Chronic graft-versus-host disease

What every physician needs to know:

Chronic graft-vs-host disease (GVHD) is a multisystem immune-mediated disorder occurring after allogeneic hematopoietic stem cell transplantation (SCT) characterized by immunosuppression and immune dysfunction, with many manifestations of the disease resembling autoimmune disorders. Patients with chronic GVHD have an increased risk of infection, impaired organ function, and reduced quality of life. It is a major cause of non-relapse morbidity and mortality after allogeneic SCT and affects 40% to 70% of patients who survive more than 3 months after transplantation. The incidence of chronic GVHD is increasing because of changes in SCT practice including increasing patient age undergoing SCT, decreased early post transplant mortality, use of peripheral blood cells as the stem cell source, and increased utilization of unrelated or mismatched donors. Prior acute GVHD is the greatest risk factor for later development of chronic GVHD.

What features of the presentation will guide me toward possible causes and next treatment steps?

Historically, any GVHD developing more than 100 days post transplant was called chronic GVHD. Although providing a clean definition for registry data or clinical trials, this designation was not biologically accurate or clinically useful. Acute GVHD can develop after day 100, particularly in patients who received reduced-intensity conditioning regimens. Likewise, chronic GVHD can develop before day 100. The National Institutes of Health’s (NIH) criteria for diagnosing and staging of chronic GVHD use clinical manifestations to determine if GVHD is acute or chronic. Within chronic GVHD, two subsets are designated classic chronic GVHD (manifestations that can be attributed only to chronic GVHD) and overlap syndrome (features of both acute and chronic GVHD).

The diagnosis of chronic GVHD requires at least one diagnostic sign (that is, manifestation that establishes the presence of chronic GVHD without the need for further testing) or at least one distinctive sign (that is, manifestation highly suggestive of chronic GVHD, but insufficient alone to establish the diagnosis) confirmed by biopsy, laboratory test, or radiology in the same or other organ. A detailed explanation of all diagnostic and distinctive signs are provided in Jagasia reference listed below. Diagnostic signs vary by organ.

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In the skin, diagnostic signs include poikiloderma, lichen planus-like changes, sclerotic changes, or morphea. Fasciitis and joint contractures secondary to sclerosis are considered diagnostic.

For the mouth, diagnostic changes include lichen-planus like changes, hyperkeratotic plaques, and restriction of mouth opening from sclerosis. Lichen planus-like features and vaginal scarring or stenosis are diagnostic for the genitalia. Esophageal web and strictures or stenosis in the upper to mid third of the esophagus are the diagnostic criteria for gastrointestinal chronic graft-versus-host disease (GVHD).

Bronchiolitis obliterans diagnosed by biopsy is also diagnostic.

Distinction from acute GVHD:

  • Maculopapular erythematous rash

  • Elevated liver function tests

  • Diarrhea, nausea, and vomiting

Exclusion of other possible diagnoses (such as infection, or drug side effect).

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

There are no laboratory tests that are diagnostic of chronic GVHD. Patients suspected of having chronic GVHD should have as a minimum:

  • Liver function tests

  • Complete blood count and differential

  • Immunoglobulin levels

  • Pulmonary function tests

The liver function tests are usually most suggestive of cholestasis, with elevations in the serum alkaline phosphatase and bilirubin. A more filament variant with marked hepatitis has also been reported. Hematopoietic abnormalities include lymphopenia, eosinophilia, and thrombocytopenia. Pancytopenia resembling graft failure may occur, requiring marrow culture to show normal progenitors. Hypogammaglobulinemia is common.

The most important study for the diagnosis of chronic GVHD is a thorough physical examination. All skin must be examined, including visual inspection and palpation. The skin should be examined also with light shining across it to look for color changes and at dermal appendages. Friable, gray hair and alopecia are common. The nails may be brittle or ridged. Hypo or hyperpigmentation may be present. The skin should be pinched to look for subdermal changes. Some patients have normal appearing, but immobile skin from deep fibrosis.

All patients suspected of having chronic GVHD should have comprehensive eye and dental examinations. Although most patients with dry eyes and or dry mouths are symptomatic, some are not. In all cases, preventative measures can help decrease or prevent further damage. Likewise, all patients suspected of having chronic GVHD should be evaluated for range of motion by a physical therapist and their nutritional status evaluated by a nutritionist.

What conditions can underlie chronic graft-versus-host disease?

Unfortunately, for many patients there are multiple factors contributing to laboratory and radiographic abnormalities. For example, liver function test elevations may be due to chronic or acute GVHD, drugs (ongoing or past damage), infection (viral, bacterial, or fungal), and/or iron overload from transfusions. Liver biopsy is usually needed in those with significant isolated liver function test abnormalities.

Eosinophilia has been reported in some patients with chronic GVHD and in those patients may track with the course of the disease. But other patients with chronic GVHD never have eosinophilia, so the lack of eosinophilia does not influence the diagnosis of chronic GVHD.

Similarly, immune cytopenias may occur with chronic GVHD, but in any given patient may be also due infection, marginal engraftment, and drug toxicities.

Thrombocytopenia at diagnosis of chronic GVHD has been found in multiple studies to be associated with poor prognosis, although the mechanism(s) responsible for this have never been elucidated.

Skin changes sometimes attributed to chronic GVHD include eczema and ichthyosis. Hypothyroidism may also cause skin changes and hair loss.

Adrenal insufficiency in patients after steroid use may cause fatigue and nausea.

There is a tendency to attribute all abnormalities to chronic GVHD in patients after transplant. This is a very dangerous practice, and should be avoided. Patients after a transplant may have all the problems that a non-transplanted patient has. Laboratory and radiographic changes should be investigated just as in any other patient and the changes should be ascribed to chronic GVHD, only after other causes have been eliminated. This is true when initially making the diagnosis of chronic GVHD and in patients with established chronic GVHD. A new elevation in liver function tests or abnormal pulmonary functions tests needs to be investigated, not simply attributed to GVHD.

When do you need to get more aggressive tests?

Biopsy is indicated whenever there is a question of the diagnosis. This issue is particularly common in isolated organ system disease, the liver being a prime example. Unexplained diarrhea also may require endoscopy if other causes (infection, lactose intolerance, drug effect) have been excluded. In patients with cytopenias, extensive work up including bone marrow aspirate and biopsy, marrow culture, flow studies (for relapse), cytogenetics, and evaluation of engraftment status may be indicated.

What imaging studies (if any) will be helpful?

Imaging studies are useful for a few specific indications. High resolution computed tomography (CT) images (with inspiratory and expiratory views) are indicated when there is a significant new obstructive change on PFT with % FEV1 less than 70%. The CT can be used to assess for possible infectious etiologies, while also looking for changes suggestive of bronchiolitis obliterans, such as bronchial wall thickening, bronchiectasis, and air-trapping. Abdominal CT may also be useful in patients with weight loss with non-localizing abdominal complaints.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Chronic GVHD affects multiple organs and causes significant morbidity in patients who are otherwise cured of their underlying disease. Because of the plethora of organs involved, a multidisciplinary therapeutic approach, coordinated by a transplant physician/care provider, is required. As is obvious from the evaluation section: multiple disciplines are needed to care for these patients. The goal of therapy is to establish immunologic tolerance, while reducing symptoms and providing as much protection as possible from infections.

Immunoincompetence (that is, infection) is the major cause of death in chronic GVHD. Antibiotic prophylaxis is the first thing that should be started and the last stopped. Each center has its own set of recommendations for antibiotic prophylaxis, but at a minimum should include pneumococcal and pneumocystis prophylaxis. The other major caveat is that some manifestations, most notably joint contractures, may remain, even if the disease is inactive. Additional treatment will not resolve the contractures and pose real risks from the immunosuppressive drugs.

Systemic therapy is indicated for moderate and severe chronic GVHD, and usually for patients with mild chronic GVHD whose platelet count has fallen to less than 100,000/μL. Prednisone alone, or in conjunction with calcineurin inhibitors (cyclosporine A [CsA] or tacrolimus [TAC] is the only therapy that has been validated in clinical trials. The addition of CsA or TAC to prednisone allows for more rapid tapering of prednisone and reduces long-term complications of corticosteroid therapy, such as glucose intolerance and avascular necrosis.

Because roughly half of the patients with chronic GVHD do not resolve or recur after initial treatment, whenever possible patients should be enrolled in clinical trials looking at either improvement in initial therapy or salvage therapy. Salvage therapy for those not responding to initial treatment or recurring is less clearly established. Many agents have been shown to have activity in phase two studies, but there have not been trials comparing the agents.

What other therapies are helpful for reducing complications?

Recently, Carpenter et al published the NIH Concensus on Chronic GvHD recommendations on ancillary and supportive care with guidance on how to help todeal with the complications induced by chronic GvHD. As stated above, patients with chronic GVHD are at high risk for infections, even after the complete withdrawal of immunosuppression. All centers have their own specific prophylaxis choices. Below are some generic antibiotic recommendations.

Antibacterial prophylaxis

Patients with chronic GVHD are at particular risk for infection by encapsulated organisms. Antibiotics are continued for as long as the patient is receiving systemic immunosuppressive therapy, and usually for several months more. Most commonly, penicillin V potassium (VK), or for those penicillin allergic, trimethoprim/sulfamethoxazole (TMP/SMX), or azithromycin are given for prophylaxis.

Antiviral prophylaxis

The majority of centers give long-term antiviral prophylaxis (at least 6 months after stopping systemic immunosuppression) to prevent herpes simplex virus (HSV) and varicella zoster virus (VZV) reactivation. After stopping prophylaxis, reactivation is not uncommon, so patients and their caregivers should be aware of this. Usually, acyclovir and valacyclovir are given daily.

VZV-seronegative patients with chronic GVHD exposed to varicella (or zoster) VZV immunoglobulin should be given within 96 hours. Patients with chronic GVHD are at risk for Cytomegalovirus (CMV) disease and should be monitored for CMV infection/reactivation by detection of CMV in blood using the pp65 antigen assay or by polymerase chain reaction. Should reactivation be detected, treatment with ganciclovir, valganciclovir, or foscarnet is indicated.

Antifungal prophylaxis

Fungal infections are common in patients with chronic GVHD receiving immunosuppressive therapy. Most centers provide prophylactic treatment, while patients are receiving prolonged high doses of steroids (for example, greater than 0.5mg/kg of prednisone equivalent). Potential prophylactic choices include posaconazole or voriconazole.

Pneumocystis prophylaxis

All patients on systemic immunosuppression should also receive pneumocystis prophylaxis and this should continue at least 6 months after stopping systemic immunosuppression. The most commonly used agents include TMP/SMX, monthly pentamidine by nebulizer, or Dapsone.

Supportive care

The types of supportive care needed by each patient depend on the organs involved and the need for multidisciplinary care should be emphasized again.


Patients should avoid sun exposure and always use sun screens of at least SPF 20. Topical steroids, calcineurin inhibitors, and emollients may be helpful. Anti-pruritic agents and topical anti-microbials may also be useful.


Preservative free artificial tears, punctual occlusion, occlusive eye wear, moisture chamber glasses, tarsorrhaphy, gas-permeable scleral contact lens, and topical steroids or cyclosporine may help dry eyes.


Endocarditis prophylaxis before any dental procedure. Topical steroids, topical tacrolimus, topical analgesics, and saliva substitutes may be useful.


Physical and occupational therapy are a must. Yearly bone density with support as needed using bisphosphonates, calcium, and vitamin D.


Nutritional consultation is very useful. Lactose intolerance is common. Enzyme supplementation may be needed for malabsorption. Esophageal dilatation may be of benefit.


Water based lubricants and topical estrogens, alternating with topical steroids or calcineurin inhibitors may help dryness.

What should you tell the patient and the family about prognosis?

Chronic GVHD is a double-edged sword. The graft-versus-tumor effect benefits patients transplanted for malignant diseases. For those with mild disease requiring no or topical treatment, chronic GVHD has a benefit. For patients with severe disease at presentation, as demonstrated by thrombocytopenia, extensive skin involvement, multiple significant organ involvement, progressive onset, or overlap syndrome, survival is adversely impacted.

For the majority of patients with disease between the two extremes, a diagnosis of chronic GVHD does worsen quality of life, increase morbidity, and prolongs the time immunosuppressive medications (with attendant side effects and risks) must be taken.

"What if" scenarios.

Many patients are simply exhausted by years of treatment for their underlying disease and transplant by the time chronic GVHD is diagnosed. They are emotionally and financially stressed and often are reluctant to return to the transplant center for treatment. Even worse, many are poorly compliant with their treatment. Care providers should be aware of how difficult it is to face a chronic illness and be supportive to help patients cope.


Defining the pathophysiology of Chronic GVHD has been hampered by a lack of good animal models and the late onset of the disorder, when most patients have returned home. Chronic GVHD is not simply late acute GVHD.

Most experts would suggest four potential mechanisms including thymic damage and defective negative selection of T cells, abnormal production of transforming growth factor-β, auto-antibody production, and deficiency of T-regulatory cells.

It is likely that each donor-patient pair represents its own unique combination of mechanisms, which may account for the wide variety of manifestations of this disorder.

What other clinical manifestations may help me to diagnose chronic graft-versus-host disease?

Essentially any and every manifestation of autoimmune disorders has been reported in patients with chronic GVHD.

What other additional laboratory studies may be ordered?

Additional testing should be driven by the manifestations of the individual patient.[

VII. What's the evidence?

Lee, SJ, Flowers, ME. “Recognizing and managing chronic graft-versus-host disease”. Hematology Am Soc Hematol Educ Program. 2008. pp. 134-141. (General comprehensive review.)

Flowers, ME, Inamoto, Y, Carpenter, PA. “Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria”. Blood.. vol. 117. 2011. pp. 117-3214. (Nice description of risk factors for chronic GVHD.)

Lee, SJ, Wolff, D, Kitko, C. “Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report”. Biol Blood Marrow Transplant.. vol. 21. 2015 Jun. pp. 984-99. (NIH response criteria for GVHD.)

Shulman, HM, Cardona, DM, Greenson, JK. “NIH Consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. The 2014 Pathology Working Group Report”. Biol Blood Marrow Transplant.. vol. 21. 2015 Apr. pp. 589-603. (NIH pathologic diagnostic criteria.)

Jagasia, MH, Greinix, HT, Arora, M. “National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report”. Biol Blood Marrow Transplant.. vol. 21. 2015 Mar. pp. 389-401. (NIH consensus on diagnosis of chronic GVHD.)

Stewart, BL, Storer, B, Storek, J. “Duration of immunosuppressive treatment for chronic graft-versus-host disease”. Blood. vol. 104. 2004. pp. 104-3501. ([Length of treatment of chronic GVHD.)

Koc, S, Leisenring, W, Flowers, ME. “Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone”. Blood. vol. 100. 2002. pp. 100-48. (Randomized trial of treatment for chronic GVHD.)

Martin, PJ, Storer, BE, Rowley, SD. “Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease”. Blood. vol. 113. 2009. pp. 113-5074. (Randomized trial of addition of mycophenolate mofetil for treatment of GVHD.)

Carpenter, PA, Kitko, CL, Elad, S. “National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report”. Biol Blood Marrow Transplant.. vol. 21. 2015 Jul. pp. 1167-87. (Description of supportive care for chronic GVHD patients.)

Ringden, O, Karlsson, H, Olsson, R, Omazic, B, Uhlin, M. “The allogeneic graft-versus-cancer effect”. Br J Haematol. vol. 147. 2009. pp. 614-633. (Review of important antineoplastic activity of GVHD.)