Although acute GVHD most often occurs within 1–2 months after HSCT [6, 15], the diagnosis can be made at any point after transplantation. Because time-based criteria are currently less emphasized, there is a greater emphasis on clinical features in making the diagnosis of acute GVHD [10, 15, 16].

Acute GVHD most commonly targets the skin, liver, and gastrointestinal tract [1, 17]. The skin is the most frequently affected organ and is often the first involved [15]. The classic rash is pruritic, may be painful, and is characterized by erythematous macules and papules coalescing on the trunk and extremities (often sparing the scalp), resembling the morbilliform rash of measles (Fig. 9.1). Acral involvement is common (Figs. 9.2 and 9.3). In severe GVHD, bullae and desquamation may develop, and with extensive involvement, may resemble toxic epidermal necrolysis (TEN) (Figs. 9.4 and 9.5). Gastrointestinal symptoms include nausea, vomiting, anorexia, abdominal pain, and diarrhea [15].

The differential diagnosis for acute GVHD includes bacterial/viral exanthem, engraftment syndrome, toxic erythema of chemotherapy, drug hypersensitivity reaction, and radiation recall dermatitis [1, 2].

Infectious exanthema occur more commonly in children [18] and solid-organ transplant and HSCT recipients are at increased risk for HHV6 and HHV7 reactivation, making infectious etiologies important to consider. Signs and symptoms of infection typically accompany the classic childhood exanthems, and the distribution and evolution of the rash may be helpful in differentiating these from acute GVHD. The viral exanthem of HHV6 is characterized by erythematous macules and papules surrounded by white halos, which begin on the trunk and spread to the neck and proximal extremities. It is accompanied by high fever (101–106 °F) and resolves over several days [18].

Engraftment syndrome occurs within days of granulocyte recovery and is characterized by fever >38.3 °C without a source of infection, rash over more than 25 % of body surface area that is not attributable to medication, and pulmonary edema [19]. Toxic erythema of chemotherapy (TEC) is a spectrum of cutaneous reactions to chemotherapeutic agents, most commonly presenting with erythema and tenderness of the palms, soles, and flexural regions including the axillae and groin (Fig. 9.6) [20]. There may be an increased incidence of TEC with conditioning regimens composed of busulfan and fludarabine, with a median onset of 22 days after dose administration [21].

Drug hypersensitivity reactions to non-chemotherapeutic agents should also be considered, although they tend to occur more in adults. Drug reactions typically occur within 1–14 days of initiating a drug, manifesting as a morbilliform rash on the trunk, which spreads to the extremities and less commonly involves the face, palms, or soles. Radiation recall dermatitis should also be considered in the setting of total body irradiation or recent history of sunburn followed by methotrexate for GVHD prophylaxis (Fig. 9.7).

Though skin biopsies may confirm a diagnosis of acute GVHD if clinical suspicion is high, the histologic findings are nonspecific. Histologic findings include sparse lymphocytic interface and perivascular inflammation with variable degrees of adnexal extension. Dyskeratosis, spongiosis, lymphocytic exocytosis, and satellitosis may also be present. In addition to lymphocytic infiltration, eosinophils may be noted, making it difficult to distinguish acute GVHD from drug hypersensitivity reactions. In more severe acute GVHD, subepidermal clefting and full-thickness epidermal necrosis may be seen, mimicking toxic epidermal necrolysis [22, 23]. Many of the differential diagnoses show similar features, making biopsy unhelpful or misleading if wrongly interpreted [24–29]. Thus, clinical observation is key in making an accurate diagnosis, with close attention paid to time course, evolution of disease, and response to withdrawal of a potential offending agent.

Laboratory evaluation shows hyperbilirubinemia and may show transaminitis [15]. Viral serologies may be helpful for suspected viral exanthema [18].

Proper classification of acute GVHD is important, as this largely directs therapy. In 1974, Glucksberg devised the original staging system for acute GVHD, which was later modified during the Keystone Conference in 1994 [30]. The Keystone staging attempted to classify acute GVHD based upon the extent of skin, liver, and gut involvement, but the staging of pediatric gut GVHD was not discussed during the Keystone Conference, and stool output varies considerably between children and adults. The current proposal set forth by the University of Michigan and now utilized by the Mount Sinai Acute GVHD International Consortium redefines the Keystone criteria based on volume of diarrhea per kilogram of body weight, rather than absolute volume (Table 9.2) [32]. An additional consideration when staging pediatric acute GVHD is the difference in the distribution of body surface area between adults and children, as children have larger heads and smaller extremities than adults.

Because of the difficulty in treating acute GVHD, there is a significant emphasis on prevention. Prophylactic regimens typically consist of one or a combination of the following agents: prednisone, cyclosporine, tacrolimus, sirolimus, methotrexate, mycophenolate mofetil, antithymocyte globulin, or alemtuzumab [2].

Once acute GVHD occurs, the prophylactic regimen can be adjusted and additional treatment may be considered, based on the grade of disease. Grade I acute GVHD, which is limited to the skin, usually has a favorable course and can be treated with topical corticosteroids and calcineurin inhibitors or narrow-band ultraviolet B phototherapy (nbUVB). For moderate to severe (grade II–IV) acute GVHD, high-dose systemic corticosteroids are employed as the first line of therapy [2, 33]. Unfortunately, only about half of patients are responsive to steroids [15, 32]. If there is no response to systemic corticosteroids after 2–7 days or if there is rapid progression within 48–72 h, second-line therapies should be considered. Table 9.3 outlines treatment agents subject to trials in pediatric patients.

Additional agents, such as cyclophosphamide and thalidomide, have been discussed in case reports and small case series [52, 53], but their efficacy and safety have yet to be demonstrated in larger studies. Some agents with trials in adults have not been studied in children.

Though acute GVHD correlates with increased engraftment and graft-versus-tumor effect [5], unfortunately it does not correlate with survival in pediatric HSCT recipients. In fact, acute GVHD increases the risk of chronic GVHD by 11-fold, and steroid-refractory acute GVHD indicates a poor prognosis [5]. Mortality from acute GVHD ranges from 8 % for mild acute GVHD to 55 % for severe acute GVHD, and is usually due to infection, hepatic failure, or malnutrition [11, 12, 54]. Many of the aforementioned prophylactic and treatment strategies result in some response, but none have been shown to be more effective than the others. Furthermore, no therapies have been shown to decrease mortality or prevent progression to chronic GVHD [12]. As our understanding of the pathogenesis of acute GVHD expands, additional targeted therapies are likely to arise [55]. Until then, additional randomized controlled studies are needed to assess the safety and efficacy of these therapies in children.