Objective
To estimate the value of skin biopsy in the evaluation of suspected acute cutaneous graft-vs-host disease (GVHD) after allogeneic stem cell transplantation.
Design
Decision analysis using parameters specified by expert opinion for skin biopsy characteristics, prevalence of acute GVHD, and value of potential outcomes. One-, 2-, and 3-way sensitivity analyses were performed.
Setting Major stem cell transplantation centers in the United States.
Patients Hypothetical cohort of patients with suspected acute cutaneous GVHD after stem cell transplantation.
Interventions
The following 3 interventions were compared: treat immediately for GVHD without performing a skin biopsy, perform a skin biopsy and treat immediately but stop treatment if skin biopsy specimen findings are inconsistent with GVHD, and perform a skin biopsy and await results of the skin biopsy specimen before treating.
Main Outcome Measures
Number of patients appropriately and inappropriately treated with each intervention, consistency of physician-reported behavior, individualized decision analyses, and preferred intervention based on the aggregate estimates of res;pondents.
Results
The decision to treat immediately for GVHD without performing a skin biopsy yielded the best clinical outcome for the specified clinical setting and under the parameters specified by expert opinion. One-way sensitivity analyses showed that these conclusions are robust if the prevalence of acute cutaneous GVHD in stem cell recipients with rash is greater than 50%, if the sensitivity of skin biopsy specimen is less than 0.8, and the specificity of skin biopsy specimen is less than 0.9. Only 25% of physicians interviewed chose an intervention consistent with their estimates of prevalence, test characteristics, and outcome evaluations, indicating an opportunity to improve management of this important clinical condition.
Conclusions
This decision analysis modeling technique predicts that in patient populations in which the prevalence of GVHD is 30% or greater (typical for allogeneic stem cell transplantation), the best outcomes were obtained with treatment for GVHD and no skin biopsy. In populations with prevalence of GVHD of 30% or less, obtaining a skin biopsy specimen to guide treatment was predicted to provide the best patient outcomes.
Acute graft-vs-host disease (GVHD) in allogeneic stem cell transplantation (SCT) is a complex immunologic phenomenon involving donor T cells, cytokines, and host tissue reactions. Graft-vs-host disease is a frequent complication of SCT. Acute GVHD manifests in the first 3 months after transplantation, and the main target organs include the skin, the liver, and the gastrointestinal tract. Clinical features of acute cutaneous GVHD include a disseminated exanthem characterized by acral erythema and often a scarlatiniform eruption that may progress to erythroderma.1 Clinically significant acute GVHD is estimated to occur in 6% to 90% of graft recipients, depending on patient age, HLA type, and prevention protocols used.2 A clinical staging system (grades 0 [best] to IV [worse]) based on degree of organ involvement has been used as an important prognostic indicator. The diagnosis of acute GVHD can have profound implications on prognosis; approximately 90% of patients with no or minimal (grade I) acute GVHD survive to day 100 compared with 60% of patients with grades II or III disease and 0% to 20% of patients with grade IV disease.3 Staging and grading criteria for acute GVHD used in this study are summarized in Table 1.
Initially, the diagnosis of acute GVHD involving the skin is difficult to make because the eruption can be morphologically nonspecific, appearing as an erythematous macular rash. Differential diagnosis of an erythematous rash is broad in patients after SCT and includes cutaneous reactions to chemotherapy or radiation therapy, adverse drug reactions, and viral infections. In a patient with a skin eruption, the presence of extracutaneous GVHD is helpful in making the diagnosis and determining the need for therapy. However, hepatic and gastrointestinal tract involvement often are not present because the skin is the most common site of GVHD and frequently is the first organ to demonstrate clinical findings. Further workup usually includes obtaining a skin biopsy specimen.
Significant controversy involves the use and timing of skin biopsy in the diagnosis of acute cutaneous GVHD in SCT recipients. The value of obtaining a skin biopsy specimen after SCT depends on at least 2 schools of thought about acute GVHD management. Some clinicians assert that cautious use of immunosuppression therapy is warranted because of the high risk for sepsis in patients recovering from SCT. Others maintain that delaying appropriate therapy for GVHD can lead to rapid progression of the disease and that, therefore, immunosuppression therapy should be considered immediately in patients with a skin eruption when the probability of GVHD is high.5 This rationale is supported by the high prevalence of GVHD in patients who have an erythematous eruption involving more than 60% of the body surface area a few days after undergoing SCT.
Although the sensitivity and specificity of a skin biopsy specimen in suspected acute GVHD has not been established, clinicians continue to obtain skin biopsy specimens when considering the possibility of acute GVHD after SCT. Previous studies have established that certain histologic changes evident in patients with acute GVHD, such as lymphocytic infiltrate at the basement membrane with exocytosis and spongiosis, are pathologically indistinguishable from common differential diagnoses of rash after SCT, including irradiation dermatitis and drug reactions.6,7 Another study demonstrated that in 80% of rush skin biopsy specimens obtained after SCT the findings were interpreted by pathologists as nonspecific and unequivocal, 76% of patients were treated empirically before biopsy specimen results were available, and in only 5.5% of patients was treatment changed based on biopsy specimen results.8 A recent retrospective analysis showed that skin biopsy specimen findings are poorly correlated with the clinical severity of rash suggestive of acute GVHD early after SCT.9 This study found no significant difference between patients with positive biopsy specimen findings and those with negative biopsy specimen findings, either in the clinical severity of acute GVHD or in the likelihood of receiving treatment for GVHD. They found that the decision to treat suspected acute GVHD depended on clinical suspicion, not on biopsy specimen findings, and, therefore, suggested that skin biopsy has a limited role in the management of eruptions in the early period after SCT.
Inasmuch as the optimal management intervention likely hinges on the pretest probability of acute GVHD, the test characteristics of the skin biopsy specimen to confirm acute GVHD (sensitivity and specificity), and the relative consequences of appropriate and inappropriate treatment, we performed a decision analysis to investigate the interaction between these factors. Decision analysis is a method to aggregate diverse considerations pertinent to a decision so that the best clinical choice can be made in the absence of clear experimental or observational data.10,11 Hence, this approach enables simultaneous consideration of the risks and benefits of skin biopsy after SCT: appropriate treatment of GVHD, missed or delayed treatment of GVHD in patients with negative skin biopsy specimen findings, and inappropriate treatment in patients without GVHD but with positive skin biopsy specimen findings. A traditional decision analysis model would use survival curves, receiver operating characteristic curves, and other evidence-based data. An extensive literature search failed to provide data necessary for the model, including sensitivity and specificity of skin biopsy specimens and occurrence of adverse outcomes. Therefore, this modeling approach used expert opinion to estimate test characteristics of skin biopsy specimens and to provide valuations for the relative benefit-risk ratio of appropriate vs inappropriate treatment of GVHD. Our results should be used to guide further research to better understand the role of skin biopsy after SCT.