How Graft-Versus-Host Disease (GvHD) Is Diagnosed

Graft-versus-host disease (GvHD) is a complication of a bone marrow or stem cell transplant in which cells from a donor attack the tissues of the recipient. GvHD can be classified as being either acute (occurring within 100 days of the transplant) or chronic (occurring 100 days or more after the transplant).

The diagnosis of GvHD is often complex and may require multiple tests and procedures. Although GvHD can sometimes be diagnosed based on symptoms alone, other cases are not so straightforward. In cases like these, there is a strict set of criteria that governs the diagnosis of GvHD.

Once diagnosed, additional tests may be performed to grade the severity GvHD and direct the appropriate course of treatment.

Imaging aids in diagnosis of graft-versus-host disease
Morsa Images / DigitalVision / Getty Images

Self-Checks

There are no home tests or self-exams available to diagnose GvHD. With that said, recognizing the signs and symptoms of GvHD can help you seek timely diagnosis and treatment. If left untreated, GvHD can cause profound tissue damage, doubling the risk of high-grade disease and early death.

Acute GvHD typically starts with the sudden outbreak of a red, inflamed rash on the palms, soles, face, ears, and shoulders. The rash can often become widespread and precede the onset of gastrointestinal or liver symptoms.

Chronic GvHD also tends to start with a burning rash on the same parts of the body, although it can be more severe and cause blistering, peeling, and the hardening of the skin. Gastrointestinal and liver symptoms can also develop, in addition to symptoms affecting other organ systems, including the eyes, lungs, joints, muscles, genitals, and nervous system.

Chronic GvHD represents the broadening of the autoimmune-like attack on normal tissues. Symptoms not only tend to be more diverse than acute GvHD but often more severe.

Acute GvHD
  • Maculopapular rash

  • Greenish, watery diarrhea

  • Abdominal cramps

  • Bloating

  • Hematochezia (blood in stools)

  • Mouth pain

  • Dry mouth

  • Changes in taste

  • Hepatomegaly (enlarged liver)

  • Persistent fatigue

  • Dark-colored urine

  • Chalky stools

Chronic GvHD

GvHD can differ from one person to the next. Acute and chronic symptoms can sometimes overlap or develop in different patterns. Because of this, you should never wait to speak to a doctor if an abnormal symptom occurs, however mild.

Diagnostic Criteria

The symptoms of GvHD may seem "obvious" enough to render an immediate diagnosis—particularly if they occur within the first 100 days—but it's not always that simple.

GvHD can be challenging to diagnose because many of the symptoms occur with other conditions or diseases, none of which have anything to do with GvHD. If treated presumptively without meeting specific diagnostic criteria, a person with GvHD may be exposed to therapies that are not only unnecessary but can mask the true cause of the symptoms.

A widespread rash, for example, may be caused by antibiotics or the myriad of other drugs used to treat allogeneic (donor-to-recipient) transplants. Immunosuppressive drugs used to prevent tissue rejection can increase the risk of severe infections. In short, a symptom suggestive of GvHD may end up having nothing to do with GvHD.

According to guidelines issued by the National Institutes of Health (NIH), the diagnosis of GvHD typically requires at least one clinical sign of GvHD paired with a confirmatory test of a pathologic feature of GvHD (either involving the same or other organ).

Not everyone with symptoms of GvHD requires confirmatory testing. In some cases, the type and/or burden of symptoms is enough to render a definitive diagnosis without the need for further investigation.

Physical Examination

Not everyone with symptoms of GvHD requires confirmatory testing. Some symptoms are characteristic enough to render a diagnosis on their own.

The NIH allows for the diagnosis of acute GvHD if a classic rash, abdominal cramps with diarrhea, and increased bilirubin levels occur within the first 100 days of an allogeneic transplant.

The NIH also allows for the diagnosis of chronic GvHD based on whether the symptoms are "diagnostic" or "distinctive." Diagnostic symptoms are those regarded as defining features of chronic GvHD and do not require additional testing. Distinctive symptoms are those that only suggest chronic GvHD and do require additional testing.

Diagnostic vs. Distinctive Symptoms of Chronic GvHD
Organ System Diagnostic Distinctive
Skin Poikoloderma (skin discoloration with spider veining) Skin discoloration without spider veining
  Lichen planus-like lesions (typically flat, purple, and itchy)  
  Scleroderma-like features (taut, shiny, darkened skin)  
  Morphea-like features (large painless areas of discolored, hardened skin)  
Mouth Lichen planus-like features (gingivitis with thickened patches on the tongue,mouth, or gums) Mouth ulcers
  Inability to open the mouth fully due to sclerosis (tissue hardening) Xerostomia (dry mouth)
Genitals Lichen planus-like features in women (moist red patches or streaks, often painful, on the vulva)  Genital ulcers
  Lichen planus-like features in men (ring-shaped lesions on the penis glans and non-itchy, flat rash) Vaginal fissures (tears)
  Vaginal scarring or stenosis (narrowing)  
Gastrointestinal Esophageal stricture (the narrowing of the esophagus) None
  Esophageal webbing (the protrusion of membranes in the upper esophagus)  
Lungs Bronchiectasis diagnosed with a biopsy Bronchiectasis diagnosed by other means
Muscles/joints Fasciitis (inflammation of the fascia) Myositis (muscle inflammation)
  Joint stiffness and loss of range of motion  

Unless the symptoms of GvHD are considered diagnostic under the NIH guidelines, additional testing must be performed to confirm the findings.

Labs and Tests

The confirmatory tests used to diagnose GvHD may involve a biopsy, lab test, or imaging study. The tests may provide histological evidence of GvHD (as seen by changes in cells under the microscope), serve as a biomarker of GvHD (as seen by changes in lab values), or detect signs of gastrointestinal injury consistent with GvHD. More than one test is sometimes needed.

Among the tests commonly used to confirm GvHD:

  • Skin biopsy: A cutaneous (skin) biopsy can provide histological evidence of GvHD, including apoptosis (cell death) in mucosal tissues of the mouth or the epidermal layer of the skin. The lab pathologist will often see a proliferation of white blood cells, called lymphocytes, in the epidermis or lower-lying dermis.
  • Gastrointestinal biopsy: The biopsy of gastrointestinal tissues, most especially those of the sigmoid colon and rectum, will typically reveal patchy ulcers and the flattening of the outermost lining of tissue, known as the epithelium.
  • Liver biopsy: The biopsy of liver tissue may also show the infiltration of lymphocytes near the portal vein as well as the inflammation and destruction of bile ducts, leading to cholestasis (reduced bile flow).
  • Lung biopsy: A lung biopsy is the only test that can definitively diagnose bronchiectasis (the permanent hardening and widening of the major airways) in people with respiratory GvHD. Airways tissues will tend to be thick and ulcerated, while cartilage will be ossified (hardened with bone matter).
  • Endoscopy: When using a flexible endoscope to examine the upper or lower gastrointestinal tract, doctors will often see generalized inflammation, ulceration, and bleeding—especially near the ileum (the final section of the small intestine)—in people with gastrointestinal GvHD.
  • Liver function test (LFTs): This panel of blood tests can detect increases in liver enzymes whenever the liver is injured. With GvHD, there will characteristically be elevations of alkaline phosphatase (ALP), and gamma‐glutamyltranspeptidase (GGT), and, most especially, bilirubin (a yellowish pigment caused by the breakdown of red blood cells).
  • Acute biomarkers: Certain blood tests can help confirm acute GvHD by detecting proteins that commonly increase whenever organs are injured. These include elafin (a biomarker for cutaneous GvHD), cytokeratin 18 (a biomarker for gastrointestinal and liver GvHD), and REG3alpha (a biomarker for lower gastrointestinal GvHD).
  • Imaging studies: Computed tomography (CT) and magnetic resonance imaging (MRI) scans can often detect luminal dilation (the narrowing of the intestinal tract) along with the "ribbon sign" (the thickening of the small bowel wall), both of which to the onset of ileus (the slowing or stopping of bowel movement).

Doctors will often perform confirmatory tests irrespective of whether a symptom is diagnostic or distinctive as they can aid in the grading of GvHD.

Differential Diagnoses

Because the symptoms of GvHD can mimic those of other diseases or conditions, the doctor will explore other causes as part of the differential diagnosis. By excluding all other possible explanations, the doctor can render a diagnosis with greater confidence, especially if the other findings are borderline or inconclusive.

Among the condition that may be investigated are:

Grading

GvHD is graded to classify the severity of the condition. This helps direct the appropriate course of treatment and helps predict the likely outcome of treatment (referred to as the prognosis).

There are different classifications used to grade and acute GvHD, each of which uses different measures and grading scales.

Acute GvHD

In the United States, a system called the modified Seattle Glucksberg criteria is recommended for the standardized grading of acute GvHD. The other commonly used classification model is the International Bone Marrow Transplant Registry (IBMTR) grading system.

The modified Seattle Glucksberg criteria grades GvHD on a scale of 0 to 4 based on the severity of skin, gastrointestinal, and liver symptoms. The way in which severity is defined differs by the organ system:

  • Skin GvHD is graded based on the body surface area (BSA) measured in meters square (m2).
  • Gastrointestinal GvHD is graded based on the volume of diarrhea per day measured in milliliters (mL).
  • Liver GvHD is graded based on the elevation of bilirubin measured in milligrams per deciliter (mg/dL).

Under the Seattle Glucksberg system, grades 1 and 2 are regarded as low-grade GvHD with better outcomes, while grades 3 and 4 are considered high-grade GvHD with generally poorer outcomes.

Seattle Glucksberg Criteria for Acute GvHD
Grade Skin (BSA) Gastrointestinal Liver (Bilirubin)
0 No skin involvment Under 500 mL Under 2 mg/dL
1 Under 25 m2 500 to 999 mL 2 to under 3 mg/dL
2 25 to under 50 m2 1,000 to 1,500 mL 3 to under 6 mg/dL
3 Over 50 m2 Over 1,500 mL 6 to under 15 mg/dL
4 Presence of bullae Severe abdominal pain with or without ileus or bloody stools 15 mg/dL and over

The IBMTR grading system classifies GvHD based on the cumulative involvement of skin, gastrointestinal, and liver symptoms. Together, these symptoms are assigned a grade of A, B, C, or D, with A being the least severe and D being life-threatening.

IBMTR Severity Index for Acute GvHD
Grade Definition Criteria
A Mild disease Skin involvement alone (with a rash covering more than 25% of the body) with no liver or gastrointestinal involvement
B Moderate disease Skin involvement (with rash covering over 50% of the body) with mild to moderate liver or gastrointestinal symptoms
C Severe disease Widespread skin inflammation (erythroderma) covering more than 90% of the body with mild to severe involvement of either the liver or gastrointestinal tract
D Life-threatening disease The severe involvement of either the skin (erythroderma with bullous lesions), liver (bilirubin levels over 15 mg/dL), or gastrointestinal tract (over 2 liters of diarrhea per day with or without severe abdominal pain), or any combination of the above

Chronic GvHD

The grading of chronic GvHD takes a slightly different approach. The system, created by the NIH, assigns a score ranging from 0 (for no symptoms) to 3 (for severe symptoms) for each of nine different organ systems: the skin, mouth, liver, upper gastrointestinal tract, lower gastrointestinal tract, esophagus, lungs, eyes, and joints.

Under the NIH grading system, chronic GvHD is classified as being either mild, moderate, or severe based on the number of organ systems with a score of 1 or more. Mild GvHD is referred to as low-grade disease, while moderate to severe GvHD are considered intermediate- and high-grade disease, respectively.

NIH Severity Scoring for Chronic GvHD
Mild disease There is one or more organ sites with a score of 1
Moderate disease There are three or more organ sites with a score of 1, or
  There is at least one organ site with a score of 2, or
  The lung score of 1
Severe disease There is at least one organ site with a score of 3, or
  The lung score is either 2 or 3

Once the grade had been established, there are guidelines to direct the first-, second-, and subsequent-lines of treatment for both acute and chronic GvHD.

A Word From Verywell

The diagnosis of graft-versus-host disease can be challenging for both the doctor and patient. It requires patience and perseverance to avoid misdiagnoses and inappropriate treatments.

By ensuring that the diagnostic criteria are met and the condition is properly graded, treatments can be tailored to not only prevent recurrence but avoid treatment-related side effects.

It is important to remember that GvHD only affects people who have undergone an allogeneic stem cell or bone marrow transplant. It cannot affect those who have had an autologous transplant (in which the transplant donor and recipient are the same).

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