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1.
Mikrobiyol Bul ; 54(1): 171-190, 2020 Jan.
Artigo em Turco | MEDLINE | ID: mdl-32050888

RESUMO

Human cytomegalovirus (CMV) infections are common in all populations and CMV seroprevalence in women of childbearing age is in the range of 45-100% worldwide. CMV is the most common cause of congenital infections and is associated with fetal development defects and hearing loss. The risk of congenital infection is directly related to maternal immunity and is between 30-40% and 1-2% range in primary and non-primary infections, respectively. Only 5-10% of newborns with congenital infection are symptomatic at birth. Nearly 4% of these babies can die early in life, while 40-60% have to live with permanent sequelae such as sensorineural hearing loss, cognitive deficit and visual impairment. Asymptomatic newborns including those born from mothers with non-primary infections are also at risk for long-term sequelae. These sequelae often develop in the first 1-2 years of life and may extend up to 5-7 years, but the severity of damage reduces in time. CMV seroprevalence in women of childbearing age and pregnant women in Turkey is between 96% and 99.8%. Until recently, our knowledge about the frequency of congenital CMV infections in Turkey was derived from the studies based on the maternal screening tests. These studies, which were far from reflecting the true prevalence of congenital CMV infections, have begun to be replaced by newborn-based systematic screening studies. CMV DNA positivity was found to be 1.6-1.9% in saliva samples, while both saliva and urine and/or blood samples positivity was found to be 0.2-1.4% in the newborn screening studies carried out in Turkey. Glycoprotein B-1 (gB1) was the most frequently detected genotype (38.4-83.3%) in newborns in Turkey. Standard measures and preventive public health practices such as education of the mother, reducing the contact of pregnant women with virus-spreading children and the hand hygiene come into prominence in the prevention of maternal and congenital infections as a result of the absence of an approved vaccine or low protection of existing vaccines. Advanced measures, such as screening blood products especially for the people with immunodeficiency and serological screening of the in-vitro fertilization applications are also being considered. Monitoring of infected newborns and their mothers during pregnancy, postnatal diagnosis and providing counseling for the parents are also critical. Hearing loss can be detected at an early stage using screening tests that become a routine practice for all newborns. Thus, cognitive and psychosocial development of children affected by infection is supported by speech therapy, the use of hearing aids and other practices. However, it should be noted that hearing functions in infected newborns may be normal at birth, but these newborns are at risk for progressive sensorineural hearing loss. For early diagnosis of asymptomatic newborns, it is important to adopt CMV tests as a part of newborn screening programs. Another preventive approach is to treat the mother and the baby with antiviral drugs and preparations that directly target the virus. Passive immunization of the pregnant and the treatment of the symptomatic newborns with valganciclovir have yielded positive results. In this review article, maternal, fetal and newborn based current approaches used in the diagnosis and follow-up of congenital CMV infections have been discussed.


Assuntos
Infecções por Citomegalovirus , Criança , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/terapia , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/epidemiologia , Humanos , Recém-Nascido , Triagem Neonatal , Gravidez , Estudos Soroepidemiológicos , Turquia/epidemiologia
2.
Lupus ; 28(11): 1354-1359, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31551032

RESUMO

With the wide use of immunosuppressive agents, life-threatening cytomegalovirus-associated acute respiratory failure occurs frequently. However, this condition is yet to be fully recognized and the therapeutic approach to it can only be based on comprehensive protocols rather than the biological characteristics of cytomegalovirus. We describe three acute respiratory failure events that were related to the pathogenicity of cytomegalovirus, the primary cytopathic effect and secondary antiviral immunity-mediated damage. All cytomegalovirus infection occurred after immunosuppressive usage while the acute respiratory failure events took place in different clinical settings. The first acute respiratory failure event originated from the immunoinflammatory response after cytomegalovirus infection was circumscribed, while the second resulted from cytomegalovirus reactivation and the third was caused by the combined effect of acute cytomegalovirus infection and the subsequent immunoinflammatory response. According to the clinical setting, corresponding therapeutic approaches (sequential or combined strategy) were carried out. All the patients here presented were responsive to the above therapeutic strategies. Consequently, cytomegalovirus-associated acute respiratory failure in systemic lupus erythematosus patients should be carefully differentiated and a sequential or combined strategy should be carried out according to the clinical setting. Overall, we find that there are three patterns of cytomegalovirus-associated acute respiratory failure in systemic lupus erythematosus patients and propose a novel therapeutic strategy in relation to cytomegalovirus biology.


Assuntos
Infecções por Citomegalovirus/complicações , Imunossupressores/efeitos adversos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Insuficiência Respiratória/etiologia , Doença Aguda , Adolescente , Antivirais/administração & dosagem , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/terapia , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Insuficiência Respiratória/terapia , Adulto Jovem
3.
BMJ Case Rep ; 12(8)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31444261

RESUMO

We report a case of juvenile dermatomyositis (JDM) with cytomegalovirus (CMV) colitis which was further complicated with perforation. The patient, a 6-year-old girl, was diagnosed with JDM 1 month prior to the current presentation. After 2 weeks of optimising her treatment with steroid, intravenous Ig and methotrexate, she was readmitted with diffuse abdominal pain. Erect abdominal X-ray revealed gas under diaphragm. An exploratory laparotomy showed perforation of the large intestine. A biopsy showed inclusion bodies of CMV with immunohistochemistry for CMV positive. Strong positive CMV DNA PCR from tissue specimen, positive IgG CMV and negative IgM CMV in blood suggested a reactivation of CMV. The treatment followed included surgery and strategic use of antiviral agents as well as immunomodulators. CMV enteritis with complications should also be suspected in optimally treated autoimmune disease patients, including JDM, when they present with abdominal symptoms.


Assuntos
Colite/diagnóstico , Infecções por Citomegalovirus/diagnóstico , Citomegalovirus/isolamento & purificação , Dermatomiosite , Perfuração Intestinal/diagnóstico , Dor Abdominal/etiologia , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Criança , Colite/complicações , Colite/terapia , Colostomia , Terapia Combinada , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/terapia , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Perfuração Intestinal/complicações , Perfuração Intestinal/terapia
4.
Int J Mol Sci ; 20(11)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151230

RESUMO

Cytomegalovirus (CMV) infection after hematopoietic stem cell transplantation (HSCT) is one of the critical infectious complications related to host immune recovery. The spectrum of CMV infection is quite extensive, from asymptomatic CMV reactivation presenting mainly as CMV DNAemia to fatal CMV diseases involving gut, liver, lungs, or brain. In addition to organ involvement, CMV reactivation can exert indirect effects such as immunosuppression or graft failure that may result in the development of concurrent infectious complications. Currently, preemptive therapy, which is based on PCR-based monitoring of CMV from blood, is a mainstay enabling improvement in CMV-related outcomes. During the past decades, new antiviral drugs, clinical trials for prophylaxis in high-risk groups, and vaccines for preventing CMV infection have been introduced. In addition, data for immunologic monitoring and adoptive immunotherapy have also been accumulated. Here, we review the current status and recent updates in this field, with future perspectives including immunotherapy in HSCT recipients.


Assuntos
Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Antivirais/uso terapêutico , Ensaios Clínicos como Assunto , Citomegalovirus/imunologia , Vacinas contra Citomegalovirus/administração & dosagem , Vacinas contra Citomegalovirus/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Hospedeiro Imunocomprometido , Imunogenicidade da Vacina , Imunoterapia , Vigilância em Saúde Pública , Padrão de Cuidado , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento
5.
Int J Mol Sci ; 20(8)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018546

RESUMO

Immune responses to human cytomegalovirus (CMV) can be used to assess immune fitness in an individual. Further to its clinical significance in posttransplantation settings, emerging clinical and translational studies provide examples of immune correlates of protection pertaining to anti-CMV immune responses in the context of cancer or infectious diseases, e.g., tuberculosis. In this viewpoint, we provide a brief overview about CMV-directed immune reactivity and immune fitness in a clinical context and incorporate some of our own findings obtained from peripheral blood or tumour-infiltrating lymphocytes (TIL) from patients with advanced cancer. Observations in patients with solid cancers whose lesions contain both CMV and tumour antigen-specific T-cell subsets are highlighted, due to a possible CMV-associated "bystander" effect in amplifying local inflammation and subsequent tumour rejection. The role of tumour-associated antibodies recognising diverse CMV-derived epitopes is also discussed in light of anti-cancer immune responses. We discuss here the use of anti-CMV immune responses as a theranostic tool-combining immunodiagnostics with a personalised therapeutic potential-to improve treatment outcomes in oncological indications.


Assuntos
Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Neoplasias/virologia , Animais , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/terapia , Humanos , Imunidade , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Medicina de Precisão/métodos
6.
Ann Hematol ; 98(7): 1755-1763, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30993417

RESUMO

It has been shown recently that donor and/or recipient cytomegalovirus (CMV) seropositivity is associated with a significant overall survival (OS) decline in acute leukemia patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We now analyzed the prognostic impact of the donor/recipient CMV serostatus in 6968 patients with chronic hematological malignancies who underwent allo-HSCT. Donor and/or recipient CMV seropositivity was associated with a significantly reduced 2-year progression-free survival (PFS, 50% vs. 52%, p = 0.03) and OS (62% vs. 65%, p = 0.01). Multivariate Cox regression analyses showed an independent negative prognostic impact of donor and/or recipient CMV seropositivity on PFS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.03), OS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.003), and non-relapse mortality (HR, 1.2; 95% CI, 1.0-1.3; p = 0.02). OS decline was strongest for CMV-seropositive recipients with a CMV-seronegative donor (HR, 1.2; 95% CI, 1.1-1.3), followed by CMV-seropositive patients with a CMV-seropositive donor (HR, 1.1; 95% CI, 1.0-1.2). Conversely, OS did not differ significantly between CMV-seronegative recipients allografted from a CMV-seropositive donor (HR, 1.0; 95% CI, 0.9-1.2) and patients with donor/recipient CMV seronegativity (p = 0.001 for the four groups together). Non-relapse mortality was also significantly (p = 0.01) higher for CMV-seropositive patients with a CMV-seronegative graft (HR, 1.2; 95% CI, 1.1-1.4) than for CMV-seropositive patients with a CMV-seropositive graft (HR, 1.1; 95% CI, 0.9-1.2) or CMV-seronegative recipients with a CMV-seropositive graft (HR, 1.0; 95% CI, 0.8-1.2). Donor and/or recipient CMV seropositivity still results in an OS decline in patients with chronic hematological malignancies who have undergone allo-HSCT. However, this OS decline seems to be lower than that described for acute leukemia patients previously.


Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Seleção do Doador , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Doadores de Tecidos , Adulto , Idoso , Aloenxertos , Criança , Pré-Escolar , Doença Crônica , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/mortalidade , Infecções por Citomegalovirus/terapia , Intervalo Livre de Doença , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
7.
J Virol ; 93(9)2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30814291

RESUMO

Chromatin-based modifications of herpesviral genomes play a crucial role in dictating the outcome of infection. Consistent with this, host cell multiprotein complexes, such as polycomb repressive complexes (PRCs), were proposed to act as epigenetic regulators of herpesviral latency. In particular, PRC2 has recently been shown to contribute to the silencing of human cytomegalovirus (HCMV) genomes. Here, we identify a novel proviral role of PRC1 and PRC2, the two main polycomb repressive complexes, during productive HCMV infection. Western blot analyses revealed strong HCMV-mediated upregulation of RING finger protein 1B (RING1B) and B lymphoma Moloney murine leukemia virus insertion region 1 homolog (BMI1) as well as of enhancer of zeste homolog 2 (EZH2), suppressor of zeste 12 (SUZ12), and embryonic ectoderm development (EED), which constitute the core components of PRC1 and PRC2, respectively. Furthermore, we observed a relocalization of PRC components to viral replication compartments, whereas histone modifications conferred by the respective PRCs were specifically excluded from these sites. Depletion of individual PRC1/PRC2 proteins by RNA interference resulted in a significant reduction of newly synthesized viral genomes and, in consequence, a decreased release of viral particles. Furthermore, accelerated native isolation of protein on nascent DNA (aniPOND) revealed a physical association of EZH2 and BMI1 with nascent HCMV DNA, suggesting a direct contribution of PRC proteins to viral DNA replication. Strikingly, substances solely inhibiting the enzymatic activity of PRC1/2 did not exert antiviral effects, while drugs affecting the abundance of PRC core components strongly compromised HCMV genome synthesis and particle release. Taken together, our data reveal an enzymatically independent, noncanonical function of both PRC1 and PRC2 during HCMV DNA replication, which may serve as a novel cellular target for antiviral therapy.IMPORTANCE Polycomb group (PcG) proteins are primarily known as transcriptional repressors that modify chromatin and contribute to the establishment and maintenance of cell fates. Furthermore, emerging evidence indicates that overexpression of PcG proteins in various types of cancers contributes to the dysregulation of cellular proliferation. Consequently, several inhibitors targeting PcG proteins are presently undergoing preclinical and clinical evaluation. Here, we show that infection with human cytomegalovirus also induces a strong upregulation of several PcG proteins. Our data suggest that viral DNA replication depends on a noncanonical function of polycomb repressor complexes which is independent of the so-far-described enzymatic activities of individual PcG factors. Importantly, we observe that a subclass of inhibitory drugs that affect the abundance of PcG proteins strongly interferes with viral replication. This principle may serve as a novel promising target for antiviral treatment.


Assuntos
Infecções por Citomegalovirus/metabolismo , Citomegalovirus/fisiologia , Replicação do DNA , DNA Viral/biossíntese , Complexo Repressor Polycomb 1/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Replicação Viral , Células Cultivadas , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/patologia , Infecções por Citomegalovirus/terapia , DNA Viral/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Humanos , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 2/genética
9.
J Pediatr Surg ; 54(9): 1941-1945, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30772005

RESUMO

AIM OF STUDY: CMV-IgM + ve associated biliary atresia (CMV-BA) is a distinct etiological subgroup characterized by older age at presentation and a greater degree of inflammation and hepatic fibrosis, leading to a worse outcome. We report our experience with adjuvant antiviral therapy after Kasai portoenterostomy (KPE). METHODS: Single-center prospective database identification of CMV-IgM + ve associated BA managed between 2003 and 2017. Since 2011, IV ganciclovir (5 mg/kg b.d.) and/or oral valganciclovir (520 mg/m2 b.d.) were started in the early postoperative period in selected cases and continued until negativity of CMV DNA load [Anti-Viral Therapy (AVT) Group 1]. Clearance of jaundice was defined as achieving a total bilirubin ≤20 µmol/L in post-KPE period and tested with a Fisher test; native liver survival (NLS) and overall actuarial survival (OS) were compared with untreated BA CMV IgM + ve patients (Group 2) using a Log-Rank test. A P value of <0.05 was regarded as significant. Data are quoted as median (IQ range). RESULTS: During the 14-year period, 376 infants with histologically confirmed BA were treated; of those 38(10%) were CMV IgM + ve at presentation. One child was considered too late at presentation for KPE and underwent primary liver transplantation while another only started AVT one month after KPE. Both were excluded from survival analysis. Therefore 36 underwent KPE [AVT Group 1 (n = 8) and Control Group 2 (n = 28)]. Overall age at surgery was 67(53-77) days. There was no difference in age at surgery (P = 0.26); bilirubin (P = 0.12); or AST (P = 0.15) between Group 1 and Group 2. Viral load data were available in 16 with a trend towards higher counts in the AVT group 1 [4935 (2668-18,817) vs. 1296 (253-10,471) c/ml; P = 0.06]. Clearance of jaundice was higher in AVT Group 1 (75% vs 21%, P = 0.009). There was no difference in OS (P = 0.24) but NLS was improved in the AVT Group 1 (75% vs. 25% at 2 years; P = 0.04). CONCLUSIONS: Although this finding may be regarded as preliminary, adjuvant antiviral therapy appeared to improve outcome in infants with CMV IgM + ve BA. LEVEL OF EVIDENCE: III.


Assuntos
Atresia Biliar , Infecções por Citomegalovirus , Anticorpos Antivirais/sangue , Antivirais/uso terapêutico , Atresia Biliar/complicações , Atresia Biliar/terapia , Terapia Combinada , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/terapia , Humanos , Imunoglobulina M/sangue , Lactente , Portoenterostomia Hepática , Guias de Prática Clínica como Assunto , Estudos Prospectivos
10.
Cell Immunol ; 336: 58-65, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30626494

RESUMO

Human cytomegalovirus (HCMV) infection is a leading cause of morbidity and mortality in immunocompromised patients, but no specific therapeutic strategy is effective clinically, despite recent achievements. HCMV-specific T-cell therapy was thought to be helpful for the management of HCMV infection. To conduct a deep exploration, we investigated the possibility of engineering peripheral blood mononuclear cells (PBMCs) from immunocompetent and immunocompromised subjects with specific T-cell receptor (TCR) genes. CD8-positive T cells that specifically bind to NLV pentamers could be generated by transferring TCR genes to PBMCs from immunocompetent and immunocompromised subjects. The generation of functional T cells varied among transduction of different PBMCs. The numbers of IFN-γ-secreting T cells increased significantly in immunocompetent and immunodeficient PBMCs, but were unchanged in immune-reconstituted PBMCs. TCR gene transfer is a potential therapeutic strategy for controlling HCMV infection in immunocompromised patients. The transfer of TCR genes into immunocompetent and immunodeficient PBMCs would be more meaningful in response to HCMV infection than would the transfer into immune-reconstituted PBMCs.


Assuntos
Infecções por Citomegalovirus/terapia , Genes Codificadores dos Receptores de Linfócitos T , Terapia Genética , Adolescente , Adulto , Infecções por Citomegalovirus/imunologia , Humanos , Hospedeiro Imunocomprometido , Interferon gama/biossíntese , Masculino , Pessoa de Meia-Idade
11.
Ann Hematol ; 98(4): 1009-1020, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30666434

RESUMO

Cytomegalovirus (CMV) infection and primary disease relapse remain challenging problems after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We sought to assess the association between CMV infection and disease relapse after transplantation. PubMed, EMBASE, the Cochrane Library, SCI, and Chinese Biomedicine Databases were searched up to July 1, 2018, for all studies that investigate pre-transplant CMV serostatus, CMV replication, and primary disease relapse in allo-HSCT patients with hematologic malignancies. Meta-analysis of 24 eligible cohort studies showed a significantly lower relapse risk after allo-HSCT in patients with CMV replication in acute myeloid leukemia (AML) (HR = 0.64, 95% CI, 0.50-0.83; P < 0.001) subgroup. However, CMV replication was associated with increased non-relapse mortality (NRM) in AML patients (HR = 1.64, 95% CI, 1.46-1.85; P < 0.001), but not associated with overall survival (OS) or graft-versus-host disease for AML patients (P > 0.05). There was no association between pre-transplant CMV serostatus and disease relapse, although D-/R- was associated with better OS in acute leukemia patients (HR = 0.89, 95% CI, 0.83-0.96; P = 0.003). In AML patients, CMV replication may be a protective predictor against disease relapse, although the potential benefit of CMV replication is offset by increased NRM.


Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Leucemia Mieloide Aguda , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/mortalidade , Infecções por Citomegalovirus/terapia , Intervalo Livre de Doença , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Estudos Observacionais como Assunto , Recidiva , Fatores de Risco , Taxa de Sobrevida
12.
Fetal Diagn Ther ; 45(2): 111-117, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29684915

RESUMO

BACKGROUND: The Congenital Human Cytomegalovirus Infection Prevention (CHIP) study, a randomized, blinded, placebo-controlled trial, demonstrated that the efficacy of hyperimmune globulin (HIG) was not different from that of placebo regarding transmission of cytomegalovirus (CMV) from mothers to newborns. Our aim was to analyze histologically HIG effects on placentas collected for the CHIP study. MATERIALS AND METHODS: Virological and histological analyses were performed on 40 placentas from transmitter and nontransmitter HIG-treated and untreated mothers by assessing the number of CMV-positive cells, tissue viral load, tissue damage, and compensatory mechanisms. RESULTS: The HIG and placebo groups showed no significant differences in the number of CMV-positive cells (median number in 10 fields at 10 high-power fields: 2.5 vs. 2, p = 0.969) and viral load (median load: 5 copies/5 ng vs. 10.5 copies/5 ng, p = 0.874). Regarding histological examination, the scores of parameters related to tissue damage and hypoxic parenchymal compensation were higher in transmitters except for chorangiosis, with statistically significant differences observed for chronic villitis (p = 0.007), calcification (p = 0.011), and the total score of tissue damage (p < 0.001). The HIG and placebo groups showed no significant differences for all tissue damage and compensation parameters and overall scores. DISCUSSION: HIGs are not able to reduce placental viral load and histological damage, which was significantly associated only with infection.


Assuntos
Infecções por Citomegalovirus/transmissão , Imunoglobulinas Intravenosas/uso terapêutico , Placenta/virologia , Complicações Infecciosas na Gravidez/virologia , Citomegalovirus/imunologia , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/terapia , Feminino , Humanos , Imunoterapia , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Placenta/patologia , Gravidez , Carga Viral
13.
J Matern Fetal Neonatal Med ; 32(4): 617-625, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28978246

RESUMO

INTRODUCTION: Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Data about the management of CMV infection in pregnant women are scarce, and treatment options are very limited. The aim of the study is to investigate the effectiveness of cytomegalovirus hyperimmune globulin (CMV-HIG) for the prevention and treatment of congenital CMV (cCMV) infection. MATERIALS AND METHODS: A retrospective observational study was conducted in three tertiary hospitals in Madrid. In the period 2009-2015, CMV-HIG (Cytotect® CP Biotest, Biotest) treatment was offered to all pregnant women with primary CMV infection and/or detection of CMV-DNA in amniotic fluid in participating centers. Women were divided into prevention and treatment groups (PG and TG, respectively). Those with primary CMV infection who had not undergone amniocentesis comprised the PG and received monthly CMV-HIG (100 UI/kg). If CMV-DNA was subsequently detected in amniotic fluid, one extra dose of CMV-HIG (200 UI/kg) was given 4 weeks after the last dose. Those women were considered to be part of the PG group despite detection of CMV-DNA in amniotic fluid. In the case of a negative result in CMV-DNA detection in amniotic fluid or if amniocentesis was not performed, monthly HIG was given up to the end of the pregnancy. RESULTS: Thirty-six pregnant women were included. Median gestational age at birth was 39 weeks (interquartile range: 38-40) and two children (5.5%) were premature (born at 28 and 34 weeks' gestation). Amniocentesis was performed in 30/36 (83.4%) pregnancies and CMV PCR was positive in 21 of them (70%). One fetus with a positive PCR in amniotic fluid that received one dose of HIG after amniocentesis presented a negative CMV-PCR in urine at birth, and was asymptomatic at 12 months of age. Twenty-four children were infected at birth, and 16/21 (76.2%) presented no sequelae at 12 months, while two (9.5%) had a mild unilateral hearing loss and three (14.3%) severe hearing loss or neurological sequelae. Seventeen women were included in the PG and 19 in the TG. In the PG 7/17 (41%) fetuses were infected, one pregnancy was terminated due to abnormalities in cordocentesis and one showed a mild hearing loss at 12 months of age. In the TG, 18/19 children (95%) were diagnosed with cCMV, while the remaining neonate had negative urine CMV at birth. Eight out of the 19 fetuses (42.1%) showed CMV related abnormalities in the fetal US before HIG treatment. Complete clinical assessment in the neonatal period and at 12 months of age was available in 16 and 15 children, respectively. At birth 50% were symptomatic and at 12 months of age, 4/15 (26.7%) showed a hearing loss and 3/15 (20%) neurologic impairment. Fetuses with abnormalities in ultrasonography before HIG presented a high risk of sequelae (odds ratios: 60; 95%CI: 3-1185; p = .007). DISCUSSION: Prophylactic HIG administration in pregnant women after CMV primary infection seems not to reduce significantly the rate of congenital infection, but is safe and it could have a favorable effect on the symptoms and sequelae of infected fetuses. The risk of long-term sequelae in fetuses without US abnormalities before HIG is low, so it could be an option in infected fetuses with normal imaging. On the other hand, the risk of sequelae among infected fetuses with abnormalities in fetal ultrasonography before HIG despite treatment is high.


Assuntos
Infecções por Citomegalovirus/terapia , Doenças Fetais/prevenção & controle , Imunoglobulinas Intravenosas/administração & dosagem , Complicações Infecciosas na Gravidez/terapia , Adulto , Amniocentese , Líquido Amniótico/virologia , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/prevenção & controle , Feminino , Doenças Fetais/virologia , Humanos , Lactente , Recém-Nascido , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Gravidez , Complicações Infecciosas na Gravidez/virologia , Estudos Retrospectivos , Espanha , Centros de Atenção Terciária , Ultrassonografia Pré-Natal
14.
Biol Blood Marrow Transplant ; 25(3): 577-586, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30342913

RESUMO

Human cytomegalovirus (CMV) infection and disease remains a significant cause of morbidity and mortality for hematopoietic cell transplantation (HCT) recipients. Disruption of or weak reconstitution of virus-specific cellular immune function, such as with certain HCT approaches, poses significant risk for CMV-related complications. The incidence of and risk factors for CMV infection and the nature of CMV disease were evaluated retrospectively among 356 consecutive HCT recipients transplanted at the National Institutes of Health using all graft sources, including bone marrow, peripheral blood stem cell (PBSC), and umbilical cord blood (UCB), and a range of in vivo and ex vivo approaches for graft-versus-host disease (GVHD) prophylaxis. The cumulative incidence of CMV infection was higher for CMV-seropositive recipients at 33%, regardless of donor CMV serostatus. Patients transplanted with CMV-seropositive donors had a significantly shorter duration of antiviral therapy. Among graft sources UCB was associated with the highest cumulative incidence of CMV infection at 65% and significantly longer treatment duration at a median of 36days, whereas PBSC HCT was associated with the lowest incidence at 26% and the shortest CMV treatment duration at a median of 21days. There were significant differences in the cumulative incidence of CMV infection by T cell manipulation strategy when systemic steroids were included as a risk-modifying event. Over one-third of CMV infections occurred in the setting of systemic steroid administration. CMV disease occurred in 5% of HCT recipients, with 70% of cases in the setting of treatment for GVHD. Although factors related to serostatus, graft source, and GVHD prophylaxis were associated with varied CMV infection incidence, unplanned post-HCT corticosteroid therapy contributed greatly to the incidence of both CMV infection and disease across HCT approaches, highlighting this post-HCT intervention as a key time to potentially tailor the approach to monitoring, preemptive therapy, and even prophylaxis.


Assuntos
Infecções por Citomegalovirus/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Antivirais/uso terapêutico , Infecções por Citomegalovirus/etiologia , Feminino , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Estudos Retrospectivos , Fatores de Risco , Esteroides/efeitos adversos , Doadores de Tecidos , Estados Unidos
16.
Viruses ; 10(12)2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30563202

RESUMO

Human Cytomegalovirus (hCMV), which is the prototype member of the ß-subfamily of the herpesvirus family, is a pathogen of high clinical relevance in recipients of hematopoietic cell transplantation (HCT). hCMV causes multiple-organ disease and interstitial pneumonia in particular upon infection during the immunocompromised period before hematopoietic reconstitution restores antiviral immunity. Clinical investigation of pathomechanisms and of strategies for an immune intervention aimed at restoring antiviral immunity earlier than by hematopoietic reconstitution are limited in patients to observational studies mainly because of ethical issues including the imperative medical indication for chemotherapy with antivirals. Aimed experimental studies into mechanisms, thus, require animal models that match the human disease as close as possible. Any model for hCMV disease is, however, constrained by the strict host-species specificity of CMVs that prevents the study of hCMV in any animal model including non-human primates. During eons of co-speciation, CMVs each have evolved a set of "private genes" in adaptation to their specific mammalian host including genes that have no homolog in the CMV virus species of any other host species. With a focus on the mouse model of CD8 T cell-based immunotherapy of CMV disease after experimental HCT and infection with murine CMV (mCMV), we review data in support of the phenomenon of "biological convergence" in virus-host adaptation. This includes shared fundamental principles of immune control and immune evasion, which allows us to at least make reasoned predictions from the animal model as an experimental "proof of concept." The aim of a model primarily is to define questions to be addressed by clinical investigation for verification, falsification, or modification and the results can then give feedback to refine the experimental model for research from "bedside to bench".


Assuntos
Infecções por Citomegalovirus/terapia , Modelos Animais de Doenças , Hospedeiro Imunocomprometido , Imunoterapia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/imunologia , Citomegalovirus , Infecções por Citomegalovirus/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Camundongos , Camundongos Transgênicos
17.
Front Immunol ; 9: 2554, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30450104

RESUMO

Early diagnosis of primary immunodeficiency disorders (PID) is vital and allows directed treatment, especially in syndromes with severe or profound combined immunodeficiency. In PID patients with perinatal CMV or other opportunistic, invasive infections (e.g., Pneumocystis or Aspergillus), multi-organ morbidity may already arise within the first months of life, before hematopoietic stem cell transplantation (HSCT) or gene therapy can be undertaken, compromising the definitive treatment and outcome. Deficiency of Wiskott-Aldrich syndrome (WAS) protein-interacting protein (WIP deficiency) causes an autosomal recessive, WAS-like syndrome with early-onset combined immunodeficiency that has been described in three pedigrees to date. While WAS typically includes combined immunodeficiency, microthrombocytopenia, and eczema, the clinical and laboratory phenotypes of WIP-deficient patients-including lymphocyte subsets, platelets, lymphocyte proliferation in vitro, and IgE-varied widely and did not entirely recapitulate WAS, impeding early diagnosis in the reported patients. To elucidate the phenotype of WIP deficiency, we provide a comprehensive synopsis of clinical and laboratory features of all hitherto-described patients (n = 6) and WIP negative mice. Furthermore, we summarize the treatment modalities and outcomes of these patients and review in detail the course of one of them who was successfully treated with serial, unconditioned, maternal, HLA-identical donor lymphocyte infusions (DLI) against life-threatening, invasive CMV infection, followed by a TCRαß/CD19-depleted, treosulfan/melphalan-conditioned, peripheral blood HSCT and repetitive, secondary-prophylactic, CMV-specific DLI with 1-year post-HSCT follow-up. This strategy could be useful in other patients with substantial premorbidity, considered "too bad to transplant," who have an HLA-identical family donor, to eliminate infections and bridge until definitive treatment.


Assuntos
Infecções por Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Proteínas do Citoesqueleto/genética , Síndromes de Imunodeficiência/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Transfusão de Linfócitos , Síndrome de Wiskott-Aldrich/genética , Animais , Proteínas de Transporte/genética , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/terapia , Feminino , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas , Histocompatibilidade , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Lactente , Camundongos , Camundongos Knockout , Linhagem , Fenótipo , Doadores de Tecidos , Condicionamento Pré-Transplante
19.
Am J Case Rep ; 19: 1393-1397, 2018 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-30467305

RESUMO

BACKGROUND Cytomegalovirus (CMV) pneumonia is common in immunocompromised patients with hematological malignancies. Although the spectrum of illness caused by CMV is well-documented in immunocompromised patients, the clinical course and evolution of lung changes after initiation of antiviral therapy remain unclear. CASE REPORT We present the cases of 3 patients with leukemia who developed CMV pneumonia following cord blood transplantation and who presented with distinctive features on chest computed tomography (CT). In all patients, chest CT showed central peribronchial changes with severe lung volume loss. Furthermore, the patients were refractory to high-dose steroids, and the lung volume loss rapidly progressed, leading to death from respiratory failure. CONCLUSIONS We observed central peribronchial changes with severe lung volume loss after the acute phase in 3 cases of CMV pneumonia. While our diagnosis was made on the basis of exclusion, it is important to bear in mind that lung involvement in CMV pneumonia may be refractory to various treatment modalities and can lead to a fatal clinical course.


Assuntos
Infecções por Citomegalovirus/diagnóstico , Pneumonia/diagnóstico , Insuficiência Respiratória/etiologia , Adulto , Idoso , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/terapia , Evolução Fatal , Feminino , Humanos , Leucemia/complicações , Leucemia/imunologia , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Pneumonia/etiologia , Pneumonia/terapia , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/terapia , Tomografia Computadorizada por Raios X
20.
Rinsho Ketsueki ; 59(10): 2373-2379, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30305548

RESUMO

Recipients of hematopoietic stem cell transplantation suffering from severe immunosuppression and immune dysregulation because of GVHD or other causes are at higher risk of viral infection. Often, cytomegalovirus and EB virus are reactivated from their latent state in these patients ; viral infections thus remain a primary cause of severe morbidity and mortality. Since the 1990s, virus-specific T cells have been generated by different methods using immunogenic epitope peptides or EBV-LCL from transplant donors, and studies have demonstrated the efficacy of these methods. However, establishing such order-made, virus-specific T cells requires 8-10 weeks, which is not feasible for application in the frontline of clinics. Recent advances, such as direct donor T cell selection using peptide-HLA multimers or cytokine capture method and virus-specific T cells bank generated using third-party donors, facilitated the broadening of the applicability of this method. The clinical development of virus-specific T-cell therapy is considered as the prototype of future T-cell immunotherapy for various infections or malignant diseases.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunoterapia , Linfócitos T/citologia , Viroses/terapia , Infecções por Citomegalovirus/terapia , Infecções por Vírus Epstein-Barr/terapia , Humanos , Imunoterapia Adotiva
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