Neurologic abnormalities in HTLV-I- and HTLV-II-infected individuals without overt myelopathy.

BACKGROUND: Human T-lymphotropic virus (HTLV) type I is the causative agent of HTLV-associated myelopathy (HAM)/tropical spastic paraparesis, and a number of HAM cases with HTLV-II infection have also been reported. However, despite some reports, it is unclear whether HTLV-I or -II infection is associated with other neurologic manifestations. METHODS: An analysis of medical histories and screening neurologic examinations from a prospective cohort of 153 HTLV-I, 388 HTLV-II, and 810 HTLV-seronegative individuals followed up for means of 11.5, 12.0, and 12.2 years was performed. Participants diagnosed with HAM were excluded. We calculated odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, race or ethnicity, income, educational attainment, body mass index, alcohol and cigarette consumption, injection drug use, diabetes, and hepatitis C virus status, using generalized estimating equations for repeated measures. RESULTS: HTLV-I and -II participants were more likely than seronegative participants to have leg weakness (ORs 1.67 [95% CI 1.28-2.18] and 1.44 [1.16-1.78]), impaired tandem gait (ORs 1.25 [95% CI 1.07-1.47] and 1.45 [1.27-1.64]), Babinski sign (ORs 1.54 [95% CI 1.13-2.08] and 1.51 [1.18-1.93]), impaired vibration sense (ORs 1.16 [95% CI 1.01-1.33] and 1.27 [1.14-1.42]), and urinary incontinence (ORs 1.45 [95% CI 1.23-1.72] and 1.70 [1.50-1.93]). For both HTLV-I and -II participants, higher odds of sensory neuropathy by monofilament examination were no longer significant after adjustment for confounding. CONCLUSIONS: These results provide strong evidence that human T-lymphotropic virus (HTLV)-I and -II are associated with a spectrum of predominantly motor abnormalities in patients without overt HTLV-associated myelopathy. Further investigation of the clinical course and etiology of these abnormalities is warranted.

Prevalence and clinical features of HTLV neurologic disease in the HTLV Outcomes Study.

BACKGROUND: Almost 20 years after its discovery, the prevalence and clinical course of human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM, also known as tropical spastic paraparesis [TSP]) remain poorly defined. Whereas the causative association of HTLV-I and HAM/TSP is generally recognized, controversy still surrounds the relationship between HTLV-II and HAM/TSP. METHODS: The HTLV Outcomes Study (HOST-formerly Retrovirus Epidemiology Donor Study [REDS]) is a prospective cohort study including 160 patients with HTLV-I, 405 patients with HTLV-II, and 799 uninfected controls who have been followed every 2 years since 1990-1992. Clinical outcomes are measured by health interviews and examinations, and blood samples are obtained. RESULTS: Six cases of HTLV-I-associated myelopathy (3.7%, 95% CI 1.4 to 8.0) and four cases of HTLV-II myelopathy (1.0%, 95% CI 0.3 to 2.5) have been diagnosed since the formation of the cohort. There have been no cases of HAM/TSP diagnosed among HTLV-negative subjects (0.0%, 95% CI 0.0 to 0.5). Clinical features of the cases include lower extremity hyperreflexia, variably associated with weakness, spasticity, and bladder dysfunction. CONCLUSIONS: Systematic screening of HTLV-infected blood donors reveals a high prevalence of HAM/TSP. The clinical course of HAM/TSP appears highly variable. HTLV-II-associated myelopathy generally presents with milder and more slowly progressive signs and symptoms.

Intravenous immunoglobulin consensus statement.

Intravenous immunoglobulin (IVIG) preparations are a mainstay for a number of disorders that include primary immuno-deficiency, acute inflammatory conditions, hematological disorders, infections, and neuroimmunological disorders. The range of therapeutic activity is attributed to IVIG's myriad action mechanisms. IVIG can interact and bind onto complement factors, which can prevent complement-mediated tissue damage, modulate T-lymphocytes, alter cytokine profiles, and modulate the immune system. These interactions can act alone or in combination to maintain immune balance while preserving homeostasis. A consensus panel was convened in 2000 to evaluate and define new advances in IVIG therapies.

Laboratory abnormalities in former blood donors seropositive for human T-lymphotropic virus types 1 and 2: a prospective analysis.

CONTEXT: The human T-lymphotropic viruses types 1 and 2 (HTLV-1 and HTLV-2) are highly prevalent among injection drug users in the United States. However, the clinical course of infection has not been well characterized. OBJECTIVE: To understand HTLV-1-and HTLV-2-associated laboratory abnormalities, which may provide insights into their underlying pathophysiology. DESIGN: Cohort study. SETTING: Five US blood centers. PARTICIPANTS: A total of 133 HTLV-1-and 332 HTLV-2-seropositive former blood donors and 717 HTLV-seronegative donors followed up prospectively since 1991. MAIN OUTCOME MEASURES: Selected serum chemistry tests and complete blood cell counts were analyzed at enrollment and approximately 2 years later in participants. Repeated-measures analyses were conducted to evaluate the effect of HTLV infection on laboratory measures. RESULTS: Compared with seronegative subjects, HTLV-1-seropositive subjects had 13% higher creatine kinase (P =.02) and slightly elevated lactate dehydrogenase (P =.03) levels at follow-up. The HTLV-2-seropositive participants had 11% higher absolute lymphocyte counts than seronegative subjects (P =.0001). Infection with HTLV-2 also appeared to be associated with slightly higher hemoglobin levels (P =.03) and hematocrit (P =.03) and with lower albumin levels (P =.01). CONCLUSIONS: These results further our understanding of the biological mechanisms underlying HTLV and suggest that HTLV-associated laboratory changes are unlikely to alter clinical evaluation or counseling of otherwise healthy HTLV-infected subjects.

Impact of innovations on transfusion medicine.

The final decade of the last century of the second millennium ad has seen dramatic changes in all aspects of science and health care. In transfusion medicine, the blood supply is the safest it has ever been. Newer refinements and innovations are continuously being researched and implemented to achieve and further enhance safety. Advances in blood conservation, pharmacologic manipulation, engineered blood derivatives, and recombinant growth factors can now provide safer and more effective alternatives to blood transfusions for many patients. This overview highlights selective innovations in transfusion medicine and emphasizes some significant advances that have occurred in blood donor screening, blood component collections and therapy, and laboratory testing. Newer technologies are anticipated that will further enhance the safety of blood and transfusions and potentially augment annually the blood supply on a worldwide basis.

Increased incidence of infectious diseases during prospective follow-up of human T-lymphotropic virus type II- and I-infected blood donors. Retrovirus Epidemiology Donor Study.

BACKGROUND: To determine whether human T-lymphotropic virus type II (HTLV-II) infection is associated with an increased incidence of bacterial infections, we prospectively observed cohorts of HTLV-I- and HTLV-II-infected and seronegative subjects in 5 US cities. METHODS: Of 1340 present and former blood donors examined at enrollment, 1213 (90.5%) were re-examined after approximately 2 years, including 136 HTLV-I- and 337 HTLV-II-seropositive subjects and 740 demographically stratified HTLV-seronegative subjects. All subjects were seronegative for human immunodeficiency virus. Odds ratios (ORs) for incident disease outcomes were adjusted for covariates, including age, sex, race or ethnicity, education, and, if significantly associated with the outcome, blood center, donation type, income, smoking, alcohol intake, and injected drug use. RESULTS: Compared with seronegative status, HTLV-II infection was associated with an increased incidence of bronchitis (OR, 1.81; 95% confidence interval [CI], 1.20-2.75), bladder and/or kidney infection (OR, 1.94; 95% CI, 1.26-2.98), oral herpes infection (OR, 9.54; 95% CI, 3.33-27.32), and a borderline increased incidence of pneumonia (OR, 2.09; 95% CI, 0.92-4.76); HTLV-I infection was associated with an increased incidence of bladder and/or kidney infection (OR, 2.79; 95% CI, 1.63-4.79). One incident case of HTLV-I-positive adult T-cell leukemia was observed (incidence, 348 per 100,000 HTLV-I person-years), and 1 case of HTLV-II-positive tropical spastic paraparesis-HTLV-associated myelopathy was diagnosed (incidence, 140 per 100,000 HTLV-II person-years). CONCLUSIONS: These data support an increased incidence of infectious diseases among otherwise healthy HTLV-II- and HTLV-I-infected subjects. They are also consistent with the lymphoproliferative effects of HTLV-I, and with neuropathic effects of HTLV-I and HTLV-II.

Low prevalence of flower cells in U.S.A. blood donors infected with human T-lymphotrophic virus types I and II.

Large lymphocytes with basophilic cytoplasm and cleaved/cerebriform nuclei called flower cells have been described in human T-lymphotrophic virus type I (HTLV-I) seropositive individuals and may be precursors of adult T-cell leukaemia (ATL). A cohort of 546 HTLV-seropositive former blood donors, 32 HTLV-positive sexual partners of these donors and 799 HTLV-seronegative controls has been followed as part of the Retrovirus Epidemiology Donor Study. A novel methodology was developed to systematically review peripheral blood slides from these subjects for HTLV-related lymphocyte abnormalities, using an algorithm based on morphologic features to objectively identify flower cells. The algorithm included: absence of azurophil granules; nuclear chromatin condensation; cell size >1.5 small lymphocytes; nuclear to cytoplasmic ratio >80%; and presence of nuclear folding/lobulation. Peripheral slides from subjects were screened by a medical technologist blinded to HTLV status. 6.8% of HTLV-I subjects (P = 0.0001 versus seronegatives), 0.9% of HTLV-II subjects and 1.1% of seronegatives were confirmed to have cells classified as flower cells by two haematologists using objective criteria, and blinded to serostatus. Despite the higher prevalence of flower cells in HTLV-I positives, no clinical correlations were found. Longitudinal follow-up may yield higher rates of cellular abnormalities as the sequelae of HTLV infection develop.

Variations in transfusion practice in neonatal intensive care.

OBJECTIVE: To compare the transfusion practices between two neonatal intensive care units (NICUs) to assess the impact of local practice styles on the timing, number, and total volume of packed red cell transfusions in very low birth weight infants. To derive multivariate models to describe practice and to identify potential areas for improvement in the future. METHODOLOGY: We reviewed phlebotomy losses and transfusion rates between two NICUs (A and B) for 270 consecutive admissions of birth weight < 1500 g. We stratified for birth weight and for illness severity by the Score for Neonatal Acute Physiology (SNAP). Measures of short-term outcome were compared. We derived multivariate models to describe and compare the practices in the two NICUs. RESULTS: Patients in NICU A had smaller phlebotomy losses than those in NICU B. A lower percentage of the patients in NICU A (65% vs 87%) received transfusions, but they tended to receive a greater total volume per kg per patient (67 mL/kg vs 54.8 mL/kg). Transfusion timing differed between the NICUs; in NICU A only approximately one-half of their transfusions occurred in the first 2 weeks, whereas in NICU B almost 70% of the transfusions were given in this time period. Multivariate models showed that phlebotomy losses were significantly related to lower gestational age (GA) and higher SNAP. Hospitalization in NICU B resulted in 10.7 cc of additional losses relative to NICU A for a comparable GA and illness severity score. The volume of blood transfused per kilogram of body weight was a function of GA, SNAP, and hospital. Care practices in NICU A added an additional 19 cc of transfused volume in the first 14 days of life, and an additional 26 cc thereafter when adjusted for GA and SNAP. These differences in phlebotomy and transfusion were not associated with differences in the days of oxygen therapy or mechanical ventilation, the oxygen requirement at 28 days, the incidence of chronic lung disease, or the rate of growth by day 28. CONCLUSIONS: We identified significant differences in phlebotomy and transfusion practices between two NICUs. We found no differences in short-term outcome, suggesting that the additional use of blood in one of the NICUs was discretionary rather than necessary. Our multivariate models can be used to characterize and quantify transfusion and phlebotomy practices. By predicting which patients are likely to require multiple transfusions, clinicians can target patients for erythropoietin therapy and identify those patients for whom donor exposure can be reduced by a unit of blood for multiple use. The models may help in monitoring changes in practice as they occur.

Increased prevalence of infectious diseases and other adverse outcomes in human T lymphotropic virus types I- and II-infected blood donors. Retrovirus Epidemiology Donor Study (REDS) Study Group.

Disease associations of human T lymphotropic virus types I and II (HTLV-I and -II) infection were studied in 154 HTLV-I-infected, 387 HTLV-II-infected, and 799 uninfected blood donors. Adjusted odds ratios (ORs) and 99% confidence intervals (CIs) were derived from logistic regression models controlling for demographics and relevant confounders. All subjects were human immunodeficiency virus type 1-seronegative. HTLV-II was significantly associated with a history of pneumonia (OR, 2.6; 99% CI, 1.2-5.3), minor fungal infection (OR, 2.9; 99% CI, 1.2-7.1), and bladder or kidney infection (OR, 1.6; 99% CI, 1.0-2.5) within the past 5 years and with a lifetime history of tuberculosis (OR, 3.9; 99% CI, 1.3-11.6) and arthritis (OR, 1.8; 99% CI, 1.2-2.9). Lymphadenopathy (> or =1 cm) was associated with both HTLV-I (OR, 6.6; 99% CI, 2.2-19.2) and HTLV-II (OR, 2.8; 99% CI, 1.1-7.1) infection, although no case of adult T cell leukemia/lymphoma was diagnosed. Urinary urgency and gait disturbance were associated with both viruses. This new finding of increased prevalence of a variety of infections in HTLV-II-positive donors suggests immunologic impairment.

HTLV-associated myelopathy in a cohort of HTLV-I and HTLV-II-infected blood donors. The REDS investigators.

OBJECTIVE: HTLV-I-associated myelopathy (HAM) is a slowly progressive spastic paraparesis caused by infection with human T-lymphotropic virus type I (HTLV-I). The prevalence of HAM among those infected with HTLV-I is poorly defined, and the association of a similar myelopathy with HTLV-II infection has not been confirmed. DESIGN: Cross-sectional examination of HTLV-I, HTLV-II, and control subjects from the baseline visit of a cohort study. SETTING/ SUBJECTS: Persons testing HTLV seropositive at the time of blood donation at five U.S. blood centers, their seropositive sex partners, and a matched control group of HTLV seronegative blood donors. MEASUREMENTS: HTLV-I and HTLV-II were differentiated by serology and/or polymerase chain reaction. All subjects received systematic neurologic screening examinations. RESULTS: A diagnosis of myelopathy was confirmed in four of 166 HTLV-I subjects (2.4%, 95% confidence interval 0.7%, 6.1%) and in one of 404 HTLV-II subjects (0.25%, 95% confidence interval 0.0%, 0.6%). None of the 798 controls had a similar myelopathy, although one had longstanding typical multiple sclerosis. CONCLUSIONS: Our data also suggest that HAM occurs more frequently among HTLV-I-infected subjects than reported by previous studies. The HTLV-II infected myelopathy patient identified in this cohort, together with three other case reports in the literature, implies a pathogenic role for this human retrovirus. The diagnosis of HTLV-associated myelopathy should be considered in cases of spastic paraparesis or neurogenic bladder when risk factors for HTLV-I or HTLV-II infection are present.

Interleukin-2-activated hematopoietic stem cell transplantation for breast cancer: investigation of dose level with clinical correlates.

Incubating hematopoietic stem cells with IL-2 in vitro for 24 h generates cytotoxic T cells. When infused into patients, these cells may stimulate a graft-versus-tumor (GVT) effect. This clinical trial was designed to assess the ability of IL-2 activated peripheral blood stem cells (PBSC) to reconstitute hematopoiesis, to investigate dose levels and dose-limiting toxicities of IL-2, and to evaluate clinical results and preliminary laboratory effects using a combination of IL-2-activated autologous PBSC followed by IL-2 after transplantation. Sixty-one women with stage II-IV breast cancer were treated. After the administration of carboplatin (200 mg/m2/day for 3 days) and cyclophosphamide (2 g/m2/day for 3 days), patients received autologous PBSC that were cultured in IL-2 for 24 h followed by parenteral administration of IL-2 beginning the day of transplantation. Three escalating doses of IL-2 were evaluated with increasing duration up to 4 weeks. Of the 57 patients receiving IL-2 after tranplantation, 19 patients (33.3%) were unable to complete the planned course of IL-2 therapy due to persistent fevers (n = 9), diarrhea (n = 2), pulmonary capillary leak syndrome (n = 3), development of a rash (n = 1), atrial fibrillation (n = 1), or patient's request (n = 3). One death occurred during hospitalization. Engraftment of neutrophils occurred on day 11.5 (mean; range 8-21 days) and platelets on day 11.7 (mean; range 7-33 days). The maximal tolerated dose of IL-2 was 6 x 10(5) IU/m2/day for 4 weeks. Disease-free survival rates for all stages were comparable to current reports in the literature. Preliminary laboratory evaluations include FACScan analysis of the IL-2 activated PBSC demonstrating an increased percentage of CD3+, CD25+, HLA-DR+ T cells. Phenotypically similar cells were present in peripheral blood samples of patients when tested 15 days after transplantation. This study demonstrates successful engraftment with IL-2-activated PBSC after high-dose chemotherapy for women with stage II-IV breast cancer. The regimen is feasible and, although toxicities are common, they are manageable and correlate with increasing dose and duration of IL-2.

Hematopoietic potential of IL-2-cultured peripheral blood stem cells from breast cancer patients.

Patients receiving autologous transplants for various malignancies generally experience an increased incidence of relapse compared with patients receiving unmanipulated allogeneic transplants. We initiated a protocol for IL-2 activation of peripheral blood stem cells (PBSC) for induction of in vitro and in vivo autologous graft-versus-tumor (GVT) activity in patients with breast cancer. In this study we analyzed the effects of 24 h of IL-2 incubation on the hematopoietic potential of PBSC from these patients. Cells collected by leukapheresis were first cryopreserved and stored in liquid nitrogen, then thawed rapidly and incubated with IL-2 in a serum-free system for 24 h, with samples analyzed before and after incubation. Although there was a significant drop in mononuclear cells (MNC) (from 4.5 to 3.7 x 10(8)/kg) and CD34+ cells (from 12.3 to 7.5 x 10(6)/kg) after 24 h in culture, there was no significant change in colony-forming units (CFU) (from 12.5 to 11.5 x 10(5)/kg). Time to engraftment (neutrophils: < 0.5 x 10(9)/l; platelets: > 20 x 10(9)/l) was comparable to a cohort of similar patients receiving non-cultured PBSC transplants. These results indicate that mobilized frozen/thawed PBSC which have been cultured in IL-2 for 24 h retain adequate potential for hematopoietic reconsistution in this group of patients.