eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Graft Versus Host Disease

Phillip Ruiz, Jr, MD, PhD, Professor of Pathology, Department of Pathology and Surgery, Miller School of Medicine, University of Miami
Yaxia Zhang, MD, PhD, Resident Physician, Department of Pathology, Jackson Memorial Hospital, University of Miami School of Medicine; Shoib Sarwar, MD, MPH, Fellow in Cytopathology, Department of Pathology, Jackson Memorial Hospital, University of Miami Miller School of Medicine

Updated: Jan 6, 2009

Introduction

Background

The occurrence of an immunologically mediated and injurious set of reactions by cells genetically disparate to their host, otherwise known as graft versus host disease (GVHD), is a phenomenon that has been described as the age of bone marrow and solid organ transplantation has emerged. In 1962, Barnes and Loutit first described GVHD in mice.¹ Simonsen introduced the term graft-versus-host reaction in the 1960s to describe the direction of the immunological damage caused by introduction of immunologically competent cells into an immunocompromised host.² In 1966, Billingham proposed 3 conditions required for the development of GVHD, as follows: (1) the graft must contain immunologically competent cells, (2) the host must possess important transplant alloantigens that are lacking in the donor graft so that the host appears foreign to the graft, and (3) the host itself must be incapable of mounting an effective immunologic reaction against the graft.³  

According to the accepted definition, the immunologic assault itself and its consequences are referred to as GVHD. In both experimental and clinical scenarios, acute GVHD describes a syndrome consisting of dermatitis, enteritis, and hepatitis occurring within the first 100 days, but typically within 30-40 days, following a bone marrow transplant (BMT). Chronic GVHD usually develops after 100 days and describes an autoimmunelike syndrome consisting of impairment of multiple organs or organ systems.⁴ However, the timing of GVHD occurrence to define the acute versus chronic is arbitrary.

With the advances of transplant practice, the clinical manifestations are now better defined than timing alone. The National Institutes of Health (NIH) published consensus criteria for the diagnosis of GVHD and proposed 2 subcategories for acute GVHD (classic acute and late acute) and chronic GVHD (classic chronic and overlap syndrome), taking an organ-functional impact into the account.⁵ However, the feasibility of the NIH consensus criteria to replace the old grading system of chronic GVHD (limited versus extensive) is still under evaluation.⁶

Pathophysiology

GVHD can develop in the course of (1) BMT or peripheral blood progenitor (hematopoietic stem cell) transplantation; (2) transfusion of unirradiated blood products (transfusion-associated GVHD), especially in immunocompromised individuals; or (3) solid organ transplantation involving organs containing lymphoid tissue. GVHD from passive transmission of immunocompetent maternal cells has also been described in neonates with severe immunodeficiency.

Graft-versus-host reaction occurs when donor immune cells recognize disparate host antigens. These differences are governed by genetic polymorphisms of human leukocyte antigen (HLA)-dependent factors (ie, major and minor histocompatibility antigens) and non-HLA–dependent factors (ie, cytokine gene polymorphisms, nucleotide-binding oligomerization domains [NOD2] genes, and killer immunoglobin receptor [KIR] family of natural killer [NK] receptors).⁷

The immunopathologic characteristics of acute GVHD have often been separated into different phases (1-3), which describes the creation of a suitable host environment with the conditioning regimens intended to remove particular host cell populations, and immune-based sensitizing and efferent (effector) phases (see Media file 1).^8,9

During phase 1 (Afferent phase), tissue injured by chemotherapy and irradiation releases proinflammatory cytokines such as tumor necrosis factor (TNF) alpha and interleukin (IL)-1, which subsequently increases expression of adhesion molecules, major histocompatibility complex (MHC) molecules, and costimulatory molecules. These cytokines further activate host antigen-presenting cells (APCs).

In phase 2 (Donor-T-cell activation, differentiation, and migration), the infused donor T lymphocytes are responsible for triggering GVHD and proliferate after activation by the recipient antigens expressed on host cells. APCs, such as dendritic cells or macrophages, present the antigen to CD4⁺ T cells, which recognize antigens in association with HLA class II or MHC class II molecules. IL-1 produced by monocytes and other factors stimulates the T-helper cells. The T-helper cells, in turn, release compounds such as IL-2 and interferon (IFN)-g; the latter enhances the expression of MHC class II on epithelial cells, macrophages, and dendritic cells, further stimulating the activation of T cells and NK cells.

IL-2 activates cytotoxic CD8-positive T cells, which react with MHC class I-positive targets. In addition, NK cells and macrophages appear to participate in the development of GVHD, although their roles are not well defined. Among the variables determining the extent to which GVHD develops are the types and properties of the transplanted T cells, the degree of MHC antigen mismatching, and the degree of interactions between T cells and the endothelial cells.

The final phase (3) of acute GVHD, is where immune effector cells and cytokines enact end-organ damage and contribute to a possible loss of self-tolerance. This injury is clinically manifested as the symptoms seen in GVHD and may be a contributing factor to the development of chronic GVHD.

As mentioned before, chronic GVHD develops after day 100 from transplantation and, like acute GVHD, appears dependent on alloreactivity for it to develop. Chronic GVHD has features similar to naturally occurring autoimmune disease with a wider range of involved organs. Clinical manifestations can include sclerodermatous lesions, liver failure, autoantibody production, and immune complex disease (including glomerulonephritis).

Host-recipient differences in MHC antigens or minor histocompatibility antigens can lead to this syndrome, albeit with slightly different kinetics. Alterations in thymic function with decreased thymopoiesis likely contribute to this syndrome with a breakdown of normal self-tolerance mechanisms. The donor CD4⁺ T-cell population is necessary for human chronic GVHD to develop; Th2 cells are the predominant subpopulation in the chronic GVHD, although the mechanisms of the disease progress remains poorly defined.

Frequency

United States

Incidence and frequency of acute GVHD in transplanted or transfused populations is related to the presence of several risk factors, as follows:¹⁰

• Histocompatibility: The most important factor correlating with incidence and severity of GVHD is the degree of HLA disparity. With HLA-identical siblings used as bone marrow donors, the incidence of moderate-to-severe acute GVHD ranges from less than 10% to 60%, depending on prophylaxis and other risk factors. Incidence of grades II-IV acute GVHD increases to 70-75% with one HLA antigen mismatch and as much as 90% with 2-3 HLA antigen mismatch. Incidence of grades II-IV GVHD of as much as 70% have been reported in unrelated donors; a difference was noted between those receiving marrow from an HLA-identical donor or from an HLA-mismatched donor.
• Graft cell composition: T-cell depletion of the bone marrow decreases the risk of GVHD but increases a risk of graft failure as well as leukemic relapse, which is due to a loss of a graft-versus-leukemia effect. Umbilical cord blood cells, when used as the source of hematopoietic stem cells, cause reduced incidence of GVHD, but the same is not true of peripheral blood stem cells.
• Age and sex: Older patients have a significantly higher risk of acute GVHD, with an incidence of approximately 20% in the pediatric population and rising to 30% in patients aged 20-50 years and to 70% in patients aged 51-62 years. An increased risk of GVHD exists in recipients of gender-mismatched marrow, possibly because of HLA association with the Y chromosome.
• Microenvironment: Host environment is important for the development of GVHD. Patients with aplastic anemia who are undergoing BMT and are treated with antibiotics, who are treated with skin and gut decontamination, and who are placed in a protective environment with laminar airflow units have reduced incidence of GVHD.
• Chronic disease: Chronic GVHD develops in 30-50% of long-term survivors after BMT. HLA disparity, prior acute GVHD, older age, and viral infections (especially herpesvirus group) are associated with increased risk of chronic GVHD. Chronic GVHD is also known to occur at a higher rate in survivors of transplant for aplastic anemia.
• Type of transplantation: Acute GVHD in stem cell transplantation develops in 30-60% of recipients of sibling matched allografts. The incidence of GVHD after intestinal transplantation and liver transplantation is reported to be 5% and 0.1-1%, respectively.¹¹ Transfusion-associated GVHD often presents with marrow aplasia; in Japan, this is estimated to occur in 1 in 500 open-heart operations in individuals who are immunocompetent.

Mortality/Morbidity

The survival rate is 90% in grade 0-I, 60% in grade II-III, and 0 in grade IV of acute GVHD. Fatality mainly results from infections, hemorrhages, and hepatic failure. Acute GVHD can have an antileukemic effect. In chronic GVHD, the overall survival rate is 42%, with the mortality rates increased in patients with more extensive disease and thrombocytopenia.

Sex

An increased risk of GVHD is noted in recipients of sex-mismatched marrow, possibly because of HLA association with the Y chromosome.

Clinical

History

• Acute graft versus host disease (GVHD): The clinical presentation is often a triad of dermatitis, hepatitis, and gastroenteritis, although symptoms may occur alone or in different combinations. Other tissues that may be involved include mucous membranes, conjunctiva, exocrine glands, bronchial tree, and urinary bladder.
  • Skin: Maculopapular rash may present with the onset occurring within 5-47 days after transplantation. Pruritus involving the palms and soles may precede the rash. In the early stage, the rash is confined to the nape of the neck, shoulder, palms, or soles. It may be confluent and involve the entire integument. In severe cases, bullous lesions similar to third-degree burns may develop.
  • Liver: The liver is the second most common organ involved. GVHD first manifests as elevated liver transaminases. Cholestatic jaundice is common, but hepatic failure with encephalopathy is unusual. Hepatic and GI involvement manifest with or following skin involvement.
  • GI: GVHD of the distal bowel and colon results in profuse diarrhea; intestinal bleeding; cramping, abdominal pain; and paralytic ileus. Diarrhea is greenish mucoid, watery, and secretory in nature. Upper GI involvement without enteric manifestation has been described in 13% of adults. Common symptoms are anorexia, nausea, vomiting, and dyspepsia.
  • Grading: Acute GVHD is graded in 5 steps from 0-IV based on involvement of the skin, liver, and GI tract. Grade 0 indicates no clinical evidence of disease. Grades I-IV are graded functionally. Grade I indicates rash on less than 50% of skin and no gut or liver involvement. Grade II indicates rash covering more than 50% of skin, bilirubin level of 2-3 mg/dL, diarrhea of 10-15 mL/kg/d, or persistent nausea. Grade III or IV indicates generalized erythroderma with bullous formation, bilirubin level of more than 3 mg/dL, or diarrhea of more than 16 mL/kg/d.
• Chronic GVHD: This is a more pleiotropic syndrome that develops after day 100. The syndrome resembles autoimmune systemic collagen vascular disease with protean manifestations, involving essentially every organ.¹² Systemic manifestations include recurrent infections with immunodeficiency, weight loss, sicca syndrome, and failure to thrive (children) or debility and weight loss (adults).
  • Chronic GVHD can present with 2 forms of skin involvement. An early phase resembles lichen planus; these lesions may be sparse and transitory, ranging from papules to more typical lesions. Poikiloderma can be present in the later phase, which is extra pigmentation of the skin demonstrating various shades and associated with telangiectasia in the affected area.
  • Hair manifestations present as alopecia.
  • The mouth may present with sicca syndrome, depapillation of the tongue with variegations, scalloping of lateral margins, lichen planus, oral ulcers, and angular tightness.
  • Joints exhibit decreased range of movements with associated myositis and tendinitis.
  • Manifestations of the eyes include decreased tearing, injected sclera, and conjunctivitis.
  • The liver involvement typically presents as cholestasis and cirrhosis.
  • GI presentations include esophageal stricture, malabsorption, and chronic diarrhea.
  • Pulmonary presentations include cough, dyspnea, wheezing, rales, pneumothorax, and, finally, bronchiolitis obliterans.
  • Hematological manifestations include refractory thrombocytopenia and eosinophilia.
  • Spleen involvement may present with functional asplenia.
  • Chronic GVHD has 2 stages. Limited chronic GVHD presents with localized skin involvement, hepatic dysfunction caused by chronic GVHD, or both. Extensive chronic GVHD presents with the following:
    • Generalized skin involvement, or localized skin involvement and/or hepatic dysfunction caused by chronic GVHD
    • Liver histologic findings showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis
    • Eye involvement - Schirmer test (<5 mm wetting)
    • Involvement of minor salivary glands or oral mucosa demonstrated by buccal/labial biopsy
    • Involvement of any other target organ

Physical

• See History.

Differential Diagnoses

Other Problems to Be Considered

Acute graft versus host disease

• Skin
  • Chemoradiotherapy toxicity
  • Drug reaction
  • Viral exanthema
• Liver
  • Venoocclusive disease
  • Viral hepatitis
  • Drug toxicity
  • Septicemia
  • Total parental nutrition complications
• GI
  • Clostridium difficile
  • Gastroenteritis, especially cytomegalovirus
  • Chemoradiotherapy

• Autoimmune diseases
• Gastroenteritis, especially cytomegalovirus
• Chemoradiotherapy

Workup

Laboratory Studies

• The diagnosis of graft versus host disease (GVHD) is established by clinical judgment, imaging studies, laboratory workup, and biopsy results.
• Anemia and thrombocytopenia are observed early in acute GVHD or in chronic GVHD.
• Eosinophilia and Howell-Jolly bodies are observed on peripheral smear in chronic GVHD.
• In hepatic involvement, elevation of transaminase levels is observed early and followed by an increase in bilirubin and, finally, cholestatic picture with increased alkaline phosphatase and glucose tolerance.
• A panel of 4 biomarkers in the serum, including interleukin (IL)-2 receptor-a, tumor necrosis factor (TNF)-receptor-1, IL-8, and hepatocyte growth factor, have been reported to be useful to confirm the diagnosis of GVHD in patients at onset of clinical symptoms.^13,14

Imaging Studies

• Pulmonary fibrosis resulting from irradiation or chemotherapeutic agents
• Bronchiolitis obliterans on radiograph or CT scan observed in chronic GVHD
• Ultrasonography, CT scanning, and Doppler studies: These may be used to distinguish GVHD from other causes of jaundice or cholestatic liver function abnormalities.
• Endoscopic studies of small bowel: These may reveal atrophy of the villi, ulceration, and bleeding. Barium swallow study may reveal the changes of chronic GVHD, such as ringlike narrowing and web formation.

Procedures

• Although a biopsy is not routinely performed, it can be very helpful to distinguish changes of GVHD from drug toxicity in skin and liver. Biopsy findings are necessary for confirming the diagnosis of chronic GVHD.
• Upper GI endoscopy is currently routinely performed in older patients with nausea, anorexia, and dyspeptic symptoms. This study is useful in grading.

Histologic Findings

• Acute GVHD
  • The skin demonstrates epidermal basal vacuolization, followed by epidermal basal cell apoptotic death with lymphoid infiltration. Eosinophilic bodies may be observed with increased severity. Bullous formation with epidermal separation and necrosis is observed in later stages.
  • Liver tissue undergoing acute GVHD can demonstrate damage to more than 50% of bile ducts with vacuolated cytoplasm, with duct cell nuclear pleomorphism and necrosis of individual cells (apoptosis). A lymphocytic infiltrate of portal tracts with endothelialitis (veins with lifting of endothelium from its basement membrane) is observed along with ballooning degeneration of hepatocytes and/or acidophil bodies.
  • GI biopsy specimens reveal diffuse edema and mucosal swelling followed by variable crypt cell apoptosis (eg, "exploding" crypts), a mixed chronic and predominantly lymphoplasmacytic infiltrate, and possibly crypt dropout.
• Chronic GVHD: Skin biopsy specimens can reveal epithelial acanthosis, dyskeratosis, and hyperkeratosis with a mononuclear infiltrate at the dermal-epidermal junction and in adnexal structures. This inflammatory process can evolve to dermal fibrosis and epidermal atrophy. Similarly, a mononuclear infiltrate is seen in the salivary glands on lip biopsy findings. The liver shows a portal mononuclear infiltrate with damage to the bile ducts and eventually ductopenia, changes that can be seen in the absence of clinical manifestations. GI findings of crypt destruction, increase in lymphoplasmacytic infiltrate with single cell drop out, and fibrosis of lamina propria are observed.

Staging

• Acute GVHD is traditionally graded in 5 stages (0-IV), based on involvement of the skin, liver, and GI tract. Grades I-IV are graded functionally.
  • Grade 0 indicates no clinical evidence of disease.
  • Grade I indicates rash on less than 50% of skin and has no gut or liver involvement.
  • Grade II indicates rash covering more than 50% of skin, bilirubin level of 2-3 mg/dL, diarrhea of 10-15 mL/kg/d, or persistent nausea.
  • Grade III or IV indicates generalized erythroderma with bullous formation, bilirubin level of more than 3 mg/dL, or diarrhea of more than 16 mL/kg/d.
    • Use the "Rule of Nines" or burn chart to determine the range of skin involvement. Downgrade one stage if an additional cause of elevated bilirubin level has been documented.
    • Volume of diarrhea applies to adults. For pediatric patients, the volume of diarrhea should be based on body surface area. Gut staging criteria for pediatric patients were not discussed at the consensus conference. Downgrade one stage if an additional cause of diarrhea has been documented.
    • Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.
    • Criteria for grading are given as the minimum degree of organ involvement required to confer that grade.
    • Grade IV may also include lesser organ involvement but with extreme decrease in performance status.

Treatment

Medical Care

Prevention and treatment of acute graft versus host disease

Successful therapeutic intervention of life-threatening graft versus host disease (GVHD) is possible, although the consequence can be the development of fatal opportunistic infections. Therefore, the best approach to manage GVHD should be its prevention. Effective prevention against GVHD includes the use of histocompatible donor and recipient combinations.^15,16,17

• Primary prophylaxis
  • Interfere with T-cell activation and function using immunosuppressive therapy. The calcineurin inhibitors (cyclosporine and tacrolimus) are the principal drugs used to prevent GVHD. They are not found to be very effective and have additional toxicity that reduces their use. Corticosteroids can also interfere with T-cell activation and function but are uncommonly used in prophylactic regimens because they seem to increase mortality from infection. Over the last few years, great attention has been focused on the potential of regulatory T cells (Tregs) for inhibiting the division, expansion and differentiation of donor T cells specific for host antigens. However, the potential use in humans is still not established.
  • Remove T cells by T–cell depletion ex vivo or T-cell depletion in vivo. The in vivo host lymphocyte depletion has the advantage of reducing the risk of graft rejection, but both techniques are associated with a reduction in graft-versus-leukemia (GVL) and a concomitant increase in relapse.
    • T–cell depletion ex vivo: Removing T cells from the graft is very effective in preventing GVHD without affecting the graft survival, disease-free survival, and treatment-related mortality rates. The number of infused T cells should not exceed 5 × 10⁴ cells/kg of recipient body weight. This procedure increases a risk of graft rejection.
    • T-cell depletion in vivo: Adding T-cell antibodies to the conventional conditioning regimen has the following 2 side effects: (1) it can reduce the host response, which improves engraftment, and (2) it affects mature donor T cells in the graft. This can be accomplished with such agents as alemtuzumab (Campath) or antithymocyte globulin (ATG). These long-lived agents can be directly administered to the patient, a tactic that depletes host and donor-derived T cells. Alternatively, the T cells (in the donor bone marrow) can be eliminated in vitro using monoclonal antibodies and using physical methods such as elutriation, or using immunotoxins.
  • Obstruct T-cell proliferation. Drugs often used for this therapy include methotrexate and mycophenolate (MMF). Methotrexate has been the primary drug in this indication for decades, and, although effective, it is also associated with delayed engraftment, mucositis, and transplant-associated toxicity. MMF inhibits T-cell purine salvage pathways and appears to have less toxicity than methotrexate and can be used with a calcineurin inhibitor.
  • Interfere with cytokine function (although this approach is relatively new and still experimental). Moreover, agents such as corticosteroids definitely reduce inflammatory cytokine levels, but, as noted above, for the most part they have not been helpful in GVHD prophylaxis.
  • Remove host antigen-presenting cells (APCs) using extracorporeal photopheresis (ECP). ECP is pheresis of approximately 5 × 10⁹ leukocytes that are treated with a photoactive compound 8-methoxypsoralen and ultraviolet A light and re-infused to the patients. This therapy induces lymphocytes undergoing apoptosis. Those apoptotic cells are taken up by host APCs, thereby triggering certain tolerance mechanisms, which results in lower incidence of GVHD.
  • Increase host immune activity using reduced-intensity conditioning regimens. This was defined as a conditioning regimen in which the dosage of chemotherapy and or total body irradiation (TBI) was reduced to 50%. These changes may result in less toxicity and less severe GVHD due to the persistence of host T cells.
  • Housing the patient in a pathogen-poor protected environment can be very helpful to reduce the risk of infections.
• Treatment
  • General: Many different therapies have been used in the treatment of acute GVHD. Unfortunately, control of GVHD in many patients does not translate into improved survival because of the subsequent development of opportunistic infections.
  • First-line treatment: Steroids associated with cyclosporine or tacrolimus are considered standard therapy. Treatment is required for established grades II-IV GVHD and often consists of continuation of original immunosuppressive agents used for GVHD prophylaxis and the addition of methylprednisolone at 2 mg/kg/d in divided doses for 10-14 days or until GVHD is controlled, followed by steroid taper. Patients who have not received cyclosporine or tacrolimus as part of their GVHD prophylaxis may benefit by combining it with prednisone. Combination triple therapy with cyclosporine, prednisone, and antithymocyte globulin has been found to be equally efficacious but more toxic in children. Successfully treated GVHD is only seen in about 25-40% of patients after donor transplantation; thus, 60-75% of patients with clinically significant GVHD require therapy in addition to corticosteroids.
  • Steroid-refractory GVHD: For steroid-refractory GVHD, rituximab along with other sporadically tried drugs have been studied. ATG has activity in steroid refractory GVHD, especially in the skin. Overall responses are seen in 20-60% of patients, but overall survival has not improved, and 1-year mortality rates approach 90%. One other form of antibody therapy that has been used is the anti-IL-2 receptor (IL-2R) monoclonal antibody, daclizumab. However, in a phase III trial of primary GVHD therapy, increased mortality from a combination of infection and relapse was noted. Denileukin diftitox (Ontak) is an engineered toxin that joins the IL-2 molecule to the diphtheria toxin. This drug was also developed to eliminate the IL-2R expressing cells.
  • Cytokine blockade: This has been attempted with interference with IL-1 either by binding it in serum (eg, soluble IL-1 receptor) or by functional inhibition (IL-1 receptor antagonist anakinra [Kineret]). This approach has not been extensively pursued. The anti-TNF alpha antibody infliximab (Remicade) has been effective in steroid-resistant GVHD but with increased subsequent infection. To date, it has shown benefit over steroids alone.
  • Cytotoxic therapy: MMF and the inosine monophosphate dehydrogenase (IMPDH) inhibitor pentostatin are cytotoxic therapies tried in acute GVHD. The latter drug appears to be highly active in acute GVHD in a single institution experience. The response rate was approximately 65%, but long-term survival was only 26%. Several small studies of MMF have shown therapeutic efficacy in the range of 40-70%, with survival rates ranging from 16-37%. As with other reagents, opportunistic infections mandate careful dosing.
  • Newer therapies: Anti-CD147 murine monoclonal antibody, which is a neurothelion member of the immunoglobulin superfamily that is upregulated on activated B cells and T cells, induced 50% response in steroid-resistant acute GVHD. Moderate-to-severe myalgia occurred in 28-60% of cases and was dose limiting. Additionally, visilizumab is a humanized anti-CD3 antibody that selectively induces apoptosis of activated T-cells. A phase I study demonstrated that all patients affected by severe acute GVHD and treated with visilizumab improved. However, posttransplant lymphoproliferative disease (PTLD) was a problem. Also, extracorporeal photopheresis has been used to treat resistant, acute GVHD; the patients who responded had a significantly better outcome.

The best prophylaxis against chronic GVHD is prevention of acute GVHD because de novo chronic GVHD is less common compared with incidence in patients with acute GVHD. Limited chronic GVHD may spontaneously resolve without specific therapy. Treatment of extensive chronic GVHD involves oral prednisone, which may be used simultaneously or on an alternate day schedule with cyclosporine or tacrolimus. Azathioprine may be used as a corticosteroid-sparing agent.

Numerous therapies, including psoralen plus ultraviolet radiation, thalidomide, and clofazimine, have been tried. MMF is an immunosuppressive agent used for prophylaxis for acute GVHD. In the treatment of steroid-refractory chronic GVHD, responses of 90% and 75% in first-line and second-line settings have been reported when MMF is added to standard tacrolimus, cyclosporine, and/or prednisone treatments.¹⁸

Supportive therapy and symptomatic management is equally important, including ursodeoxycholic acid for cholestasis, artificial tears and saliva for sicca syndrome, physiotherapy to prevent contractures, and immunoglobulin replacement and infection prophylaxis against opportunistic infections.

Surgical Care

Surgical care is restricted to insertion of a central line to aid in parental nutrition and intravenous treatments.

Diet

During acute GVHD, persistent diarrhea requires total parenteral nutrition until symptoms have subsided.

Activity

Activity is restricted depending on the patient's conditions, and isolation for infection control may be necessary.

Medication

Immunosuppressive agents

Methotrexate is a folate antagonist and a potent inhibitor of the cell-mediated immune system. Selective inhibitors of T-cell lymphocytes (eg, cyclosporine) suppress early cellular response to antigenic and regulatory stimuli.

Traditionally, high-dose steroids were thought to be lympholytic, but recent studies have suggested that steroids may inhibit T-cell proliferation and T-cell dependent gene expression of cytokines. They produce nonspecific anti-inflammatory effects and anti-adhesion effects that contribute to immune suppression.

Methotrexate (Folex PFS)

Prevents T-cell proliferation. Acts on purine and pyrimidine synthesis and has been employed as an immunosuppressive agent.

Dosing

Adult

Pediatric

15 mg/m² IV on day 1 and 10 mg/m² on days 3, 6, and 11 after BMT; dose and protocols may vary in different transplant teams

Interactions

PO aminoglycosides may decrease absorption and blood levels of concurrent PO MTX; charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX; coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can increase MTX plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity of MTX; may increase plasma levels of thiopurines

Contraindications

Documented hypersensitivity; pregnancy, lactation, liver dysfunction, infections, pleural and peritoneal effusion

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Neurotoxicity, seizures, renal failure, hepatotoxicity, pulmonary fibrosis, pneumonitis, marrow suppression, mucositis

Cyclosporine (Sandimmune, Neoral)

Inhibits calcineurin activity. A serine-threonine phosphatase whose activity is essential for T-cell cytokine transcription.

Dosing

Adult

Pediatric

1.5 mg/kg IV q12h initially; gradually increase until dose of 6.25 mg/kg PO q12h is tolerated; dose is adjusted to achieve desired blood levels; dose and protocols may vary in different transplant teams

Interactions

Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase cyclosporine toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin

Contraindications

Documented hypersensitivity; uncontrolled hypertension or malignancies

Precautions

Pregnancy

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

Precautions

Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzyme levels; may increase risk of infection and lymphoma; hirsutism, hypertension; reserve IV use only for those who cannot take PO

Methylprednisolone (Solu-Medrol)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Dosing

Adult

Pediatric

2 mg/kg/d PO/IV in divided doses for 10-14 d or until GVHD is controlled, then taper dose gradually

Interactions

Coadministration with digoxin, may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

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

Precautions

Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

Tacrolimus (Prograf)

Previously known as FK506. Macrolide immunosuppressant produced by Streptomyces tsukubaensis. Reported to prolong survival of the host and transplanted graft in some animal transplant models.

Dosing

Adult

Pediatric

Prophylaxis: 0.15-0.4 mg/kg/d PO divided q12h; 0.03-0.1 mg/kg/24 h IV via continuous infusion

Interactions

Caution with drugs associated with renal dysfunction, including aminoglycoside, amphotericin B, cisplatin, and others (can enhance nephrotoxicity); concentrations may be increased in presence of diltiazem, nicardipine, nifedipine, verapamil, clotrimazole, fluconazole, itraconazole, ketoconazole, clarithromycin, erythromycin, troleandomycin, cisapride, metoclopramide, bromocriptine, cimetidine, cyclosporine, danazol, methylprednisolone, and protease inhibitors; concentrations may decrease when administered with carbamazepine, phenobarbital, phenytoin, rifabutin, and rifampin

Contraindications

Documented hypersensitivity (including hypersensitivity reactions to tacrolimus or HCO-60 [polyoxyl 60 hydrogenated castor oil])

Precautions

Pregnancy

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

Precautions

Insulin-dependent diabetes reported in 20% of patients using tacrolimus for transplants, which is reversible in 15% after 1 year and in 50% after 2 years; increased risk for black and Hispanic patients; nephrotoxicity, neurotoxicity, hyperglycemia, hyperkalemia, tremor, headache, and increased risk of lymphomas and other malignancies (especially skin tumors) may occur; anaphylaxis, hypertension, myocardial hypertrophy, gastrointestinal abnormalities, arthralgias, cramps, asthma, and bronchitis have been reported with its use

Sirolimus (Rapamune)

Inhibits lymphocyte proliferation by interfering with signal transduction pathways. Binds to immunophilin FKBP to block action of mTOR.

Dosing

Adult

Pediatric

Prophylaxis:
<13 years: Not established
>13 years and <40 kg: 3 mg/m² PO on day 1, then 1 mg/m²/d PO qd or divided q12h, adjust to maintain trough blood levels between 8-10 ng/mL
>13 years and >40 kg: 6 mg PO on day 1, then 2 mg PO qd

Interactions

Drug levels and toxicity may increase with diltiazem, nicardipine, clotrimazole, verapamil, erythromycin, ketoconazole, itraconazole, fluconazole, bromocriptine, grapefruit juice, metoclopramide, methylprednisolone, danazol, cyclosporine, cimetidine, and clarithromycin; levels may decrease with rifabutin, rifampin, phenobarbital, phenytoin, and carbamazepine; administer sirolimus 4 h after cyclosporine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

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

Precautions

May exacerbate hyperlipidemia and thrombocytopenia; caution with hepatic impairment (decrease maintenance dose by one third); monitor blood sirolimus blood levels in pediatric patients, in patients with hepatic impairment, during coadministration of strong CYP450-3A4 inducers or inhibitors, or if cyclosporine dosing is markedly reduced or discontinued
Increased susceptibility to infection and possible lymphoma development may result from immunosuppression; risk for renal impairment increased when sirolimus and cyclosporine used concomitantly, compared with cyclosporine alone

Alemtuzumab (Campath)

Monoclonal antibody against CD52, an antigen found on B-cells, T-cells, and almost all CLL cells. Binds to the CD52 receptor of the lymphocytes, which slows the proliferation of leukocytes.

Dosing

Adult

Pediatric

Not established; not routinely used for GVHD treatment or prophylaxis in children; limited experimental data have used dosage ranges of 2.1-7.1 mg/kg IV; various regimens exist and require a specialist in pediatric bone marrow transplant to advise and monitor

Interactions

May increase virulence of live viral vaccine

Contraindications

Documented hypersensitivity; active systemic infections; underlying immunodeficiency (eg, AIDS)

Precautions

Pregnancy

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

Precautions

May cause pancytopenia, thrombocytopenia, autoimmune hemolytic anemia, and serious infusion reactions (premedicate with acetaminophen, diphenhydramine, hydrocortisone, and gradually increase dose); fatal bacterial, viral, fungal, and protozoan infections reported; hypotension may occur with IV administration (can control by discontinuing or slowing rate of infusion); antibody is not selective for cancerous B-cells and T-cells and may eradicate all normal lymphocytes of B-cell and T-cell lineage (resulting lymphopenia and risk of infection can be profound and long-lasting); PTLD, nausea, and diarrhea may occur

Mycophenolate mofetil (CellCept)

The 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent. Inhibits purine synthesis and proliferation of human lymphocytes. Prolonged survival of allogeneic transplants has been demonstrated in experimental animal models.

Dosing

Adult

Pediatric

Prophylaxis: Not established; limited data suggest 15 mg/kg/dose IV bid or 600 mg/m²/dose PO bid; not to exceed 2 g/d; or alternatively,
BSA 1.25-1.5 m²: 750 mg PO bid
BSA >1.5 m²: 1 g PO bid
Food decreases MPA C_max by 40%, administration on an empty stomach is recommended

Interactions

In combination with either acyclovir or ganciclovir may result in higher levels for both interacting drugs due to competition for renal tubular excretion; aluminum/magnesium present in some antacids, and cholestyramine containing products may decrease absorption, reducing levels (do not administer together); probenecid may increase levels of mycophenolate; salicylates and azathioprine may increase toxicity; may decrease levonorgestrel AUC; may decrease live virus vaccine immune response; when administered in combination with theophylline may increase free fraction levels of theophylline; may reduce blood levels hormones contained in oral contraceptives and could reduce effectiveness

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Increases risk for infection (monitor CBC count); severe renal impairment (CrCl <25 mL/min) may have increased adverse effects due to increased free MPA; caution in active peptic ulcer disease; incidence of malignancies and lymphoma consistent with that reported for other immunosuppressants (0.9%); commonly causes constipation, nausea, diarrhea, urinary tract infection, and nasopharyngitis; rare reports include interstitial lung disorders, colitis, pancreatitis, intestinal perforation, GI hemorrhage, gastric ulcers, duodenal ulcers, and ileus; do not chew, crush, or cut Myfortic tab; women of childbearing potential must have a negative serum or urine pregnancy test must be completed within one week of beginning MMF and must receive contraceptive counseling and use effective contraception; continue contraception for 6 wk following discontinuing

Antithymocyte globulin, rabbit (Thymoglobulin)

Purified concentrated gamma-globulin (primarily monomeric IgG) from hyperimmune horses immunized with human thymic lymphocytes. Mechanism of action is thought to be its effect on lymphocytes responsible in part for cell-mediated immunity and lymphocytes involved in cell immunity.
Immunosuppressive action generally is similar to other antilymphocyte preparations. However, they may differ qualitatively and/or quantitatively in extent to which they produce specific effects, in part because of factors such as source of antigenic material used, type of animal used to produce antiserum, and method of production.
A hematologist or another physician with extensive experience must be involved in the administration and monitoring of antilymphocyte serum because of the many complications and adverse effects of this therapy. Dose and duration of therapy vary with different investigational protocols.

Dosing

Adult

Pediatric

Treatment: 1.5 mg/kg/dose IV qd or qod
Prophylaxis: 30 mg/kg/d IV on days -3, -2, and -1 before transplantation

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

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

Precautions

To reduce risk of phlebitis, administer only via IV; medical emergency resources should be available immediately to manage rash, dyspnea, hypotension, or anaphylaxis if they develop

Follow-up

Further Inpatient Care

• Further inpatient care of graft versus host disease (GVHD) depends on initial response.
• Maintenance immunosuppression with close monitoring is required.
• Opportunistic infections may become severe and require intravenous (IV) antibiotics and supportive care.

Further Outpatient Care

• Regular follow-up with monitoring of immunosuppressive therapy is needed, as well as vigilance for developing chronic GVHD.

Deterrence/Prevention

• Effective prevention against GVHD includes the following:
  • Use of histocompatible donor and recipients
  • Use of immunosuppressive agents after bone marrow infusion (Most bone marrow transplant [BMT] teams currently use cyclosporine plus a brief course of methotrexate as the standard GVHD prophylaxis regime. Adding steroids has been proven beneficial in some trials. Other drugs alone or in combination include tacrolimus, antithymocyte globulin [ATG], and sirolimus.)
  • In vitro manipulation of the donor graft, such as marrow T-cell depletion
  • Possibly housing the patient in a pathogen-poor protected environment
• The best prophylaxis against chronic GVHD is prevention of acute GVHD because de novo chronic GVHD is less common compared with incidence in patients with acute GVHD.

Prognosis

• Severe acute GVHD is the important cause of treatment failure after BMT. Survival rates vary from 90% in stage I, 60% in stage II or III, to almost 0% in stage IV. Death is often caused by infections, hemorrhage, and hepatic failure.
• Severe chronic GVHD is associated with a higher mortality rate, mostly because of infection complications. Survivors are often severely disabled. The survival rate after onset of chronic GVHD is approximately 42%. Factors that predict death are progressive presentation (ie, acute GVHD followed by chronic GVHD), lichenoid skin changes on biopsy, and elevated serum bilirubin. A patient with one or more of these factors has a projected 6-year survival rate of 60%.
• Mild chronic GVHD as with mild acute GVHD is associated with improved outcome in patients with leukemia because of graft-versus-leukemia (GVL) effect.

Miscellaneous

Medicolegal Pitfalls

• Immunization must be performed with caution, especially with live virus vaccine, and the American Academy of Pediatric Committee on Infectious Diseases’ Red Book guidelines should be followed.
• Overwhelming bacterial sepsis is not infrequent, and index of suspicion should be high with rapid institution of therapy.
• Patients with chronic graft versus host disease (GVHD) may have functional asplenia, and some facilities administer penicillin prophylaxis.

Multimedia

Media file 1: Pathophysiological pathways and mechanisms of acute GVHD.

Media file 2: This boy developed stage III skin involvement with acute graft versus host disease (GVHD) in spite of receiving prophylaxis with cyclosporin A. The donor was an human leukocyte antigen (HLA)-matched sister; however, the sex disparity increased the risk for acute GVHD. Image courtesy of Mustafa S. Suterwala, MD.

Media file 3: This photo depicts a boy (the same as in Media file 2) who has progressed to grade IV graft versus host disease (GVHD). Both cyclosporin A and methylprednisolone had been administered in high dose intravenously. He later died with chronic pulmonary disease caused by chronic GVHD. Image courtesy of Mustafa S. Suterwala, MD.

Media file 4: Autologous graft versus host disease (GVHD) involving the skin of a patient's arm shortly after showing signs of engraftment after an autologous peripheral blood stem cell transplant for ovarian cancer. Image courtesy of Romeo A. Mandanas, MD, FACP.

Media file 5: Acute graft versus host disease (GVHD) involving desquamating skin lesions in a patient following allogeneic bone marrow transplantation for myelodysplasia. Image courtesy of Romeo A. Mandanas, MD, FACP.

Media file 6: Oral mucosal changes in a patient with chronic graft versus host disease (GVHD). Note the skin discoloration (vitiligo), which can result from GVHD. Image courtesy of Romeo A. Mandanas, MD, FACP.

Media file 7: Acute graft versus host disease (GVHD). Hematoxylin-stained and eosin-stained tissue shows dyskeratosis of individual keratinocytes and patchy vacuolization of the basement membrane. A moderate superficial dermal and perivascular lymphocytic infiltrate is also seen in this case. Image courtesy of Melanie K. Kuechler, MD.

References

1. Barnes DW, Loutit JF, Micklem HS. "Secondary disease" of radiation chimeras: a syndrome due to lymphoid aplasia. Ann N Y Acad Sci. Oct 24 1962;99:374-85. [Medline].

2. Simonsen M. Graft versus host reactions and their possible implications in man. Bibl Haematol. 1965;23:115-21. [Medline].

3. Billingham RE. The biology of graft-versus-host reactions. Harvey Lect. 1966;62:21-78.

4. Ferrara JL, Deeg HJ. Graft-versus-host disease. N Engl J Med. Mar 7 1991;324(10):667-74. [Medline].

5. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. Dec 2005;11(12):945-56. [Medline].

6. Cho BS, Min CK, Eom KS, et al. Feasibility of NIH consensus criteria for chronic graft-versus-host disease. Leukemia. Oct 2 2008;[Medline].

7. Ball LM, Egeler RM. Acute GvHD: pathogenesis and classification. Bone Marrow Transplant. Jun 2008;41 Suppl 2:S58-64. [Medline].

8. Sun Y, Tawara I, Toubai T, et al. Pathophysiology of acute graft-versus-host disease: recent advances. Transl Res. Oct 2007;150(4):197-214. [Medline].

9. Ferrara JL, Reddy P. Pathophysiology of graft-versus-host disease. Semin Hematol. Jan 2006;43(1):3-10. [Medline].

10. Ferrara JL, Yanik G. Acute graft versus host disease: pathophysiology, risk factors, and prevention strategies. Clin Adv Hematol Oncol. May 2005;3(5):415-9, 428. [Medline].

11. Kohler S, Pascher A, Junge G, et al. Graft versus host disease after liver transplantation - a single center experience and review of literature. Transpl Int. May 2008;21(5):441-51. [Medline].

12. Parkman R. Chronic graft-versus-host disease. Curr Opin Hematol. Jan 1998;5(1):22-5. [Medline].

13. Choi SW, Kitko CL, Braun T, et al. Change in plasma tumor necrosis factor receptor 1 levels in the first week after myeloablative allogeneic transplantation correlates with severity and incidence of GVHD and survival. Blood. Aug 15 2008;112(4):1539-42. [Medline].

14. Paczesny S, Krijanovski OI, Braun TM, et al. A biomarker panel for acute graft versus host disease. Blood. Oct 2 2008;[Medline].

15. Antin JH. Approaches to graft-vs-host disease. Pediatr Transplant. Dec 2005;9 Suppl 7:71-5. [Medline].

16. Deeg HJ. How I treat refractory acute GVHD. Blood. May 15 2007;109(10):4119-26. [Medline].

17. Ferrara JL. Novel strategies for the treatment and diagnosis of graft-versus-host-disease. Best Pract Res Clin Haematol. Mar 2007;20(1):91-7. [Medline].

18. Lopez F, Parker P, Nademanee A, et al. Efficacy of mycophenolate mofetil in the treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant. Apr 2005;11(4):307-13. [Medline].

19. Diaz MA, Vicent MG, Gonzalez ME, et al. Risk assessment and outcome of chronic graft-versus-host disease after allogeneic peripheral blood progenitor cell transplantation in pediatric patients. Bone Marrow Transplant. Jul 26 2004;():[Medline].

20. Faraci M, Dallorso S, Morreale G, et al. Surgery for acute graft-versus-host disease of the bowel: description of a pediatric case. J Pediatr Hematol Oncol. Jul 2004;26(7):441-3. [Medline].

21. Flowers ME, Kansu E, Sullivan KM. Pathophysiology and treatment of graft-versus-host disease. Hematol Oncol Clin North Am. Oct 1999;13(5):1091-112, viii-ix. [Medline].

22. Graubner UB, Liese J, Belohradsky BH. [Vaccination]. Klin Padiatr. Sep 2001;213 Suppl 1:A77-83. [Medline].

23. Guinan EC, Bierer BE. Principles of Bone Marrow and Stem Cell Transplantation. Hematology of Infancy and Childhood. 1998;346-351.

24. Horwitz ME, Sullivan KM. Chronic graft-versus-host disease. Blood Rev. Jan 2006;20(1):15-27. [Medline].

25. Klingebiel T, Schlegel PG. GVHD: overview on pathophysiology, incidence, clinical and biological features. Bone Marrow Transplant. Apr 1998;21 Suppl 2:S45-9. [Medline].

26. Kollman C, Howe CW, Anasetti C, et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood. Oct 1 2001;98(7):2043-51. [Medline].

27. Lazarus HM, Vogelsang GB, Rowe JM. Prevention and treatment of acute graft-versus-host disease: the old and the new. A report from the Eastern Cooperative Oncology Group (ECOG). Bone Marrow Transplant. Mar 1997;19(6):577-600. [Medline].

28. Messina C, Faraci M, de Fazio V, et al. Prevention and treatment of acute GvHD. Bone Marrow Transplant. Jun 2008;41 Suppl 2:S65-70. [Medline].

29. Ringden O, Deeg HJ. Clinical Spectrum of Graft-Versus-Host Disease. 1997;525-550.

30. Simpson D. New developments in the prophylaxis and treatment of graft versus host disease. Expert Opin Pharmacother. Jul 2001;2(7):1109-17. [Medline].

31. Wysocki CA, Panoskaltsis-Mortari A, Blazar BR, Serody JS. Leukocyte migration and graft-versus-host disease. Blood. Jun 1 2005;105(11):4191-9. [Medline].

Keywords

GVHD, secondary reaction, allogenic hematopoietic cell transplantation, HCT, autologous hematopoietic cell transplantation, solid organ transplants, blood transfusions, maternal-fetal transfusions, bone marrow transplant, bone marrow transplantation, graft versus host reaction, graft-versus-host reaction, graft-versus-host disease, acute graft versus host disease, acute GVHD, dermatitis, enteritis, hepatitis, chronic graft versus host disease, chronic GVHD, autoimmunelike syndrome

Contributor Information and Disclosures

Author

Phillip Ruiz, Jr, MD, PhD, Professor of Pathology, Department of Pathology and Surgery, Miller School of Medicine, University of Miami
Phillip Ruiz, Jr, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American Society for Clinical Pathologists, American Society of Nephrology, American Society of Transplant Surgeons, American Society of Transplantation, Clinical Immunology Society, Florida Medical Association, New York Academy of Sciences, Pan American Medical Association, Southern Medical Association, and United States and Canadian Academy of Pathology
Disclosure: Nothing to disclose.

Coauthor(s)

Yaxia Zhang, MD, PhD, Resident Physician, Department of Pathology, Jackson Memorial Hospital, University of Miami School of Medicine
Disclosure: Nothing to disclose.

Shoib Sarwar, MD, MPH, Fellow in Cytopathology, Department of Pathology, Jackson Memorial Hospital, University of Miami Miller School of Medicine
Shoib Sarwar, MD, MPH is a member of the following medical societies: American College of Healthcare Executives, American Medical Association, American Society for Clinical Pathologists, American Society of Cytopathology, College of American Pathologists, and United States and Canadian Academy of Pathology
Disclosure: Nothing to disclose.

Medical Editor

Ann O'Neill Shigeoka, MD †, Former Clinical Associate Professor, Department of Pediatrics, Division of Immunology-Rheumatology, University of Utah School of Medicine
Ann O'Neill Shigeoka, MD † is a member of the following medical societies: American Federation for Medical Research, Clinical Immunology Society, Pediatric Infectious Diseases Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

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

Managing Editor

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

CME Editor

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

Chief Editor

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

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Mustafa Suterwala, MD, to the development and writing of this article.

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