Pediatric Residency Training Program

15

Allergy and Immunology

Elizabeth A. Mumper M.D.

Frank T. Saulsbury M.D.

  1. Anaphylaxis
  2. Definition

Anaphylaxis is a potentially life-threatening, acute systemic IgE-mediated reaction. Antigen binding to IgE on the surface of mast cells and basophils results in the release of potent mediators that affect vascular tone and bronchial reactivity.

  1. Etiology

Anaphylaxis is a rare reaction that occurs most commonly to drugs, insect venom, foods, latex, and biologic agents.

  1. Clinical Features
  2. Pruritus, flushing, urticaria, and angioedema
  3. Dyspnea and wheezing
  4. Nausea, vomiting, diarrhea, and crampy abdominal pain
  5. Cardiovascular symptoms, ranging from mild hypotension to shock
  6. Diagnosis

is on the basis of the presence of clinical signs and symptoms that appear within 30 minutes after exposure to the offending agent.

  1. Management
  2. Epinephrine is the principal treatmentfor acute respiratory and cardiovascular complications.
  3. Systemic antihistamines, corticosteroids, and β-adrenergic agonistsare also used to treat the signs and symptoms of anaphylaxis.
  4. Allergic Rhinitis
  5. Definition

Allergic rhinitis is an IgE-mediated inflammatory response in the nasal mucosa to inhaled antigens.

  1. Epidemiology

Allergic rhinitis affects 10–20% of children. It is one of the most common allergic conditions of childhood (Figure 15-1).

  1. Etiology

Allergic rhinitis may be seasonal or perennial.

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Figure 15-1. Allergic conditions of childhood.

  1. Seasonal rhinitisoccurs in specific seasons in response to tree, grass, or weed pollens (e.g., grass pollen in the spring, ragweed pollen in the fall).
  2. Perennial rhinitisoccurs across seasons in response to indoor allergens, most commonly dust mites and animal dander. Molds may also be allergens and are associated with high-humidity indoor environments.
  3. Pathophysiology
  4. Sensitizationto airborne allergens induces IgE formation.
  5. Allergen-specific IgEbinds to receptors on mast cells and basophils in the nasal mucosa.
  6. Subsequent exposureproduces an IgE-mediated inflammatory response, which occurs within minutes. Mast cells degranulate and release histamine, leukotrienes, kinins, and prostaglandins.
  7. Clinical Features
  8. Signs and symptomsinclude sneezing, nasal congestion, rhinorrhea, nasal itching, and pale nasal mucosa.
  9. Allergic shinersare dark circles under the eyes caused by venous congestion.
  10. Dennie's linesare creases under the eyes as a result of chronic edema.
  11. Allergic saluteoccurs when the patient uses the palm of the hand to elevate the tip of the nose to relieve itching.
  12. Allergic rhinitis is commonly associated withasthma, chronic sinusitis, otitis media with effusion, and nasal polyps.
  13. Diagnosis

The diagnosis of allergic rhinitis is on the basis of clinical signs and symptoms.

  1. Medical historymay include multiple episodes of otitis media, sinusitis, atopic dermatitis (eczema), and food or drug allergies.
  2. Laboratory evaluation
  3. Total IgE concentrationmay be elevated.
  4. Allergen skin testing (prick or intradermal testing)

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  1. Skin testsusing purified allergens are the most effective method to diagnose allergic rhinitis.
  2. To avoid false-negative results, patients must discontinue antihistamines4–7 days before skin testing.
  3. Nasal smear for cytologymay be helpful in differentiating allergic rhinitis from other disorders.
  4. More than 10% eosinophils suggests allergic rhinitis.
  5. A preponderance of polymorphic leukocytessuggests an infectious cause.
  6. Management
  7. Allergen avoidanceis the first step in the management of allergic rhinitis.
  8. Avoidance measures
  9. The child's bedroomshould be free of allergens to the extent possible.
  10. Remove petsor keep them outdoors.
  11. Dust mite control measuresinclude the use of plastic mattress covers and the removal of carpets and stuffed animals.
  12. Reduce humidity to inhibit growth of dust mites and mold.
  13. Avoid open windowsduring pollen season.
  14. IgE antibodyproduction may decrease with time in the absence of continual antigen exposure.
  15. Pharmacotherapy
  16. Intranasal steroidsare the most effective class of drugs for controlling rhinitis symptoms. Side effects include local irritation, which may be minimized by careful technique of administration. Systemic absorption is minimal. The hypothalamic-pituitary-adrenal axis is not measurably affected at recommended doses.
  17. Antihistamines
  18. First-generation antihistamines(over-the-counter products [e.g., diphenhydramine]) are often first-line therapy; however, they may cause sedation and impair academic performance.
  19. Second-generation antihistamines(e.g., cetirizine, fexofenadine, loratadine) are safer and better tolerated than first-generation agents but no more effective.
  20. Intranasal antihistaminesmay be effective.
  21. Intranasal cromolyn sodium prevents mast cell degranulationand can be helpful.
  22. Decongestants(e.g., pseudoephedrine) cause vasoconstriction and relieve nasal congestion. Because side effects include insomnia, nervousness, and rebound rhinitis, decongestants should be used judiciously and only for short periods of time.
  23. Leukotriene receptor antagonists are emerging as effective therapy.
  24. Immunotherapy is effectivefor allergic rhinitis, allergic asthma, and insect venom allergy.
  25. The principle of immunotherapy is that repeated injections of allergens with time lead to better tolerance of the allergen by the patient.

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  1. Indications
  2. Other therapy is ineffective in controlling symptoms.
  3. Environmental controls have been tried and failed, or exposure is unavoidable.
  4. Patient educationshould include written instructions to enhance compliance.

III. Atopic Dermatitis

  1. Definition

Atopic dermatitis is a chronic inflammatory dermatitis (also known as eczema) characterized by dry skin and lichenification (i.e., thickening of the skin). The skin is overly sensitive to many stimuli that produce pruritus, which leads to scratching, which causes many of the skin manifestations.

  1. Epidemiology
  2. Atopic dermatitis affects 5–8% of children.
  3. Atopic dermatitis typically begins in early infancy, and 85% of patients have signs and symptoms before 5 years of age.
  4. Atopic dermatitis is often worse in winter, or with extremes of temperature.
  5. Family historycommonly reveals family members with atopic dermatitis, asthma, or other allergic diseases.
  6. Clinical Features
  7. Pruritus is universal.
  8. Skin manifestationsmay be acute or chronic (Table 15-1).
  9. Acute changesinclude erythemaweeping and crusting, and secondary bacterial (Staphylococcus aureus) or viral (herpes simplex virus) infection.
  10. Chronic changesinclude lichenification, dry scaly skin, and pigmentary changes (most commonly, hyperpigmentation; less commonly, hypopigmentation).
  11. Clinical presentation varies with age.
  12. Infantile form. Truncal and facial areas, along with the scalp, are involved. Extensor surfacesare more involved than flexural surfaces.

Table 15-1. Acute Versus Chronic Manifestations of Atopic Dermatitis

Acute

Chronic

Erythema

Lichenification

Weeping and crusting

Dry, scaly skin

Secondary bacterial or viral infection

Pigmentary changes

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  2. Early childhood. Flexural surfacesare more severely involved, and lichenification, the hallmark of chronic itching, is seen.
  3. Late childhood.Disease may be more localized, or there may be a tendency toward remission.
  4. Diagnosis
  5. Three of four major criteriashould be present.
  6. Pruritus
  7. Personal or family history of atopy
  8. Typical morphology and distribution
  9. Relapsing or chronic dermatitis
  10. Minor criteria, such as xerosis (i.e., abnormal dryness), pruritus with sweating, wool intolerance, dermatographism (stroking of the skin with a dull instrument that produces a pale wheal with a red flare), or skin infections, are also helpful in making the diagnosis.
  11. Management
  12. Known triggers, which may include wool, foods (especially eggs, milk, and peanuts), excessive heat or cold, and harsh chemicals or soaps, should be avoided.
  13. Low- to medium-potency corticosteroidsare indicated as needed on affected areas, except on the face. Systemic corticosteroids are used in severe cases.
  14. Antihistaminesmay be used at bedtime to decrease the itch-scratch cycle.
  15. Bathsshould be in tepid water. After bathing, the patient should blot the skin dry with absorbent towels, and skin lubricants should be applied.
  16. Food Allergy
  17. Definition

Food allergy is an IgE-mediated response to food antigens.

  1. Etiology
  2. Most allergic reactionsto food (85–90%) are caused by egg, milk, peanut, soy, wheat, and fish.
  3. Exclusive breastfeedingfor 6 months may decrease food allergies (as well as atopic dermatitis) in the infant.
  4. Clinical Features
  5. Oral symptomssuch as itching and swelling of the lips, tongue, or throat
  6. Gastrointestinal symptomssuch as nausea, vomiting, diarrhea, and abdominal pain
  7. Respiratory symptomssuch as nasal congestion, rhinorrhea, sneezing, and wheezing
  8. Atopic dermatitis
  9. Acute urticariaand angioedema
  10. Anaphylaxis

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  1. Diagnosis
  2. Historyshould elicit the types of symptoms, the timing of symptoms in relation to food ingestion, and the reproducibility and severity of symptoms. Histories are often not specific, and there may be confusion between an allergic reaction and an intolerance to a food.
  3. Laboratory evaluation
  4. Skin testsmay be helpful in identifying foods responsible for IgE-mediated hypersensitivity reactions.
  5. Radioallergosorbent (RAST) testsidentify serum IgE antibodies to specific food antigens.
  6. Provocative oral food challengeis necessary to determine whether a patient has true food hypersensitivity. Double-blind placebo-controlled food challenge is the definitive test.
  7. Management
  8. Strict avoidanceof the responsible food allergen is the best therapy.
  9. Injectable epinephrineshould be carried by food-allergic patients who have a history of severe reactions to foods.
  10. Insect Venom Allergy
  11. Definition

Insect venom allergy is an IgE-mediated response to the venom of stinging or biting insects.

  1. Etiology

The venom of many insects, including yellow jackets, hornets, wasps, bees, and fire ants, may cause allergic reactions.

  1. Clinical features

range from localized erythema and swelling to urticaria or anaphylaxis.

  1. Management
  2. Local skin reactionscan be treated with cold compresses, analgesics, and antihistamines.
  3. Diffuse urticariacan be treated with antihistamines, but may require treatment with systemic steroids.
  4. Anaphylaxiscan be treated as described in section I.E.
  5. Immunotherapyis effective.
  6. Urticaria (Hives)
  7. Definition

Urticaria is circumscribed, raised, evanescent (vanishing) areas of edema that are almost always pruritic. Hives are usually symmetric and migratory.

  1. Etiology

The causes of urticaria are extensive, and some are listed in Table 15-2.

  1. Classification

There are two types of urticaria.

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Table 15-2. Causes of Urticaria

Acute

Chronic

Drugs
   Penicillin
   Aspirin
   Nonsteroidal anti-inflammatory drugs

Malignancy
Rheumatologic disease
   Systemic lupus erythematosus
   Rheumatoid arthritis

Foods and food additives
   Eggs
   Shellfish
   Milk
   Nuts

IgG antibodies to IgE receptors
Idiopathic
Thyroid disease

Contactants
   Animal dander
   Latex

 

Idiopathic

 

Infection
   Group A β-hemolytic streptococcal pharyngitis
   Infectious mononucleosis
   Mycoplasma pneumoniae
   Hepatitis
   Coxsackievirus

 

Insect venoms

 

Transfusion reaction

 

Heat and cold

 

Skin pressure

 

Exercise

 

  1. Acute urticariais often precipitated by exercise, heat, cold, pressure, occupational exposure, medications, insect bites, foods, or recent infections. Health-care workers and patients with myelomingocele (who are commonly exposed to latex because of the need for repeated urinary catheterization) are at risk for latex allergy, which can present as urticaria.
  2. Chronic urticaria(urticaria that lasts > 6 months) may be associated with underlying conditions such as malignancy and rheumatologic diseases. A substantial proportion of patients with chronic urticaria have an IgG antibody to the IgE receptor.
  3. Management

The precipitating factor should be avoided, if it can be identified.

  1. Antihistaminesare the mainstays of therapy.
  2. Further evaluationfor underlying systemic disease is indicated in patients with chronic urticaria, especially if the urticaria is associated with other symptoms such as fever, arthralgias, weight loss, or abdominal pain.

VII. Drug Allergy

  1. Definition

Reactions to drugs are mediated by IgE or by direct mast cell degranulation.

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  1. Etiology

Many pharmaceutical agents have been documented to cause allergic reactions or anaphylaxis. The most common offending agents include penicillin, sulfonamides, cephalosporins,aspirin and other nonsteroidal anti-inflammatory drugs, and narcotics.

  1. Clinical features include

urticaria, angioedema, and anaphylaxis. (Angioedema is a vascular reaction of the deep dermis or subcutaneous tissue, associated with localized edema from dilated capillaries with increased permeability and characterized by giant wheals.)

  1. Diagnosis

is made by clinical features and history of drug ingestion.

  1. Management
  2. Antihistaminesmay be effective.
  3. Anaphylaxisshould be treated as described in section I.E.
  4. Medic alert braceletsshould be worn by patients with previously identified significant drug reactions.

VIII. Asthma

Asthma (see Chapter 9, section IV.A) may have an allergic cause in some patients.

  1. Immunology Overview
  2. Main components

of the immune system. The immune system is a complex organization of cells and molecules that serves to protect the host from infection. The components of the immune system can be divided functionally into innate and adaptive components.

  1. Innate responsesare the first defense against infection. The cells and molecules of the innate system include phagocytic cells, natural killer cells, toll-like receptors, mannose-binding protein, and the alternative pathway of complement.
  2. Adaptive responsesdevelop more slowly, are highly specific, and improve with repeated exposure to an antigen. The adaptive system includes T cells, B cells, and immunoglobulin molecules.
  3. Immunodeficiency states may be primary or secondary

(Table 15-3).

C

In the evaluation of a patient with a suspected immunodeficiency, there is a variety of diagnostic tests used to identify the type of primary immunodeficiency state (Table 15-4).

Table 15-3. Categories of Immunodeficiency States

Primary

B-cell defects (disorders of humoral immunity)
T-cell defects (disorders of cell-mediated immunity)
Disorders of granulocytes
Complement deficiencies

Secondary

Acquired immunodeficiency syndrome (AIDS)
Medications (steroids, chemotherapy)
Malnutrition
Nephrotic syndrome

Table 15-4. Laboratory Evaluation of Primary Immunodeficiency States

Evaluation

Diagnostic Tests

Humoral immunity

Quantitative immunoglobulins
B-cell enumeration
Antibody titers to immunization (diphtheria, tetanus)
Isohemagglutinin titers

Cell-mediated immunity

Peripheral smear (to look for lymphopenia)
Anergy panel (delayed type hypersensitivity skin testing)
T-cell subsets (CD3, CD4, CD8)
In vitro T-cell proliferative responses to mitogens and antigens

Phagocyte function

Peripheral smear (to look for neutropenia)
Nitroblue tetrazolium test
Measurements of neutrophil chemotaxis

Complement

Total hemolytic complement (CH50)
Assays of specific components of complement

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  1. Disorders of Lymphocytes (Figure 15-2)

Abnormalities of B cells and T cells may lead to deficiencies of antibody production, T-cell function, or both. Whereas pure B-cell defects are uncommon, hypogammaglobulinemiais a feature of most disorders involving lymphocyte function. Thus, 75% of all primary immunodeficiency diseases involve abnormalities of antibody concentration or function.

  1. IgA Deficiency
  2. Definition.Selective IgA deficiency is characterized by serum IgA concentrations < 7 mg/dL but usually normal levels of other immunoglobulin isotypes. However, IgA deficiency may be associated with other defects in many patients. Fifty percent of patients with IgA deficiency have IgE deficiency and 20–30% have IgG2 and IgG4 subclass deficiencies.
 

Figure 15-2. Disorders of lymphocytes.

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  1. Epidemiology. IgA deficiency is the most common immune deficiency, with a prevalence of 1 in 500–1, 000.
  2. Etiology.A genetic basis for IgA deficiency is sometimes present, but for most patients, the precise cause usually is unclear.
  3. Clinical features
  4. Respiratory infections, such as sinusitis, pneumonia, otitis media, and bronchitis
  5. Gastrointestinal manifestations, such as chronic diarrhea and infection with Giardia lamblia
  6. Autoimmune and rheumatic diseases, such as systemic lupus erythematosus, juvenile rheumatoid arthritis, and celiac disease may be associated with IgA deficiency.
  7. Atopic diseases, such as allergic rhinitis, eczema, urticaria, and asthma, may occur in up to 50% of patients with IgA deficiency.
  8. Diagnosis. Quantitative measurement of serum immunoglobulins, which reveals the deficiency of IgA (< 7 mg/dL), is the basis of diagnosis.
  9. Management.IgA cannot be replaced, thus management of infections and other complications are the mainstays of therapy. Intravenous immunoglobulin (IVIG) is not indicated (it contains almost all IgG).
  10. Common Variable Immunodeficiency
  11. Definition.This heterogeneous group of disorders is characterized by hypogammaglobulinemia. Most patients have normal numbers of B and T cells but have variable degrees of T-cell dysfunction.
  12. Epidemiology.Most cases are sporadic, with prevalence between 1 in 10, 000 and 1 in 100, 000.
  13. Etiology.A variety of defects in B-cell function or in B cell–T cell interaction can produce the clinical picture of common variable immunodeficiency. The genetic basis of this disorder is largely unknown, but a number of genetic defects have recently been elucidated.
  14. Clinical features
  15. Respiratory infections(frequently caused by Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae) and gastrointestinal infections accompanied by chronic diarrhea (often caused by G. lamblia and Campylobacter jejuni)
  16. Autoimmune disorders, such as rheumatoid arthritis, autoimmune thyroiditis, autoimmune thrombocytopenia, and autoimmune hemolytic anemia
  17. Increased risk of malignancy
  18. Diagnosis
  19. Quantitative immunoglobulin measurementshows decreased serum immunoglobulin concentrations.
  20. Diminished antibody functionmay be assessed by measuring titers generated in response to childhood immunizations (i.e., diphtheria and tetanus).
  21. T-cell proliferation to mitogens (nonspecific stimulators of lymphocyte production) may be diminished.

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  1. Management
  2. Monthly IVIGreplacement.
  3. Aggressive management of infectionswith antibiotics.
  4. Chronic diarrhea managementincluding nutritional support.
  5. Severe Combined Immunodeficiency Disease (SCID)
  6. Definition.SCID is a group of inherited disorders characterized by profoundly defective T-cell and B-cell function.
  7. Etiology.More than 12 distinct genetic abnormalities that produce SCID have been identified.
  8. X-linked SCID, caused by deficiency of the common gamma chain of the receptor for cytokines interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15, accounts for about 50% of all cases of SCID.
  9. Autosomal recessive SCIDis caused by a variety of genetic defects involving T-cell ontogeny or function. Adenosine deaminase deficiency accounts for approximately 30% of cases of autosomal recessive SCID.
  10. Clinical features
  11. Increased susceptibility to infection within the first few months of lifewith common pathogens and with opportunistic organisms such as Candida albicans and Pneumocystis carinii
  12. Chronic diarrheaand failure to thrive are common.
  13. Diagnosis
  14. Persistent lymphopenia(< 1, 500 lymphocytes/mL) is a nearly constant feature in patients with SCID.
  15. Enumeration of lymphocyte populationsby flow cytometry shows decreased numbers of T cells.
  16. Quantitative measurement of serum immunoglobulinsshows severe hypogammaglobulinemia.
  17. T-cell responses to mitogens and antigensare severely depressed.
  18. Management
  19. Supportive carewith appropriate antibiotics, nutritional interventions, and psychosocial support is necessary.
  20. Blood products should be irradiatedto prevent graft-versus-host disease.
  21. Monthly IVIG replacementis administered to maintain a normal serum IgG level.
  22. P. cariniipneumonia (PCP) prophylaxis with trimethoprim-sulfamethoxazole is indicated.
  23. Bone marrow transplant can be curative.Complications include graft-versus-host disease, infection, and medication toxicity. Other options include cord blood stem cell or peripheral blood stem cell transplant.
  24. Gene therapyis a potential future cure.
  25. Ataxia Telangiectasia
  26. Definition.Ataxia telangiectasia is an autosomal recessive disorder characterized by combined immunodeficiency, cerebellar ataxia, oculocutaneous telangiectasias, and predisposition to malignancy.

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  1. Etiology.Ataxia telangiectasia results from a mutation of a gene on the long arm of chromosome 11. The gene product is involved in cell cycle control, DNA recombination, and cellular responses to DNA damage.
  2. Clinical features
  3. Variable immunodeficiencythat most commonly manifests as chronic sinopulmonary infections
  4. Severe progressive cerebellar ataxiathat results in a need for wheelchair assistance by early adolescence in most patients
  5. Telangiectasiasthat appear on the bulbar conjunctiva between 2 and 5 years of age, and later on exposed skin and areas of trauma
  6. High risk of malignancy, particularly lymphoma and carcinoma, owing to defects in DNA repair
  7. Other clinical featuressuch as café-au-lait spots, vitiligo, prematurely gray hair, and multiple endocrine abnormalities
  8. Diagnosis
  9. Quantitative measurement of serum immunoglobulinsreveals IgE deficiency in 85% of patients and IgA deficiency in 75% of patients.
  10. Evaluation of T-cell functionmay reveal skin test anergy and diminished T-cell proliferation to mitogens.
  11. Management
  12. Treat the neurologic complications.
  13. Aggressively treat infections.
  14. Monitor for malignancies.
  15. Avoid ionizing radiation, which exacerbates DNA breakage and repair, thus increasing the risk of malignancy.
  16. DiGeorge syndrome

is a congenital immunodeficiency syndrome characterized by cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia because of a submicroscopic deletion on chromosome arm 22q11 (mnemonic: CATCH-22). See Chapter 5, section III.A.5.

  1. Wiskott-Aldrich syndrome
  2. Definition.Wiskott-Aldrich syndrome is an X-linked disorder characterized by combined immunodeficiency, eczema, and congenital thrombocytopenia with small platelets.
  3. Etiology.Wiskott-Aldrich syndrome is caused by the mutation of a gene on the short arm of the X chromosome. The gene product is important in T-cell receptor signaling and cytoskeletal organization.
  4. Clinical features
  5. Susceptibility to infections with encapsulated organisms such asH. influenzae and S. pneumoniae, because patients do not produce antibodies to polysaccharide antigens
  6. Thrombocytopenia characterized by small defective platelets.Bleeding episodes are frequent and are associated with a risk of intracranial hemorrhage.

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  1. Eczema, which predisposes to skin infections
  2. Diagnosis
  3. Complete blood countreveals thrombocytopenia and small platelets.
  4. Decreased IgMis demonstrated by measurement of immunoglobulins.
  5. Antibody response to polysaccharide antigens(i.e., polysaccharide vaccines) is defective.
  6. Cellular immune function is defectiveand anergy is present. Patients have near-normal numbers of T cells, but they respond poorly to antigens and do not develop antigen-specific cytotoxic T cells.
  7. Management
  8. Human leukocyte antigen (HLA)–matched bone marrow transplantation is the therapy of choice.
  9. IVIGis administered for hypogammaglobulinemia.
  10. Splenectomycures the thrombocytopenia in more than 90% of patients. Quality of life is improved, and medical management is simplified. Prophylactic antibiotics or IVIG must be administered regularly after splenectomy.
  11. X-Linked (Bruton's) Agammaglobulinemia
  12. Definition.X-linked agammaglobulinemia is characterized by severe hypogammaglobulinemia and a paucity of mature B cells (< 1% B cells in peripheral blood) with normal T-cell number and function.
  13. Etiology.X-linked agammaglobulinemia is due to mutations in the Bruton's tyrosine kinase (BTK ) gene on the X chromosome. The BTK gene is critical to normal B-cell ontogeny. Mutations lead to a block in the development from pre–B cell to mature B cell.
  14. Clinical features.Increased susceptibility to infections with encapsulated bacteria (S. pneumoniaeH. influenzae), S. aureus, and chronic enteroviral infection may occur.
  15. Diagnosis
  16. Quantitative immunoglobulinmeasurement reveals profound decreases in all immunoglobulin isotypes.
  17. B cells are absentor greatly diminished.
  18. T cells are present, and cell-mediated functions are preserved.
  19. Mutations in theBTK gene are demonstrated by mutation analysis.
  20. Management.Treatment includes monthly IVIG replacement to prevent infection.
  21. Disorders of Granulocytes

(Figure 15-3)

  1. Chronic Granulomatous Disease (CGD)
  2. Definition.CGD is a group of disorders characterized by defective neutrophil oxidative metabolism as a result of defects in the multicomponent reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase system. Defective oxidative metabolism results in severely impaired intracellular killing of catalase-positive bacteria and some fungal pathogens.

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Figure 15-3. Disorders of granulocytes.

  1. Etiology. The inheritance of CGDis predominantly X-linked (70%).
  2. Clinical features
  3. Increased susceptibility to infectionsinvolving the lungs, lymph nodes, liver, spleen, bones, and skin. Abscess formation is characteristic.
  4. Major pathogensinclude S. aureus, Pseudomonas aeruginosa, Salmonella species, Klebsiella pneumoniae, Serratia marcescens, Escherichia coli, C. albicans, and Aspergillusspecies.
  5. Diagnosis.Tests demonstrate defective neutrophil oxidative burst. The nitroblue tetrazolium (NBT) test is the classic test and is still widely used. The NBT test is being replaced by the flow cytometric assay.
  6. Management
  7. Abscessesoften require surgical drainage and antibiotics.
  8. Prophylactic trimethoprim-sulfamethoxazolereduces the incidence of serious infections.
  9. Prophylactic itraconazolereduces the incidence of Aspergillus infections.
  10. Interferon-γ is given prophylactically.
  11. Bone marrow transplantationis curative.
  12. Gene therapyis a potential future cure.
  13. Disorders of adherence and motility
  14. Schwachman-Diamond syndrome.This syndrome is an autosomal recessive condition characterized by decreased neutrophil chemotaxis, cyclic neutropenia, and pancreatic exocrine insufficiency. Patients present with recurrent soft tissue infection, chronic diarrhea, and failure to thrive. (See also Chapter 13, section V.B.6.)
  15. Chédiak-Higashi syndrome.This syndrome is characterized by variable neutropenia and thrombocytopenia and giant lysosomal granules in neutrophils. Neutrophils and monocytes have functional defects, and natural killer cell function is impaired. S. aureus causes the majority of infections. Patients also have partial oculocutaneous albinism(see also Chapter 13, section V.B.5.a).

C

Neutropenia is discussed in Chapter 13, section V.

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XII. Disorders of the Complement System

The complement system is composed of plasma proteins and cellular receptors functioning in an integrated series of reactions to prevent infection.

  1. Definition

These disorders involve absence or dysfunction of individual complement components or regulatory proteins.

  1. Etiology

Complement deficiencies are genetically determined. Most are autosomal recessive.

  1. Clinical features

are variable and depend on the biologic function of the components that are deficient.

  1. Deficiencies of the early componentsof the classic pathway (C1q, C2, and C4) are associated with autoimmune diseases, such as systemic lupus erythematosus.
  2. Deficiencies of the late componentsof the classic pathway (C5, C6, and C8) are associated with increased susceptibility to disseminated meningococcal and gonococcal infections.
  3. Deficiency or dysfunction of C1 esterase inhibitor causes hereditary angioedema.Patients may experience episodic swelling of various body parts, especially the hands and feet. The bowel wall may also swell, leading to severe abdominal pain. Angioedema affecting the airway can be fatal.
  4. Diagnosis
  5. Quantitative.Specific assays measure levels of specific components.
  6. Qualitative.A normal total serum hemolytic complement (CH50) indicates that all components of the classic complement pathway are present and functional.
  7. Management
  8. Prompt diagnosis and treatmentof bacterial infections.
  9. Management of autoimmune disease.
  10. Therapy with fibrinolysis inhibitors and attenuated androgens(such as danazol) for hereditary angioedema.

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Review Text

  1. An 8-year-old boy presents to the emergency department in acute severe respiratory distress after being stung by a bee. Vital signs are notable for a respiratory rate of 60 breaths/min, heart rate of 120 beats/min, and a blood pressure of 70/50 mm Hg. Physical examination shows severe respiratory distress, wheezing, and a diffuse urticarial eruption on the trunk and extremities. Which of the following is the best initial treatment for this patient?

(A) Antihistamines

(B) Systemic corticosteroids

(C) Epinephrine

(D) β-Adrenergic agonists

(E) Inhaled corticosteroids

  1. A 10-year-old girl presents with a history of chronic rhinorrhea, nasal itchiness, and sneezing. Physical examination reveals dark circles under her eyes and pale boggy nasal mucosa. Which of the following categories of medications is the most effective for controlling this patient's signs and symptoms?

(A) First-generation antihistamines

(B) Second-generation antihistamines

(C) Intranasal steroids

(D) Intranasal cromolyn sodium

(E) Decongestants

  1. During a routine health maintenance visit, the mother of a 1-year-old girl is particularly concerned about the family's history of food allergies. Which of the following foods are the most likely to cause food allergic reactions?

(A) Soy

(B) Citrus fruits

(C) Chocolate

(D) Tomatoes

(E) Cruciferous vegetables

  1. The parents of a 5-year-old boy are concerned that their son may have food allergies. On two separate occasions, he exhibited a transient erythematous papular itchy rash and a stuffy nose within several hours after eating fish. Which of the following is the most definitive method for diagnosis of food allergy?

(A) Skin tests using extracts from the suspected offending food

(B) Radioallergosorbent testing (RAST) to identify IgE-specific food antibodies

(C) Double-blind, placebo-controlled provocative oral food challenges

(D) Total serum IgE measurements

(E) Parental reports of the suspected food allergy

  1. A 12-year-old girl presents with a 9-month history of chronic diarrhea and an increased susceptibility to infections. During this period, she has had two episodes of pneumonia and multiple prolonged episodes of diarrhea. Physical examination is normal. You suspect an immunodeficiency disorder. Laboratory evaluation reveals normal numbers of B cells and platelets, decreased serum concentrations of IgG, IgA, and IgM, low antibody titers in response to immunizations, and poor T-cell function. The total serum hemolytic complement (CH50) is normal. Which of the following is the most likely diagnosis?

(A) Severe combined immunodeficiency disease

(B) Common variable immunodeficiency disease

(C) Chronic granulomatous disease

(D) Complement deficiency

(E) Wiskott-Aldrich syndrome

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  1. A 4-year-old boy presents with a one-day history of fever to 103° F (39.4° C), a stiff neck, and altered mental status. Gram stain of the cerebrospinal fluid shows Gram-negative bacteria. His parents are concerned because he was also hospitalized with meningococcal sepsis at 2 months of age. Which of the following immunodeficiency disorders is the most likely diagnosis?

(A) Chédiak-Higashi syndrome

(B) Chronic granulomatous disease

(C) Selective IgA deficiency

(D) Ataxia telangiectasia

(E) Complement deficiency

  1. A 1-year-old boy has a history of multiple episodes of otitis media, sinusitis, and pneumonia. He has not had any fungal, protozoan, or mycobacterial infections. You suspect a disorder of humoral immunity. Which of the following is the best initial screening test?

(A) Nitroblue tetrazolium test (NBT)

(B) Quantitative serum immunoglobulins

(C) Examination of the peripheral blood smear

(D) Total hemolytic complement (CH50)

(E) Anergy panel

  1. A 10-year-old boy presents with rhinorrhea, sneezing, and an early morning cough, which is present throughout the year. He sleeps with a collection of stuffed monkeys, and his bedroom is carpeted. There are no pets in the household. Physical examination reveals Dennie's lines and an allergic salute. Nasal smear shows 90% eosinophils. Which of the following is the most likely cause of his allergies?

(A) Dust mites

(B) Tree pollens

(C) Weed pollens

(D) Molds

(E) Grasses

  1. A 1-year-old girl has erythema and dry patches on her trunk, face, scalp, and extensor surfaces. She scratches frequently and seems sensitive to wool. Her parents also note that at times her cheeks get red, cracked, and weepy. Which of the following is the most likely diagnosis?

(A) Early childhood eczema

(B) Infantile eczema

(C) Idiopathic urticaria

(D) Drug allergy

The response options for statements 10–13 are the same. You will be required to select one answer for each statement in the set.

For each patient, select the most likely diagnosis.

  1. A 1-year-old boy with a history of recurrent pneumonia, chronic diarrhea, and failure to thrive has a white blood cell count of 1, 200 cells/mm3.

(A) Ataxia telangiectasia

(B) Deficiencies of the early components of the complement cascade

(C) Deficiencies of the late components of the complement cascade

(D) Adenosine deaminase deficiency

(E) Schwachman-Diamond syndrome

(F) DiGeorge syndrome

(G) Chronic granulomatous disease

(H) Wiskott-Aldrich syndrome

  1. A 2-year-old boy with a history of recurrent cervical adenitis and pneumonia presents with a perianal abscess.

(A) Ataxia telangiectasia

(B) Deficiencies of the early components of the complement cascade

(C) Deficiencies of the late components of the complement cascade

(D) Adenosine deaminase deficiency

(E) Schwachman-Diamond syndrome

(F) DiGeorge syndrome

(G) Chronic granulomatous disease

(H) Wiskott-Aldrich syndrome

  1. An 18-month-old girl has a history of recurrent pneumococcal pneumonia, severe eczema, and a petechial rash on her trunk and face.

(A) Ataxia telangiectasia

(B) Deficiencies of the early components of the complement cascade

(C) Deficiencies of the late components of the complement cascade

(D) Adenosine deaminase deficiency

(E) Schwachman-Diamond syndrome

(F) DiGeorge syndrome

(G) Chronic granulomatous disease

(H) Wiskott-Aldrich syndrome

  1. A 3-month-old boy with a history of chronic diarrhea and failure to thrive presents with Pneumocystis cariniipneumonia.

(A) Ataxia telangiectasia

(B) Deficiencies of the early components of the complement cascade

(C) Deficiencies of the late components of the complement cascade

(D) Adenosine deaminase deficiency

(E) Schwachman-Diamond syndrome

(F) DiGeorge syndrome

(G) Chronic granulomatous disease

(H) Wiskott-Aldrich syndrome

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Answers and Explanations

  1. The answer is C[I.E]. This patient's clinical presentation is consistent with anaphylaxis, a rare life-threatening, acute IgE-mediated reaction that occurs within 30 minutes after exposure to an offending agent. The most common causative agents are drugs, insect venoms, foods, latex, and biologic agents. Immediate administration of epinephrine is the principal initial treatment indicated for the hypotension, wheezing, and respiratory distress. Antihistamines, systemic corticosteroids, and β-adrenergic agonists are additional treatments for anaphylaxis. Inhaled corticosteroids are not helpful.
  2. The answer is C[II.G.2]. The diagnosis of allergic rhinitis is made on the basis of the clinical signs and symptoms, which often include sneezing, nasal congestion, rhinorrhea, nasal itchiness, pale nasal mucosa, and allergic shiners (dark circles under the eyes caused by venous congestion). Intranasal steroids are the most effective therapy for allergic rhinitis. First-generation antihistamines (sedating) and second-generation antihistamines (nonsedating) are frequently also very effective. Intranasal cromolyn sodium is an alternative therapeutic option. Decongestants may cause insomnia, agitation, and rebound rhinitis; therefore, they should only be used for short periods.
  3. The answer is A[IV.B.1]. Egg, milk, peanut, soy, wheat, and fish cause 85–90% of food allergies in children. Although allergies to citrus fruits, chocolate, and tomatoes may occur, these foods do not commonly induce allergy. Cruciferous vegetables are unlikely to cause food allergy reactions.
  4. The answer is C[IV.D]. Provocative food challenges, which should be double-blinded and placebo-controlled, are the most definitive tests to confirm the cause of food allergy reactions. Skin tests and radioallergosorbent tests (RAST) can be helpful in evaluating food allergy but are not definitive. Total serum IgE is not specific and is therefore not helpful. Parental reports of suspected food allergy are helpful but are neither specific nor definitive. Parents may confuse food allergy with food intolerance.
  5. The answer is B[X.B.1, X.B.4, X.B.5]. This patient's clinical presentation and laboratory findings are most consistent with common variable immunodeficiency disease. Patients with common variable immunodeficiency disease have increased susceptibility to respiratory and diarrheal infections. Laboratory evaluation shows variable degrees of hypogammaglobulinemia and T-cell dysfunction. Most have normal B-cell and T-cell numbers. Patients with severe combined immunodeficiency disease tend to present early in infancy with repeated infections, chronic diarrhea, and failure to thrive. Chronic granulomatous disease is a disorder of neutrophils and involves defective oxidative metabolism. It classically presents with abscesses and multiple infections. Complement deficiency is ruled out by the normal total hemolytic complement (CH50). Wiskott-Aldrich syndrome is characterized by thrombocytopenia and is therefore ruled out by the normal platelet count.
  6. The answer is E[XII.C.2]. This patient's clinical presentation suggests complement deficiency, particularly a deficiency of one of the late components of the classic complement pathway (C5, C6, C8). Patients with deficiencies of late complement components often present with meningococcal sepsis or meningitis. Chédiak-Higashi syndrome is characterized by neutropenia, thrombocytopenia, and partial oculocutaneous albinism. The majority of infections are associated with Staphylococcus aureus. Patients with chronic granulomatous disease tend to present with infections of the skin, bone, lymph nodes, and liver as a result of S. aureusAspergillus, and Gram-negative enteric organisms. Selective IgA deficiency presents with respiratory and gastrointestinal illnesses. Patients with ataxia telangiectasia present with cerebellar ataxia, telangiectasias on the bulbar conjunctiva and later on the skin, and chronic sinopulmonary infections.
  7. The answer is B[Table 15-4, X.A.5]. Most primary immunodeficiency diseases involve abnormalities of immunoglobulin concentration or function (humoral immunity). The hallmark of immunoglobulin deficiency is increased susceptibility to sinopulmonary infections caused by encapsulated bacteria. Serum immunoglobulin concentrations should be measured in such patients. The NBT test is used to diagnose chronic granulomatous disease, a disorder of phagocyte oxidative metabolism. Examination of the peripheral smear can yield valuable information about neutropenia, lymphopenia, or thrombocytopenia. This information is useful adjunctive information, but it does not provide a definitive diagnosis. Total hemolytic complement assays are useful to exclude isolated deficiencies of complement components. Sinopulmonary infections are generally not associated with complement deficiency. Anergy panels are used to evaluate cell-mediated immune function.

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  1. The answer is A[II.C.2, II.G.1]. Allergic rhinitis symptoms that are present throughout the year (perennial rhinitis) suggest indoor allergens; the most common are dust mites and animal dander. This patient would benefit from allergy control measures in his bedroom, such as removing the stuffed animals and carpet. Tree pollen, weed pollen, and grasses are associated with seasonal allergies. Molds are associated with high-humidity indoor environments.
  2. The answer is B[III.C.3]. Involvement of extensor surfaces and cheeks is characteristic of the infantile presentation of eczema. Common triggers include wool, foods, harsh chemicals, and extremes of temperature. Early childhood eczema typically involves the flexural surfaces, especially the elbows and knees. Urticaria is well-circumscribed, raised transient itchy areas of edema. Drug allergy is usually related to pharmaceutical agents such as penicillins and nonsteroidal anti-inflammatory drugs. Urticaria, angioedema, and anaphylaxis are the major clinical manifestations.

10–13. The answers are E, G, H, and D, respectively [XI.B.1, XI.A, X.F, X.C.2.b]. Schwachman-Diamond syndrome is an autosomal recessive condition characterized by decreased neutrophil activity and by cyclic neutropenia. Patients with Schwachman-Diamond syndrome have recurrent soft tissue infections as a result of the neutropenia, and also have pancreatic exocrine insufficiency with failure to thrive. Chronic granulomatous disease (CGD) refers to a group of disorders characterized by defective neutrophil oxidative metabolism resulting in severely impaired intracellular killing of catalase-positive bacteria and some fungal pathogens. CGD is predominantly X-linked. Patients with CGD have an increased susceptibility to infections of the lungs, liver, skin, lymph nodes, and skin, characteristically with abscess formation. Wiskott-Aldrich syndrome is an X-linked disorder characterized by combined immunodeficiency, eczema, and congenital thrombocytopenia (with small platelets). Patients typically present with recurrent infections with encapsulated organisms, thrombocytopenia, and eczema. Adenosine deaminase deficiency is a subtype of severe combined immunodeficiency disease (SCID) that is inherited in an autosomal recessive manner. SCID refers to a group of inherited disorders characterized by profoundly defective B-cell and T-cell function. Patients with adenosine deaminase deficiency usually present within the first few months of life with persistent lymphopenia, chronic diarrhea, failure to thrive, and infections with both common pathogens and opportunistic organisms (e.g., Candida albicansPneumocystis carinii).