitis (AD), allergic rhinitis (AR) (or “hay fever”), and asthma. The two most common childhood rheumatic diseases that primary care providers are likely to encounter are juvenile idiopathic arthritis and systemic lupus erythematosus (SLE). Juvenile dermatomyositis is also a classic rheumatic disease but is less frequent in occurrence. These are collagen-vascular disorders that have localized or generalized findings marked by inflammation and an autoimmune response. Vasculitis, an inflammation of the blood vessels, is characteristic of many of the rheumatic diseases.
Fibromyalgia is a rheumatic disease that causes widespread musculoskeletal pain with generalized tender points associated with fatigue (Buskila, 2009). Brief discussions of this disease, in addition to chronic fatigue syndrome (CFS), are presented. Although the incidence of rheumatic fever has diminished significantly in the U.S., it is still a disease that merits attention by providers. Therefore, a review of its clinical presentation and treatment also is included. The immunopathogenesis and management of Henoch-Schönlein purpura (HSP), the most common systemic vasculitis syndrome of childhood, also are discussed.
Allergy involves a specific acquired alteration in the body that has an immunologic basis. An allergen acts as an antigen that then triggers an immunoglobulin E (IgE) response in genetically predisposed individuals. The union of antigen and antibody creates a cascade of events that culminates in biochemical reactions. There are four types of allergic reactions: I (manifested as typical allergic symptoms to the extreme of anaphylactic reactions), II (antibody cytotoxicity reactions), III (immune complex reactions with Arthus-reactions and serum sickness as examples), and IV (cellular immune-mediated or delayed-type hypersensitivity). All four types of allergic or hypersensitivity reactions are mediated by circulating or cellular antibodies and generally can occur in any individual (Lasley and Hetherington, 2011). Type I involves local and systemic manifestations resulting from an interaction between antigen and tissue cells that have been sensitized with reaginic antibody, generally IgE (e.g., urticaria and angioedema). Type II involves reactions from antibody interacting with antigenic components on cell surfaces (e.g., hemolytic anemia and transfusion reactions). Type III is characterized by deposition of immune microprecipitates in or around blood vessels. Complement or toxic products are released. Henoch-Schönlein purpura is one example of type III-mediated reactions. A type IV allergic reaction is a delayed-type hypersensitivity interaction involving sensitized lymphocytic cells that results in the release of toxic lymphoid cell products. Cytokines are released which stimulate bone marrow precursors to produce more leukocytes that become macrophages. Examples of type IV reactions are tuberculin skin test reactions and contact dermatitis) (Lasley and Hetherington, 2011).
Atopy represents a complex interaction between multiple genes and environmental exposures. Atopic disorders are forms of allergic reactivity that occur only in certain susceptible individuals with an unknown and probably genetic predisposition. Environmental factors also play a role in atopy of these individuals who exhibit a hyperresponsiveness in target organs (lungs, skin, or nose). Certain antigens (e.g., cat dander, ragweed) are problematic for atopic individuals but not for others. These atopic individuals become sensitized to the offending allergen, resulting in an atopic disorder.
The development of an atopic disorder or allergic response involves a susceptible individual who is both exposed to an offending antigen and has a predisposition to selective synthesis of IgE when in contact with common environmental antigens. If these conditions are in place and contact with an offending antigen occurs, the following biochemical chain of cascading events unfolds:
• Chemical mediators that cause biochemical reactions and allergic-related injury to target organs (skin and respiratory tract) are released. Examples of chemical mediators include but are not limited to:
The end result of this biochemical process is tissue injury of a target organ. Examples of tissue injury include inflammation and hyperresponsiveness, resulting in such symptoms as obstruction, increased mucus discharge, and pruritus.
Immediate allergic reactions can involve sneezing, hives, wheezing, vomiting, or anaphylaxis. Acute reactions (<30 minutes) can be followed by a late-phase response several hours (2 to 12) after the initial response. This late-phase response is due to the influx of other inflammatory cells such as basophils, eosinophils, monocytes, lymphocytes, and neutrophils and their inflammatory mediators that are recruited to the site of the acute allergic reaction (Lasley and Hetherington, 2011).
The pathogenesis of atopic diseases involves a complex interrelationship of genetic, environmental, and immunologic factors. The main defense mechanism to protect against atopic disorders is the elimination of the offending substance to prevent IgE development and antigen-antibody interaction. For example, if there is a family history of atopic disorders, breastfeeding offers the protection of limited exposure to cow’s milk protein and the benefit of maternal IgA and IgG antibodies. Once chemical mediators are released, the body’s protective responses reduce inflammation and repair tissue damage. Pharmacologic therapy cannot cure atopic disorders, but reduces symptoms and checks the allergic process. For example, drugs may be used to control inflammation (corticosteroids), compete with histamine for receptor sites on target tissues (antihistamines), act as a selective leukotriene receptor antagonist (e.g., montelukast), and prevent mast cell degranulation and mediator release (cromolyn sodium).
Juvenile idiopathic arthritis (JIA) is the term increasingly being used as the nomenclature for what was formerly called juvenile rheumatoid arthritis (JRA). JRA was used to describe a group of conditions involving chronic inflammation of synovial joints in children younger than 16 years old. Its newer nomenclature is juvenile idiopathic arthritis which includes enthesitis-related, undifferentiated, and psoriatic arthritis that had not been included in the American College of Rheumatolgy classification for chronic childhood arthritis. JIA now encompasses additional types of juvenile arthritis (e.g., enthesitis-related arthritis and psoriatic arthritis) beyond what had been identified under the nomenclature of JRA (Haftel, 2011; Rabinovich, 2010). Both JIA and SLE are connective tissue disorders marked by inflammatory changes in connective tissues throughout the body. The exact cause of these collagen diseases is not completely understood; however, an autoimmune basis is postulated as a key factor in rheumatic disease.
There are no natural defense mechanisms identified to prevent either of these diseases; however, periods of remission do occur in some children with SLE for unknown reasons, and many children with JIA achieve complete remission with puberty (approximately 85% complete remission rate) (Haftel, 2011). Because inflammation is a significant factor in these two rheumatic diseases of childhood, administration of corticosteroid preparations is a key therapy to control inflammation responsible for tissue injury and possible permanent tissue changes.
The exact etiology of most forms of JIA is unknown; however, there are two theories about its causation. Genetics is believed to be a predisposing factor. Some genetic factors, such as human leukocyte antigen (HLA) alleles, appear to play a role in influencing the susceptibility to develop disease, and others influence disease severity. An external trigger such as infection or trauma seems to initiate the autoimmune reaction and cause an exaggerated immune response (Rabinovich, 2010).
The pathogenesis of JIA involves a combination of humoral and cell-mediated immunity responses with proliferation of macrophage-like and fibroblastoid synoviocytes. There is subsequent infiltration of neutrophils and lymphocytes, which is evidence of an autoimmune response. The humoral response is responsible for the release of autoantibodies (especially antinuclear antibodies), an increase in serum immunoglobulins, the formation of circulating immune complexes and complement activation. The cell-mediated reaction is associated with a T-lymphocyte response that plays a key role in cytokine production resulting in the release of tumor necrosis factor α (TNF-α), IL-1, and IL-6. B lymphocytes are activated by T-helper cells and produce autoantibodies that link to self-antigens. The B lymphocytes infiltrate the synovium with the end result of nonsuppurative chronic inflammation of the synovium that can lead to articular cartilage and joint structure erosion. Children with JIA have no demonstrable immunodeficiency (Rabinovich, 2010).
Children with SLE exhibit a marked increase in the production of autoantibodies that attack the body’s deoxyribonucleic acid (DNA). This leads to immune complex formation and tissue damage from either direct bonding in tissues, immune complex deposition, or a combination of both (Klein-Gitelman, 2010). Various immune phenomena are associated with SLE, including altered immunologic reactions in the T- and B-lymphocyte function. There is a loss of T-lymphocyte control and hyperactivity of B lymphocytes resulting in nonspecific and specific antibody and autoantibody production. There is a strong link between a faulty immune mechanism and SLE because this disease is characterized by inflammatory damage to target organs brought on by autoantibodies attacking self-antigens. The exact etiology of SLE is unknown, but many factors including genetics, hormones, and environment are linked to the immune dysregulation that characterizes this rheumatic disease. Environmental factors that are thought to play a role in its pathogenesis are oral contraceptive use, pregnancy, microbials (viral agents mostly), temperate climates, exposure to ultraviolet light, and certain drugs (e.g., hydralazine and procainamide).
There is an association between HLA type and complement deficiency. Characteristic pathologic findings include the production of numerous autoantibodies and impairment in the normal suppression of autoreactive B-cell clones. Immune complexes are abundant, and their clearance may be impaired. In addition, fibrinoid deposits collect in blood vessel walls in many organs that result in ischemic damage (Haftel, 2011).
• History of a characteristic rash or joint involvement (arthritis), or both (common findings). May have symptoms of serositis, enthesitis, myositis, and vasculitis, which are other inflammatory markers
Various diagnostic studies or procedures can be used in the outpatient evaluation and management of children with either atopic disorders or rheumatic diseases. Indications for specific tests are discussed under the specific atopic or rheumatic problem.
Routine chest radiographs are not indicated in most children with asthma because most often they are normal or only show hyperinflation. However, chest radiographs can be useful in selected cases of asthma or suspected asthma. These should be performed with the first episode of asthma or with recurrent attacks; in a child with atypical signs or symptoms; if a secondary infection does not clear with standard therapy; or if there are signs and symptoms of significant pulmonary involvement (Lasley and Hetherington, 2011).
Pulmonary function tests, such as forced vital capacity, forced expiratory volume in 1 second, and forced expiratory flow, are important diagnostic tests to establish the diagnosis of asthma, especially in young children. Children older than 5 years can typically perform spirometry testing. Peak expiratory flow (PEF) rate and pulse oximetry measurements can be easily and quickly done in most pediatric settings and provide additional information useful to monitor and manage asthma.
Eosinophil count, determination of serum IgE concentration, in vitro serum testing (fluorescent enzyme immunoassay) (CAP-RAST, ImmunoCAP or CAP-FEIA), and in vivo skin testing (prick test) are not needed to confirm the diagnosis or to monitor treatment of the majority of children with an atopic disorder. Children with significant dermatitis or who are highly allergic may need additional or extensive diagnostic testing.
Laboratory blood studies, including antinuclear antibodies (ANAs), anti–double-stranded DNA, anti-Smith (Sm) antibody, and determination of serum complement levels, are common tests ordered in children with SLE. Other related blood, serologic, and urine laboratory studies are indicated depending on organ involvement (e.g., renal involvement is a frequent complication). While there is no laboratory test that has 100% sensitivity and specificity, doing an ANA, rheumatoid factor (RF), and an anti-cyclic citrullinated peptide (anti-ccp) is recommended (Stanley and Ward-Smith, 2011). The anti-ccp is helpful for diagnosing JIA in the early stages of disease (Waits, 2010), Guidelines for the laboratory workup of SLE and JIA are discussed later in this chapter.
The atopic and rheumatoid disorders tend to be chronic conditions with exacerbation and remission of symptoms. Individual management strategies are based on the specific disease process and are discussed in each of their respective sections. However, certain key concepts apply to these conditions.
The control of inflammation associated with atopic disorders and rheumatoid diseases is a key principle in the management of these illnesses. Corticosteroids, whether used topically on the skin, inhaled via the nostrils or throat, taken orally for systemic effect, or taken intramuscularly or intravenously for rapid systemic absorption are a mainstay of treatment. Other pharmacologic agents commonly used are as follows:
• Omalizumab is a recombinant DNA-derived, humanized IgG monoclonal antibody that binds to human IgE on the surface of mast cells and basophils. This anti-IgE monoclonal antibody is used as a second-line treatment for children older than 12 years who have moderate to severe allergy-related asthma and react to perennial allergens. It is used when symptoms are not controlled by inhaled corticosteroids (ICSs).
• Medications—clear instructions are needed on how to administer, how much and when to give, monitoring side effects, and how long medication should be taken. A written plan is highly recommended based on either symptoms or, in the example of asthma, peak expiratory flow rate (PEFR).
• Correct administration of inhaled medications—for example, when two puffs or sprays are ordered, the child should activate one puff or spray and then inhale, followed in 1 to 2 minutes by a second puff or spray and second inhalation. A parent or child may think incorrectly that being told to take two puffs or two sprays means to activate two puffs or sprays and then inhale.
• Airway inflammation also triggers hyperresponsiveness (to any of a variety of stimuli, such as physical, chemical, or pharmacologic agents; allergens; exercise; and cold air) and is a factor in disease chronicity. Inflammation causes bronchospasms with resultant characteristic symptomatology of wheezing, breathlessness, chest tightness, or cough typically worse at night or after exercise (Sharma and Gupta, 2010).
Asthma in children is classified as intermittent, mild persistent, moderate persistent, or severe persistent depending on symptoms, recurrences, need for specific medications, and pulmonary function measurements (Table 24-1). Children classified at any level of asthma can have episodes involving mild, moderate, or severe exacerbations. Exacerbations involve progressive worsening of shortness of breath, cough, wheezing, chest tightness, or any combination of these symptoms. The degree of airway hyperresponsiveness is usually related to the severity of asthma. Children younger than 5 years of age experience greater airway hyperresponsiveness than older children. Airway remodeling can result from chronic inflammation caused by asthma. Irreversible structural changes take place and result in decreased pulmonary function (Lasley, 2006). A child’s classification can change over time.
Many children experience early- and late-phase responses to their asthma episode. The early asthmatic response (EAR) phase is characterized by activation of mast cells and their mediators, with bronchoconstriction being the key feature. EAR starts within 15 to 30 minutes of mast cell activation and resolves within approximately 1 hour if the individual is removed from the offending allergen. The late-phase asthmatic response is a prolonged inflammatory state that usually follows the EAR within 4 to 12 hours after exposure to the allergen, is often associated with airway hyperresponsiveness more severe than the EAR presentation, and can last from hours to several weeks (Liu et al, 2004).
Exercise-induced bronchospasm describes the phenomenon of airway narrowing during or minutes after the onset of vigorous activity. Most asthmatics exhibit airway hyperirritability after rigorous activity and display exercise-induced bronchospasm. However, for some children, exercise is the only stimulus that triggers their asthma. Although asthma is not always associated with an allergic disorder in children, many pediatric patients with chronic asthma have an allergic component.
It is not known for certain whether hyperresponsiveness of the airways is present at birth in genetically predisposed children or acquired. However, the genetic predisposition for the development of an IgE-mediated response to common aeroallergens, known as atopy, remains the strongest identifiable predisposing risk factor for asthma. A combination of genetic predisposition and exposure to certain environmental factors are the necessary components responsible for the pathophysiologic response associated with asthma.
The morbidity and mortality statistics of asthma in childhood demonstrate an alarming increase in the prevalence of asthma and its complications. In 2008, 8.7 million 5- to 17-year-olds had been diagnosed with asthma (American Lung Association [ALA], 2010). The prevalence rate for asthma is highest among children 5 to 17 years with the highest rate among African-American children (ALA, 2010). Occupational or environmental exposure can cause airway inflammation associated with asthma. Factors known to precipitate or aggravate asthma in children include the following:
In order to assess the degree of asthma severity and impairment of function, a standardized instrument can be used. Tests for this purpose are available in the guidelines summary (NHLBI, 2007, p 17). Other instruments such as the Asthma Control Questionnaire, Asthma Therapy Assessment Questionnaire, Asthma Control Test, and the Asthma Control Score are available via the Internet. The advantages of a standardized questionnaire are that it allows the health care provider to assess changes in the patient’s asthma, then alter the management plan as needed. The history of a patient being seen for asthma can include the following:
Laboratory and radiographic tests should be individualized to the child and based on symptoms, severity or chronology of the disease, response to therapy, and age. Tests to consider include the following:
• Oxygen saturation by pulse oximetry to assess severity of acute exacerbation. This should be a routine part of every assessment on a patient with asthma. Pulse oximetry measures the oxygen saturation (Sao2) of hemoglobin—the percent of total hemoglobin that is oxygenated—as follows:
• Sinusitis should be considered as a cause of an asthma exacerbation. However, imaging of the sinus is not routinely needed to make the diagnosis of sinusitis. (See Chapter 31 for a discussion on sinusitis and the criteria needed for ordering computed tomography [CT] scans, which are more sensitive and specific than sinus radiographs.)
• PEF can be used in some children as young as 4 to 5 years. Noteworthy is the fact that values are instrument specific. Use child’s personal best value as a guideline to help detect possible changes in airway obstruction; can use predicted range for height and age if personal best rate is not available (Table 24-2).
• Chest radiograph findings: Typically normal and may show hyperinflation of the lungs with flattening of the diaphragm and peribronchial thickening on radiograph with or without atelectasis (Liu et al, 2007)
|Height (Inches)||Males and Females (L/Minute)|
note: It is recommended that peak expiratory flow (PEF) rate objectives for therapy be based on each individual’s “personal best,” which is established after a period of PEF rate monitoring while the individual is under effective treatment.
From National Heart, Lung, and Blood Institute (NHLBI): Executive summary: guidelines for the diagnosis and management of asthma, NIH Pub No 94-3042A, National Institutes of Health, 1994, Bethesda, Md; adapted from Polger G, Promedhar V: Pulmonary function testing in children: techniques and standards, Philadelphia, 1971, Saunders.
The highest value that an individual achieves in measuring PEF rate over a 2-week period when his or her asthma is under good control is known as one’s “personal best” value or rate. Good control is defined as when one feels well without asthma symptoms. To determine personal best, take readings twice daily, in the morning and late afternoon or evening, and 15 to 20 minutes after taking an inhaled short-acting β2-agonist. Using the personal best value is the most accurate gauge to use to interpret changes in peak flow measurements because the child’s own scores are used as the standard for comparison.
The Full Report of the Expert Panel: Guidelines for the Diagnosis and Management of Asthma (ERP-3) (NHLBI, 2007) provides the most recent standards for the treatment of asthma in children. Management strategies are based on whether the child has intermittent, mild persistent, moderate persistent, or severe persistent asthma (see Table 24-1). A stepwise approach is recommended. If control of symptoms is not maintained at a particular step of classification and management, the health care provider first should reevaluate for compliance and administration factors. If these factors do not appear to be responsible for the lack of symptom control, the health care provider should go to the next step. Likewise, gradual step-downs in pharmacologic therapy may be considered when the child is well controlled for 3 months. ICS may be reduced about 25% to 50% every 3 months to the lowest possible dose needed to control the child’s asthma (NHLBI, 2007).
In this chapter the outpatient management of intermittent, mild persistent, moderate persistent, and severe persistent asthma is discussed, as is the outpatient management of acute exacerbations. The practitioner should refer to other textbooks for management of severe asthma requiring hospitalization.
The pharmacologic management of asthma in children is based on the severity of asthma and the child’s age. The stepwise approach to treatment (Figs. 24-1 and 24-2) is based on severity of symptoms and the use of pharmacotherapy to control chronic symptoms, maintain normal activity, prevent recurrent exacerbations, and minimize adverse side effects, and nearly “normal” pulmonary function. Within any classification, a child may experience mild, moderate, or severe exacerbations. NHLBI guidelines for assessing asthma control and initiating and adjusting asthma therapy for the various pediatric age groups are found in Figs. 24-3 and 24-4.
(From National Heart, Lung, and Blood Institute, National Asthma and Prevention Program: Expert panel report 3: guidelines for the diagnosis and management of asthma. Summary report 2007, NIH Pub No. 08-5846, 2007, Bethesda, MD, U.S. Department of Health and Human Services, p 42, www.nhlbi.nih.gov/guidelines/asthma/asthsumm.pdf.)
(From National Heart, Lung, and Blood Institute, National Asthma and Prevention Program: Expert panel report 3: guidelines for the diagnosis and management of asthma. Summary report 2007, NIH Pub No. 08-5846, 2007, Bethesda, MD, U.S. Department of Health and Human Services, p 45, www.nhlbi.nih.gov/guidelines/asthma/asthsumm.pdf.)
FIGURE 24-3 Classifying asthma severity and initiating treatment in children 0 to 4 years of age and 5 to 11 years of age. (From National Heart, Lung, Blood Institute, National Asthma Prevention Program: Expert panel report 3: guidelines for the diagnosis and management of asthma. Summary report 2007, NIH Pub No. 08-6846, Bethesda, MD, 2007, U.S. Department of Health and Human Services, pp 40-41. www.nhlbi.nih.gov/guidelines/asthma/asthsumm.pdf.)
FIGURE 24-4 Classifying asthma severity and initiating treatment in children more than or equal to 12 years of age and adults. (From National Heart, Lung, Blood Institute, National Asthma Prevention Program: Expert panel report 3: guidelines for the diagnosis and management of asthma. Summary report 2007, NIH Pub No. 08-6846, Bethesda, Md, 2007, U.S. Department of Health and Human Services, p. 43.)
• Control of asthma should be gained as quickly as possible by starting at the classification step most appropriate to the initial severity of the child’s symptoms or at a higher level (e.g., a course of systemic corticosteroids or higher dose of inhaled corticosteroid). After control of symptoms, decrease treatment to the least amount of medication needed to maintain control.
• Children with intermittent asthma may have long periods in which they are symptom-free; they can also have life-threatening exacerbations, often provoked by respiratory infection. In these situations a short course of systemic corticosteroids should be used (NHLBI, 2007).
• The β2-agonist can be given by nebulization with a compressor. Nebulization can be a more effective route than metered-dose inhaler (MDI) therapy for young infants (2 years old or younger) or children who progress to moderate or severe airway obstruction.
• A spacer or holding chamber with an attached mask enhances the delivery of MDI medications to the lower airways of a child. Spacers eliminate the need to synchronize inhalation with activation of MDI. Older children can use the spacer without the mask.
• Dry powder inhalers (DPIs) do not need spacers or shaking before use. Instruct children to rinse their mouth with water and spit after inhalation. DPIs should not be used in children younger than 4 years old.
• Different inhaled corticosteroids are not equal in potency to each other on a per puff or microgram basis. Table 24-3 compares the daily low, medium, and high doses of the various inhaled corticosteroids used for children. Combination inhaled corticosteroid and long-acting β2-agonist can be used in children from 4 years of age (NHLBI, 2007; Taketomo et al, 2010).
The treatment of acute episodes of asthma is also based on classification of the severity of the episode. Acute episodes are classified as mild, moderate, and severe. Signs and symptoms are summarized in Table 24-6. Early recognition of warning signs and treatment should be stressed in both patient or parent education, or both.
The initial pharmacologic treatment for acute asthma exacerbations is shown in Fig. 24-5. It consists of inhaled short-acting β2-agonists, two to six puffs every 20 minutes for three treatments by way of MDI with or without a spacer, or a single nebulizer treatment (0.15 mg/kg; minimum 1.25 to 2.5 mg of 0.5% solution of albuterol in 2 to 3 mL of normal saline).
If the initial treatment results in a good response (PEF/FEV1 greater than 70% of the patient’s best), the inhaled short-acting β2-agonists can be continued every 3 to 4 hours for 24 to 48 hours. Consider a 7- to 10-day burst of oral corticosteroids.
An incomplete response (PEF or FEV1 between 40% and 69% of personal best or symptoms recur within 4 hours of therapy) is treated by continuing β2-agonists and adding an oral corticosteroid. The β2-agonist can be given by nebulizer. Parents should contact their child’s health care provider for additional instructions. If there is marked distress (severe acute symptoms) or a poor response (PEF or FEV1 <40%) to treatment, the child should have the β2-agonist repeated immediately and should be taken to the emergency department. Emergency medical rescue (911) transportation should be used if the distress is severe and nonresponsive.
Complications from asthma can range from mild secondary respiratory infections to respiratory arrest. Unresponsiveness to pharmacologic agents can lead to status asthmaticus and ultimately to death. Chronic high-dose steroid use leads to growth retardation and other related side effects.
The practitioner needs to remember that day-to-day management of asthma is the responsibility of the child or parent. Education should be tailored to meet the patient’s individual and family needs. Therefore the primary care provider should provide instruction on the following:
• What to do if symptoms worsen (what medications to add or increase; how frequently to use inhaled medication; specific indications about when to seek additional medical treatment for worsening of symptoms); development of a written action/treatment plan with the child or parent to cover these issues (Fig. 24-6 shows a sample home treatment plan)
BOX 24-2 How to Use a Metered-Dose Inhaler
Adapted from National Asthma Education and Prevention Program: Facts about controlling asthma, NIH Pub No 97-2339. National Heart, Lung, and Blood Institute (NHLBI). Bethesda, Md. A reproducible handout.