Hypogammaglobulinemia

Background

Hypogammaglobulinemia is a clinicolaboratory entity with varied causes and manifestations. Several codes in the International Classification of Diseases, 9^th edition (ICD-9) relate to disorders in which hypogammaglobulinemia is a primary feature. These include deficiencies of humoral immunity, which is coded 279.0. The common clinical feature of hypogammaglobulinemia relates to a predisposition toward infections, which normally are defended against by antibody responses. These include Streptococcus pneumoniae and Haemophilus influenzae infections, which frequently involve the respiratory tract. While primary immunodeficiencies causing hypogammaglobulinemia are relatively uncommon, the demand for gammaglobulin treatment has grown and placed demands on the limited supply of this treatment. Therefore, an awareness of the appropriate diagnostic and therapeutic approaches to hypogammaglobulinemia is important.

Specific immune response is based on 2 major components, ie, (1) humoral immunity supported by B lymphocytes or B cells and (2) cellular immunity supported by T lymphocytes or T cells. Immunoglobulins (Igs) produced by B cells play a central role in humoral immunity, and deficiency may result in dramatic consequences for the body's defense against infections. Disorders of the immune system that can result in hypogammaglobulinemia can involve B cells, T cells, or both.

The finding of low levels of gammaglobulin is often of concern to the general pediatrician, as the particular form of immune deficiency is not immediately apparent. Furthermore, the prognosis of the particular immunologic derangement is not clear to the patient or her family. The typical causes of hypogammaglobulinemia are presented. The information in this article is not meant to be a comprehensive review but, rather, a guide on the differential diagnoses of hypogammaglobulinemia. This article provides a review of the causes, clinical symptoms, diagnosis, complications, and treatment of hypogammaglobulinemia.

Pathophysiology

Immunoglobulins play a dual role in the immune response by recognizing foreign antigens and triggering a biological response that attempts, and usually succeeds, to eliminate the antigen. The human immune system is capable of producing up to 10⁹ different antibody species to interact with a wide range of antigens. The 9 known isotypes, named after the heavy-chain isotype, are IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE.

The structural diversity of Ig isotypes is reflected in their functions. IgG isotypes represent the major component (approximately 85%) of all serum antibodies. By binding to the Fc receptors, they mediate many functions, including antibody-dependent cell-mediated cytotoxicity, phagocytosis, and clearance of immune complexes. IgM plays a pivotal role in the primary immune response. IgG1, IgG3, and IgM, and, to a lesser degree IgG2, fix and activate complement.

In general, IgG1 is the major component of the response to protein antigens (eg, antitetanus and antidiphtheria antibodies). IgG2 is produced in response to polysaccharide antigens (eg, antipneumococcal antibodies); however, some patients who lack IgG2 still respond to polysaccharide antigens. IgG3 seems to play an important role in the response to respiratory viruses. IgA and, to a lesser extent IgM, produced locally and secreted by mucous membranes, are the major determinants of mucosal immunity. IgG is the only Ig class that crosses the placenta to provide the infant with effective humoral immunity during the first 7-9 months of life. The levels of maternal antibodies slowly descend over 6-12 months. During this time, the infant begins endogenous production of IgG.

Serum gammaglobulins are primarily composed of immunoglobulins, of which IgG is largest component, constituting about 80% of the immunoglobulins. Immunoglobulins are produced by plasma cells. Catabolism of intravenous immunoglobulins occurs in a concentration-dependent manner, with higher concentrations being cleared faster. This phenomenon has therapeutic implications. Fc receptor function is thought to prevent excessive immunoglobulin catabolism by intracellular lysosomes. Normal renal clearance occurs for immunoglobulin fragments, not intact molecules. These fragments may be elevated in certain disease states and may be detected, for example, as myeloma-associated Bence Jones proteins in the urine.

Acquired or secondary hypogammaglobulinemia usually involves a few general categories. These include medications, renal loss of immunoglobulins, gastrointestinal immunoglobulin loss, B-cell–related malignancies, and severe burns. Renal loss of immunoglobulins is exemplified by nephrotic syndrome, in which IgG loss is usually accompanied by albumin loss. Gastrointestinal loss occurs in protein-losing enteropathies and intestinal lymphangiectasia. Increased catabolism occurs in various diseases, including the B-cell lineage malignancies and severe burns but also in dystrophic myotonia.

Hypogammaglobulinemia may result from lack of production, excessive loss of Igs, or both. Congenital disorders affecting B-cell development can result in complete or partial absence of one or more Ig isotypes. Because B, T, and natural killer (NK) cells share a common progenitor, defects occurring at early developmental stages may result in combined immunodeficiency involving all cell types.

Regardless of the primary cause, the symptoms depend on the type and severity of the Ig deficiency and the presence or deficiency of cellular immunity. In general, hypogammaglobulinemia results in recurrent infections with specific microorganisms primarily localized to the upper and lower airways. Patients with associated defects in cellular immunity usually present with opportunistic viral and fungal infections.

Frequency

The incidence of genetically determined immunodeficiency is relatively low when compared with acquired immunodeficiency. Humoral immunity deficiencies represent 50% of all primary immunodeficiencies. IgA deficiency is the most common antibody deficiency syndrome, followed by common variable immunodeficiency (CVID). The incidence of these 2 disorders is estimated to be 1 case in 700 persons and 1 case in 50,000-100,000 persons of European ancestry, respectively. Selective IgM deficiency is a rare disorder. IgG4 deficiency is very common and is detected in 10-15% of the general population. It usually does not cause hypogammaglobulinemia and usually is asymptomatic.

Mortality/Morbidity

Patients with hypogammaglobulinemia experience increased incidence of a large spectrum of infections starting at an early age.

• In many of these conditions, the risk of autoimmune disorders and cancer is increased, adding to the morbidity and mortality of infection. Recurrent infections may ultimately lead to significant end-organ damage, particularly involving the respiratory system.
• Patients with certain inherited disorders may not survive infancy or early childhood, and growth may be affected for those who survive. Patients with X-linked severe combined immunodeficiency (XSCID) die before the second year of life if they do not receive allogeneic bone marrow transplantation, while most patients with reticular dysgenesis die in early infancy. Of patients with X-linked agammaglobulinemia (XLA), 15% die of infectious complications by age 20 years. Most patients with Wiskott-Aldrich syndrome (WAS) die when aged approximately 11 years.
• Although intravenous Ig (IVIG) replacement, bone marrow transplantation, and gene therapy have had a significant impact on the natural history of these diseases, therapies are costly and require highly advanced facilities.

Race

No racial or ethnic predilection is recognized.

Sex

In children, primary immunodeficiencies are more common in boys than in girls (male-to-female ratio of approximately 5:1), while in adults, primary immunodeficiencies are diagnosed almost equally in both sexes (male-to-female ratio of approximately 1:1.4).

• Bruton disease, X-linked immunodeficiencies with hyper IgM, XSCID, and WAS are X-linked disorders for which females are carriers and only males are affected. However, WAS has been reported in a girl with skewed inactivation of the X chromosome resulting in an active X chromosome carrying the Wiskott-Aldrich mutation.
• CVID and IgA deficiency affect both sexes equally. They may be familial and frequently are associated with autoimmune disorders.

Age

• Symptoms in Bruton disease begin at age 7-9 months, after a significant decline of maternal antibodies. However, infections in XSCID begin in the first months of life.
• The symptoms of hyper IgM syndromes usually begin during the first 2 years of life.
• Patients with WAS start experiencing recurrent bacterial infections during the first year of life. The incidence of opportunistic infections, such as with Pneumocystis carinii, increases with time as patients survive childhood.
• Patients with reticular dysgenesis begin experiencing recurrent infections soon after birth, which ultimately leads to death in early infancy.
• The age of onset of adenosine deaminase (ADA) deficiency is variable. Most patients are diagnosed during childhood. Because the failure of the immune system is gradual, some cases are not diagnosed until early adulthood.
• IgA deficiency usually is asymptomatic in childhood, and many patients are diagnosed in early adulthood.
• CVID is characterized by varying age of onset, usually occurring by the third decade of life.
• Ig deficiency with thymoma (Good syndrome) affects adults aged 40-70 years.

Treatment

Medical Care

• IVIG replacement therapy is the treatment of choice for all primary immunodeficiency syndromes (except IgA deficiency), including Bruton disease, CVID, SCID, hyper IgM, and Wiskott-Aldrich syndrome (WAS).
• Patients with IgG subclass deficiency should not be given IVIG unless they fail to produce antibodies to protein and polysaccharide antigens and if they do not respond to prophylactic antibiotics.
• In selective IgA deficiency, IVIG therapy is not indicated. Oral administration of Ig may improve chronic diarrhea.
• Effort should be focused on the treatment of infections, allergic reactions, autoimmune diseases, and gastrointestinal diseases. Aggressive and prolonged antibiotic therapy covering S pneumoniae and H influenza is indicated. Due to the high frequency of G lamblia infection in these patients, an empiric course of metronidazole may result in dramatic improvement of the diarrhea and, to a certain extent, of malabsorption syndrome.
• The treatment of acquired hypogammaglobulinemia is directed at the underlying cause. Successful treatment of nephrotic syndrome, and protein-losing enteropathy, may result in improvement of Ig levels.
• IVIG is not indicated in the treatment of lymphoproliferative disorders, unless Ig levels are low in association with recurrent infections.
• Live vaccines (eg, bacille Calmette-Guérin, polio, measles, rubella, mumps) should not be given to patients (or their family members) with T-cell disorders, XLA, or other severe B-cell disorders. In patients with IgA deficiency, live vaccines are not an absolute contraindication if given intramuscularly.
• Interleukin-2 may improve in vitro lymphocyte function in patients with CVID.
• High doses of IVIG or intrathecal Ig may be beneficial in patients with enteroviral meningoencephalitis.
• Bone marrow transplantation is the treatment of choice for patients with SCID. More recently, the success with gene therapy in the treatment of certain patients with SCID revived the hope of definitive cure for these disorders.
• TNF inhibitors have been used to treat granulomatous diseases in patients with CVID.

Activity

Special restrictions on physical activity are not needed.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. The standard treatment for hypogammaglobulinemia is intravenous gammaglobulin (IVIG). IVIG is approved by the US Food and Drug Administration (FDA) for treatment of primary immunodeficiency disease or primary humoral immunodeficiency. As reviewed by the American Academy of Allergy, Asthma, and Immunology, 11 IVIG products are approved for this indication as of November 2005, and the benefit of this treatment for these primary immune deficiencies is based on category IIb evidence. IVIg is approved for only 2 secondary immune deficiencies: B-cell CLL and pediatric HIV. The use of IVIG for primary immune defects with normogammaglobulinemia and impaired specific antibody production is based on category III evidence only.

The usual IVIG dose is 0.4-0.6 g/kg every 3-4 weeks, titrating the dose and interval between infusions to achieve a trough IgG level greater than 500 mg/dL. Some practitioners target trough levels 300 mg/dL higher than pretreatment levels, and trough levels >800 mg/dL may improve pulmonary outcomes. Some centers administer a loading dose of 1g/kg if the patient is agammaglobulinemic.

Gammaglobulin may also be given intramuscularly or subcutaneously. The latter format is useful when allergic reactions limit the dose or rate. Subcutaneous gammaglobulin can be given with home infusions, usually requiring several hours of infusion. Intramuscular gammaglobulin injections were the standard of care before IVIG became readily available and are still useful in certain patients because of the simplicity of administration and fewer reactions. However, local injection site pain can be significant.

Up to 44% of patients report adverse reactions to IVIG that are not rate-related. Usually, the IVIG-associated reactions are anaphylactoid and include back pain, abdominal aching, nausea, rhinitis, asthma, chills, low grade fever, myalgias, and headaches. Renal failure is a less common but serious adverse reaction. Steroid, histamine blockers, and antipyretics can help treat or prevent the reactions, as can slowing the rate. Although most reactions occur during the first infusion, they may occur in repeat infusions of the same product. Although anti-IgA antibodies can be associated with increased reactions, most patients (regardless of anti-IgA antibody status) tolerate IVIG that is not depleted of IgA (IgA-depleted IVIG is available for treatment in patients who cannot tolerate IVIG that is not depleted of IgA).

Drug Category: Immunoglobulins

Improve clinical and immunologic aspects of the disease.

Drug Name	Immune globulin intravenous (Gamimune, Gammagard, Sandoglobulin, Gammar-P)
Description	Results in elevated antiviral or antibacterial antibody titers for 1 mo. Trough levels >500 mg/dL do not necessarily improve infection control except in certain long-standing infections but may significantly increase cost.
Adult Dose	200-400 mg/kg IV q3-4wk to achieve trough level of >400 mg/dL
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; IgA deficiency
Interactions	Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccination)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Check serum IgA before IVIG (when absent, use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; lab result changes associated with infusions include 6-fold increase in ESR for 2-3 wk and apparent hyponatremia

Hypocomplementemia

Background

In the late 19th century, serum was found to contain a nonspecific heat-labile complementary principle that interacted with antibodies to induce bacteriolysis. Ehrlich and Morgan termed this factor complement.

The complement system as understood today is a multimolecular system composed of more than 20 proteins and consisting of serum proteins, serosal proteins, and cell membrane receptors that bind to complement fragments. They constitute 10% of the globulin fraction of serum. Many of these proteins are designated by the letter C and are assigned numbers in the order of their discovery.

Pathophysiology

The complement system consists of 7 serum and 5 membrane regulatory proteins, 1 serosal regulatory protein, and 8 cell membrane receptors that bind complement fragments. Most are synthesized mainly by the liver. Exceptions are C1, factor D, and properdin. These are probably synthesized by macrophages and even by T lymphocytes.

Activation

The complement system functions as an interactive sequence, with one reaction leading to another in the form of a cascade. It is initiated by a wide variety of substances and has 2 phases. In the first phase, a series of specific interactions leads to formation of intrinsic complement proteinase, termed C3 convertase. Depending on the nature of complement activators, the classic pathway, the alternative pathway, or the newly discovered lectin pathway is activated predominantly to produce C3 convertase. Each of these pathways uses different proteins. The second phase for each involves cleavage of C3b, generating multiple biologically important fragments and large, potentially cytolytic complexes.

Classic pathway

This pathway has 2 units. One, the recognition unit, consists of a trimolecular complex of C1q, 2 molecules of C1r, and 2 molecules of C1s held together by calcium. The other is an activation unit of C2, C3, and C4. The sequence starts with the binding of 2 or more C1q recognition units to the Fc nonantigen binding part of antibody. This induces a conformational change, leading to autoactivation of C1r that then cleaves C1s to its active state. This then acts similarly to C1 esterase and cleaves C2 and C4 to form C2aC4b, which is the C3 esterase that cleaves C3 to form C3b. C1q can also be activated by mycoplasmal organisms, RNA viruses, bacterial endotoxins, and cell membranes of some organelles without the presence of antibody.

Alternate pathway

This was discovered by Pillemer and colleagues in 1954 but was recognized universally some years later. This pathway is activated by viruses, fungi, bacteria, parasites, cobra venom, immunoglobulin A, and polysaccharides and forms an important part of the defense mechanism independent of the immune response. Here, C3b binds to factor B that is cleaved by factor D to Bb. C3bBb complex then acts as the C3 convertase and generates more C3 through an amplification loop. Binding of factor H to C3b increases its inactivation by factor I. Properdin stabilizes it, preventing its inactivation by factors H and I. The alternate pathway does not result in a truly nonspecific activation of complement because it requires specific types of compounds for activation. It simply does not require specific antigen-antibody interactions for initiation.

Lectin pathway

The lectin or mannan-binding pathway is activated similar to the classic pathway except that lectin replaces the antibody and an associated protease replaces C1. Instead, mannose-binding protein binds to sugar residues on the surface of a pathogen. Such lectins are associated with a serine protease, similar to the C1r and C1s subcomponents of the classic pathway, that also activates C4 and C2.

Membrane attack complex

Only 5 proteins are involved in the direct killing of cells. C2a4b3b complex from the classic pathway or C3bBb cleaves C5. C5b activates the terminal complement pathway by associating with C6, C7, and C8 to form macromolecular complexes denoted as C5b-8. C9 binds to this complex, inducing a conformational change that exposes a new antigenic site known as C9 neoantigen. Additional C9 molecules form ringlike pores, leading to transmembrane channels that cause cell lysis.

Regulation

The complement system serves a very important role in host defense, but if it is directed against itself, it can lead to serious illness. Therefore, it is closely regulated at almost every step.

Classic pathway

The classic pathway requires the identification of a target by the presence of an antibody. C1 inhibitor (C1-INH) inhibits C1r and C1s by binding covalently to them, causing disassembly of C1 macromolecular complex. The inhibitor is synthesized in the liver and blood monocytes; its gene is located on chromosome 11. C2a4b is very labile and undergoes spontaneous decay with release of C2a and loss of enzymatic activity. C4 binding protein binds C4, accelerates its rate of dissociation from C2a, and makes C4b more susceptible to proteolysis by factor I. Membrane-bound decay-accelerating factor (DAF) promotes release of C2a from C4b2a by physically interfering with C4b and C2a association.

Alternate pathway

Carbohydrate composition and its sialic acid content on the cell surface play an important role in the activation of the alternate pathway. Sialic acid blocks activation by favoring the binding of factor H to C3b, which is then inactivated by factor I. Microorganisms lacking sialic acid are killed, whereas human cells covered with glycophorin A, a sialoglycoprotein, are protected.

C3bBb is relatively labile and undergoes spontaneous decay through dissociation of Bb. Properdin is synthesized by monocytes and T lymphocytes. Properdin binds to C3bBb and stabilizes it, preventing its decay. Factor H competes with factor B for binding to C3b and displaces Bb from C3bBb. It accelerates the inactivation of C3b by factor I. Factor I inactivates C3b to iC3b, a molecule that cannot function enzymatically. Complement receptor 1 (CR1) has factor H–like activity, permitting factor I to cleave C3b. Membrane cofactor protein also has factor H–like activity, mainly for alternative C3 convertase.

Membrane attack complex

Homologous restriction factor, C8 binding protein, is a cell membrane protein with significant sequence homology to both C8 and C9 and is widely distributed on peripheral blood cells. It prevents the interaction of C8 and C9. Membrane-bound CD59, also known as homologous restriction factor 20, prevents the binding of C5b-8 to C9 and inhibits the unfolding of C9 that is required for polymerization and formation of macroscopic pores in the cell membrane. S protein (vitronectin) binds to C5b-7 and abolishes its activity. SP-40,40 (clusterin) has effects similar to vitronectin.

Biologic effects

The biologic effects of complement include promotion of chemotaxis and anaphylaxis, opsonization and phagocytosis of microorganisms, and removal of immune complexes from the circulation. Most complement components are acute phase reactants, and their concentration increases in states of infection, trauma, and injury.

C4a, C3a, and C5a are anaphylatoxins and bind to mast cells, triggering the release of histamine and other mediators, leading to vasodilation, erythema, and swelling. C5a is a major stimulus for influx of neutrophils, basophils, monocytes, and eosinophils.

C3b fixes to the antigen-antibody complex and permits its adherence to cells (eg, neutrophils, basophils, eosinophils, monocytes) that have receptors for C3b. This particular action of opsonization helps in phagocytosis. C3b-coated particles also bind to B lymphocytes and activate them to enhance the primary antibody response. Immune complexes formed in the circulation are coated with C3b and bind to erythrocytes, which then transport them to the liver and spleen for removal. This process maintains the solubility of the immune complexes. In the early phases of viral infection, when the amount of antibody is limited, the fixation of C3b to the viral antigen-antibody complex increases neutralization.

The terminal components of the complement system result in lysis of virus-infected cells, tumor cells, and most microorganisms. They also have a role in neutralization of endotoxins in vitro and protection from their lethal effects in experimental animal models.

Treatment

Medical Care

No specific therapy is recommended at present for most of the complement disorders. However, hereditary angioedema does respond to specific therapy.

• With regard to hereditary angioedema, epinephrine administered early may produce some improvement.
• • Clonal C1-INH administered by infusion aborts acute attacks, and it also is safe and effective for surgical or dental prophylaxis. It has not yet been approved by the US Food and Drug Administration for use in the United States.

  • In the absence of clonal C1-INH, infusion of fresh frozen plasma has been used successfully in acute attacks of angioedema. Fresh frozen plasma has been used prior to dental and surgical procedures; however, this also provides substrate for C1-INH protein and may worsen angioedema, and, hence, it is not recommended for life-threatening laryngeal edema.

  • Danazol, a synthetic androgen, increases the serum concentration of C1-INH and prevents attacks in adults. It is not recommended in children.

  • Stanozolol may be given to the pediatric population.

  • Precipitating factors, such as trauma, estrogens, and angiotensin-converting enzyme inhibitors, should be avoided.

  • The antifibrinolytic agents, epsilon-aminocaproic acid and tranexamic acid, may be effective in both hereditary and acquired C1-INH deficiency. However, these drugs may be associated with intravascular thrombosis.

• Fresh frozen plasma also has been used to restore C3 levels in persons with C3 deficiency. Therapeutic plasma exchange using fresh frozen plasma has been used to replace the deficient complement proteins, but, overall, it has not proved to be a safe and efficient mode of therapy. Its use in patients with SLE has not met with definite success.
• Supportive management can prove helpful in these patients.
• Every attempt should be made to identify the specific defect.

• With the development of fever in these patients, cultures should be obtained and the threshold for beginning antibiotic therapy should be low. The use of prophylactic antibiotics is controversial. Prophylactic antibiotics reduce the frequency of infection in patients with C6 deficiency, who are susceptible to meningococcal infection. However, concern for the development of antibiotic resistance and the duration of prophylaxis remain unresolved issues.

• Make certain adequate information is provided to the patient or guardian for possible use by school, camp, or other health care personnel or physicians.

• Immunization of the patient and household contacts for pneumococci, H influenzae, and N meningitidis is recommended.

• Replacement therapy with recombinant complement proteins may soon be possible; gene therapy may become a viable option in the near future.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Androgens, synthetic

In hereditary angioedema, stanozolol and danazol increase level of deficient C1-INH and prevent attacks. Danazol not recommended in children.

Drug Name	Danazol (Danocrine)
Description	Increases C4 levels and reduces attacks associated with angioedema.
Adult Dose	200 mg PO bid/tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; seizure disorders; hepatic, renal, or cardiovascular insufficiency; pregnancy; lactation; undiagnosed genital bleeding; porphyria; a history of thromboembolism
Interactions	Inhibits hepatic metabolism of carbamazepine, warfarin, cyclosporin, and (possibly) tacrolimus; reduces maintenance requirement for alfacalcidol
Pregnancy	X - Contraindicated in pregnancy
Precautions	Caution in renal, hepatic, or cardiac insufficiency; caution in seizure disorders and epilepsy; use care in patients with diabetes mellitus, polycythemia, and a history of thrombosis

Drug Name	Stanozolol (Winstrol)
Description	Synthetic androgen with immunosuppressive properties. Increases C1 esterase inhibitor and C4 levels.
Adult Dose	2 mg PO tid initially; reduce to maintenance dose of 2 mg/d or 2 mg qod after 1-3 mo
Pediatric Dose	<6 years: 1 mg/d PO 6-12 years: 2 mg/d PO >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; nephrosis, breast or prostate cancer
Interactions	Increases hypoprothrombinemic effects of oral anticoagulants and hypoglycemic effects of insulin and sulfonylureas
Pregnancy	X - Contraindicated in pregnancy
Precautions	May cause peliosis hepatitis, liver cell tumors, and blood lipid changes, with increased risk of arteriosclerosis; caution in cardiac, renal, or hepatic disease or epilepsy; may increase PT; phallic or clitoral enlargement, hirsutism, gynecomastia, acne, edema, nausea, vomiting, and diarrhea may occur

Hypersensitivity Reactions, Immediate

Background

The immune system is an integral part of human protection against disease, but the normally protective immune mechanisms can sometimes cause detrimental reactions in the host. Such reactions are known as hypersensitivity reactions, and the study of these is termed immunopathology. The traditional classification for hypersensitivity reactions is that of Gell and Coombs and is currently the most commonly known classification system. It divides the hypersensitivity reactions into the following 4 types:

• Type I reactions (ie, immediate hypersensitivity reactions) involve immunoglobulin E (IgE)–mediated release of histamine and other mediators from mast cells and basophils.

• Type II reactions (ie, cytotoxic hypersensitivity reactions) involve immunoglobulin G or immunoglobulin M antibodies bound to cell surface antigens, with subsequent complement fixation.

• Type III reactions (ie, immune-complex reactions) involve circulating antigen-antibody immune complexes that deposit in postcapillary venules, with subsequent complement fixation.

• Type IV reactions (ie, delayed hypersensitivity reactions, cell-mediated immunity) are mediated by T cells rather than by antibodies.

Some authors believe this classification system may be too general and are now in favor of a more recent classification system proposed by Sell et al. This system divides immunopathologic responses into the following 7 categories:

• Inactivation/activation antibody reactions

• Cytotoxic or cytolytic antibody reactions

• Immune-complex reactions

• Allergic reactions

• T-cell cytotoxic reactions

• Delayed hypersensitivity reactions

• Granulomatous reactions

This system accounts for the fact that multiple components of the immune system can be involved in various types of hypersensitivity reactions. For example, T cells play an important role in the pathophysiology of allergic reactions . In addition, the term immediate hypersensitivity is somewhat of a misnomer because it does not account for the late-phase reaction or for the chronic allergic inflammation that often occurs with these types of reactions.

Allergic reactions manifest clinically as anaphylaxis, allergic asthma, urticaria, angioedema, allergic rhinitis, some types of drug reactions, and atopic dermatitis. These reactions tend to be mediated by IgE, which differentiates them from anaphylactoid reactions that involve IgE-independent mast cell and basophil degranulation. Such reactions can be caused by iodinated radiocontrast dye, opiates, or vancomycin and appear similar clinically by resulting in urticaria or anaphylaxis.

Patients prone to IgE-mediated allergic reactions are said to be atopic. Atopy is the genetic predisposition to make IgE antibodies in response to allergen exposure.

The focus of this article is allergic reactions in general. Although some of the clinical manifestations listed previously are briefly mentioned, refer to the articles on these topics for more detail.

Pathophysiology

Immediate hypersensitivity reactions are mediated by IgE, but T and B cells play important roles in the development of these antibodies. CD4 cells or helper T (TH) cells have been divided into 2 broad classes based on the cytokines they produce.

TH1 cells produce interferon gamma, interleukin (IL)–2, and tumor necrosis factor-beta and promote a cell-mediated immune response (eg, delayed hypersensitivity reaction). TH2 cells, on the other hand, produce IL-4 and IL-13, which then act on B cells to promote the production of antigen-specific IgE. Therefore, TH2 cells play an important role in the development of immediate hypersensitivity reactions, and patients who are atopic are thought to have a higher TH2-to-TH1 cell ratio. Interestingly, the cytokines produced by TH1 cells (specifically interferon gamma) seem to diminish the production of TH2 cells.

The allergic reaction first requires sensitization to a specific allergen and occurs in genetically predisposed individuals. The allergen is either inhaled or ingested and is then processed by the dendritic cell, an antigen-presenting cell. The antigen-presenting cells then migrate to lymph nodes, where they prime naive TH cells (TH0 cells) that bear receptors for the specific antigen.

TH0 cells are undifferentiated CD4 cells that release both TH1 and TH2 cytokines and can develop into either cell type. In the case of allergen sensitization, the TH0 cells are thought to be exposed to IL-4 (from as yet unidentified sources, but including germinal-center B cells) and possibly to histamine-primed dendritic cells, both of which cause them to develop into TH2 cells. These primed TH2 cells then release more IL-4 and IL-13. IL-4 and IL-13 then act on B cells to promote production of antigen-specific IgE antibodies.

For this to occur, B cells must also bind to the allergen via allergen-specific receptors. They then internalize and process the antigen and present it to the TH2 cells on the major histocompatibility class II molecules found on B-cell surfaces. The B cell must also bind to the TH2 cell and does so by binding the CD40 expressed on its surface to the CD40 ligand on the surface of the TH2 cell. IL-4 and IL-13 released by the TH2 cells can then act on the B cell to promote class switching from immunoglobulin M production to antigen-specific IgE production.

The antigen-specific IgE antibodies can then bind to high-affinity receptors located on the surfaces of mast cells and basophils. Reexposure to the antigen can then result in the antigen binding to and cross-linking the bound IgE antibodies on the mast cells and basophils. This causes the release of chemical mediators from these cells. These mediators include preformed mediators, newly synthesized mediators, and cytokines. The major mediators and their functions are described as follows:

Preformed mediators

• Histamine: This mediator acts on histamine 1 (H1) and histamine 2 (H2) receptors to cause contraction of smooth muscles of the airway and GI tract, increased vasopermeability and vasodilation, nasal mucus production, airway mucus production, pruritus, cutaneous vasodilation, and gastric acid secretion.
  

• Tryptase: Tryptase is a major protease released by mast cells; its exact role is uncertain, but it can cleave C3 and C3a. Tryptase is found in all human mast cells but in few other cells and thus is a good marker of mast cell activation.
  

• Proteoglycans: Proteoglycans include heparin and chondroitin sulfate. The role of the latter is unknown; heparin seems to be important in storing the preformed proteases and may play a role in the production of alpha-tryptase.
  

• Chemotactic factors: An eosinophilic chemotactic factor of anaphylaxis causes eosinophil chemotaxis; an inflammatory factor of anaphylaxis results in neutrophil chemotaxis. Eosinophils release major basic protein and, together with the activity of neutrophils, can cause significant tissue damage in the later phases of allergic reactions.

Newly formed mediators

• Arachidonic acid metabolites
  

• • Leukotrienes - Produced via the lipoxygenase pathway
  • Leukotriene B4 - Neutrophil chemotaxis and activation, augmentation of vascular permeability
  • Leukotrienes C4 and D4 - Potent bronchoconstrictors, increase vascular permeability, and cause arteriolar constriction
  • Leukotriene E4 - Enhances bronchial responsiveness and increases vascular permeability
  • Leukotrienes C4, D4, and E4 - Comprise what was previously known as the slow-reacting substance of anaphylaxis
    
  • Cyclooxygenase products
  • Prostaglandin D2 - Produced mainly by mast cells; bronchoconstrictor, peripheral vasodilator, coronary and pulmonary artery vasoconstrictor, platelet aggregation inhibitor, neutrophil chemoattractant, and enhancer of histamine release from basophils
  • Prostaglandin F2 - Bronchoconstrictor, peripheral vasodilator, coronary vasoconstrictor, and platelet aggregation inhibitor
  • Thromboxane A2 - Causes vasoconstriction, platelet aggregation, and bronchoconstriction
    

• Platelet-activating factor: This is synthesized from membrane phospholipids via a different pathway from arachidonic acid. It aggregates platelets but is also a very potent mediator in allergic reactions. It increases vascular permeability, causes bronchoconstriction, and causes chemotaxis and degranulation of eosinophils and neutrophils.
  

• Adenosine: This is a bronchoconstrictor, and it potentiates IgE-induced mast cell mediator release.
  

• Bradykinin: Kininogenase released from the mast cell can act on plasma kinins to produce bradykinin. Bradykinin increases vasopermeability, vasodilation, hypotension, smooth muscle contraction, pain, and activation of arachidonic acid metabolites. However, its role in IgE-mediated allergic reactions has not been clearly demonstrated.

Cytokines

• IL-4: This stimulates and maintains TH2 cell proliferation and switches B cells to IgE synthesis.
• IL-5: This cytokine is key in the maturation, chemotaxis, activation, and survival of eosinophils. IL-5 primes basophils for histamine and leukotriene release.
• IL-6: IL-6 promotes mucus production.
• IL-13: This cytokine has many of the same effects as IL-4.
• Tumor necrosis factor-alpha: This activates neutrophils, increases monocyte chemotaxis, and enhances production of other cytokines by T cells.

The actions of the above mediators can cause variable clinical responses depending on which organ systems are affected, as follows:

• Urticaria/angioedema: Release of the above mediators in the superficial layers of the skin can cause pruritic wheals with surrounding erythema. If deeper layers of the dermis and subcutaneous tissues are involved, angioedema results. Angioedema is swelling of the affected area; it tends to be painful rather then pruritic.
  

• Allergic rhinitis: Release of the above mediators in the upper respiratory tract can result in sneezing, nasal congestion, rhinorrhea, and itchy or watery eyes.
  

• Allergic asthma: Release of the above mediators in the lower respiratory tract can cause bronchoconstriction, mucus production, and inflammation of the airways, resulting in chest tightness, shortness of breath, and wheezing.

• Anaphylaxis: Release of the above mediators that affect more than one system is known as anaphylaxis. In addition to the foregoing, the GI system can also be affected with symptoms of nausea, abdominal cramping, and diarrhea. Systemic vasodilation and vasopermeability can result in significant hypotension and is referred to as anaphylactic shock. This can be life threatening.

Allergic reactions can occur as immediate reactions, late-phase reactions, or chronic allergic inflammation. Immediate or acute-phase reactions occur within seconds to minutes after allergen exposure. Some of the mediators released by mast cells and basophils cause eosinophil and neutrophil chemotaxis.

These and other cells (eg, monocytes, T cells) are believed to cause the late-phase reactions that can occur hours after antigen exposure and after the signs or symptoms of the acute-phase reaction have resolved. The signs and symptoms of the late-phase reaction can include redness and swelling of the skin, nasal discharge, airway narrowing, sneezing, coughing, and wheezing. These effects can last a few hours and usually resolve within 24-48 hours.

Finally, continuous or repeated exposure to an allergen (eg, a cat-owning patient who is allergic to cats) can result in chronic allergic inflammation. Tissue from sites of chronic allergic inflammation contains eosinophils and T cells (particularly TH2 cells). Eosinophils can release many mediators (eg, major basic protein), which can cause tissue damage and thus increase inflammation. This can result in structural and functional changes to the affected tissue. Furthermore, a repeated allergen challenge can result in increased levels of antigen-specific IgE, which ultimately can cause further release of IL-4 and IL-13, thus increasing the propensity for TH2 cell/IgE–mediated responses.

Frequency

United States

• The prevalence of atopic diseases has increased significantly over the past 2 decades in Western societies.

• Allergic rhinitis is the most prevalent allergic disease; it affects approximately 22% or more of the population.

• Asthma is estimated to affect more than 20 million people. Ninety-five percent of asthma cases in children are estimated to be allergic, compared with 50-70% in adults.

• Atopic dermatitis has also increased in prevalence over the past 20 years; prevalence in the United States is likely similar to that in Europe (see below, Internationally).

• The prevalence of anaphylaxis has been much more difficult to assess.

International

• The estimated prevalence of atopic dermatitis among school children in various European countries is 15-20%.

• Asthma, as with other atopic diseases, is increasing in prevalence.
  • Studies in Africa and Europe have shown a greater prevalence of reversible bronchospasm in urban populations compared with rural populations. This was initially thought to be related to environmental pollution, but the results from studies of asthma prevalence before and after the unification of Germany contradict this theory.

  • The prevalence of asthma in East Germany prior to 1990 was lower than in West Germany, despite the fact that East Germany had more air pollution.

  • Over the 10 years after unification, the prevalence of asthma in the former East Germany increased and is now comparable with that of former West Germany.

• In addition, children placed in day care and with older siblings have a lower likelihood of developing atopic disease.

• These findings have led to the hygiene hypothesis, which proposes that early exposure to infectious agents helps direct the immune system toward a TH1 cell–predominant response that, in turn, inhibits the production of TH2 cells.

Mortality/Morbidity

• Mortality from allergic diseases occurs primarily from anaphylaxis and asthma, although deaths from asthma are relatively rare. In 1995, 5579 people died from asthma in the United States. Approximately 500 people die annually from anaphylaxis in the United States.

• Allergic diseases are a significant cause of morbidity. In 1990, the economic impact of allergic diseases in the United States was estimated to be $6.4 billion from health care costs and lost productivity. Children with untreated allergic rhinitis do worse on aptitude tests than their nonatopic peers.

Race

• Any differences in the prevalence of allergic diseases with respect to race seem to be more related to environmental factors than to true racial differences. For example, in the United States, the prevalence of asthma is 2.5 times higher in African Americans than in whites. Asthma is more prevalent in inner-city populations, and this may explain the difference.

Sex

• Some unexplained differences exist in the prevalence of allergic diseases between the sexes. Asthma is more prevalent in boys during the first decade of life; after puberty, prevalence is higher in females. The male-to-female ratio of children who have atopic disease is approximately 1.8:1.

• Skin test reactivity in women can fluctuate with the menstrual cycle, but this is not clinically significant.

Age

• In general, allergic rhinitis symptoms (and skin test reactivity) tend to wane with increasing age.

• Food allergies and subsequent anaphylaxis are more prevalent in children. Some children may outgrow their allergies to certain foods, or their reactions may diminish over time. However, anaphylaxis from food and other triggers is still a threat in adults.

• Childhood asthma is more prevalent in boys and can often resolve by adulthood. However, females tend to develop asthma later in life (beginning in adolescence) and can also have asthma that is more severe.

Treatment

Medical Care

• Anaphylaxis
  • Assessment of the reaction is described as follows:
    • Withdraw the offending agent if applicable (eg, stop drug infusion).

    • Check the airway and secure if needed. Patients with respiratory compromise may need to be intubated. If laryngeal edema causes oral intubation to be difficult, a tracheostomy must be performed.

    • Assess the level of consciousness and vital signs.

  • Treatment is as follows:
    • Administer epinephrine immediately .

    • Start intravenous fluids; these should be administered rapidly and as blood pressure and overall fluid status warrant.

    • Consider other vasopressors (eg, dopamine) if hypotension does not respond to the above measures. Norepinephrine may be used if dopamine is not effective. Importantly, isoproterenol should not be used because it is a peripheral vasodilator. Patients with beta-adrenergic blockade may be particularly difficult to treat. They have both chronotropic and inotropic cardiac suppression and may not respond to the above treatments. Glucagon has positive inotropic and chronotropic effects and is the drug of choice in these cases. Atropine can also be used but will only be effective in treating bradycardia.

    • H1- and H2-receptor blockers can be helpful in alleviating pruritus, urticaria, rhinorrhea, and other symptoms. Cimetidine, when combined with any of several H1 antihistamines, has been demonstrated to block histamine-induced hypotension. Other H2 blockers have not been studied in this context.

    • Use albuterol nebulizers if needed.

    • Administer a corticosteroid, which is believed to help prevent or control the late-phase reaction.

    • Transfer the patient to the hospital for further observation and care.

  • Prevention is as follows:
    • Avoid the triggering allergen as much as possible.

    • Patients should be given a prescription for at least 2 predosed epinephrine pens (EpiPens) and instructed in their proper use. Importantly, patients must carry these pens at all times.

    • Patients should be taught what measures to take in case of a future anaphylactic reaction, ie, immediately administer epinephrine, call emergency services (eg, 911), or go to the nearest emergency department (even if feeling better after the epinephrine).

• Allergic rhinitis
  • Avoid the offending allergen, if possible.

  • H1-receptor blockers are helpful for controlling itchiness, rhinorrhea, and lacrimation but most have little effect on nasal congestion.

  • Administer an intranasal glucocorticosteroid to control nasal symptoms, including nasal congestion.

  • Other topical nasal agents include azelastine (an H1-receptor blocker) and cromolyn (a mast cell stabilizer).

  • Topical decongestants, mast cell stabilizers, or antihistamines can be used for ocular symptoms; artificial tears might be helpful in mild cases, and this product can be refrigerated for an extra cooling effect. Cold compresses can also be used.

  • Antigen-injection immunotherapy should be considered for symptoms not well controlled with medications. The mechanism of action of immunotherapy is not yet fully elucidated. Immunotherapy causes antigen-specific immunoglobulin G to be formed and lowers antigen-specific IgE over time. Some authorities theorize that immunotherapy results in an increase in the TH1-to-TH2 cell ratio. Regulatory T cells may also play an important role.

• Asthma
  • Avoid the offending allergen, if possible.

  • A key factor in controlling allergic asthma is controlling allergic rhinitis symptoms.

  • Therapy depends on the severity of disease.
    • Patients should have an albuterol metered-dose inhaler (MDI) (or nebulizers for young children) to use as needed.

    • Long-acting beta-agonists and inhaled glucocorticosteroids should be added if appropriate. In general, these medications are used if symptoms occur more than twice weekly or if spirometry findings are abnormal in the absence of symptoms.

    • Leukotriene inhibitors can also be added.

    • Systemic steroid bursts may need to be used for exacerbations of severe cases.

    • In patients refractory to the usual medications and who have antigen-specific IgE to environmental aeroallergens (positive skin test or RAST result), therapy with omalizumab (Xolair), a humanized monoclonal antibody that prevents binding of IgE to high-affinity IgE receptors on mast cells and basophils, may result in improvement.

• Urticaria/angioedema
• • Avoid the offending allergen if known.

  • An H1-receptor blocker should be added. If symptoms are not controlled with this alone, an H2-receptor blocker, leukotriene inhibitor, or oral glucocorticosteroid can be added.

• Atopic dermatitis
  • Avoid the offending allergen if possible, and properly hydrate and care for the skin.

  • Topical glucocorticosteroids and topical immunomodulators (eg, tacrolimus) can be used.

Consultations

• Consultation with a pulmonologist and/or critical care medicine specialist may be necessary for anaphylactic shock or severe asthma exacerbations.

• Consult an allergist or immunologist for the following conditions:
• • Allergic rhinitis not easily controlled with medications

  • Asthma: Of patients with asthma, 50% have allergies as factors causing or contributing to their asthmatic inflammation.

  • Chronic urticaria (>6 wk)

  • History of anaphylaxis from insect bite or sting

  • History of anaphylaxis with unknown cause

  • Possible drug desensitization (if known allergy to drug for which no good alternatives are available)

  • Atopic dermatitis

Diet

• Patients should avoid foods to which they are allergic.
• • Certain food proteins can cross-react with other proteins (eg, latex with avocado, banana, kiwi, chestnut, pineapple, passion fruit, apricot, and grape; ragweed with watermelon, cantaloupe, honeydew melon).

  • Patients must be counseled about these possible cross-reactivities and should avoid the food if it causes symptoms.

Medication

Medical therapy varies somewhat depending on which type of allergic reaction is being treated. Some of the drugs and their categories are listed here, but refer to the articles on the specific allergic reaction for more detail.

Drug Category: Vasopressors

First-line choice to reverse effects of systemic vasodilation and increased vasopermeability observed with anaphylaxis. Although not the first choice for bronchoconstriction, epinephrine can also relieve some symptoms of bronchospasm and rhinitis. In the past, protocols called for subcutaneous or intravenous administration of epinephrine. However, studies have shown that intramuscular epinephrine leads to higher plasma levels than subcutaneous delivery. Intramuscular administration is now preferred over subcutaneous administration.

Drug Name	Epinephrine (Adrenalin, Bronitin, EpiPen)
Description	Should be administered immediately for anaphylaxis/anaphylactic shock. Multiple preparations allow for delivery SC, IM, IV, or ET. Doses can be repeated q5min prn to maintain blood pressure (and as heart rate allows).
Adult Dose	IM: 0.25-0.50 mL of a 1:1000 solution for moderate symptoms; repeat prn; anterior lateral thigh is preferred site for severe anaphylaxis IV: 0.5-1 mL of 1:10,000 solution for severe symptoms; repeat prn; continuous infusion at 0.1-1 mcg/kg/min may be required for anaphylactic shock ET: 1 mL of 1:10,000 solution in 10 mL NS; repeat prn Self-injection (IM): Preloaded auto-injector (EpiPen)
Pediatric Dose	IM: 0.01 mg/kg of 1:1000 solution; repeat q5min prn; not to exceed 0.3-0.5 mg; anterior lateral thigh is preferred site for severe anaphylaxis IV: 0.01 mg/kg of 1:10,000 solution; repeat prn ET: 0.01 mg/kg of a 1:1000 solution in 5 mL NS; repeat prn Self-injection (IM): Preloaded auto-injector (EpiPen Jr)
Contraindications	Documented hypersensitivity; relative (not absolute) contraindications include severe CAD, hypertension, narrow-angle glaucoma, and presence of life-threatening arrhythmias
Interactions	Beta-blockers decrease effectiveness; may decrease effectiveness of diabetic medications; MAOIs, methyldopa, methylphenidate, TCAs, thyroxine, and sodium bicarbonate can potentiate effects of all sympathomimetics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Consult PDR for all possible adverse effects; caution should be used in patients with known severe CAD, advanced age, prostatic hypertrophy, hypertension, cardiovascular disease, diabetes mellitus, hyperthyroidism, and cerebrovascular insufficiency; rapid IV infusions may cause death from cerebrovascular hemorrhage or cardiac arrhythmias

Drug Category: Bronchodilators

Inhaled bronchodilators are beta-agonists that come in short- and long-acting forms. Short-acting bronchodilators are used to treat acute bronchospasm. Can also be used prophylactically. For example, a patient with a history of asthma exacerbation in the presence of cats can use a short-acting bronchodilator before exposure to cats. Long-acting bronchodilators (eg, salmeterol) can be used twice daily and to help maintain bronchodilation over 12 h. Pirbuterol is now available and is both a short- and long-acting form. Onset of action is approximately 15 min, but effects last up to 12 h. Finally, levalbuterol is the R-enantiomer of albuterol and is available in nebulizer form. Advantage of levalbuterol is that it is less likely to cause paradoxical bronchospasm than racemic albuterol.

Previously, MDIs were made using chlorofluorocarbons (CFCs) as the propellant. However, the use of CFCs is being phased out because of environmental concerns. For this reason companies are now making MDIs with hydrofluoroalkane-134A, which is not damaging to the ozone layer. By 2006, products will no longer contain CFCs. Importantly, note that while a spacer should be used with traditional MDIs, spacers are not necessary for inhalers with hydrofluoroalkane-134A.

Drug Name	Albuterol (Ventolin, Ventolin HFA, Airet, Proventil, Proventil HFA)
Description	Sympathomimetic that stimulates beta-2 receptors, leading to bronchodilation. Used for bronchospasm refractory to epinephrine with anaphylaxis. First-line choice for acute bronchospasm associated with asthma.
Adult Dose	1.25-5 mg in 2-5 mL of sterile 0.9% NS solution via nebulization 2-4 puffs via MDI q4-6h prn; not to exceed 12 puffs/d
Pediatric Dose	PO 2-5 years: 0.1-0.2 mg/kg/dose divided tid; not to exceed 12 mg/d 5-12 years: 2 mg/dose divided tid or qid; not to exceed 24 mg/d MDI <12 years: 1-2 puffs qid with tube spacer >12 years: Administer as in adults Nebulizer <5 years: 1.25-2.5 mg in 1-2.5 mL q4-6h; to make solution, dilute 0.25-0.5 mL (1.25-2.5 mg) of 0.5% inhalation solution in 1-2.5 mL of NS >5 years: Administer as in adults
Contraindications	Documented hypersensitivity; relative contraindications include severe CAD, hypertension, narrow-angle glaucoma, and presence of life-threatening arrhythmias
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Anecdotally, has been used during pregnancy for approximately 40 y and detrimental effects have not been reported; consult PDR for all possible adverse effects; caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders

Drug Category: Corticosteroids

Immunosuppressing agents and, thus, can decrease inflammation. Have particular efficacy in skin eruptions and bronchospasm. Role in anaphylactic shock is limited, although believed to help prevent delayed type of anaphylaxis.

Several different formulations are available; only one is listed. Others include methylprednisolone, dexamethasone, prednisolone (often used in children), and hydrocortisone. Depending on type of corticosteroid, oral, intravenous, and topical forms may be available. In more severe cases of anaphylaxis and asthma, intravenous forms of corticosteroids can be used initially. These can later be switched to oral forms as doses are tapered.

Inhaled corticosteroids are another form of corticosteroids and are key in controlling inflammation of bronchial airways and nasal mucosa. Similarly, topical corticosteroids are useful in treating atopic dermatitis.

Drug Name	Prednisone (Deltasone, Orasone, Meticorten)
Description	Believed to ameliorate delayed effects of anaphylactic reactions and may limit biphasic anaphylaxis. Doses below are general guidelines for usage; dosing is highly individualized.
Adult Dose	5-60 mg/d PO qd or divided bid/qid; taper over 2 wk as symptoms resolve
Pediatric Dose	1-2 mg/kg PO qd or divided bid/qid; taper over 2 wk as symptoms resolve
Contraindications	Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective-tissue infections, and fungal or tubercular infections; GI disease
Interactions	Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Abrupt discontinuation after long-term use (4-6 wk) can result in adrenal insufficiency/crisis; although relatively safe for short-term usage, long-term use can result in undesirable adverse effects, including osteoporosis, cataracts, and weight gain; patients who are on long-term steroids should be placed on a bisphosphonate and calcium/vitamin D supplementation for osteoporosis prevention; consult PDR for all possible adverse effects; may worsen diabetes mellitus, congestive heart failure, infections, peptic ulcer disease, volume status, myasthenia gravis, and psychoses; hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications

Drug Category: Histamine1-receptor antagonists (antihistamines)

Type 1 histamine-receptor blockers act to block action of histamine on H1 receptor after its release from mast cells and basophils. Most effective when used prophylactically. Sedating and nonsedating second-generation H1 antihistamines are available. Typically, sedating antihistamines have more adverse anticholinergic effects. Sedating antihistamines include diphenhydramine, hydroxyzine, cyproheptadine, chlorpheniramine, and brompheniramine. Nonsedating antihistamines include cetirizine (cause drowsiness in 15% people), fexofenadine, loratadine, and desloratadine. Desloratadine and fexofenadine may also help decrease nasal congestion.

Drug Name	Diphenhydramine (Benadryl, Dihydrex injection, Belix)
Description	Most widely available antihistamine (available OTC). Sedating antihistamines may be necessary to control more severe allergic reactions because they are very potent. Dosing interval of diphenhydramine is 4-6 h. Nonsedating antihistamines are all now available in a 24-h formulation but can only be administered PO.
Adult Dose	12.5-50 mg PO/IV/IM q4-6h; not to exceed 400 mg qd
Pediatric Dose	<6 years: 5 mg/kg/d PO/IV; not to exceed 300 mg qd 6-12 years: 12.5-25 mg PO q6-8h; not to exceed 300 mg qd >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; MAOIs
Interactions	Potentiates effect of CNS depressants; because of alcohol content, do not administer syrup dosage form to patients taking medications that can cause disulfiramlike reactions
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Warn patients to not drive or operate heavy machinery; administer with caution to elderly patients, patients with a seizure history, and children; can have additive adverse anticholinergic effects and can cause somnolence; may exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, or urinary tract obstruction; xerostomia may occur; consult PDR for all possible adverse effects

Drug Category: Histamine2- antagonists

Can be administered in addition to H1-receptor blockers for additional control of urticaria and angioedema. Examples include ranitidine, famotidine, and cimetidine. Cimetidine has been studied more extensively for this indication than other members of this class.

Drug Name	Ranitidine (Zantac)
Description	Multiple formulations are available. Cimetidine was first to be widely used but tends to have more drug interactions than other H2-receptor blockers. If no response to H1-receptor antagonist alone, coadministration with an H2-receptor antagonist can help relieve symptoms of itching and flushing in anaphylaxis, pruritus, and urticaria. Cimetidine plus an H1 blocker blocks cardiovascular effects of histamine.
Adult Dose	150 mg PO bid; not to exceed 600 mg/d; alternatively, 50 mg/dose IV/IM q6-8h
Pediatric Dose	<12 years: Not established >12 years: 1.25-1.5 mg/kg/dose PO q12h; not to exceed 300 mg/d; alternatively, 0.75-1.5 mg/kg/dose IV/IM q6-8h; not to exceed 400 mg/d
Contraindications	Documented hypersensitivity
Interactions	May decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment; consult PDR for all possible adverse effects

Drug Category: Leukotriene inhibitors

Synthesized by degranulated mast cells and basophils and likely contribute significantly to symptoms of allergic reactions. Three leukotriene inhibitors are now available in the United States. Montelukast and zafirlukast act as leukotriene-receptor blockers, whereas zileuton acts to inhibit production of leukotrienes. Disadvantage of the latter medication is its qid dosing.

Drug Name	Montelukast (Singulair)
Description	Leukotriene inhibitors can be a helpful addition to asthma and allergic rhinitis not well controlled with H1-receptor blockers and inhaled corticosteroids.
Adult Dose	10 mg PO qd
Pediatric Dose	<2 years: Not established 2-5 years: 4 mg PO every pm 6-14 years: 5 mg PO every pm
Contraindications	Documented hypersensitivity
Interactions	Phenobarbital and rifampin reduce effects
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Not indicated to reverse acute asthma attacks; not for use as monotherapy in management of exercise-induced bronchospasm; consult PDR for all possible adverse effects

Drug Category: Immunomodulators

Tacrolimus is an immunomodulator initially used in oral form as an immunosuppressant for transplantation patients. It has since been developed in topical form (Protopic) and can be used to treat atopic dermatitis that does not respond well to topical corticosteroids. A similar topical agent, pimecrolimus (Elidel), became available in the past few years and is indicated for mild atopic dermatitis. Trials are currently underway to assess possible benefit of inhaled tacrolimus for asthma.

Drug Name	Tacrolimus (Protopic)
Description	Reduces itching and inflammation by suppressing release of cytokines from T cells. Can be used in patients as young as 2 y. More expensive than topical corticosteroids.
Adult Dose	Apply 0.03% ointment or 0.1% ointment to affected areas bid
Pediatric Dose	<2 years: Not established >2 years: Administer as in adults
Contraindications	Documented hypersensitivity to tacrolimus or components of ointment
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause burning sensation during first few days of application; skin can become photosensitive, and patients should be cautioned about exposure to direct or artificial sunlight and to use sunscreen; safety and efficacy in infected atopic dermatitis is not known; application under occlusion, which may promote systemic exposure, has not been evaluated (do not use with occlusive dressings); absorption following topical applications is minimal (relative to systemic administration), but tacrolimus is excreted in human milk, and thus, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account importance of drug to mother (potential for serious adverse reactions in nursing infants should also be a concern); consult PDR for listing of all adverse effects

Drug Category: Monoclonal antibodies

Omalizumab (Xolair) is a monoclonal anti-IgE antibody indicated for refractory asthma. Has been shown to greatly improve severity of asthma in patients and can be used to help patients dependent on oral steroids to be weaned from steroids. Omalizumab has also been shown to decrease allergic response to peanuts in patients with severe peanut allergy. This could be helpful in preventing anaphylaxis from accidental peanut exposure in patients who normally would not tolerate even the slightest exposure to peanut allergen, but it only has FDA approval for asthma at this time. Patients should undergo a full allergy evaluation prior to starting omalizumab, if needed, because it interferes with prick skin test and RAST results.

Drug Name	Omalizumab (Xolair)
Description	Binds to IgE and thereby prevents IgE from binding to mast cells and basophils.
Adult Dose	Dependent on serum IgE level and body weight Serum IgE 30-100 30-90 kg: 150 mg SC monthly 90-150 kg: 300 mg SC monthly Serum IgE levels 101-200 30-90 kg: 300 mg SC monthly 90-150 kg: 225 mg twice monthly Serum IgE 201-300 30-60 kg: 300 mg monthly 61-90 kg: 225 mg twice monthly 91-150 kg: 300 mg q2wk Serum IgE levels 301-400 30-70 kg: 225 mg twice monthly 71-90 kg: 300 mg q2wk Serum IgE 401-500 30-70 kg: 300 mg q2wk 70-90 kg: 375 mg twice monthly Serum IgE 501-600 30-60 kg: 300 mg q2wk 61-70 kg: 375 mg q2wk Serum IgE 601-700 30-60 kg: 375 mg q2wk Manufacturer did not seek approval for dosing with IgE >700 or for IgE 601-700 for people weighing >60 kg because high resultant doses would be cost prohibitive
Pediatric Dose	>12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	No formal drug interaction studies have been performed
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Not indicated to reverse acute asthma attacks; systemic or inhaled corticosteroids should not be abruptly discontinued with initiation of omalizumab; serum IgE levels increase after initiation of therapy because of omalizumab-IgE complex formation and may remain high up to 1 y after discontinuation; therefore, serum IgE levels should not be routinely checked; patients may have false-negative skin prick test and RAST results

FOLLOW-UP

Section 8 of 11

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

Deterrence/Prevention

• Avoidance of the allergen is the best method of prevention, but this is not always possible (eg, avoiding insect stings). For this reason, patients should always have their rescue medications with them (eg, EpiPen, albuterol MDI).

Patient Education

• Patients with a known inciting agent should be advised in avoidance techniques, including immunologic cross-reactivity as is encountered in latex allergies.

• 
  
• Patients must be educated in the proper use of their maintenance and rescue medications.

Hypersensitivity Reactions, Delayed

Background

Delayed hypersensitivity reactions are inflammatory reactions initiated by mononuclear leukocytes. The term delayed is used to differentiate a secondary cellular response, which appears 48-72 hours after antigen exposure, from an immediate hypersensitivity response, which generally appears within 12 minutes of an antigen challenge. These reactions are mediated by T cells and monocytes/macrophages rather than by antibodies. They are also termed type IV hypersensitivity reactions.

Delayed hypersensitivity is a major mechanism of defense against various intracellular pathogens, including mycobacteria, fungi, and certain parasites, and it occurs in transplant rejection and tumor immunity. The central role of CD4⁺ T cells in delayed hypersensitivity manifests in patients with AIDS. Because of the loss of CD4⁺ cells, the host response against intracellular pathogens such as Mycobacterium tuberculosis is markedly impaired. The bacteria are engulfed by macrophages but are not killed.

If T-cell function is abnormal, the patient presents with opportunistic infections, including infection with mycobacteria, fungi, parasites, and, often, mucocutaneous candidiasis. Undesirable consequences of delayed-type hypersensitivity (DTH) reactions include illness such as contact dermatitis and allograft rejection. Examples of DTH reactions are contact dermatitis (eg, poison ivy rash), tuberculin skin test reactions, granulomatous inflammation (eg, sarcoidosis, Crohn disease), allograft rejection, graft versus host disease, and autoimmune hypersensitivity reactions. Of note, the Rhus genus of plants, which includes poison ivy, poison oak, and poison sumac, all cause identical rashes.

Pathophysiology

The cellular events that result in delayed hypersensitivity reactions primarily involve T cells and macrophages. First, local immune and inflammatory responses at the site of foreign antigen up-regulate endothelial cell adhesion molecule expression, promoting the accumulation of leukocytes at the tissue site. The antigen is engulfed by macrophages and monocytes and is presented to a T cell that has a specific receptor for that antigen. Macrophages secrete interleukin (IL)–1, IL-2, IL-6, and other lymphokines. Cytotoxic T cells can also be activated. The recruited macrophages can form giant cells. The characteristic histologic appearance of the macrophage–T-cell infiltrate is a granuloma. This type of infiltrate in the tissue is called granulomatous inflammation.

Several variants of DTH exist, and their precise pathophysiologic mechanisms are slightly different. For example, in contact hypersensitivity reactions, the epidermis is involved; in pulmonary tuberculosis (TB), lung tissue is involved.

Frequency

International

DTH reactions are extremely common.

Mortality/Morbidity

Delayed hypersensitivity reactions are normal physiological events. Anything that alters these normal events can lead to multiple opportunistic infections. DTH reactions may include, but are not limited to, contact dermatitis (eg, poison ivy rash), tuberculin skin test reactions, granulomatous inflammation (eg, sarcoidosis, Crohn disease), allograft rejection, graft versus host disease, and autoimmune hypersensitivity reactions. Morbidity and mortality vary (eg, ranging from a rash to chronic debilitating diseases) based on the active disease present.

Race

No racial predilection is recognized.

Sex

No sexual predilection is recognized.

Age

Persons of any age can be affected.

Treatment

Medical Care

Medical treatment is specific for the disease entity. Some common examples follow.

• Contact dermatitis: The treatment of contact dermatitis varies depending on the severity of the disease. The best advice is to avoid the offending antigen. Pharmaceutical treatment varies, including over-the-counter corticosteroid preparations, prescription corticosteroid preparations, injectable corticosteroids, oral corticosteroids, and Burow solution.

• Tuberculin hypersensitivity skin reactions: Treatment is rarely needed because this response is usually short-lived and self-limited. Topical corticosteroid preparations can be applied as needed. On rare occasions, the reaction to a delayed hypersensitivity skin test may be extreme and result in axillary lymphadenopathy and fever. Such reactions are self-limited and may be treated with an antipyretic medication such as aspirin or ibuprofen.

• Granulomatous diseases: Treatment varies greatly depending on the specific disease. Refer to the appropriate eMedicine article for a full discussion .

Consultations

Whether or not to consult a specialist and which specialist to consult also depend on the specific disease and its severity.

• Contact dermatitis: Most cases of contact dermatitis can be managed in an outpatient setting by a primary care physician. However, for severe cases, immediate consultation with a physician board-certified in allergy and immunology and/or dermatology is warranted.

• Tuberculin hypersensitivity skin reactions: If the Mantoux reaction is positive, patients may require consultation with a pulmonologist or an infectious disease specialist. A primary care physician trained in assessing the significance of a positive Mantoux reaction can also effectively treat these patients.

• Granulomatous diseases: Depending on the specific disease entity, an infectious disease specialist (eg, TB, fungal disease, schistosomiasis), pulmonologist (eg, TB, sarcoidosis), gastroenterologist (eg, granulomatous hepatitis, Crohn disease), and/or an allergist/clinical immunologist may need to be consulted.

Activity

As tolerated

Medication

Medical treatment differs greatly depending on the specific disease entity. Only a few medications are discussed. In addition to drugs mentioned below, a drug that may augment cell-mediated immunity is cimetidine, which is an H2 receptor blocker that acts as a reverse antagonist and may augment cell-mediated immunity.

Drug Category: Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Modify the body's immune response to diverse stimuli.

Drug Name	Triamcinolone (Aristocort)
Description	Helps treat inflammatory dermatosis responsive to steroids. Decreases inflammation by suppressing migration of PMN leukocytes and reversing capillary permeability.
Adult Dose	Topical: Apply a thin film bid/tid until a favorable response is obtained; not for use >3 consecutive wk

Alternatively, 40-80 mg IM once

Strength of dose should be individualized for patient
Pediatric Dose	Administer as in adults; not for use >2 consecutive wk
Contraindications	Documented hypersensitivity; fungal, viral, or bacterial skin infections
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.

Precautions	Do not use in patients with decreased skin circulation; avoid using on face, neck, axillae, and groin; prolonged use, applications over large areas, and use of potent steroids and occlusive dressings may cause systemic absorption; systemic absorption may cause Cushing syndrome, reversible HPA axis suppression, hyperglycemia, and glycosuria

Drug Name	Mometasone (Elocon)
Description	May depress formation, release, and activity of endogenous chemical mediators of inflammation.
Adult Dose	Apply sparingly to affected areas bid; do not use occlusive dressing; usually, do not use >2 consecutive wk
Pediatric Dose	Not recommended but frequently used for short periods
Contraindications	Documented hypersensitivity; fungal, viral, or tubercular skin lesions; herpes simplex or zoster infections
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.

Precautions	If used over large or denuded areas of body, for prolonged periods, with occlusive dressings, or in infants, adverse systemic effects may result

Drug Name	Prednisone (Deltasone, Orasone, Meticorten, Sterapred)
Description	May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Adult Dose	5-60 mg/d PO qd or divided bid/qid; taper over 2 wk as symptoms resolve
Pediatric Dose	4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve
Contraindications	Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease
Interactions	Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Usually safe but benefits must outweigh the risks.

Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur