AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 is dependent on interferon gamma (IFN-g), a major cytokine produced by CD4⁺ helper T cells, subtype 1 (T_H1). However, phagocytic cell activation and inflammation induced by CMI can cause tissue injury called delayed-type hypersensitivity (DTH). In experimental animal models, DTH reactions are characterized by a granulomatous response consisting of macrophages, monocytes, and T lymphocytes.

DTH 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 DTH 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. DTH antigens for several fungi and streptococci are no longer available or recommended for clinical use.

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

Pathophysiology

A DTH reaction in the skin is initiated when certain antigens are presented by antigen-presenting cells (APCs) in the skin (ie, Langerhans cells) to sensitized memory T cells. The antigen presentation and subsequent T-cell activation elicit an influx of macrophages, monocytes, and lymphocytes at the site of antigen exposure. These cells then produce inflammatory cytokines including tumor necrosis factor–alpha (TNF-a) and IFN-g. At the onset of the reaction, vasopermeability is increased by serotonin and histamine release, and adhesion molecules are up-regulated in the vascular endothelium so that additional cellular components migrate into the local site of antigen presentation.

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 DTH, 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) composed of heterodimers containing constant and variable regions analogous to the constant and variable regions of immunoglobulin: TCR ab or TCR g/d. Most DTH responses are elicited through TCR ab. TCR g/d is more commonly expressed on T cells in the epithelium boundaries with limited diversities. The function of TCR g/dT 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 are required, and 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. T_H1 cells that are mainly involved with a DTH reaction produceT_H1 cytokines, including IFN-g. 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 PD-1 (programmed death-1).

DTH responses to some organisms seem to be more predominantly mediated through CD8 T cells, and effector stage T_H1 cells also augment CD8 T-cell activation. CD8⁺ T cells activate macrophages by contact-mediated signals through CD40L-CD40 interactions and IFN-g 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-g is the key cytokine that plays the dominant role in DTH and is a major activator of macrophage-monocyte lineage cells, augmenting its phagocytic function and production of reactive oxygen intermediates (ROIs). IFN-g is produced by both natural killer (NK) cells and T_H1 cells. Its function is to up-regulate T-cell activation markers, including CD69, CD71, the interleukin-2 receptor a (CD25), and HLA-DR; promote differentiation of T_H1 cells; and suppress T_H2 differentiation partly through down-regulating production of T_H2 cytokines, including interleukin (IL)-4 and IL-5. IFN-g 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.

TNF-a has been shown to be essential for an effective DTH response. Major cellular sources of TNF-a are macrophages and T_H1 cells, but TNF-a is also produced by many lineage cells. TNF-a 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-a also induces other inflammatory cytokines such as interleukin-1. In DTH responses to poison ivy and nickel, mast cells may be a major source of TNF-a, in addition to production of other inflammatory mediators including histamine.

Another key cytokine associated with DTH response is IL-12. IL-12 is mainly produced by APCs augments IFN-g production by NK cells and T cells, and promotes T_H1 cell differentiation. It also enhances cytolytic functions of NK and CD8⁺ T cells. IL-18 was recently shown to also augment IFN-g production in the presence of IL-12.

A defect in DTH 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, bacille Calmette-Guérin (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-g 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-g, although leaky proteins are predicted in missense mutations. In the absence of IFN-gR expression, IFN-g fails to activate monocytes to secrete TNF-a and produce ROIs. Mutations in IFNGR1 at a downstream hotspot disrupt the intracytoplasmic domain and result in a dominantly expressed disorder. The gene mutation of IFNGR2 also induces similar clinical features.

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 DTH. Cytokine produced by T_H2 cells such as IL-4 and IL-10 down-regulate production of T_H1 cytokines or counteract actions of T_H1 cytokines. Recent studies also indicate importance of naturally occurring and inducible regulatory T cells that suppress effector cell proliferation directly or indirectly by producing cytokines such as interleukin-10 and transforming growth factor–beta (TGF-b). Drugs that block components of DTH include the histamine-2 (H2)–receptor antagonist cimetidine and the prostaglandin antagonist indomethacin.

Frequency

United States

Seventy-five percent of healthy children aged 12-36 months mount positive DTH 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 DTH 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.

Recently discovered primary immunodeficiencies involving the interleukin-12/IFN-g axis are caused by mutations in IFNGR1, IFNGR2, STAT-1, STAT-4, IL-12p40 (IL12P40) subunit, and IL-12 receptor beta-1 (IL12RB1). These immunodeficiencies are rare, and the frequency is not known.

International

The presence of DTH 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.

Gene mutations in IFNGR1/IFNGR2 have been initially identified in the Mediterranean area. These mutations are associated with defective granuloma formation and impaired clearance against nontuberculous mycobacteria (NTM) and nontyphus Salmonella species.

Mortality/Morbidity

DTH skin testing is almost never associated with mortality or morbidity. The major error is associated with failure of differentiating anergy from negative DTH reactivity. Anergy may result from overwhelming infection or immunodeficiency. Secondary immunodeficiency is commonly due to therapy with corticosteroids, chemotherapy, calcineurin inhibitors (eg, cyclosporine, tacrolimus), and various monoclonal antibodies directed against the immune system.

• 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, DTH reactivity through activation of other components of DTH responses despite decreased production of IFN-g, although they develop severe, disseminated mycobacterial and BCG infection.


• Mutations in IFNGR2, STAT-1, IL12P40, and IL12RB1 are autosomal recessive. Mutations found in complete IFN-gR deficiency are also autosomal recessive. Mutations in IFNGR1 that affect the downstream intracytoplasmic domain are autosomal dominant and are clinically manifested as partial IFN-gR deficiency. Patients with complete IFN-gR deficiency often succumb to death from overwhelming infection caused by NTM BCG at young age. Severe CMV infection is also described in these patients. Mutations partially impairing IFN-g 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/interleukin-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

• DTH reactivity to Candida antigens can be detected in infants as young as 3-4 months, but reactivity is dependent on exposure to the antigen.
• Positive DTH 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 mutations 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 DTH skin test reactivity is crucial. HIV infections and malignancies, such as Hodgkin lymphoma, also negate DTH responses. The presence of any cause for immunosuppression modifies the interpretation of tuberculin DTH skin tests; in an immunosuppressive condition, 5-mm induration is interpreted as a positive response.

• DTH 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 MMR recently (£3 wk). Systemic steroid therapy can cause anergy; however, inhaled steroids with high bioavailability could also decrease DTH 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 SCID or another severe T-cell immunodeficiency.


• A patient with disseminated BCG or 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 DTH 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 DTH response.


• DTH 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 DTH skin testing.


• DTH skin test reactivities for histoplasmosis and blastomycosis cross-react. In addition, positive DTH 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 DTH 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.

• DTH skin test reactivity to most antigens is read as positive when induration is 5 mm or more at 48 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 DTH 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 DTH reactions; thus, a patient who received hematopoietic stem cell transplant from a donor with positive DTH responses to the specific antigen could reveal positive DTH responses to the same antigen.


• Contact DTH reactions occur in patients with poison ivy and nickel hypersensitivity


• DTH to sulfonamides, phenytoin, and carbamazepine has been described. Reactions to penicillin-type antibiotics may be cell-mediated, but IgG-mediated responses are much more common.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Consider primary T-cell immunodeficiency, including 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 IFN-g or its production include IFNGR1, IFNGR2, STAT-1, IL12P4, and IL12RB1. As a result, these patients may manifest altered (often excessive) DTH skin test reactivity.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Characteristics of the antigens determine the delayed-type hypersensitivity (DTH) skin test reactivity. Conjugation of the antigen to lipids facilitates the DTH 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 IgE-mediated response and may diminish the DTH skin test reactivity. High doses of antigens that induce predominant T_H2 responses, such as in miliary tuberculosis, abrogate the DTH responses by a negative feedback mechanism that suppresses T_H1 responses.
• • By convention, the antigens used for DTH skin testing are injected ID 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 DTH induced by CMI (type IV reactivity). The Food and Drug Administration (FDA)–approved antigens for DTH skin testing are limited to PPD of M tuberculosis and mumps.
  
  
  • 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 DTH 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 DTH responses, for example, to PPD even though the patient is also infected with tuberculosis.
  
  
  • Antigens that are poorly immunogenic in children and in some adults include mumps and Trichophyton. 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 DTH 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 DTH 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 DTH 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 IFN-g, TNF-a, and 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.


• 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, and IL12RB1 mutations. In profound primary T-cell deficiencies such as SCID, the pattern of cell surface marker expression of lymphocyte and NK cells may identify the type of T-cell defect in conjunction with the clinical manifestations.


• Mutational analysis for IFNGR1, IFNGR2, STAT-1, IL12P40, and IL12RB1 is available in specific research laboratories.


• Additional genes that control downstream immune responses initiated by IFN-g in the DTH response are recognized; IFNGR2 does not bind IFN-g but is needed for the activation of STAT-1 and its translocation to the nucleus. Various mutations in TNF-a, TNF-a receptor, or in genes that regulate APC function may be identified in the future.

Procedures

• When disseminated BCG or 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 DTH 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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Delayed-type hypersensitivities (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 DTH reactions.

• DTH 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 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 DTH 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 IFN-g/IL-12 signaling pathway, medical care includes consideration of hematopoietic stem cell transplantation in patients with severe deficiencies and consideration of exogenous IFN-g therapy in patients with partial deficiencies with milder clinical features. In the presence of 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 DTH response.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

PPD (to evaluate exposure to M tuberculosis) and the mumps antigen are the only currently available FDA-approved antigens for delayed-type hypersensitivity (DTH) skin testing. The most clinically informative antigens used for DTH reactivity are Candida and tetanus antigens, since 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 DTH antigens withdrawn from clinical use include the CMI multitest, coccidioidin, and histoplasmin.

Drug Category: Tuberculin tests

These agents are used to detect infection with M tuberculosis.

Drug Category: Mumps antigens

Mumps antigen is a relatively poor antigen in eliciting a positive DTH 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 MMR immunization.

Drug Category: 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.

Drug Category: 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 DTH 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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Consider patients with most T-cell disorders for stem cell transplantation, usually by bone marrow transplantation using an MHC-matched related or unrelated donor.


• Only a few cases of bone marrow transplantation have been reported in patients with mutations in the IFN-g and IL-12 signaling pathway, with rather unfavorable results. Intact T-cell functions other than IFN-g/IL-12 axis increases the risk of graft rejection and appears to demand a more potent conditioning regimen.

Further Outpatient Care

• See Medical Care and Medication.

In/Out Patient Meds

• See Medical Care and Medication.

Deterrence/Prevention

• Patients in whom cell-mediated immunodeficiency diseases are suspected should never receive the BCG or smallpox vaccine. Similarly, MMR vaccine is contraindicated, although this vaccine is not administered until age 1 year, by which time most T-cell disorders have been diagnosed.
• Patients with IFNGR1, IFNGR2, STAT-1, IL12P40, or IL12RB1 mutations are advised to receive prophylaxis against 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 DTH suggest that other infections may also occur in the absence of effective CMI. These infections include L monocytogenes, L pneumophila, T gondii, and Leishmania species.
• • In humans with idiopathic disseminated BCG or mutations in the IFN-g signaling pathway, the risk of contracting nontyphus Salmonella infections increases.
  
  
  • One report describes severe infections with viruses (eg, respiratory syncytial virus [RSV], parainfluenza virus, HSV, cytomegalovirus [CMV], and varicella-zoster virus [VZV]) in a patient with an IFN-g 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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to investigate cell-mediated immunity in patients with disseminated BCG, 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 signaling pathway, including those with IFNGR1, IFNGR2, STAT-1, STAT-4, IL-12P40, and IL12R mutations.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: May 21, 2007