Chronic Graft-vs-Host Disease

Allogeneic hematopoietic cell transplantation (HCT) is a treatment used increasingly for a variety of malignant and nonmalignant diseases of the bone marrow and immune system.¹ Although the procedure cures many patients with otherwise incurable diseases, it is often associated with serious immunological complications, particularly graft-vs-host disease (GVHD).² A chronic form of GVHD afflicts many allogeneic HCT recipients, resulting in dysfunction of numerous organ systems and an oftentimes profound state of immunodeficiency.^{3 - 5} Chronic GVHD is the most frequent cause of poor long-term outcome and quality of life after allogeneic HCT. The syndrome typically develops several months after transplantation, when the patient may no longer be under the direct care of the transplant team. The patient's primary physician plays an important role in diagnosis and treatment of the patient with chronic GVHD.

Allogeneic HCT involves ablation of the patient's lymphohematopoietic system by chemotherapy and radiation and its replacement by healthy hematopoietic stem cells and lymphocytes transfused from a related or unrelated donor. Although donor and recipient are usually matched at the human leukocyte antigen major histocompatibility loci, mismatches at so-called minor histocompatibility loci may lead to activation of minor histocompatibility antigen-specific donor T cells, despite prophylactic administration of immunosuppressive medications. These activated T cells, through dysregulated cytokine production and recruitment of additional effector cells, cause damage to a variety of epithelial tissues, a syndrome called acute GVHD.²

Although the mechanisms of acute GVHD are fairly well understood, the mechanisms of chronic GVHD may be different and require more research. One hypothesis, suggested by the clinical similarity of chronic GVHD to many autoimmune diseases and by observations in certain animal models, postulates that chronic GVHD may be mediated largely by autoimmune T cells (donor T cells that recognize antigens shared by donor and host and persist because of impaired mechanisms of deletion or regulation).^{6 - 7} These cells cause tissue damage by direct infiltration and by dysregulation of various cytokines.⁸ The greatest risk factor for the development of chronic GVHD is the prior development of acute GVHD. A target of acute GVHD is the thymus, and it has been suggested that a damaged thymus may lead to chronic GVHD by failing to delete autoreactive T cells and failing to produce immunoregulatory T cells.⁷

In addition to causing dysfunction of various tissues, chronic GVHD is associated with a pronounced state of immunodeficiency⁹ because of impaired T cell and B cell production, altered T cell function, impaired antibody production, and a state of functional asplenia, all exacerbated by immunosuppressive medications used in the treatment of the disease.

Chronic GVHD occurs in at least 30% to 50% of recipients of transplants from human leukocyte antigen–matched siblings and at least 60% to 70% of recipients of transplants from unrelated donors.⁵ Risk factors include older age of patient or donor, higher degree of histoincompatibility, unrelated vs related donor, use of hematopoietic cells obtained from the blood rather than the marrow, and previous acute GVHD.^{10 - 11} The incidence of severe chronic GVHD has probably increased somewhat in recent years because of the use of more unrelated transplants, donor leukocyte infusions, nonmyeloablative transplants, and stem cells obtained from the blood rather than the marrow.⁵ The syndrome typically occurs 4 to 7 months after transplantation but may begin as early as 2 months or as late as 2 or more years after transplantation. An early onset is more likely in unrelated or mismatched transplant recipients. Chronic GVHD may occur by itself, evolve from acute GVHD, or occur after resolution of acute GVHD. Depletion of T cells from the transplant is associated with a significantly lower incidence of both acute and chronic GVHD.¹²

The onset of the syndrome may be abrupt but is frequently insidious, with manifestations evolving gradually for several weeks. The extent of involvement varies significantly, from mild involvement limited to a few patches of skin to severe involvement of numerous organ systems and profound immunodeficiency. The most commonly involved tissues are the skin, liver, mouth, and eyes ( Article ). ^{4 - 5} The most frequently used staging system divides chronic GVHD into limited vs extensive stage.³ Patients with limited disease have localized skin involvement, evidence of liver dysfunction, or both, whereas those with more involvement of the skin or involvement of other organs have extensive disease. Patients with lichenoid skin changes, persistent thrombocytopenia (<100 000/µL), or hyperbilirubinemia, or whose chronic GVHD has evolved from acute GVHD, have a worse prognosis.^{13 - 15}

Skin and Dermal Appendages
Lichenoid eruption: erythematous papular rash
Sclerodermatous changes: tight, thickened, fragile skin associated with poor joint mobility
Poorly healing ulcers
Hypopigmentation or hyperpigmentation
Heat sensitivity because of loss of sweat glands
Brittle hair, premature graying, alopecia, decreased body hair
Fingernails and toenails: ridging, onychodystrophy

Mouth
Sicca syndrome with dry mouth, increased risk of dental caries
Lichen planus
Erythema and ulcers
Fibrosis
Viral or fungal infection

Eyes
Sicca syndrome with burning, irritation, dryness, photophobia

Liver
Bile duct damage with cholestatic liver test abnormalities

Esophagus
Webs and strictures
Abnormal motility
Secondary viral or fungal infection

Intestines
Fibrosis, malabsorption

Respiratory Tract
Sinusitis
Bronchiolitis obliterans

Bladder
Cystitis

Vagina
Erythema, lichen planus–like rashes
Dryness
Strictures

Musculoskeletal
Polymyositis, fasciitis, arthritis

Serous Membranes
Transudative pericardial, pleural, and peritoneal effusions

Nervous System
Peripheral neuropathy
Myasthenia gravis

Hematopoietic
Cytopenias due to poor marrow function
Autoimmune cytopenias
Eosinophilia

Immune System
Cellular and humoral immunodeficiency
Frequent upper respiratory tract infections
Risk for opportunistic infections
Autoantibody production

Psychiatric
Depression and anxiety*

GVHD indicates graft-vs-host disease.

*Although not a manifestation of chronic GVHD, these symptoms are commonly observed in patients with chronic GVHD.

Transplant patients who have returned to the care of their primary physician should be followed up at least monthly. The physician should perform a thorough history and physical examination directed to potential chronic GVHD manifestations, with the understanding that chronic GVHD onset is frequently subtle. Differential diagnosis should be kept in mind as any potential manifestations of chronic GVHD are considered. For example, oral infection with herpes simplex or Candida is common in patients with transplants and may occur separately from or concomitantly with GVHD. Ideally, biopsies of involved tissues, particularly skin or mouth, are performed and reviewed by pathologists experienced in GVHD pathology. The Schirmer test, a test of tear production, is frequently performed in patients with suspected GVHD. Additional tests, such as pulmonary function tests or liver ultrasound, may be indicated in certain patients.

Whenever possible, patients with chronic GVHD should be cared for in concert with transplant physicians who are experienced in GVHD-related issues. Treatment is aimed at 2 main issues: the dysregulated immune cells and cytokines causing damage to various tissues, and the immunodeficiency state that is associated with an increased risk of severe infection ( Article ).

Immunosuppressive Medications*

Localized Disease
Topical corticosteroids

Systemic Disease—Initial Therapy
Cyclosporine and prednisone
Prednisone alone

Systemic Disease—Salvage Therapy

No standard therapy
Options include tacrolimus, rapamycin, mycophenolate mofetil, thalidomide, anti–T cell or cytokine antibodies, 2-deoxycoformycin, psoralen and ultraviolet A, extracorporeal photopheresis

Infectious Disease Issues

General
Counseling of patient about infection risk
Low threshold for evaluation, empirical antibiotics

Laboratory Monitoring
CD4 count, IgG levels with subclasses every 4 months (sooner if recurrent upper respiratory tract infections)
Cytomegalovirus antigenemia or polymerase chain reaction every 2 weeks while receiving immunosuppression, if at risk†

Prophylactic Medication
Varicella zoster: acyclovir, 400 mg orally 3 times daily‡
Pneumocystis carinii: trimethoprim/sulfamethoxazole, dapsone, or atovaquone
Candida: topical nystatin for patients taking topical corticosteroids
Invasive fungi: consider itraconazole or voriconazole for patients taking prolonged high doses of corticosteroids‡
Bacteria: intravenous immunoglobulin for patients with recurrent sinopulmonary infections or reduced immunoglobulin or immunoglobulin subclass levels; penicillin or alternative drug for patients with severe chronic GVHD (functionally asplenic); antibiotic prophylaxis if dental procedures

Vaccination¹⁶
Diphtheria, tetanus toxoid: 12, 14, and 24 months
Haemophilus influenzae type b conjugate: 12, 14, and 24 months
Hepatitis B virus: 12, 14, and 24 months
23-Valent pneumonococcal polysaccharide: 12 and 24 months
Influenza virus: lifelong, seasonal administration beginning 6 months after transplantation
Inactivated poliovirus: 12, 14, and 24 months
Measles, mumps, and rubella: 24 months if receiving no immunosuppression and without chronic GVHD

Other Issues

Consultations
Ophthalmology: sicca syndrome, cataract management
Dentistry: high incidence of dental caries with sicca syndrome
Physical therapy: early physical therapy may prevent contractures in patients with sclerodermatoid skin changes

Medication Monitoring
Careful consideration of possible adverse effects and interactions of the multiple medications that are commonly required by patients with GVHD

GVHD indicates graft-vs-host disease.

*Immunosuppressive medications are best managed in concert with the transplant physician.

†Cytomegalovirus monitoring is only necessary in patients at risk. It is not necessary for cytomegalovirus-seronegative patients who had cytomegalovirus-seronegative donors and are receiving cytomegalovirus-safe blood products.

‡Data are limited regarding this use.

Patients undergoing allogeneic HCT typically receive immunoprophylaxis with tacrolimus or cyclosporine and other agents. Patients who have completely successful transplants develop tolerance and are able to be weaned from medication. However, patients who develop chronic GVHD require reinstitution of immunosuppressive medication (if already discontinued) or an increase in dosage and possibly addition of other agents. The current literature regarding chronic GVHD therapy is less than optimal; therefore, many recommendations about therapy are based on common practices that await definitive testing.⁵ Patients with localized skin or mouth involvement may respond to administration of topical corticosteroids. Patients with disease that is extensive by definition but is indolent in clinical behavior may respond to modest doses of prednisone, such as 20 to 30 mg/d. However, patients with more aggressive disease are treated with higher doses of corticosteroids, such as prednisone at 1 mg/kg per day. Cyclosporine (10 mg/kg per day in divided doses) is commonly added to treatment regimens in such patients,^{5 ,17} although 1 recent study has suggested the combination may not be better than prednisone alone.¹⁸ After 2 weeks of therapy and if response is observed, the prednisone is tapered by 25% per week, aiming for a dose of 1 mg/kg on alternating days. If patients respond well and remain stable for 3 months, cyclosporine and prednisone are gradually tapered with dose reductions every 2 weeks. Patients should be monitored very closely for recurrence of chronic GVHD during the tapering process.

Numerous salvage therapies have been evaluated in patients with refractory chronic GVHD, including tacrolimus, mycophenolate mofetil, rapamycin, thalidomide, anti–T cell or cytokine antibodies, 2-deoxycoformycin, psoralen and ultraviolet A, and extracorporeal photopheresis, with response rates generally in the range of 25% to 50%.⁵ No one of these therapies is clearly better than any other and ideally patients with refractory chronic GVHD should be entered into clinical trials.

Patients with chronic GVHD are severely immunodeficient and at significant risk for potentially fatal infections; therefore, close attention to infectious disease issues is paramount. Patients should be cautioned about their risk for infection, counseled about general infection precaution measures (especially hand washing), and told to have a low threshold for contacting their physician. Physicians should have a low threshold for evaluating patients with symptoms of potential infection and administering empirical antibiotics. Patients are at risk for viral, bacterial, and fungal infections as well as infections with Pneumocystis carinii. Comprehensive guidelines for monitoring, prophylaxis, and treatment of these infections in posttransplantation patients are available at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.html.

Viral Infections. Late reactivation of cytomegalovirus is not unusual in patients at risk (seropositive donor, seropositive recipient, or both).¹⁹ Patients with active chronic GVHD should be monitored by polymerase chain reaction or antigenemia assay every 2 weeks, and ganciclovir (preferably) or foscarnet should be administered if there is evidence of early reactivation. Varicella zoster reactivates in 20% to 50% of patients after transplantation and should be treated early and aggressively to prevent dissemination.²⁰ It is possible that long-term prophylaxis with acyclovir reduces the risk of varicella zoster reactivation but data to support this are limited. Herpes simplex viruses may be a cause of apparent worsening of oral GVHD.

Bacterial Infections. Patients with chronic GVHD may have hypogammaglobulinemia, reduction of IgG subclasses, or deficiencies of secretory IgA.⁹ These deficiencies can be associated with chronic recurrent upper respiratory tract infections including sinusitis, bronchitis, and bronchiectasis. Such patients may benefit from monthly immunoglobulin infusions.²¹ In addition, patients with significant chronic GVHD are often functionally asplenic and should receive long-term antibiotic prophylaxis to prevent overwhelming infection with encapsulated organisms.²²

Fungal Infections. Patients with chronic GVHD receiving topical or systemic corticosteroids are at increased risk for Candida infection. Oral candidiasis may be a cause of apparent worsening of oral GVHD. Patients receiving high doses of corticosteroids are at an increased risk of invasive fungal infections with organisms such as Aspergillus species. Conceivably, the risk of fungal infections in patients with chronic GVHD could be reduced with prophylactic antifungal agents such as fluconazole, itraconazole, or voriconazole; however, data regarding prophylactic use of these agents in this setting are relatively scarce.

P carinii. Patients with chronic GVHD are at risk of P carinii infection. This risk is significantly reduced by prophylactic administration of trimethoprim/sulfamethoxazole, dapsone, or atovaquone.

Vaccination. The Centers for Disease Control and Prevention Web site also contains guidelines for revaccination after allogeneic HCT. Posttransplantation patients should be revaccinated with inactive vaccine or toxoid for diphtheria, tetanus, Haemophilus influenzae type b, hepatitis B, pneumococcus, influenza, and polio.^{16 ,23} Patients with chronic GVHD may respond poorly to vaccination, and optimal timing of vaccination in these patients is not known. Live attenuated vaccines for measles, mumps, and rubella may be administered but not until at least 2 years after HCT and only in the absence of chronic GVHD and immunosuppressive medications. Family members may receive live vaccines but patients should avoid children who have had polio vaccine for 1 month; inactivated polio vaccine avoids this risk.

Early evaluation and frequent follow-up by ophthalmologists and dentists are necessary for patients with manifestations of significant eye and oral involvement. Additional consultants may be helpful, depending on sites of involvement (eg, gastroenterologists for patients with symptoms of esophageal dysfunction and potential need for endoscopic dilation procedures). Extensive physiotherapy may be necessary for patients with sclerodermatoid skin involvement; early referral of such patients can prevent the development of debilitating contractures. The many medications administered to recipients of allogeneic HCT transplants may be associated with adverse effects and interactions that require careful consideration by the patient's physician.

The course of chronic GVHD is determined mainly by its extent and the severity of the associated immunodeficiency. Approximately 50% of patients with chronic GVHD have limited disease and a good prognosis. Of the patients with extensive disease, approximately 60% will respond to treatment and eventually be able to discontinue immunosuppressive therapy. However, the remaining patients will either die, usually from opportunistic infection, or require prolonged treatment with immunosuppressive agents.

The significance of chronic GVHD as a clinical problem cannot be overemphasized. Many patients, otherwise cured of their underlying diseases by the transplant procedure, die or are severely disabled for years because of chronic GVHD. Current treatments for chronic GVHD, although often effective in lessening disease manifestations, are immunosuppressive and increase the already high risk of opportunistic infection. Approaches to chronic GVHD have changed little during the last several years and it is unlikely that this situation will change until the mechanisms of the syndrome are better understood. We are optimistic that creative use of new immunological techniques and concepts may shed light on chronic GVHD mechanisms and lead to more rational prevention and treatment.^{24 - 26}