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MD Consult: Books: Goldman: Cecil Medicine: Section XXI – Diseases of Allergy and Clinical Immunology

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Section XXI – Diseases of Allergy and Clinical Immunology

Chapter 270 – APPROACH TO THE PATIENT WITH ALLERGIC OR IMMUNOLOGIC DISEASE

Stephen I. Wasserman

Allergic diseases and disorders of the immune system affect multiple organ systems and may arise in a variety of manners. The reader is directed to Chapters 42 to 47 for detailed discussion of the immune system and for specific autoimmune and acquired immune disorders. This chapter addresses allergic disorders, the most common manifestation of immune system dysfunction, and primary immune deficiencies, which are uncommon manifestations of immune dysfunction. For clarity, these two issues are treated separately.

   ALLERGIC DISEASE

Definition

Allergic disorders are common, and their prevalence is increasing, particularly in urbanized, Western societies. It is said that allergic diseases are the most common disorders seen by a primary care physician. Moreover, even in nonallergic patients, consideration of allergy frequently enters the differential diagnosis of a problem under consideration. Therefore, an appreciation of how to approach the diagnosis and treatment of allergic patients is of major importance to the practice of internal medicine. Allergic disorders are those caused by the interaction of a sensitized host (one who has made immunoglobulin E [IgE] antibody recognizing a specific antigen) with a specific allergen. Not all patients possessing specific IgE antibody react adversely on interaction with the allergen, and such individuals are termed sensitized but not allergic. The primary allergic conditions are seasonal allergic rhinoconjunctivitis (hay fever), perennial allergic rhinitis or sinusitis, asthma, anaphylaxis (especially secondary to foods, medications, and hymenopteran stings), urticaria or angioedema, atopic dermatitis (eczema), and food allergy.

Epidemiology

It is currently estimated that more than 50% of the population is atopic (i.e., able to mount an IgE immune response and to exhibit a positive prick puncture immediate hypersensitivity response to common aeroallergens). Clinically, 10 to 20% of the general population will develop allergic rhinoconjunctivitis, 5 to 7% will have active asthma, and 20% will experience urticaria at some time.

The increase in allergic diseases noted in the past 2 decades is thought to result from advancing hygienic conditions, decreases in infant and childhood infections, and an increasingly sedentary and indoor lifestyle. These changes appear to be associated with a less effective activation of the innate immune system, thereby altering the protective maturation of the acquired immune system. The immune bias in utero and in infancy is toward a type 2 helper T-lymphocyte (TH2)-directed immune response, which is the immune pathway required for the expression of allergic disease. Ineffective generation of regulatory T lymphocytes underlies the genesis and persistence of allergy. It is therefore postulated that without sufficient early childhood infection to induce a switch to an effective and protective TH1 immune response, allergic disease is more likely to emerge during childhood. Substantial epidemiologic evidence has been gathered to support this concept, now termed the hygiene hypothesis. Thus, allergy is more prevalent in individuals of higher socioeconomic status, in those living in urban areas, in less polluted communities (e.g., Western Germany), in first-born children compared with later siblings, in those multiply immunized, and in those free of mycobacterial disease. Conversely, children living on farms, in rural communities, and in more highly polluted areas (e.g., Eastern Germany), as well as those children with mycobacterial infection and those who have experienced multiple early childhood infections, are less likely to develop allergic disorders. A concentration-effect relationship appears to exist between exposure to endotoxin (as a marker for hygiene) and the incidence of allergic sensitization. Low and very high levels of exposure to endotoxin are associated with abnormal immune maturation and allergic expression, whereas moderate levels of exposure predispose to a nonallergic phenotype.

Pathobiology

The persistence or aberrant activation of TH2 lymphocytes leads to the generation of cytokines (e.g., interleukins-4, 5, 13) that stimulate B-lymphocyte synthesis of IgE antibody and the production of eosinophilic polymorphonuclear leukocytes. The expression of allergic disorders results from the interaction of specific allergen with allergen-reactive IgE bound to high-affinity receptors on mast cells and basophils. This interaction leads to activation of these target cells and to their release of preformed, granule-associated mediators (exemplified by histamine), synthesis of lipid mediators from membrane lipids (sulfidopeptide leukotrienes), and the transcription and secretion of cytokines including tumor necrosis factor-α and interleukins-4, 5, and 13. These mediators directly induce smooth muscle contraction, vascular dilation, and endothelial leakage; they also cause vascular adhesion molecule expression, and they attract and activate inflammatory leukocytes, particularly CD4+ T lymphocytes, basophils, and eosinophils. These and other IgE-dependent mediators are thought to be responsible for stimulating smooth muscle proliferation and tissue remodeling.

Diagnosis

Allergy is a systemic immune disorder, and thus its expression can be multifocal. It is essential to remember this fact during the approach to the patient with suspected allergic problems because a focus only on the major presenting symptom may be insufficient to identify all the pertinent medical issues present in a given patient.

History

Allergic disease has a high degree of heritability, with a great degree of concordance in identical twins. The risk of expressing allergic disease is highest if both parents are atopic. The inheritance of specific manifestations of allergy and of the specific allergen to which a patient is sensitized is less simple. Quite often, the diagnosis of allergic disorders is straightforward and may be made by asking about the nature of the patient’s complaints, when and where reactions occur, and what exposures the patient believes are relevant to symptom induction or exacerbation ( Table 270-1 ).


TABLE 270-1   — 
SYMPTOMS, SIGNS, AND TREATMENT OF ALLERGIC DISEASE

Symptoms Approach to Treatment
Cutaneous: itch, rash H1-antihistaminic agent
Ocular: gritty sensation, itch Topical H1-antihistaminic or mast cell stabilizing agent
Upper respiratory: palatal pruritus, clear rhinorrhea, sneeze, nasal obstruction Topical corticosteroid, oral H1-antihistaminic agent, leukotriene receptor antagonist, topical nasal H1-antihistaminic agent
Lower respiratory: wheeze, cough, dyspnea B2-agonist, inhaled corticosteroid, inhaled B2-agonist, leukotriene receptor antagonist, oral methylxanthine, parenteral corticosteroid, parenteral anti–immunoglobulin E
Gastrointestinal: nausea, vomiting, cramping pain Epinephrine (if caused by anaphylaxis), oral corticosteroid, oral cromolyn
SIGNS
Cutaneous: flushing, urticaria, angioedema, eczema  
Ocular: conjunctival erythema, chemosis  
Upper respiratory: pallor, edema, clear rhinorrhea, polyps  
Lower respiratory: wheeze  
Seasonal and Perennial Rhinitis

Patients with seasonal and perennial rhinitis commonly present with complaints of itchy nose and palate, sneezing, watery rhinorrhea, itching, watery and burning eyes, and nasal obstruction, which, when severe, may cause anosmia. In the evaluation of possible causes of seasonal rhinoconjunctivitis or sinusitis, the time of the year when symptoms occur is pertinent to the association of symptoms with pollination of trees (early spring), grasses (late spring and summer), and weeds (fall). In some patients with perennial symptoms, the multiple overlapping pollen seasons are responsible for their symptoms. Indoor exposures at home, school, workplace, or recreational site to furred animals, house dust mites or insects, and mold should be addressed in the search for additional causes of perennial symptoms. Molds and mites are to be expected in humid environments, and mites are nearly ubiquitous in bedding and in homes with pets, carpeting, and overstuffed furnishings. Additional occupational or recreational exposures may be pertinent in selected situations (i.e., bakers, health care workers, food handlers, horse fanciers, laboratory animal handlers, and others) in which specific, inciting allergens may be identified. Because many patients with rhinitis have concomitant asthma, it is important to obtain historical information regarding the presence of this disease in patients with rhinitis.

Asthma

Patients with asthma ( Chapter 87 ) may present with cough or wheeze with dyspnea, which is reversible spontaneously or with treatment. In addition to the historical associations noted for rhinitis, the influence of exercise, exposure to tobacco smoke, the effect of respiratory infection (particularly viral), occupational exposures (e.g., ≤30% of atopic animal handlers develop asthma), and medication use (e.g., β-adrenergic blocking drugs) are of particular pertinence. Because most patients with asthma have concurrent rhinitis, it is essential that the physician evaluate this issue in all asthmatic patients. Wheezing may accompany other disorders besides asthma, including pulmonary edema in congestive heart failure.

Urticaria and Angioedema

Patients with urticaria ( Chapter 273 ) describe pruritic, erythematous cutaneous lesions with regular or irregular borders occurring anywhere on the body that may vary in size from small (1 × 1 mm) to extremely large. Skin lesions are often preceded by intense intertriginous pruritus. Individual urticarial lesions generally persist for a few hours and rarely last for more than 24 hours. However, many disorders can cause a sensation of itching; skin and systemic diseases associated with pruritus are listed in Table 461-3 . Angioedema ( Chapter 273 ) is most frequently appreciated in the face, hands, and other soft tissues and is generally accompanied by symptoms of stretching, tingling, and tightness of the skin rather than pruritus. Lesions, especially in the face, typically last 24 to 36 hours. Although most cases of urticaria or angioedema are not IgE mediated, it is nonetheless important to identify foods and medications used by patients with acute urticaria or angioedema, particularly those substances ingested within 2 to 4 hours of the development of lesions, and to inquire about insect stings. Chronic urticaria is less often IgE mediated; questions about medications, especially nonsteroidal anti-inflammatory drugs, recent infection (especially with Epstein-Barr virus), and the presence of autoantibodies to the IgE receptor must be addressed. Approximately one half to two thirds of patients with such autoantibodies also have antibodies to thyroid antigens. In angioedema, the use of angiotensin-converting enzyme inhibitors must be sought. Atopic dermatitis is another allergic cutaneous disorder in which patients complain of intense pruritus, especially in flexural surfaces. In adults, foods (IgE mediated) and cutaneous infection with Staphylococcus aureus (superantigen mediated) are the most commonly identified precipitating events for atopic dermatitis.

Anaphylaxis

Anaphylaxis ( Chapter 274 ) is the most important allergic emergency and is potentially fatal. It is an acute allergic response associated with cutaneous (urticaria, angioedema, flushing), respiratory (laryngeal edema, asthma), cardiovascular (arrhythmia, hypotension, extravascular fluid loss), gastrointestinal (nausea, vomiting, abdominal pain, diarrhea), and nonspecific symptoms (metallic taste, sense of impending doom) that may occur singly or together. Historical information of note includes all medications, foods, and other encounters occurring within 2 hours of the reaction. Epidemiologic data suggest that foods (especially peanuts, tree nuts, shellfish, milk, and egg), hymenoptera stings, and medications (antibiotics, muscle relaxants, radiocontrast media) are the most frequently identified causes of this important problem.

Food Allergy

Patients presenting with food allergy often complain of oral pruritus and the specific gastrointestinal manifestations of nausea, vomiting, diarrhea, and abdominal pain. Eczema, urticaria, and anaphylaxis, as noted previously, may also be consequences of food allergy. In general, allergic symptoms consequent to foods occur within minutes to 2 hours of ingestion of the causative food; delayed symptoms are unlikely to be mediated by IgE-allergen interaction. Other symptoms attributable to foods are less easily explained by allergic mechanisms and are termed food intolerance.

Physical Examination

The physical examination of the patient with suspected allergic disease should emphasize the organ systems pertinent to the complaints of the patient. The skin should be examined for the presence of urticarial or angioedematous lesions and for signs of atopic dermatitis including flexural papules, excoriations, and lichenification. Keratosis pilaris, particularly on the outer aspect of the upper arm, commonly accompanies atopic dermatitis. Urticaria typically consists of small, pink, irregular lesions that blanch on pressure and clear, leaving normal skin. In a patient with urticaria, a simple test for dermatographism should be undertaken. Angioedematous lesions are larger, more diffuse, and pale, and they are most often found affecting the face and acral areas.

The eyes, ears, nose, and throat should be examined in all patients suspected of having allergic disease, particularly in those whose symptoms suggest seasonal or perennial allergic rhinoconjunctivitis-sinusitis or asthma. In allergic disease, the conjunctivae are often injected and may be edematous. “Cobblestoning” of the epithelium may be present. The periorbital tissues may be swollen and darkened. Examination of the nares may show pale and edematous nasal mucous membranes and swollen turbinates, and polyps may be seen. Secretions, generally clear, may be seen in the nasal passages or in the posterior pharynx. Such secretions generally contain copious numbers of eosinophils (see later), and their absence is a point against allergic causation. Fever and discolored secretions, particularly thick and yellow or green, in the presence of neutrophilic polymorphonuclear leukocytes suggest infection. Percussion over the maxillary or frontal sinuses may elicit tenderness in acute sinusitis, and in such a case transillumination of the sinus, albeit a test of low sensitivity, may be impaired. In chronic sinusitis, the physical examination may be unrevealing. In acute otitis media, patients may have erythema and bulging or perforation of the tympanic membrane with fluid in the canal, and in chronic cases the drum may be scarred and retracted. Alteration in air-bone conduction may be noted as well.

Patients with acute asthma may display tachypnea and auditory wheezes, and they may be unable to speak in full sentences because of shortness of breath. Use of accessory muscles of respiration and evidence of cyanosis should be sought. Examination of the chest includes inspection for evidence of chronic hyperinflation and auscultation for wheezing (which, if unilateral, may suggest a foreign body or tumor). In mild asthma, the examination may be normal, or the only physical finding may be wheezing on forced expiration and a slight prolongation of the expiratory phase.

Patients experiencing acute anaphylaxis usually demonstrate flushing, and concomitant urticaria and angioedema are often present. Assessment of vital signs may disclose hypotension and tachycardia. In some situations, hoarseness or stridor related to laryngeal edema or wheezing secondary to asthma can be identified. Hyperactive bowel sounds may be noted. Progressive hypoxia and cyanosis may ensue. In severe anaphylaxis, cardiovascular collapse secondary to hypoxia and hypotension may result in death.

Laboratory Evaluation

In the evaluation of patients with allergic disorders, the laboratory may be of assistance in both the identification and the quantification of the degree of specific organ dysfunction, as well as in the assessment of the presence and specificity of IgE antibody.

Assessment of Total and Allergen-Specific Immunoglobulin E

Essentially all (>95%) IgE antibody is bound to specific high-affinity receptors on tissue mast cells and circulating peripheral blood basophils. The small amount of free serum IgE antibody circulates in nanogram quantities and can be identified only with techniques of sufficient sensitivity. Generally, such tests employ a solid phase to which an antibody to human IgE is coupled. The patient’s serum is then added, the contained IgE is bound, and nonbound materials are removed by washing. The amount of IgE bound is then determined by addition of a second antibody to IgE to which a quantifying reagent, such as a radioactive isotope or an enzyme capable of creating a colorimetric end point, is bound. A large proportion of IgE in a given individual may be directed toward a single antigen, and thus total IgE levels may be normal in the presence of allergic disease. Therefore, the measurement of total serum IgE is rarely of help in diagnosis. In a few situations, such as adult atopic dermatitis or allergic bronchopulmonary aspergillosis, measurement of total serum IgE levels may give insight into disease severity or into the risk of disease exacerbation.

Of more importance is the identification of allergen-specific IgE in a patient in whom allergic disease is suspected ( Table 270-2 ). Such specific IgE may be identified in vitro or in vivo. A search for allergen-specific IgE is particularly useful in the evaluation of patients with suspected allergic rhinitis, asthma, eczema, food reactions, and anaphylaxis. In vitro assessment is performed much as for the quantification of total IgE, except the initial capture reagent bound to a solid phase is a specific pollen, mold, insect, venom, food, or other allergen. Development of the assay is identical to that used to quantify total IgE, and results are generally reported in a semiquantitative manner. The magnitude of the reaction is weakly correlated with the degree of sensitization and expression of allergy, although for certain foods more precise correlative data exist on the risk of allergy and the amount of the allergen-specific IgE detected. The in vivo assessment of allergen-specific IgE is undertaken by introducing into the skin a minute quantity of the allergen in question by a prick puncture technique and assessing the cutaneous response 15 to 30 minutes thereafter. A positive response is one in which a wheal and flare at least 2 mm larger than those caused by a saline control occur at the injection site. In vivo tests are rapid and inexpensive; they require the absence of dermatographism, that patients not be using antihistaminic medications, and that patients display a positive response to a control employing histamine. In some situations (e.g., penicillin or hymenopteran sting), a more diluted allergen is directly injected intradermally, and wheal-and-flare responses are assessed similarly. The presence of allergen-specific IgE antibody and a clear temporal correlation of exposure to allergen and genesis of symptoms are required to conclude that a patient is allergic to a specific allergen. In the absence of symptoms, the patient with allergen-specific IgE is termed sensitized but not allergic.


TABLE 270-2   — 
ADVANTAGES AND DISADVANTAGES OF DIFFERENT ALLERGY TESTING METHODS

Method Patient Selection Clinical Advantages Clinical Disadvantages
Skin testing Clinical indication suggesting allergic disease

   Rapid (15–30 min) turnaround
   Sensitive and specific; prick puncture for aeroallergens, prick puncture followed by intradermal testing for drugs, sera, and venoms

   Patient must not be taking H1-antihistaminic agents for 5–7 days
   Not interpretable in the presence of dermatographism
   Requires sufficient normal skin to enable testing
In vitro testing Clinical indication suggesting allergic disease

   Antihistaminic therapy not contraindicated
   Dermatographism not a problem
   Sensitive and specific; equal to prick puncture skin testing

   Requires blood drawn
   Slow turnaround (7–14 days)

Specific in vivo challenge tests may also be used to identify allergen responsiveness. Such tests in the presence of specific IgE antibody may be useful in research settings, or they may be used clinically to clarify the exact relationship between exposure and symptoms. Such tests may be dangerous because they introduce the allergen to which the patient is presumed allergic. In food allergy, such challenges, best done in a double-blind and placebo-controlled manner, may be useful in separating allergy from sensitization or in eliminating a suspect food from consideration. However, food challenge tests are unnecessary in the situation of anaphylaxis and a positive test for IgE antibody to the putative allergen. Because many patients falsely believe that foods are responsible for their symptoms, such double-blind challenges may be useful in directing patients’ concerns to more productive areas. Inhalation tests employing specific allergens or chemicals have been helpful in elucidation of some cases of occupational allergy or asthma.

Other Laboratory Aids in Allergic Disease

In a patient with acute asthma, chest radiographs generally demonstrate hyperinflation. In some instances, evidence of bronchiectasis may be present, a finding that raises the specter of allergic bronchopulmonary aspergillosis. The presence of a tumor or radiopaque foreign body may be noted on a chest radiograph and should be sought in a patient with unilateral localized wheezing. In the examination of the patient with asthma, assessment of both airflow and volumes can provide a clear picture of the severity of asthma and its response to treatment. Flow-volume loops can also identify the presence of vocal cord dysfunction. When patients with airway obstruction are evaluated, their response to inhaled β2-adrenergic agonist medication can be helpful in elucidating the reversible nature of their disorder. Essentially all asthmatic patients exhibiting bronchoconstriction display a bronchodilatory response to inhalation of such agents. In suspected cases of asthma, when pulmonary function is normal, challenge with histamine or methacholine can be performed. These agents take advantage of the nonspecific bronchial hyperresponsiveness characteristic of patients with asthma. Failure of a patient to develop bronchoconstriction on inhalation of either of these agents strongly argues against the diagnosis of this disorder.

Other laboratory tools may be of benefit to the clinician in the identification and classification of allergic disorders. Audiometry may clarify the degree of hearing loss caused by otitis media in a patient with allergic rhinitis. When sinusitis is suspected, computed tomography of the sinuses gives the most complete imaging and has the highest degree of sensitivity for the identification of mucosal thickening, opacification of air spaces, and the presence of polyps and bone erosions. Computed tomography is particularly useful in the examination of the ethmoid and sphenoid sinuses, which are often affected in chronic allergic dis-ease and are difficult to assess on physical examination or with plain radiographs.

The hematology and biochemistry laboratory may also be helpful in the evaluation of a patient with allergic disease. The quantification of blood, sputum, nasal mucus, or tissue eosinophilia and the response to corticosteroid therapy are useful correlates in the identification and management of allergic disease. The quantification of tryptase, a mast cell–specific protease with a serum half-life of 2 hours, if performed on serum or plasma obtained within hours of a systemic response with associated hypotension, can assist in the diagnosis of anaphylaxis.

   IMMUNOLOGIC DISEASE

Epidemiology

Diseases related to disordered immune function (immunodeficiency) are far less common than allergic disorders. The most frequent is IgA deficiency, which occurs in approximately 1 in 1000 individuals and is often asymptomatic. Next most frequently encountered are disorders of B and T lymphocytes such as common variable hypogammaglobulinemia, and other disorders including DiGeorge’s syndrome and severe combined immunodeficiency ( Chapter 271 ). Much less common are defects in neutrophil function or complement.

Diagnosis

In essence, the clinical expression of immune deficiency disorders is primarily infection related to impaired host defense. Thus, the evaluation of suspected immune deficiency is the evaluation of recurrent, persistent, severe, and otherwise unexplained infections. Although many immune disorders arise in early childhood, not all do so, and with improved management many patients presenting in childhood live into adulthood. It is important for the general internist and internal medicine subspecialist to be cognizant of the presentation of these disorders.

History

The most important historical information includes the following: the age of onset of the problem in question; a family history of frequent infection or death at an early age from infection; the number, sites, and type of infection; and the presence of other physical abnormalities ( Table 270-3 ). The earlier the onset of infections, the more severe the immune defect is likely to be. T-lymphocytic defects, with or without B-cell deficiencies, usually arise in the first 3 to 5 months of life, whereas B-cell function is supported by maternal antibody until after the first 6 months of life. Many of the immune disorders are X-linked, and a careful family history is critical in such situations. Death related to infection of a male sibling of the patient or of the patient’s mother should lead to the question of such an X-linked disorder.


TABLE 270-3   — 
KEY POINTS REGARDING IMMUNOLOGIC DISORDERS

ANTIBODY DEFICIENCY DISORDERS
Onset after 6 mo of age
Recurrent respiratory infection
Infection with bacteria, especially encapsulated organisms
Absence of isohemagglutinins
Evaluation of B-cell function, not numbers
CELLULAR IMMUNE DEFECTS
Onset before 6 mo of age
Recurrent viral, fungal, or parasitic (opportunistic) infection
Defective delayed hypersensitivity skin responses
Malabsorption or diarrhea
COMPLEMENT DEFICIENCIES
Recurrent bacterial infection
Recurrent neisserial infection (deficiency of late components)
Associated rheumatic disorder (especially systemic lupus erythematosus)
FACTORS SUGGESTING NEUTROPHIL DYSFUNCTION
Late separation of umbilical cord
Persistent neutrophilic leukocytosis
Recurrent or persistent gingivitis or periodontitis
Recurrent bacterial infection with granuloma formation

In a patient with a T-cell disorder, viral, fungal, mycobacterial, and other opportunistic infections (Pneumocystis jirovecii, Toxoplasma gondii) are most commonly noted, and live virus vaccination may be associated with disseminated and progressive viral disease. Persistent thrush, diarrhea, malabsorption, and failure to thrive occurring in early childhood may suggest the presence of T-cell abnormalities.

In B-cell or antibody deficiency, pyogenic bacterial infections predominate, particularly infections involving encapsulated microorganisms. Usually, such infections affect the upper and lower respiratory tract and skin and are severe and persistent. Infections with unusual organisms, with unexpected complications, or involving multiple sites (lung, sinus, joint, bone, meninges, abscess formation, or sepsis) should raise the index of suspicion. In adults, the most common disorder in this class is termed common variable immunodeficiency.

As in any patient with infection, information should be sought about exposure to ill individuals or to irritants such as tobacco smoke, the hygiene of the environment to which the patient is exposed, and the presence of an anatomic abnormality or allergy that could predispose to infection.

Physical Examination

Physical examination beyond that necessary to assess the extent and severity of a particular infection should be focused on immune organs. Assessment of tonsillar tissue and determination of the presence and size of lymph nodes, spleen, and liver is important. Patients with common variable immunodeficiency often present with hepatosplenomegaly and lymph node hyperplasia, whereas in X-linked hypogammaglobulinemia lymph tissue is absent. Telangiectasia (ataxia-telangiectasia), cardiac defects (DiGeorge’s syndrome), chronic eczema (Wiskott-Aldrich syndrome), and chronic periodontitis (neutrophil defects) all suggest immune deficiency syndromes.

Laboratory Evaluation

The proper use of the laboratory is essential in the elucidation of a suspected immune deficiency disorder. Screening tests appropriate to the generalist’s initial approach include complete blood count, total neutrophil and lymphocyte enumeration, quantitative immunoglobulin levels, and assessment of isohemagglutinins (especially when common variable immunodeficiency is suspected). In some situations, quantification of IgG subclasses may be warranted to identify specific subclass deficiency. In consideration of T-lymphocyte defects, it is important to enumerate total T cells and specific T-cell subsets. Delayed hypersensitivity skin testing to recall antigens is also helpful in assessing cellular immunity. When neutrophil defects are suspected, a nitroblue tetrazolium test or measurement of phagocytic potency can be performed. Complement defects are best addressed by obtaining a CH50 level. CH50 is the amount of patient serum required to cause lysis of 50% of test erythrocytes. It is compared with the amount of pooled normal serum required to cause the same degree of lysis. Tests for specific individual components of complement, or of complement regulatory proteins, can also be obtained under special circumstances.

Additional tests of antibody production to defined stimuli, including vaccinations, may be helpful when selective antibody deficiency is suspected or when borderline immunoglobulin levels are encountered in the presence of frequent infection. In some situations, assessment of T-cell proliferation to mitogens or antigen may be of benefit. Further testing could include assessment of natural killer cell function and the production of cytokines by activated lymphocytes. In general, such additional laboratory tests should be performed in conjunction with consultation with an expert in immune disorders.

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