There is only limited data on cytomegalovirus (CMV) prophylaxis with high-dose (HD) aciclovir after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We performed a retrospective analysis on a total of 179 patients who underwent their allo-HSCT with HD-aciclovir prophylaxis at our center. A clinically significant CMV infection (cs-CMVi) was observed in 56 (31%) cases with a median time of 49 (range 25-147) days after HSCT. A significantly higher CMV infection rate was observed in seropositive recipients with a seronegative donor (74%) compared to seropositive recipients with a seropositive donor, and seronegative recipients with seropositive and seronegative donors (24%, 18%, 7% respectively; p < 0.001). The CMV serostatus was the only significant risk factor for CMV infection in our analysis. CMV disease developed in three patients with CMV-related death in two cases. During HD-aciclovir prophylaxis, we did not observe any medical condition attributable to HD-aciclovir's adverse effects. Compared to published results, we observed a low incidence of cs-CMVi with HD-aciclovir prophylaxis in several patient subgroups, especially in seropositive recipients with a seropositive donor. With respect to the determined threshold, HD-aciclovir prophylaxis seems to have good efficacy in an intermediate cs-CMVi risk patients, but prospective randomized trials would be needed for definite conclusions.
- MeSH
- acyklovir terapeutické užití MeSH
- antivirové látky terapeutické užití MeSH
- cytomegalovirové infekce * etiologie prevence a kontrola farmakoterapie MeSH
- Cytomegalovirus MeSH
- lidé MeSH
- prospektivní studie MeSH
- retrospektivní studie MeSH
- transplantace hematopoetických kmenových buněk * škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
POZOR! při kopírování abstrakt kontrolovat slova na konci řádků originálu!!!
POZOR! při kopírování abstrakt kontrolovat slova na konci řádků originálu!!!
SIGNIFICANCE STATEMENT: Although cytomegalovirus (CMV) infection is an important factor in the pathogenesis of kidney allograft rejection, previous studies have not determined the optimal CMV prevention strategy to avoid indirect effects of the virus. In this randomized trial involving 140 kidney transplant recipients, incidence of acute rejection at 12 months was not lower with valganciclovir prophylaxis (for at least 3 months) compared with preemptive therapy initiated after detection of CMV DNA in whole blood. However, prophylaxis was associated with a lower risk of subclinical rejection at 3 months. Although both regimens were effective in preventing CMV disease, the incidence of CMV DNAemia (including episodes with higher viral loads) was significantly higher with preemptive therapy. Further research with long-term follow-up is warranted to better compare the two approaches. BACKGROUND: The optimal regimen for preventing cytomegalovirus (CMV) infection in kidney transplant recipients, primarily in reducing indirect CMV effects, has not been defined. METHODS: This open-label, single-center, randomized clinical trial of valganciclovir prophylaxis versus preemptive therapy included kidney transplant recipients recruited between June 2013 and May 2018. After excluding CMV-seronegative recipients with transplants from seronegative donors, we randomized 140 participants 1:1 to receive valganciclovir prophylaxis (900 mg, daily for 3 or 6 months for CMV-seronegative recipients who received a kidney from a CMV-seropositive donor) or preemptive therapy (valganciclovir, 900 mg, twice daily) that was initiated after detection of CMV DNA in whole blood (≥1000 IU/ml) and stopped after two consecutive negative tests (preemptive therapy patients received weekly CMV PCR tests for 4 months). The primary outcome was the incidence of biopsy-confirmed acute rejection at 12 months. Key secondary outcomes included subclinical rejection, CMV disease and DNAemia, and neutropenia. RESULTS: The incidence of acute rejection was lower with valganciclovir prophylaxis than with preemptive therapy (13%, 9/70 versus 23%, 16/70), but the difference was not statistically significant. Subclinical rejection at 3 months was lower in the prophylaxis group (13% versus 29%, P = 0.027). Both regimens prevented CMV disease (in 4% of patients in both groups). Compared with prophylaxis, preemptive therapy resulted in significantly higher rates of CMV DNAemia (44% versus 75%, P < 0.001) and a higher proportion of patients experiencing episodes with higher viral load (≥2000 IU/ml), but significantly lower valganciclovir exposure and neutropenia. CONCLUSION: Among kidney transplant recipients, the use of valganciclovir prophylaxis did not result in a significantly lower incidence of acute rejection compared with the use of preemptive therapy. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Optimizing Valganciclovir Efficacy in Renal Transplantation (OVERT Study), ACTRN12613000554763 .
- MeSH
- antivirové látky škodlivé účinky MeSH
- cytomegalovirové infekce * epidemiologie MeSH
- Cytomegalovirus genetika MeSH
- lidé MeSH
- neutropenie * chemicky indukované komplikace MeSH
- příjemce transplantátu MeSH
- transplantace ledvin * škodlivé účinky MeSH
- valganciklovir škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
Human cytomegalovirus (HCMV) can cause significant end-organ diseases such as pneumonia in HIV-exposed infants. Complex viral factors may influence pathogenesis including: a large genome with a sizeable coding capacity, numerous gene regions of hypervariability, multiple-strain infections, and tissue compartmentalization of strains. We used a whole genome sequencing approach to assess the complexity of infection by comparing high-throughput sequencing data obtained from respiratory and blood specimens of HIV-exposed infants with severe HCMV pneumonia with those of lung transplant recipients and patients with hematological disorders. There were significantly more specimens from HIV-exposed infants showing multiple HCMV strain infection. Some genotypes, such as UL73 G4B and UL74 G4, were significantly more prevalent in HIV-exposed infants with severe HCMV pneumonia. Some genotypes were predominant in the respiratory specimens of several patients. However, the predominance was not statistically significant, precluding firm conclusions on anatomical compartmentalization in the lung.
- MeSH
- cytomegalovirové infekce * epidemiologie MeSH
- Cytomegalovirus genetika MeSH
- HIV infekce * komplikace MeSH
- kojenec MeSH
- lidé MeSH
- pneumonie * MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Jihoafrická republika MeSH
BACKGROUND: There is a paucity of data on the impact of cytomegalovirus (CMV) serostatus and CMV infection on outcomes in facial vascularized composite allotransplantation. METHODS: This international, multicenter, retrospective cohort study presents data on CMV and basic transplant-related demographics, including pretransplant viral D/R serostatus, and duration of antiviral prophylaxis. CMV-related complications (viremia, disease), allograft-related complications (rejection episodes, loss), and mortality were analyzed. RESULTS: We included 19 patients, 4 of whom received CMV high-risk transplants (D+/R-). CMV viremia was noted in 6 patients (all 4 D+/R- patients and 2 D-/R+), mostly within the first-year posttransplant, shortly after discontinuation of antiviral prophylaxis (median 2 mo). CMV disease occurred in 2 D+/R- patients. The high-risk group experienced relatively more rejection episodes per month follow-up. None of D+/R- patients suffered allograft loss due to rejection (longest follow-up: 121 mo). CONCLUSIONS: D+/R- patients were at increased risk of CMV-related complications. Although a higher number of rejections was noted in this group, none of the D+/R- patients lost their allograft or died because of CMV or rejection. Thus, CMV D+/R- face transplantation can likely be safely performed with prophylaxis, active surveillance, and prompt treatment.
- MeSH
- antivirové látky terapeutické užití MeSH
- cytomegalovirové infekce * farmakoterapie MeSH
- Cytomegalovirus MeSH
- lidé MeSH
- retrospektivní studie MeSH
- valganciklovir terapeutické užití MeSH
- vaskularizovaná kompozitní alotransplantace * škodlivé účinky MeSH
- viremie farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
Viral infections enhance cancer risk and threaten host genome integrity. Although human cytomegalovirus (HCMV) proteins have been detected in a wide spectrum of human malignancies and HCMV infections have been implicated in tumorigenesis, the underlying mechanisms remain poorly understood. Here, we employed a range of experimental approaches, including single-molecule DNA fiber analysis, and showed that infection by any of the four commonly used HCMV strains: AD169, Towne, TB40E or VR1814 induced replication stress (RS), as documented by host-cell replication fork asymmetry and formation of 53BP1 foci. The HCMV-evoked RS triggered an ensuing host DNA damage response (DDR) and chromosomal instability in both permissive and non-permissive human cells, the latter being particularly relevant in the context of tumorigenesis, as such cells can survive and proliferate after HCMV infection. The viral major immediate early enhancer and promoter (MIEP) that controls expression of the viral genes IE72 (IE-1) and IE86 (IE-2), contains transcription-factor binding sites shared by promoters of cellular stress-response genes. We found that DNA damaging insults, including those relevant for cancer therapy, enhanced IE72/86 expression. Thus, MIEP has been evolutionary shaped to exploit host DDR. Ectopically expressed IE72 and IE86 also induced RS and increased genomic instability. Of clinical relevance, we show that undergoing standard-of-care genotoxic radio-chemotherapy in patients with HCMV-positive glioblastomas correlated with elevated HCMV protein markers after tumor recurrence. Collectively, these results are consistent with our proposed concept of HCMV hijacking transcription-factor binding sites shared with host stress-response genes. We present a model to explain the potential oncomodulatory effects of HCMV infections through enhanced replication stress, subverted DNA damage response and induced genomic instability.
Herpesviruses can either cause primary infection or may get reactivated after both hematopoietic cell and solid organ transplantations. In general, viral infections increase post-transplant morbidity and mortality. Prophylactic, preemptive, or therapeutically administered antiviral drugs may be associated with serious side effects and may induce viral resistance. Virus-specific T cells represent a valuable addition to antiviral treatment, with high rates of response and minimal side effects. Even low numbers of virus-specific T cells manufactured by direct selection methods can reconstitute virus-specific immunity after transplantation and control viral replication. Virus-specific T cells belong to the advanced therapy medicinal products, and their production is regulated by appropriate legislation; also, strict safety regulations are required to minimize their side effects.
Vývoj imunitního systému probíhá od dětských let až do pozdního stáří. Každé z těchto období má své zvláštnosti. Stárnutí je pro imunitu typické, a to v závislosti na přeměně hematogenní kostní dřeně na tukovou, na involuci thymu (brzlíku) a perzistujících virových infekcích (např. CMV). U starých lidí, jejichž počet v posledních dekádách narůstá, je potřeba porozumět změnám imunitního systému, které nazýváme imunosenescencí. Podstatná přestavba imunitního systému v průběhu stárnutí vede k poklesu jeho funkční aktivity v oblasti vrozené (komplement, cytokiny, granulocyty, NK buňky, makrofágy) i adaptivní imunity (B lymfocyty a tvorba protilátek, T lymfocyty, produkce cytokinů a cytotoxická reakce, NKT buňky, T regulační lymfocyty se supresorovou aktivitou) s postupujícím věkem, což má za následek zvýšené riziko chronických onemocnění, infekcí, autoimunity a selhání vakcinace.
The immune system develops from childhood until the late age. Each of these periods has its own specialities. Aging is typical for immunity, depending on the conversion of hematogenous bone marrow to adipose, involution of the thymus and persistent viral infections (e.g. CMV). In the elderly, whose numbers have been increasing in recent decades, there is a need to understand the changes in the immune system also called as immunosenescence. The substantial remodeling of the immune system during aging leads to a decline in its functional activity in both innate (complement, cytokines, granulocytes, NK cells, macrophages) and adaptive immunity (B lymphocytes and antibody production, T lymphocytes, cytokine production and cytotoxic response, NKT cells, regulatory T lymphocytes with suppressor activity) with advancing age, resulting in increased risk of chronic diseases, infections, autoimmunity and vaccination failure.
- MeSH
- adaptivní imunita imunologie MeSH
- Cytomegalovirus MeSH
- imunosenescence * imunologie MeSH
- lidé MeSH
- Orthomyxoviridae MeSH
- přirozená imunita imunologie MeSH
- rizikové faktory MeSH
- senioři MeSH
- Streptococcus pneumoniae MeSH
- vakcinace * MeSH
- věkové faktory MeSH
- virové vakcíny MeSH
- virus varicella zoster MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Letermovir (LMV) is licensed for prophylaxis of CMV infection in allogeneic hematopoietic cell transplant adult CMV-seropositive patients. Due to its favorable safety profile, LMV brings potential for use in other clinical situations, outside the approved indication. The objective of the study was to analyze the efficacy and safety of the use of LMV in off-label indications in EBMT centers. A total of 49 patients were reported including 44 adults and 5 children. LMV was administered for: secondary prophylaxis (37 adults, 3 children), primary prophylaxis (2 children), pre-emptive treatment (5 adults), and therapy of CMV disease (2 adults; pneumonia, colitis). Cyclosporine was concomitantly used in 26 patients. Overall, LMV was used for a median 112 days (range: 10-473). Cumulative incidence of breakthrough infections during secondary prophylaxis was 10.1% (95% CI = 3.1-21.9). Prophylactic treatment with LMV resulted in 94.9% (95% CI = 81.0-98.7), and 81.9% (95% CI = 65.7-90.9) probability of, respectively, 60 and 120-day survival without CMV infection in patients receiving secondary prophylaxis. During therapy of CMV infection/disease, probability of 60 and 120-day overall survival was 100% and 71.4% (95% CI = 25.8-92.0), respectively. No breakthrough infection occurred in children on LMV prophylaxis. Adverse events were reported in 15/49 (30.4%) patients: the most common being nausea/vomiting (22.4%). In conclusion, the efficacy of the use of LMV as secondary prophylaxis was high, and the preliminary experience with the use of LMV for the treatment of patients with refractory CMV infection/disease was positive. Our data showed that higher dose or prolonged therapy did not result in increased rate of adverse events.
- MeSH
- acetáty MeSH
- antivirové látky terapeutické užití MeSH
- chinazoliny MeSH
- Cytomegalovirus MeSH
- dítě MeSH
- dospělí MeSH
- infekční nemoci * MeSH
- kostní dřeň MeSH
- lidé MeSH
- off-label použití léčivého přípravku MeSH
- retrospektivní studie MeSH
- transplantace hematopoetických kmenových buněk * MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Werner's Complex, as a cationic coordination complex (CCC), has hitherto unappreciated biological properties derived from its binding affinity to highly anionic biomolecules such as glycosaminoglycans (GAGs) and nucleic acids. Competitive inhibitor and spectroscopic assays confirm the high affinity to GAGs heparin, heparan sulfate (HS), and its pentasaccharide mimetic Fondaparinux (FPX). Functional consequences of this affinity include inhibition of FPX cleavage by bacterial heparinase and mammalian heparanase enzymes with inhibition of cellular invasion and migration. Werner's Complex is a very efficient condensing agent for DNA and tRNA. In proof-of-principle for translational implications, it is demonstrated to display antiviral activity against human cytomegalovirus (HCMV) at micromolar concentrations with promising selectivity. Exploitation of non-covalent hydrogen-bonding and electrostatic interactions has motivated the unprecedented discovery of these properties, opening new avenues of research for this iconic compound.
- MeSH
- antivirové látky chemie farmakologie MeSH
- Cytomegalovirus účinky léků MeSH
- fondaparinux antagonisté a inhibitory MeSH
- glykosaminoglykany chemie farmakologie MeSH
- komplexní sloučeniny chemie farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
