Page 1277 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

884 PART 7: Hematologic and Oncologic Disorders

■ ACUTE GVHD Diagnosis and Management: The diagnosis of acute GVHD is rarely

Incidence: Overall, the incidence of moderate-to-severe acute GVHD straightforward. Dermatitis, jaundice, and enteritis in the transplant
with HLA identical siblings ranges from <10% to 60% depending on setting have a variety of potential etiologies including but not limited to
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prophylaxis and risk factors. The frequency of acute GVHD is directly GVHD. Toxicity from chemoradiotherapy, supportive medications, or
related to the degree of mismatch between the patient and donor infection must be considered, as well as transplant-specific complica-
HLA proteins. The incidence increases with patient age and degree tions such as hepatic venoocclusive disease. Biopsies can be helpful but
of HLA disparity between the host and the donor. Other contributing fac- often fail to provide a definitive diagnosis. Furthermore, a diagnosis
tors are the use of an unrelated donor, the number of T cells transplanted, supported by clinical presentation and even biopsy does not eliminate
the sex mismatching and donor parity, the severity of tissue injury the possibility of coexisting conditions. Repeat blood cultures and histo-
during cytoreduction, and the type of prophylaxis used. logic evaluation for organ invasive viral or other opportunistic infections
should be prompted by persistent fever and symptoms. In addition, signs
Pathophysiology: Although the principal effector cells responsible for and symptoms in any organ not responding to treatment for presumed
GVHD are the immunocompetent donor cytotoxic T lymphocytes, the acute GVHD should trigger further evaluation.
first step of acute GVHD entails the activation of antigen presenting cells Treatment for established acute GVHD necessitates additional immu-
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(APCs) in the host. Host tissues, damaged by the underlying disease, nosuppressive therapy. First-line treatment is generally corticosteroids.
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previous infections, as well as the transplant conditioning regimen itself, With mild to moderate involvement of skin and upper GI tract, topical
respond by producing “danger signals” including proinflammatory formulations may be adequate, steroid creams for skin and oral
cytokines and costimulatory molecules, resulting in APC activation. budesonide for upper GI tract. Systemic corticosteroids are the standard
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The second step follows APC activation and includes the prolifera- treatment if there is lack of response to local steroids, or for treatment of
tion and activation of donor T cells. Activation of donor immune cells hepatic or lower GI involvement. No randomized trials have established
results in rapid biochemical cascades that induce transcription of genes a regimen superior to corticosteroids as primary treatment for acute
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for many cytokines and their receptors (interferon-γ, interleukin-2, GVHD nor has any study determined the most efficacious dose. The
and TNF-α). These molecules work synergistically with donor cells in conventional starting dose is methylprednisolone 1 to 2 mg/kg daily
producing the third effector step of GVHD, thereby amplifying local with a taper of approximately 10% per week once symptoms improve
tissue injury and promoting target tissue destruction. although this approach is highly personalized. Unfortunately, complete
remission rates from systemic steroids are less than 50%, and more
Clinical Features: The hallmarks of acute GVHD at onset include involve- severe GVHD is less likely to respond to treatment. The survival rates
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ment of the skin (81% of patients), gastrointestinal tract (54%), and liver for steroid-resistant GVHD are quite poor, and death is most often due
(50%). Skin involvement is the most frequent and earliest manifestation to infection.
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of acute GVHD. The typical presentation of skin GVHD is a pruritic, mac- There is no standard of care for second-, third-, or fourth-line therapy
ulopapular rash that can spread throughout the body but spares the scalp. for acute GVHD in the setting of steroid resistance and disease progres-
Severe cases can cause diffuse blistering and ulceration. Gastrointestinal- sion. Agents that have been used include calcineurin inhibitors, sirolimus
tract involvement usually presents with large volume (>2 L/day) diarrhea or mycophenolate (if not used for prophylaxis), antithymocyte globulin,
but can also include vomiting, anorexia, abdominal pain, or bleeding. daclizumab, infliximab, etanercept, ontak, and pentostatin. Mesenchymal
Hepatic GVHD often manifests with jaundice, cholestasis, and to a lesser stem cell infusions are a more recent approach that has shown promising
degree transaminitis. It can be difficult to distinguish GVHD from other results in clinical trials, especially in patients with GI involvement. 32,33
causes of hepatic dysfunction and a biopsy may be helpful for diagnosis. Immunosuppression in patients undergoing treatment for acute
The severity of GVHD is commonly determined by staging the extent GVHD can be profound and continued surveillance for viral, bacte-
of involvement of the three main target organs described (skin, GI tract, rial, or fungal infection is obligatory. Prophylactic broad-spectrum
and liver). Historically, the most commonly used grading system was antibiotics should be used during periods of neutropenia and antibiotic
the Glucksberg grading system first published in 1974 then revised by coverage for encapsulated organisms at a minimum should be provided
Thomas et al in 1975. 25-27 This system formulated a grade based on once neutrophil counts have recovered. Any fever should be aggressively
stage of severity (0-4) of the skin, liver, and GI tract using both objec- evaluated with strong consideration given to adjustment of antibiotics,
tive and subjective assessment of performance status. These stages are especially in the absence of intact mucosal and skin barriers. Adequate
then combined to calculate an overall grade, 0-IV. A revised system nutrition, hydration, and electrolyte balance are vital but often difficult
was developed by the International Bone Marrow Transplant Registry to maintain with severe enteric GVHD. Malabsorption is common and
(IBMTR) in 1997 that retained the objective criteria but eliminated oral nutrition and electrolyte support is often not practical. Careful
the subjective component in an effort to simplify grading and monitoring of diarrhea volume and electrolyte levels should be main-
allow for comparison between transplant centers. A clinical grading tained and prolonged periods of total parenteral nutrition may be
system (0-IV) is based on highest stage of any single organ system involved required. Cramping and diarrhea may necessitate antidiarrhea medica-
(Table 94-3). Severity is described as Grade I (mild) to Grade IV tions and use of parenteral opiate analgesics, even at the risk of an ileus.
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(severe). Severe GVHD has a poor prognosis with 25% long-term In severe enteric GVHD, bleeding from the GI tract will require frequent
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survival (5 years) for grade III disease and 5% for grade IV disease. 29 transfusion support. Bleeding in the setting of decreasing diarrhea

TABLE 94-3 Staging of Acute GVHD
Stage Skin Liver GI tract
0 No rash due to GVHD Bilirubin <2 mg/dL None (<280 mL/m )
2
I Maculopapular rash <25% of body surface area without associated symptoms Bilirubin from 2 to <3 mg/dL Diarrhea >500-1000 mL/day; nausea and emesis
II Maculopapular rash or erythema with pruritus or other associated symptoms ≥25% of Bilirubin from 3 to <6 mg/dL Diarrhea >1000-1500 mL/day; nausea and emesis
body surface area or localized desquamation
III Generalized erythroderma; symptomatic macular, papular, or vesicular eruption with Bilirubin 6-15 mg/dL Diarrhea >1500 mL/day
bullous formation or desquamation covering ≥50% of body surface area
IV Generalized exfoliative dermatitis or bullous eruption Bilirubin >15 mg/dL Diarrhea >1500 mL/day; abdominal pain or ileus

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