Clinical Manifestations, Diagnosis, and Grading of Chronic Graft-Versus-Host Disease - UpToDate

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Clinical manifestations, diagnosis, and grading of chronic graft-

versus-host disease
Author: Nelson J Chao, MD
Section Editor: Robert S Negrin, MD
Deputy Editor: Alan G Rosmarin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2020. | This topic last updated: Apr 08, 2020.
INTRODUCTION
Acute and chronic graft-versus-host disease (GVHD) are multisystem disorders that are common
complications of allogeneic hematopoietic cell transplant (HCT). GVHD occurs when immune cells
transplanted from a non-identical donor (the graft) recognize the transplant recipient (the host) as foreign,
thereby initiating an immune reaction that causes disease in the transplant recipient. (See "Pathogenesis of
graft-versus-host disease (GVHD)".)
GVHD has been classically divided into acute and chronic variants based upon the time of onset using a
cutoff of 100 days. However, this conventional division has been challenged by the recognition that signs of
acute and chronic GVHD may occur outside of these designated periods. This observation has led to the
increased use of clinical findings, rather than a set time period, to differentiate between acute and chronic
GVHD. The widely accepted National Institutes of Health (NIH) consensus criteria for the diagnosis of GVHD
include an overlap syndrome in which diagnostic or distinctive features of chronic GVHD and acute GVHD
appear together [1].
Clinical manifestations of chronic GVHD include skin involvement (eg, resembling lichen planus or cutaneous
manifestations of scleroderma); dry oral mucosa with ulcerations and sclerosis; gastrointestinal tract effects
(eg, exudates, erosions, ulceration); and a rising serum bilirubin concentration. In contrast, patients with
acute GVHD commonly demonstrate a classic maculopapular rash; abdominal cramps with diarrhea; and a
rising serum bilirubin concentration. (See "Clinical manifestations, diagnosis, and grading of acute graft-
versus-host disease", section on 'Clinical and histological manifestations'.)
This topic review will discuss the clinical manifestations, diagnosis, and grading of chronic GVHD. The
treatment of chronic GVHD and issues concerning acute GVHD are presented separately. (See "Treatment of
chronic graft-versus-host disease" and "Prevention of acute graft-versus-host disease" and "Clinical
manifestations, diagnosis, and grading of acute graft-versus-host disease".)
EPIDEMIOLOGY
Chronic GVHD can occur after previous or ongoing acute GVHD or in patients without a history of acute
GVHD (eg, de novo disease). The exact incidence of chronic GVHD after allogeneic hematopoietic cell
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transplant (HCT) is unknown. While chronic GVHD occurs in approximately 40 percent of allogeneic HCT
recipient, reported incidence rates range from 6 to 80 percent, depending upon the presence of risk factors
and the diagnostic criteria used [1-4]. While risk factors for the development of GVHD have been identified,
reliable estimates of GVHD incidence in various cohorts are not available due to variability in the
identification, measurement, and documentation of chronic GVHD.
RISK FACTORS
Some of the major risk factors for the development of chronic GVHD include [5-10]:
● Higher degree of HLA mismatching

● Older age of donor and/or recipient
● Donor and recipient gender disparity (female donor to male recipient)
● Alloimmunization of the donor (history of pregnancy, transfusions)
● Source of stem cells (peripheral blood precursor cells [PBPC] rather than bone marrow or umbilical cord
blood)
● Prior acute GVHD
● Administration of unirradiated donor buffy coat transfusions (eg, donor lymphocyte infusions)
● Previous splenectomy
● Cytomegalovirus seropositivity (donor and/or recipient)
● Donor Epstein-Barr virus seropositivity
Less well established predictive factors include total body irradiation-containing regimens, second bone
marrow infusions, preceding herpesvirus infection, the type of underlying malignancy, and the absence of
blood transfusions administered prior to transplantation [2,8,11,12]. (See "Sources of hematopoietic stem
cells", section on 'PBPC versus bone marrow for malignant disease'.)
The presence of more than one of these risk factors increases the probability of developing chronic GVHD.
As examples:
● A retrospective study evaluated the risk factors for chronic GVHD among 551 consecutive recipients of
allogeneic bone marrow transplants [2]. Among 34 analyzed variables, high recipient age, previous
acute GVHD, female donor to male recipient, and a history of chronic myeloid leukemia were identified
as significant risk factors for the development of chronic GVHD. At five years post-transplant, the
incidence of chronic GVHD was 75, 68, 53, 29, and 9 percent among patients with four, three, two, one,
and none of these four factors, respectively.
● In a study of 116 consecutive evaluable HLA-identical allogeneic PBPC transplants, the cumulative
incidence of chronic GVHD was 57 percent [13]. On multivariate analysis, GVHD prophylaxis with
methotrexate and tacrolimus was associated with a reduced risk of chronic GVHD (hazard ratio [HR]
0.35, 95% CI 0.2-0.6), while prior acute GVHD was associated with an increased risk (HR 1.67, 95% CI: 1.0-
2.8). The presence of high-risk chronic GVHD (ie, platelet count <100,000/microL) had an adverse impact
on overall mortality (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).
CLINICAL AND HISTOLOGIC FEATURES

Distribution of disease and definitions — The skin, liver, gastrointestinal tract, and lungs are the principal
target organs involved in patients with chronic GVHD [14-16]. This was illustrated in a prospective study of
458 patients with chronic GVHD that reported involvement in the following areas [17]:
● Skin – 67 percent (see 'Skin' below)

● Mouth – 60 percent (see 'Gastrointestinal tract' 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 disease' below)
● Gastrointestinal tract – 30 percent (see 'Gastrointestinal tract' below)
● Genitalia – 12 percent (see 'Genitalia' below)
The presenting symptoms are in some ways similar to those found in other well-established autoimmune
syndromes. However, in chronic GVHD, there is not a uniform presentation, but rather a variable
involvement of these and other organs. This variation makes clinical therapeutic studies difficult, since
comparisons of responses may be different depending on the severity of involvement as well as the involved
target organ.
The NIH consensus criteria used to diagnose chronic GVHD classify manifestations as "diagnostic" or
"distinctive" (table 1) [1]. Diagnostic features are those that establish the diagnosis of chronic GVHD without
need of further investigation. In contrast, distinctive features are seen in patients with chronic GVHD and are
absent in patients with acute GVHD, but require further investigation to confirm the diagnosis. Diagnostic,
distinctive, and other clinical manifestations of chronic GVHD are described in the following sections. (See
'NIH consensus criteria' below.)
Patients with features of acute and/or chronic GVHD are subclassified based upon the timing of presentation
and the features present:
● Classic acute GVHD – Cases present within 100 days of hematopoietic cell transplant (HCT) and display
features of acute GVHD. Features of chronic GVHD are absent.
● Persistent, recurrent, late onset acute GVHD – Cases present greater than 100 days post-HCT with
features of acute GVHD. Features of chronic GVHD are absent.
● Classic chronic GVHD – Cases may present at any time post-HCT. Features of chronic GVHD are present.
There are no features of acute GVHD.
● Overlap syndrome – Cases may present at any time post-HCT with features of both chronic GVHD and
acute GVHD.
Mucocutaneous manifestations — Mucocutaneous manifestations of chronic GVHD include changes in the

skin, nails, scalp and body hair, mouth, eyes, and genitalia.
Skin — Skin involvement is the most common clinical feature of chronic GVHD and is seen in
approximately 67 percent of patients [17]. Traditionally, chronic cutaneous GVHD has been classified as
lichen planus-like or sclerotic (resembling scleroderma); however, many different clinical presentations of
chronic GVHD are now recognized, reflecting a spectrum of epidermal and dermal (sclerotic) changes.
Details regarding the cutaneous manifestations of chronic GVHD are presented separately. (See "Cutaneous
manifestations of graft-versus-host disease (GVHD)", section on 'Skin'.)

Briefly, the onset of skin involvement may be heralded by generalized erythema, plaques, and waves of
desquamation with continued underlying erythema. Affected patients often give a history of
photoactivation. Alternating areas of hyperpigmentation and hypopigmentation are commonly observed.
Without effective treatment, the affected skin may become progressively indurated and fixed to the
underlying fascia. The epidermis becomes significantly atrophic with prominent poikiloderma, with some
patients possessing localized lesions that resemble morphea. The skin may be hyperpigmented,
hypopigmented, and/or hide-like, with the development of joint contractures similar to those observed with
scleroderma.
The following cutaneous findings can establish the presence of chronic GVHD without the need for further
testing or evidence of other organ involvement (ie, diagnostic features) [1]:
● Poikiloderma – A combination of atrophy, hypopigmentation, and hyperpigmentation in the skin

usually appearing as patches with mottled pigmentation and telangiectasias (picture 1).
● Lichen planus-like features – Erythematous to violaceous papules or plaques with a predilection for
the dorsal hands and feet, forearms, and trunk (picture 2). Fine scale may be present.
● Sclerotic features – A cellulite-like rippled appearance of the skin due to thickening of the fibrous
septae within fat, particularly on the medial arms and thighs (picture 3). Fascial involvement tends to
occur late in the chronic period, and may lead to the appearance of prominent linear demarcations,
often referred to as the "groove sign," and contractures that limit range of motion (picture 4).
● Morphea-like features – Firm, hyperpigmented, hypopigmented, or skin-colored plaques (picture 5).

Affected skin often has a shiny appearance and demonstrates hair loss secondary to elimination of
adnexal structures.
● Lichen sclerosis-like features – A dermatosis characterized by epidermal atrophy and superficial

dermal fibrosis (picture 6).
Depigmentation is seen in patients with chronic GVHD, but is not considered sufficient to establish an
unequivocal diagnosis. Other features of chronic GVHD include sweat impairment, ichthyosis, keratosis
pilaris, hypopigmentation, and hyperpigmentation. Skin changes seen in patients with both chronic and
acute GVHD include erythema, maculopapular rash, and pruritus. The presence of these common features
suggests the overlap subtype of chronic GVHD. (See 'NIH consensus criteria' below.)
Eyes — Approximately 40 to 60 percent of adult patients with chronic GVHD will have involvement of their
eyes [17,18]. In a prospective study of 387 patients with chronic GVHD, 69 percent of patients reported eye-
related symptoms, while clinicians documented eye involvement in 52 percent [18]. Symptoms can range
from mild dry eyes to eye pain and loss of vision.
In a retrospective analysis of 429 patients with chronic GVHD, visual acuity of ≥20/40 in at least one eye was
seen in 422 patients (98.4 percent) [19]. Ocular findings on examination included:
● Aqueous tear deficiency (Schirmer score ≤5 mm) – 53.4 percent

● Cataracts – 39.4 percent
● Corneal epithelial staining – 33.6 percent
● Conjunctival hyperemia – 10.5 percent
● Chemosis – 3 percent
● Corneal epithelial sloughing, conjunctival subepithelial fibrosis, and symblepharon formation – <1
percent each
Of these factors, only the presence of cataracts was a risk factor for developing impairment in visual acuity
(20/50 or worse). This suggests that, while chronic GVHD involves the eyes in the majority of patients, severe
eye involvement is uncommon.
There are no diagnostic signs of eye involvement [1]. Distinctive signs include new onset dry, gritty, painful
eyes; cicatricial conjunctivitis; keratoconjunctivitis sicca; or confluent areas of punctate keratopathy. Other
features include photophobia, periorbital hyperpigmentation, and blepharitis (erythema of the eyelids with
edema). While new ocular sicca documented by a low Schirmer score (≤5 mm) or new onset of
keratoconjunctivitis by slit-lamp examination is not diagnostic on its own, these features confirm eye
involvement in patients with diagnostic manifestations of chronic GVHD in another organ.
Hair and nails — While patients with chronic GVHD commonly have changes in their hair and nails, none
is diagnostic [1]. Distinctive nail signs include dystrophy (picture 7), longitudinal ridging, splitting, or brittle
features; onycholysis; pterygium unguis; and nail loss (usually symmetric and affects most nails). Distinctive
findings in the scalp and body hair include new onset of scarring or nonscarring scalp alopecia (after
recovery from chemotherapy and/or radiotherapy); scaling; and papulosquamous lesions. Other findings
include premature gray hair and thinning scalp hair, which is typically patchy, coarse, or dull. This is
discussed in more detail separately. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)",
section on 'Hair disorders' and "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on
'Nail disorders'.)
Genitalia — Gynecological manifestations, such as vaginal inflammation and stenosis, have been

observed in patients with chronic GVHD [20-24]. The exact incidence is unknown and reported rates range
from 11 to 48 percent [17,22,25]. Symptoms include vaginal dryness, dyspareunia, itching, burning, pain to
touch, loss of libido, and amenorrhea.
Findings on gynecologic examination that can establish the presence of chronic GVHD without the need for
further testing or evidence of other organ involvement (ie, diagnostic features) are lichen planus-like
features, vaginal scarring, or stenosis [1]. Other distinctive, but not diagnostic, signs are erosions, fissures,
and ulcers.
In a single center study of 32 patients with genital chronic GVHD, 23 patients (72 percent) had involvement
of other organs [22]. Most patients complained about vaginal dryness, and approximately one-third had
dyspareunia or a sensation of vaginal narrowing with impairment in sexual activity. In approximately half of
patients, findings on examination were limited to generalized erythema and edema of the vulva, mucosal
paleness, reticulated leukokeratosis, or erythema and tenderness on light pressure over the openings of
Skene’s and/or Bartholin’s ducts. The remainder had more severe disease including erosions, fissures, and
vaginal stenosis.
Liver — Approximately half of patients with chronic GVHD have some involvement of the liver [17]. Often
liver involvement is manifested as liver function test abnormalities without other major complications. The
liver function tests are most consistent with those of cholestasis, with elevations in the serum alkaline
phosphatase, ALT or AST, and bilirubin concentrations. There are no signs that are diagnostic or distinctive
and the same liver findings occur in patients with acute and chronic GVHD [1]. Liver biopsies are performed
to confirm involvement when isolated hepatic GVHD is suspected. Biopsies variably showing lobular
hepatitis, chronic persistent hepatitis, chronic active hepatitis, and a reduction or absence of small bile ducts
with cholestasis [26,27]. In most patients, the pathophysiology is thought to resemble that of primary biliary
cirrhosis, including biliary cell necrosis and basement membrane thickening [28]. In all cases, infection, drug

effects, malignancy, or other causes must be excluded. (See "Enzymatic measures of cholestasis (eg, alkaline
phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase)".)
Gastrointestinal tract — The gastrointestinal tract is involved in the majority of patients with chronic GVHD.
In a prospective study, oral lesions were seen in approximately 60 percent of patients and involvement of
other areas of the gastrointestinal tract was present in 30 percent [17].
The oral mucosa is commonly dry, often resulting in pain secondary to ulceration [5,17,29]. Findings on
examination of the oral cavity that can establish the presence of chronic GVHD without the need for further
testing or evidence of other organ involvement (ie, diagnostic features) are lichen-type features,
hyperkeratotic plaques, or restriction of the mouth opening from sclerosis [1,30]. Other signs include
xerostomia, mucocele, mucosal atrophy, pseudomembranes, ulcers, gingivitis, mucositis, erythema, and
pain. Importantly, gingivitis, mucositis, erythema, and pain may be seen in both acute and chronic GVHD
and, when present with other features of chronic GVHD, are used to designate the overlap subtype of
chronic GVHD. (See 'NIH consensus criteria' below.)
Patients with chronic GVHD may also have involvement of the esophagus, resulting in dysphagia, painful
ulcers, and gradual weight loss. Findings on radiography may include webs, ring-like narrowing, and a
tapering structure of the mid and upper esophagus [31]. The presence of an esophageal web and strictures
or stenosis in the upper to mid third of the esophagus is diagnostic of chronic GVHD [1].
Among patients with small bowel and colonic involvement, common symptoms and signs include anorexia,
nausea, vomiting, chronic diarrhea, malabsorption, weight loss, and failure to thrive (usually in infants and
children). These symptoms can be seen in acute GVHD and the overlap subtype of chronic GVHD. Chronic
GVHD can also result in exocrine pancreatic insufficiency.
Endoscopy is commonly performed to investigate gastrointestinal tract involvement. 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 [32]. 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 8 and picture 9) [33].
Lung — Pulmonary involvement is present in approximately half of patients with chronic GVHD and may
manifest as obstructive and/or restrictive changes [17,34]. While a clinical diagnosis of bronchiolitis
obliterans is suggestive of chronic GVHD, pathologic evidence of bronchiolitis obliterans is diagnostic [1]. In
contrast, organizing pneumonia (also called bronchiolitis obliterans organizing pneumonia, BOOP) is seen in
both acute and chronic GVHD [35].
With bronchiolitis obliterans, there is typically a temporal evolution of symptoms and signs. Initially, patients
are asymptomatic with impairments seen only on pulmonary function tests. Early symptoms are generally
mild dyspnea on exertion or dry and non-productive cough. Symptoms may progress to significant dyspnea
on exertion, decreased exercise tolerance, and non-productive cough. Pulmonary involvement can ultimately
progress to oxygen dependency, immobility, and death related to pulmonary infections. This is described in
more detail separately. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation"
and "Overview of bronchiolar disorders in adults".)
A clinical diagnosis of bronchiolitis obliterans is made in a HCT recipient when all of the following are met
[1]:

● Forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio <0.7 and FEV1 <75 percent
of predicted.
● Evidence of air trapping or small airway thickening or bronchiectasis on high resolution chest computed
tomography, residual volume >120 percent, or pathologic confirmation of constrictive bronchiolitis.
● Absence of infection in the respiratory tract, documented with investigations directed by clinical
symptoms.
● Histologically, the bronchioles are destroyed with fibrous obliteration of the lumen; granulation tissue
frequently extends into the alveolar ducts. This histologic pattern is also seen as a manifestation of
chronic lung transplant rejection. (See "Chronic lung transplant rejection: Bronchiolitis obliterans".)
Musculoskeletal disease — Muscle-related complications are seen in up to 50 percent of patients with

chronic GVHD, often presenting several months to many years after HCT [17]. Signs that are common, but
not specific, include edema, muscle cramps, arthralgia, and arthritis [1,36]. The two most notable
musculoskeletal findings are fasciitis and myositis that resemble autoimmune eosinophilic fasciitis and
idiopathic polymyositis, respectively. Retrospective analyses have reported these complications in less than 5
percent of patients undergoing allogeneic HCT [37-40].
The clinical and histologic findings depend upon the type of disorder:
● Fasciitis – Fasciitis manifests clinically as limitations in joint mobility and skin changes [41]. There is
typically a temporal evolution of skin findings. Initially, there may be marked, nonpitting edema of the
extremities. With progression of the disease, the swelling resolves and is replaced by symmetrical
induration with puckering that gives the skin the texture of orange peel (peau d’orange). Contractures
and joint stiffness are also observed resulting in limited range of joint motion, most commonly involving
the wrists or fingers (picture 4) [16]. Magnetic resonance imaging (MRI) shows high intensity in muscle
in fat suppressed T2 weighted images. Biopsy is often deferred due to concerns regarding the risk of
impaired wound healing. When a biopsy is performed, histology demonstrates lymphocytic infiltration,
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".)
● Myositis – Myositis manifests clinically as weakness with or without myalgias [36,40]. The muscle
weakness is described as moderate to severe symmetrical weakness of the 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 is usually 5 to 50 times the upper limit of normal, but
may be within normal limits early in the disease process. Elevations in other enzymes, such as lactate
dehydrogenase, 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. Histopathology
demonstrates the degeneration, necrosis and regeneration of muscle fibers and infiltrates of
inflammatory cells of donor origin. (See "Clinical manifestations of dermatomyositis and polymyositis in
adults".)
Fasciitis or joint contractures found on musculoskeletal examination can establish the presence of chronic
GVHD without the need for further testing or evidence of other organ involvement (ie, diagnostic features)

[1]. The severity of musculoskeletal disease may be measured using one of many joint/fascia status scales. In
one study that evaluated several scales in a prospective observational cohort, the NIH joint/fascia scale was
best able to detect clinical improvement with therapy, while the photographic range of motion (P-ROM) scale
was best able to capture progression [42].
Hematopoietic and immune — Although not diagnostic, patients with chronic GVHD commonly have
laboratory abnormalities reflecting changes in the hematopoietic and immune systems. These findings
include thrombocytopenia, eosinophilia, lymphopenia, hypo/hypergammaglobulinemia, and autoantibodies.
In one study of 138 patients with chronic GVHD, eosinophilia (range 0.5 to 4.4 x 109/L) and
thrombocytopenia were present in 44 and 11 percent, respectively [43]. In another study, thrombocytopenia
was seen in 15 percent of patients with chronic GVHD and predicted worse survival [44]. While the etiology
of these findings is not entirely clear, myelosuppression in patients with GVHD appears to be at least
partially caused by damage to the bone marrow niche by infiltrative T cells from the graft [45-47].
Autoantibodies — Autoantibodies found in patients with chronic GVHD are similar to those observed in
systemic lupus erythematosus and other rheumatologic disorders [48-50]. One study, for example, screened
the sera of 32 transplant recipients for autoantibodies, 20 of whom had chronic GVHD [51]. Antinucleolar
antibodies were observed in 12 patients with chronic GVHD and none in those without GVHD. The
emergence of autoantibody formation was concurrent with the onset of clinical symptoms of GVHD. A high
frequency of antimitochondrial antibodies (80 percent) was found in another small series of patients with
GVHD [52].
T cells — Chronic GVHD leads to marked immunodeficiency due to both direct immunosuppressive effects
and the consequences of the agents administered to treat the disease. Since chronic GVHD also causes a
delay in the recovery of immune function, patients remain immunodeficient as long as the disease is active
[53]. Dysregulation of T and B lymphocyte control may be observed [54]. Because of the profound
immunosuppression observed with this disorder, recurrent infections occur in almost all affected patients.
These complications account for most of the morbidity and mortality associated with chronic GVHD.
IgA deficiency — IgA deficiency occurs in many patients following allogeneic HCT [55,56], and may be
related to the development of acute and chronic GVHD [57,58]. In a study of 134 HCT recipients, for example,
those with chronic GVHD had significantly lower IgA levels than patients without the disease at one and two
years post-transplantation [58]. However, IgA deficiency alone may not have an independent role in the
development of chronic GVHD since normal IgA levels were found in all patients with chronic GVHD who did
not have a history of acute GVHD.
Other — Other uncommon clinical manifestations that can occur in patients with chronic GVHD include
polyserositis [41], polymyositis [37,59], myasthenia gravis [60], large to medium vessel vasculitis [36],
demyelinating disease of the central nervous system [36], immune-mediated encephalitis [36], peripheral
neuropathy, cardiac conduction abnormalities, cardiomyopathy, and the nephrotic syndrome due to
membranous nephropathy, or less commonly, minimal change disease [61-65].
Polyserositis can manifest with pericardial or pleural effusions, ascites, and facial, scrotal, or limb edema
[41]. The sicca syndrome in patients with chronic GVHD is similar to that found in those with the disorder
due to other autoimmune diseases. (See "Clinical manifestations of dermatomyositis and polymyositis in
adults" and "Clinical manifestations of myasthenia gravis" and "Clinical manifestations of Sjögren's
syndrome: Exocrine gland disease".)

DIAGNOSIS
Evaluation — The diagnosis of chronic GVHD should be considered in any patient who has undergone
allogeneic hematopoietic cell transplantation (HCT). Chronic GVHD can occur at any time point in the post-
HCT setting and screening for signs and symptoms of chronic GVHD should be incorporated into the long-
term follow-up of transplant survivors [66]. Chronic GVHD can be readily made on clinical grounds in the
patient who presents with the classic features of skin involvement, manifestations of gastrointestinal
involvement, and a rising serum bilirubin concentration. In many cases, however, the diagnosis is less
straightforward and competing causes for isolated abnormalities must be considered and excluded.
Since the clinical diagnosis is one of exclusion, histologic confirmation is often necessary to corroborate a
clinical impression of possible chronic GVHD.
● Chronic GVHD is commonly detected pathologically via a 4 mm punch skin biopsy, which secures 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'.)
● Oral biopsies are also very effective in detecting the presence of chronic GVHD.
● A transjugular liver biopsy may be necessary in patients with isolated liver abnormalities. (See 'Liver'
above.)
● A lung biopsy demonstrating pathologic evidence of bronchiolitis obliterans can be diagnostic. (See
'Lung' above.)
The need for biopsy in a specific patient and type of biopsy performed is dependent upon the signs and
symptoms present. The National Institutes of Health (NIH) consensus criteria described in the following
section provide guidance.
NIH consensus criteria — Chronic GVHD is diagnosed using criteria created through the NIH consensus
development project and published in 2005 [1,67]. These NIH consensus criteria are used by most transplant
centers in the United States and Europe [68]. The following principles of diagnosis apply [1]:
● Chronic GVHD can occur at any time point following allogeneic hematopoietic cell transplantation (HCT).
● In most cases, chronic GVHD is a diagnosis of exclusion and other possible causes of clinical symptoms
must be considered. (See 'Differential diagnosis' below.)
● The NIH consensus criteria have identified signs and symptoms of chronic GVHD that are diagnostic or
distinctive (table 1). "Diagnostic features" are those that establish the diagnosis of chronic GVHD without
need of further investigation (eg, poikiloderma, esophageal web). In contrast, "distinctive features" are
seen in patients with chronic GVHD and are absent in patients with acute GVHD, but require further
investigation to confirm the diagnosis (eg, skin depigmentation, keratoconjunctivitis sicca).
● To make a diagnosis of chronic GVHD, at least one diagnostic clinical sign of chronic GVHD must be
present or at least one distinctive manifestation must be confirmed by pertinent biopsy or other
relevant tests (eg, Schirmer test) in the same or another organ.
Patients diagnosed with chronic GVHD are then subclassified based upon the presence or absence of
features of acute GVHD into one of two categories:

● Classic chronic GVHD – Features of chronic GVHD are present without signs or symptoms of acute
GVHD.
● Overlap syndrome – Features of both chronic GVHD and acute GVHD are present.
Features of acute GVHD seen in the overlap syndrome include changes in the skin (skin erythema,
maculopapular rash, pruritus), mouth (gingivitis, mucositis, oral erythema, oral pain), gastrointestinal
symptoms (anorexia, nausea, vomiting, diarrhea, weight loss, failure to thrive), liver dysfunction (elevations
in bilirubin, alkaline phosphatase, ALT, or AST), and organizing pneumonia (also called bronchiolitis
obliterans organizing pneumonia, BOOP).
DIFFERENTIAL DIAGNOSIS
In most cases, chronic GVHD 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 chronic
GVHD. Most alternative diagnoses can be excluded on biopsy of the involved tissue.
● Skin involvement – The differential diagnosis of patients presenting with signs and symptoms of GVHD
of the skin includes lichen planus, lichen sclerosus, morphea, systemic sclerosis, eosinophilic fasciitis,
and other causes of poikiloderma. Findings on gynecologic examination may resemble postmenopausal
symptoms [22]. This is discussed in more detail separately. (See "Cutaneous manifestations of graft-
versus-host disease (GVHD)", section on 'Differential diagnosis' and "Clinical manifestations and
diagnosis of menopause".)
● Liver involvement – The differential diagnosis of hepatic GVHD includes other causes of cholestasis,
including infection, drug effects, and malignancy (table 2 and table 3). At times a specific diagnosis is
difficult without biopsy. (See "Classification and causes of jaundice or asymptomatic hyperbilirubinemia"
and "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia".)
● Gastrointestinal tract – The differential diagnosis of GVHD of the gastrointestinal tract includes other
causes of nausea, vomiting, diarrhea, and weight loss. These include infectious causes (eg, Clostridioides
difficile infection, CMV reactivation), drug effects, chemoradiation toxicity, inflammatory diarrhea, short
bowel syndrome, peptic ulcer disease, neoplasms, systemic disease (eg, diabetes mellitus). (See
"Approach to the adult with chronic diarrhea in resource-rich settings" and "Approach to the adult with
nausea and vomiting".)
● Lung – The differential diagnosis of pulmonary GVHD includes other causes of restrictive and
obstructive lung function. These include infections (eg, cytomegalovirus, toxoplasmosis), interstitial lung
disease, granulomatous disease (eg, sarcoidosis), and diffuse alveolar hemorrhage. An approach to the
patient with respiratory symptoms post-hematopoietic cell transplant (HCT) is presented separately.
● Musculoskeletal disease – The differential diagnosis of musculoskeletal involvement of GVHD includes

other causes of fasciitis and myositis, including dermatomyositis, inclusion body myositis, and other
causes of rhabdomyolysis. (See "Clinical manifestations of dermatomyositis and polymyositis in adults"
and "Clinical manifestations and diagnosis of inclusion body myositis" and "Causes of rhabdomyolysis".)
A continuum of clinical findings may be observed in patients with acute and chronic GVHD, as both
disorders commonly affect the skin, liver, gastrointestinal tract, and other organs [1]. However, the
target organs affected by, and the clinical and histologic features associated with, chronic GVHD may

differ from those observed with acute disease. As an example, autoimmune phenomena, such as
autoantibody formation, are more common with chronic GVHD. Clinical aspects of chronic GVHD may
also mimic features frequently observed with systemic lupus erythematosus, scleroderma, sicca
syndrome, eosinophilic fasciitis, rheumatoid arthritis, and primary biliary sclerosis [69]. Importantly,
diagnostic or distinctive signs of chronic GVHD must be absent in order to make the diagnosis of acute
GVHD [1]. Patients with signs or symptoms seen in both entities are considered to have the overlap
subtype of chronic GVHD. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-
host disease".)
PROGNOSIS AND GRADING
Several systems for grading chronic GVHD have been developed. None has been compared with the others,
although initial data suggest that they predict prognosis [70]. In addition, these scoring systems allow for
the detailed review and documentation of organ involvement. Clinicians should incorporate detailed
documentation to avoid relying on their memory of organ involvement between patient visits. A few
institutions incorporate digital photography into their records.
In a study of 7489 allogeneic transplants from the CIBMTR, the presence of chronic GVHD was similarly
associated with a higher treatment-related mortality (relative risk [RR] 2.43; 95% CI 2.09-2.82) and inferior
overall survival (RR 1.56; 95% CI 1.41-1.73) [71]. A lower rate of disease relapse was only present in patients
with chronic myeloid leukemia (RR 0.47; 95% CI 0.37-0.59). In contrast, GVHD did not appear to decrease the
risk of late relapse among patients with acute myeloid leukemia, acute lymphoblastic leukemia, or
myelodysplastic syndrome. (See "Donor selection for hematopoietic cell transplantation", section on
'Identical twin donors'.)
NIH consensus criteria for GVHD severity — A scoring system for chronic GVHD severity was created at a
consensus conference supported by the National Institutes of Health (NIH) in 2005 and revised in 2014
[1,72].
The NIH GVHD scoring system includes information on the number of organs or sites involved and the
severity within each affected organ (eg, skin, mouth, eyes, gastrointestinal tract, liver, lungs, joints/fascia,
and genital tract) (form 1) [1]. Organ specific severity is scored from 0 to 3 with higher scores reflecting more
severe disease. Based upon this information, the overall severity is scored as mild, moderate, or severe:
● Mild – Involves two or fewer organs/sites with no clinically significant functional impairment
● Moderate – Involves three or more organs/sites with no clinically significant functional impairment or at
least one organ/site with clinically significant functional impairment, but no major disability
● Severe – Major disability caused by chronic GVHD
Data are being collected prospectively in an attempt to validate these criteria [17,18,70,73-75]. Initial results
support the use of this grading system:
● In a report of the initial 298 adult patients enrolled in a prospective study, chronic GVHD severity was
mild, moderate, and severe in 10, 59, and 31 percent of patients at diagnosis, respectively [74]. Patients
with a higher severity score had a significantly higher rate of non-relapse mortality and shorter survival.
Overall survival at two years was 97, 86, and 62 percent for patients with mild, moderate, and severe

chronic GVHD, respectively. An additional report suggested that moderate to severe chronic GVHD, as
defined by these criteria, is associated with significantly decreased quality of life [75].
● Further expansion of this cohort to include 458 patients with chronic GVHD validated the prognostic
value of the composite skin score contained within the NIH consensus criteria [17]. Of the 285 patients
who had skin involvement at enrollment, 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. At a median follow-up of 18.8 months, rates
of overall survival at two years correlated with skin scores being 86, 83, 81, and 69 percent among
patients with scores of 0, 1, 2, and 3, respectively. Corresponding rates of non-relapse mortality at two
years were 10, 13, 15, and 30 percent. A worsening score at six months was associated with increased
mortality (hazard ratio [HR] 4.7, 95% CI 0.9-25.1) and higher non-relapse mortality (HR 7.2, 95% CI 1.2-
43.9).
● In a prospective chronic GVHD observational trial, the chronic GVHD consortium tested the ability of the
2005 NIH response measures, 2014 NIH response measures, clinician-reported response, and patient-
reported response to predict subsequent overall survival, nonrelapse mortality, and failure-free survival
in 575 patients undergoing HCT [70]. Both clinician-reported response and patient-reported outcomes
were predictive of long-term survival.
CIBMTR chronic GVHD risk score — The Center for International Blood and Marrow Transplant Research
(CIBMTR) has proposed a chronic GVHD risk score based upon the retrospective evaluation of 5343 patients
with chronic GVHD (calculator 1) [76]. A chronic GVHD risk score was developed using 10 variables measured
at the time of chronic GVHD diagnosis:
● Age of recipient at transplantation (<29 years = 0 points; 30 to 59 years = 1 point; >60 years = 2 points)
● Prior acute GVHD (none = 0 points; present = 1 point)
● Time from transplant to development of chronic GVHD (≥5 months = 0 points; <5 months = 1 point)
● Serum bilirubin at diagnosis of chronic GVHD (≤2 mg/dL = 0 points; >2 mg/dL = 2 points)
● Karnofsky performance score (table 4) (≥80 = 0 points; <80 = 1 point)
● Platelet count (≥100 x 109/L = 0 points; <100 x 109/L = 1 point)
● Type of donor (HLA-identical sibling/well-matched or partially matched unrelated donor = 0 points; other
= 1 point)
● Disease status at transplant (early = 0 points; intermediate = 1 point; advanced = 2 points)
● Donor/recipient sex mismatch (female/male = 1 point; others = 0 points)
● GVHD prophylaxis (cyclosporine plus methotrexate combination = 0 points; other = 1 point)
In this study, early disease included patients undergoing transplant in first remission of acute leukemia, first
chronic phase of chronic myelogenous leukemia (CML), or for myelodysplastic syndromes (MDS) with
refractory anemia or refractory anemia with ring sideroblasts. Intermediate disease included those with
second or later complete remission for acute leukemia, second or later chronic phase or accelerated phase
for CML. Advanced disease included patients in relapse or primary induction failure for acute leukemia or
blast crisis for CML or MDS with refractory anemia with excess blasts or excess blasts in transformation.
Using these variables, patients could be divided into six risk groups (RG) based upon overall risk score with
associated rates of overall survival (OS) and non-relapse mortality (NRM) at five years:
● RG1 – 0 to 2 points; 91 percent OS; 5 percent NRM



● RG5 – 11 points; 21 percent OS; 63 percent NRM
● RG6 – >12 points; 4 percent OS; 67 percent NRM
This score is attractive because it incorporates several known risk factors and is relatively easy to apply
clinically. The CIBMTR score was further validated in an analysis of 376 consecutive patients with leukemia or
myelodysplastic syndrome who received initial systemic therapy for chronic GVHD between 2006 and 2010
at two transplant centers [77]. In this analysis, no patients met criteria for RG5 or RG6, and only four patients
were classified as RG4. The RG classification system delineated three risk groups (RG1, RG2, and RG3) with
different associated rates of non-relapse mortality and overall survival. However, in this analysis most
patients were classified as RG2 (77 percent), suggesting that further ways of differentiating this risk group
would be helpful.
Johns Hopkins grading system — A proposed grading system for assessing long-term prognosis in chronic
GVHD (eg, non-relapse mortality, GVHD-specific survival), has been tested retrospectively in several
transplantation centers, using the following three adverse prognostic factors [78,79]:
● Skin involvement >50 percent of body surface area

● Progressive-type onset of chronic GVHD
● Platelet count <100,000/microL
Prospective validation of this grading system, along with its relation to other adverse features (eg, Karnofsky
performance score, prior occurrence of acute GVHD, serum bilirubin, other transplantation-associated risk
factors) [78,80] will be required before it can be used routinely.
Limited versus extensive disease — Historically, chronic GVHD has been graded as either limited or
extensive based upon the clinical severity and target organs affected:
● Limited disease is characterized by localized skin involvement and/or evidence of hepatic dysfunction.
● Extensive disease presents either with generalized skin involvement, or with localized skin involvement
or hepatic dysfunction plus at least one of the following:
• Liver histology showing chronic progressive hepatitis, bridging necrosis, or cirrhosis
• Involvement of the eye (Schirmer's test with less than 5 mm wetting) (see "Diagnosis and
classification of Sjögren's syndrome")
• Involvement of minor salivary glands or oral mucosa (as demonstrated on labial or mucosal biopsy
specimen)
• Involvement of any other target organ
While many clinicians continue to use this grading system for GVHD, it was created based upon a small
cohort of patients.
SUMMARY
● Graft-versus-host disease (GVHD) occurs when immune cells transplanted from a non-identical donor
(the graft) recognize the transplant recipient (the host) as foreign, thereby initiating an immune reaction
that causes disease in the transplant recipient.

● Chronic GVHD occurs in more than 50 percent of long-term survivors of HLA-identical sibling
transplants. It can occur after previous or ongoing acute GVHD or in patients without a history of acute
GVHD (eg, de novo disease). (See 'Epidemiology' above.)
● The skin, liver, gastrointestinal tract, and lungs are the principal target organs involved in patients with
chronic GVHD:
• Skin involvement most closely resembles lichen planus or the cutaneous manifestations of
scleroderma. (See 'Mucocutaneous manifestations' above.)
• Liver involvement is suggested by elevations in the serum alkaline phosphatase and bilirubin
concentrations. (See 'Liver' above.)
• Gastrointestinal involvement often manifests as dry oral mucosa with ulcerations, dysphagia with
weight loss, chronic diarrhea and malabsorption. (See 'Gastrointestinal tract' above.)
• Pulmonary involvement can result in bronchiolitis obliterans. (See 'Lung' above.)
• Other clinical manifestations include changes in the eye and female genitalia, thrombocytopenia,
sicca syndrome, polymyositis, myasthenia gravis, nephrotic syndrome or minimal change disease,
and vaginal inflammation and stenosis. (See 'Other' above.)
● The diagnosis of chronic GVHD can be readily made on clinical grounds in the patient who presents with
the classic features of skin involvement, manifestations of gastrointestinal involvement, and a rising
serum bilirubin concentration. In many cases, however, the diagnosis is less straightforward and
histologic confirmation is often necessary to corroborate a clinical impression of possible chronic GVHD.
(See 'Diagnosis' above.)
● The National Institutes of Health (NIH) consensus criteria have identified signs and symptoms of chronic
GVHD that are diagnostic or distinctive (table 1). "Diagnostic features" are those that establish the
diagnosis of chronic GVHD without need of further investigation (eg, poikiloderma, esophageal web). In
contrast, "distinctive features" are seen in patients with chronic GVHD and are absent in patients with
acute GVHD, but require further investigation to confirm the diagnosis (eg, skin depigmentation,
keratoconjunctivitis sicca).
● To make a diagnosis of chronic GVHD, at least one diagnostic clinical sign of chronic GVHD must be
present or at least one distinctive manifestation must be confirmed by pertinent biopsy or other
relevant tests (eg, Schirmer test) in the same or another organ.
● In most cases, chronic GVHD 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
chronic GVHD. Most alternative diagnoses can be excluded on biopsy of the involved tissue. (See
'Differential diagnosis' above.)
● Several systems for grading chronic GVHD have been developed. None has been compared with the
others, although initial data suggest that they predict prognosis. Of these, the NIH GVHD scoring system
is the only one that has been prospectively validated. (See 'NIH consensus criteria for GVHD severity'
above.)
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Topic 3548 Version 30.0

GRAPHICS
Diagnostic and distinctive clinical manifestations of chronic graft-versus-host disease
Distinctive (seen in chronic GVHD, but

Diagnostic (sufficient to establish the
Organ or site insufficient alone to establish a diagnosis of
diagnosis of chronic GVHD)
chronic GVHD)
Skin Poikiloderma Depigmentation

Lichen planus-like features
Sclerotic features
Morphea-like features
Lichen sclerosus-like features
Nails Dystrophy
Longitudinal ridging, splitting, or brittle features
Onycholysis
Pterygium unguis
Nail loss (usually symmetric; affects most nails)*
Scalp and body hair New onset of scarring or nonscarring scalp alopecia
(after recovery from chemoradiotherapy)
Scaling, papulosquamous lesions
Mouth Lichen-type features Xerostomia

Hyperkeratotic plaques Mucocele
Restriction of mouth opening from sclerosis Mucosal atrophy
Pseudomembranes*
Ulcers*
Eyes New-onset dry, gritty, or painful eyes ¶

Cicatricial conjunctivitis
Keratoconjunctivitis sicca ¶
Confluent areas of punctate keratopathy
Genitalia Lichen planus-like features Erosions*

Vaginal scarring or stenosis Fissures*
Ulcers*
GI tract Esophageal web

Strictures or stenosis in the upper to mid third of the
esophagus*
Lung Bronchiolitis obliterans diagnosed with lung biopsy Bronchiolitis obliterans diagnosed with PFTs and
radiology ¶
Muscles, fascia, joints Fasciitis Myositis or polymyositis ¶

Joint stiffness or contractures secondary to sclerosis
Diagnosis of chronic GVHD requires the presence of at least one diagnostic clinical sign of chronic GVHD or the presence of at least one distinctive
manifestation confirmed by pertinent biopsy or other relevant tests in the same or another organ. Furthermore, other possible diagnoses for
clinical symptoms must be excluded. No time limit is set for the diagnosis of chronic GVHD.
GVHD: graft-versus-host disease; PFTs: pulmonary function tests.

* In all cases, infection, drug effects, malignancy, or other causes must be excluded.
¶ Diagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmer test for eyes).
Original figure modified for this publication. Filipovitch 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: 1. Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2005; 11:945. Table used with the
permission of Elsevier Inc. All rights reserved.
Graphic 63007 Version 6.0

Chronic graft-versus-host disease
Poikilodermatous changes in chronic graft-versus-host disease. Mottled pigmentation

and erythema are present on the extremity.

Violaceous papules and plaques, many with a reticulated appearance, are present on
the trunk and extremities.

A cellulite-like plaque is present on the upper arm in this patient with subcutaneous fibrosis
secondary to chronic graft-versus-host disease.

Deep sclerosis leading to joint contractures limited the ability to extend the fingers in
this patient with chronic graft-versus-host disease ("prayer sign"). The overlying skin
appears normal.

Multiple firm, sclerotic plaques are present with areas of shallow ulceration.
Dyspigmentation is also present.

Lichen sclerosus
Oval, porcelain-white plaques are present on the trunk of this patient with extragenital
lichen sclerosus.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.

Dystrophic nails are present in this patient with chronic graft-versus-host disease.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.

Endoscopic and histological staging of upper gastrointestinal graft-

versus-host disease (GI-GVHD)
Upper panel: Endoscopic views of duodenum with the four grades of GI-GVHD. Grade 1 = loss of
vascular markings and/or focal mild erythema; grade 2 = moderate edema and/or erythema; grade
3 = edema, erythema, erosions, and/or bleeding; grade 4 = ulceration, exudates, and bleeding.
Lower panel: Photomicrographs of the duodenum corresponding to the above endoscopic images.
Grade 1 = increased crypt apoptosis (arrow); grade 2 = apoptosis with crypt abscess (arrow); grade 3
= individual crypt necrosis (arrows); grade 4 = total denudation of areas of mucosa (hematoxylin
and eosin [H & E]; x220).
Reproduced with permission from: Cruz-Correa M, Poonawala A, Abraham SC, et al. Endoscopic findings predict
the histologic diagnosis in gastrointestinal graft-versus-host disease. Endoscopy 2002; 34:808. Copyright © 2002
Thieme Publishers.

Endoscopic and histological staging of lower gastrointestinal graft-

versus-host disease (GI-GVHD)
Upper panel: Endoscopic views of the colon with the four grades of GI-GvHD. Grade 1 = loss of
vascular markings and/or focal mild erythema; grade 2 = moderate edema and/or erythema; grade
3 = edema, erythema, erosions, and/or bleeding; grade 4 = ulceration, exudates, and bleeding.
Lower panel: Photomicrograph of the colon corresponding to the above endoscopic images: grade
1 = increased crypt apoptosis (arrows); grade 2 = apoptosis with crypt abscess (arrow); grade 3 =
individual crypt necrosis (arrow); grade 4 = total denudation of areas of mucosa (H & E; x220).
Reproduced with permission from: Cruz-Correa M, Poonawala A, Abraham SC, et al. Endoscopic findings predict
the histologic diagnosis in gastrointestinal graft-versus-host disease. Endoscopy 2002; 34:808. Copyright © 2002
Thieme Publishers.

Cholestatic conditions that can produce jaundice
Intrahepatic
Viral hepatitis
Alcoholic hepatitis
Drug toxicity
Pure cholestasis - anabolic and contraceptive steroids
Mixed cholestasis/hepatitis - chlorpromazine, erythromycin estolate
Chronic cholestasis - chlorpromazine and prochlorperazine
Primary biliary cholangitis
Primary sclerosing cholangitis
Vanishing bile duct syndrome

Chronic rejection of liver transplants
Sarcoidosis
Drugs
Inherited
Benign recurrent cholestasis
Progressive intrahepatic familial cholestasis
Gilbert syndrome
Crigler-Najjar syndrome types 1 and 2
Dubin-Johnson syndrome
Rotor syndrome
Alagille syndrome
Cholestasis of pregnancy
Total parenteral nutrition
Non-hepatobiliary sepsis
Benign postoperative cholestasis
Paraneoplastic syndrome (Stauffer's syndrome)
Extrahepatic
Malignant
Cholangiocarcinoma
Pancreatic cancer
Gallbladder cancer
Ampullary cancer
Malignant involvement of the porta hepatis lymph nodes
Benign
Choledocholithiasis
Primary sclerosing cholangitis
Chronic pancreatitis
AIDS cholangiopathy
AIDS: acquired immunodeficiency syndrome.

Differential diagnosis of cholestatic jaundice: Intrahepatic
Acute hepatocellular Miscellaneous

Viral hepatitis Hypotension/hypoxemia/HF
Alcoholic fatty liver and/or hepatitis Budd-Chiari syndrome
Non-alcoholic steatohepatitis Parasitic infection (Clonorchis sinensis; Fasciola hepatica)
Drugs Inherited/endocrine
Chronic hepatocellular Benign recurrent intrahepatic cholestasis (BRIC)
Primary sclerosing cholangitis Progressive familial intrahepatic cholestasis (PFIC)
Primary biliary cholangitis Low phospholipid-associated cholestasis (LPAC)
Drugs Thyrotoxicosis
Hepatitis (viral, alcohol, autoimmune) Alagille syndrome
Cirrhosis of any cause Disorders of carbohydrate, lipid, or bile acid metabolism
Multifactorial Caroli's disease
Total parental nutrition Pregnancy
Systemic infection Protoporphyria
Postoperative Infiltrative/granulomatous
Sickle cell disease/crisis Amyloidosis
Organ transplantation (rejection; graft-versus-host disease; Lymphoma*

venoocclusive disease)
Sarcoidosis
Tuberculosis
* Rarely patients with lymphoma may have hyperbilirubinemia (direct) in the absence of tumor involvement of the liver or extrahepatic obstruction.

NIH consensus criteria for organ scoring of chronic GVHD


GVHD: graft-versus-host disease; KPS: Karnofsky Performance Status; ECOG: Eastern Cooperative Oncology Group; LPS: Lansky Performance Status; BSA: body
surface area; ADL: activities of daily living; LFTs: liver function tests; AP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase;
ULN: upper limit of normal.
* Skin scoring should use both percentage of BSA involved by disease signs and the cutaneous features scales. When a discrepancy exists between the
percentage of total body surface (BSA) score and the skin feature score, OR if superficial sclerotic features are present (score 2), but there is impaired mobility or
ulceration (score 3), the higher level should be used for the final skin scoring.
¶ Weight loss within three months.
Δ Lung scoring should be performed using both the symptoms and FEV1 scores whenever possible. FEV1 should be used in the final lung scoring where there is

discrepancy between symptoms and FEV1 scores.
◊ To be completed by specialist or trained medical providers.
Reproduced from: Jagasia MH, Greinix HT, Arora M, et al. 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 2015; 21:389. Illustration used with the permission of
Elsevier Inc. All rights reserved.

Karnofsky Performance Status scale
Value Level of functional capacity Definition
100 Normal, no complaints, no evidence of disease Able to carry on normal activity and to work; no special care needed
90 Able to carry on normal activity, minor signs or

symptoms of disease
80 Normal activity with effort, some signs or symptoms of

disease
70 Cares for self, unable to carry on normal activity or to Unable to work; able to live at home and care for most personal needs; various
do active work degrees of assistance needed
60 Requires occasional assistance but is able to care for

most needs
50 Requires considerable assistance and frequent medical

care
40 Disabled, requires special care and assistance Unable to care for self; requires equivalent of institutional or hospital care;
disease may be progressing rapidly
30 Severely disabled, hospitalization is indicated although
death is not imminent
20 Hospitalization is necessary, very sick, active supportive

treatment necessary
10 Moribund, fatal processes progressing rapidly
0 Dead

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12/10/2020 Clinical manifestations, diagnosis, and grading of chronic graft-versus-host disease - UpToDate

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Clinical manifestations, diagnosis, and grading of chronic graft-

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● Higher degree of HLA mismatching

CLINICAL AND HISTOLOGIC FEATURES

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● Skin – 67 percent (see 'Skin' below)

Mucocutaneous manifestations — Mucocutaneous manifestations of chronic GVHD include changes in the

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● Poikiloderma – A combination of atrophy, hypopigmentation, and hyperpigmentation in the skin

● Morphea-like features – Firm, hyperpigmented, hypopigmented, or skin-colored plaques (picture 5).

● Lichen sclerosis-like features – A dermatosis characterized by epidermal atrophy and superficial

● Aqueous tear deficiency (Schirmer score ≤5 mm) – 53.4 percent

Genitalia — Gynecological manifestations, such as vaginal inflammation and stenosis, have been

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Endoscopy is commonly performed to investigate gastrointestinal tract involvement. Findings on endoscopy

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Musculoskeletal disease — Muscle-related complications are seen in up to 50 percent of patients with

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● Musculoskeletal disease – The differential diagnosis of musculoskeletal involvement of GVHD includes

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PROGNOSIS AND GRADING

● Severe – Major disability caused by chronic GVHD

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● RG1 – 0 to 2 points; 91 percent OS; 5 percent NRM

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● RG4 – 9 to 10 points; 40 percent OS; 43 percent NRM

● Skin involvement >50 percent of body surface area

• Liver histology showing chronic progressive hepatitis, bridging necrosis, or cirrhosis

• Involvement of any other target organ

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

Use of UpToDate is subject to the Subscription and License Agreement.

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41. Marks C, Stadler M, Häusermann P, et al. German-Austrian-Swiss Consensus Conference on clinical

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49. Shimada M, Onizuka M, Machida S, et al. Association of autoimmune disease-related gene

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Topic 3548 Version 30.0

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Diagnostic and distinctive clinical manifestations of chronic graft-versus-host disease

Distinctive (seen in chronic GVHD, but

Skin Poikiloderma Depigmentation

Mouth Lichen-type features Xerostomia

Eyes New-onset dry, gritty, or painful eyes ¶

Genitalia Lichen planus-like features Erosions*

GI tract Esophageal web

Muscles, fascia, joints Fasciitis Myositis or polymyositis ¶

GVHD: graft-versus-host disease; PFTs: pulmonary function tests.

Graphic 63007 Version 6.0

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Chronic graft-versus-host disease

Poikilodermatous changes in chronic graft-versus-host disease. Mottled pigmentation

Graphic 66942 Version 2.0

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Chronic graft-versus-host disease

Graphic 55336 Version 1.0