Aplastic Crisis Research Articles

Stroke in a cohort of patients with homozygous sickle cell disease

Strokes occurred in 17 of 310 children with homozygous sickle cell disease who were followed from birth, representing an incidence of 7.8% by the age of 14 years. Two children had subarachnoid hemorrhage, one having resolution of symptoms after aneurysm surgery and another dying of a presumed second hemorrhage 14 days later. The remaining 15 strokes were presumed to be cerebral infarction, although autopsy, angiographic, or computed tomographic evidence was available in only 8 children. There were 6 deaths, 2 in the acute event and 4 after recurrence, which occurred in 6 (46%) of 13 patients who survived the initial episode. There were 10 recurrent episodes at a median interval of 9 months after the initial event. Steady-state hematologic data revealed significantly higher leukocyte counts than in control subjects without strokes at age 1 year and in the last study preceding the stroke. The initial stroke coincided with an acutely lowered hemoglobin value in 5 patients (3 aplastic crises, 1 acute splenic sequestration, 1 probable pulmonary sequestration) and with painful crises in another 7 patients. We conclude that a high leukocyte count and an acute decrease of hemoglobin are risk factors for stroke in patients with homozygous sickle cell disease.

Immunohistological detection of human parvovirus B19 in formalin-fixed, paraffin-embedded tissues.

Human parvovirus B19 is a cause of aplastic crises in patients with haemolytic anaemias, prolonged bone marrow failure in the immunosuppressed, and fetal death secondary to non-immune hydrops. The immunohistological detection of parvovirus B19 in formalin-fixed, paraffin-embedded tissues has not previously been reported, and definitive diagnosis of infection in such specimens has relied on the use of specialized DNA hybridization and amplification techniques. A new monoclonal antibody to B19 capsid proteins, R92F6, was found to be capable of labelling infected cells in paraffin-embedded tissues from all 19 cases of parvovirus-related fetal hydrops tested, and in bone marrow from a child with congenital immunodeficiency and chronic parvovirus infection. Viral antigen was detected both in cytoplasmic and in nuclear distributions using the alkaline phosphatase anti-alkaline phosphatase (APAAP) technique without preceding proteolytic digestion. The viral epitope recognized appears to be highly conserved, as specimens were obtained over a 13-year period from widely spaced locations in the U.K. Antibody R92F6 should facilitate rapid diagnosis of parvovirus B19 infection in routinely processed and archival specimens.

B19 evolving picture of disease

Parvovirus B19 first came to light in plasma from healthy blood donors and it was several years before it was associated with any disease at all. The wide spectrum of illness now attributed to B19 includes Fifths Disease of childhood, aplastic anaemia, arthritis and hydrops fetalis. Two pathogenic mechanisms are responsible. Immune complexes which circulate in very large amounts at the height of acute infection produce the rash and arthritis which characterise epidemics of disease in school children and young adults. The exquisite tissue trophism of the virus targets cells (probably pronormoblasts) of the erythroid lineage. Virus replication is dependent upon host cell turnover and is greatly increased in patients with haemolytic anaemia and in these patients the virus induced arrest of erythropoeisis quickly translates into aplastic crisis. The stem cells appear to be insusceptible to infection and these patients recover rapidly and completely as soon as antibody appear and virus is cleared from the circulation. In pregnancy B19 may cross the placenta and produce mid-trimester hydrops fetalis. Fetal loss has also been attributed to infection early in pregnancy and there an; hints of myocarditis as a specific feature of B19 infection of the infant. The latest addition to the spectrum of parvovirus related disease occurs in immune compromised individuals where chronic viraemia is associated with chronic aplastic anaemia and/or thrombocytopenia. As integration of viral DNA is the first step in replication of all parvoviruses these clinical findings raise the possibility that they are due to reactivation rather than primary infection. It seems that the clinical spectrum of B19 infection is not yet completely unfolded with its many diverse streams of interest.

Parvovirus B19 infection and bone marrow transplantation.

Parvovirus B19 lytically infects erythroid progenitor cells and thereby causes cessation of erythropoiesis in infected individuals. Anemia develops only if red cell turnover is increased, as in patients with chronic hemolysis (transient aplastic crisis). In addition to transient marrow failure, B19 can cause chronic anemia and, rarely, pancytopenia in immunodeficient patients who are not able to mount an adequate immune response to clear the virus. Bone marrow transplantation, although causing significant immunosuppression, is rarely complicated by symptomatic B19 infection. This is probably due to effective passive immunotherapy by immunoglobulin infusions immediately after transplantation and early reconstitution of antibody responses after uncomplicated transplantation.

Acute parvovirus B19 infection mimicking myelodysplastic syndrome of the bone marrow

A 36-year-old, previously healthy woman was referred to our institution with pancytopenia and splenomegaly for suspected acute leukemia. Bone marrow aspiration showed marked dysplastic changes, excess of blasts, and only spurious red blood cell precursors. Action was taken to prepare allogeneic bone marrow transplantation from an HLA identical sibling for myelodysplastic syndrome. Repeat cytological examination of the bone marrow revealed striking hyperplasia of the red cell line with presence of abnormal giant proerythroblasts. Acute parvovirus B19 infection was suspected and confirmed by detection of anti-B19 IgM and B19 DNA. The underlying disease for this transient aplastic crisis was a formerly unknown hereditary spherocytosis.

Aplastic crisis due to extensive bone marrow necrosis and human parvovirus infection in sickle cell disease

Aplastic crisis due to extensive bone marrow necrosis and human parvovirus infection in sickle cell disease

Supplementation of patients with homozygous sickle cell disease with zinc,α-tocopherol, vitamin C, soybean oil, and fish oil

Thirteen patients (aged 0.7-17.9 y) with homozygous sickle cell disease were supplemented with alpha-tocopherol, vitamin C, zinc, and soybean oil (suppl 1; for 8 mo) and alpha-tocopherol, vitamin C, and fish oil (suppl 2; for 7 mo). Urinary zinc (suppl 1), plasma vitamin C, plasma cholesterol ester and erythrocyte (RBC) omega 3 fatty acids (suppl 2), and plasma and RBC alpha-tocopherol (suppl 1 and 2) increased. Suppl 1 decreased irreversibly sickled cells by 37.5%, decreased RBC protoporphyrin and urinary porphyrins, and increased the RBC total fatty acid-cholesterol ratio. Suppl 2 decreased plasma triglycerides, further increased the RBC alpha-tocopherol, moderately increased the RBC double-bond index, but decreased the RBC total fatty acid-cholesterol ratio. Zinc, copper, and porphyrins showed prolonged changes. The supplements did not change hemoglobin concentrations, RBC age (reticulocytes, polyamines), or number of aplastic and vasoocclusive crises. Zinc reduces irreversibly sickled cells. Augmentation of RBC antioxidant status by alpha-tocopherol and vitamin C and incorporation of omega 3 fatty acids into RBCs do not affect hemolytic component. Effects on vasoocclusive component are unclear.

Self-assembled B19 parvovirus capsids, produced in a baculovirus system, are antigenically and immunogenically similar to native virions.

B19 parvovirus is pathogenic in humans, causing fifth disease, transient aplastic crisis, some cases of hydrops fetalis, and acquired pure red cell aplasia. Efforts to develop serologic assays and vaccine development have been hampered by the virus's extreme tropism for human bone marrow and the absence of a convenient culture system. We constructed recombinants containing either the major (VP2) or minor (VP1) structural proteins of B19 in a baculovirus-based plasmid, from which the polyhedrin gene had been deleted; these recombinant plasmids were used to generate recombinant infectious baculovirus. Subsequent infection of insect cells in vitro resulted in high-level expression of either B19VP1 or VP2. Parvovirus capsids were obtained by self-assembly in cell cultures coinfected with either VP1- and VP2-containing baculoviruses or, surprisingly, VP2-containing baculoviruses alone. Empty B19 capsids composed of VP1 and VP2 could replace serum virus as a source of antigen in a conventional immunoassay for detection of either IgG or IgM antiparvovirus antibodies in human serum. Immunization of rabbits with capsids composed of VP1 and VP2 resulted in production of antisera that recognized serum parvovirus on immunoblot and neutralized parvovirus infectivity for human erythroid progenitor cells. Baculovirus-derived parvovirus antigen can substitute for scarce viral antigen in immunoassays and should be suitable as a human vaccine.

Neutralizing activity of immunoglobulin preparation against erythropoietic suppression of human parvovirus

American Journal of HematologyVolume 37, Issue 1 p. 68-68 Letter to the EditorFree Access Neutralizing activity of immunoglobulin preparation against erythropoietic suppression of human parvovirus Masuhiro Takahashi, Masuhiro Takahashi First Department of Internal Medicine Niigata University, School of Medicine 1-754 Asahimachi, Niigata 951 JapanSearch for more papers by this authorTadashi Koikem, Tadashi Koikem First Department of Internal Medicine Niigata University, School of Medicine 1-754 Asahimachi, Niigata 951 JapanSearch for more papers by this authorYoshiaki Moriyama, Yoshiaki Moriyama First Department of Internal Medicine Niigata University, School of Medicine 1-754 Asahimachi, Niigata 951 JapanSearch for more papers by this authorAkira Shibata, Akira Shibata First Department of Internal Medicine Niigata University, School of Medicine 1-754 Asahimachi, Niigata 951 JapanSearch for more papers by this author Masuhiro Takahashi, Masuhiro Takahashi First Department of Internal Medicine Niigata University, School of Medicine 1-754 Asahimachi, Niigata 951 JapanSearch for more papers by this authorTadashi Koikem, Tadashi Koikem First Department of Internal Medicine Niigata University, School of Medicine 1-754 Asahimachi, Niigata 951 JapanSearch for more papers by this authorYoshiaki Moriyama, Yoshiaki Moriyama First Department of Internal Medicine Niigata University, School of Medicine 1-754 Asahimachi, Niigata 951 JapanSearch for more papers by this authorAkira Shibata, Akira Shibata First Department of Internal Medicine Niigata University, School of Medicine 1-754 Asahimachi, Niigata 951 JapanSearch for more papers by this author First published: May 1991 https://doi.org/10.1002/ajh.2830370124Citations: 15AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Rao KRP, Patel AR, Anderson MJ, Hodgson J, Jones SE, Pattison JR: Infection with parvovirus-like virus and aplastic crisis in chronic hemolytic anemia. Ann Intern Med 98: 930– 932, 1983. 2 Kurtzman GJ, Ozawa K, Cohen B, Hanson G, Oseas R, Young NS: Chronic bone marrow failure due to persistent B 19 parvovirus infection. N Engl J Med 317: 289– 294, 1987. 3 Kurtzman GJ, Cohen B, Meyers P, Amunullah A, Young NS: Persistent B 19 parvovirus infection as a cause of severe chronic anemia in children with acute lymphocytic leukaemia. Lancet 2: 1159– 1162, 1988. 4 Takahashi M, Shibata A, Takai K, Sanada M: Anemia caused by parvovirus in an adult patient with acute lymphoblastic leukemia in complete remission. Eur J Haematol, (in press). 5 Hamon MD, Newland AC, Anderson MJ: Severe aplastic anemia after parvovirus infection in the absence of underlying haemolytic anaemia. J Clin Pathol 41: 1242, 1988. 6 Takahashi M, Koike T, Moriyama Y, Shibata A, Koike R, Sanada M, Tsukada T: Inhibition of erythropoiesis by human parvovirus-containing serum from a patient with hereditary spherocytosis in aplastic crisis. Scand J Haematol 37: 118– 124, 1986. Citing Literature Volume37, Issue1May 1991Pages 68-68 ReferencesRelatedInformation

Recent advances in pediatric infectious disease and their impact on dermatology

The past five years have seen numerous advances in the field of pediatric infectious diseases, and many of these have a substantial impact on the practice of dermatology. We review some of these advances and discuss their implications on etiology, diagnosis, therapy, and complications of some relatively common conditions, The etiologic agent of exanthum subitum (roseola infantum) has been clearly implicated as a herpesvirus-6. Although in the classically described situation high fever in a young child is followed by defervescence and rash, two new scenarios have been described associated with this virus. The first is fever without rash and the second is rash without fever. The etiologic agent of erythema infectiosum (“slapped cheek”) has been shown to be a human parvovirus B19. The virus has also been associated with aplastic crises (in hemoglobinopathies), hydrops fetalis, and a syndrome of subacute arthralgias in women. The etiologic agent in cat-scratch disease has recently been shown to be a small pleomorphic bacillus that also can produce pyogenic granuloma-like lesions in patients with acquired immunodeficiency syndrome. The number of cases of congenital syphilis, particularly in large cities, is increasing tremendously. Many of these infants have received no prenatal care because of drug abuse problems in their parents. Finally, we describe the changing etiology of impetigo that is predominantly associated with Staphylococcus aureus. We further describe the growing resistance to erythromycin and several new erythromycin drug-drug interactions.

DEPARTMENT OF CORRECTIONS

In the article on "Aplastic Crisis" published in the November 1990 issue of Pediatrics in Review, the second sentence of the final paragraph in the middle column of page 144 should read as follows: "IgM usually is detectable for 1 to 2 months and serves as a marker of recent infection."

Aplastic crisis induced by human parvovirus B19 in family outbreaks

Aplastic crisis induced by human parvovirus B19 in family outbreaks

A Family with Hereditary Spherocytosis, Which Was Found in an Aplastic Crisis due to Human Parvovirus B19 Infection

A Family with Hereditary Spherocytosis, Which Was Found in an Aplastic Crisis 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

To determine the role of B19 parvovirus in red cell aplasia of patients infected with human immunodeficiency virus type 1 (HIV-1). 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. Government medical referral center, and university and private hospitals. Seven patients with pure red cell aplasia and serologic evidence of infection with HIV-1. 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. 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.

Parvovirus B19-Induced Perturbation of Human Megakaryocytopoiesis In Vitro

Parvovirus B19 infection leads to transient aplastic crises in individuals with chronic hemolytic anemias or immunodeficiency states. An additional unexplained sequela of B19 infection is thrombocytopenia. Because B19 is known to have a remarkable tropism for human erythropoietic elements, and is not known to replicate in nonerythroid cells, the etiology of this thrombocytopenia is uncertain. We sought to define the pathobiology of B19-associated thrombocytopenia by examining the role of B19 on in vitro megakaryocytopoiesis. B19 infection of normal human bone marrow cells significantly suppressed megakaryocyte (MK) colony formation compared with mock-infected cells. No such inhibition was observed with a nonpathogenic human parvovirus, the adeno-associated virus 2 (AAV). The B19-MK cell interaction was also studied at the molecular level. Whereas low-density bone marrow cells containing erythroid precursor cells supported B19 DNA replication, no viral DNA replication was observed in B19-infected MK-enriched fractions as determined by the presence of viral DNA replicative intermediates on Southern blots. However, analysis of total cytoplasmic RNA isolated from B19-infected MK fractions showed a low-level expression of the B19 genome as detected by quantitative RNA dot blots as well as by Northern analysis. Furthermore, a frame-shift mutation in a recombinant AAV-B19 hybrid genome segment that encodes the viral nonstructural (NS1) protein significantly reduced the observed inhibition of MK colony formation. These studies indicate tissue-tropism of B19 beyond the erythroid progenitor cell, and lend support to the hypothesis that B19 genome expression may be toxic to cell populations that are nonpermissive for viral DNA replication.

Parvovirus B19-induced perturbation of human megakaryocytopoiesis in vitro

Parvovirus B19 infection leads to transient aplastic crises in individuals with chronic hemolytic anemias or immunodeficiency states. An additional unexplained sequela of B19 infection is thrombocytopenia. Because B19 is known to have a remarkable tropism for human erythropoietic elements, and is not known to replicate in nonerythroid cells, the etiology of this thrombocytopenia is uncertain. We sought to define the pathobiology of B19-associated thrombocytopenia by examining the role of B19 on in vitro megakaryocytopoiesis. B19 infection of normal human bone marrow cells significantly suppressed megakaryocyte (MK) colony formation compared with mock-infected cells. No such inhibition was observed with a nonpathogenic human parvovirus, the adeno-associated virus 2 (AAV). The B19-MK cell interaction was also studied at the molecular level. Whereas low-density bone marrow cells containing erythroid precursor cells supported B19 DNA replication, no viral DNA replication was observed in B19-infected MK-enriched fractions as determined by the presence of viral DNA replicative intermediates on Southern blots. However, analysis of total cytoplasmic RNA isolated from B19-infected MK fractions showed a low-level expression of the B19 genome as detected by quantitative RNA dot blots as well as by Northern analysis. Furthermore, a frame-shift mutation in a recombinant AAV-B19 hybrid genome segment that encodes the viral nonstructural (NS1) protein significantly reduced the observed inhibition of MK colony formation. These studies indicate tissue- tropism of B19 beyond the erythroid progenitor cell, and lend support to the hypothesis that B19 genome expression may be toxic to cell populations that are nonpermissive for viral DNA replication.

Aplastic Crisis

Red blood cell aplasia in pediatric patients who have chronic hemolysis is associated most frequently with B19 infection. Although this entity is usually recognized easily, other red cell hypoplastic anemias, such as TEC and Diamond-Blackfan anemia, must be considered as part of the differential diagnosis. Although usually a transient event, an aplastic crisis has the potential for significant morbidity. The patient usually can be supported through the episode without incident with the judicious use of erythrocyte transfusions. The recognition of the infectious nature of the event is important for an understanding of the clinical manifestation, course of illness, and need for isolation. Several questions remain unanswered regarding the pathogenesis and treatment of this disorder. Could the use of intravenous gamma-globulin prove effective in treating select cases of B19-induced red cell aplasia? Are there effective measures to prevent B19 infection in children at risk for significant morbidity from such infection? There is interest in development of a vaccine to B19, and children with hereditary hemolytic anemias represent a potential target group for its use. Are there other viruses that cause red cell aplasia, especially in the case of TEC? It is hoped that current research will provide the answers for more effective treatment and possible prevention of these aplastic crises.

B19 parvovirus infection causing aplastic crisis in 3 out of 5 family members with hereditary spherocytosis

B19 parvovirus infection is a principal cause of transient bone marrow suppression in patients with chronic haemolytic anaemias. Acute infection is described in a family of five individuals with hereditary spherocytosis; three of them developed marked hypoplastic anaemia.

Down Syndrome Complicated by Hemoglobin S/Beta+ Thalassemia

The chance occurrence of Down syndrome and sickle cell disease is an extremely rare event. The patient presented in this article is the only reported case, based on medical literature review, of Down syndrome coexisting with sickle cell disease due to hemoglobin S/beta+ thalassemia. He had multiple recurrent aplastic crises and severe psychomotor and growth retardation. The physiologic basis for the atypical manifestations of both of his disorders is the subject of this report.

Manifestations and treatment of human parvovirus B19 infection in immunocompromised patients

We diagnosed infections from human parvovirus B19 in three patients by using dot-blot hybridization and a polymerase chain reaction to detect B19 DNA and using an enzyme immunoassay to detect IgG and IgM to B19. For 5 months a 5-year-old boy with acute lymphoblastic leukemia in remission had anemia without reticulocytes or bone marrow erythrocyte precursors. His serum lacked IgG and IgM to B19 but contained B19 DNA. He received gamma globulin intravenously (0.4 gm/kg/day for 5 days); his viremia promptly cleared and reticulocytosis developed. A 14-year-old boy with acute lymphoblastic leukemia in remission had fever, rash, neutropenia (less than 300 leukocytes/mm3), and a hemophagocytic syndrome lasting 3 weeks. His serum contained IgM to B19 and B19 DNA. Without therapy, IgG to B19 developed; although low levels of B19 DNA persisted, the leukocyte count returned to normal. In a 19-year-old patient with systemic lupus erythematosus and hemolytic anemia, an aplastic crisis lasted 2 weeks. Her serum lacked IgG and IgM to B19 but contained B19 DNA. Without therapy, IgG and IgM to B19 appeared, viremia diminished, and reticulocytosis occurred. These patients illustrate the varied manifestations of chronic B19 infections, the importance of DNA detection for diagnosis, and the possible efficacy of gamma globulin therapy.