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Clinical manifestations and diagnosis of chronic graft-versus-host disease

Clinical manifestations and diagnosis of chronic graft-versus-host disease
Author:
Robert Zeiser, MD
Section Editors:
Robert S Negrin, MD
Nelson J Chao, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Mar 2023. | This topic last updated: Feb 17, 2022.

INTRODUCTION — Graft-versus-host disease (GVHD) can develop after allogeneic hematopoietic cell transplant (HCT), when immune cells from a non-identical donor (the graft) initiate an immune reaction against a transplant recipient (the host). Acute GVHD (aGVHD) and chronic GVHD (cGVHD) are multisystem disorders that are distinguished by their clinical findings, according to the widely-accepted National Institutes of Health (NIH) consensus criteria; an overlap syndrome with features of both aGVHD and cGVHD is also recognized [1-3]. Formerly, aGVHD and cGVHD were distinguished by onset <100 days versus ≥100 days from transplantation, but these syndromes may occur outside of those time periods. cGVHD is a distinct syndrome that is not simply an evolution of preceding aGVHD [2].

cGVHD is a syndrome of variable clinical features that resembles autoimmune and other immunologic disorders (eg, scleroderma, Sjögren's syndrome, primary biliary cirrhosis, bronchiolitis obliterans) [4]. Clinical manifestations may be widespread or they may be restricted to a single organ or site. The primary clinical manifestations are skin involvement (resembling lichen planus or cutaneous scleroderma), dry oral mucosa, gastrointestinal tract ulcerations and sclerosis, elevated serum bilirubin, and bronchiolitis obliterans. By contrast, patients with aGVHD commonly demonstrate a maculopapular rash, abdominal cramps with diarrhea, and elevated serum bilirubin.

cGVHD is a major cause of morbidity and mortality after allogeneic HCT, which worsen with increasing disease severity. Patients have impaired physical, social, and psychological well-being and impaired quality of life. Diagnosing and grading the severity of cGVHD is essential for optimal management.

This topic will discuss the clinical manifestations and diagnosis of cGVHD.

Treatment of cGVHD is presented separately. (See "Treatment of chronic graft-versus-host disease".)

Related topics include:

(See "Pathogenesis of graft-versus-host disease (GVHD)".)

(See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

(See "Prevention of graft-versus-host disease".)

(See "Treatment of acute graft-versus-host disease".)

EPIDEMIOLOGY — The incidence of cGVHD after allogeneic hematopoietic cell transplant (HCT) is approximately 40 percent. However, incidence rates have been reported from 6 to 80 percent [1,5-7]. The variable incidence rates may be due to different risk factors, diagnostic criteria, underlying conditions, and prevention strategies for GVHD. (See 'Risk factors' below.)

RISK FACTORS — Certain features of the transplant recipient and/or graft donor and aspects of the allogeneic hematopoietic cell transplant (HCT) are associated with risk for developing cGVHD. The risk for developing cGVHD increases with the number of risk factors.

Increased risk for cGVHD has been associated with [8-13]:

Immune mismatch – Higher degree of human leukocyte antigen (HLA) mismatch

Age – Older age of donor and/or recipient

Sex disparity between donor and recipient (ie, female donor to male recipient)

Prior donor alloimmunization – History of pregnancy or transfusions in the donor

Graft source – Peripheral blood precursor cell (PBPC) grafts are associated with higher risk than bone marrow or umbilical cord blood

Prior acute GVHD (aGVHD)

Donor lymphocyte infusion – Administration of unirradiated donor buffy coat transfusions

Splenectomy

Cytomegalovirus (CMV) – CMV seropositivity in the donor and/or recipient

Epstein-Barr virus (EBV) – Donor EBV seropositivity

Other risk factors include conditioning regimens that include total body irradiation (TBI), second bone marrow infusions, preceding herpesvirus infection, underlying malignancy, and the absence of blood transfusions administered prior to transplantation [5,11,14,15]. (See "Sources of hematopoietic stem cells", section on 'PBPC versus bone marrow for malignant disease'.)

The probability of developing cGVHD rises with increasing numbers of risk factors. As examples:

Higher recipient age, previous aGVHD, female donor to male recipient, and a history of chronic myeloid leukemia (CML) were identified as risk factors in a retrospective study of 551 consecutive recipients of allogeneic HCT [5]. Five years post-transplantation, the incidence of cGVHD was 75, 68, 53, 29, and 9 percent, respectively, among patients with four, three, two, one, and none of these factors, respectively.

In a study of 116 HLA-identical allogeneic PBPC transplants, the cumulative incidence of cGVHD was 57 percent [16]. Prior aGVHD was associated with an increased risk (hazard ratio [HR] 1.67, 95% CI: 1.0-2.8), while GVHD prophylaxis with methotrexate and tacrolimus was associated with a reduced risk of cGVHD (HR 0.35, 95% CI 0.2-0.6).

CLINICAL MANIFESTATIONS — Clinical features of cGVHD can involve nearly every organ system. Symptoms and signs may differ in onset and severity and can resemble findings of other post-transplant conditions and complications.

Onset — The onset of cGVHD is typically ≥3 months after transplantation. Nearly all cases present during the first year after transplantation, but in some cases cGVHD may not present for many months or even years after HCT. Formerly, the distinction between acute GVHD (aGVHD) and cGVHD was based on onset <100 days versus ≥100 days from transplantation, respectively. However, these conditions are now defined by their clinical and/or pathologic features, not the time of onset after transplantation, and both syndromes can occur outside of those time periods [1].

cGVHD can arise de novo (ie, in a patient with no prior GVHD), which is referred to as classic cGVHD. It can also arise in a patient with ongoing or prior aGVHD, which is referred to as overlap syndrome. (See 'Subcategories' below.)

Affected organs — The skin, liver, gastrointestinal (GI) tract, and lungs are the principal organ systems involved with cGVHD, but nearly every organ system can be affected [17-19].

A prospective study of 458 patients with cGVHD reported organ involvement, as follows [20]:

Skin – 67 percent (see 'Skin' below)

Mouth – 60 percent (see 'Mouth' below)

Liver – 52 percent (see 'Liver' below)

Lung – 50 percent (see 'Lung' below)

Eye – 48 percent (see 'Eyes' below)

Joints and fascia – 48 percent (see 'Musculoskeletal' below)

GI tract – 30 percent (see 'Gastrointestinal tract' below)

Genitalia – 12 percent (see 'Genitalia' below)

For each involved organ system there may be diagnostic features (which are sufficient to diagnose cGVHD), distinctive features (which, alone, are not sufficient to diagnose cGVHD), and "common" features (which may be associated with both cGVHD and aGVHD). The following sections describe organ-specific findings associated with cGVHD.

Mucocutaneous — cGVHD affects skin, nails, hair, mouth, and/or eyes in most patients.

Skin — Skin involvement is present in two-thirds of patients with cGVHD [20]. Clinical presentations vary widely, which may reflect a spectrum of epidermal and dermal (sclerotic) changes (table 1).

The onset of skin involvement may be heralded by generalized erythema, plaques, and waves of desquamation; some patients give a history of photoactivation. Mottled pigmentation and telangiectasias can become progressively indurated and fixed, with lichen planus-like (picture 1), sclerotic manifestations (picture 2 and picture 3), or joint contractures (picture 4) that resemble scleroderma (table 1). Further details of cutaneous manifestations of cGVHD are described separately. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Skin'.)

Diagnostic, distinctive, and "common" cutaneous features of cGVHD are described below. (See 'Diagnostic findings' below and 'Distinctive findings' below and '"Common" features' below.)

Nails and hair — Features of cGVHD in nails and hair include:

Nails – Nails may manifest dystrophy (picture 5), longitudinal ridging, splitting, or brittle features; onycholysis; pterygium unguis (abnormal adherence of the nail plate to the proximal nail fold or hyponychium); and nail loss.

Hair and scalp – New onset of scarring or non-scarring scalp alopecia (not associated with prior chemotherapy or radiation therapy); scaling of scalp; loss of body hair; and premature graying, thinning, or brittleness of hair may be seen.

There are no manifestations in nails or hair that are considered diagnostic for cGVHD. Distinctive features that may contribute to the clinical diagnosis of cGVHD are listed below (table 1). (See 'Distinctive findings' below.)

Mouth — Oral manifestations of cGVHD were seen in approximately 60 percent of patients [20]. Changes are most often observed on the buccal mucosa and tongue, but all intraoral surfaces and the vermilion lip may be involved.

Xerostomia (dry oral mucosa) is common. Other manifestations may include erythema, mucositis, gingivitis, ulcers, pain (especially in association with ulceration), mucosal atrophy, mucocele, and pseudomembranes [20,21]. Oral manifestations may progress to lichen planus-type features, hyperkeratotic plaques, or restriction of the mouth opening from sclerosis (table 1) [1,22].

Oral features that are diagnostic (see 'Diagnostic criteria' below) and distinctive (see 'Distinctive findings' below) for cGVHD are presented below.

Eyes — Approximately half of adults with cGVHD have ocular involvement (table 1) [20,23].

Symptoms can range from mild dry eyes to pain and loss of vision. Photophobia, blepharitis (erythema of the eyelids with edema), and periorbital hyperpigmentation may be experienced.

In a prospective study of 387 patients with cGVHD, 69 percent of patients reported eye-related symptoms, while clinicians documented eye involvement in 52 percent [23]. A retrospective analysis of 429 patients with cGVHD reported that 98 percent had visual acuity better than 20/40 in at least one eye [24]. Other findings included tear deficiency (Schirmer score ≤5 mm; 53 percent), cataracts (39 percent), corneal epithelial staining (34 percent), conjunctival hyperemia (11 percent), chemosis (3 percent), and corneal epithelial sloughing, conjunctival subepithelial fibrosis, and symblepharon formation (<1 percent each). Only the presence of cataracts was a risk factor for developing impaired visual acuity.

There are no ocular manifestations that are considered diagnostic for cGVHD (table 1). Distinctive features that may contribute to the clinical diagnosis of cGVHD are listed below. (See 'Distinctive findings' below.)

Genitalia — Involvement of genitalia was reported in 11 percent of patients, but it may have been underreported (table 1) [20]; all patients should be asked about sexual function. For both males and females, genital involvement is often associated with oral cGVHD.

Female – Vaginal dryness, dyspareunia, itching, burning, pain, loss of libido, amenorrhea, inflammation, and stenosis have been reported in 11 to 48 percent of women who undergo allogeneic HCT [20,25-28]. Symptoms may be greater in the setting of estrogen insufficiency.

In a single center study of 32 females with genital cGVHD, most noted vaginal dryness, and approximately one-third had dyspareunia or a sensation of vaginal narrowing with impairment in sexual activity [25]. Generalized vulvar erythema and edema, mucosal paleness, reticulated leukokeratosis, or tenderness over Skene's and/or Bartholin's ducts was noted in half; the remainder had more severe disease, including erosions, fissures, and vaginal stenosis.

Diagnostic (see 'Diagnostic criteria' below) and distinctive (see 'Distinctive findings' below) features of cGVHD affecting female genitalia are described below.

Male – The glans penis, urethra, or meatus may be affected and patients may report painful sexual intercourse and a burning sensation [29].

Diagnostic (see 'Diagnostic criteria' below) and distinctive (see 'Distinctive findings' below) features of cGVHD affecting male genitalia are described below.

Liver — Liver abnormalities are present in half of patients with cGVHD and are commonly associated with anorexia, nausea, or vomiting [20].

Liver involvement can be due to aGVHD, with or without manifestations of cGVHD. Liver GVHD typically presents as either:

Acute hepatitis with steeply rising serum alanine aminotransferase (ALT), with or without jaundice, which usually arises after tapering of immunosuppressive drugs or after donor lymphocyte infusion. This presentation requires a prompt diagnosis and treatment intervention, and liver biopsy may be needed in the absence of GVHD in another organ.

Slowly progressive cholestatic disorder with elevated serum alkaline phosphatase and gamma-glutamyl transpeptidase, followed by jaundice.

Both acute hepatitis and progressive cholestatic features are included in the "common" category because abnormalities that suggest cholestasis (ie, elevated serum alkaline phosphatase and/or bilirubin) are common to both cGVHD and aGVHD. (See '"Common" features' below.)

There are no diagnostic or distinctive liver findings for cGVHD.

Gastrointestinal tract — The GI tract is involved in one-third of patients with cGVHD [20]. GI involvement can range from the esophagus to the lower GI tract (table 1).

Patients may have nausea/vomiting without weight loss. Small bowel and colonic involvement may manifest anorexia, nausea, vomiting, chronic diarrhea, malabsorption, weight loss, and failure to thrive (usually in infants and children). cGVHD can also result in exocrine pancreatic insufficiency. Some patients have dysphagia, painful ulcers, and weight loss caused by an esophageal stricture or ring.

Findings on endoscopy are variable and range from loss of vascular markings and/or focal mild erythema to severe erythema, edema, exudates, erosions, and ulceration [30]. Biopsy specimens may demonstrate increased crypt apoptosis (grade 1), apoptosis with crypt abscesses (grade 2), individual crypt necrosis (grade 3), and total denudation of areas of mucosa (grade 4) (picture 6 and picture 7) [31].

Diagnostic (see 'Diagnostic criteria' below) and distinctive (see 'Distinctive findings' below) features of cGVHD affecting the GI tract are described below.

Lung — Pulmonary involvement is present in approximately half of patients with cGVHD [20,32].

Early symptoms of lung involvement are mild dyspnea on exertion or dry, non-productive cough; symptoms may progress to significant dyspnea, decreased exercise tolerance, and non-productive cough (table 1). Patients may manifest obstructive and/or restrictive changes and can progress to oxygen-dependency, immobility, and death related to pulmonary infections.

Because of the insidious nature of bronchiolitis obliterans syndrome (BOS), screening pulmonary function testing (PFT) is recommended at day 100 post-transplant, at initial diagnosis of cGVHD, one year after transplant, and at six-month intervals during the first two years after the initial diagnosis of cGVHD [1]. More frequent PFT monitoring is recommended in patients diagnosed with BOS and in those with a significant decline in lung volumes who do not yet meet diagnostic criteria for BOS.

Diagnostic (see 'Diagnostic criteria' below) and distinctive (see 'Distinctive findings' below) features of cGVHD affecting the lungs are described below.

Pulmonary manifestations of cGVHD are discussed in detail separately. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes".)

Musculoskeletal — Muscle-related complications are seen in up to half of patients with cGVHD, often presenting several months to many years after HCT [20].

Edema, muscle cramps, arthralgia, arthritis, and joint stiffness are common [1,33]. Fasciitis and myositis (table 1), which resemble autoimmune eosinophilic fasciitis and idiopathic polymyositis, respectively, are reported in <5 percent of patients who undergo allogenic HCT, according to retrospective analyses [34-37].

Fasciitis – There is typically a temporal evolution, in which there is initial non-pitting edema of the extremities [34-36]. With progression, the swelling resolves and is replaced by symmetrical induration with puckering (peau d'orange) appearance. Fasciitis manifests clinically as limitations in joint mobility and skin changes in the forearms and legs and is often associated with sclerosis of the overlying skin and subcutaneous tissue. Contractures and joint stiffness can limit range of joint motion, most commonly involving the wrists or fingers (picture 4) [19]. Magnetic resonance imaging (MRI) shows high intensity in muscle in fat-suppressed T2 weighted images.

Myositis – Myositis manifests clinically as weakness with or without myalgias [33,37]. The muscle weakness is described as moderate to severe symmetrical weakness of proximal muscles, the neck flexors, and/or limb girdle. Involvement of the muscles of the upper esophagus, pharynx, respiratory system, and heart are rare.

Serum creatine kinase may be normal early in the disease process, but it can be 5 to 50 times the upper limit of normal with disease progression; elevations of lactate dehydrogenase (LDH), aldolase, and aminotransferases are also common. Autoantibodies directed against the nucleus, smooth muscle cells, or mitochondria may be present. Electromyography (EMG) is usually abnormal and demonstrates findings consistent with an inflammatory myopathy (eg, fibrillation potentials, positive sharp waves, short-duration and small amplitude motor unit action potentials, and full interference patterns in weak muscles). Biopsy is necessary to confirm involvement. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

Diagnostic (see 'Diagnostic criteria' below) and distinctive (see 'Distinctive findings' below) features of cGVHD affecting the musculoskeletal system are described below.

Other conditions — Less common conditions that can occur in patients with cGVHD but are not diagnostic or distinctive [3] include polyserositis [38], polymyositis [34,39], myasthenia gravis [40], large to medium vessel vasculitis [33], demyelinating disease of the central nervous system [33], immune-mediated encephalitis [33], peripheral neuropathy, cardiac conduction abnormalities, cardiomyopathy, pericardial or pleural effusions, and the nephrotic syndrome due to membranous nephropathy or minimal change disease [41-45].

Immune findings can include hypo- or hypergammaglobulinemia, autoantibodies, and Raynaud's phenomenon; hematologic manifestations can include thrombocytopenia, eosinophilia, and lymphopenia, but these are not diagnostic or distinctive for cGVHD [3].

It should be noted that platelets <100,000/microL are considered to indicate severe cGVHD. (See 'Prognostic features' below.)

EVALUATION — History and physical examination are the mainstays of evaluation for cGVHD. Nearly every organ system can manifest cGVHD, but the spectrum of findings and severity of symptoms vary between individuals. Histologic confirmation is important in some, but not all, cases.

Categories of clinical findings — It is important to categorize clinical symptoms and signs that are components of the National Institutes of Health (NIH) consensus criteria for diagnosis of cGVHD (table 1). The extent and severity should be documented with the scoring form (form 1), which is useful for diagnosing cGVHD (see 'Diagnostic findings' below), determining the disease subcategory (ie, classic cGVHD versus overlap syndrome) (see 'Subcategories' below), and grading disease severity (see "Treatment of chronic graft-versus-host disease", section on 'Grading').

Clinical findings should be catalogued as one of the following:

Diagnostic for cGVHD – Sufficient to establish the diagnosis of cGVHD. (See 'Diagnostic findings' below.)

Distinctive for cGVHD – May be seen in cGVHD, but findings alone are insufficient to establish the diagnosis of cGVHD. (See 'Distinctive findings' below.)

"Common" to both cGVHD and to acute GVHD (aGVHD). (See '"Common" features' below.)

Organ-specific features are listed in the sections below, according to whether they are diagnostic, distinctive, or common.

Diagnostic findings — Diagnostic findings are clinical features that establish the diagnosis of cGVHD without the need for further testing or evidence of other organ involvement. (See 'Diagnostic criteria' below.)

Specific diagnostic findings in organ systems follow; note that organ systems that are not listed in this section are not associated with diagnostic findings:

Skin – Cutaneous findings that are considered diagnostic for cGVHD (table 1) are [3]:

Poikiloderma – A combination of atrophy, hypopigmentation, and hyperpigmentation in the skin usually appearing as patches with mottled pigmentation and telangiectasias (picture 8).

Lichen planus-like features – Erythematous to violaceous papules or plaques with a predilection for the dorsal hands and feet, forearms, and trunk (picture 1). Fine scale may be present.

Sclerotic features – A rippled appearance with thickening of fibrous septa in fat, particularly on the medial arms and thighs (picture 2). Fascial involvement tends to occur later and may lead to prominent linear demarcations ("groove sign") and contractures that limit range of motion (picture 4).

Morphea-like features – Firm, hyperpigmented, hypopigmented, or skin-colored plaques (picture 9). Affected skin often has a shiny appearance and demonstrates hair loss secondary to elimination of adnexal structures.

Lichen sclerosis-like features.

Additional discussion of cutaneous cGVHD is presented separately. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)".)

Oral mucosa Lichen planus-type features are diagnostic for cGVHD (table 1) [3].

GenitaliaLichen planus-like features and lichen sclerosus-like features affecting genitalia are diagnostic for cGVHD in both males and females (table 1) [3]. Additional sex-specific diagnostic findings are:

FemaleVaginal scarring or clitoral/labial agglutination.

MalePhimosis or urethral/meatus scarring or stenosis.

Gastrointestinal (GI) findings that are diagnostic for cGVHD (table 1) [3] are:

Esophageal web.

Strictures or stenosis in the upper to mid-third of the esophagus demonstrated by endoscopy or barium contrast radiograph.

LungBronchiolitis obliterans that is diagnosed with lung biopsy is diagnostic for cGVHD (table 1) [3].

Note that bronchiolitis obliterans syndrome (BOS; ie, the clinical syndrome without histologic confirmation, as described below), is considered a distinctive feature, not a diagnostic finding. (See 'Distinctive findings' below.)

Musculoskeletal findings that are considered diagnostic for cGVHD (table 1) are [3]:

Fasciitis – When a biopsy is performed, histology demonstrates lymphocytic infiltration (of donor origin), edema, and fibrosis in the fascia and subcutaneous septa; the infiltration is diffuse and it often extends into the subcutaneous fat and pericapillary space, but usually spares the muscle itself. (See "Eosinophilic fasciitis".)

Joint stiffness or contractures secondary to fasciitis or sclerosis.

Distinctive findings — Distinctive findings, alone, are not considered diagnostic for cGVHD [3]. Distinctive findings should be complemented by histologic findings, other testing (in the same organ or another organ), or evaluation by a specialist (eg, gynecologist, ophthalmologist) to establish the diagnosis of cGVHD.

Organ systems that are not listed in this section are not associated with distinctive features for cGVHD.

Skin – Distinctive cutaneous findings are depigmentation and papulosquamous lesions (table 1) [3].

Other characteristic findings of skin that are not considered distinctive or "common," per NIH criteria [3] include sweat impairment, ichthyosis, keratosis pilaris, hypopigmentation, and hyperpigmentation.

A skin biopsy can confirm the presence of cutaneous cGVHD. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Skin biopsy'.)

Nails – Distinctive nail findings (table 1) [3] are:

Dystrophy (picture 5).

Longitudinal ridging, splitting or brittle features.

Onycholysis.

Pterygium unguis (abnormal adherence of the nail plate to the proximal nail fold or hyponychium).

Nail loss, which is usually symmetric and affects most nails.

Hair and scalp – Distinctive findings of hair and scalp (table 1) [3] are:

Alopecia – New onset of scarring or non-scarring scalp alopecia (not associated with recovery from chemotherapy or radiation therapy).

Loss of body hair.

Scaling of scalp.

Other characteristic findings of hair and scalp that are not considered distinctive or "common," per NIH criteria [3]) are thinning scalp hair (typically patchy, coarse, or dull) and premature graying of hair.

Mouth – Distinctive oral lesions (table 1) [3] are:

Xerostomia.

Mucoceles.

Mucosal atrophy.

Ulcers.

Pseudomembranes.

Oral biopsies are effective in detecting/confirming the presence of oral cGVHD.

Eyes – Distinctive ocular lesions in cGVHD (table 1) [3] are:

Dry, gritty, or painful eye of new onset.

Cicatricial conjunctivitis.

Keratoconjunctivitis sicca.

Confluent areas of punctate keratopathy.

Evaluation by an ophthalmologist can complement distinctive findings and should include a low Schirmer's test (eg, ≤5 mm at five minutes, preferably normal value documented at an established baseline) or confirmation of keratoconjunctivitis sicca by slit lamp exam.

Other characteristic ocular findings that are not considered distinctive or "common," per NIH criteria [3] are photophobia, periorbital hyperpigmentation, and blepharitis (erythema of the eye lids with edema).

LungBronchiolitis obliterans syndrome (BOS) is diagnosed by the following clinical testing criteria [3]:

Forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio <0.7 and FEV1 <75 percent of predicted (with ≥10 percent decline over <2 years).

Absence of infection in the respiratory tract, documented with chest radiograph, computed tomography (CT), and/or microbiologic cultures, as clinically indicated.

One of the following:

-Evidence of air trapping by high resolution expiratory chest CT or small airway thickening or bronchiectasis on high resolution CT.

or

-Evidence of air trapping by PFTs with residual volume >120 percent.

Other characteristic pulmonary findings that are not considered distinctive or "common," per NIH criteria [3] are cryptogenic organizing pneumonia (COP) and restrictive lung disease.

MusculoskeletalMyositis or polymyositis are distinctive features of cGVHD, but they require a confirmatory biopsy to diagnose cGVHD [3].

Muscle biopsy is often deferred due to concerns regarding the risk of impaired wound healing. When a biopsy is performed, histologic findings include degeneration, necrosis, and regeneration of muscle fibers and infiltrates of inflammatory cells of donor origin. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

"Common" features — Common features are those that can be seen with both cGVHD and aGVHD.

Note that the term "common" refers to the association with both cGVHD and aGVHD; it does not refer to the frequency of presentation. The presence of common features may raise suspicion for overlap syndrome. (See 'Subcategories' below.)

Organ systems that are not listed in this section are not associated with common features.

Skin – Erythema, maculopapular rash, and pruritus are common to both cGVHD and aGVHD [3].

Mouth – Gingivitis, mucositis, erythema, and pain are common to both cGVHD and aGVHD [3].

Gastrointestinal – Anorexia, nausea, vomiting, chronic diarrhea, malabsorption, weight loss, and failure to thrive (in infants and children) are common to both cGVHD and aGVHD [3].

Liver – Liver abnormalities are present in half of patients with cGVHD [20], but there are no diagnostic or distinctive features of liver involvement [3].

Liver involvement is typically manifested as abnormal liver function tests (LFTs) that suggest cholestasis, without other major complications. Elevations (>2 x upper limit of normal) of serum bilirubin, alkaline phosphatase, alanine aminotransferase (ALT) are typical. (See 'Differential diagnosis' below.)

For patients with suspected isolated hepatic cGVHD (ie, no other diagnostic features of cGVHD in other organs), a liver biopsy should be performed. (See 'Pathology' below.)

Pathology — A biopsy is often valuable to diagnose cGVHD, but it is not always feasible and it is not required for patients who have diagnostic clinical features. (See 'Diagnostic findings' above.)

A pathology specimen may be required when there are only distinctive findings for cGVHD (ie, no diagnostic clinical features are present); for distinctive clinical features, either biopsy evidence, other organ-specific laboratory studies, or evaluation by an appropriate specialist may be required to diagnose cGVHD. (See 'Diagnostic criteria' below.)

Examples of organs/sites that might be biopsied to establish the diagnosis of cGVHD include:

Skin – A 4 mm punch skin biopsy that provides a full dermal thickness specimen, including subcutaneous fat. A biopsy of sun-exposed forearm areas may reveal diagnostic changes, even in the absence of a rash. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Skin biopsy'.)

Mouth – Oral biopsies can confirm the presence of cGVHD when distinctive features, such as xerostomia, mucoceles, mucosal atrophy, ulcers, or pseudomembranes are seen.

Liver biopsy – A transjugular liver biopsy may be necessary in patients with isolated liver abnormalities (ie, no other clinical manifestations of cGVHD). (See 'Liver' above.)

Lung biopsy that demonstrates bronchiolitis obliterans is diagnostic for cGVHD. (See 'Lung' above and 'Diagnostic findings' above.)

DIAGNOSIS AND CLASSIFICATION — The diagnosis of cGVHD should be considered in any patient who has undergone allogeneic hematopoietic cell transplantation (HCT) and has symptoms or signs that affect the skin, mucous membranes, eyes, gastrointestinal (GI) tract, liver, lungs, muscles/joints, or other organ systems. Clinical manifestations can affect different combinations of organs, vary in severity, and may present early (<100 days after HCT) or later (up to years later).

For some patients, cGVHD can be readily diagnosed on clinical grounds (eg, classic features of skin involvement, GI involvement, and a rising serum bilirubin concentration). However, for many patients, other post-transplantation conditions and complications must be excluded; if the diagnosis is less apparent, histologic confirmation may be needed to diagnose cGVHD and/or exclude other conditions in the differential diagnosis. (See 'Differential diagnosis' below.)

Diagnostic criteria — The diagnosis of cGVHD requires one of the following, (form 1) according to National Institutes of Health (NIH) consensus criteria [3]:

A diagnostic clinical manifestation (see 'Diagnostic findings' above)

or

The presence of at least one distinctive clinical manifestation, confirmed by biopsy or other relevant tests in the same or another organ (see 'Distinctive findings' above)

Alternatively, a lung biopsy that demonstrates pathologic evidence of bronchiolitis obliterans is sufficient to diagnose cGVHD, regardless of other clinical manifestations. (See 'Lung' above.)

Subcategories — Once the diagnosis is established, cGVHD should be further categorized as either:

Classic cGVHD – Features of cGVHD are present and there are no findings of acute GVHD (aGVHD).

Overlap syndrome – Features of both cGVHD and aGVHD are present. A continuum of clinical findings may be observed in patients with overlap syndrome, as both aGVHD and cGVHD commonly affect the skin, liver, GI tract, and other organs [2].

Features of aGVHD in overlap syndrome may include changes in the skin (erythema, maculopapular rash, pruritus), mouth (gingivitis, mucositis, oral erythema, oral pain), GI symptoms (anorexia, nausea, vomiting, diarrhea, weight loss, failure to thrive), liver dysfunction (elevations in bilirubin, alkaline phosphatase, or transaminases), and organizing pneumonia (also called bronchiolitis obliterans organizing pneumonia [BOOP]).

The clinical features associated with cGVHD may differ from those observed with aGVHD. As an example, autoimmune phenomena, such as autoantibody formation, are common with cGVHD (62 percent in one study) [46] but rare in aGVHD. Clinical aspects of cGVHD may also mimic features frequently observed with systemic lupus erythematosus, scleroderma, sicca syndrome, eosinophilic fasciitis, rheumatoid arthritis, and primary biliary sclerosis [47].

Diagnosis of overlap syndrome has prognostic importance. (See 'Prognosis' below.)

Grading — All cases of cGVHD should be graded, as this has important implications for selection of therapy and for prognosis.

Grading is according to the NIH scoring system (form 1) [3]. Broadly, severity is scored as:

Mild – Involves ≤2 organs/sites with no clinically significant functional impairment

Moderate:

Involves 3 organs/sites with no clinically significant functional impairment

or

≤1 organ/site with clinically significant functional impairment, but no major disability

Severe – Major disability caused by cGVHD

Details and grading criteria in the NIH grading system are described separately. (See "Treatment of chronic graft-versus-host disease", section on 'Grading'.)

Findings that establish the diagnosis of cGVHD are not necessarily the most appropriate parameters for assessing disease severity of cGVHD [3]. Conversely, a sensitive measure of cGVHD response might not necessarily serve as a diagnostic finding.

DIFFERENTIAL DIAGNOSIS — In most cases, cGVHD is a diagnosis of exclusion and other possible causes of clinical symptoms must be considered. The differential diagnosis depends upon the presenting signs and symptoms of cGVHD. Infections and other disorders can confound or complicate the differential diagnosis of cGVHD and must be excluded. Most alternative diagnoses can be excluded with a biopsy of the involved tissue.

Some clinical features are common to both cGVHD and acute GVHD (aGVHD); these conditions should be distinguished according to the particular organ-specific findings, not the time of onset after transplantation [3].

Skin involvement – The differential diagnosis includes lichen planus, lichen sclerosus, morphea, systemic sclerosis, eosinophilic fasciitis, and other causes of poikiloderma as discussed in more detail separately. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Differential diagnosis'.)

Liver involvement – Other causes of cholestasis occurring beyond >100 days after hematopoietic cell transplantation (HCT) include viral infections, biliary obstruction, drug toxicity, nonalcoholic steatohepatitis, and malignancy (table 2 and table 3). A biopsy may be required to exclude other causes, especially when the presentation of cGVHD is liver-only disease. (See "Classification and causes of jaundice or asymptomatic hyperbilirubinemia" and "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia".)

Gastrointestinal (GI) tract – The differential diagnosis of cGVHD of the GI tract includes other causes of nausea, vomiting, diarrhea, and weight loss, including infectious causes (eg, Clostridioides difficile infection, cytomegalovirus [CMV] reactivation), drug effects, adverse effects of chemotherapy or radiation, inflammatory diarrhea, short bowel syndrome, peptic ulcer disease, neoplasms, and systemic disease (eg, diabetes mellitus). The approach to distinguishing cGVHD from these other conditions is described separately. (See "Approach to the adult with chronic diarrhea in resource-abundant settings" and "Approach to the adult with nausea and vomiting".)

Lung – Other causes of restrictive and obstructive lung function must be excluded, including infections (eg, CMV, toxoplasmosis), interstitial lung disease, granulomatous disease (eg, sarcoidosis), and diffuse alveolar hemorrhage. Details of the evaluation to exclude other causes are presented separately. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Post hematopoietic cell engraftment'.)

Musculoskeletal disease – Other causes of fasciitis and myositis, including dermatomyositis, inclusion body myositis, and other causes of rhabdomyolysis should be considered, as described separately. (See "Clinical manifestations of dermatomyositis and polymyositis in adults" and "Clinical manifestations and diagnosis of inclusion body myositis" and "Rhabdomyolysis: Epidemiology and etiology".)

PROGNOSIS — The presence of cGVHD is associated with inferior outcomes in patients who undergo allogeneic hematopoietic cell transplantation (HCT). For patients who are diagnosed with cGVHD, severe grade of disease, thrombocytopenia, and overlap syndrome are associated with adverse prognosis.

Compared with patients who did not develop GVHD, the presence of cGVHD was associated with inferior overall survival (OS; relative risk [RR] 1.56; 95% CI 1.41-1.73) and higher treatment-related mortality (RR 2.43; 95% CI 2.09-2.82) in a registry study of 7489 allogeneic transplants [48].

Prognostic models — Adverse outcomes for patients with cGVHD have been associated with:

NIH disease grade – Higher severity score is associated with shorter survival and higher rate of nonrelapse mortality (NRM). In a prospective study of 298 adult patients, cGVHD was graded as mild, moderate, and severe in 10, 59, and 31 percent of patients at diagnosis, respectively, [49]. OS at two years was 97, 86, and 62 percent for patients with mild, moderate, and severe chronic GVHD, respectively. Inferior quality of life was also associated with moderate to severe cGVHD (per National Institutes of Health [NIH] criteria) in another report [50].

The NIH scoring system has been validated by numerous studies [20,49-60].

CIBMTR score – The Center for International Blood and Marrow Transplant Research (CIBMTR) has proposed a cGVHD risk score, based upon retrospective evaluation of 5343 patients with cGVHD (calculator 1) [61]. This model uses 10 variables measured at the time of cGVHD diagnosis, including patient age, prior acute GVHD (aGVHD), performance status, time of onset of cGVHD, degree of donor match, and other features; however, patients are not well-distributed among the six prognostic categories. Nevertheless, the overall risk score is associated with OS and NRM at five years.

The CIBMTR score was further validated in an analysis of 376 consecutive patients at two transplant centers [62].

The NIH and CIBMTR prognostic models have not been directly compared.

Other prognostic models require prospective validation before they are widely adopted [63-65].

Prognostic features — Specific features that have prognostic value for outcomes with cGVHD include:

Thrombocytopenia (platelet count <100,000/microL) had an adverse impact on overall mortality (hazard ratio [HR] 6.6, 95% CI 3.5-12.4) and treatment failure (ie, relapse or death without relapse; HR 5.2, 95% CI 2.9-9.4) [16]. In another study, thrombocytopenia (present in 15 percent of patients with chronic GVHD) predicted worse survival [66].

Overlap syndrome – The overlap subcategory of cGVHD has been associated with worse survival compared with classic cGVHD (ie, no co-existent aGVHD) in most studies [2,52-54], but not in all studies [55].

Clinician- and patient-reported outcomes – In a prospective observational study, the cGVHD consortium tested the ability of the 2005 NIH response measures, 2014 NIH response measures, clinician-reported response, and patient-reported response to predict subsequent OS, NRM, and failure-free survival in 575 patients undergoing HCT [63]. Both clinician-reported response and patient-reported outcomes were predictive of long-term survival.

Skin involvement – Composite skin score (according to NIH criteria) was validated as having prognostic value [20]. Among 458 patients with cGVHD, 285 patients had skin involvement and composite skin scores of 1, 2, and 3 were identified in 37, 39, and 24 percent, respectively. Changes in scores over time correlated with the perceived change in severity, in either direction, by both clinicians and patients. Two year OS was 86, 83, 81, and 69 percent among patients with scores of 0, 1, 2, and 3, respectively; corresponding rates of NRM at two years were 10, 13, 15, and 30 percent. A worsening score at six months was associated with increased mortality (HR 4.7, 95% CI 0.9-25.1) and higher NRM (HR 7.2, 95% CI 1.2-43.9).

GI involvement – Hyperbilirubinemia and small intestinal/colonic involvement have been associated with increased mortality [4,51,61,67].

SUMMARY

Chronic graft-versus-host disease (cGVHD) is a multisystem syndrome that occurs in more than half of patients who undergo allogeneic hematopoietic cell transplantation (HCT).

Risk factors for cGVHD include the degree of human leukocyte antigen (HLA)-mismatch, increasing age, sex-disparity, and others. (See 'Risk factors' above.)

Clinical features can involve nearly every organ system; examples of notable and potentially severe findings include:

Skin resembling lichen planus or the cutaneous manifestations of scleroderma. (See 'Mucocutaneous' above.)

Liver function test elevations. (See 'Liver' above.)

Gastrointestinal (GI) involvement includes dry mucosa, ulcerations, dysphagia with weight loss, chronic diarrhea and malabsorption. (See 'Gastrointestinal tract' above.)

Lung involvement can result in bronchiolitis obliterans. (See 'Lung' above.)

Musculoskeletal findings include fasciitis and myositis. (See 'Musculoskeletal' above.)

Evaluation – Clinical findings are defined by the National Institutes of Health (NIH) consensus criteria (table 1) and should be catalogued (form 1) as:

Diagnostic for cGVHD – Sufficient to establish the diagnosis of cGVHD. (See 'Diagnostic findings' above.)

Distinctive for cGVHD – May be seen in cGVHD, but findings are insufficient to establish the diagnosis of cGVHD. (See 'Distinctive findings' above.)

"Common" to both cGVHD and to acute GVHD (aGVHD). (See '"Common" features' above.)

Diagnosis of cGVHD requires one of the following (form 1), according to NIH consensus criteria [3]:

A diagnostic clinical manifestation. (See 'Diagnostic findings' above.)

or

At least one distinctive clinical finding coupled with a pertinent biopsy, laboratory/radiology finding, or evaluation by a relevant specialist in the same organ or another organ system. (See 'Distinctive findings' above.)

A lung biopsy that demonstrates bronchiolitis obliterans is also sufficient to diagnose cGVHD, regardless of other clinical manifestations. (See 'Lung' above.)

Subcategories include classic cGVHD (no evidence of concurrent aGVHD) or overlap syndrome (features of both cGVHD and aGVHD are present). (See 'Subcategories' above.)

Grade – cGVHD should be graded as mild, moderate, or severe, according to the NIH scoring system (form 1), as described separately. (See "Treatment of chronic graft-versus-host disease", section on 'Grading'.)

Differential diagnosis depends upon the clinical findings. cGVHD is a diagnosis of exclusion and other possible causes of clinical symptoms must be considered. (See 'Differential diagnosis' above.)

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Topic 3548 Version 33.0

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