VZV Infections Research Articles

Viral Infections in Renal Transplant Recipients in Belarus

The presented study had its aim in establishing the prevalence and etiological structure of post-transplant viral complications and the kinetics of infection development. Two groups of recipients were examined: Group 1 comprised patients without any clinical signs of infection (n=84) monitored for a year, Group 2 included recipients with a clinical presentation of infection (n=92). 591 blood samples and 446 urine samples from 196 patients (20 donors and 176 renal transplant recipients) were analyzed. All donor-recipient pairs were tested for CMV, EBV, and HSV-1, 2. Latent viral infection reactivation was detected by the presence of viraemia (DNAemia) induced by CMV, EBV, HSV-1, 2, HHV-6, VZV, PVB19, or viruria (DNAuria) induced by BKV. The percentage of Group 1 patients with viral DNA detected amounted to 41.9% for CMV, 30.4% for EBV, 17.4% for BKV, 5.6% for HHV-6, 1.9% for AdV, and 1.7% for PVB19. HSV-1, 2 and VZV infections in this group were not observed. The rate of CMV, EBV, and BKV infection reactivation, determined by the viraemic patients percentage, increased with time and peaked 1, 1.5 and 2 months after transplantation for EBV, BKV, and CMV, respectively. Three to six months after transplantation, the percentage of patients with active CMV, EBV, or BKV infection decreased significantly; and later on, viraemia was only occasional finding in Group 1 patients. Examination of Group 2 patients revealed that the predominant etiological agents of post-transplant viral complications were CMV (24.4%), EBV (18.8%), and BKV (17.6%). The current study is the first complex investigation into the etiological structure and activation kinetics of viral infections in renal transplant recipients in Belarus. The results have major implications for early prevention of potential viral complications and adjustment of the therapy regimens for kidney transplant recipients currently in use.

Incidence of Varicella Zoster Virus (VZV) and Herpes Simplex Virus (HSV) Infections and Use of Prophylaxis in Lenalidomide-Treated Multiple Myeloma (MM) Patients (pts): An Analysis of MM Trials

Background: The publication of a retrospective analysis of the occurrence of VZV and HSV infections among 93 pts treated with lenalidomide (LEN; König, 2014) reported an increased VZV/HSV rate (10 pts) and recommended mandatory prophylaxis with acyclovir as well as analogous multicenter data reviews. According to the Centers for Disease Control and Prevention (CDC), an estimated 1 in 3 persons in the US will experience shingles during their lifetime. A Swedish study found that MM pts are 12.8 times more likely to have a VZV infection than the general population (Blimark, 2012). For pts with hematologic malignancies, the risk of developing shingles increases from 13% to 55% the year after a stem cell transplant (Harpaz, 2008). An alternative to antiviral prophylaxis, VZV vaccine has only been available since 2006 in US. In 2008, the CDC recommended vaccination for adults without contraindications aged > 60 years, and in Sep 2013, the UK similarly recommended vaccination for adults aged 70 to 79 years.Aim: To further understand the risk of VZV/HSV and assess the potential benefit of viral prophylaxis in LEN-treated MM pts. An analysis was conducted on data from MM pts, 1727 treated with LEN combination and 1044 with a comparator, who participated in four phase 3 Celgene-sponsored studies (MM-009, MM-010, MM-015, and MM-020). No VZV/HSV prophylaxis was mandated in these studies.Methods: The incidence rates (IR) and frequencies of VZV/HSV infections were determined by searching the MedDRA high-level terms of herpes viral infections. VZV/HSV or other antiviral prophylaxis data were derived from the concomitant medication report form. Data on VZV vaccination before study entry were not available. Among pts who did not experience a VZV/HSZ infection, antiviral prophylaxis was defined as taking at least 1 antiviral medication during the study, regardless of antiviral duration. Among pts who did have VZV/HSZ infection, prophylaxis was defined as taking at least 1 antiviral medication within the week prior to VZV/HSZ adverse event (AE).Results: Overall, the cumulative incidence of treatment-emergent VZV/HSV AEs in 1,727 LEN-treated pts was 8.0% and the IR per 100 person-years (PY) was 6.03% (95% CI: 5.11-7.13). The highest IR was for D (16.03%, CI: 11.56-22.23), followed by MP (8.98%, CI: 5.42-14.90), RD (8.73%, CI: 6.35-11.99), Rd (5.49%, CI: 4.40-6.85), MPR (5.12%, CI: 3.37-7.78), and MPT (4.38%, CI: 2.94-6.54) (Table). Of the VZV/HSV AEs, the most commonly reported type in LEN arms was oral herpes (34%) followed by VZV (28%). The majority of LEN VZV/HSV AEs were non-serious, with 11% of AEs being grade 3 or 4. Antiviral prophylaxis was used in 13.9%. Of pts who reported HZV/HSV, 2.2% received antiviral prophylaxis.Conclusions: The incidence of VZV/HSV infections in MM pts was similar to that reported by König et al. However, there is no indication from these prospective, randomized studies that this rate is specifically associated with LEN, as no increased IRs could be documented. Therefore, there is insufficient evidence to mandate prophylaxis beyond existing guidelines for immunocompromised pts. Clinicians are encouraged to follow their regional recommendations on the prevention of VSV/HSV infections and discuss the benefit-risk of prophylaxis with their MM pts.Abstract 3451. Table 1:Incidence Rates of Treatment-emergent VSV/HSV Infections in LEN MM StudiesMM-009/010MM-015MM-020R-pooledRDDMPRMPRdMPTN=353N=350N=302N=153N=1072N=541N=1727Pts with VSZ/HSV Infection n (%)38 (10.8)36 (10.3)22 (7.3)15 (9.8)79 (7.4)24 (4.4)139 (8.0)Total person-years435.50224.55429.32166.961438.62547.592303.40IR (/100py) (%)8.7316.035.128.985.494.386.0395% CI6.35-11.9911.56-22.233.37-7.785.42-14.904.40-6.852.94-6.545.11-7.13Legend: R=Len, D=high dose dexamethasone, M=melphalan, P=prednisone, d=low dose dexamethasone, T=thalidomide.Note: CI= Confidence interval; Person-years (PY) were calculated as the time from the first dose to the onset date of first AE for pts with AE, and to the earlier date of last dose + 28 days for pts without AE. IR per 100 PY is calculated as 100* n/T, where n=# of pts with AE (only the first AE is counted per pt) and T = total PY. 95% CI for IR per 100 PY is calculated using the method by RG Miller: IR*exp{±1.96*n^(-1/2)}.Blimark C, et al. Blood. 2012; 120 (21) 945.Harpaz R, et al. MMWR Recomm Rep. 2008;57(RR-5):1-30.König C, et al. Ann Hematol. 2014;93(3):479–84. DisclosuresGary:Celgene Corporation: Employment, Equity Ownership. Weiss:Celgene Corporation: Employment. Yu:Celgene Corp: Employment, Equity Ownership. Xu:Celgene Corp.: Employment. Minton:Celgene Corp: Employment, Equity Ownership. Gillen:Celgene Corp: Employment, Equity Ownership. Glasmacher:Celgene Corp: Employment, Equity Ownership. Freeman:Celgene Corp: Employment, Equity Ownership.

Rituximab Maintenance Bimonthly for Two Years after Prolonged Immunochemotherapy in Elderly Patients with Mantle Cell Lymphoma (MCL) Results in Long Remissions: Update with Six-Year Follow-up of a Prospective Study By the Finnish Lymphoma Group

Abstract Background Rituximab (R) maintenance therapy bimonthly until progression has been shown in a recent randomized study to prolong duration of remission (with median follow-up of 37 months) and overall survival in elderly patients (pts) with MCL after R-CHOP, but not after R-FC, induction therapy (Kluin-Nelemans et al, N Engl J Med 2012; 367:520-31). We have previously reported initial results of 60 elderly pts with MCL treated with induction therapy consisting of 10 cycles of alternating standard CHOP and intermediate-dose AraC (combining fludarabine in 3 cycles) with 8 doses of R, followed by bimonthly R maintenance for 2 years (yrs) (Räty et al. Leuk Lymphoma 2012; 53:1920-8). High response rate to induction therapy with ORR of 95% (CR/CRu 87%) was seen. PFS was 70% and OS 72% at 4 yrs with the median follow-up of 40 months. Herein, we update our results of this prospective study with completed maintenance therapy in all pts with a median follow-up time of 6 yrs for surviving pts. Methods The pts were recruited at 10 Finnish centres during Dec 2004 and Aug 2010. Eligible pts were > 65 yrs old with histologically confirmed newly diagnosed (WHO criteria, CD5+, CD19/20+, Cyclin D1+) and previously untreated stage II-IV MCL with adequate organ functions and performance status (WHO) <4. Induction: standard dose R-CHOP (cycles 1, 3, 5), R-AraC (R 375 mg/m2 x1, AraC 1 g/ m2 4 doses with 12 hrs intervals; cycles 2, 4), R-AraC with fludarabine (F) (F 25 mg/m2 2 doses, cycles 6-8), CHOP (cycles 9, 10). Maintenance for pts in CR/PR: R 375 mg/m2 bimonthly x 12. Response was evaluated according to Cheson’s criteria after 5th, 8th and 10th cycle, every 6 months during maintenance and 1 year follow-up, and clinically for later follow-up every 6 months. Median follow-up time at the time of this analysis was 70 months (range 41 – 113 months) for living pts. Results At the time of diagnosis the median age of 60 recruited pts was 74 yrs (range 65-83), 62% were males, 97% had advanced disease (stage III-IV), 77% had good performance status (PS 0-1). Most (87%) had a history of some other notable illness, most typically cardiovascular disease. Another cancer had been diagnosed earlier in 9 pts (prostate n=3, breast n=3, other n=3). The MIPI risk was low in 2%, intermediate in 45% and high in 53% of the pts, respectively. ORR was 95% (CR/CRu n= 52, PR n=5, PD n=2). One patient could not be evaluated for response due to withdrawal of consent after the first cycle. Seven pts did not receive R maintenance (died/progressed/relapsed during induction n=5, withdrawal of consents n= 2). All 12 doses were given to 34 of 53 pts (64%, CR/CRu n=32, PR n=2). Four pts discontinued maintenance due to recurrent infections / neutropenia,10 pts due to relapse and 5 due to other reasons (secondary MDS n=1, general fatigue n=2, unknown n=2). A transient grade 4 neutropenia was seen in 20 pts during maintenance with no serious infections. HZV or VZV infections were recorded in 9 pts. Altogether 22 of responding pts have progressed/relapsed (during induction n=2, during maintenance n=10, during follow-up n=10), 6 of them with isolated CNS relapse. Twenty-one pts have died (sudden cardiac death during induction n=1, progressive MCL n=17, secondary MDS/AML n=1, unknown n=2). At 6 yrs (intention to treat) PFS was 64% (median 97 months, 95% CI 75 – 120 months), EFS 59% (median 95 months, 95% CI 75 – 114 months) and OS 62% (median not reached), respectively. DFS was 72% at 6 yrs (median 91 months, 95% CI 89 – 93 months) for 52 pts in CR/CRu. Two pts have developed secondary MDS (at 27 and 67 months). Eight new cancers (prostate n=3, breast n=1 and skin n=4) have been recorded in 6 patients during maintenance or follow-up. Conclusions Long PFS and OS over 60% at 6 yrs with median DFS of more than 7 yrs can be achieved with prolonged cytarabine-containing immunochemotherapy followed by 2 yrs R maintenance in elderly pts with MCL. Maintenance therapy was well tolerated in general. Transient neutropenia during maintenance was not uncommon, but serious infections were not seen and only 4 pts discontinued maintenance therapy because of recurrent neutropenia or infections. Attention for second malignancies is requested as 9 pts had cancer before MCL diagnosis, MDS/AML was developed in 2 pts and 6 pts showed carcinomas during follow-up in this elderly patient population. Disclosures Räty: Roche Ltd: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline Ltd: Honoraria; Mundipharma: Honoraria. Mikkola:Roche Ltd: Honoraria. Poikonen:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Baxter: Speakers Bureau; Novartis: Speakers Bureau; GlaxoSmithKline: Consultancy; Mundipharma: Honoraria; Novartis: Honoraria. Räsänen:Novartis: Honoraria; Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Janssen-Cilag: Honoraria; Amgen: Honoraria; Mundipharma: Honoraria.

Brincidofovir (CMX001) for the Treatment of Serious or Life-Threatening Double-Stranded DNA Virus Infections in Patients Receiving Liver Transplant as Part of Multiorgan Transplantation.

Background: Infectious complications remain an important cause of morbidity/mortality following SOT. Brincidofovir (BCV), a nucleotide analog active in vitro against all major human pathogenic dsDNA viruses, is in Phase 3 development for CMV prevention in HCT. Over 400 patients (pts) have received BCV for serious or life-threatening infections with dsDNA viruses under compassionate use (Study CMX001-350, clinicaltrials.gov ID: NCT01143181 or under emergency INDs). Methods: Ten multiorgan transplant pts (liver ± kidney/pancreas/small bowel) were treated for serious or life-threatening AdV, BKV, CMV, EBV or VZV infections after failing existing antiviral therapies. BCV was given orally at 2-4 mg/kg or 100-200 mg twice-weekly. Results: Pt demography and virologic responses [viral load (VL) at baseline (BL) and maximal (Max) and through end-of-treatment (EOT) decreases]/infection outcomes are summarized in the table:Table: No Caption available.ND=no data; NV=no viremia; R=infection resolved; VR=virologic response; *=undetectable (<100 c/mL) Two pts died on treatment (#7 intracranial haemorrhage, #10 hepatic failure secondary to aortic thrombus, both unrelated to BCV); 2 pts died >30 days posttreatment (#1 PTLD/Pseudomonas pneumonia, #3 septic shock). No adverse events (AEs) required BCV treatment discontinuation and there were no serious drug-related hepatic AEs. Conclusions: These data support the continued study of BCV in the treatment of dsDNA virus infections in SOT and other immunocompromised pts. There were no treatment-limiting AEs and some evidence of improved outcomes, although conclusions are limited by the small sample size and uncontrolled data collection. DISCLOSURES:Florescu, D.: Grant/Research Support, Chimerix, Inc., Other, Chimerix, Inc., Former/current investigator for CMX001 trial. Grimley, M.: Other, Chimerix, Inc., Former/current investigator for CMX001 trials. Nemecek, E.: Other, Chimerix, Inc., Former/current investigator for CMX001 trials. Chittick, G.: Employee, Chimerix, Inc., Stockholder, Chimerix, Inc. Brundage, T.: Employee, Chimerix, Inc., Stockholder, Chimerix, Inc. Mommeja-Marin, H.: Employee, Chimerix, Inc., Stockholder, Chimerix, Inc.

Antiviral drug resistance in herpesviruses other than cytomegalovirus

The discovery of acyclovir (ACV), a nucleoside analogue, more than 30 years ago, represents a milestone in the management of HSV and VZV infections. The modest activity of ACV against CMV prompted the development of another nucleoside analogue, ganciclovir, for the management of systemic and organ-specific CMV diseases. Second-line agents such as the pyrophosphate analogue foscarnet and the nucleotide analogue cidofovir have been approved subsequently. In contrast to ACV and ganciclovir, the latter drugs do not require selective phosphorylation by viral protein kinases to be converted into their active forms. Since the introduction of these antivirals, the emergence of drug-resistant mutants has been constantly reported particularly in severely immunocompromised patients such as bone marrow and solid organ transplant recipients as well as HIV-infected individuals. In this manuscript, we discuss the characteristics of the antiviral agents currently approved for the management of HSV, VZV and CMV diseases. In recent years, the resistance of CMV to antiviral drugs has been extensively reviewed. The emergence of antiviral drug resistance is also observed with other members of the Herpesviridae family, namely HSV-1, HSV-2, VZV and HHV-6, which are the focus of this review. More specifically, we describe the laboratory methods for assessing drug susceptibilities, the frequency and clinical significance of drug-resistant infections and their management.

Idiopathic CD4 Lymphocytopenia: Spectrum of opportunistic infections, malignancies, and autoimmune diseases

Idiopathic CD4 lymphocytopenia (ICL) was first defined in 1992 by the US Centers for Disease Control and Prevention (CDC) as the repeated presence of a CD4+ T lymphocyte count of fewer than 300 cells per cubic millimeter or of less than 20% of total T cells with no evidence of human immunodeficiency virus (HIV) infection and no condition that might cause depressed CD4 counts. Most of our knowledge about ICL comes from scattered case reports. The aim of this study was to collect comprehensive data from the previously published cases to understand the characteristics of this rare condition. We searched the PubMed database and Science Direct for case reports since 1989 for Idiopathic CD4 lymphocytopenia cases. We found 258 cases diagnosed with ICL in 143 published papers. We collected data about age, sex, pathogens, site of infections, CD4 count, CD8 count, CD4:CD8 ratio, presence of HIV risk factors, malignancies, autoimmune diseases and whether the patients survived or died. The mean age at diagnosis of first opportunistic infection (or ICL if no opportunistic infection reported) was 40.7 ± 19.2 years (standard deviation), with a range of 1 to 85. One-sixty (62%) patients were males, 91 (35.2%) were females, and 7 (2.7%) patients were not identified whether males or females. Risk factors for HIV were documented in 36 (13.9%) patients. The mean initial CD4 count was 142.6 ± 103.9/mm3 (standard deviation). The mean initial CD8 count was 295 ± 273.6/mm3 (standard deviation). The mean initial CD4:CD8 ratio was 0.6 ± 0.7 (standard deviation). The mean lowest CD4 count was 115.4 ± 87.1/mm3 (standard deviation). The majority of patients 226 (87.6%) had at least one infection. Cryptococcal infections were the most prevalent infections in ICL patients (26.6%), followed by mycobacterial infections (17%), candidal infections (16.2%), and VZV infections (13.1%). Malignancies were reported in 47 (18.1%) patients. Autoimmune diseases were reported in 37 (14.2%) patients.

Prolonged Hypogammaglobulinemia After Rituximab Therapy for Post-Transplant EBV-Lymphoproliferative Disorder Following Hematopoietic Stem Cell Transplantation in Pediatric Patients

Abstract 4480Post-transplant lymphoproliferative disorder (PTLD) caused by Epstein Barr Virus (EBV) is a severe complication in allogeneic hematopoietic stem cell transplantation (HSCT). Rituximab is an effective treatment, now commonly used as early therapy against B-cell PTLD and preemptive treatment of EBV reactivation. In first trials, rituximab was considered to have little adverse events. As exposure to this therapy is increasing worldwide, special toxicities are recognized including prolonged hypogammaglobulinemia (PH). Few details are known about duration and severity of rituximab induced low serum immunoglobulin status, especially in pediatric population treated with this drug for PTLPD after HSCT.This retrospective study was conducted in one pediatric HSCT center (Robert Debré Hospital, Paris, France). Between December 2008 and June 2011, among 138 transplanted children, 39 children received rituximab (Mabthera®, Roche, Paris, France) for either EBV reactivation or B-cell PTLD. 28 children were then followed for immune status more than 12 months after rituximab based therapy. Median age at HSCT was 7 years (range 1 to 18). There were 17 males and 11 females. Indications for HSCT were hematological malignancy (n=17), sickle cell disease (n=3), B thalassemia (n=1), severe aplastic anemia (n=4) and inherited bone marrow failure (n=3). 23 children underwent 1 HSCT, 4 children received 2 while 1 received 3 HSCT. They received HSCT from either MSD (n=10), 9 to 10/10 HLA MUD (n=16), haploidentical familial donor (n=1) or unrelated 5/6 cord blood (n=1). PH was defined as serum Ig G level < 3.3g/l (1 year old), < 5g/l (1 to 5 year old), < 5.5 g/l (5 to 15 years old) and <6.5 g/l after 15 years old or serum IgM level < 0.5g/l, more than 12 months after HSCT. IV-Ig replacement therapy was used when serum immunoglobulin level was under the median range for age.Median duration of hypogammaglobulinemia was 13 months (range 0 to 38): 60% (17/28) of patients had PH that last in 3 cases more than 24 months (24, 27 and 38 months) after HSCT. 6 children still have a low immunoglobulin status. Among patients with PH, 6 underwent HSCT from 9/10 MUD, 1 from haploidentical family donor and 1 from unrelated cord blood. 3 patients received 2 HSCT and 1 patient 3 HSCT. 10 children with PH had abnormal levels of immunoglobulin before rituximab therapy. Regarding B-cell reconstitution, normalization of B cell count for age was obtained in every child, by a median time of 7.5 months (range 5 to 19) after HSCT in PH cases and 7 months (range 4 to 9) in non PH cases. Among patients with PH, 5 presented repeated lower or upper respiratory track infections (vs. 1 without PH). 2 had pancytopenia secondary to a Parvovirus B 19 infection, 1 presented an extensive VZV infection 17 month after HSCT, and 1 had Pneumocystis jirovecii pneumonia 9 month after HSCT. 1 child presented invasive aspergillosis 8 months after HSCT and 2 months after IV-Ig supplementation interruption.Although rituximab induces almost complete depletion of normal B lymphocytes in peripheral blood for an average of 6–9 months, prolonged serum immunoglobulin suppression is unusual. However, PH has been reported in patients treated with rituximab in association with chemotherapy, or after either autologous or allogeneic HSCT. In some of these studies, phenotypical analysis of B cell recovery help to find abnormalities in naïve B cell differentiation into memory B cells and plasma cells. It may help to explain that normalization of B-cell count is not systematically followed by a rapid increase in immunoglobulin. It seems that during the period of post HSCT immune reconstitution, rituximab could affect, in association with other immunosuppressive factors, not only B cell quantity but also B cell quality. PH may be then a frequent event as we report in our study. Consequences of PH on infection severity and frequency are controversial. Infectious complications secondary to rituximab-associated PH are rare but some are reported as a fatal invasive aspergillosis, frequent pulmonary infections, parvovirus or VZV infections. We also report such severe infections in our patients with PH. Thus, every EBV-PTLD patient treated with rituximab must be monitored closely with regard to serum Ig levels and probably have to receive IV-Ig supplementation, even if its interest remains unproved. B-cell sub-population monitoring may probably help to understand mechanism of PH and identify high-risk patients. Disclosures:No relevant conflicts of interest to declare.

Morbidity of HSV or VZV infections in pancreas and kidney/pancreas organ transplant recipients

Morbidity of HSV or VZV infections in pancreas and kidney/pancreas organ transplant recipients

In Vitro -Selected Drug-Resistant Varicella-Zoster Virus Mutants in the Thymidine Kinase and DNA Polymerase Genes Yield Novel Phenotype-Genotype Associations and Highlight Differences between Antiherpesvirus Drugs

Varicella zoster virus (VZV) is usually associated with mild to moderate illness in immunocompetent patients. However, older age and immune deficiency are the most important risk factors linked with virus reactivation and severe complications. Treatment of VZV infections is based on nucleoside analogues, such as acyclovir (ACV) and its valyl prodrug valacyclovir, penciclovir (PCV) as its prodrug famciclovir, and bromovinyldeoxyuridine (BVDU; brivudin) in some areas. The use of the pyrophosphate analogue foscarnet (PFA) is restricted to ACV-resistant (ACV(r)) VZV infections. Since antiviral drug resistance is an emerging problem, we attempt to describe the contributions of specific mutations in the viral thymidine kinase (TK) gene identified following selection with ACV, BVDU and its derivative BVaraU (sorivudine), and the bicyclic pyrimidine nucleoside analogues (BCNAs), a new class of potent and specific anti-VZV agents. The string of 6 Cs at nucleotides 493 to 498 of the VZV TK gene appeared to function as a hot spot for nucleotide insertions or deletions. Novel amino acid substitutions (G24R and T86A) in VZV TK were also linked to drug resistance. Six mutations were identified in the "palm domain" of VZV DNA polymerase in viruses selected for resistance to PFA, PCV, and the 2-phophonylmethoxyethyl (PME) purine derivatives. The investigation of the contributions of specific mutations in VZV TK or DNA polymerase to antiviral drug resistance and their impacts on the structures of the viral proteins indicated specific patterns of cross-resistance and highlighted important differences, not only between distinct classes of antivirals, but also between ACV and PCV.

Hautinfektionen in der Schwangerschaft

The article outlines examples of a viral (varicella-zoster virus, VZV), a bacterial (Lyme borreliosis) and a parasitic (scabies) infection in pregnancy with their risk for the mother and/or child as well as their management. VZV infections cause various clinical scenarios depending on the maternal immune status and the time of infection. Herpes zoster usually poses no risk to the pregnant woman and there is no need for antiviral therapy. VZV infection of a seronegative mother, however, may lead to severe varicella in the pregnant woman and to congenital malformations (congenital varicella syndrome) in case of early infection or neonatal varicella in case of perinatal infection. Prompt therapy with acyclovir or administration of VZV immunoglobulin for prophylaxis is mandatory in those patients. In case of Lyme borreliosis of the mother, adequate antibiotic therapy with amoxicillin prevents harm to the fetus. Doxycycline is contraindicated during pregnancy. Scabies represents an important differential diagnosis of pruritic dermatoses in pregnancy and should be treated with permethrin 5% cream.

Chronic mucocutaneous herpes simplex virus and varicella zoster virus infections

Chronic herpes simplex virus (CHSV) and chronic varicella zoster virus (CVZV) are defined as atypical mucocutaneous wart-like and/or ulcerative HSV or VZV infections, persisting for at least 1 month. Both are commonly associated with HIV infection and may occasionally present with other types of immunosuppression. CHSV and CVZV occur despite the immune restoration effect of highly active antiretroviral therapy for HIV. The clinical polymorphism of CHSV and CVZV makes recognition difficult. Histology, immunohistology, PCR and viral culture all help to confirm the diagnosis. Treatment is frequently complicated by resistance to thymidine kinase (TK)-dependent antivirals, including acyclovir, valacyclovir and famciclovir. Viral culture remains an essential tool for antiviral drug susceptibility testing. Therapeutic alternatives include non-TK-dependent antivirals, such as foscarnet or cidofovir, which directly target viral DNA polymerase. With few exceptions, CHSV and CVZV infections do not constitute significant risk factors for disseminated cutaneous or systemic infection. This review compares the similarities of and differences between CHSV and CVZV infections.

Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia

These guidelines on the management of HSV, VZV and EBV infection in patients with hematological malignancies and after SCT were prepared by the European Conference on Infections in Leukemia following a predefined methodology. A PubMed search was conducted using the appropriate key words to identify studies pertinent to management of HSV, VZV and EBV infections. References of relevant articles and abstracts from recent hematology and SCT scientific meetings were also reviewed. Prospective and retrospective studies identified from the data sources were evaluated, and all data deemed relevant were included in this analysis. The clinical and scientific background was described and discussed, and the quality of evidence and level of recommendation were graded according to the Centers for Disease Control criteria.

Disseminated Varicella infection in an adult burn victim—A transfused disease?

Varicella Zoster (VZV), a virus from the Herpesviridae virusfamily, comprises large enveloped, double-stranded DNAvirus [1]. VZV commonly infects children. It manifests aschickenpox, a generalized vesicular rash. Nearly 90% of casesoccur before the age of 10. In the healthy population VZV isassociated with little morbidity or mortality. In immunocom-primized patients Varicella can cause life threatening com-plications; encephalitis, pneumonitis, bacterial super-infectionanddehydration[2].Therehavebeenseveralreportsregarding generalized VZV infections in immunosuppressedpatients, mainly postrenal transplant patients [2].There are only a few cases of reported Varicella infectionsin burn patients [3,4], all in pediatric burn patients. Here wereportfor the first timea caseof Varicellainfectioninan adultburn patient.

Rituximab compared to observation after high-dose consolidative first-line chemotherapy (HDC) with autologous stem cell transplantation in poor-risk diffuse large B-cell lymphoma: Updated results of the LNH98-B3 GELA study

8012 Background: Rituximab has been evaluated as a single agent and also in combination with chemotherapy in aggressive and indolent lymphomas with evidence of efficacy. More recently, rituximab maintenance therapy has been successfully used to keep responding patients in remission. We have shown that consolidative HDC improves outcome of poor risk responder-patients (pts) with aggressive lymphoma. Methods: The aim of the present study was to evaluate the potential benefit, as randomly compared to observation, rituximab - 375 mg/m2/week for 4 weeks - 2 months after HDC, in decreasing the relapse rate (second randomization: R2). A secondary objective was to improve the response rate before HDC using the intensified ACE chemotherapy regimen (doxorubicin 75mg/m2 d1, cyclophosphamide 1g/m2 d1-d2, etoposide 150mg/m2 d1-d3) as compared to the standard ACVBP induction regimen (R1). Four cycles were delivered every 15 days. In responding pts, HDC (mitoxantrone 45 mg/m2, cyclophosphamide 1500 mg/m2 × 4d, etoposide 250 mg/m2 × 4d and carmustine 300 mg/m2) was started between d80 and d90. Results: From 10/99 to 05/03 (closing date), 476 pts younger than 60 years with diffuse large B-cell lymphoma and aa-IPI 2 or 3 (aa-IPI 3: 29%). were enrolled. 237 pts were assigned to ACE and 239 to ACVBP. Complete response (CR+CRu) rates to induction treatment did not significantly differ between the 2 regimens (65% and 63%, respectively). Death rate during induction phase was 4% in both arms. Among the 331 pts who received HDC, 269 were randomized (R2) to receive either rituximab (n=139) or observation (n=130). 545 infusions of rituximab were administered with no clinically relevant infectious toxicity except two severe VZV infections. With a median follow-up of 4 years after R2, a trend toward a better 4y-EFS was observed in the rituximab group (80% vs 71%, p=0.098). In addition, a two-sided log-rank test stratified by aa-IPI, induction treatment and response after HDC was performed and confirmed the results of the unstratified analysis. Conclusions: We conclude that early and brief rituximab maintenance is feasible after HDC and may prolong remission status. [Table: see text]

Herpes folliculitis: clinical, histopathological, and molecular pathologic observations

Herpes folliculitis is a rare manifestation of herpes virus infection and it is often misdiagnosed. Diagnostic criteria are not well established, only 24 patients being reported in the literature. Recently it has been suggested that herpetic folliculitis is more common in infections with varicella zoster (VZV) than in those with herpes simplex viruses (HSV-1 and -2). To refine diagnostic criteria for folliculitis caused by VZV, HSV-1 and HSV-2, and to study whether follicular involvement enables morphological differentiation between VZV and HSV infections. Twenty-one patients with herpetic infection of follicular epithelium were assessed clinically and histopathologically. Polymerase chain reaction (PCR) studies for specific DNA of herpes viruses were performed on paraffin-embedded biopsy specimens. In 17 of our cases PCR was positive for VZV, four were positive for HSV-1, none for HSV-2. The clinical presentation of herpes folliculitis often lacked vesicles or pustules (14/21). Histopathological features were often devoid of ballooning (12/21), multinucleated giant cells (12/21) and keratinocytes with steel grey nuclei (15/21). The most consistent findings were lymphocytic folliculitis and perifolliculitis (20/21) and necrotic keratinocytes in follicular epithelium (12/21). In zoster, but not in varicella eruption or HSV infections, follicular involvement was unaccompanied by marked changes in the epidermal surface. In biopsy specimens taken from herpes virus infections, involvement of follicular units is more commonly encountered in VZV infections compared with HSV infections. Early in the course, herpes folliculitis presents as lymphocytic folliculitis devoid of epithelial changes considered to be diagnostic of herpes virus infections. Exclusive involvement of follicles is rather typical of zoster.

Rituximab vs Observation after High-Dose Consolidative First-Line Chemotherapy (HDC) with Autologous Stem Cell Transplantation in Poor Risk Diffuse Large B-Cell Lymphoma. Final Analysis of the LNH98-B3 GELA Study.

We have shown (Haioun, JCO 2000) that consolidative HDC provides a better survival for patients (pts) with aggressive non-Hodgkin's lymphoma presenting with 2 or 3 adverse age-adjusted International-Prognostic-Index (aa-IPI) factors in complete remission after induction treatment. In the same time, rituximab had been evaluated as a single therapeutic agent in aggressive lymphomas with promising efficacy (Coiffier, Blood 1998). More recently, rituximab maintenance therapy has been successfully used after chemotherapy or after ASCT to keep responding patients in remission.The primary objective of the present study was to evaluate the potential benefit, as randomly compared to observation, of rituximab - 375 mg/m2/week for 4 weeks - 2 months after HDC, in decreasing the relapse rate (second randomization: R2). A secondary objective was to improve the response rate before HDC treatment using the intensified ACE chemotherapy regimen (doxorubicin 75mg/m2 d1, cyclophosphamide 1g/m2 d1-d2, etoposide 150mg/m2 d1–d3) as compared to the standard GELA ACVBP induction regimen (first randomization: R1). Induction regimens were delivered every 15 days for 4 cycles. In responding pts, peripheral blood stem cell (PBSC) collection was performed after the third or fourth cycle. HDC (mitoxantrone 45 mg/m2, cyclophosphamide 1500 mg/m2 x 4d, etoposide 250 mg/m2 x 4d and carmustine 300 mg/m2) was started between d80 and d90 after one or two courses of high-dose methotrexate.From 10/99 to 05/03 (closing date), 476 pts younger than 60 years with diffuse large B-cell lymphoma and aa-IPI 2 or 3 (aa-IPI 3: 29%). were enrolled. We here present the results of the final analysis, performed in July 2005 with 235 pts assigned to receive ACE and 241 to ACVBP. Complete response (CR+CRu) rates to induction treatment did not significantly differ between the 2 regimens (65% and 63%, respectively, p=0.71) and toxic death rates were similar (2% and 3%, respectively) despite higher NCIC grade 3–4 infectious toxicity with the ACE regimen. Among the 331 pts who received HDC, 269 were randomized (R2) to receive either rituximab (n=139) or observation (n=130). 545 infusions of rituximab were administered with no clinically relevant infectious toxicity except two resolutive VZV infections. With a median follow-up of 3 years after R2, a trend toward a better 3y-EFS was observed in the rituximab group (80% vs 72%, p=0.10).Early and brief rituximab maintenance is feasible after HDC. We hypothesize that prolongation of treatment may improve the results as well as selection of patients more likely to respond to rituximab therapy.

Infectious Complications in the Renal Transplant Recipient

The aim of this study was to estimate the incidence of infectious diseases in a group of patients who underwent kidney transplantation from January 1, 2004 to September 30, 2004, including 121 operations, with 119 from cadaveric and 2 from living donors. The protocol sought herpes viruses (CMV, VZV, and EBV), hepatitis viruses, human immunodeficiency virus, T. gondii, M. tubercolosis, and T. pallidum. Therapy for CMV was used both as prophylaxis in immunoglobulin (Ig)G-negative recipients from IgG-positive donors and preemptive therapy, that is, before the appearance of clinical symptoms, but after viremia reached borderline levels. For VZV infections, the treatment started after the appearance of papulo-vesicular cutaneous eruptions and antibody positivity. The treatment for pneumonia consisted of empirical therapy after radiography; for pyelonephritis, antibiotic therapy was based on the results of kidney echography, blood culture, and urine culture. Infectious complications appeared in 25 patients (20.7%), 3 of the which were polymicrobic: 12 CMV infections, 9 VZV infections, 3 pneumoniae, 4 pyelonephritis, and 1 salmonellosis. The most frequent infection was CMV, which occurred in the first 3 months after transplantation in 9 of 12 cases. This study showed that a knowledge of infection prevalence can help the physician to establish a more specific, efficacious antimicrobial therapy, despite the laboratory response not being available in a short time.

Infections after Allogeneic Hematopoietic Stem Cell Transplantation with a Nonmyeloablative Conditioning Regimen.

Hematopoietic stem cell transplantation with a non-myeloablative conditioning (NMSCT) could theoretically be associated with a reduced risk of infection because it causes less mucosal damage or severe neutropenia compared to standard myeloablative allogeneic transplantation. Previous studies have sometimes indicated a reduced incidence of infection after NMSCT but other reports have not. We analyzed the incidence and risk factors (Cox model) of infection in 62 patients (16 F and 46 M, aged 54±11 yrs) undergoing NMSCT with a conditioning regimen of low-dose TBI±fludarabine and immunosuppression with CsA+MMF (Seattle protocol). We compared them to 119 recipients (72 peripheral blood (PBSCT) and 47 bone marrow (BMT) transplants) of a conventional HCT. The proportion of NMSCT patients with repeated infections (at least 1, 2, 3 or 4 infections) was significantly lower than in the 2 other groups, but the difference was confined to the first 30 days post-transplant (34% vs 89% and 74%, p<0.001). In NMSCT recipients, donor other than sibling (p<0.0001), older age (p=0.0024), a diagnosis of MDS (p=0.0123), early disease (p=0.0233) and male gender (p=0.0441) were significant risk factors. The incidence of bacteremia was lower (55% vs 70% and 66% at 1 yr, p=0.0264), but the total number of bacteremic episodes (0.9, 1.2 and 1.0 per patient) did not differ in the NMSCT compared to the PBSCT and BMT groups. However, in the first 30 days post-transplant, 4–6 times fewer episodes were encountered in the NMSCT group (p<0.0001). In the NMSCT group, donor other than sibling (p<0.0001), older age (p=0.0126), a diagnosis of leukemia (p=0.0099) and conditioning without fludarabine (p=0.0022), but not neutropenia, were significant risk factors. The incidence of infections other than bacteremia was quite comparable in the 3 groups, but with a significant delay in the NMSCT group (p=0.0002) in which only corticosteroid usage was associated with an increased risk (p=0.0066). The vast majority of infections were bacterial (less frequent in the NMSCT group in the first 30 days), but the rates of fungal or VZV infections were similar in the 3 groups. No case of CMV reactivation or disease occurred among the low risk (donor and recipient seronegative), very few in the intermediate risk (donor alone seropositive), but many in the high risk category (recipient seropositive) and similarly so in the 3 groups. Among NMSCT patients, the risk of CMV infection increased with high risk category (p<0.0001), older age (p=0.0002), donor other than sibling (p=0.0003) and a diagnosis of lymphoma (p=0.0035). Infection was the primary cause of death in 10% or less of the patients, but it contributed to death in 24%, 41% and 27% of the NMSCT, PBSCT and BMT patients, respectively (NS). We conclude that the risk of infection after NMSCT is significantly smaller than after standard allogeneic transplants within 30 days posttransplant, but very similar thereafter.

Highly Potent and Selective Inhibition of Varicella-Zoster Virus by Bicyclic Furopyrimidine Nucleosides Bearing an Aryl Side Chain

In addition to our recent report on the potent anti-varicella-zoster virus (VZV) activity of some unusual bicyclic furopyrimidine nucleosides bearing long alkyl side chains, we herein report the further significant enhancement of the antiviral potency by inclusion of a phenyl group in the side chain of these compounds. The target structures were prepared by the Pd-catalyzed coupling of a series of para-substituted arylacetylenes with 5-iodo-2'-deoxyuridine, to give intermediate 5-alkynyl nucleosides which were cyclized in the presence of Cu to give the desired bicyclic systems. The compounds display extraordinary potency and selectivity for VZV; the most active are ca. 10 000 times more potent than the reference compound acyclovir and ca. 100 times more potent than the alkyl analogues earlier reported by us. The current compounds show little cytotoxicity, leading to selectivity index values >/= 1 000 000. From a range of DNA and RNA viruses tested, only VZV was inhibited by these compounds indicating their extreme selectivity for this target virus. The novelty of the molecules, coupled with their extreme potency and selectivity, their desirable physicochemical properties, and their relative ease of synthesis, makes them of considerable interest for potential drug development for VZV infections.

Long-term results of CD34(+) cell transplantation in children with neuroblastoma.

This is the first report of the long-term results of CD34(+) cell transplantation in children with neuroblastoma. We investigated the hematologic and immune recovery, posttransplant morbidity, and clinical outcome of these children. Twenty-three children with advanced neuroblastoma had PBPCs (20 patients) or BM (3 patients) collected, followed by CD34(+) cell selection on Ceprate column. The purge of residual neuroblastoma cells was evaluated using an RT-PCR for tyrosine hydroxylase (TH) mRNA assay. Reinfusion of CD34(+) cells followed busulfan + melphalan myeloablative chemotherapy. A median of 2.9 x 10(6) CD34(+) cells/kg was reinjected. Median days to achieve ANC > 0.5 x 10(9)/liter and platelets > 50 x 10(9)/liter were 13 (range 9-33) and 59 (range 22-259), respectively. Circulating T cells were primarily CD4(-)/CD8(+) with fewer than 0.2 10(9)CD4(+) cells/liter throughout the first 6 months. CD19(+) cells and CD56(+) cells were not detectable up to day +35 posttransplant. At 1 year posttransplant, 16 evaluable patients had stable hematopoiesis with 2.3 x 10(9) ANC/liter (range 0.8-4.1), 1.4 x 10(9) lymphocytes/liter (range 0.5- 2.0) and 251 x 10(9) PLT/liter (range 35-490). After the completion of hematopoietic reconstitution, six events of severe septicemia/septic shock were noted. Six children had severe VZV infections, and 2 had EBV-associated lymphoproliferation. Thirteen patients are alive with a median follow-up of 40 months (range 2-54). Ten patients have died; 8 relapsed or developed progressive disease, 1 died from nondocumented pneumopathy at day 56, and 1 developed AML-M4 at 3 years posttransplant. In children, CD34(+) cell transplantation can be accomplished with a reduction of neuroblastoma cell inoculum in the selected graft as assessed by RT-PCR analysis. CD34(+) cell grafts provide successful neutrophil reconstitution. However, delayed platelet recovery, persistent decrease in CD4(+) lymphocyte levels and a high incidence of serious and life-threatening late infections were observed in these children. There remains a critical need to evaluate any real clinical benefit of CD34(+) cell autografts in neuroblastoma patients.