eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Delayed-type Hypersensitivity

Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School

Updated: Jun 2, 2009

Introduction

Background

Cell-mediated immunity (CMI) is a T-cell–mediated defense mechanism against microbes that survive within phagocytes or infect nonphagocytic cells. CMI functions to enhance antimicrobial actions of phagocytes to eliminate microbes. This T-cell–mediated activation of phagocytes depends on interferon gamma (IFN-γ), a major cytokine produced by CD4⁺ helper T cells, subtype 1 (Th1). However, anti-IFN-g neutralizing antibodies (Abs) do not completely abrogate delayed-type hypersensitivity responses. IFN-γ or IFN-γR knock out (KO) mice do reveal attenuated delayed-type hypersensitivity responses. These results indicate that delayed-type hypersensitivity action cannot be solely attributed to IFN-γ.

The identification of Th17 cells shed a light on the previously observed delayed-type hypersensitivity responses in the absence of IFN-γ actions. Interleukin (IL)-17 KO mice did display attenuated delayed-type hypersensitivity against bovine serum albumin and bacille Calmette-Guérin (BCG).¹ The role of Th17 and Th1 cells in delayed-type hypersensitivity may vary depending on stimulants.²

Phagocytic cell activation and inflammation induced by CMI can cause tissue injury called delayed-type hypersensitivity (DTH). In experimental animal models, delayed-type hypersensitivity reactions are characterized by a granulomatous response consisting of macrophages, monocytes, and T lymphocytes.

Delayed-type hypersensitivity reactions in the skin have been used to assess CMI in vivo. An antigen is introduced intradermally (ID), and induration and erythema at 48-72 hours postinjection indicate a positive reaction. Positive responses require the subject's exposure to the antigen 4-6 weeks prior to skin testing. The lack of a delayed-type hypersensitivity response to a recall antigen is termed anergy. In the absence of underlying disease, anergy may indicate a possible T-cell immunodeficiency. The prototype recall antigen is Mycobacterium tuberculosis; other commonly used antigens in humans include tetanus, Candida and Trichophyton species, and mumps. Delayed-type hypersensitivity antigens for several fungi and streptococci are no longer available or recommended for clinical use.

Delayed-type hypersensitivity reaction in the skin can also occur in contact hypersensitivity (CH) to certain chemicals, including nickel, dinitrochlorobenzene (DNCB), and picryl chloride. Delayed-type hypersensitivity reaction can also occur with various medications, including sulfonamides, phenytoin, and carbamazepine. These small chemicals are believed to act as haptens.

Originally, CH was thought to be skin delayed-type hypersensitivity reaction. However, recent studies indicate that CH may be caused by different immune mechanisms. That is, in delayed-type hypersensitivity, CD4⁺ T cells are major effector cells, with CD8⁺ cell playing a regulatory role. In rodents, chemically induced CH was reported by attenuated by recombinant IFN-γ.²  In contrast, chemically induced CH was enhanced by IL-17A, which induces production of IL-6, IL-8, granulocyte macrophage colony-stimulating factor (GM-CSF), and upregulated expression of intercellular adhesion molecule (ICAM)-1 in human keratinocytes, and IL-4 KO mice revealed attenuated CH responses.^1,3  Cytotoxic CD8⁺ T cells that produce IL-17A (Tc17 cells) are also implicated in induction of CH in rodentmodels.⁴ Thus, at least in rodent models, induction of CH appears to be mediated by Th17 and Th2 cytokines; Th17 cells produce IL-17A, and Th2 cells are a major source of IL-4.

Pathophysiology

The APCs present antigens complexed in the groove of major histocompatibility complex (MHC) molecules expressed on the cell surface of the APCs. For most protein antigens or haptens associated with skin delayed-type hypersensitivity, CD4⁺ T cells are presented with antigens bound to MHC class II alleles, human leukocyte antigen (HLA)-DR, HLA-DP, and HLA-DQ. Specific MHC class II alleles are recognized to produce excessive immune activation to antigens.

T cells recognize antigens through T-cell receptors (TCRs), which are composed of heterodimers containing constant and variable regions analogous to the constant and variable regions of immunoglobulin (TCR ab or TCR gd). Most delayed-type hypersensitivity responses are elicited through TCR ab. TCR gd is more commonly expressed on T cells in the epithelium boundaries with limited diversities. The function of TCR gdT cells is not well elucidated.

TCRs on the cell surface form a complex with CD3 composed of g, d, and e proteins and cytoplasmic z chain. To activate T cells through TCR, additional signaling through CD4 (helper) or CD8 (cytotoxic) molecules is required; these molecules are physically closely associated with CD3/TCR complex. Other signals for T-cell activation include costimulatory molecules expressed on APC and T cells. Costimulatory molecules are not physically associated with CD3/TCR complex but provide antigen-independent signals. Activation of naïve T cells usually requires expression of B7.1 (CD80) and B7.2 (CD86) on the APC, which interact with CD28 on T cells.

For memory or effector T-cell activation, expression of inducible costimulator (ICOS)–L on APC that interacts with ICOS expressed on T cells is required. Th1 cells  produce Th1 cytokines, including IFN-γ. Th17 cells produce IL-17A, IL-21, IL-22, and other cytokines. These cytokines further activate T cells and phagocytes. Activation of T cells is also counter-regulated by expression of inhibitory costimulatory molecules expressed on T cells, including CTLA-4 (CD152) and programmed death-1 (PD-1). These inhibitory costimulatory molecules are not expressed at the initial stage of delayed-type hypersensitivity responses but become up-regulated when inflammatory responses progress to abrogate excessive inflammatory responses.

delayed-type hypersensitivity responses to some organisms seem to be more predominantly mediated through CD8 T cells, and effector stage Th1 cells augment CD8 T-cell activation. CD8⁺ T cells activate macrophages by contact-mediated signals through CD40L-CD40 interactions and IFN-γ production. The differences in T-cell immune responses to intracellular microbes may determine disease outcomes in certain diseases. For example, ineffective T-cell–mediated immunity is seen in patients with lepromatous leprosy with high Mycobacteria leprae load in macrophages and destructive skin lesions. In contrast, in tuberculoid leprosy, strong CMI induces granulomas with less M leprae but sensory nerve defects.

IFN-γ is the key cytokine that plays the dominant role in delayed-type hypersensitivity and is a major activator of macrophage-monocyte lineage cells, augmenting its phagocytic function and production of reactive oxygen intermediates (ROIs). IFN-γ is produced by both natural killer (NK) cells and Th1 cells. Its function is to up-regulate T-cell activation markers, including CD69, CD71, the IL-2 receptor a (CD25), and HLA-DR; promote differentiation of Th1 cells; and suppress Th2 differentiation partly through down-regulating production of Th2 cytokines, including IL-4 and IL-5. IFN-γ acts on B cells to promote isotype switching of antibodies that facilitate phagocytic cell–mediated immune responses and also to up-regulate MHC molecules on APCs.

IFN-γ exerts regulatory actions on CD4⁺ Th cells.⁵ IFN-γ affects activation-induced cell death of Th cells, contributing to lymphocyte homeostasis. In addition, IFN-γ was implicated with conversion of CD4⁺ CD25^- T cells to inducible CD4⁺ CD25⁺ regulatory T (Treg) cells by augmenting expression of Foxp3. Such actions of IFN-γ may be associated with beneficial effects of IFN-γ observed in the late phase of certain autoimmune diseases.

TNF-α has been shown to be essential for an effective delayed-type hypersensitivity response. Major cellular sources of TNF-α include macrophages and Th1 cells, but TNF-α is also produced by many other lineage cells. TNF-α induces chemokine production from macrophages and endothelial cells and also up-regulates adhesion molecules on vascular endothelial cells, resulting in cellular influx of further inflammatory cells. TNF-α also induces other inflammatory cytokines, such as IL-1. In delayed-type hypersensitivity responses to poison ivy and nickel, mast cells may be a major source of TNF-α, in addition to production of other inflammatory mediators including histamine.

Another key cytokine associated with delayed-type hypersensitivity response is IL-12. IL-12 is mainly produced by APCs augments IFN-γ production by NK cells and T cells, and promotes Th1 cell differentiation. It also enhances cytolytic functions of NK and CD8⁺ T cells. IL-18 was recently shown to also augment IFN-γ production in the presence of IL-12.

A defect in delayed-type hypersensitivity reaction is best illustrated in the gene mutation in IFN-g receptor 1 (IFNGR1). IFNGR1 deficiency is characterized by ineffective granuloma formation with disseminated infection of atypical Mycobacterium species, BCG, and Salmonella species. This mutation resides on band 6q23-24. The gene consists of 50 kilobases (kb), composing 7 exons. It is highly polymorphic and encodes a 90-kilodalton transmembrane protein, which binds IFN-γ with high affinity. IFNGR1 is expressed on T cells, monocytes, macrophages, and polymorphonuclear neutrophils (PMN).

Mutations identified thus far include frameshift deletions or insertions, a splice mutation, and missense mutations at the upstream end of the gene. These mutations usually lead to absent surface expression of IFNGR1 or nonfunctional binding sites for IFN-γ, although leaky proteins are predicted in missense mutations. In the absence of IFN-γR expression, IFN-γ fails to activate monocytes to secrete TNF-α and produce ROIs. The gene mutation of IFNGR2 also induces similar clinical features. Mutations in IFNGR1 at a downstream hotspot disrupt the intracytoplasmic domain and result in a dominantly expressed disorder with milder clinical features.⁶

Murine models of IFNGR1 deficiency are susceptible to infection with a wider range of organisms than reported for humans with IFNGR1 mutations. The former develop infections with Listeria monocytogenes, Legionella pneumophila, Toxoplasma gondii, and Leishmania species, as well as with lymphocytic choriomeningitis virus, mouse hepatitis virus, and herpes simplex virus (HSV).

Down-regulation of CMI in the immunocompetent host is an active process and important for minimizing tissue injury associated with delayed-type hypersensitivity. Cytokine such as IL-10 down-regulate production of Th1 cytokines or counteract actions of Th1 cytokines. Recent studies also indicate importance of naturally occurring and inducible Treg cells that suppress effector cell proliferation directly or indirectly by producing cytokines such as IL-10 and transforming growth factor–β (TGF-β). Drugs that block components of delayed-type hypersensitivity include the histamine-2 (H2)–receptor antagonist cimetidine and the prostaglandin antagonist indomethacin. Interestingly, as indicated above, IFN-γ can augment induction of inducible Treg cells that produce IL-10 and TGF-β in the late stage of inflammation.⁵

As indicated above, Th17 and Tc17 cells are implicated in delayed-type hypersensitivity and CH responses in rodent models. This appears to also be true in humans. For example, nickel-specific Th clones established from patients with contact dermatitis against nickel were shown to produce IL-17A.⁷

Frequency

United States

Seventy-five percent of healthy children aged 12-36 months mount positive delayed-type hypersensitivity skin test reactivity to a Candida antigen. Evaluating CMI with in vitro lymphocyte proliferative responses to the specific antigen is necessary in the absence of a skin delayed-type hypersensitivity response.

Anergy is observed in patients who are malnourished, have severe atopic dermatitis, and those with severe infections caused by M tuberculosis, measles, mumps, HIV, influenza, mononucleosis, lepromatous leprosy, and certain fungi. Anergy is also observed in patients who have recently received the measles, mumps, and rubella (MMR) vaccine, patients with sarcoidosis, or patients with parasitic infestations. In addition, immunosuppressive drugs, such as cytotoxic medications and corticosteroids, lead to anergy. Malignancy, especially malignant lymphomas, also induces anergy.

Interestingly, delayed-type hypersensitivity reactions in patients with impaired IFN-γ and IL-12/IL-23 pathways tend to reveal excessive delayed-type hypersensitivity reactions. In contrast, in patients with autosomal dominant hyper immunoglobulin E (IgE) syndrome with STAT3 mutations, decreased delayed-type hypersensitivity responses against Candida may be observed due to Th17 cell deficiency.⁸

International

The presence of delayed-type hypersensitivity reactivity to tuberculin follows BCG vaccination. BCG is the most commonly administered vaccine throughout the world; however, it is not commonly used in the United States.

Mortality/Morbidity

Patients with T-cell immunodeficiency diseases such as severe combined immunodeficiency (SCID) are anergic.

Patients with mutations in IL12P40 or in IL12RB1 may show a positive, often excessive, delayed-type hypersensitivity reactivity through activation of other components of delayed-type hypersensitivity responses such as IL-17 and perhaps due to lack of regulatory effects of IFN-γ.

Mutations in IFNGR2, STAT-1, IL12P40, and IL12RB1 are autosomal recessive. Mutations found in complete IFN-γ R deficiency are also autosomal recessive. Mutations in IFNGR1 that affect the downstream intracytoplasmic domain are autosomal dominant and are clinically manifested as partial IFN-γ R deficiency. Patients with complete IFN-γ R deficiency often succumb to death from overwhelming infection caused by nontuberculosis mycobacteria (NTM) BCG at young age. Severe cytomegalovirus (CMV) infection is also described in these patients.

Mutations partially impairing IFN-γ signaling pathway may be manifested with milder mycobacterial infection, nontyphus Salmonella infection, Legionella infection, and listeriosis.

Race

Some individuals from the Mediterranean area have mutations leading to insufficient IFN-g function. Specifically, a family from Tunisia, several families from Malta, and 1 family from Italy have been reported. Genetic defects involving the IFN-g/IL-12 axis are now increasingly reported in other races.

Sex

Anergy to BCG and of idiopathic disseminated BCG infection are equally distributed among males and females. As expected in autosomal recessive gene mutations, IFNGR1, IL12P40, and IL12RB1 mutations are found with equal frequency in males and females.

Age

Delayed-type hypersensitivity reactivity to Candida antigens can be detected in infants as young as 3-4 months, but reactivity depends on exposure to the antigen. Positive delayed-type hypersensitivity reactivity to tetanus toxoid requires completion of the primary immunization series of 3 injections administered 4-6 weeks apart; only one third of infants have a positive response to tetanus after the first dose of immunization. Patients with IFNGR1/IFNGR2 mutations that cause complete loss of IFN-receptor expression or IFN-γ– mediated signaling have presented as infants or in early childhood with disseminated BCG or NTM infections, respectively. This age-related infection seems to reflect the age of exposure to the causative organisms.

Clinical

History

Delayed-type hypersensitivity (DTH) skin testing is usually performed to detect exposure to tuberculosis and, occasionally, when unusually extensive Candida infection has occurred. In these settings, the patient often has no prior history of unusually severe or opportunistic infections. In developing countries, ruling out confounding clinical malnutrition and rubeola infection that negate delayed-type hypersensitivity skin test reactivity is crucial. HIV infections and malignancies, such as Hodgkin lymphoma, also negate delayed-type hypersensitivity responses.

The presence of any cause for immunosuppression modifies the interpretation of tuberculin delayed-type hypersensitivity skin tests; in an immunosuppressive condition, 5-mm induration is interpreted as a positive response.

Delayed-type hypersensitivity skin test reactions are absent in patients with lepromatous leprosy (M leprae), sarcoidosis, coccidioidomycosis, schistosomiasis, rheumatological diseases, severe viral infections (eg, influenza, mononucleosis, mumps), and those given the measles, mumps, rubella (MMR) vaccine recently (£ 3 wk). Systemic steroid therapy can cause anergy; however, inhaled steroids with high bioavailability could also decrease delayed-type hypersensitivity reactions and less frequently produce anergy when administered in large doses. Longer duration (>2 wk) and higher doses of steroids increase the risk for anergy, but no exact doses or duration predict induction of anergy in a given individual.

Other immunosuppressive agents that cause anergy include cancer chemotherapy agents, calcineurin inhibitors, and monoclonal antibodies against the immune system such as anti-TNF (infliximab) and anti-CD20 (rituximab).

Usually, a patient with anergy caused by a T-cell immunodeficiency can be identified before wasting sets in. A pattern of unusually frequent or severe common infections, extensive mucocutaneous candidiasis, or dermatitis together with lymphopenia raises the suspicion of severe combined immunodeficiency (SCID) or another severe T-cell immunodeficiency.

A patient with disseminated bacille Calmette-Guérin (BCG) or nontuberculosis mycobacteria (NTM) infection may have a history of consanguinity or familial infection indicating autosomal recessive genetic disorders. Evaluate these patients for IFNGR1, IFNGR2, STAT-1, IL12P40, and IL12RB1 mutations. Patients with BCG infection usually present in early infancy after administration of the BCG vaccine. NTM infection develops more typically in mid childhood when community exposure to these mycobacteria occurs. A patient with one of the above mutations responds poorly to appropriate antimycobacterial therapy and often has a fulminant fatal infection.

Nontyphus Salmonella infections are more frequently observed in patients with the above-described disorders. Asthma, atopy, and immune complex disease (eg, glomerulonephritis, vasculitis, positive rheumatoid factors) are sometimes present.

Repetitive delayed-type hypersensitivity skin testing does not change the parameters used to define a positive test result. The immediate hypersensitivity reaction of erythema may increase, which is what determines the delayed-type hypersensitivity response.

Delayed-type hypersensitivity antigens for coccidioidomycosis are no longer available. Diagnosis depends on identifying the organism or serology. Negative skin test reactivity to coccidioidin does correlate with a less favorable clinical outcome. However, the positive skin test result usually persists following an initial infection so that recurrence cannot be determined by the delayed-type hypersensitivity skin testing.

Delayed-type hypersensitivity skin test reactivities for histoplasmosis and blastomycosis cross-react. In addition, positive delayed-type hypersensitivity skin reactions in exposed but not infected individuals living in endemic areas confound interpretation. Both fungal infections have increased in incidence in HIV patients; these patients are frequently anergic. Diagnosis now requires culturing the organism, antigen detection, and/or serologic confirmation.

Physical

The delayed-type hypersensitivity skin test response is determined by the extent of induration. Erythema indicates an immediate hypersensitivity reaction and begins earlier than but often persists after induration has developed.

Delayed-type hypersensitivity skin test reactivity to most antigens is read as positive when induration is 5 mm or more at 48 hours and 72 hours following inoculation. For tuberculin, 15 mm is considered a positive response for persons aged 4 years or older without risk factors; 10 mm is considered a positive response for younger children and those in populations with increased exposure or in whom immunosuppression is likely. A tuberculin reaction of 5 mm is considered positive when clinical evidence of tuberculosis, HIV infection, or close contact with people with infectious tuberculosis is noted.

Disseminated BCG and NTM infection are characterized by fever, wasting, lymphadenopathy, and hepatosplenomegaly.

Causes

A positive delayed-type hypersensitivity response to the purified protein derivative (PPD) of M tuberculosis is elicited 4-6 weeks after exposure to tuberculosis. Populations at increased risk for tuberculosis include immigrants from countries with a high incidence of tuberculosis, such as African, Asian, and South American countries, and those with HIV infection. High-risk populations in the United States include those who are incarcerated, those who are homeless, migrant workers, and those who use illicit drugs. Individuals who are exposed to these populations are also at increased risk.

Anergy is discussed under History and Pathophysiology.

A single functional mature T cell can transfer delayed-type hypersensitivity DTH reactions; thus, a patient who received hematopoietic stem cell transplant from a donor with positive delayed-type hypersensitivity responses to the specific antigen could reveal positive delayed-type hypersensitivity responses to the same antigen.

Contact delayed-type hypersensitivity reactions occur in patients with poison ivy and nickel hypersensitivity

delayed-type hypersensitivity to sulfonamides, phenytoin, and carbamazepine has been described. Reactions to penicillin-type antibiotics may be cell-mediated, but immunoglobulin G (IgG)-mediated responses are much more common.

Differential Diagnoses

Other Problems to Be Considered

Consider primary T-cell immunodeficiency, including severe combined immunodeficiency (SCID), when anergy is present. Other well-recognized primary immunodeficiency diseases with anergy include Wiskott-Aldrich syndrome, DiGeorge syndrome, ataxia telangiectasia, and other chromosomal breakage disorders.

Exclude malnutrition and immunosuppression with corticosteroids and other drugs. Certain malignancies, such as Hodgkin disease, are associated with anergy. Consider rheumatologic disease, especially systemic lupus erythematosus as a cause of anergy in specific clinical situations.

Mutations that effect responses to interferon (IFN)-g or its production include IFNGR1, IFNGR2, STAT-1, IL12P4, and IL12RB1. As a result, these patients may manifest altered (often excessive) delayed-type hypersensitivity (DTH) skin test reactivity.

In patients with STAT3 mutations, as seen in patients with autosomal dominant hyper immunoglobulin E (IgE) syndrome, delayed-type hypersensitivity responses may be attenuated due to impaired Th17 cell development.

Workup

Laboratory Studies

• Characteristics of the antigens determine the delayed-type hypersensitivity (DTH) skin test reactivity. Conjugation of the antigen to lipids facilitates the delayed-type hypersensitivity reaction. This explains the consistent response to mycobacteria in which antigens are isolated from the lipid cell wall. Size, valence, chemical composition, and dose are additional factors that are relevant to immunogenicity. Repetitive testing with the same antigen can cause an immediate immunoglobulin E (IgE)-mediated response and may diminish the delayed-type hypersensitivity skin test reactivity. High doses of antigens that induce predominant Th2 responses, such as in miliary tuberculosis, abrogate the delayed-type hypersensitivity responses by a negative feedback mechanism that suppresses Th1 responses.
  • By convention, the antigens used for delayed-type hypersensitivity skin testing are injected intradermally into the volar surface of the forearm with a volume of 0.1 mL each. Erythema and induration are measured at 24, 48, and 72 hours. A reaction at 24 hours does not represent delayed-type hypersensitivity induced by cell-mediated immunity (CMI), or type IV reactivity. The Food and Drug Administration (FDA) –approved antigens for delayed-type hypersensitivity skin testing are limited to PPD of M tuberculosis and Candida.
  • Conventionally, children are tested with Candida and Dermatophytin in a 1:10 or 1:100 dilution and tested with tetanus in a 1:10 or 1:100 dilution of the diphtheria-tetanus (DT) vaccine. The higher dilution is used when the child has undergone a significant infection or unusually frequent immunization respectively.
  • Adults are initially tested with the 1:100 concentrations of these antigens.
  • When interpreting delayed-type hypersensitivity skin testing, whether adequate exposure to the antigens has taken place prior to the procedure must be considered. A vigorous immune response to one antigen, such as in measles infection, leads to the abrogation of other delayed-type hypersensitivity responses, for example, to purified protein derivative (PPD) even though the patient is also infected with tuberculosis.
  • Antigens that are poorly immunogenic in children and in some adults include mumps (no longer on the US market) and Trichophyton. Dinitrochlorobenzene (DNCB) and dinitrofluorobenzene (DNFB) have been superseded by in vitro assessments of cell-mediated immunity because of the risk of local tissue necrosis.
• When an absent delayed-type hypersensitivity reaction is noted, screening tests for a T-cell disorder should include an absolute lymphocyte count and a chest radiograph to detect the thymus. Cell surface marker analysis of peripheral mononuclear cells by flow cytometry and in vitro lymphocyte proliferation responses against mitogens (polyclonal stimulants) and specific antigens are then performed.
• Contact sensitivity to poison ivy and nickel is determined clinically; skin testing is not considered necessary.
• Adverse drug reactions to antibiotics, phenytoin, and carbamazepine may involve nonimmune or immune-mediated mechanisms. The clinical setting of a reaction at 3 days or later with manifestation of a fixed rash with induration is more suspicious of involvement of a delayed-type hypersensitivity response.

Imaging Studies

• A chest radiograph to determine whether the thymus is present is an appropriate screening test for T-cell disorders only in the newborn; however, the thymus may involute in stressed infants in the context of overwhelming infection or severe congenital cardiac disease.

Other Tests

• When delayed-type hypersensitivity is absent and a T-cell disorder is suspected, assess in vitro lymphocyte proliferation responses against polyclonal stimulants such as mitogens (eg, phytohemagglutinins [PHA], concanavalin A [conA], pokeweed mitogen [PWM]) and specific antigens (eg, Candida, tetanus). Measurement of production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-12 in response to various stimulants can be helpful for screening mutations in IFNGR1, IFNGR2, STAT-1, IL12P40, or ILRB1 when such mutations are suspected. Low levels of one or more of these cytokines increase the likelihood of these mutations.
• In patients with severe eczema, recurrent skin abscesses, elevated IgE, and history of frequent bone fractures, assessment of IL-17 production may be helpful. This is because patients with autosomal dominant hyper IgE syndrome have impaired development of Th17 cells, which is a major cellular source of IL-17.⁸
• Cell surface markers for monocytes, T-cells (CD4, CD8, CD28, TCR a/b, TCR g/d), and activated T cells (CD25, HLA-DR, and CD5) are reported to be normal in IFNGR1, IL12P40,STAT1, IL12RB1, STAT3 mutations. In profound primary T-cell deficiencies such as severe combined immunodeficiency (SCID), the pattern of cell surface marker expression of lymphocyte and natural killer (NK) cells may identify the type of T-cell defect in conjunction with the clinical manifestations.
• Mutational analysis for IFNGR1, IFNGR2, STAT-1,STAT-3, IL12P40, and IL12RB1 is available in specific research laboratories.
• Additional genes that control downstream immune responses initiated by IFN-γ in the delayed-type hypersensitivity response are recognized; IFNGR2 does not bind IFN-γ but is needed for the activation of STAT-1 and its translocation to the nucleus.

Procedures

• When disseminated bacille Calmette-Guérin (BCG) or nontuberculosis mycobacteria (NTM) is suspected, perform biopsy of infected sites in order to examine granuloma formation and detect acid-fast mycobacteria.
• Tissue culture to detect mycobacteria is also indicated when disseminated BCG or NTM is suspected.

Histologic Findings

• Granuloma formation in an intact delayed-type hypersensitivity response shows predominant infiltrates of activated macrophages and lymphocytes that can be identified as CD4⁺ T cells by immunohistochemical staining.
• When NTM infection is present, multinucleated giant cells formed by fused activated macrophages are observed in the immunocompetent host.
• In the patient with a T-cell defect, the formed granuloma lacks CD4⁺ T cells and these giant cells (due to ineffective macrophage activation by T cells). Instead, granulomatous lesions are characterized by infiltrate of polymorphonuclear cells, vacuolated cells, and macrophages.
• Mycobacteria may be present in abundance but are not frequently stained, although they are isolated by culture techniques.

Treatment

Medical Care

Delayed-type hypersensitivity (DTH) skin testing requires the use of antigen doses as defined under Lab Studies. See Lab Studies for a more complete discussion of the interpretation of delayed-type hypersensitivity reactions.

• Delayed-type hypersensitivity responses represent cellular immune responses to recall antigens to which the subject has been introduced at least 4-6 weeks previously. The reaction occurs 48-72 hours after exposure and induces induration of 5 mm or more.
• The inflammatory reaction may be sufficient to induce pain at the local site. Topical steroids and diphenhydramine have been used to decrease an unusually severe reaction. If an excessive reaction is anticipated, such as in caseating tuberculosis, decrease the amount of antigen; for M tuberculosis, for example, decrease the strength of the purified protein derivative (PPD) from the customary 5 units to 1 unit.
• Negative reactions to a recall antigen to which the patient is known to have adequate exposure require investigation for an underlying illness or a T-cell deficiency.
• Positive delayed-type hypersensitivity reactions do not indicate protection against the recall antigen that is tested. Antibody responses to the specific antigen usually reveal better correlation with immune protection.
• In patients with mutations in the interferon (IFN)-γ/interleukin (IL)-12/IL-23 signaling pathways, medical care includes consideration of hematopoietic stem cell transplantation in patients with severe deficiencies and consideration of exogenous IFN-γ therapy in patients with partial deficiencies with milder clinical features. In the presence of nontuberculosis mycobacteria (NTM) infection, patients require treatment with an aggressive regimen of antimycobacterial drugs.

Consultations

• In a context in which a T-cell disorder is likely, a clinical immunologist should manage the diagnostic workup in order to obtain informative cell-mediated immunologic testing and appropriate mutational analysis.
• Both types of evaluations for rare T-cell disorders are commonly available only in laboratories of specific investigators.

Diet

• Resolution of protein-energy malnutrition induces an intact delayed-type hypersensitivity response.

Medication

Purified protein derivative (PPD), used to evaluate exposure to M tuberculosis, and Candida antigen are the only currently available US Food and Drug Administration (FDA)-approved antigens for delayed-type hypersensitivity (DTH) skin testing. The most clinically informative antigens used for delayed-type hypersensitivity reactivity are Candida and tetanus antigens because most individuals are exposed to these antigens as infants. By age 9-12 months, more than 80% of immunocompetent children mount positive responses to these antigens.

Previously available delayed-type hypersensitivity antigens withdrawn from clinical use include the Cell-mediated immunity (CMI) multitest, coccidioidin, mumps, and histoplasmin. Mumps antigen is a relatively poor antigen in eliciting a positive delayed-type hypersensitivity skin test reactivity. Studies have shown only 60% of previously infected adults to have a positive test reactivity. An even lower response is predicted when the only exposure to mumps is by measles, mumps, and rubella (MMR) immunization.

Tuberculin tests

These agents are used to detect infection with M tuberculosis.

Tuberculin, purified protein derivative (PPD Mantoux test, Aplisol, Tubersol)

The standard skin test uses 5 U of PPD in a volume of 0.1 mL. A lower concentration of 1 U/0.1 mL is used when a high exposure to antigen, as in caseating tuberculosis, is suspected; 250 U can be used if standard test result is negative and person is known to be immunocompromised. A negative DTH reaction does not rule out infection but may indicate disseminated infection as in miliary tuberculosis.

Dosing

Adult

0.1 mL, containing 5 U PPD, injected ID into volar surface of the forearm; test read at 48 and 72 h; induration measured at >5 mm, 10 mm, or 15 mm considered a positive result depending on patient age, immunologic status, and membership in at-risk population (see Clinical above)

Pediatric

Administer as in adults

Interactions

Malnutrition, steroid therapy, sarcoidosis, Hodgkin lymphoma, other malignancies, and a number of other infections may cause anergy in the presence of active infection; the most likely infections to cause anergy are HIV, measles, and mumps; severe influenza, infectious mononucleosis, or the MMR vaccine may cause negative DTH

Contraindications

None reported; anaphylaxis is not reported; sterile abscesses that can occur with vaccines or antibiotics are rarely reported

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Know tuberculin positive reactors (higher degree of ulceration or necrosis at site of injection); extensive painful reaction can be treated with topical steroid creams, diphenhydramine, or, possibly, ibuprofen; avoid SC injection; reading test at 24 h and measuring erythema and induration distinguishes immediate IgE-mediated reaction at 24-48 h from DTH

Tetanus antigens

These are used to assess cellular immune responses following the primary series of diphtheria-tetanus-pertussis vaccine (3 doses). Conventionally used as a control for tuberculin testing in patients who are immunocompromised or suspected to have disseminated tuberculosis.

Tetanus toxoid USP, fluid (8 LFU/mL, NDC#49281-0812-84)

The standard TD vaccine is diluted to 1:100 or 1:10. A positive DTH reaction indicates recognition by cell-mediated immunity; protection correlates with antibody responses.

Dosing

Adult

Injected ID in a volume of 0.1 mL into volar surface of forearm; lower concentration of 1:100 dilution used for DTH testing because most adults have had several TD boosters since childhood; test read at 24, 48, and 72 h; induration > 5 mm positive at 48-72 h

Pediatric

<2 years: 1:10 dilution ID
>2 years: 1:100 dilution ID initially; if no response consider retesting with higher concentration

Interactions

Malnutrition, steroid therapy, sarcoidosis, Hodgkin lymphoma, other malignancies, and a number of other infections may cause anergy in presence of active infection; the most likely infections to cause anergy are HIV, measles, and mumps; severe influenza, infectious mononucleosis, or the MMR vaccine may cause negative DTH

Contraindications

None reported

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Painful reaction can be treated with topical steroids, diphenhydramine, or ibuprofen; reading the test at 24 h and measuring erythema and induration distinguishes the immediate IgE-mediated reaction at 24-48 h from DTH

Candida antigens

Most infants have been exposed to Candida antigen even without clinical thrush or Candida diaper dermatitis. Japanese studies showed that 80% of children had positive delayed-type hypersensitivity responses by age 1 year; therefore, Candida is a conventional antigen used as a positive control for tuberculin testing in individuals who are immunocompromised or when disseminated tuberculosis is suspected.

Candida skin test antigen (Candin, NDC#38697-200-1; Allermed)

Also known as Dermatophytin. It is diluted 1:10 or 1:100 with sterile water.

Dosing

Adult

0.1 mL injected ID into the volar surface of the forearm; initial skin test dilution is 1:100 ID; induration > 5 mm at 48-72 h read as positive result

Pediatric

<2 years: 1:10 dilution in a volume of 0.1 mL ID
>2 years: Administer as in adults
Extensive active
Candida infection: 1:100 dilution in a volume of 0.1 mL ID initially

Interactions

Malnutrition, steroid therapy, sarcoidosis, Hodgkin lymphoma, other malignancies, and a number of other infections may cause anergy in the presence of active infection; the most likely infections to cause anergy are HIV, measles, and mumps; severe influenza, infectious mononucleosis, or the MMR vaccine may cause negative DTH

Contraindications

None reported

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Painful reaction can be treated with topical steroid cream, diphenhydramine, or ibuprofen; reactions to Candida antigen seem to be more common than to other recall antigens; reading test at 24 h and measuring erythema and induration distinguishes the immediate IgE-mediated reaction at 24-48 h from DTH

Follow-up

Further Inpatient Care

• Consider patients with most T-cell disorders for stem cell transplantation, usually by bone marrow transplantation using an major histocompatibility complex (MHC)-matched related or unrelated donor.
• Only a few cases of bone marrow transplantation (BMT) have been reported in patients with mutations in the interferon (IFN)-g and interleukin (IL)-12/IL-23 signaling pathways with rather unfavorable results. Intact T-cell functions other than IFN-g/IL-12/IL-23 axis increases the risk of graft rejection and concurrent atypical mycobacterial infection usually present at the time of BMT may increase the risk of post-BMT complications.^9,10

Further Outpatient Care

• See Medical Care and Medication.

Inpatient & Outpatient Medications

• See Medical Care and Medication.

Deterrence/Prevention

• Patients in whom cell-mediated immunodeficiency diseases are suspected should never receive the bacille Calmette-Guérin (BCG) or smallpox vaccine. Similarly, the measles, mumps, rubella (MMR) vaccine is contraindicated, although this vaccine is not administered until age 1 year, by which time most T-cell disorders have been diagnosed. Guidelines regarding the administration of the MMR vaccine have been updated.¹¹
• Patients with IFNGR1, IFNGR2, STAT-1, IL12P40, or IL12RB1 mutations are advised to receive prophylaxis against nontuberculosis mycobacteria (NTM) using rifabutin and clarithromycin.

Complications

• Antigens that are currently available for delayed-type hypersensitivity (DTH) skin testing are not associated with significant morbidity and do not cause mortality.
• Experimental animal models of immunodeficiency with absent delayed-type hypersensitivity suggest that other infections may also occur in the absence of effective cell-mediated immunity (CMI). These infections include L monocytogenes, L pneumophila, T gondii, and Leishmania species.
  • In humans with idiopathic disseminated BCG or mutations in the IFN-γ signaling pathway, the risk of contracting nontyphus Salmonella infections increases.
  • One report describes severe infections with viruses (eg, respiratory syncytial virus [RSV], parainfluenza virus, herpes simplex virus (HSV), cytomegalovirus [CMV], and varicella-zoster virus [VZV]) in a patient with an IFN-γ signaling pathway defect.
  • Some patients with IFNGR1 mutations have antibody responses to HSV, CMV, VZV, and Epstein-Barr virus (EBV) without clinical infection, suggesting that their host response to these viruses is intact.

Prognosis

• Adequate nourishment and discontinuation of drug therapy can reverse anergy caused by malnutrition and immunosuppression by immunomodulating agents, respectively.
• As noted in Mortality/Morbidity, severe mutations in IFNGR1, IFNGR2, STAT-1, IL12P40, and IL12RB1 lead to lethal disseminated infections with NTM. Mutations in the IFN-g signaling pathway that cause milder clinical infections are described; many of these patients benefit from exogenous IFN-g therapy.

Patient Education

• Regarding IFNGR1, IFNGR2, STAT-1, IL12P40, and IL12RB1 mutations, inform families about the risks of infection so that appropriate steps to avoid exposure to infection are instituted.
  • Families should be aware that BCG and live viral vaccines are contraindicated.
  • Genetic counseling is an essential part of medical care for the family. Inform parents of the 1 out of 4 risk for affected infants in autosomal recessive gene mutations. Mutations in the intracytoplasmic domain of IFNGR1 result in autosomal dominant transmission.
  • If bone marrow transplantation is considered a therapeutic option, an adequate informed consent consultation for stem cell reconstitution must include the high risk for life-threatening infection during the preparative immunosuppressive regimen in addition to the risk for failure to engraft and graft versus host disease (GVHD). Although successful complete immune reconstitution from bone marrow transplantation can be obtained using fully matched related and unrelated donors, patients may not engraft or may experience GVHD posttransplant. Other forms of stem cell reconstitution that can be offered include cord cell transplantation. Gene therapy is expected to be an option in the future.
• The Immune Deficiency Foundation is an important resource for education and for support for patients and families with any primary immunodeficiency disease. The current address is 40 W. Chesapeake Ave, Suite 308, Towson, MD 21204. Some states have local chapters.
• The Jeffrey Modell Foundation at 747 Third Avenue, New York, NY 10017 provides support and raises funds.
• For excellent patient education resources, visit eMedicine's Allergy Center.

Miscellaneous

Medicolegal Pitfalls

• Failure to investigate cell-mediated immunity in patients with disseminated bacille Calmette-Guérin (BCG), nontuberculosis mycobacteria (NTM), or unusually severe candidal infections raises the specter of legal liability. Look for a clinical history of consanguinity and other family members with similar clinical infections.
• Offer mutational analysis for suspected T-cell defects and discuss the opportunity for prenatal diagnosis with the family. Any autosomal recessive mutation places siblings at a 1 out of 4 risk. An autosomal dominant mutation results in a 1 out of 2 risk.

Special Concerns

• BCG is commonly administered to infants at birth or in the first 3 months of life in some countries but not in the United States; it is contraindicated when T-cell disorders are suspected.
• Infections with T gondii and Leishmania species and fungal infections, such as coccidioidomycosis and histoplasma, are theoretical risks for patients with primary immunodeficiencies involving the IFN-g/IL-12/IL-23 signaling pathway, including those with IFNGR1, IFNGR2, STAT-1, IL-12P40, and IL12R mutations.

References

1. Nakae S, Komiyama Y, Nambu A, et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity. Sep 2002;17(3):375-87. [Medline].

2. Iwakura Y, Nakae S, Saijo S, Ishigame H. The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev. Dec 2008;226:57-79. [Medline].

3. Takeshita K, Yamasaki T, Akira S, Gantner F, Bacon KB. Essential role of MHC II-independent CD4+ T cells, IL-4 and STAT6 in contact hypersensitivity induced by fluorescein isothiocyanate in the mouse. Int Immunol. May 2004;16(5):685-95. [Medline].

4. He D, Wu L, Kim HK, Li H, Elmets CA, Xu H. CD8+ IL-17-producing T cells are important in effector functions for the elicitation of contact hypersensitivity responses. J Immunol. Nov 15 2006;177(10):6852-8. [Medline].

5. Chen J, Liu X. The role of interferon gamma in regulation of CD4+ T-cells and its clinical implications. Cell Immunol. 2009;254(2):85-90. [Medline].

6. Al-Muhsen S, Casanova JL. The genetic heterogeneity of mendelian susceptibility to mycobacterial diseases. J Allergy Clin Immunol. Dec 2008;122(6):1043-51; quiz 1052-3. [Medline].

7. Albanesi C, Cavani A, Girolomoni G. IL-17 is produced by nickel-specific T lymphocytes and regulates ICAM-1 expression and chemokine production in human keratinocytes: synergistic or antagonist effects with IFN-gamma and TNF-alpha. J Immunol. Jan 1 1999;162(1):494-502. [Medline].

8. Milner JD, Brenchley JM, Laurence A, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. Apr 10 2008;452(7188):773-6. [Medline].

9. Roesler J, Horwitz ME, Picard C, et al. Hematopoietic stem cell transplantation for complete IFN-gamma receptor 1 deficiency: a multi-institutional survey. J Pediatr. Dec 2004;145(6):806-12. [Medline].

10. Chantrain CF, Bruwier A, Brichard B, et al. Successful hematopoietic stem cell transplantation in a child with active disseminated Mycobacterium fortuitum infection and interferon-gamma receptor 1 deficiency. Bone Marrow Transplant. Jul 2006;38(1):75-6. [Medline].

11. [Guideline] CDC. Update: recommendations from the Advisory Committee on Immunization Practices (ACIP) regarding administration of combination MMRV vaccine. MMWR Morb Mortal Wkly Rep. Mar 14 2008;57(10):258-60. [Medline].

12. Altare F, Durandy A, Lammas D, et al. Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science. May 29 1998;280(5368):1432-5. [Medline].

13. Altare F, Lammas D, Revy P, et al. Inherited interleukin 12 deficiency in a child with bacille Calmette-Guerin and Salmonella enteritidis disseminated infection. J Clin Invest. Dec 15 1998;102(12):2035-40. [Medline].

14. Askenase PW. Effector and regulatory molecules and mechanisms in delayed type hypersensitivity. In: Middleton E, et al, eds. Allergy: Principles and Practice. Vol 1. 1998:323-41.

15. Casanova JL, Abel L. The human model: a genetic dissection of immunity to infection in natural conditions. Nat Rev Immunol. Jan 2004;4(1):55-66. [Medline].

16. Chantrain CF, Bruwier A, Brichard B, et al. Successful hematopoietic stem cell transplantation in a child with active disseminated Mycobacterium fortuitum infection and interferon-gamma receptor 1 deficiency. Bone Marrow Transplant. Jul 2006;38(1):75-6. [Medline].

17. Chapgier A, Wynn RF, Jouanguy E, et al. Human complete Stat-1 deficiency is associated with defective type I and II IFN responses in vitro but immunity to some low virulence viruses in vivo. J Immunol. Apr 15 2006;176(8):5078-83. [Medline].

18. de Jong R, Altare F, Haagen IA, et al. Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science. May 29 1998;280(5368):1435-8. [Medline].

19. Dorman SE, Holland SM. Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection. J Clin Invest. Jun 1 1998;101(11):2364-9. [Medline].

20. Dorman SE, Picard C, Lammas D, et al. Clinical features of dominant and recessive interferon gamma receptor 1 deficiencies. Lancet. Dec 11-17 2004;364(9451):2113-21. [Medline].

21. Dorman SE, Uzel G, Roesler J, et al. Viral infections in interferon-gamma receptor deficiency. J Pediatr. Nov 1999;135(5):640-3. [Medline].

22. Dupuis S, Doffinger R, Picard C, et al. Human interferon-gamma-mediated immunity is a genetically controlled continuous trait that determines the outcome of mycobacterial invasion. Immunol Rev. Dec 2000;178:129-37. [Medline].

23. Horwitz ME, Uzel G, Linton GF, et al. Persistent Mycobacterium avium infection following nonmyeloablative allogeneic peripheral blood stem cell transplantation for interferon-gamma receptor-1 deficiency. Blood. Oct 1 2003;102(7):2692-4. [Medline].

24. Huang D, Cancilla MR, Morahan G. Complete primary structure, chromosomal localization, and definition of polymorphisms of the gene encoding the human interleukin-12 p40 subunit. Genes Immun. Dec 2000;1(8):515-20. [Medline].

25. Jouanguy E, Altare F, Lamhamedi S, et al. Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guerin infection. N Engl J Med. Dec 26 1996;335(26):1956-61. [Medline].

26. Jouanguy E, Dupuis S, Pallier A, et al. In a novel form of IFN-gamma receptor 1 deficiency, cell surface receptors fail to bind IFN-gamma. J Clin Invest. May 2000;105(10):1429-36. [Medline].

27. Jouanguy E, Lamhamedi-Cherradi S, Altare F, et al. Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guerin infection and a sibling with clinical tuberculosis. J Clin Invest. Dec 1 1997;100(11):2658-64. [Medline].

28. Jouanguy E, Lamhamedi-Cherradi S, Lammas D, et al. A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection. Nat Genet. Apr 1999;21(4):370-8. [Medline].

29. Lammas DA, De Heer E, Edgar JD, et al. Heterogeneity in the granulomatous response to mycobacterial infection in patients with defined genetic mutations in the interleukin 12-dependent interferon-gamma production pathway. Int J Exp Pathol. Feb 2002;83(1):1-20. [Medline].

30. Newport MJ, Huxley CM, Huston S, et al. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med. Dec 26 1996;335(26):1941-9. [Medline].

31. Novelli F, Casanova JL. The role of IL-12, IL-23 and IFN-gamma in immunity to viruses. Cytokine Growth Factor Rev. Oct 2004;15(5):367-77. [Medline].

32. Roesler J, Horwitz ME, Picard C, et al. Hematopoietic stem cell transplantation for complete IFN-gamma receptor 1 deficiency: a multi-institutional survey. J Pediatr. Dec 2004;145(6):806-12. [Medline].

33. Rosenzweig SD, Holland SM. Congenital defects in the interferon-gamma/interleukin-12 pathway. Curr Opin Pediatr. Feb 2004;16(1):3-8. [Medline].

34. Rosenzweig SD, Holland SM. Defects in the interferon-gamma and interleukin-12 pathways. Immunol Rev. Feb 2005;203:38-47. [Medline].

35. Schnorr JJ, Cutts FT, Wheeler JG, et al. Immune modulation after measles vaccination of 6-9 months old Bangladeshi infants. Vaccine. Jan 8 2001;19(11-12):1503-10. [Medline].

36. Sharma KC, Stevens D, Casey L, Kesten S. Effects of high-dose inhaled fluticasone propionate via spacer on cell-mediated immunity in healthy volunteers. Chest. Oct 2000;118(4):1042-8. [Medline].

37. Vankayalapati R, Wizel B, Samten B, et al. Cytokine profiles in immunocompetent persons infected with Mycobacterium avium complex. J Infect Dis. Feb 1 2001;183(3):478-84. [Medline].

Keywords

delayed-type hypersensitivity, DTH, DTH reaction, DTH response, delayed-type hypersensitivity reaction, delayed type hypersensitivity, delayed hypersensitivity, hypersensitive response, hypersensitive reaction, cell mediated immunity, CMI, antigen-presenting cells, APCs, cell-mediated immunity to recall antigens, anergy, anergic reaction, T cell, T-cell receptor, Candida antigen, Candida infection, DTH skin test, T-cell disorder, T-cell defect, bone marrow transplantation, BMT
Mycobacterium tuberculosis, tetanus, Candida, Trichophyton, mumps, contact hypersensitivity, nickel, dinitrochlorobenzene, DNCB, picryl chloride, leprosy, poison ivy, Listeria monocytogenes, Legionella pneumophila, Toxoplasma gondii, Leishmania, lymphocytic choriomeningitis virus, mouse hepatitis virus, herpes simplex virus, HSV, malnutrition, atopic dermatitis, MMR vaccine, sarcoidosis, mononucleosis, HIV, influenza, malignant lymphomas, severe combined immunodeficiency, SCID, cytomegalovirus, CMV, Hodgkin lymphoma, asthma, atopy, glomerulonephritis, treatment, diagnosis

Contributor Information and Disclosures

Author

Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School
Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Terry Chin, MD, PhD, Associate Professor of Pediatrics, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, University of California Irvine School of Medicine; Associate Director, Miller Children's Hospital at Long Beach Memorial Medical Center
Terry Chin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American College of Chest Physicians, American Thoracic Society, California Thoracic Society, Clinical Immunology Society, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

John Wilson Georgitis, MD, Consulting Staff, Lafayette Allergy Services
John Wilson Georgitis, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Chest Physicians, American Lung Association, American Medical Writers Association, and American Thoracic Society
Disclosure: Nothing to disclose.

CME Editor

David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville
David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology
Disclosure: Nothing to disclose.

Chief Editor

Russell W Steele, MD, Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine
Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association
Disclosure: None None None

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Ann O'Neill Shigeoka, MD, to the original writing and development of this article.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)