Haemophagocytic Lymphohistiocytosis Post Liver Transplantation.
Authors: Barnardo Adrian , Lim Z.Y. , Foxton Matthew , Ramasamy K. , Mufti Ghulam 
Published: October 2019

Abstract
Haemophagocytic syndromes are rare but often-fatal conditions characterised by an inappropriate and sustained activation of the cellular immune system leading to accumulation of activated macrophages and a cytokine storm. Familial haemophagocytic lymphohistiocytosis (FHLH) is an autosomal recessive condition, which presents in infancy and childhood whereas Reactive Haemophagocytic Lymphohistiocytosis (RHLH) occurs at any age and the genetic contribution remains uncertain. Presentation of RHLH is characterised by a sepsis like syndrome with cytopenia, coagulation and lipid abnormalities. We report on the haematological abnormalities and the clinical course of 37 patients who received liver transplantation and developed RHLH between 1998 and 2003.
15/37 patients had been transplanted for acute liver failure(7 drug induced, 7 seronegative hepatitis, 1 Budd Chiari syndrome) and the remaining 22 patients had chronic liver disease(Viral hepatitis 7, Primary bilary cirrhosis 7, Alcohol related liver disease 2, others 7). 34/37 patients presented with thrombocytopenia(< 50x109/l, median 30x109/l), 34/37 were lymphopenic(<1x109/l, median 0.5x109/l), median transfused haemoglobin was 8.3 g/dl, median ferritin was 1294ug/l. Hypertriglyceridemia(>2 mmol/l) and hypofibrinogenemia(<1.5g/l) was noted in 16/37 and 5/37 patients respectively. Median corrected INR was 1.14. Hepatosplenomegaly was a frequent finding in this group but is felt to be associated with the underlying liver disease. 26/37 patients presented within 30 days of transplantation and the remainder developed RHS following either a protracted admission to intensive care or a late complication of transplantation years later(range 33–2737 days). At the time of diagnosis of RHS multiorgan failure was typical with an average 2.4-organ failure.
All patients displayed morphological features of RHLH on bone marrow examination, (> 2% macrophages, with tri-lineage histiophagocytosis). Screening for potential infectious triggers revealed contemporaneous positive cytomegalovirus (CMV) serology in 48% (18/37) patients with RHLH compared to annual incidence of CMV post transplant of 4.5% at the same centre. None of these patients received a CMV mismatched organ. Bacterial cultures were positive in 6/18 patients that did not develop CMV.
Following PCR amplification and sequencing, one patient was identified as having a single nucleotide base substitution at 272 of exon 2 of PRF1, resulting in an alanine to valine amino acid substitution. This mutation has previously been reported but is felt to be a RFLP.
All patients received multiorgan support, targeted anti viral/antibiotic therapy, human immunoglobulin and GM-CSF was reserved for those with severe pancytopenia. In addition all transplant recipients received Tacrolimus and prednisolone. Actuarial one year survival was significantly worse for those who developed RHLH post liver transplant than those that did not (45% vs. 85% p<0.0001; median survival 223 days and 12 month survival 33%). However CMV infection was not associated with length of ITU stay or survival.
Our findings suggest that cytopenia post liver transplantation are often associated with RHLH and this population represents a unique group, in whom the histiocyte society criteria for RHLH may not be appropriate and histological diagnosis by bone marrow examination may be required to establish the diagnosis of RHLH. CMV infection is a common trigger of RHLH but is not associated with the poor outcome associated with RHLH.