EBMT GvHD Summit 2019 | Acute GvHD diagnosis

At the 1st European Society for Blood and Marrow Transplantation (EBMT) GvHD Summit, Warsaw, Poland, 16–18 May 2019, Doctor Pavan Reddy from the University of Michigan, Ann Arbor, MI, USA, took the podium and outlined the Aristotelian concept of phronesis or practical wisdom in the setting of acute graft-versus-host disease (GvHD) diagnosis, which is “partly science, partly experience and judgement.”

The basic principles of acute GvHD were first described in mouse models as weight loss, diarrhea, skin lesions, and death. Dr. Reddy outlined Billingham’s Postulates for the development of GvHD:

• Immunocompetent donor T cells
• Immunocompromised patients (Impaired T cell function)
• Histocompatibility differences between donor and host (major or minor histoincompatibility)

Dr. Reddy explained that these 50-year old statements are also valid in humans, adding that “humans are good models for mice.” The principles recognize that GvHD represents an injury by donor T cells on the recipient’s tissue and a donor response against major and minor human leukocyte antigen complexes as well as that the host is myeloablative.

To find the right balance of GvL with GvHD is an evolving topic where clinicians are often left without an obvious right answer. The challenge of allogeneic stem cell transplantation for treatment of malignant- and other non-malignant diseases of the hematopoietic system, which is the prevention of GvHD without losing the graft-versus-leukemia (GvL) effect, said Dr. Reddy. He suggested that finding the right balance requires the application of the “Goldilocks principle”, which states that the immune suppression should be “just right.” 

Symptoms of acute GvHD occur within 100 days after transplantation with a median onset of 27 days and most frequently present in the skin, gastrointestinal system, and liver. The involvement of other organs such as lung and central nervous system has been posited.

Diagnosis, clinical features, histopathology, and biomarkers of acute skin GvHD

• Stages

  • Stage 0: No GvHD skin rash
  • Stage 1: Maculopapular rash < 25% of BSA
  • Stage 2: 25-50% BSA
  • Stage 3: > 50% BSA
  • Stage 4: Generalized erythroderma plus bullous formation and desquamation > 5% BSA

• Histopathology

  • Biopsy is usually typical but not specific
  • Epidermal basal vacuolation
  • Spongiosis
  • Keratinocyte apoptosis and individual cell necrosis associated with mononuclear cell infiltration of the upper dermis and lower epidermis
  • The lymphocytic infiltration appears fairly light

• Biomarkers

  • Elafin (proteinase inhibitor)
    • Skin specific marker
    • An endogenous human protein with inflammatory properties
    • Induced by TNF-α, IL-1β and LPS

Diagnosis, clinical features, histopathology, and biomarkers of acute gastrointestinal (GI) GvHD

• Clinical manifestations of lower GI GvHD

  • Diarrhea (secretory) usually occurs two weeks after transplantation
  • Hematochezia can also occur; main symptoms: severity, low platelet count, microangiopathy, secondary infections

  • Severity

    • Stage 1 – Diarrhea 500 to 1000 ml/day
    • Stage 2 – Diarrhea 1000 to 1500 ml/day
    • Stage 3 – Diarrhea 1500 to 2000 ml/day
    • Stage 4 – Diarrhea >2000 ml/day or pain or ileus
  • Large watery diarrhea can be difficult to manage
  • Stool volumes should be averaged over three days to assess score
  • MMF causes secretory diarrhea
  • Oral magnesium supplements should be discontinued

• Clinical manifestations of upper GI GvHD

  • Involvement of the upper GI tract often presents with
    • Anorexia
    • Dyspepsia
    • Food intolerance
    • Nausea
    • Vomiting
    • Epigastric pain
    • Gingivitis
    • Mucositis

  • Biopsy

    • The diagnosis is verified by positive upper endoscopic biopsies of the esophagus and stomach, however, diagnostic reliability of macroscopic endoscopic findings are unclear

  • Histopathology (Freiburg classification)

    • Grade 1: No clear-cut criteria! It suffices to state that there is no GVHD grade ⩾2
      • Cut off between watch-and-wait and immediate therapy
    • Grade 2: Spotted erythema, initial aphthous lesions
    • Grade 3: Aphthous lesions (Crohn-like) or focal erosions
    • Grade 4: Confluent defects, ulcerations, complete denudation of the mucosa

  • Histological grading system for gastrointestinal acute GVHD

    • Grade 1: Isolated apoptotic epithelial cells without crypt loss
    • Grade 2: Loss of isolated crypts without the loss of contiguous crypts
    • Grade 3: Loss of two or more contiguous crypts
    • Grade 4: Extensive crypt loss with mucosal denudation

  • Differential diagnosis

    • Drugs: MMF
    • Infections: Cytomegalovirus (viral), Clostridium difficile (bacterial)

  • Biomarkers

    • Paneth cells
    • Reg3α

Diagnosis, clinical features, histopathology, and biomarkers of acute liver GvHD

• Clinical manifestations

  • Liver involvement usually presents in patients with signs of cutaneous and/or GI acute GvHD
  • Cholestatic disease without hepatomegaly or RUQ tenderness
  • Required lab parameters
    • Conjugated bilirubin
    • Increased alkaline phosphatase
    • Elevated aminotransferases

  • Differential diagnosis

    • Hepatic sinusoidal obstructive syndrome (also known as a hepatic veno-occlusive disease) is a relatively common toxicity associated with the use of high dose therapy
    • Hepatic infections (viral hepatitis)
    • Cholangitis lenta
    • Drug toxicity, including the drugs used for GvHD prophylaxis such as cyclosporine

  • Histology of liver GvHD

    • Liver biopsy is sometimes needed to establish a definite diagnosis
    • Early phase
      • Lymphoplasmacytic infiltration of portal tracts
      • Damage to bile duct epithelium
      • Cytoplasmic swelling and vacuolation
      • Enlarged and overlapping nuclei (reactive epithelial atypia)
      • Apoptosis

    • Late phase

      • Loss of bile ducts
      • Increased fibrosis

    • Staging based on bilirubin levels

      • Stage 0: < 2 mg/dl
      • Stage 1: 2-3 mg/dl
      • Stage 2: 3.1-6 mg/dl
      • Stage 3: 6.1-15 mg/dl
      • Stage 4: > 15 mg/dl

Other organs

• The skin, liver, and GI tract are the principal target organs in patients with acute GvHD
• Involvement of other organs less commonly occur and changes in these other organ systems cannot be used to establish the diagnosis of acute GvHD:
  • Lungs
  • CNS
  • The hematopoietic system
  • Eyes
  • Kidneys

Pavan Reddy concluded by sharing his motto based on a William Osler quote: “the diagnosis of GvHD is an art based on science”, adding, “we have more scientific tools, information, to integrate and refine but never forget that they are going to be tools in our hands and not the other way around.”