Case-control study of immediate and delayed vasovagal reactions in blood donors.

BACKGROUND AND OBJECTIVE(S): Vasovagal reactions (VVRs) are the most common adverse events associated with blood donations. To assess the relative importance of VVR risk factors, a retrospective case-control study of severe immediate and delayed VVRs was performed. STUDY DESIGN: Vasovagal reactions were defined as immediate when occurring at the transfusion site and as delayed when occurring outside the transfusion site and within 24 h following donation. VVRs with probable or certain imputability and moderate to death severity were considered. One control/case was drawn randomly from among donors without VVR. Explanatory variables (sex, age, body mass index (BMI), donation status, type of phlebotomy) as well as the matching variables (donation region, date) and the interaction term (sex and BMI) were integrated into the multivariate model. RESULTS: In French hemovigilance data collected from 2011 to 2013, 8410 immediate and 833 delayed VVRs occurred among 8 834 214 donations. In multivariate analysis, occurrence of immediate VVR was strongly associated with first-time donation (OR 4·34; 95% CI: 3·93-4·79, P < 0·0001) and the 18-24 age group (OR 2·24; 95% CI: 2·00-2·45, P < 0·0001) and of delayed VVR with women with a normal BMI (OR 7·31; 95% CI: 4·96-10·77, P < 0·0001), overweight BMI (OR 7·89; 95% CI: 4·84-12·87, P < 0·0001) or obese BMI (OR 3·72; 95% CI: 1·42-9·74, P < 0·0001), and in men with an underweight BMI (OR 6·39; 95% CI: 1·56-26·13, P < 0·0001). Apheresis was a risk factor for occurrence of both immediate and delayed VVR. CONCLUSION: Our study highlights that first-time donation by a young person is particularly at risk of immediate VVR while a female donor is at risk of delayed VVR.

Monitoring of human cytomegalovirus infection in immunosuppressed patients using real-time PCR on whole blood.

BACKGROUND: Quantitative monitoring of human cytomegalovirus (HCMV) is currently used in the follow-up of immunosuppressed patients. OBJECTIVE: To investigate whether real-time PCR quantification (QPCR) of HCMV DNA could replace pp65 antigenemia. STUDY DESIGN: We compared HCMV QPCR on whole blood (WB) and on plasma with a pp65-antigenemia assay on 192 samples. Afterwards, we tested 1310 samples from 308 immunosuppressed patients both by antigenemia assay and QPCR on WB. RESULTS: The first study comparison showed that QPCR results on WB and plasma were significantly correlated with antigenemia. QPCR on WB was more sensitive than QPCR on plasma or antigenemia, detecting 31 and 49 additional positive samples, respectively. During the second comparison, QPCR on WB and antigenemia were again correlated (r=0.70; p<0.0001), but QPCR detected 244 additional positive samples. HCMV DNA was detected earlier than pp65 antigen (median difference: 14 days; range: 7-30). One, 5, 10, 50 and 100 pp65-positive cells/200,000 leukocytes corresponded to 439, 1531, 2623, 9150 and 15,671 HCMV DNA copies/mL of WB, respectively, but this equivalence differed according to the sub-group of patients considered. CONCLUSION: QPCR on WB is the most sensitive method for the monitoring of HCMV infection in immunosuppressed patients.

[Prevention of anemia in blood donors]. / Prévention de l'anémie chez les donneurs de sang.

The prevention of anemia of blood donor is a main issue for donor safety and self-supplying. This prevention is done in one hand by donor deferral whose haemoglobin level is under defined threshold and in other hand by preventing iron deficiency. Some subgroups of donors are at increased risk for developing iron deficiency and adverse effects of iron deficiency: premenopausal females; donors with haemoglobin values near the minimum for eligibility and frequent donors. Different interventions could be used: lengthening the inter-donational interval and/or decreasing the number of donations per year; donor ferritin testing to evaluate iron store and at least donor iron supplementation.

Induction and maintenance therapy of cytomegalovirus central nervous system infection in HIV-infected patients.

OBJECTIVE: To evaluate the efficacy and safety of the foscarnet-ganciclovir combination in induction therapy (IT) and maintenance therapy (MT) for cytomegalovirus (CMV) central neurological disorders in HIV-infected patients. DESIGN: An open pilot non-comparative multicentre study. METHODS: Thirty-one patients with acute CMV encephalitis (CMVe) (n = 17) or CMV myelitis (CMVm) (n = 14) during the era before highly active antiretroviral therapy (HAART) received intravenous IT with foscarnet 90 mg/kg plus ganciclovir 5 mg/kg twice a day followed by MT. The primary endpoint was clinical efficacy, assessed at the end of the induction phase. RESULTS: The foscarnet-ganciclovir combination in IT resulted in a 74% (23 out of 31 patients) clinical improvement or stabilization. Eight patients did not respond clinically. Side-effects leading to drug discontinuation occurred in 10 patients during IT. Among the 23 patients who qualified for the maintenance phase, CMV disease progressed in 10, with a median time to the first relapse of 126 days (range 64-264 days). Overall, the median survival time was 3 months [95% confidence interval (CI), 2-4 months]. CONCLUSION: The combination of foscarnet and ganciclovir can safely be used for CMV central nervous system (CNS) infection, with an improvement or stabilization in 74% of patients. Life-long MT with this combination is recommended as long as the immune system is profoundly impaired.

Discontinuation of maintenance therapy for cytomegalovirus retinitis in HIV-infected patients receiving highly active antiretroviral therapy.

OBJECTIVE: To study the safety of discontinuing cytomegalovirus (CMV) maintenance therapy among patients with cured CMV retinitis receiving highly active antiretroviral therapy (HAART). METHODS: Patients with a history of CMV retinitis who were receiving anti-CMV maintenance therapy and who had a CD4 cell count > 75 x 10(6) cells/l and a plasma HIV RNA level < 30000 copies/ml while on HAART were included in a multicentre prospective study. Maintenance therapy for CMV retinitis was discontinued at enrolment and all the patients were monitored for 48 weeks by ophthalmological examinations and by determination of CMV markers, CD4 cell counts and plasma HIV RNA levels. T helper-1 anti-CMV responses were assessed in a subgroup of patients. The primary study endpoint was recurrence of CMV disease. RESULTS: At entry, the 48 assessable patients had been taking HAART for a median of 18 months. The median CD4 cell count was 239 x 10(6) cells/l and the median HIV RNA load was 213 copies/ml. Over the 48 weeks, 2 of the 48 patients had a recurrence of CMV disease. The cumulative probability of CMV retinitis relapse was 2.2% at week 48 (95% confidence interval, 0.4-11.3) and that of all forms of CMV disease 4.2%. CMV blood markers remained negative throughout follow-up. The proportion of patients with CMV-specific CD4 T cell reactivity was 46% at baseline and 64% at week 48. CONCLUSIONS: CMV retinitis maintenance therapy may be safely discontinued in patients with CD4 cell counts above 75 x 10(6) cells/l who have been taking HAART for at least 18 months.

Plasma cytomegalovirus DNA, pp65 antigenaemia and a low CD4 cell count remain risk factors for cytomegalovirus disease in patients receiving highly active antiretroviral therapy.

OBJECTIVE: To study the natural history and the current risk factors for cytomegalovirus (CMV) disease in the context of highly active antiretroviral therapy (HAART). SETTING: Prospective multicentre cohort in 15 university hospitals in France. METHODS: A group of 198 patients with CD4 cell count < 100 x 10(6) cells/l (or < 200 x 10(6) cells/l under HAART for at least 2 months), no previous CMV disease and CMV-positive serology were followed every 4 months clinically and for virological testing including HIV RNA and CMV blood markers (culture, pp65 antigenaemia, plasma CMV DNA and CMV late mRNA by the polymerase chain reaction). RESULTS: At inclusion, median CD4 was 77 x 10(6) cells/l (0-308) and 85% of the patients received protease inhibitors. The percentage of patients receiving HAART reached 99% at 12 months. After a follow-up of 23.6 months, the incidence of CMV disease was 3.2/100 patient-years [95% confidence interval (CI) 1.3-5.0]. In univariate Cox models, all the CMV markers, a CD4 cell count remaining < 75 x 10(6) cells/l and an HIV viral load > 100,000 copies/ml were predictive for CMV disease. The hazard ratios for CMV disease were 11 for blood culture; 14 and 70 for pp65 antigenaemia of > or = 1 and > or = 100 nuclei/200,000 cells, respectively; 35 for plasma CMV DNA; 6 for CMV mRNA; 29 for CD4 < 75 x 10(6) cells/l; and 12 for HIV RNA > 100,000 copies/ml. In a stepwise multivariate analysis, only three covariates were independently associated with the occurrence of a disease: plasma CMV DNA, pp65 antigenaemia > or = 100 nuclei/200,000 cells and a CD4 count < 75 x 10(6) cells/l. CONCLUSION: CMV blood markers and CD4 count < 75 x 10(6) cells/l remain risk factors for CMV disease in patients receiving HAART. Analysis of plasma CMV DNA by the polymerase chain reaction is a reproducible and standardized tool that could be used as a decision marker for initiating CMV pre-emptive therapy.

Clinical and virologic characterization of acyclovir-resistant varicella-zoster viruses isolated from 11 patients with acquired immunodeficiency syndrome.

We studied the clinical resistance to acyclovir of infections with varicella-zoster viruses (VZV) in patients with acquired immunodeficiency syndrome, and we correlated it to virologic analyses. Eleven patients with VZV infections (treated with acyclovir, 30 mg/kg/day, given intravenously, or 4 g/day, given orally) were included in the study because of the failure of 10 days of acyclovir therapy. Susceptibility of VZV isolates to acyclovir was tested using a plaque reduction assay to determine the 50% inhibitory concentration (IC(50)) of acyclovir and the SI(50) (IC(50) of the patient isolate/IC(50) of the reference strain) to acyclovir. The thymidine kinase (TK) gene, which supports the resistance, was sequenced on amplified products. Only 3 patients had a significant increase in the IC(50), as compared with the IC(50) of the reference strain (SI(50) of > or =4), and a mutation in the TK gene. For the other 8 patients, the clinical resistance was not confirmed by the virologic results: the SI(50) was < 4, and no mutation was detected in the TK gene. Because no acyclovir-resistant strain appeared during a shorter period of time, we suggest an increase in the duration of the treatment to 21 days before acyclovir resistance is suspected.

Multiple herpes simplex virus infections with various resistance patterns in a matched unrelated donor transplant recipient.

A 45-year-old matched unrelated BMT recipient had sequential mucocutaneous herpes simplex virus (HSV) type 2 infections. Five months after BMT, a penile lesion occurred and was cured using acyclovir, as expected from in vitro susceptibility results. The same lesion recurred 1 month later but worsened with acyclovir. The HSV isolate was resistant to acyclovir (IC(50) = 105 microM), and a nucleotide (G) was added to the thymidine kinase gene leading to a premature stop codon. The lesion improved markedly with foscarnet. During this treatment a second HSV infection occurred on the buttocks 2 weeks after the first one and healed completely with acyclovir. This course correlated with in vitro results of the buttock HSV isolate which was foscarnet-resistant (IC(50) = 300 microg/ml) and acyclovir-sensitive. Surprisingly, no mutation gene of the foscarnet-resistant isolate was detected in the DNA polymerase gene. This case shows that an HSV acyclovir-resistant infection may be followed by an acyclovir-sensitive one. Determination of antiviral susceptibility is needed to monitor the treatment of various HSV infections in immunocompromised BMT recipients.

Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms.

BACKGROUND: There is a current debate regarding the association of human herpesvirus 6 (HHV-6) infection and drug reaction with eosinophilia and systemic symptoms (DRESS). METHODS: Seven consecutive patients hospitalized with DRESS were enrolled in a prospective study to evaluate evidence of active HHV-6 infection. OBSERVATIONS: The imputable drugs were carbamazepine (5 patients), ibuprofen (1 patient), and sulfasalazine (1 patient). All patients were seropositive for anti-HHV-6 IgG antibodies. Anti-HHV-6 IgM antibodies were detected in 4 of the 7 patients with a seroconversion in 2 patients. Neither anti-cytomegalovirus nor anti-Epstein-Barr virus early antigen IgM antibody was detected. Human herpesvirus 6 genome was not detected by polymerase chain reaction in the first serum sample of all patients. It was weakly detected in skin lesions in the last patient tested by polymerase chain reaction but was not found in uninvolved skin. CONCLUSIONS: The results suggest an association between HHV-6 active infection (primo-infection or reactivation) and severe DRESS. Absence of anti-cytomegalovirus or anti-Epstein-Barr virus early antigen IgM antibodies argues against a nonspecific viral reactivation. Human herpesvirus 6 infection may play a role in the development of DRESS in susceptible patients. Some drugs with reactive metabolites could favor reactivation and propagation of HHV-6.

Expression of inducible nitric oxide synthase in cytomegalovirus-infected glial cells of retinas from AIDS patients.

The inducible isoform of nitric oxide synthase has been detected in cytomegalovirus (CMV)-infected retinas from acquired immunodeficiency syndrome (AIDS) patients by immunohistochemistry and NADPH-diaphorase staining. Subsequent immunohistochemistry using antibodies against CMV antigens and glial fibrillary acidic protein (GFAP) demonstrated that inducible NOS was localized in CMV-infected glial cells, particularly Müller cells. These findings indicate that inducible NOS is expressed in vivo in the human retina as a result of viral infection, and suggest that high levels of NO production might be involved in CMV-induced retinitis.

Borna disease virus and psychiatry.

Borna disease virus (BDV), a noncytolytic neurotropic nonsegmented negative-stranded RNA virus with a wide geographic distribution, infects several vertebrate animal species and causes an immune-mediated central nervous system (CNS) disease with various manifestations, depending on both host and viral factors. In animal infections, BDV can persist in the CNS and induce alterations in brain cell functions, neurodevelopmental abnormalities and behavioral disturbances. An association between BDV and psychiatric disorders (essentially schizophrenia and affective disorders) has been suggested by some serologic and molecular studies but further investigations are required to substantiate the possible contribution of this virus to the pathogenesis of these disorders.

[Efficacy of cidofovir in an HIV infected patient with an acyclovir and foscarnet resistant herpes simplex virus infection]. / Efficacité du cidofovir dans un herpès cutané résistant à l'aciclovir et au foscarnet chez un malade séropositif pour le VIH.

BACKGROUND: We report the case of an AIDS patient, whose persistant HSV2 ulceration was clinically and phenotypically resistant to acyclovir and foscarnet. Only five clinical isolates of simultaneous acyclovir and foscarnet resistance have been previously described. CASE REPORT: This patient, without history of opportunistic infection, was hospitalized for a recurrent scrotal ulceration resistant to several antiviral treatment such as acyclovir, valacyclovir or foscarnet. The CD4 count was stable at 150/mm(3) and the HIV viral load was below detection level. The last recurrence appeared rapidly under valacyclovir therapy which had been introduced after 65 days of foscarnet therapy. Thus, the patient received a new dose of foscarnet. After initial efficacy, the ulceration increased once again. HSV2 phenotypic determination was done and detected, at that time, a double resistance to acyclovir and foscarnet. Healing was obtained with intravenous cidofovir. DISCUSSION: Foscarnet and acyclovir resistance in an HSV2 isolate is rare. This report presents several particularities. First, whereas the earlier published patients with an acyclovir and foscarnet resistant strain were widely immunocompromised, this was not the case for our patient. Secondly, in contrast with most precedent observations in which acyclovir-resistant strain disappeared after foscarnet therapy, in our case the acyclovir resistant strain remained after foscarnet therapy. Finally, few reports concerned the clinical efficacy of cidofovir in HSV infection. In this case, we proved that intravenously cidofovir was highly and rapidly effective on acyclovir and foscarnet resistant strains.

[Acyclovir-resistance zona in a immunocompromised HIV seronegative patient]. / Zona résistant à l'aciclovir chez un malade immunodéprimé non infecté par le VIH.

INTRODUCTION: Resistance to antiviral therapy is getting actually more frequent. Immunocompromised host are more concerned with this problem. OBSERVATION: We present a case of disseminated zoster resisting to acyclovir (ACV) therapy, but healing with foscarnet in a man treated with chemotherapy for lymphoma and seronegative for HIV. CI50 of VZV strain was 48 microM for ACV, which was 2.8 times higher than value of the reference OKA strain tested simultaneously, which confirmed the resistance for ACV. DISCUSSION: Immunocompromised patients often present varicella zoster virus (VZV) infection. They usually heal in response to ACV therapy, but some HIV infected patients have already presented with resistant strains of VZV. This case is the first described in a non-HIV infected patient. Foscarnet therapy resulted twice in complete healing because of its direct activity on viral DNA polymerase, so it is efficaceous therapy for patients with thymidine-kinase-deficient ACV-resistant VZV infection.

[The discovery of three novel human viruses, human herpesviruses 6, 7, and 8]. / La découverte de trois nouveaux virus humains, les herpèsvirus humains 6, 7 et 8.

Three novel human herpesviruses have been discovered in the last years: human herpesvirus 6 (HHV-6) in 1986, human herpesvirus 7 (HHV-7) in 1990, human herpesvirus 8 (HHV-8) in 1994. HHV-6 and HHV-7 were identified after their isolation from blood lymphocyte cultures, while HHV-8 was first detected by means of a specific molecular biology approach in the search for the etiologic agent of Kaposi's sarcoma. The three viruses infect lymphocytes, T-cells in the case of HHV-6 and HHV-7, B-cells in the case of HHV-8. Human infection with HHV-6 and HHV-7 is ubiquitous and widespread while HHV-8 infection seems to be more restricted, at least in Western countries. The propagation in cell culture in vitro can be done easily with HHV-6, with more difficulties in the case of HHV-7 and has not been completely obtained in the case of HHV-8. The polymerase chain reaction is the common method for the detection of these three viruses in human samples. The oncogenic role of HHV-6 and HHV-7 which were both classified in Betaherpesvirinae subfamily has not been convincingly demonstrated. HHV-8, classified as a member of Gammaherpesvirinae subfamily, is strongly associated with three lymphoproliferative diseases: Kaposi's sarcoma, Castleman's disease and primary effusion lymphomas.

[Drugs active against herpesviruses]. / Médicaments actifs contre les herpesvirus.

Drugs active against herpesvirus are undergoing rapid development. Acyclovir is the antiviral drug of choice for treatment of herpes simplex virus (HSV) infections and the varicella and zona virus (VZV) because of its efficacy and lack of toxicity. Valaciclovir, precursor of acyclovir, allows reducing the daily intake to 2 doses for HSV infections and to 3 doses for VZV. For cytomegalovirus infections and HSV that are resistant to acyclovir in immunodepressed patients, ganciclovir and foscarnet are available and effective but can involve respectively haematologic and renal toxicity. Penciclovir, the active form of famciclovir, is a new antiviral drug indicated in the treatment of zona.

[Varicella-zoster virus]. / Virus varicelle-zona.

Varicella-zoster virus, an ubiquitous human pathogen, causes vesicular rash during varicella, the primary infection of the host and zoster corresponding to reactivation. The symptoms could be various, nervous systems and lung being involved. Usually mild, varicella could be severe in immunocompromised patients, during pregnancy for the mother and the foetus, for the newborn and also for adults. Post herpetic neuralgia in old patient is the main complication of zoster. Various methods for virological diagnosis (culture, cytology, serology, PCR) with different sensibilities and specificities depending mainly of sample type are available. Various antiviral drugs are available, acyclovir being the reference one.

[What is a virus?]. / Qu'est-ce qu'un virus?

Viruses are simple biological particles, consisting of a genome, a protein capsid and, in the case of enveloped viruses, an external lipidic envelope. Owing to the presence of envelope, most enveloped viruses are fragile although some exceptions may be observed. Viruses behave as complete intracellular parasites. Their multiplication results from the replication and self-assembly of viral components, this process being directed by the viral genome after it has been released within an infected cell. Virus classification is now essentially based on molecular properties, concerning both the structure and replication strategy of viruses. In virus taxonomy, serial hierarchical levels are family, subfamily, genus and species. Within species, lower hierarchical levels are type, subtype, variant and strain. Knowledge of virus structure and classification is essential for considering the physiopathology, diagnosis and therapy of viral infections.