HEPATITIS-ASSOCIATED APLASTIC ANEMIA AND ACUTE PARVOVIRUS B19 INFECTION: A REPORT OF TWO CASES AND A REVIEW OF THE LITERATURE

Hepatitis-associated aplastic anemia is rare in general, but occurs in up to 28% of patients receiving liver transplantation for fulminant non-A, non-B hepatitis. Cases are commonly young men with mild hepatitis but severe aplastic anemia. Although cases have been reported in association with hepatitis A, B, and C, most appear to be due to a non-A-B-C virus. We report two cases of acute hepatitis subsequently complicated by marrow hypoplasia in patients with acute parvovirus B19 infection. Hepatic manifestations of parvovirus B19 infection range from liver chemistry abnormalities to fulminant hepatic failure and aplastic anemia. Our cases demonstrate a less severe form of hepatitis-associated aplastic anemia, and together with other data, suggest that parvovirus B19 is at least one cause of hepatitis-associated aplastic anemia, and may be a heretofore underrecognized hepatotrophic virus.     

Sequential liver and haematopoietic stem cell transplantation in a case of fulminant hepatitis associated liver failure and aplastic anaemia

The management of severe aplastic anaemia is particularly challenging when it occurs in the context of recent liver transplantation. Rapid identification of a suitable donor followed by allogeneic haematopoietic stem cell transplantation is the only curative option. This scenario is often complicated by potentially life‐threatening infections that develop as a consequence of immunosuppression. Alternative donor transplantation using suitably matched unrelated donors can be potentially life‐saving when suitably matched sibling donors are unavailable. Above all, a dedicated interdisciplinary approach with seamless communication between hepatology, transplant surgery, haematology, and stem cell transplant services is essential to achieving optimal outcomes. Herein, we describe a case of severe hepatitis leading to hepatic failure who was treated with liver transplantation from a deceased donor, and later received an allogeneic haematopoietic stem cell transplantation from a matched unrelated donor for hepatitis‐associated aplastic anaemia.     

Parvovirus B19 induced hepatic failure in an adult requiring liver transplantation

Parvovirus B19 induced acute hepatitis and hepatic failure have been previously reported, mainly in children. Very few cases of parvovirus induced hepatic failure have been reported in adults and fewer still have required liver transplantation. We report the case of a 55-year-old immunocompetent woman who developed fulminant hepatic failure after acute infection with Parvovirus B19 who subsequently underwent orthotopic liver transplantation. This is believed to be the first reported case in the literature in which an adult patient with fulminant hepatic failure associated with acute parvovirus B19 infection and without hematologic abnormalities has been identified prior to undergoing liver transplantation. This case suggests that Parvovirus B19 induced liver disease can affect adults, can occur in the absence of hematologic abnormalities and can be severe enough to require liver transplantation.     

Human parvovirus B19: relevance in internal medicine.

Infection by the human parvovirus B19 can lead to several clinical manifestations which are relevant in internal medicine. These include aplastic crisis in chronic haemolytic anaemias, exanthemathous disease and arthropathy, mainly in women, and chronic anaemia in the immunocompromised host. After initial replication, probably in the respiratory tract, the virus enters its target cells in the bone marrow, erythroid precursor cells, through its receptor, the blood group P antigen. Viral replication in these cells leads to an arrest in erythropoiesis, normally lasting approximately 1 week. In this stage, an aplastic crisis can be produced in all patients under 'erythropoietic stress'. The viraemia disappears as specific antibodies to the virus become detectable in serum, which may give rise to a rash or arthralgia, symptoms that are probably immune-mediated. In immunologically normal individuals the infection is cleared by the humoral immune system within several weeks, whereafter detectable specific IgG confers lifelong immunity to reinfection. In patients with absent or dysfunctional humoral immunity to this virus, however, persistent infection can occur, which results in chronic suppression of erythropoiesis with chronic anaemia. Passive immunization, by means of normal immunoglobulin preparations has been reported to be effective in treating this condition. Diagnosis of parvovirus infection is usually possible by the detection of specific antibodies of IgM class in cases of recent infection. In patients with aplastic crisis and patients with chronic anaemia diagnosis rests upon the detection of parvovirus B19 DNA in serum by polymerase chain reaction. Parvovirus B19 is a ubiquitous virus. By the age of 15, about 50% of individuals have serologic evidence of a past infection, which may present as the common childhood disease erythema infectiosum. At the age of 70, seroprevalence reaches 80 to 100%. A vaccine against this virus is currently being developed.     

Peliosis hepatis following treatment with androgen-steroids in patients with bone marrow failure syndromes

Androgens widely used in the treatment of bone marrow failure syndromes can in rare cases cause hepatic peliosis, a pathological entity characterized by multiple blood-filled cavities in the liver parenchyma. Bone marrow failure syndromes per se are associated with a low coagulation status, which is further magnified by bone marrow transplantation for aplastic anaemia due to deep thrombocytopenia. Both these conditions can cause bleeding; their combination is especially dangerous. We describe two cases of aplastic anaemia due to paroxysmal nocturnal hemoglobinuria and Fanconi syndrome, in which patients developed peliosis hepatis after prolonged treatment with androgens. One patient developed severe subcapsular bleeding, successfully treated with catheterization of the right hepatic artery and embolization of the bleeding site. The second patient bridged over deep post-transplant aplasia with high frequency platelet transfusions, and demonstrated an uncomplicated post-BMT course. We suggest avoiding or interrupting treatment with androgens in patients preparing for BMT.     

Bone marrow transplantation from identical twins in the treatment of aplastic anaemia: implication for the pathogenesis of the disease

S ummary . Treatment of aplastic anaemia by bone marrow transplantation from a syngeneic (identical twin) donor has provided insights into the pathophysiology of the disease.
We report from patients with severe anaemia who were treated by syngeneic bone marrow transplantation. None of the patients had sustained recovery of peripheral blood counts. All four received second transplants from the same twin donor after immunosuppressive conditioning treatment. Each had prompt recovery of haematopoiesis. A review of the literature indicates that failure of syngeneic bone marrow transplantation in patients with aplastic anaemia is not uncommon. These data indicate that aplastic anaemia may be caused by a mechanism other than an absence or intrinsic abnormality of haematopoietic stem cells in many patients.     

Human parvovirus and thalassaemia

The human parvovirus (HPV) is responsible for aplastic crises in patients with chronic haemolytic anaemia. We describe the cases of four children with aplastic crises in various types of thalassaemia (alpha and beta thalassaemias, major and intermediate forms). In all four patients, specific anti-human parvovirus IgM was detected in their serum, thereby indicating recent infection.     

Chronic hepatitis caused by persistent parvovirus B19 infection

Background  

Human infection with parvovirus B19 may lead to a diverse spectrum of clinical manifestations, including benign erythema infectiosum in children, transient aplastic crisis in patients with haemolytic anaemia, and congenital hydrops foetalis. These different diseases represent direct consequences of the ability of parvovirus B19 to target the erythroid cell lineage. However, accumulating evidence suggests that this virus can also infect other cell types resulting in diverse clinical manifestations, of which the pathogenesis remains to be fully elucidated. This has prompted important questions regarding the tropism of the virus and its possible involvement in a broad range of infectious and autoimmune medical conditions.     

Fulminant hepatic failure following bone marrow transplantation for hepatitis-associated aplastic anemia

A case of aplastic anemia associated with non-A, non-B hepatitis was initially successfully treated by bone marrow transplantation. The patient subsequently developed fulminant hepatic failure. Fulminant hepatic failure is rare in bone marrow transplantation and only occurs in association with aplastic anemia associated with viral hepatitis. This case helps to highlight the relationships between the immune system, hepatitis, and bone marrow failure.     

B19 virus--a pathogenic human parvovirus

B19 virus is the first human virus to be shown to be a member of the parvovirus genus. This review is concerned with the diseases associated with B19 virus, their nature, pathogenesis and diagnosis. The virus was discovered by chance in blood donors but has been shown to be a common infection of childhood. Infection may be asymptomatic or associated with mild, non-specific symptoms. The most common specific clinical manifestation is an erythematous rash illness which often has the classical features of erythema infectiosum. Often, however, it is described simply as rubelliform and only laboratory tests can distinguish B19 and rubella virus infections. Joint involvement is the most common complication of B19 virus infection occurring especially in adult females. It often involves the joints of the hands and wrists, clears rapidly in most patients but may persist for months or years in a few. B19 virus is also the principle cause of the transient aplastic crisis which complicates chronic haemolytic anaemia. This has been demonstrated repeatedly in sickle cell anaemia and hereditary spherocytosis and in individual cases of other haemolytic anaemias. The pathogenesis of the aplastic crisis is related to the ability of B19 virus to infect and damage early erythroid progenitor cells. Volunteer studies in normal individuals have demonstrated that this is a regular event occurring about a week after infection via the respiratory tract. Rash illness and joint involvement occur 7 to 10 days later and are presumably immune mediated. Diagnosis of B19 virus infection can be achieved by detection of the viraemia (aplastic crisis) or by detection of virus specific IgM antibody (all diseases).(ABSTRACT TRUNCATED AT 250 WORDS)     

A boy with fatal infectious mononucleosis suspected as the first Japanese case of X-linked lymphoproliferative syndrome

We report a case of a 10-month-old boy who died of severe hepatic failure after a prolonged course of infectious mononucleosis. He also presented interstitial pneumonitis, meningoencephalitis and aplastic anaemia. Epstein-Barr virus (EBV)-specific cytotoxic T lymphocyte (CTL) activity had not been detected in his peripheral blood during the course of the illness. Studies of his mother revealed a severe reactivation pattern of anti-EBV antibodies and decreased EBV-specific CTL activity. An X-linked familial susceptibility to EBV infection such as X-linked lymphoproliferative syndrome (XLP) might be associated with his fatal EBV infection.     

Recurrent idiopathic acute hepatitis-associated aplastic anemia/pancytopenia fourteen years after initial episode

Aplastic anemia following viral hepatitis is a condition well recognized in the medical literature. Although hepatitis-associated aplastic anemia is an uncommon syndrome, there are several reports in the literature describing such cases. In these reports, aplastic anemia generally occurs following a viral infection, including parvovirus B19, but may also be idiopathic. The etiology of both the hepatic injury and the bone marrow failure is speculated to be immune-mediated. We report a patient who suffered acute idiopathic hepatitis and severe pancytopenia fourteen years after a similar episode in childhood. This is only the second case report of acute hepatitis in association with bone marrow failure and aplastic anemia in childhood with sudden recurrence many years later in adulthood.     

Evolution in the management of acute liver failure-associated aplastic anaemia in children: a single centre experience

BACKGROUND/AIMS: Bone marrow failure (BMF) is a potentially life-threatening complication of acute liver failure (ALF). METHODS: To investigate prevalence and evolving management of BMF associated with ALF, we reviewed all cases seen in our centre over 17 years. BMF was classified as: (a) bone marrow hypoplasia, (b) severe aplastic anaemia (SAA) and (c) very severe aplastic anaemia (VSAA), using standard criteria. We compared outcomes in children receiving: (1) medical treatment only with or without immunomodulation (anti-lymphocyte globulin, calcineurin inhibitors, G-CSF); (2) medical treatment with or without immunomodulation plus liver transplantation (LT); (3) haematopoietic stem cell transplantation (HSCT). RESULTS: Of 213 patients with ALF, 20 [(9.4%); 14 (70%) boys] developed BMF after a median of 1 month (range, 0.5 to 7). Seven had VSAA, 7 SAA and 6 bone marrow hypoplasia. Five children were treated medically, including 3 by immunomodulation; 10 (50%) received LT, with immunomodulation in 6; 5 (25%) received HSCT, in one after LT. Four (20%) children died, only one as consequence of AA. There was no difference in recovery, complication rates or outcome among the three groups. CONCLUSIONS: Aggressive management of ALF-associated AA, including immunomodulation, HSCT and LT, is successful in most cases. HSCT has the advantage of removing the risk of late clonal disorders.     

Post-hepatitic aplastic anaemia in children in Taiwan, a hepatitis prevalent area

Aplastic anaemia is a rare but serious complication of hepatitis, and hepatitis is an unusual cause of aplastic anaemia in children in the West. However, the relative frequencies of acquired aplastic anaemia in children in Taiwan, a hepatitis prevalent area, differ from those in the West, in the very high frequency of post-hepatitic aplastic anaemia (23.9% of all cases of aplastic anaemia). This may account for the higher incidence of aplastic anaemia in children in Taiwan. Although the prognosis of post-hepatitic severe aplastic anaemia was very poor, the present study using bone marrow transplantation, antithymocyte (or antilymphocyte) globulin, high-dose methylprednisolone and cyclosporin, etc., has improved the response rate and the survival.     

How to optimize outcome of patients undergoing HLA-matched related haematopoietic stem cell transplantation in acquired and inherited bone marrow failure syndromes

Up-front allogeneic haematopoietic stem cell transplantation (allo-HSCT) after a reduced intensity conditioning regimen is the standard treatment in children with acquired severe aplastic anaemia (aSAA) and inherited bone marrow failure syndromes (iBMFs) in the presence of a healthy matched related donor (MRD). The paper by Alsultan et al. report the safety and efficacy of MRD HSCT conditioned with low-dose cyclophosphamide, fludarabine and thymoglobulin in both aSAA and non-Fanconi iBMFs, strengthening the concept of the pivotal role of immunosuppressive approach in allo-HSCT for specific subgroups of non-malignant diseases requiring a reduced risk of toxicities, offering the opportunity to discuss the essential points for achieving patients' long-term survival after MRD HSCT in BMF. Commentary on: Alsultan et al. Human leucocyte antigen-matched related haematopoietic stem cell transplantation using low-dose cyclophosphamide, fludarabine and thymoglobulin in children with severe aplastic anaemia. Br J Haematol 2023;203:255-263.     

Late graft rejection and second infusion of bone marrow in children with aplastic anaemia

Late graft rejection following allogeneic bone marrow transplantation (BMT) for aplastic anaemia is a significant clinical problem and is associated with a high risk of mortality. We report two children with severe aplastic anaemia (SAA) who developed very late graft rejection 2 years and 4 months and 10 years respectively after allogeneic BMT from HLA-identical siblings. Following a second BMT from their initial donors, engraftment has been sustained in both cases. The patients are alive with full donor chimaerism, 18 and 19 years from initial transplant. These cases illustrate that graft failure can be an extremely late event after allogeneic BMT for SAA, and that long-term sustained engraftment can be achieved in these patients with second BMT from the original donors.     

Prevalence of GBV-C/HGV, a novel 'hepatitis' virus, in patients with aplastic anaemia

GBV-C or hepatitis G virus (GBV-C/HGV) is a novel RNA virus with similarities to members of the Flaviviridae family, especially hepatitis C. Viral RNA is detected in about 1.5% of American blood donors, with higher prevalence in multiply transfused patients and in individuals with hepatitis or liver disease. Some cases of aplastic anaemia follow apparent non-A, non-B, non-C viral hepatitis, and GBV-C viraemia has been described in three case reports of hepatitis-associated aplastic anaemia. We tested clinical samples from patients with aplastic anaemia with or without recent hepatitis for the presence of GBV-C/HGV. Virus was detected in a total of 15/57 (26.3%) of patients with aplastic anaemia and 12/52 (23.1%) of multiply transfused control patients. Sequencing of the 188 base pair NS3 helicase PCR product in the serum of five individuals indicated the same high degree of sequence variation as has been seen among other isolates of the virus. GBV-C/HGV does not appear to be implicated in the aetiology of aplastic anaemia.     

Autologous Bone Marrow Repopulation following High Dose Cyclophosphamide and Allogeneic Marrow Transplantation in Aplastic Anaemia

Two patients are described who received allogeneic bone marrow transplantation for aplastic anaemia. Both patients rejected their grafts but subsequently repopulated their marrow with autologous haematopoietic cells. The significance of this phenomenon and its relationship to the possible pathogenesis and therapy of aplastic anaemia and discussed.     

Donor-Type Myelodysplastic Syndrome with t(2;3) and Monosomy 7 after Allogeneic Peripheral Blood Stem Cell Transplantation and Liver Transplantation in a Patient with Severe-Type Aplastic Anemia

Secondary clonal hemaloiogical disease in donor cells has rarely been reported as a complication of allogeneic stem cell transplantation in hematological disease. We report a case of myelodysplastic syndrome that showed cytogenetic abnormalities of t(2;3) and monosomy 7, which developed 2 years after peripheral blood stem cell transplantation for aplastic anemia and 1 year after liver transplantation for drug-induced hepatic failure. This secondary malignancy of donor origin is most frequently seen in patients with leukemia. We suspect that the chromosomal abnormalities are related to hepatitis-associated aplastic anemia, administration of granulocyte colony-stimulating factor and erythropoietin for posttransplantion pancytopenia, and repeated infections after liver transplantation.