Engraftment syndrome: double-edged sword of hematopoietic cell transplants

Abstract

Engraftment syndrome (ES) after hematopoietic cell transplantation (HCT) is increasingly diagnosed. Common features include fever, pulmonary vascular leak, rash and organ dysfunction. Different diagnostic criteria likely account for the wide (7–90%) range of reported incidences. ES typically occurs within 4 days of granulocyte recovery although a recently described seemingly similar syndrome occurs >1 week before granulocyte recovery after umbilical cord blood cell transplants. Although the clinical manifestations of ES may be identical to those of acute GVHD, ES also has been well described in patients without acute GVHD. The data are conflicting as to whether ES is associated with a higher nonrelapse mortality and worse survival after HCT. The pathophysiology of ES is unclear, but endothelial injury and activated granulocytes in the setting of proinflammatory cytokines may be important. ES typically is self-limited, but, like acute GVHD, responds to corticosteroids. Because ES and acute GVHD may have overlapping features and response to therapy, these disease processes may often not be distinct events. Moreover, features of ES may overlap with those of drug- and radiation-induced toxicities and infection. Further research to better characterize the clinical spectrum and etiology of ES and to determine its relationship to GVHD is needed.

Background

Engraftment syndrome (ES) encompasses a range of signs and symptoms occurring proximal to granulocyte recovery after high-dose therapy and a hematopoietic cell transplant (HCT).1, 2, 3 Most data suggest ES results from a proinflammatory state caused by release of diverse cytokines and other mediators of inflammation. ES was previously referred to as capillary leak syndrome,4, 5 autoaggression syndrome (after autotransplants)6, 7 and (when severe) aseptic shock syndrome.8 ES is described after umbilical cord blood transplants and auto-, allo- and syngeneic-transplants of blood cells and BM cells. The relationship of ES to other post-transplant events with similar clinical features such as acute GVHD, pre-engraftment syndrome (PES), radiation- and drug-induced toxicities and infections, alone or combined, is controversial (Table 1). Although GVHD may be more common in persons with ES, ES as a self-limited syndrome or one that resolves after a short course of treatment without the developement of acute GVHD has been well described.9, 10, 11 ES is also reported after autotransplants seemingly excluding GVHD in some instances. There are also conflicting data regarding an association between ES, NRM and survival.1, 2, 10, 11, 12, 13, 14, 15 Some of these discordances likely reflect different definitions of ES.

Table 1 Complications of HCT with clinical manifestations similar to ES

In this review, I discuss criteria for diagnosing ES and summarize recent reports about this syndrome. I also discuss insights into the pathophysiology of ES and possible therapeutic interventions.

Engraftment syndrome

Definition. Definitions of ES are summarized in Tables 2 and 3. Although the clinical features of ES are similar in children and adults, the impact on survival may differ. Consequently, these studies are separately discussed.

Table 2 Clinical characteristics and diagnostic criteria for ES: adult patients
Table 3 Clinical characteristics and diagnostic criteria for ES: pediatric patients

Criteria for the diagnosis of ES typically include fever (thought to be not from infection) and features of systemic vascular leak (Table 4). In 2004, Maiolino et al.2 described criteria based on an analysis of commonly observed symptoms and signs after autotransplants, including fever of unexplained origin and rash, lung infiltrates or diarrhea. Carreras et al.3 reported data from 328 blood cell autotransplant recipients. They identified 43 subjects with clinical data consistent with ES. The Maiolino criteria identified 95% of subjects believed to have ES compared with 51% diagnosed by criteria I proposed in 2001 (ref. 1) (Table 5). The wide range of reported incidences of ES, 7–59%, underscores the differences in opinion about what constitutes ES. Other variables that are associated with the likelihood of diagnosing ES are discussed below. Regardless of the criteria that are used to diagnose ES, it is important to distinguish ES from other allotransplant complications including acute GVHD, and radiation- and drug-related toxicities and infections, alone or combined. After autotransplants the clinical features of ES, such as rash and diarrhea parallel to those of another well described but controversial entity, autologous GVHD and histological findings of cutaneous GVHD have been reported in ES.16, 17, 18

Table 4 Clinical manifestations of ES
Table 5 Diagnostic criteria for engraftment syndrome: Spitzer vs Maolino

ES in different transplant settings

Autotransplants. The incidence of ES after autotransplants in adults is 9–70% and correlates with the disease being treated.2, 3, 19, 20, 21, 22, 23, 24 Pretransplant therapies also likely confound the incidence and presentation of ES. The highest incidences of ES are reported after autotransplants for breast cancer,7, 23 lymphomas other than Hodgkin lymphoma,2 POEMS24 and multiple sclerosis.22 Other risk factors for ES, including numbers of mononuclear cells in the graft,21 CD34+ cell dose,20 and earlier and more rapid granulocyte recovery,20 also predict for acute GVHD. There is no convincing association of survival with ES with the exception of a study in women with breast cancer receiving autotransplants. Severe periengraftment respiratory distress syndrome associated with ES has been reported and carries a high mortality risk.25

Children and adults seem to have similar rates of ES.14, 26, 27 Although ES in both has similar clinical features and probably a similar etiology, there may be considerably more NRM in children compared with adults. Madero et al.14 reported 8% NRM in persons with ES compared with 5% in controls. Foncillas et al.26 reported a relative risk of NRM of 2.81 in persons with ES compared with controls.

Allotransplants. Early reports of capillary leak syndrome after allotransplants identified clinical outcomes used to diagnose ES. Nurberger et al.5 reported capillary leak syndome (unexplained weight gain >3% of baseline weight within 24 h of engraftment and unresponsive to furosemide therapy) was more common after allo- vs autotransplants. In contrast, Cahill et al.4 reported similar rates.

Because ES can resemble acute (or hyperacute28, 29) GVHD, the question arises whether ES is an early manifestation of GVHD. Gorak et al.10 described ES following reduced-intensity conditioning (RIC) allotransplants. Fifteen of 149 (10%) subjects developed ES. In multivariate analysis, older recipient age, female gender and treatment with amphotericin-B were associated with ES. NRM was significantly higher among the patients with ES.

Chang et al.9 reported a 13% incidence of ES after allotransplants. The incidence of grade 2 acute GVHD was significantly higher in subjects with ES (75% vs 34%; P<0.001). NRM was higher and 2-year survival was lower in subjects with ES; 79% of subjects with ES received systemic corticosteroids. Complete resolution of ES occurred in only 10% of subjects who did not later develop acute GVHD. A trend toward a lower incidence of grade 2 acute GVHD and higher NRM and decreased survival was observed in patients whose baseline methylprednisolone equivalent steroid dose was >1.5 mg/kg/day. We recently reported a 22% incidence of ES among 217 adult allotransplant recipients with diverse hematological neoplasms and other blood disorders.11 There was a strong association between ES and onset of acute GVHD before day 28. The cumulative incidences of acute and chronic GVHD, however, were not increased in subjects with ES. Risk factors for ES in multivariate analyses were year of transplant (lower incidence after 2006) and use of non-CYA-containing GVHD prophylaxis. The reason for these associations is unclear. Tacrolimus was used more commonly for GVHD prevention after 2006, suggesting the possibility that more effective suppression of graft-vs-host alloreactivity may have influenced the incidence of ES, but an independent inverse relationship between ES and use of tacrolimus could not be confirmed. There was no significant impact of ES on disease-free survival or OS.

Three studies report ES in children receiving allotransplants.13, 30, 31 Schmid et al.13 reported a 48% incidence of ES. Amphotericin treatment and more mononuclear cells in the graft were associated with an increased risk of ES in multivariate analysis. Nishio et al.30 reported a 20% incidence of ES among children receiving allotransplants. Risk factors for ES included age <8 years and transplants from an HLA-mismatched donor. Hong et al.31 used the Spitzer criteria to characterize a periengraftment syndrome after allotransplants. A cumulative ES incidence of 17% was reported with the highest incidence among recipients of double-unit umbilical cord blood transplants, in whom use of total body radiation in the conditioning regimen and early complete chimerism were also risk factors. In none of the three studies was there a significant impact of ES on survival.

Thus, ES occurs commonly after allotransplants. There are conflicting data whether persons with ES have a higher incidence of GVHD or whether having ES impacts on NRM, DFS or survival. These discordances likely reflect different populations and variable definitions of ES. Most patients with ES are treated with systemic corticosteroids. Resolution of ES without therapy or after a short course of corticosteroids without subsequent development of GVHD favor a diagnosis of ES.

Syngeneic HCT

Koreth et al.15 using modified Spitzer criteria reported a 47% incidence (15 of 32 adults) of ES amongst recipients of twin transplants for hematologic neoplasms. There was no significant difference in PFS or survival in subjects with ES. Older age and possibly TBI were associated with a diagnosis of ES.

Pathophysiology of ES

Mechanisms and possible interactions

Despite many descriptions and proposed criteria for ES, there are few data regarding pathophysiology. Pretransplant conditioning therapy contributes to endothelial cell injury and cytokine production with recruitment of effector cells much as GVHD begins.32, 33 Because ES is seen after diverse donors and grafts and may be distinct from GVHD, and because ES coincides with granulocyte recovery, ES is likely mediated by activated leukocytes and proinflammatory cytokines. These cause vascular leak, organ dysfunction and constitutional signs such as fever. Lack of the typical clinical features of ES following granulocyte recovery in nontransplant settings suggest that other factors contribute to this syndrome.

Elevated concentrations of several cytokines including IL-1, TNF-alpha, and IFN-gamma are reported in persons with ES.34, 35 Chang et al.9 reported increased levels of suppression of tumorigenicity, IL-2 receptor-alpha and TNF-receptor-1 levels in persons with ES similar to persons with acute GVHD. However, there is no unique or consistent pattern of cytokine abnormalities in persons with ES.

The inflammatory nature of ES is supported by high levels of C-reactive protein levels compared with controls and by the response to corticosteroids.1, 36 However, these findings are also true for GVHD, infection and so on. Other potential mechanisms underlying ES include complement activation; C1 esterase-inhibitor concentrates have been shown to ameliorate capillary leak syndrome after allotransplants.37 Soluble thrombomodulin and plasminogen activator type 1, markers of endothelial injury are elevated in persons with capillary leak syndrome and other complications of transplantation, such as GVHD, hepatic veno-occlusive disease and sepsis.38 Recombinant human soluble thrombomodulin has also been shown to ameliorate the vascular leak manifestations of ES.39 As more biomarkers of GVHD are identified,40 it may be possible to better determine how to distinguish ES from GVHD and whether they are are different or identical processes.

Pre-ES (PES) after umbilical cord blood transplantation

A syndrome resembling ES, termed PES, is described a median of 7 days, but as early as 3 days, following a transplant and 4–15 days before BM recovery.41, 42, 43, 44, 45, 46 PES is reported after conventional and RIC transplants. Data are conflicting as to whether acute GVHD incidence is increased in persons with prior PES and whether PES influences NRM and survival. PES is described as being corticosteroid responsive. Factors implicated in developing PES include types of conditioning and GVHD prophylaxis and numbers of transplanted cells. Cause of PES and relationship to ES is unknown. As PES precedes granulocyte recovery by >1 week in most cases, a role for granulocytes in PES is unclear. Other immune mechanisms such as early competing graft-vs-host and host-vs-graft reactions may contribute.

ES after combined haploidentical BM and kidney transplantation for tolerance induction

An idiopathic capillary leak syndrome also termed ES is described after combined HLA-haploidentical BM and kidney transplants in people with end-stage kidney disease.47 Most recipients developed transient azotemia with fever and fluid retention 10–16 days post transplant. Kidney biopsies showed marked acute tubular injury with interstitial edema, hemorrhage and capillary congestion, but no evidence of graft rejection. As this constellation of clinical findings occurred coincident with rejection of the BM graft, the term 'bone marrow recovery syndrome' was suggested to encompass a range of clinical scenarios that might produce a syndrome similar to ES. A similar syndrome was also observed by our group in early trials of RIC HLA-matched and -mismatched BMTs during graft rejection coincident with recipient BM recovery).48 Of interest is the marked acute kidney injury that occurred in the setting of combined BM and kidney transplantation raising the question of whether the vascular bed of the freshly transplanted kidney is more susceptible to injury by calcineurin inhibitor therapy and the vascular leak that accompanies this syndrome.

Management of ES

ES may be self-limited and require no therapy as in about one-third of subjects in our series.11 Indications for treatment include a temperature of >39 °C without an identifiable infectious etiology and clinically significant manifestations of vascular leak, especially pulmonary edema. ES is very corticosteroid responsive and treatment is given only as long as symptoms persist, usually <1 week. Methylprednisolone, 1 mg/kg/day as a starting dose is usually sufficient, although higher doses may be needed for respiratory compromise, especially for diffuse alveolar hemorrhage. Despite the role of proinflammatory cytokines in the pathogenesis of ES, there is no proved benefit of targeted anticytokine therapy, such as etanercept or tocilizumab. There are also no data supporting interventions to prevent ES (Table 6).

Table 6 Management of ES and consequences of treatment

Conclusions and future direction

Although abundant literature exists describing ES after auto- and allotransplantation, controversy remains about its pathogenesis and relationship to acute GVHD. A constellation of symptoms and signs, most notably fever without an identifiable infectious source and manifestations of vascular leak, occurs during granulocyte recovery in both the auto- and allotransplant settings. Whether the cytokine cascade of ES contributes to the initiation of GVHD after allotransplantation or is an early manifestation of it, or, conversely, whether graft-vs-host alloreactivity contributes to the severity or duration of ES is unclear. Given the importance of accurate diagnosis and treatment of GVHD and the possibility that some of the manifestations of ES are early features of GVHD, one should have a high index of suspicion for early GVHD.

Future research directions should include better characterization of PES after umbilical cord blood transplants, identifying biomarkers of inflammation and GVHD and studies to more clearly distinguish it from other causes of vascular leak and from acute or hyperacute GVHD. Because ES may, in some circumstances, increase NRM and decrease survival preemptive treatment interventions based on these biomarkers and certain clinical manifestations of ES could be beneficial.

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Spitzer, T. Engraftment syndrome: double-edged sword of hematopoietic cell transplants. Bone Marrow Transplant 50, 469–475 (2015). https://doi.org/10.1038/bmt.2014.296

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