Disseminated sporotrichosis in a patient with hairy cell leukemia treated with amphotericin B and posaconazole.

We describe a case of disseminated Sporothrix schenckii infection in a man with underlying hairy cell leukemia. The immunological defects associated with this malignancy, as well as the management of refractory sporotrichosis are reviewed.

Incidence, risk of infection and survival of hairy cell leukaemia in Denmark.

INTRODUCTION: Few population-based studies exist on incidence, risk of infection and mortality in hairy cell leukaemia (HCL). MATERIAL AND METHODS: We used population-based medical databases to identify 209 patients who were diagnosed with HCL in the period from January 1997 to August 2007 in Denmark. An age- and sex-matched comparison cohort of 2,090 persons was selected from the general population. We computed the incidence of HCL using demographic data. Hospitalizations with pneumonia and bacteraemia were determined from the Danish National Patient Registry. Cox regression analysis was used to estimate the relative risk (RR) of infection and mortality ratios (MRR) adjusting for age, sex and comorbidity. RESULTS: The HCL incidence rates were 1.97 (95% confidence interval 1.51-2.53) and 5.37 (4.57-6.28) per million person-years for women and men, respectively. During a median follow-up of 4.5 years, 48 HCL patients were hospitalized with pneumonia or bacteraemia. The adjusted RR of infection was 8.04 (4.99-12.95) the first year after diagnosis and 1.17 (0.71-1.94) for the remaining follow-up period. The adjusted MRRs were 4.26 (2.61-6.96) and 1.12 (0.75-1.65) the first year after diagnosis and the remaining follow-up period, respectively. CONCLUSION: In the second and subsequent years after HCL diagnosis, the risk of infection and mortality was similar to that of the general population.

A new subtype of human T-cell leukemia virus (HTLV-II) associated with a T-cell variant of hairy cell leukemia.

Human T-cell leukemia virus (HTLV) is a human type-C RNA tumor virus (retrovirus) previously identified in and isolated from several patients with T-cell leukemias or lymphomas. The known virus isolates from the United States and Japan are closely related and are found in adults with an acute malignancy of mature T cells. A related retrovirus has been found in a patient (Mo) with a somewhat different disease (a T-cell variant of relatively benign hairy cell leukemia). Serum from Mo contains antibodies to the major internal core protein (p24) of HTLV. A T-cell line established from the spleen of Mo expresses HTLV antigens. However, HTLV from Mo is significantly different from all previous HTLV isolates in immunological cross-reactivity tests of p24. The usual prototype HTLV isolate is represented as HTLV-I, and the HTLV from Mo is represented as HTLV-II. Individual members of each subgroup may then be identified by subscript initials of the patient [for example, HTLV-I(CR), HTLV-I(MB), and HTLV-II(Mo)].

An unusual presentation of Legionella pneumonia in a returning traveller.

A male patient in his mid-60s presented with a severe pneumonia following return to the UK after travel to Crete. He was diagnosed with Legionnaire's disease (caused by an uncommon serogroup of Legionella pneumophila). He was pancytopenic on admission, and during a long stay on critical care he was diagnosed with a disseminated Aspergillus infection. Bone marrow aspiration revealed an underlying hairy cell leukaemia that undoubtedly contributed to his acute presentation and subsequent invasive fungal infection.

Epstein-Barr virus infections in hairy cell leukemia patients in the presence of complement-dependent neutralizing antibody.

Immune system status was characterized in patients with hairy cell leukemia (HCL) with respect to explaining their chronic or recurrent infections with Epstein-Barr virus. Measures of cellular immune responsiveness for a group of 11 HCL patients were, in general, decreased when expressed as the proportion of tested patients with values less than 2 S.D. below mean values for a group of 17 healthy adults: T-cell enumeration, seven of 13; mitogen responsiveness of phytohemagglutinin, 10 of 11; concanavalin A, 10 of 11; pokeweed mitogen, 10 of 11; B-cell responsiveness by anti-immunoglobulin immunobead stimulation, two of six; responsiveness to streptolysin O antigen, four of seven; mixed-lymphocyte reaction, six of seven; natural killer cell activity, six of eight. Specific immunity to Epstein-Barr virus was measured by complement-independent, antibody-mediated virus neutralization (mean index for HCL patients being 56% of control value) and complement-dependent virus neutralization (98% of control value). We concluded that, in spite of depressed levels of immune responses measured with general, cellular assays, functional levels of complement-dependent virus-neutralizing antibody were present in these HCL patients.

Relationship between human T cell leukemia virus-II and atypical hairy cell leukemia: a serologic study of hairy cell leukemia patients.

Human T cell leukemia virus (HTLV-II) is an infrequently encountered human T cell leukemia virus first isolated from a patient with atypical hairy cell leukemia. Recently, we identified a second patient infected with HTLV-II who had a similar clinical syndrome of atypical hairy cell leukemia associated with peripheral T cell lymphocytosis. HTLV-II was detected by molecular hybridization studies, and more recently, by electron microscopy, in cell lines derived from the patient. Both patients came from the Los Angeles area and had spent several years in Alaska. As opposed to our two patients, 21 patients with more typical cases of hairy cell leukemia were seronegative for HTLV-II. Two additional cases of unusual T cell malignancy linked to HTLV-II have been described by other investigators and bear limited similarity to our index cases. Further studies are necessary to define the spectrum of malignancies linked to HTLV-II and to identify infected individuals for prospective study.

Cross-reacting antibodies to human T cell leukemia virus-I and -II in Japanese patients with hairy cell leukemia.

Sera from 11 Japanese patients with hairy cell leukemia and 4B122, an anti-hairy cell serum produced by the authors, were surveyed by Western blot analyses for cross-reacting antibodies to human T cell leukemia virus (HTLV)-I and -II virions released, respectively, from Lma-66 and Mo-T cell lines. Sera from the majority of the patients showed positive reactions with p15, p19, and/or p24 of HTLV-I and with p21 and/or p22 or HTLV-II. 4B122 was weakly cross-reactive with HTLV-II but not with HTLV-I. These results militate against the involvement of HTLV-I or -II but may implicate a role by a cross-reacting, previously unrecognized retrovirus in the pathogenesis of hairy cell leukemia in Japanese patients.

Transformation of hairy cell leukemia to EBV genome-containing aggressive B cell lymphoma.

Hairy cell leukemia is a preplasmacytic B cell leukemia which is not EBV associated, although elevated titers of Epstein-Barr virus (EBV) antibodies have been seen in this leukemia and chronic lymphocytic leukemia. Hairy cells are not readily susceptible to EBV infection in vitro, even though they are EBV receptor-positive B cells. We have observed a 59-year-old patient who after 9 years of hairy cell leukemia developed a well-differentiated IgG-kappa monoclonal B cell lymphoma without further evidence of hairy cell leukemia. Pathologically, the lymphoma showed plasmacytic differentiation, and in the patient's serum, a 2 g/dl monoclonal IgG-kappa component was present. DNA extracted from the lymphomatous lymph node hybridized with DNA fragments of a reiterated sequence of EBV, IR1. The transformation, with no chemotherapy involved, from a preplasmacytic leukemia into a lymphoplasmacytic lymphoma with monoclonal gammopathy may be related to the entry of EBV into these cells. Studies at the molecular level may help understand mechanisms of malignant transformation or interconversion in lymphoproliferative disorders of the B cell type.

Hairy cell leukemia and human T cell leukemia virus.

HCL is a lymphoproliferative disorder, primarily of B cells. T cell variant HCL is a rare clinical entity, which has a clinical picture similar to that of the common B cell HCL disease. HTLV-II has been isolated from a case of T cell variant HCL. This subtype of HTLV-II-associated disease is indolent in character in comparison to the very aggressive HTLV-I-associated disease. Investigation of the biology and molecular genetics of HTLV is in progress. It is hoped that better understanding of HTLV and the comparative differences between HTLV-I and HTLV-II will provide specific insights into the mechanisms of human leukemogenesis.

Disseminated atypical mycobacterial infection in patients with hairy cell leukemia.

Disseminated atypical mycobacterial infections developed in nine of 186 patients with hairy cell leukemia who were seen over 10 years at the University of Chicago Hospital. Clinically, these patients had symptoms of fever and chills; an infiltrate was usually present on chest radiography. Invasive diagnostic studies, including thoracotomy and laparotomy, were necessary for confirmation of the diagnosis of atypical mycobacteria infection. Confirmatory culture specimens were obtained from lymph nodes, liver, and splenic tissue. Six patients had infections with Mycobacterium kansasii; two with M. avium-intracellulare; and one with M. chelonei. Treatment with multiple anti-tuberculosis drugs was initiated either empirically (six patients); after obtaining pathologic evidence of granuloma or acid-fast bacilli (two patients); or after obtaining a positive culture result (one patient). Five of the nine patients survived the infection and continued taking anti-tuberculosis drugs for total periods of nine months to two years. Awareness of the association between hairy cell leukemia and atypical mycobacteria infection, with early consideration of invasive diagnostic studies, as well as empiric anti-tuberculosis therapy, may prolong the survival time for many patients with hairy cell leukemia.

Lack of evidence of Epstein-Barr virus in hairy cell leukemia and monocytoid B-cell lymphoma.

An association between the Epstein-Barr virus (EBV) and hairy cell leukemia (HCL) has been reported. Due to the similarities between HCL and monocytoid B-cell lymphoma (MBCL), an association between EBV and MBCL has been postulated. To address these issues we studied 27 spleens from cases with HCL and 13 tissue specimens from cases with MBCL from various sites for evidence of EBV DNA and RNA by in situ hybridization. Using a genomic EBV internal repeat probe and an oligonucleotide probe directed against the EBER1 gene, we were unable to identify EBV DNA or RNA, respectively, in the tumor cells of any of the cases. The results of our study suggest that EBV may not be strongly linked with either HCL or MBCL.

Electron microscopical and biochemical investigations on retra viruses in spleen tissue in malignancy.

Simultaneous biochemical and electron microscopical investigations on surgically removed spleens yielded evidence for the presence of reverse transcriptase containing (Retra) virus in two patients with hematological malignancies with spleen involvement. In three other patients with hematological diseases and in one control patient, the spleens were negative in both assays. The results of these combined studies support the view, that retraviruses are present in human malignancies.

Human retroviruses: a common virology.

There are five known human retroviruses: human T-lymphotropic virus-I (HTLV-I), HTLV-II, HTLV-V, human immunodeficiency virus-1 (HIV-1), and HIV-2. These are related to animal lentiviruses. The simian retroviruses, simian T-lymphotropic virus-I (STLV-I) and STLV-III are related closely to HTLV-I and HIV-2 respectively. HTLV-I and HTLV-II and, possibly, HTLV-V are transforming agents that immortalize the CD4 cell. In contrast, HIV-1 and HIV-2 cause this cell to lyse, resulting in immunodeficiency (ID). HIV-1 and HIV-2 cause severe ID resulting in acquired immunodeficiency syndrome (AIDS). In HTLV-I and HTLV-II, ID is less severe and rarely progressive. Both of these retroviruses induce proliferation of CD4 cells. In HTLV-I, this results in acute T cell leukemia and mycosis fungoides (MF) with hypercalcemia. HTLV-V produces a less severe form of MF without hypercalcemia. Associated lymphomas (AL) occur with HTLV-I. HIV-1 and HIV-2 produce AL as well as Kaposi's sarcoma. Both also cause subcortical dementia because they are neurotropic. All human retroviruses appear to be transmitted sexually and by blood. Transfusional AIDS may be almost entirely eliminated by serologic testing of the blood supply, and transfusional lymphoma can be almost entirely eliminated by universal testing for HTLV-I.

Mycobacterium avium-intracellulare infection associated with hairy-cell leukemia.

A 66-year-old man with hairy-cell leukemia was treated successfully with interferon alfa, with normalization of his hematologic parameters. After 2.5 months he became ill again and, following extensive investigation, Mycobacterium avium-intracellulare grew from a bone marrow specimen. Although initiation of quadruple antituberculous chemotherapy resulted in an improvement of his general condition, after two months he started to develop widespread cutaneous and subcutaneous nodules, biopsy of which showed appearances compatible with mycobacterial infection. Over the next two months the skin lesions progressed slowly so erythromycin, to which in vitro testing showed the organism to be sensitive, was added to his therapy. This resulted in a marked improvement of all skin lesions. This case is the first to be reported of disseminated atypical mycobacterial infection in a patient receiving interferon treatment for hairy-cell leukemia.

HTLV-II and human lymphoproliferative disorders.

HTLV-II is a rarely encountered human retrovirus that has been linked to atypical presentations of hairy-cell leukemia, as well as a variety of T-cell malignancies. Recently, HTLV-II prevalence has increased in the United States, particularly in populations of intravenous drug abusers. Comparative study of HTLV-I and HTLV-II has allowed for important insights into the mechanisms of retroviral replication and T-cell transformation.

Disseminated candidiasis caused by four different Candida species.

Fatal disseminated candidiasis developed in a patient with hairy-cell leukemia. Four different Candida species were isolated from multiple sites during hospitalization and from cultures made post mortem.

Hairy cell transformation of human peripheral blood lymphocytes by Coxiella burnetii.

Hairy cell (HC) transformation of human peripheral blood lymphocytes (PBL) by Coxiella burnetii was studied to clarify the significance of persistency of C. burnetii in a hairy cell line (designated "TOL"). TOL cells which exhibited HC characteristics in hairy cell leukemia (HCL) were persistently infected with C. burnetii. Two strains of C. burnetii, our isolate from TOL cells and the original isolate in 1935, the Nine Mile strain from American Type Culture Collection (ATCC, U.S.A), were inoculated to PBL cultures. HC transformation not only by our isolates (87%) but also by Nine Mile strain (100%) was demonstrated in an average of 20 days. The original observation that Coxiella induced HC transformation in vitro was also confirmed in experiments with PBL exposed to C. burnetii in vivo. Spontaneous development of HC were observed in cultures of PBL only from coxiellemic cases (12/24) but not from C. burnetii negative cases (0/57). All HC cell lines (34) as determined by their morphology and cytochemical markers of HC in HCL remained infected with C. burnetii invariably.

[Disseminated Mycobacterium avium infection in three patients with hematologic diseases]. / Dissemineret Mycobacterium avium-infektion hos tre haematologiske patienter.

We report three cases of disseminated Mycobacterium avium complex infection in immunocompromised haematological patients. We conclude that in haematological patients with longlasting fever of unknown cause Mycobacterium avium complex infection should be considered and the relevant cultures from blood and bone marrow should be done.

[Atypical mycobacteria. Disseminated infection in patients with hematologic diseases]. / Atypiske mykobakterier. Dissemineret infektion hos hoematologiske patienter.

During the last decade interest in atypical mycobacteria (AM), especially Mycobacterium avium complex (MAC) has been intense, as a large number of AIDS patients develop disseminated infection with MAC. Disseminated infection has also been reported in other immunocompromised patients, but in much fewer cases. Among haematological diseases hairy cell leukemia (HCL) and chronic myelogenous leukemia (CML) seem to predispose to disseminated AM infection. We review 53 cases of disseminated AM infection in haematological patients reported in the literature, 39 with HCL, ten CML, and four other haematological diseases, and a review of possible treatment is given. The prognosis seems to depend on the course of the underlying haematological disease, and we conclude that early diagnosis and treatment of the infection is of great importance. Blood and bone marrow should therefore be cultivated for mycobacteria in such patients with persistent fever of unknown cause, and in cases with negative cultures and elevated serum values of alkaline phosphatase liver biopsy should be considered.