Identification of Suitable Areas for West Nile Virus Circulation in Tunisia.

West Nile virus (WNV) is a mosquito-transmitted Flavivirus belonging to the Japanese encephalitis antigenic complex of the Flaviviridae family. It is transmitted primarily by the bite of infected mosquitoes, particularly Culex spp. and Aedes/Ochlerotatus spp., which acquire the virus by feeding on viraemic birds. Humans, horses and other mammals are regarded as incidental or dead-end hosts. In the last decades, an increasing number of cases of WNV infection in horses and humans have been notified in the Mediterranean basin. In Tunisia, human cases of WNV-related meningoencephalitis were detected in 1997, 2003, 2007, 2010, 2011 and 2012. Based on the analysis of climatic and environmental conditions found in the locations where human cases have been reported in 2012, the aim of this study was to identify similar areas in Tunisia potentially at risk of disease occurrence. Data related to 85 neuroinvasive West Nile fever (WNF) human cases were georeferenced and a set of environmental and climatic variables (wetlands and humid areas, normalized difference vegetation index (NDVI), temperatures and elevation, migratory bird settlements) were used in the analysis. Areas, ecologically similar to those where human cases were detected, were identified using the Mahalanobis distance statistic. A leave-one-out cross-validation was performed to validate the sensitivity of the model, and 78 of 85 points were correctly classified.

Development of an active risk-based surveillance strategy for avian influenza in Cuba.

The authors designed a risk-based approach to the selection of poultry flocks to be sampled in order to further improve the sensitivity of avian influenza (AI) active surveillance programme in Cuba. The study focused on the western region of Cuba, which harbours nearly 70% of national poultry holdings and comprise several wetlands where migratory waterfowl settle (migratory waterfowl settlements - MWS). The model took into account the potential risk of commercial poultry farms in western Cuba contracting from migratory waterfowl of the orders Anseriformes and Charadriiformes through dispersion for pasturing of migratory birds around the MWS. We computed spatial risk index by geographical analysis with Python scripts in ESRI(®) ArcGIS 10 on data projected in the reference system NAD 1927-UTM17. Farms located closer to MWS had the highest values for the risk indicator pj and in total 31 farms were chosen for targeted surveillance during the risk period. The authors proposed to start active surveillance in the study area 3 weeks after the onset of Anseriformes migration, with additional sampling repeated twice in the same selected poultry farms at 15 days interval (Comin et al., 2012; EFSA, 2008) to cover the whole migration season. In this way, the antibody detectability would be favoured in case of either a posterior AI introduction or enhancement of a previous seroprevalence under the sensitivity level. The model identified the areas with higher risk for AIV introduction from MW, aiming at selecting poultry premises for the application of risk-based surveillance. Given the infrequency of HPAI introduction into domestic poultry populations and the relative paucity of occurrences of LPAI epidemics, the evaluation of the effectiveness of this approach would require its application for several migration seasons to allow the collection of sufficient reliable data.

ANALYSIS OF BIOTIC AND ABIOTIC FACTORS INFLUENCING THE OCCURRENCE OF WEST NILE VIRUS INFECTION IN TUNISIA.

Eco-climatic conditions are often associated with the occurrence of West Nile Disease (WND) cases. Among the complex set of biotic and abiotic factors influencing the emergence and spread of this vector-borne disease, two main variables have been considered to have a great influence on the probability of West Nile Virus (WNV) introduction and circulation in Tunisia: the presence of susceptible bird populations and the existence of geographical areas where the environmental and climatic conditions are more favourable to mosquito multiplications. The aim of this study was to identify and classify the climatic and environmental variables possibly associated with the occurrence of WNVhuman cases in Tunisia. The following environmental and climatic variables have been considered: wetlands and humid areas, Normalised Difference Vegetation Index (NDVI), temperatures and elevation. A preliminary analysis for the characterization of main variables associated with areas with a history of WNV human cases in Tunisia between 1997 and 2011 has been made. This preliminary analysis clearly indicates the closeness to marshes ecosystem, where migratory bird populations are located, as an important risk factor for WNV infection. On the contrary the temperature absolute seems to be not a significant factor in Tunisian epidemiological situation. In relation to NDVI values, more complex considerations should be made.

A geographical information system-based multicriteria evaluation to map areas at risk for Rift Valley fever vector-borne transmission in Italy.

Rift Valley fever (RVF) is a severe mosquito-borne disease that is caused by a Phlebovirus (Bunyaviridae) and affects domestic ruminants and humans. Recently, its distribution widened, threatening Europe. The probability of the introduction and large-scale spread of Rift Valley fever virus (RVFV) in Europe is low, but localized RVF outbreaks may occur in areas where populations of ruminants and potential vectors are present. In this study, we assumed the introduction of the virus into Italy and focused on the risk of vector-borne transmission of RVFV to three main European potential hosts (cattle, sheep and goats). Five main potential mosquito vectors belonging to the Culex and Aedes genera that are present in Italy were identified in a literature review. We first modelled the geographical distribution of these five species based on expert knowledge and using land cover as a proxy of mosquito presence. The mosquito distribution maps were compared with field mosquito collections from Italy to validate the model. Next, the risk of RVFV transmission was modelled using a multicriteria evaluation (MCE) approach, integrating expert knowledge and the results of a literature review on host sensitivity and vector competence, feeding behaviour and abundance. A sensitivity analysis was performed to assess the robustness of the results with respect to expert choices. The resulting maps include (i) five maps of the vector distribution, (ii) a map of suitable areas for vector-borne transmission of RVFV and (iii) a map of the risk of RVFV vector-borne transmission to sensitive hosts given a viral introduction. Good agreement was found between the modelled presence probability and the observed presence or absence of each vector species. The resulting RVF risk map highlighted strong spatial heterogeneity and could be used to target surveillance. In conclusion, the geographical information system (GIS)-based MCE served as a valuable framework and a flexible tool for mapping the areas at risk of a pathogen that is currently absent from a region.

Influence of biotic and abiotic factors on the distribution and abundance of Culicoides imicola and the Obsoletus Complex in Italy.

Culicoides imicola Kieffer (Culicoides, Diptera: Ceratopogonidae) is the principal vector of bluetongue virus (BTV) to ruminant livestock in southern Europe. The secondary potential vectors are Culicoides obsoletus (Meigen) and Culicoides scoticus Downes and Kettle of the Obsoletus Complex, Culicoides pulicaris (Linnaeus) of the Pulicaris Complex and Culicoides dewulfi Goetghebuer of the subgenus Avaritia Fox. Between 2000 and 2004 >38,000 light-trap collections were made for Culicoides across Italy including the islands of Sardinia and Sicily. Mapping of the 100 largest collections of C. imicola and of the Obsoletus Complex showed them to be disjunct overlapping in only 2% of the 200 municipalities selected. For each municipality the average values were calculated for minimum temperature, aridity index, altitude, terrain slope, normalised difference vegetation index (NDVI) and percentage forest cover. A factor analysis identified two principal factors ('biotic' and 'abiotic') and explained 84% of the total variability; a discriminant analysis classified correctly 87.5% of the observations. The results indicate adult populations of C. imicola to occur in more sparsely vegetated habitats that are exposed to full sunlight, whereas species of the Obsoletus Complex favour a more shaded habitat, with increased green leaf density. Heliophily and umbrophily, by shortening or lengthening the respective adult life cycles of these two vectors, will likely impact on the ability of each to transmit BTV and is discussed in the light of the current outbreak of BTV across the Mediterranean Basin.

Allogeneic hematopoietic stem cell transplantation after rituximab-containing myeloablative preparative regimen for acute lymphoblastic leukemia.

We explored the safety and efficacy of rituximab administered in combination with the standard transplant conditioning regimen of cyclophosphamide (Cy) 120 mg/kg and total body irradiation (TBI) 12 Gy for adult patients with acute lymphoblastic leukemia (ALL). Patients were eligible if their disease expressed CD20. Rituximab was administered at 375 mg/m2 weekly for four doses beginning on day -7 of the conditioning regimen. Graft-versus-host-disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Thirty-five patients undergoing matched sibling (n = 23) or unrelated donor (n = 12) transplantation were studied, with a median age of 30 years (range 15-55 years). At 2 years, progression-free survival, treatment-related mortality, and overall survival were 30, 24, and 47%, respectively. There was no delay in engraftment or increased incidence of infection. The cumulative incidence of grade II-IV acute GVHD was 17%, and limited and extensive chronic GVHD was 43% at 2 years. The addition of rituximab to the standard Cy/TBI transplant conditioning regimen in ALL was safe and well tolerated, and there was a suggestion of decreased incidence of acute GVHD when compared to historically reported GVHD rates for this group of patients.

Development of a web-based geographic information system for the epidemiological surveillance of bluetongue in the Balkans and eastern Mediterranean countries.

Bluetongue (BT) is an infectious, non-contagious, arthropod-borne disease transmitted by biting midges. When BT spread throughout the Balkans (affecting Albania, Bosnia-Herzegovina, Bulgaria, Croatia, the Former Yugoslav Republic of Macedonia and Serbia and Montenegro), it caused serious concerns for veterinary authorities in all countries in the eastern Mediterranean. In 2003-2004 a web-based BT geographic information system network was developed and implemented to provide veterinary services with a tool to manage and analyse data on the disease and to exchange information. The system was centralised to ensure there was a common epidemiological surveillance strategy. Spatial and alphanumerical data on the disease were organised in a single relational geographic database. The system was equipped with a number of applications for the display of dynamic maps and data information via the web, with multi-user access for simultaneous queries from additional users.

Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality in haematopoietic transplant recipients. Sirolimus is a macrocyclic triene antibiotic with immunosuppressive, antifungal and antitumour properties, that has activity in the prevention and treatment of acute GVHD. We conducted a phase II trial of sirolimus combined with tacrolimus and methylprednisolone in patients with steroid-resistant cGVHD. Thirty-five patients who developed GVHD after day 100 post-transplant were studied. Six patients had a complete response and 16 a partial response with an overall response rate of 63%. Major adverse events related to the combination of tacrolimus and sirolimus were hyperlipidaemia, renal dysfunction and cytopenias. Four patients had thrombotic microangiopathy (TMA) and 27 (77%) had infectious complications. The median survival for the whole group was 15 months. A significantly better outcome was observed in patients with a platelet count > or = 100 x 10(9)/l, as well as in those with true chronic manifestations of GVHD compared to those with acute GVHD beyond day 100. Controlled trials comparing this approach with alternative strategies to determine which can best achieve the goal of GVHD-free survival are warranted.

Reduced-intensity allogeneic stem cell transplantation in relapsed and refractory Hodgkin's disease: low transplant-related mortality and impact of intensity of conditioning regimen.

A total of 40 patients with relapsed/refractory Hodgkin's disease (HD) underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) from an HLA-identical sibling (n=20) or a matched unrelated donor (n=20). The median age was 31 years (range 18-58). Disease status at allo-SCT was refractory relapse (n=14) or sensitive relapse (n=26). The conditioning regimens were fludarabine-cyclophosphamide+/-antithymocyte globulin (n=14), a less intensive regimen, and fludarabine-melphalan (FM) (n=26), a more intensive one. The two groups had similar prognostic factors. The median time to neutrophil recovery (ie absolute neutrophil count >/=500/microl) was 12 days (range 10-24). The median time to platelet recovery (ie platelet count >/=20 000/microl) was 17 days (range 7-132). Day 100 and cumulative (18-month) transplant-related mortalities (TRMs) were 5 and 22%. Twenty-four patients (60%) are alive (14 in complete remission or complete remission, unconfirmed/uncertain) with a median follow-up of 13 months (4-78). In all, 16 patients expired (TRM n=8, disease progression n=8). FM patients had better overall survival (73 vs 39% at 18 months; P=0.03), and a trend towards better progression-free survival (37 vs 21% at 18 months; P=0.2). RIC allo-SCT is feasible in relapsed/refractory HD patients with a low TRM. The intensity of the preparative regimen affects survival.

The use of a web-based interactive geographical information system for the surveillance of bluetongue in Italy.

Since 2000 Italy has experienced five epidemics of bluetongue, an arthropod-borne disease that affects primarily sheep and asymptomatically cattle, goats and wildlife ruminants. In four years the disease spread through Southern and Central Italy, involving 14 Italian regions out of 20. To control the disease, the Ministry of Health established a surveillance system that included clinical, entomological and serological surveillance elements. The National Reference Centre for Veterinary Epidemiology--Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise 'G. Caporale'--developed a Web-based National Information System (NIS) and a Geographical Information System (GIS)to collect and manage data from Veterinary Services across Italy. The system was designed to gather and spread information in order to support the management of control activities and to provide an early warning system. Surveillance data are displayed to the user in different ways: reports, tables and interactive maps.

Analysis of 96 patients with advanced ovarian carcinoma treated with high-dose chemotherapy and autologous stem cell transplantation.

The purpose of this study was to identify characteristics significant to survival and progression-free survival in patients with advanced ovarian cancer receiving high-dose chemotherapy. In all, 96 patients received autologous stem cell transplantation. Regimens included paclitaxel with carboplatin (PC), topotecan, melphalan, cyclophosphamide (TMC) and cyclophosphamide, BCNU, thiotepa (CBT). At the time of transplantation, 43% of patients were in clinical CR, 34% were in clinical PR, 18% had progressive disease and 5% had stable disease. There were no treatment-related deaths. The 6-year survival by Kaplan-Meier was 38%. For patients who received transplantation for remission consolidation, the 6-year survival was 53% with a PFS of 29%. On univariate analysis, the CBT regimen, clear cell histology and disease status other than CR prior to treatment were statistically significant adverse prognostic factors. This analysis has demonstrated that patients in clinical remission are most likely to benefit from autologous transplantation, with the exception of patients with clear cell histology. The TMC combination appeared to be superior to the PC and CBT combinations. Comparative studies of different consolidation approaches will be necessary to determine if autologous transplantation is the preferred treatment for this patient population.

Low-dose alemtuzumab (Campath) in myeloablative allogeneic stem cell transplantation for CD52-positive malignancies: decreased incidence of acute graft-versus-host-disease with unique pharmacokinetics.

Alemtuzumab is effective in reducing the risk of acute graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (ASCT). Alemtuzumab may also delay immune reconstitution and reduce graft-versus-leukemia effects. The optimal dose has not been established. We investigated engraftment, acute GVHD incidence and severity, and pharmacokinetics of alemtuzumab associated with the use of low-dose alemtuzumab/cyclophosphamide/total body irradiation and ASCT for patients with aggressive CD52-positive hematologic malignancies. In all, 12 patients were treated. Alemtuzumab 10 mg daily on days -7 to -3 was given intravenously. Tacrolimus and methotrexate were used for GVHD prophylaxis. Alemtuzemab was not detected in any of the 36 sequential serum samples tested between days -1 and +21 of transplant. All patients engrafted rapidly; the median time to an absolute neutrophil count >0.5 x 10(9)/l was 14 days (range 11-17 days), and the median time to a platelet count >20 x 10(9)/l was 16 days (range 6-30 days). By 1 month after transplant, nine patients had 100% donor chimerism, while three had mixed donor chimerism. At 3 months, 11 had achieved 100% donor chimerism. No cases of grade III/IV acute GVHD occurred. At a median follow-up interval of 14.7 months (range 4-24), seven patients remained alive, and five remained free of disease.

Towards the identification of potential infectious sites for bluetongue in Italy: a spatial analysis approach based on the distribution of Culicoides imicola.

A geographic information system (GIS) based on grids was developed by the National Reference Center for Veterinary Epidemiology at the Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise 'G. Caporale' (IZS) in Teramo to identify potential infectious sites for bluetongue (BT) disease in Italy. Geographical and climatic variables were used to build a spatial process model (SPM); the different layers were combined by sequential addition. The final grids (with a cell size of 0.0387 decimal degrees) were generated for each season of the year, and the suitability of each cell for the presence of C. imicola given a value ranking from 0 to 10. While this model more accurately predicts the presence of C. imicola in the Basilicata and Sicily regions, it still over-predicted its presence in the Puglia region. This could be due to the occurrence of calcareous soils which dominate the Puglia landscape. The present SPM is an additive model that assigns an equal weight to each variable. However, the results suggest the existence of hitherto unconsidered variables that significantly influence the prevalence of C. imicola. To reflect their importance, these variables should be assigned a higher weighting in future models. However, the decision in regard to precisely what this weighting should be depends on a very thorough knowledge of the ecology of C. imicola.

Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality.

This study investigated the use of a nonablative conditioning regimen to decrease toxicity and achieve engraftment of an allogeneic blood stem cell transplant, allowing a graft-versus-malignancy effect to occur. All patients had follicular or small cell lymphocytic lymphoma after relapse from a prior response to conventional chemotherapy. Patients received a preparative regimen of fludarabine (25 mg/m(2) given daily for 5 days or 30 mg/m(2) daily for 3 days) and intravenous cyclophosphamide (1 g/m(2) given daily for 2 days or 750 mg/m(2) daily for 3 days). Nine patients received rituximab in addition to the chemotherapy. Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Twenty patients were studied; their median age was 51 years. Twelve were in complete remission (CR) at transplantation. All patients achieved engraftment of donor cells. The median number of days with severe neutropenia was 6. Only 2 patients required more than one platelet transfusion. The cumulative incidence of acute grade II to IV GVHD was 20%. Only one patient developed acute GVHD of greater than grade II. All patients achieved CR. None have had a relapse of disease, with a median follow-up period of 21 months. The actuarial probability of being alive and in remission at 2 years was 84% (95% confidence interval, 57%-94%). Nonablative chemotherapy with fludarabine/cyclophosphamide followed by allogeneic stem cell transplantation is a promising therapy for indolent lymphoma with minimal toxicity and myelosuppression. Further studies are warranted to compare nonablative allogeneic hematopoietic transplantation with alternative treatment strategies.

High-dose topotecan, melphalan, and cyclophosphamide (TMC) with stem cell support: a new regimen for the treatment of advanced ovarian cancer.

OBJECTIVE: The goal of this study was to determine the optimal dose of topotecan when used in combination with high-dose melphalan and cyclophosphamide (TMC), and to assess the toxicity and efficacy of the regimen in patients with advanced ovarian cancer. METHODS: Fifty-three patients with persistent or recurrent ovarian cancer were treated. Disease status at study entry included: platinum-sensitive recurrent disease (15 patients), platinum-resistant or refractory recurrent disease (15 patients), positive second-look surgery (16 patients), failure to achieve a primary clinical complete response (CR) (7 patients). Following stem cell mobilization and collection, patients were given cyclophosphamide 1 g/m(2)/day on Days -6, -5, -4; melphalan 70 mg/m(2)/day on Days -3, -2; and topotecan at escalating doses from 1.25 to 4.0 mg/m(2)/day on Days -6 to -2. Peripheral blood stem cells were infused on Day 0. RESULTS: The optimal topotecan dose selected for future trials was 4.0 mg/m(2)/day x 5 days. The regimen had acceptable toxicity with no regimen-related death. Toxicity (Bearman toxicity criteria) was limited mostly to grade 1-2 mucositis and diarrhea. The overall response rate of patients with measurable or evaluable disease was 93%. Median survival has not yet been reached, but with a median follow up of 18 months (range: 11-37) 77% of patients are alive. CONCLUSION: With a topotecan dose of 4.0 mg/m(2)/day x 5 days, the TMC regimen has acceptable toxicity and produces high response rates. In the setting of ovarian cancer, high-dose chemotherapy should be administered only as part of well-designed clinical trials. TMC should be considered a potential regimen for future randomized trials in patients with advanced ovarian cancer.

Practice guidelines for lipid-based amphotericin B in stem cell transplant recipients.

OBJECTIVE: To provide clinicians who practice in the stem cell transplantation (SCT) setting with practical guidelines for the use of lipid-based amphotericin B (AmB) formulations in SCT patients who have documented or probable invasive fungal infections, are experiencing neutropenic fever, or require secondary prophylaxis for fungal infections. DATA SOURCES: Recommendations are based on the results of a two-day consensus meeting that convened clinicians versed in the management of infectious complications in patients undergoing SCT. This meeting, which was held October 21-23, 1998, in Orlando, Florida, was sponsored by an educational grant from The Liposome Company. In addition, primary articles were identified by MEDLINE search (1980-December 1999) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from the data sources were evaluated, and all information deemed relevant was included in this review. DATA SYNTHESIS: Immunocompromised patients, particularly patients undergoing high-dose chemotherapy with SCT, experience a high degree of morbidity and mortality from invasive fungal infections. Historically, treatment for such infections with conventional AmB had been limited primarily by its associated nephrotoxicity. Lipid-based formulations of AmB have helped to advance the management of invasive fungal infections in the SCT population by offering a treatment alternative that allows for administration of adequate amounts of active drug to produce clinical and mycologic responses, compared with conventional AmB, in a delivery system that is less nephrotoxic. Unfortunately, these agents are relatively expensive. Therefore, patients who are candidates for lipid-based products must be selected carefully. CONCLUSIONS: Practical guidelines are provided for the use of lipid-based AmB formulations in SCT patients who have documented or probable invasive fungal infections, are experiencing neutropenic fever, or require secondary prophylaxis for fungal infections.

High-dose ifosfamide and etoposide with filgrastim for stem cell mobilization in patients with advanced ovarian cancer.

High-dose chemotherapy combined with autologous peripheral blood stem cell transplantation has shown promise as treatment for recurrent or persistent epithelial ovarian cancer. We evaluated the stem cell mobilization regimen of high-dose ifosfamide plus etoposide in 32 patients with epithelial ovarian cancer, who had a positive second-look laparatomy or recurrent disease. Ifosfamide was given at 10 g/m2 by continuous i.v. from days 1 to 3. Etoposide was given at 150 mg/m2 every 12 h for six doses on days 1-3. Filgrastim was given at 10 microg/kg/d s.c. from day 5 until the completion of peripheral blood stem cell harvest. Fourteen of 32 patients had measurable or evaluable disease before mobilization therapy and were assessed for response. In nine (64%) of the 14 patients, treatment response was demonstrated, and these patients received a second cycle of mobilization therapy. The target CD34+ cell dose (>8 x 106 cells/kg) was achieved with a median of one apheresis (range 1-5). A median of 25.1 (range 8.0-122.5) x 106 CD34+ cells/kg body weight was collected. Non-hematologic toxicity was limited to grade 2 renal dysfunction in one patient and grade 2 hepatic dysfunction in three patients. In this patient group, high-dose ifosfamide plus etoposide with filgrastim support was well tolerated, lead to successful stem cell harvest and had antitumor activity.

Granisetron (Kytril) plus dexamethasone for antiemetic control in bone marrow transplant patients receiving highly emetogenic chemotherapy with or without total body irradiation.

This prospective trial evaluated the efficacy and toxicity of granisetron for antiemetic control in patients receiving high-dose cyclophosphamide (CY)-containing regimens with/without TBI for bone marrow (BM) or peripheral blood stem cell (PBSC) transplantation or PBSC mobilization. Granisetron 1 mg i.v. plus dexamethasone 10 mg i. v. were administered daily 30 min before chemotherapy or radiation for a median of 5 days. Response was defined as the number of emetic episodes per 24 h: complete response, 0 and no emetic rescue; major response, 1-2; minor response, 3-5; failure, >5. One hundred patients were enrolled. Ninety-eight received CY-containing regimens and 26 of these additionally received TBI (12 Gy divided over 4 days). Response was complete on 216 (47%) of a total 456 patient days, major on 222 (49%), minor on 14 (3%), and failure on 4 (1%). Mean number of emetic episodes per patient per day and breakthrough medication required per patient per day was 0.24 (range 0-8) and 0. 40 (range 0-8), respectively. Adverse effects were minimal, with headache (20%) reported most frequently. Based on these results, granisetron plus dexamethasone is an effective and well-tolerated antiemetic regimen in BMT/PBSCT recipients conditioned with high-dose chemotherapy with/without TBI. Bone Marrow Transplantation (2000) 25, 1279-1283.

Tacrolimus does not abrogate the increased risk of acute graft-versus-host disease after unrelated-donor marrow transplantation with allelic mismatching at HLA-DRB1 and HLA-DQB1.

One hundred patients of median age 34 years (range, 14-53) received bone marrow transplants from unrelated donors serologically matched for human leukocyte antigen HLA-A, HLA-B, and HLA-DR using tacrolimus and minimethotrexate for prevention of acute graft-versus-host disease (GVHD). Sixty-eight patient-donor pairs had allelic matches at HLA-DRB1 and HLA-DQB1, 20 pairs had a single mismatch at HLA-DRB1 or HLA-DQB1, and 12 were mismatched at both HLA-DRB1 and HLA-DQB1. Minimum follow-up time was 6 months. Grades 2 to 4 GVHD occurred in 43% of patients with matched donors, 69% with single allele-mismatched donors, and 71% with double allele-mismatched donors; grades 3 to 4 GVHD occurred in 22%, 43%, and 64%, respectively. On multivariate analysis, the relative risk of grades 2 to 4 GVHD was 2.2 (95% CI, 1.1-4.5; P = .03) with a single allele mismatch and 2.7 (95% CI, 1.2-6.0; P = .02) with a double allele mismatch. The relative risks of grades 3 to 4 GVHD were 3.0 (95% CI, 1.2-7.6; P = .02) and 5.0 (95% CI, 1.9-12.6; P = .001), respectively. Day 100 treatment-related mortality was also adversely affected by allelic mismatching, occurring in 21% of those with matched donors, 50% with single allele-mismatched donors, and 42% with double allele-mismatched donors (P = .02), but overall survival at day 180 did not differ significantly among the 3 groups. Tacrolimus does not abrogate the adverse impact of allele mismatching at HLA-DRB1 and HLA-DQB1 on the risk of moderate-to-severe acute GVHD.

Respiratory syncytial virus upper respiratory tract illnesses in adult blood and marrow transplant recipients: combination therapy with aerosolized ribavirin and intravenous immunoglobulin.

Respiratory syncytial virus (RSV) is an important cause of serious respiratory illness in blood and marrow transplant (BMT) recipients. In some subsets of these immunocompromised patients, RSV upper respiratory illnesses frequently progress to fatal viral pneumonia. The frequency of progression to pneumonia is higher during the pre-engraftment than during the post-engraftment period. Once pneumonia develops, the overall mortality is 60-80%, regardless of the treatment strategy. We performed a pilot trial of therapy of RSV upper respiratory illnesses using aerosolized ribavirin and IVIG (500 mg/kg every other day), with the goal of preventing progression to pneumonia and death. Two dosages of ribavirin were used: a conventional regimen (6 g/day at 20 mg/ml for 18 h/day) and a high-dose short-duration regimen (6 g/day at 60 mg/ml for 2 h every 8 h). Fourteen patients were treated for a mean of 13 days (range: 7-23 days). In 10 (71%) patients, the upper respiratory illness resolved. The other four (29%) patients, three of whom were in the pre-engraftment period, developed pneumonia, which was fatal in two. The most common adverse effect was psychological distress at being isolated within a scavenging tent. In conclusion, prompt therapy of RSV upper respiratory illnesses in BMT recipients with a combination of aerosolized ribavirin and IVIG was a safe and promising approach to prevent progression to pneumonia and death.