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.     

Acute Parvovirus B19 Infection Leading to Severe Aplastic Anemia in a Previously Healthy Adult Female

Human Parvovirus B19 has been linked to a variety of diseases. One of the most common complications is transient aplastic crisis in patients with chronic hemolytic anemia. Very few case reports have implicated this virus as a putative etiology behind hepatitis and severe aplastic anemia in immuno competent individuals. We report a case of severe aplastic anemia in a previously healthy adult female due to acute parvovirus B19 infection. Laboratory examination showed pancytopenia in peripheral blood and severe hypoplastic bone marrow on biopsy. Serological analysis (ELISA) revealed acute Parvovirus B19 infection. In the face of unavailable HLA matched bone marrow donor, immuno-supressive therapy was contemplated, but could not be given because of financial constraints. Pancytopenia persists till date, 4 months after the diagnosis, with the patient requiring repeated packed red cell and irradiated platelet transfusions. Thus, acute infection with this virus must be considered a cause of acquired aplastic anemia even in individuals without underlying disease.     

Aplastic anemia and non-A, non-B hepatitis

Severe aplastic anemia is a rare but important complication of hepatitis. The agent(s) responsible for the hepatitis in these cases have not been well defined. Sixteen patient with hepatitis-associated aplastic anemia were studied for evidence of recent infection with hepatitis A virus, hepatitis B virus, cytomegalovirus, Epstein-Barr virus, and Toxoplasma. Results were compared with data from 10 randomly selected patients with aplastic anemia unassociated with hepatitis. Of the 16 patients, recent acute hepatitis A infection could be excluded in at least 14 patients. Hepatitis B surface antigen (HBsAg) was present in only one patient. A diagnosis of recent hepatitis B infection could not be excluded with confidence in two others. Tests for cytomegalovirus, Epstein-Barr virus, and Toxoplasma gave negative results. No patient with aplasia unassociated with hepatitis had evidence of recent hepatitis A infection, and the frequency of hepatitis B antibodies in this group was indistinguishable from that in patients with hepatitis. These data indicate that most cases of hepatitis that preceded aplastic anemia were not caused by hepatitis A virus or hepatitis B virus; non-A, non-B agents were probably involved in at least 13 of the 16 cases studied.     

Is hepatitis C virus involved in hepatitis-associated aplastic anemia?

OBJECTIVE: To determine whether hepatitis C virus is involved in hepatitis-associated aplastic anemia. DESIGN: Retrospective analysis. SETTING: Bone marrow transplantation unit. PATIENTS: One hundred and eighteen patients with severe aplastic anemia, including 19 with hepatitis-associated aplasia, 61 with aplastic anemia of undetermined cause, and 38 with aplastic anemia related to an inherited syndrome or an acquired etiology. MEASUREMENTS and MAIN RESULTS: There was no statistically significant difference in antihepatitis C virus antibodies between hepatitis-related aplastic anemia (15.8%; 95% CI, 4% to 36%) and aplasia of unknown (9.8%; CI, 5% to 22%) or known (7.9%; CI, 2% to 22%) cause. The antihepatitis C virus levels did not differ according to the cause of aplastic anemia. There was no relation between hepatitis C and hepatitis B virus serologies, regardless of cause. CONCLUSIONS: Hepatitis C virus is not a frequent cause of non-A, non-B hepatitis-associated aplastic anemia. Either a non-A, non-B, non-C hepatitis virus is involved in non-A, non-B hepatitis-related aplasia or hepatitis C virus prevalence is underestimated in patients with hepatitis-related aplasia, possibly as a result of immunologic defects.     

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.     

Severe aplastic anemia associated with human parvovirus B19 infection in a patient without underlying disease

 Human parvovirus B19 (B19 virus) infection is known to induce aplastic crisis in patients with hemolytic anemia. In healthy subjects, B19 infection may sometimes cause mild pancytopenia, but these changes are transient and recovery is spontaneous. We report the first case of aplastic anemia in a previously healthy boy without any underlying diseases, following asymptomatic infection with the B19 virus. Laboratory examination initially showed thrombocytopenia, mild leukopenia in the peripheral blood, and severe hypoplastic bone marrow. Since pancytopenia developed and worsened progressively, immunosuppressive therapy was given, resulting in a complete remission. Despite the lack of an infectious prodrome, serological and histological analysis revealed an underlying infection with the B19 virus. Thus, B19 virus infection must be considered one of the causes of aplastic anemia in patients without underlying hemolytic anemia and an apparent episode of the viral infection. Received: August 28, 1998 / Accepted: November 18, 1998     

人微小病毒B19感染所致肝损害19例临床分析

目的探讨B19病毒感染所致肝损害的临床表现、实验室检查特点及治疗与转归。方法对人微小病毒B19感染患者19例的临床资料进行回顾性分析。结果在人微小病毒B19感染的19例患者,主要症状有乏力(12例)、黄疸(10例)、脾肿大(10例),伴有发热(10例)、皮疹(6例)及肌肉关节疼痛(6例),有6例伴有如下疾病或并发症:如妊娠(1例)、急性肝功能衰竭(2例)、精神分裂症(1例)、急性骨髓停滞(1例)和肺炎(1例)。以血清天门冬氨酸氨基转移梅(AST)升高为主,黄疸大多数表现为轻到中度,容易出现凝血酶原活动度(PTA)下降,但胆碱脂酶(CHE)下降不明显。经积极对症支持治疗,肝功能等各项指标正常后治愈出院。人微小病毒B19可致肝功能受损,导致急性肝炎或急性重型肝炎。结论对临床上非甲～戊型肝炎病人,应注意检查血清抗B19病毒IgM。该病毒感染是一个急性或亚急性过程,呈良性经过,有自愈倾向。     

Lack of known hepatitis virus in hepatitis-associated aplastic anemia and outcome after bone marrow transplantation

Viral infection has been shown to induce aplastic anemia, unidentified types of hepatitis being the most common cause for aplastic anemia-associated viral hepatitis. The survival rate for this group of patients after bone marrow transplantation with stem cells from an HLA-matched sibling is not well known. The aim of this study was to determine the prevalence of hepatitis G virus (HGV) and transfusion transmitted virus (TTV) infection in non-A, non-B, non-C hepatitis associated-aplastic anemia (HAAA) patients, and to define the role of bone marrow transplantation (BMT) as a therapeutic modality for this disease. Sixty-eight patients (43 males and 25 females) with aplastic anemia, underwent allogeneic BMT at the Hadassah University Hospital between 1981 and 1997. Onset of hepatitis was defined as jaundice and elevated alanine aminotransaminase (ALT) levels. Onset of aplastic anemia was defined as the first date on which varying degrees of pancytopenia occurred: hemoglobin level below 10 g/dl, WBC below 2 x 10(9)/l and low platelet count 10 x 10(10)/l. Serial serum samples from HAAA patients were assayed for virological and/or serological markers of hepatitis A, B, C, D, E, G viruses, TTV and parvovirus B19. Seventeen of the 68 patients with aplastic anemia (25%) suffered from hepatitis, 12 males and five females, ages 5 to 36 years. The mean interval between onset of hepatitis and first indication of aplastic anemia was 62 days (range 14-225 days). The development of aplastic anemia was unrelated to age, sex or severity of hepatitis. Ten of the 17 patients (59%) achieved complete ALT recovery prior to the diagnosis of aplastic anemia. Serum samples were available for 15 patients; none had evidence of acute or active hepatitis A, B, C, D, E, G and TTV virus infection at the time of diagnosis. Parvovirus B19 DNA sequences were not detectable in 10 of 12 tested cases; two positive results were detected in serum samples obtained after blood transfusion, making the analysis of these positive results difficult. All 17 patients underwent BMT. The mean post-BMT follow-up period was 38 months (range 1 day-123 months), five patients (30%) died 1 to 160 days post BMT, and 12 (70%) are alive 31 to 123 months after BMT. Relapsing hepatitis was not observed in any of the patients. In conclusion, HAAA is a disease of the young and the etiologic agent associated with HAAA remains unknown. HGV, TTV and parvovirus B19 sequences were not detected in any of the HAAA cases. The survival rate after BMT with stem cells from an HLA-matched sibling is similar to that for patients with non-hepatitis-associated aplastic anemia.     

Remission of severe aplastic anemia associated with hepatitis B virus infection after viral clearance: potential role of lamivudine

Although viral hepatitis infection is known to be associated with aplastic anemia, a causal link between viral hepatitis and aplastic anemia has not been convincingly demonstrated. A case of hepatitis B-associated severe aplastic anemia is described which only partially responded to conventional immunosuppressive treatment but went into complete clinical remission after clearance of the hepatitis B virus. Disappearance of the hepatitis B virus occurred during lamivudine treatment and coincided with immune activation secondary to discontinuation of immunosuppressive therapy. This case was somewhat atypical in that a history of acute hepatitis preceding the aplastic anemia was absent. The observation made in this case report supports a cause-effect relationship between hepatitis B virus infection and aplastic anemia.     

Parvovirus B19 in an immunocompetent adult patient with acute liver failure: an underdiagnosed cause of acute non-A-E viral hepatitis.

There are occasional pediatric reports of parvovirus B19-associated transient acute hepatitis and hepatic failure. A case of a 34-year-old immunocompetent woman who developed severe and prolonged but self-limited acute hepatitis and myelosuppression following acute parvovirus B19 infection is reported. Parvovirus B19 may be the causative agent in some adult cases of acute non-A-E viral hepatitis and acute liver failure.     

Hepatitis C

The major cause of chronic post-transfusion hepatitis, the hepatitis C virus (HCV), has been identified. HCV is a single-stranded linear RNA virus with characteristics similar to the flaviviruses. A different agent, the hepatitis E virus, is associated with epidemic (enterically-transmitted) non-A, non-B hepatitis. At present, infection with HCV is recognized by the finding of anti-HCV antibodies, positive in up to 90% of patients with chronic non-A, non-B post-transfusion hepatitis. Antibodies to HCV are detected in 1% of normal volunteer blood donors and in the majority of donors implicated in post-transfusion hepatitis. HCV antibodies are also found in patients with autoimmune liver disease and hepatocellular carcinoma. Moreover, HCV infection may contribute to the pathogenesis of liver disease in alcoholic patients. The role of HCV infection in fulminant non-A, non-B hepatitis and hepatitis-associated aplastic anemia has not been elucidated as yet. Therapy of chronic non-A, non-B hepatitis with recombinant human alpha-interferon has been shown to improve or normalize aminotransferase levels in approximately 50% of patients, most of whom have evidence of HCV infection. However, relapse after cessation of treatment is common. In the future, screening blood for evidence of HCV infection may prevent most cases of non-A, non-B post-transfusion hepatitis.     

Investigation of SEN virus infection in patients with cryptogenic acute liver failure, hepatitis-associated aplastic anemia, or acute and chronic non-A-E hepatitis

SEN virus (SENV) has been tentatively linked to transfusion-associated non-A-E hepatitis. We investigated SENV's role in unexplained hepatitis in other settings. Polymerase chain reaction amplification was used to detect 2 SENV variants (SENV-D and SENV-H) in 1706 patients and control subjects. SENV was detected in 54 (22%) of 248 patients with acute or chronic non-A-E hepatitis, 9 (35%) of 26 patients with hepatitis-associated aplastic anemia, and 0 of 17 patients with cryptogenic acute liver failure, compared with 150 (24%) of 621 control subjects with liver disease and 76 (10%) of 794 healthy control subjects. When controlling for geographic region, the prevalence of SENV among case and control subjects was not significantly different. The severity of acute or chronic hepatitis A, B, or C was not influenced by coexisting SENV infection. No etiological role for SENV in the cause of cryptogenic hepatitis could be demonstrated.     

Life-threatening human parvovirus B19 infection transmitted by intravenous immune globulin

Infection of human parvovirus B19 (B19) is usually a self-limiting febrile illness, but can sometimes be life-threatening under certain circumstances, such as aplastic crisis in patients with haemolytic anaemia, hydrops fetalis in pregnant women and fulminant hepatitis. B19 can be transmitted through respiratory secretions, transplacentally and by transfusion of blood or blood products. In the present case, administration of intravenous immune globulin (i.v.Ig) transmitted B19 infection and consequently caused pure red cell aplasia and aggravation of hepatitis to fulminant hepatitis. Our case may raise important questions as to the safety of i.v.Ig and possible contamination by B19.     

Interferon and cyclosporin A in the treatment of fulminant viral hepatitis

The prognosis of fulminant hepatitis due to non-A, non-B virus infection and acute reactivation of hepatitis B virus in HB carriers is generally poor, and the treatment of choice in Western countries is recognized as liver transplantation. In countries such as Japan where liver transplantation is not readily available, however, these intractable types of fulminant hepatitis have to be treated medically. Based on the assumption that persistent replication of causal viruses and enhanced host immune responses, especially cellular immunity, to eradicate the viruses are the key mechanism in progressive liver cell destruction and the poor prognosis, we attempted a combination treatment with interferon and cyclosporin A for these types of fulminant viral hepatitis. Subjects in the present study consisted of 1 patient with acute severe hepatitis without coma and 13 patients with coma (13 with fulminant hepatic failure) due to non-A, non-B virus and acute reactivation of hepatitis B virus. The patients were given interferon-beta, 300 × 10⁴U daily, and cyclosporin A, at an initial dose of 3 mg/kg, with tapering. Fourteen patients with coma received artificial liver support that we devised. The patient with acute severe hepatitis survived, showing histologically remarkable liver regeneration. Eight of the 14 patients with hepatic coma, all of whom were indications for liver transplantation according to the criteria of the King's College group, survived. Decreased transaminase level, increased liver volume, and histological liver regeneration were observed in all the survivors. The combination of interferon and cyclosporin A is worth attempting in fulminant hepatitis caused by non-A, non-B virus and acute reactivation of hepatitis B virus in HB carriers.     

Human parvovirus B19: historical and clinical review

Human parvovirus B19 has been associated with disease only for the past few years. First isolated from sera obtained for studies on hepatitis B in 1975, it was not until 1981 that infection with this small, single-stranded DNA virus was related to aplastic crisis associated with hemolytic anemia. A nonspecific viral prodrome, the occurrence in family members, and epidemics of aplastic crisis suggested the infectious etiology. Human parvovirus infection has since been associated with arthritis, erythema infectiosum (fifth disease), fetal death, and hydrops fetalis. Through the use of recently developed serologic tests, epidemics of erythema infectiosum and parvoviral infection have been related not only to aplastic crisis but also to intrauterine infection and hydrops; DNA hybridization studies have allowed the detection of viral DNA in serum and tissue extracts. Studies have been hampered by the lack of an ability to culture the virus, but this is now possible utilizing bone marrow culture and erythropoietin. This article is a historical and clinical review of human parvovirus infection and disease and considers potential questions regarding their consequences.     

Bone marrow transplantation for hepatitis-associated aplastic anemia

Five patients with hepatitis-associated aplastic anemia were transplanted with HLA-identical, mixed lymphocyte culture-compatible sibling marrow. One patient who had suffered from severe chronic graft-versus-host disease died from intracranial bleeding at 42 months following the transplant. The other four patients are surviving from 15 to 54 months after transplant with a median follow-up of 21 months. Previous hepatic damage from viral hepatitis and liver function abnormalities existing at the time of grafting do not appear to increase the risk of hepatic venocclusive disease or the side effects of ciclosporin in patients with hepatitis-associated aplastic anemia.     

Immunologic defects in young male patients with hepatitis-associated aplastic anemia

Extensive immunologic studies were done in 97 patients with severe aplastic anemia between 1973 and 1979. Sixteen young male patients with hepatitis-associated aplastic anemia appeared to constitute a unique subset. Compared with most patients with aplastic anemia from other causes, these 16 patients had significant reductions in the mean values of circulating T lymphocytes, serum IgG and IgM, mitogen reactivity, and decreased cutaneous hypersensitivity. The ratio of peripheral blood helper to suppressor T lymphocytes identified by monoclonal antibodies was within normal limits in 3 patients studied with hepatitis-associated aplastic anemia. Interestingly, the ratio was low (less than 1) in 3 of 7 patients studied with aplastic anemia from other causes, although the mean for these 7 patients was normal. These data suggest that patients in this subset with hepatitis-associated severe aplastic anemia have a severe immunodeficiency. Whether this immunodeficiency is the cause or result of the hepatitis or aplastic anemia, or both, is unknown.     

Human parvovirus B19 in patients with aplastic anemia

Aplastic anemia is characterized by pancytopenia with hypoplastic bone marrow. Various factors including viral infections have been implicated as the precipitating factors. Human parvovirus B19 has been associated with red-cell aplasia, leukopenia, and thrombocytopenia. The present study was carried out to determine the role of parvovirus B19 in aplastic anemia patients. Twenty-seven aplastic anemia patients and 20 healthy controls were tested for the presence of parvovirus B19 infection by detecting parvovirus B19-specific IgM by ELISA and viral DNA by PCR. Parvovirus B19 IgM and viral DNA were detected in significantly higher numbers of patients in comparison to the controls (40.7% vs. 5%, P < 0.01; 37% vs. 0%, P < 0.001, respectively). The presence of parvovirus DNA in aplastic anemia patients indicates active or recent infection. However, more studies are needed to explore the mechanism of bone-marrow aplasia due to human parvovirus B19 infection.     

Persistent B19 parvovirus infection in patients infected with human immunodeficiency virus type 1 (HIV-1): a treatable cause of anemia in AIDS

OBJECTIVE: To determine the role of B19 parvovirus in red cell aplasia of patients infected with human immunodeficiency virus type 1 (HIV-1). DESIGN: Uncontrolled clinical trial, with assay of serum, peripheral blood cells, and bone marrow for virus using DNA hybridization and immunocytochemistry techniques; these assays were then correlated with clinical findings, results of immunoassays for antivirus antibodies, and with immunoglobulin (Ig) therapy. SETTING: Government medical referral center, and university and private hospitals. PATIENTS: Seven patients with pure red cell aplasia and serologic evidence of infection with HIV-1. MEASUREMENTS AND MAIN RESULTS: All patients had giant pronormoblasts in the bone marrow (present in transient aplastic crisis caused by acute B19 parvovirus infection). High concentrations of B19 parvovirus were demonstrated in sera, in several cases in samples separated by weeks or months. Viral DNA and capsid protein were present in the bone marrow of three patients studied, and active viral replication was detected by southern analysis. There was no antivirus IgG in capture immunoassay and no or very low levels of antivirus IgM. The patients did not have symptoms of fifth disease, the illness caused by this virus in immunologically normal persons. Six patients were treated with a regimen of intravenous commercial immunoglobulin. In all cases, this therapy resulted in rapid reduction in serum virus concentrations and full recovery of erythropoiesis. Relapses in two cases were predicted by DNA hybridization studies, and these cases were successfully retreated. CONCLUSIONS: The B19 parvovirus is a remediable cause of severe chronic anemia in HIV-infected patients. Recognition of and therapy for parvovirus in this population will avoid erythrocyte transfusion and should prevent transmission of the virus to other persons, including immunosuppressed persons and women of child-bearing age.