Engraftment Syndrome: An Updated Review

Engraftment syndrome is a constellation of clinical manifestations that occur at the time of neutrophil recovery following hematopoietic stem cell transplantation. There are several risk factors, but the reports on some of them are rather conflicting. Additionally, not only the clinical manifestations but also the laboratory findings are nonspecific and may overlap with several conditions such as acute graft versus host disease, drug toxicity, radiation-induced damage and infectious disorders. Treatment of symptomatic and severe forms is similar to that of graft versus host disease. Hence, there is a need for: revision of the diagnostic criteria, establishment of scoring system to determine prognosis and to direct therapy as well as the addition new criteria to differentiate it from other similar conditions.

PES was first described by Kishi, et al. [35] in 2005, as immune reaction that occurred in 78% of adults receiving reduced intensity conditioning UCBT. The clinical manifestations were: fever, skin rash, diarrhea, jaundice and weight gain of >10% from baseline [20,35]. PES is not usually explained by infection or adverse drug reactions. It also differs from ES and acute GVHD and it occurs before neutrophil engraftment. However, it has remained poorly characterized with unclear prognosis or appropriate therapy [20,35]. Several recent studies on PES have come to the following conclusions: (1) common occurrence after UCBT, (2) development before neutrophil recovery, (3) associations with: cyclosporine in GVHD prophylaxis and total body irradiation in conditioning therapy, (4) enhancement of engraftment without significant morbidity as well as early achievement of complete donor chimerism, and (5) controversial association with development of acute GVHD [20,[36][37][38].

Treatment and Prevention of ES
Treatment of ES depends on the severity of the illness as it may be self-limited and up to one third of cases require no treatment at all [3]. Indications for treatment of ES include: (1) temperature >39°C, and (2) clinically significant manifestations of vascular leak, especially pulmonary edema [3]. The main therapeutic modalities of ES are: (1) steroids in the one of the following formulations: (a) intravenous (IV) methylprednisolone: 1-2 mg/ kilogram (kg) body weight per day, (b) oral prednisolone: 0.5-10 mg/kg/day, or (c) dexamethasone palmitate: 2.5 mg/m 2 /day for 3 days then to taper quickly over 7-8 days, (2) supportive measures such as: antipyretics, oxygen, diuretics and topical therapy for skin eruptions, and (3) additional measures such as: intubation and mechanical ventilation, renal doses of dopamine to improve renal function, and C1 esterase inhibitor concentrates [2,3,9-

SPITzER MAIolIno
Requirements 3 major or 2 major + 1 minor within 4 days of engraftment major + 1 minor within 1 day of presence of neutrophils

Major Criteria
-Non-infectious fever, temperature ≥ 38.3 o C -Skin rash involving > 25% of body surface not attributable to medications -Non-cardiogenic pulmonary edema manifested by diffuse pulmonary infiltrates -Hypoxemia -Non-infectious fever

Minor Criteria
-Weight gain ≥ 2.5% of baseline body weight -Hepatic dysfunction with either bilirubin ≥ 2 mg/dL or transaminase level ≥ 2 times normal -Renal insufficiency with serum creatinine ≥ 2 times baseline -Transient encephalopathy unexplained by other causes.
-Skin rash -Pulmonary infiltrates -Diarrhea commencing 24 hours before or at any time after the first appearance of neutrophils (1) GVHD prophylaxis using methotrexate in UCBT, (2) use of cyclophosphamide and prednisolone in induction followed by cyclophosphamide mobilization in patients with POEM syndrome, (3) use of donor lymphocyte infusions in relapsed CML after allogeneic HSCT, and (4) steroid prophylaxis significantly decreases the risk of ES following autologous HSCT and is associated with shortened hospitalization without increasing the risk of infection [42][43][44][45].

Course and Prognosis
Most cases of ES are mild and resolve spontaneously or with steroid therapy [1,3]. However, ES can occasionally be fatal and deaths are usually related to respiratory dysfunction and multi-organ failure. Therefore, ES is still an important cause of morbidity and mortality in recipients of various forms of HSCT [1,2,6,13,46]. Early detection of ES is essential to reduce the associated morbidity and mortality [17,31,47,48]. Studies have shown a favorable outcome with: (1) early diagnosis and detection, (2) prompt initiation of corticosteroid therapy, (3) reduction in the unnecessary use of antimicrobial agents, and

Conclusions and Future Directions
In order to improve the outcome of ES, the following are needed: (1) identification of biomarkers that are specific for ES in order to start pre-emptive therapy so as to decrease the morbidity and mortality related to severe forms of ES, and (2) revision of the current diagnostic criteria to increase the sensitivity of its detection.
Unfortunately, there is no consensus over: the diagnostic criteria or even the risk factors for ES, thus leading to wide variation in the reported incidence of ES that ranges between 7% and 72%. Also, the clinical manifestations as well as the laboratory findings are ill defined and can overlap with many other disorders such as acute GVHD. Therefore, there is urgent need not only for having strict diagnostic criteria and severity scores, but also for a possible change in the nomenclature of the syndrome into: autologous GVHD in the setting of autologous transplantation and hyperacute GVHD in allogeneic HSCT as this approach looks more acceptable particularly in severe forms of ES.