Massive bone marrow necrosis revealing an HIV-related primary bone marrow lymphoma: a diagnostic challenge.

Bone marrow necrosis (BMN) is a condition that can be difficult to diagnose, requiring a hematologist experienced in bone marrow morphology. This diagnostic challenge should alert the clinician of a severe disease or a possible underlying malignancy, either hematological or a solid tumor. We describe the concomitant presence of a primary bone marrow lymphoma (diffuse large B-cell lymphoma-DLBCL), along with an extensive BMN in an HIV patient for the first time in a living individual. HIV infection, BMN and DLBCL presented a multifactorial crossword of molecular events underlying the complex pathophysiology. The exact precipitating pathophysiological events resulting in BMN remain obscure and provide their clear impact for future research. The present report is instructive and also contains a critical review of the literature related to the case presented.

Immature platelet fraction levels in a variety of bone marrow pathologies in South African HIV-positive patients with thrombocytopenia.

OBJECTIVES: Thrombocytopenia is common in HIV-infected individuals and often requires a diagnostic bone marrow examination. Interpretation may, however, be limited due to the multifactorial nature of HIV-associated thrombocytopenia and the difficulty in assessing megakaryocyte function morphologically. The immature platelet fraction (IPF) is a parameter which reportedly reflects megakaryocyte activity, with an IPF >7.7% suggesting increased platelet production. The aim of this study was to correlate the IPF with the bone marrow findings as well as other clinical variables of interest in South African patients with HIV-associated thrombocytopenia. METHODS: Seventy-eight HIV-positive patients with thrombocytopenia were enrolled from the Charlotte Maxeke Johannesburg Academic Hospital. The IPF levels were measured using a Sysmex XE-5000 haematology analyzer and were correlated with bone marrow and other findings. RESULTS: The median IPF was 7.6%, ranging from 1.3 to 44%. It was raised in 78% of patients with immune thrombocytopenia (ITP) (median = 16.3%) and low in 79% of patients with hypocellular marrow (median = 6.5%). Surprisingly, it was highly variable among patients with malignant marrow infiltration and mycobacterial infection of the bone marrow (BMTB) (median = 8.4 and 7.1%, respectively). Multivariate linear regression analysis confirmed a significant independent inverse relationship between the IPF and hypocellular marrow (P < 0.0001), a marginally significant positive association with ITP (P = 0.059), and the absence of any relationship with malignant infiltration or BMTB. The IPF had a significant inverse association with the platelet count (P = 0.0006), but was unrelated to the CD4 count and exposure to anti-retroviral therapy. Unexpectedly, it showed a significant positive association with the HIV viral load (P = 0.005). We speculate this to reflect increased megakaryocyte activity in compensation for accelerated platelet clearance due to HIV-driven platelet activation. CONCLUSION: This study investigates the role of the IPF in HIV-associated thrombocytopenia, and emphasizes the limitations of morphological analysis in determining megakaryocyte function.

Epstein-Barr virus infection associated with bone marrow fibrin-ring granuloma.

We previously reported 24 cases of marrow fibrin-ring granuloma (FRG) encountered in 1 institution and concluded that, contrary to previous studies showing marrow FRG as a diagnostic marker for Q fever, Epstein-Barr virus (EBV) was the most common proven cause of such FRG. The present study characterized patients with EBV-associated marrow FRG. We retrospectively reviewed 17 cases of EBV-associated FRG (43% of 40 cases with marrow FRG) diagnosed by bone marrow biopsy. Patients with EBV-associated hemophagocytic lymphohistiocytosis (5/17 patients) and chronic active EBV infection (4/17) constituted 53% of patients with EBV-associated FRG. Three patients had lymphoma without marrow involvement. All patients except 1 presented first with fever; splenomegaly was the next most common clinical finding (12/17). Cytopenia was observed in the 17 cases: anemia in 16, thrombocytopenia in 9, and leukopenia in 8. Patients with EBV-associated FRG showed lower survival outcomes than did patients without EBV (median, 3.0 vs 11.8 months; P = .009). Patients with bone marrow FRG accompanied by fever require careful evaluation to discern whether active EBV infection is involved because the prognosis is poor.

Multiple organ failure and severe bone marrow dysfunction in two 18 year-old Caucasian patients: Epstein-Barr virus and the haemophagocytic syndrome.

Haemophagocytic lymphohistiocytosis secondary to viral infection is an unusual but well recognised cause of bone marrow dysfunction and multiple organ failure in young patients. Two 18 year-old patients were admitted to a tertiary liver unit with features of acute liver failure, cardio-respiratory collapse and pancytopenia. Serological tests and bone marrow examination with in-situ hybridisation revealed severe acquired haemophagocytic lymphohistiocytosis secondary to acute Epstein-Barr virus infection. Both patients died despite full supportive therapy; the first due to pulmonary haemorrhage, the second due to acute respiratory distress syndrome refractory to high frequency oscillatory ventilation. The clinical spectrum, diagnostic features and current evidence based recommendations for treatment of this condition are explored. The diagnosis of haemophagocytic lymphohistiocytosis should be considered in young patients with marked bone marrow dysfunction and multiple organ failure. Further research into appropriate therapy for patients with acute severe forms of the disease who require intensive organ support is required.

Simultaneous toxicities in a child on multiple anticonvulsants.

It is rare to develop simultaneous toxicities while on anticonvulsants. This article presents a 3(1/2)-year-old child on valproic acid, lamotrigine, and phenytoin who developed simultaneous hepatotoxicity and bone marrow toxicity during a parainfluenza virus type 3 infection. These toxicities resolved after the cessation of anticonvulsants, and her seizures were managed acutely with scheduled lorazepam. This article discusses the possibility that simultaneous use of valproic acid, lamotrigine, and phenytoin could give this combination of toxicities and that concurrent viral infection may increase this risk.

Late-onset fatal Epstein-Barr virus-associated hemophagocytic syndrome following cord blood cell transplantation for adult acute lymphoblastic leukemia.

A 43-year-old Japanese woman underwent unrelated cord blood transplantation (CBT) during remission for acute lymphoblastic leukemia with t(4; 11)(q21;q23). Tacrolimus was given for prophylaxis of graft-versus-host disease. The posttransplantation clinical course was mostly uneventful, and the leukemia remained in remission. Fourteen months after CBT, the patient developed pancytopenia and hepatic dysfunction with persistent high-grade fever. The bone marrow was hypocellular with increased numbers of macrophages and hemophagocytes. The numbers of Epstein-Barr virus (EBV) copies in peripheral blood samples were remarkably high. Although the patient showed complete donor-type hematopoiesis, the titer of viral capsid antigen immunoglobulin G was low, and the results of a test for EBV nuclear antigen were negative. There was no clinical response to the reduction of immunosuppressive therapy or to the administration of high-dose methylprednisolone, human immunoglobulin, or acyclovir. The patient died 466 days after CBT of massive gastrointestinal hemorrhage due to bone marrow and hepatic failures. This case demonstrates that fatal EBV-associated hemophagocytic syndrome (HPS) can occur more than 1 year after CBT. This report is the first of a case of late-onset EBV-associated HPS following CBT.

Impaired in-vitro growth of megakaryocytic colonies derived from CD34 cells of HIV-1-infected patients with active viral replication.

OBJECTIVE: To address the mechanisms of the thrombocytopoietic dysfunction that may follow HIV infection and to compare peripheral blood and bone marrow as sources of CD34 progenitor cells in HIV-infected patients. METHODS: The study used CD34 progenitor cells from 20 previously untreated HIV-infected individuals, 20 HIV-infected individuals treated with antiretroviral therapy and a control group of 20 HIV-uninfected healthy individuals to examine in-vitro megakaryocytopoiesis. There were no hematological abnormalities at baseline in the study groups. CD34 progenitor cells derived from peripheral blood and bone marrow were purified and cultured in medium containing thrombopoietin, interleukin-3, and interleukin-6. HIV-1 plasma viral load was determined by b-DNA technique. Expression of receptors for thrombopoietin, interleukin-3, and interleukin-6 was assessed on CD34 cells by flow cytometry, and numbers of receptors per single cell were calculated by Quanticalc software. RESULTS: Growth of megakaryocytopoietic colony-forming units (CFU-MK) were impaired in untreated HIV-infected individuals despite normal platelet counts. Viral load levels inversely correlate with CFU-MK growth and platelet counts. Antiretroviral drug-treated individuals showed normal megakaryocyte development. Similar results were obtained whether the CD34 progenitor cells derived from peripheral blood or bone marrow. CONCLUSIONS: These findings suggest that megakaryocyte differentiation is impaired before the onset of overt thrombocytopenia in HIV-infected patients and provide evidence for a direct link between viral replication and perturbed megakaryocytopoiesis, which appears to be prevented and/or restored by antiretroviral therapy. The results indicate that peripheral blood represents a suitable source of CD34 hematopoietic progenitors for studies of megakaryocytopoiesis in HIV disease.

Study of bone marrow abnormalities in patients with HIV disease.

AIM: Present work was carried out to study the bone marrow abnormalities in patients with HIV/AIDS and to find their association with peripheral hematological abnormalities. METHODS: Seventy four patients of HIV/AIDS were included in the study. The patients had anemia, leucopenia, thrombocytopenia or pyrexia of unknown origin (PUO) as indications for bone marrow examination. A complete blood count, relevant biochemical investigations, HIV RNA load and CD4 positive lymphocyte counts were done, besides a thorough history and clinical examination. HIV positive patients were classified as those having AIDS and those without AIDS according to NACO criteria. RESULTS: Majority of patients (72.9%) had AIDS. Bone marrow was normocellular in 78.95% of non-AIDS and 74.55% of AIDS, hypocellular in 5.26% of non-AIDS and 7.27% of AIDS, hypercellular in 15.79% of non-AIDS and 18.18 % of AIDS patients. Myelodysplasia was present in 21.05% of non AIDS and 36.46% of AIDS and the most common series affected was granulocytic (15.79% of total in non-AIDS and 30.9% in AIDS). Dysplasia was statistically significantly associated with lower CD4 count (p = 0.031) and anemia (p = 0.013). Myelodysplasia was apparent even before patients developed anemia (16.67%). Increased plasma cells in bone marrow were observed in 57.89% of non-AIDS and 65.45% of AIDS, whereas decreased lymphoid cells were seen in 36.84% of non AIDS and 60.00% of AIDS patients. CONCLUSIONS: Myelodysplasia is found in 32.43% of cases of HIV/AIDS and is more common in AIDS than in non AIDS patients. Granulocytic series is most commonly associated with evidence of dysplasia. Myelodysplasia is more common in patients with CD4 count < 200/microl and in patients with anemia. 54.05% of patients had decreased lymphoid cells in bone marrow and it was more commonly seen in AIDS than in non AIDS.

Bone marrow abnormalities in HIV disease.

Bone marrow abnormalities are frequently observed in HIV infected individuals at all stages of the disease. The most common abnormal finding is dysplasia affecting one or more cell lines. Erythroid dysplasia is the most common type of dysplasia and is recognized in over 50% of HIV infected patients, abnormal granulocytic and megakaryocytic development is encountered in one-third of patients. Plasma cells are strikingly increased in bone marrow of HIV infected patients. It may represent a physiological response to antigenic stimulation by viruses, other infective agents or secondary to dysregulated B-cell proliferation due to HIV. Herein we present a review discussing the various bone marrow abnormalities associated with the HIV disease.

Bone marrow failure associated with herpesvirus 8 infection in a patient undergoing autologous peripheral blood stem cell transplantation.

We describe a fatal case of human herpesvirus 8-associated bone marrow failure in a patient who had received intense treatment for Hodgkin lymphoma and was undergoing bone marrow transplantation. Bone marrow failure was resistant to antiviral treatment and a second infusion of autologous stem cells. Human herpesvirus 8 infection continues to be a major concern in transplant recipients in critical condition.

The cause of death in smallpox: an examination of the pathology record.

OBJECTIVE: Because the cause of death in smallpox remains controversial, the human pathology record was examined. METHODS: The surviving case series of smallpox pathology in humans as well as other review articles from English language journals written during the last 200 years were reviewed. RESULTS: The skin lesions in smallpox developed as a result of viral damage and inflammation. Secondary bacterial infection did not occur until the scabs started shedding. During the papular stage of skin eruption, a secondary viremia caused focal lesions in the pharynx, larynx, tongue, trachea, and esophagus in descending frequency. The virus also caused potentially lethal interstitial pneumonitis as well as tubulointerstitial nephritis. CONCLUSIONS: The cytopathic effects of smallpox cause death. The data did not support previously promulgated theories attributing death to a bacterial sepsis syndrome seeded from the pustules or immune complex deposition. In a future outbreak, antibiotic therapy would minimally influence mortality.

HHV-8 infection in the transplantation setting: a concern only for solid organ transplant patients?

Early epidemiologic studies have shown an increased risk of Kaposi sarcoma (KS) in recipients of solid organ transplants, while KS is exceptional in the setting of autologous and allogeneic bone marrow (BM) and peripheral blood stem cell (PBSC) transplant patients. The recent discovery of human herpesvirus 8 (HHV-8) as the necessary etiologic agent of KS has stimulated studies to assess whether KS is the result of HHV-8 transmission from the donor or of reactivation of a pre-existing HHV-8 infection in the recipient host. An association of HHV-8 infection with lymphoid neoplasias has also been observed, identifying this herpesvirus as a possible causal agent of some Epstein-Barr virus negative post-transplant lymphoproliferative diseases. The recent description of non-neoplastic complications associated with HHV-8 reactivation after autologous PBSC transplantation, has raised concerns about the spectrum of diseases potentially associated with this herpesvirus, even in the setting of BM and or PBSC transplantation. The issue of HHV-8 transmission with the grafts, the problems inherent with the diagnosis and monitoring of active viral infection, the need for prevention and treatment of the clinical consequences of HHV-8 primary infection and reactivation cannot be underestimated, at least in areas endemic for HHV-8 infection.

[Extrahepatic manifestations of HGV infections]. / Manifestacje pozawatrobowe zakazenia HGV w materiale wlasnym.

Many articles concerning possible extrahepatic manifestations of HGV infections were published during the last years. The aim of the study was to evaluate the influence of HGV infection on extrahepatic organs function: the bone marrow and the kidney. 150 children aged from 2 to 15 years, with liver diseases (31 with HGV infection) and 119 without HGV infection (control group) were examined. Medical documentation of children was analyzed with regard to blood morphology and renal parameters. It was pointed that HGV infection was not a cause of extrahepatic organs and systems dysfunction, such as bone marrow and urinary system.

Human herpesvirus-6 and -7 in transplantation.

Infections with the beta-herpesviruses human herpesvirus-6 (HHV-6) and human herpesvirus-7 (HHV-7) are ubiquitous in childhood. The immunosuppression secondary to organ or bone marrow transplantation together with posttransplantation management may favour viral replication and reactivation. HHV-6 and -7 induce immunosuppression by targeting lymphocytes, natural killer cells and monocytes. HHV-6 is commonly detected posttransplantation but variability in definitions of clinical syndromes related to this virus and detection methods have complicated understanding of the clinical relevance of HHV-6 posttransplantation. Clinical symptoms associated with HHV-6 include febrile illness, pneumonitis, hepatitis, encephalitis and bone marrow suppression. However, the majority of HHV-6 infections are asymptomatic. The incidence of HHV-7 infection and its clinical manifestations posttransplantation are even less well characterised. In addition, HHV-6 and HHV-7 are related to CMV disease or acute graft-versus-host disease and, indirectly, to increases in resource utilisation. Based on the potential relevance of these two beta-herpesviruses in transplant recipients, further studies are required to establish their real impact in transplantation. For this, sensitive and specific molecular diagnostic techniques allowing for the rapid detection and quantitation of virus and for the analysis of susceptibility to current antiviral agents are required.

Bone marrow failure associated with human herpesvirus 8 infection after transplantation.

BACKGROUND: Human herpesvirus 8 (HHV-8) infection has been linked to the development of Kaposi's sarcoma and to rare lymphoproliferative disorders. METHODS: We used molecular methods, serologic methods, in situ hybridization, and immunohistochemical analyses to study HHV-8 infection in association with nonmalignant illnesses in three patients after transplantation. RESULTS: Primary HHV-8 infections developed in two patients four months after each received a kidney from the same HHV-8-seropositive cadaveric donor. Seroconversion and viremia occurred coincidentally with disseminated Kaposi's sarcoma in one patient and with an acute syndrome of fever, splenomegaly, cytopenia, and marrow failure with plasmacytosis in the other patient. HHV-8 latent nuclear antigen was present in immature progenitor cells from the aplastic marrow of the latter patient. Identification of the highly variable K1 gene sequence of the HHV-8 genome in both the donor's peripheral-blood cells and the recipients' serum confirmed that transmission had occurred. HHV-8 viremia also occurred after autologous peripheral-blood stem-cell transplantation in an HHV-8-seropositive patient with non-Hodgkin's lymphoma. Reactivation of the infection was associated with the development of fever and marrow aplasia with plasmacytosis; there was no evidence of other infections. HHV-8 transcripts and latent nuclear antigen were expressed in the aplastic marrow but not in two normal marrow samples obtained before transplantation. CONCLUSIONS: Primary HHV-8 infection and reactivation of infection may be associated with nonneoplastic complications in immunosuppressed patients.

Parvovirus B19 infection of bone marrow in systemic sclerosis patients.

OBJECTIVE: To investigate the prevalence of human parvovirus B19 (B19) infection in the bone marrow of systemic sclerosis (SSc) patients. METHODS: Twenty-one consecutive SSc patients and 15 sex- and age-matched subjects without immunological rheumatic diseases were studied for: (i) the presence of circulating anti-B19 antibodies (anti-B19 IgG and IgM type and anti-B19 NS1 IgG) detected by means of standard methodologies, and (ii) B19 genomic sequences in sera and bone marrow biopsy specimens using a nested-PCR technique. RESULTS: The presence of B19 DNA was demonstrated in a significant percentage of bone marrow biopsies from SSc patients (12/21; 57%) and was never detected in the control group (p < 0.01). In no case was the B19 viremia observed, while serum anti-B19 NS1 antibodies, possible markers of B19 persistent infection, were more frequently detected in SSc patients than in controls (33% vs 13%). SSc patients with bone marrow B19 infection showed a shorter mean disease duration than B19-negative patients (5.6 +/- 4.2 vs 12.7 +/- 7.8 yrs; p < 0.01). CONCLUSIONS: This is the first demonstration of bone marrow B19 infection in a significant percentage of SSc patients. The possible etiopathogenetic role of B19 should be verified in a larger patients series and further investigated by means of molecular biology studies.

HHV-6-related secondary graft failure following allogeneic bone marrow transplantation.

We report the case of an 11-year-old boy who underwent allogeneic bone marrow transplantation (BMT) for relapsed acute lymphoblastic leukaemia. Despite adequate engraftment, on day 45 he developed marrow aplasia with haemophagocytosis. HHV-6 was detected in blood and bone marrow by nested PCR. Retrospective testing showed that viraemia had started on day 24. Following therapy with foscarnet and ganciclovir, viral load declined to undetectable levels and his donor marrow recovered contemporaneously. This case suggests that HHV-6 may be a treatable cause of graft failure following BMT and provides clinical and virological evidence for the anti-HHV-6 activity of ganciclovir and foscarnet.