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Abstract
Hyperacute GVHD (HaGVHD) is a rare complication of hematopoietic stem cell transplantation (HSCT) occurring before engraftment, a syndrome commonly involving skin and/or gut and/or liver, with increased morbidity and mortality. Myeloablative conditioning (MAC) regimes and mismatched donor transplants have an increased risk for HaGVHD. There is a higher chance of steroid-refractoriness and chronic GVHD in those who develop HaGVHD. There is limited literature about HaGVHD, especially in the paediatric age group. This retrospective single-centre case series included five paediatric patients who underwent HSCT between 1st April 2013 and 31st July 2015 at a tertiary care centre in South India, who fulfilled the criteria for HaGVHD as per criteria by Kim et al. and whose follow up data was available. We noted their risk factors, clinical course and prognosis. There were five paediatric HaGVHD patients. The risk factors noted among them were MAC regimen in three and mismatched unrelated donor sources in three. Two had steroid-refractory disease, four went on to develop chronic GVHD and three died of GVHD or treatment-related complications. A high index of suspicion is necessary to recognize HaGVHD, especially in patients with known risk factors developing a fever with rash post-HSCT.
Keywords: Graft-versus-host disease, hyperacute GVHD, paediatric transplantation
Introduction 
Hyperacute graft-versus-host disease (HaGVHD) is a rare complication of hematopoietic stem cell transplantation (HSCT). It is a syndrome of noninfectious fever with skin rash and/or hepatic dysfunction and/or large-volume diarrhoea, occurring before neutrophil engraftment.[1] Engraftment is defined as the first of three consecutive days of achieving a sustained peripheral blood neutrophil count of >500 × 106/L.[2] HaGVHD is associated with increased post-transplant morbidity and mortality.[1],[3] There is a paucity of literature on HaGVHD, especially in the paediatric age group.[4],[5],[6]
Materials and Methods This retrospective single-centre case series included five paediatric patients who underwent HSCT between 1st April 2013 and 31st July 2015 at a tertiary care centre in South India. All patients were diagnosed as HaGVHD as per the criteria by Kim et al.[1] HaGVHD was diagnosed based on the presence of fever and a skin rash consistent with GVHD on histopathology prior to engraftment, with or without the involvement of the liver and/or gastrointestinal tract (GIT). The other causes like drug rash, viral exanthem and engraftment syndrome were excluded. The transplant details of the patients are summarised in [Table 1].
Report of Cases Case 1
An eleven-year-old girl with Fanconi anaemia underwent a peripheral blood stem cell transplant (PBSCT) using nonmyeloablative conditioning (NMC) with a 9/10 HLA mismatched unrelated donor (MMUD). She became febrile on day 5 post-PBSCT and developed erythematous maculopapular rash over the trunk [Figure 1]a and upper limbs including palms and soles, involving 75% body surface area (BSA) within the next 48 hours. Skin biopsy showed Grade II GVHD [Figure 1]b. Within the next 2 days, she developed diarrhoea with biopsy-proven GIT GVHD and rising bilirubin prior to engraftment on day 10. Despite starting injection methylprednisolone (2 mg/kg), vesiculobullous skin lesions appeared on day 13 with the progression of GIT and liver GVHD (overall grade IV). During the prolonged immunosuppression for her steroid-refractory GVHD, she developed intercurrent infections with fusarium and staphylococcal septicaemia which were treated with appropriate antimicrobial therapy. Her GVHD responded to the treatment initially (mycophenolate mofetil, basiliximab, cyclosporine). However, by day 150, she developed gradually progressive papulosquamous lesions involving the entire body which later became fissured. She was diagnosed to have chronic GVHD and treated initially with methylprednisolone (2 mg/kg), cyclosporine and narrow-band UVB therapy (NB-UVB). In view of steroid refractoriness, mycophenolate mofetil and basiliximab were added. However, her GVHD continued to worsen and she succumbed to complications of GVHD and septicaemia.
Figure 1: (a) Erythematous maculopapular rash over the trunk. (b) Spongiosis with basal cell vacuolation, lymphocytic exocytosis and occasional dyskeratotic cells and apoptotic keratinocytes (Haematoxylin and eosin stain, 200 X). (c) Erythema involving the ear. (d) Interface changes involving the hair follicular epithelium with basal cell vacuolation and apoptotic keratinocytes (Hematoxylin and eosin stain, 200 X)Case 2
A seven-year-old boy with Fanconi anaemia underwent a PBSCT with a 9/10 HLA MMUD using an NMC regimen. He became febrile on day 6. Within a day, he developed pruritic erythematous maculopapular exanthem over the face, trunk and extremities including ear lobes [Figure 1]c and palms and soles, involving 50% BSA. Skin biopsy showed Grade II GVHD [Figure 1]d. He was treated with methylprednisolone (2 mg/kg) but continued to progress beyond engraftment (day 12) with the development of vesiculobullous skin lesions and GIT and liver GVHD (overall grade IV). In view of steroid refractoriness, he was started on cyclosporine, which had to be stopped due to severe microangiopathic haemolytic anaemia. He was given basiliximab and cyclophosphamide. However, by day 40, he succumbed to the complications of GVHD and septicaemia.
Case 3
A twelve-year-old girl with acute lymphoblastic leukaemia underwent PBSCT with 9/10 HLA MMUD using myeloablative conditioning (MAC) regimen. She became febrile from day 5 post-HSCT, developed nonpruritic, follicular rash over the neck, back and lower limbs four days later [>50% BSA]. GVHD was proven by skin biopsy. It progressed beyond engraftment on day 12 with GIT and liver involvement (overall grade IV). Resolution of the acute GVHD was achieved with methylprednisolone (2 mg/kg). She is presently alive, 9 and a half years post-HSCT, after developing steroid-responsive chronic sclerodermoid GVHD a year after the transplant.
Case 4
A ten-year-old boy had a second PBSCT, 4 years after the first transplant, using a fully Human leukocyte antigen (HLA)-matched sibling donor for relapse of juvenile myelomonocytic leukaemia. Fever developed from day 7, followed three days later by a pruritic follicular rash on upper limbs and back, progressing beyond engraftment (day 14) to a generalized erythematous maculopapular rash involving ~75% BSA. Histopathology showed GVHD. Since GVHD only involved the skin (maximum overall grade II), resolution was achieved with topical steroids and NB-UVB by day 29 and cyclosporine was discontinued on day 70. Day 90 onwards, he developed chronic GVHD involving the oral cavity, initially followed by liver involvement, for which he was treated with systemic immunosuppression with steroids and cyclosporine, initially followed by addition of mycophenolate mofetil and sirolimus. At 9 months post-HSCT, he developed thrombotic microangiopathy followed by diffuse alveolar haemorrhage and died.
Case 5
A three-year-old girl with thalassemia major underwent transplantation from her fully matched mother using MAC regimen. She developed a fever on day 13 post-HSCT, followed by erythematous maculopapular rashes over the trunk and extremities on day 15 (~65% BSA). Skin biopsy showed GVHD. Rash continued to progress postengraftment (day 17). Other organs were not involved (maximum overall grade II). She was started on methylprednisolone (initially 1 mg/kg, which was increased to 2 mg/kg as the rash continued to progress), topical steroid wet wraps and NB-UVB. Her GVHD was completely resolved in 60 days. At day 100, she developed chronic lichenoid GVHD, which responded to systemic immunosuppression and topical steroids. She is presently alive 7 years and 5 months post-HSCT.
Discussion GVHD is the most common cause of nonrelapse mortality following HSCT.[7] Skin is the first and most frequently affected organ, generally coinciding with engraftment.[8] Sullivan et al.[4] first reported HaGVHD in patients who underwent bone marrow transplantation without posttransplant immunosuppression. HaGVHD is defined as the occurrence of GVHD before engraftment by Kim et al.[1] Saliba et al.[3] have considered any GVHD within the first 14 days post-HSCT as HaGVHD irrespective of time to engraftment. However, in one of the five patients in our report, HaGVHD occurred on day 15, but prior to engraftment. So it is better to use the definition as described by Kim et al.
We diagnosed HaGVHD based on typical clinical features prior to engraftment confirmed by histopathology. Differential diagnoses considered included drug rash, viral exanthema and engraftment syndrome. In our patients, drug rash was excluded based on lack of temporal association with medications. Viral exanthem and toxic erythema of chemotherapy were excluded based on histopathology and clinical features like involvement of palms, soles and ear lobes in GVHD and response to immunosuppression. Engraftment syndrome occurs immediately before or at the time of neutrophil engraftment and is clinically diagnosed using Spitzer criteria, as given in [Table 2].[9] We noted that the skin rash progressed beyond engraftment with three patients having coexisting GI and/or liver GVHD.
Table 2: Criteria for diagnosis of engraftment syndrome as per Spitzer et al[9]Most of our understanding of HaGVHD comes from adults. As in previous reports on children [Table 3], we also found similar risk factors and higher mortality in our cases.[4],[5],[6] Risk factors for HaGVHD include alternative donor, female-to-male transplantation, MAC, multiple chemotherapies before transplantation, diagnosis of aplastic anaemia and a second transplantation after graft failure.[1],[3],[10] Four of our patients had an HLA mismatched transplant or nonsibling donor, which is an important risk factor. The patient with a matched sibling donor, however, was undergoing a second transplant. Three patients received MAC regimen. HaGVHD is associated with severe skin involvement, steroid-refractory disease, chronic GVHD and posttransplant mortality.[1],[3],[6],[10] Consistent with existing literature,[3] our patients had severe cutaneous involvement. Both steroid-refractory GVHD patients succumbed despite additional immunosuppression. Four patients developed chronic GVHD.
Early intervention may improve outcomes in HaGVHD.[1] A high index of suspicion is necessary in patients with risk factors to diagnose HaGVHD. A skin biopsy should be considered for fever and rash post-HSCT even before engraftment, especially when other organ involvement is minimal. Close observation is necessary even after the resolution of HaGVHD as recurrences can be frequent and severe. Further studies to evaluate biomarkers for early prediction of HaGVHD and alternate GVHD prophylaxis in cases with risk factors for HaGVHD are needed.
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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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