Successful Bone Marrow Transplantation for Severe Aplastic Anemia in a Patient with Persistent Human Parvovirus B19 Infection

Persistent infection with human parvovirus B19 (B19) is primarily associated with chronic bone marrow failure in immunocompromised patients, but occasionally this organism may also affect immunocompetent hosts. B19 is also suggested as a causative agent of organ failure during bone marrow transplantation (BMT).We herein report the case of a 9-year-old girl with no previous history of immunodeficiency who developed severe aplastic anemia concurrent with B19 persistent infection. Both immunoglobulin (Ig)M antibody to B19 and B19 DNA identified by real-time polymerase chain reaction were found in the patient's serum at time of diagnosis of aplastic anemia. No giant proerythroblasts were found in her bone marrow at diagnosis. Although intravenous administration of Ig (IVIg) reduced serum B19 DNA, the aplastic status of her bone marrow did not improve. Both aplastic anemia and persistent B19 viremia were successfully treated by BMT from an HLA-identical sibling donor. Serum B19 DNA increased temporarily after BMT; however, neither organ nor marrow failure was observed. B19 DNA disappeared from the serum 2 months after BMT, suggesting that a normal immune response was restored by BMT and terminated the B19 viremia. During BMT, use of high-titer IVIg for B19 might prevent B19-associated organ failure.     

Severe Drug-Induced Hemolysis in a Patient with Compound Heterozygosity for Hb Peterborough (HBB: c.334G>T) and Hb Lepore-Boston-Washington (NG_000007.3: g.63632_71046del)

Unstable hemoglobins (Hbs) are often overlooked in the differential diagnoses of drug-induced hemolysis. Hb Peterborough [β111(G13)Val→Phe; HBB: c.334G>T] is a rare unstable Hb variant, predominantly found in individuals of Italian descent, due to a structural defect involving a single amino acid substitution (phenylalanine for valine at position 111 of the β-globin chain). Unstable Hb variants are often inherited in the heterozygous state with Hb A (α2β2) and rarely in compound heterozygosity with other Hb variants. The presence of another variant Hb often alters the phenotype, occasionally resulting in more severe disease. Using a combination of molecular techniques; multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing, we identified a compound heterozygosity for Hb Peterborough and Hb Lepore-Boston-Washington (Hb LBW) [δ87, β116; NG_000007.3: g.63632_71046del] in a middle-aged gentleman with a history of chronic microcytic anemia and splenomegaly, presenting with severe drug-induced hemolysis, which was managed conservatively. The clinical history and presentation reflect the dual pathology due to the presence of two variant Hbs and their associated phenotypes. In this article, we discuss the phenotype resulting from the interaction of Hb Peterborough and Hb LBW and emphasize the importance of molecular testing in the diagnosis of rare Hb variants.     

Hb Stara Zagora: A New Hyper-Unstable Hemoglobin Causing Severe Hemolytic Anemia

We describe a new hyper-unstable β chain variant (codons 137–139, ? 6 bp) in a 2-year-old Bulgarian boy. The abnormal hemoglobin (Hb) is associated with severe hemolytic anemia as a consequence of its hyper instability. The child was admitted to the Pediatric Clinic (Faculty of Medicine, Stara Zagora, Bulgaria) at the age of 2 months. Because of anemia (Hb 6.9 g/dL) and high serum iron level (58 μM/L) the child was transfused. However, a month later his Hb level had dropped to 7.5 g/dL, and since then he has been on a regular monthly blood transfusion regimen. Hemoglobin analysis of a blood sample collected 2 months after the last transfusion at the age of 2 years, revealed no abnormalities except for the presence of inclusion bodies after incubation of peripheral blood with brilliant cresyl blue. Sequencing of the β-globin gene revealed heterozygosity for a 6 bp deletion (–TGGCTA) at codons 137 [the second and third base pair (bp)], 138 and 139 (the first bp), forming a new codon at position 137 (GAT). This event eliminates three amino acids (Val-Ala-Asn) and introduces a new residue (Asp). It creates a new restriction site for HphI. The parents and his dizygotic twin brother had no history of hemolysis. The paternity of the child was confirmed by DNA analysis.     

Case Report: Prenatal Diagnosis of Hb Hammersmith [β42(CD1)Phe→Ser; HBB: c.128T > C] in a Family with an Adult Male Patient

Hb Hammersmith [β42(CD1)Phe?→?Ser; HBB: c.128T?>?C] is a rare, unstable hemoglobin (Hb) variant. In this case report, we describe another male case of Hb Hammersmith. A 39-year-old male had hemolytic anemia, cyanosis and splenomegaly since 6 months after birth. He passed the disease allele to his daughter, a 3-year-old girl, who also had hemolytic anemia and splenomegaly. This mutation was not identified in the parents and two brothers of the father. Early prenatal diagnosis was performed in the second pregnancy in this family. This is the first case of Hb Hammersmith in an adult male patient.     

Successful Treatment with Cyclosporine and High-Dose Gamma Immunoglobulin for Persistent Parvovirus b19 Infection in a Patient with Refractory Autoimmune Hemolytic Anemia

We describe a patient with persistent pure red cell aplasia due to human parvovirus B19 (HPVB19) infection during immunosuppressive therapy for refractory autoimmune hemolytic anemia (AIHA). The patient had been given corticosteroid (CS) and/or azathioprine for AIHA. During the course of treatment, reticulocyte count and hemoglobin levels decreased suddenly. Bone marrow aspirate showed erythroid lineage-specific aplasia with a few giant proerythroblasts, suggesting the presence of HPVB19 infection. The diagnosis of aplastic crisis due to HPVB19 infection was based on positive test results by polymerase chain reaction for HPVB19 immunoglobulin M (IgM) antibody and B19 DNA. Although splenectomy followed by administration of high-dose gamma globulin (HDIG) and plasma exchange were performed, the crisis and hemolysis recurred. Aplastic crises occurred several times when the B19 IgG result became negative and the CD4+ lymphocyte count was less than 300/microL. The patient showed complete recovery from anemia after CS was switched to cyclosporin A (CsA) and intermittent administration of HDIG. The result for B19 IgG antibody was continuously positive, and the DNA result became negative after these treatments. The results in this case indicated that concomitant administration of CsA and intermittent administration of HDIG can lead to cure of chronic anemia due to HPVB19 infection in patients with refractory AIHA.     

Acute Exacerbation of Anemia with Parvovirus B19 Infection One Year after Sleeve Gastrectomy for Severe Obesity

Pancytopenia due to malnutrition sometimes occurs after gastric bypass but is rare after sleeve gastrectomy. A 35-year-old patient underwent sleeve gastrectomy for severe obesity. Twelve months after the operation, rapid progression of macrocytic anemia with leukopenia and thrombocytopenia occurred, and a decrease in some vitamins and trace elements due to an insufficient food intake was also detected. Haptoglobin decreased, suggesting the presence of hemolysis. In addition, IgM antibody against parvovirus B19 was detected, followed by IgG antibody. Parvovirus B19 infection was suggested to be involved in the rapid progression of anemia in this malnourished patient after bariatric surgery.     

Parvovirus B19 associated neutropenia. Treatment with Rh G-CSF

In a 39-year-old patient under follow-up for metastatic adenocarcinoma of the colon, a post-operative fever and a profound neutropenia occurred during hospitalization. A diagnosis of primary infection with parvovirus B-19 was made in view of the association of reticulocytopenia, together with anti-B19 IgM antibodies and positive serum results for viral DNA. The granulocytic lineage appeared to be normal on bone-marrow smears, and anti PMN autoantibodies were not found. Rh G-CSF therapy resulted in a sharp increase in the PMN count. Although the pathophysiology of B19-associated neutropenia remains unclear, Rh G-CSF seems to be effective in this disorder.     

Multiple small pulmonary emboli associated with transient antiphospholipid syndrome in human Parvovirus B19 infection

Antiphospholipid antibodies (aPL) have been reported to occur in several conditions other than antiphospholipid syndrome, including infections. We herein report the case of a 21-year-old Japanese woman with Parvovirus B19 infection, who developed multiple pulmonary emboli associated with aPL, a lupus anticoagulant and IgM anticardiolipin antibody. Eight weeks later, antiphospholipid antibodies spontaneously disappeared and normal pulmonary flow was observed. Considering the high prevalence of Parvovirus B19 infection, we should be aware of thrombosis associated with transient aPL antibodies in this infectious disease.     

Screening for Human Parvovirus B19 Infection in Egyptian Family Replacement Blood Donors

Up till now, screening for human parvovirus B19 is not routine in national Egyptian blood bank strategy. Blood samples were collected from 500 healthy blood donors within the age range from 18 to 45 years old attending the blood bank of Suez Canal University Hospital, Ismailia, Egypt. Sera were separated and stored at − 20 °C. Serum samples were screened for anti-human parvovirus B19 IgM and IgG antibodies and B19 genome using ELISA and real-time PCR respectively. Frequency of B19 IgM and B19 IgG antibodies was 6.20%, and 80.20% respectively, and the prevalence of B19 genome was 3.00%. There is a high frequency of human parvovirus B19 among Egyptian blood donors; therefore, serological screening for B19 is warranted.     

Parvovirus B19-induced multisystem disease simulating systemic vasculitis in a young child

Parvovirus B19 mostly presents as a transient viral illness or as pure red cell aplasia. However, this virus can sometimes cause an illness that may pose diagnostic difficulties. We describe one such patient who had clinical features simulating a vasculitic disorder secondary to parvovirus B19 infection.     

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.     

Parvovirus B19-related chronic monoarthritis: immunohistochemical detection of virus-positive lymphocytes within the synovial tissue compartment: Two reported cases

Apart from systemic symptoms of viral infection parvovirus B19, the infectious agent in erythema infectiosum, can lead to mainly self-limited acute and chronic arthropathy. Because mild subclinical features of the disease can be easily overlooked, joint affections might appear as isolated symptoms. We here report two cases of chronic monoarthritic symptoms of unknown origin, where immunohistochemical detection of B19-positive lymphocytic cells in the synovial tissue led to the diagnosis of B19 arthropathy. In conclusion, respective virus diagnostics should be considered even in chronic monosymptomatic arthritic lesions. The pathology of B19 arthropathy seems to be due to direct virus infection of cells within the synovia.     

福建省B19微小病毒感染的病原学证据

应用套式PCR方法，对44份与B19微小病毒感染症相关的病人血清标本进行检测，其中5份血清标本和扩增产物合有B19病毒的104bpDNA生段，根据B19病毒基因组DNA核苷酸序列分析资料，使用HaeⅢ限制性内切酶切PCR扩增产物，结果产生81和23bp两段DNA，与序列分析结果一致，证实5例患者为B19病毒感染者，从病原学上支持了不久前我们使用血清学方法发现福建省B19病毒感染的报道。     

Hb Sun Prairie: A rare cause of chronic hemolysis in an Indian patient

Haemolytic anaemia is a commonly encountered condition in clinical haematology practise. Dissecting the aetiology of haemolytic anaemia is of paramount importance for appropriate management. We describe a 29-years-old lady of Indian origin, who presented with fatigue and recurrent jaundice for 2 years. Examination revealed pallor, mild icterus, and splenomegaly. Blood tests showed anaemia, reticulocytosis, indirecthyperbilirubinemia, and high serum lactate dehydrogenase, consistent with haemolytic anaemia. Peripheral smear showed severely microcytic hypochromic red cells and polychromasia. Heinz bodies and inclusion bodies were seen with supravital staining. Haemoglobin high pressure liquid chromatography showed low HbA2 and normal HbF. Work-up for iron deficiency was negative. Polymerase chain reaction of the genomic DNA failed to identify common deletions in the HBA genes. Sangers sequencing of HBA2 gene revealed a homozygous missense mutation NM_000517.6: c.391G > C (p.Ala131Pro) leading to a highly unstable hemoglobin, Hb Sun Prairie. Mother was heterozygous for the same mutation, and father was unavailable for genetic testing. We highlight the role of sangers sequencing in unravelling the underlying aetiology of haemolytic anaemia. Pathophysiology and existing literature of Hb Sun Prairie has been discussed.     

A Coincidental Discovery of a New Stable Variant (Hb Hachioji or HBB: c.187C>T) in a Patient with Chronic Hemolytic Anemia of Unexplained Origin

We report a new hemoglobin (Hb) variant, Hb Hachioji (HBB: c.187C>T), which was detected in a 32-year-old male with hemolytic anemia. The proband had undergone splenectomy in his childhood after being diagnosed with hereditary spherocytosis (HS) with no clinical improvement. A recent study showed that Heinz bodies were frequently observed in his red cells, however, no abnormal band was separated by isoelectric focusing (IEF), and the isopropanol (instability) test was negative. Direct sequencing revealed that the proband was a heterozygous carrier of a novel mutation (GCT>GTT) at codon 62 of the β-globin gene, leading to an alanine to valine substitution. This variant was named Hb Hachioji. Characterization at the mRNA level by cDNA sequencing detected β^Hachioji mRNA, as well as β^A mRNA. Subsequently, study of the proband’s family indicated that his father was a carrier of this Hb variant, although unexpectedly, the father was asymptomatic and clinically healthy. Oxygen affinity measurement of total Hb showed no alteration in the P₅₀ and oxygen equilibrium curve. The presence of Hb Hachioji was confirmed by mass spectrometry (MS). Hb Hachioji comprised approximately 50.0% of the total Hb and was a stable variant. The phenotypic discrepancy between these two carriers suggests that Hb Hachioji may not be associated with the hemolytic involvement in the proband. P4.2Nippon, which is the primary cause of most cases of Japanese HS, was absent in the proband’s parents. The coexistence of glucose-6-phosphate dehydrogenase (G6PD) deficiency was ruled out. Thus, the cause of hemolytic involvement in this patient remains unclear.     

Clinical and hematological study for Parvovirus b19 infection in children with acute leukemia

The role of Parvovirus B19 in acute leukemia is under debate. This study aimed to detect parvovirus B19 DNA together with its antibodies in the sera of children with recent acute leukemia and those with acute leukemia receiving chemotherapy to clarify the contribution of this infection to changes observed in hematological and clinical presentations in these populations. Two groups were included: Group I comprised 45 children with acute leukemia receiving chemotherapy and Group II comprised 40 children with recently diagnosed acute leukemia. Serum parvovirus B19 IgG and IgM were investigated by enzyme-linked immunosorbant assay and the virus DNA was sought by polymerase chain reaction assay. Viral DNA was found in 22.2% of Group I patients and in 45% of Group II patients. Hemoglobin levels were significantly reduced in patients with recent infection, accompanied by statistically significant lymphocytosis in Group I patients. Group II patients with recent infection had marked neutropenia with lymphocytosis and thrombocytopenia. There was statistically significant lymphadenopathy and hepatosplenomegaly in patients with recent infection in both groups. Parvovirus B19 infection is an important cause of cytopenia in children with acute leukemia both when recently diagnosed and receiving chemotherapy. This can affect the schedule of chemotherapy. Moreover, the presence of Parvovirus B19 is associated with marked lymphadenopathy and hepatosplenomegaly.     

Human parvovirus B19 infection mimicking systemic lupus erythematosus

Although several recent reports have discussed the similarities between human parvovirus B19 (HPV-B19) infection and systemic lupus erythematosus (SLE), the relationship between these conditions has not been established owing to the small number of patients investigated. In 1998–1999, an outbreak of Erythema infectiosum occurred close to our hospital, enabling us to investigate the clinical, hematological, and serological findings, including serum complement and antinuclear antibodies (ANA), in 22 patients with acute HPV-B19 infection. The principal symptoms included rash (86.3%), edema (59%), arthralgia (45.4%) and fever (31.8%). Lymphadenopathy was seen in three of the 22 cases. The laboratory findings showed high incidences of leukopenia (50%), hypocomplementemia (95%), and ANA (64.7%). At the time of disease onset, patients with acute HPV-B19 infection presented with features which were similar to those of SLE. The possibility of HPV-B19 infection should therefore be considered in patients presenting with SLE-like features. Received: January 18, 2001 / Accepted: April 19, 2001