Efficacy and safety of adoptive T-cell therapy in treating cytomegalovirus infections post-haematopoietic stem cell transplantation: A systematic review and meta-analysis.

Cytomegalovirus (CMV) infection poses significant risks in allogeneic haematopoietic stem cell transplant (allo-HSCT) recipients. Despite advances in antiviral therapies, issues such as drug resistance, side effects, and inadequate immune reconstitution remain. This systematic review and meta-analysis aim to evaluate the efficacy and safety of adoptive cell therapy (ATC) in managing CMV infections in allo-HSCT recipients. Adhering to preferred reporting items for systematic reviews and meta-analyses guidelines, we conducted a comprehensive database search through July 2023. A systematic review and meta-analysis were conducted on studies involving HSCT patients with CMV infections treated with ATC. The primary outcome was the response rate to ATC, and secondary outcomes included adverse events associated with ATC. The Freeman-Tukey transformation was applied for analysis. In the meta-analysis of 40 studies involving 953 participants, ATC achieved an overall integrated response rate of 90.16%, with a complete response of 82.59% and a partial response of 22.95%. ATC source, HLA matching, steroid intake, and age group markedly influenced response rates. Donor-derived T-cell treatments exhibited a higher response rate (93.66%) compared to third-party sources (88.94%). HLA-matched patients demonstrated a response rate of 92.90%, while mismatched patients had a lower rate. Children showed a response rate of 83.40%, while adults had a notably higher rate of 98.46%. Adverse events were minimal, with graft-versus-host disease occurring in 24.32% of patients. ATC shows promising response rates in treating CMV infections post-HSCT, with an acceptable safety profile. However, to establish its efficacy conclusively and compare it with other antiviral treatments, randomised controlled trials are essential. Further research should prioritise such trials over observational and one-arm studies to provide robust evidence for clinical decision-making.

From diagnosis to management: current perspectives on congenital cytomegalovirus infection.

PURPOSE OF REVIEW: Congenital CMV (cCMV) infection is the most common infection of newborns and a leading cause of hearing loss and other neurologic disabilities in children. This review focuses on the diagnosis, presentation and management of cCMV infection. RECENT FINDINGS: Cytomegalovirus is one of the leading causes of sensorineural hearing loss in children. It also leads to neurodevelopmental disabilities and learning problems throughout childhood in both symptomatic and asymptomatic newborns. Urine and saliva PCR testing are the preferred methods of testing newborn infants for cCMV. In recent years, newborn-targeted and universal screening programs have been implemented in several states and major medical centers with the goal of identifying infected infants at risk for hearing loss. Treatment for infants diagnosed with cCMV infection should be limited to those who are moderately to severely symptomatic at birth with cCMV infection, though treatment may be beneficial for children who are asymptomatic with isolated sensorineural hearing loss. SUMMARY: As more children with cCMV are being identified through newborn screening, understanding the clinical presentation and sequelae is important for appropriate management of children with cCMV.

Rapid response in relapsed follicular lymphoma to novel anti-CD19 CAR-T therapy with pseudo-progression and cytomegalovirus infection: A case report.

CD19-directed chimeric antigen receptor (CAR) T cell therapy has been shown to achieve a considerably durable response in patients with refractory or relapsed B cell non-Hodgkin lymphomas. Most of these CARs were generated by lentivirus. With the exception of Yescarta and Tecartus, few patients with relapsed-/refractory- lymphoma have been treated clinically with a CARs using retroviral vector (RV). Here, we reported a relapsed/refractory grade 2 follicular lymphoma patient with multiple chemotherapy failures, and was treated with a novel CD19 CAR-T cell manufactured from a RV. After tumor burden was reduced with Obinutuzumab and Duvelisib, the patient was infused novel CD19 CAR-T cells at a dose of 3 × 106 cells/ kg. Then he experienced a rapid response and achieved almost complete remission by day 26. Only grade 2 CRS, bilateral submaxillary lymph node enlargement and cytomegalovirus (CMV) infection occurred without neurotoxicity, and the patient's condition improved after a series of symptomatic treatments. In addition, CAR copy number peaked at 532,350 copies/µg on day 15 and continued to expand for 5 months. This may be the first case report of RV preparation of novel CD19 CAR-T cells for direct treatment of recurrent follicular lymphoma. We will observe its long-term efficacy and conduct trials in more patients in the future.

Mesenchymal Stem Cell-Derived Exosomes Attenuate Murine Cytomegalovirus-Infected Pneumonia via NF-κB/NLRP3 Signaling Pathway.

Reactivation and infection with cytomegalovirus (CMV) are frequently observed in recipients of solid organ transplants, bone marrow transplants, and individuals with HIV infection. This presents an increasing risk of allograft rejection, opportunistic infection, graft failure, and patient mortality. Among immunocompromised hosts, interstitial pneumonia is the most critical clinical manifestation of CMV infection. Recent studies have demonstrated the potential therapeutic benefits of exosomes derived from mesenchymal stem cells (MSC-exos) in preclinical models of acute lung injury, including pneumonia, ARDS, and sepsis. However, the role of MSC-exos in the pathogenesis of infectious viral diseases, such as CMV pneumonia, remains unclear. In a mouse model of murine CMV-induced pneumonia, we observed that intravenous administration of mouse MSC (mMSC)-exos reduced lung damage, decreased the hyperinflammatory response, and shifted macrophage polarization from the M1 to the M2 phenotype. Treatment with mMSC-exos also significantly reduced the infiltration of inflammatory cells and pulmonary fibrosis. Furthermore, in vitro studies revealed that mMSC-exos reversed the hyperinflammatory phenotype of bone marrow-derived macrophages infected with murine CMV. Mechanistically, mMSC-exos treatment decreased activation of the NF-κB/NLRP3 signaling pathway both in vivo and in vitro. In summary, our findings indicate that mMSC-exo treatment is effective in severe CMV pneumonia by reducing lung inflammation and fibrosis through the NF-κB/NLRP3 signaling pathway, thus providing promising therapeutic potential for clinical CMV infection.

Guías Latinoamericanas de Infecciones Congénitas y Perinatales de la Sociedad Latinoamericana de Infectología Pediátrica (SLIPE). Parte II / Latin American Guidelines on Congenital and Perinatal Infections from the Latin-American Society of Pediatric Infectious Diseases (SLIPE). Part II

Las infecciones perinatales son una causa de morbilidad, tanto fetal como neonatal, y que compromete la salud de la mujer embarazada, por lo que su diagnóstico, tratamiento, e intento de eliminación son una prioridad en América Latina y el Caribe. Este documento representa la segunda entrega realizada por expertos en la región dentro de la Sociedad Latinoamericana de Infectología Pediátrica (SLIPE), brindando una mirada actualizada en el manejo de las infecciones congénitas y entrega herramientas para detectar posibles momentos estratégicos de intervención y cambio en el manejo de las infecciones congénitas.

Perinatal infections are a major cause of morbidity and mortality in the fetus, neonate, and the health of the pregnant woman. Diagnosis, treatment, and the search for elimination of these diseases are a priority in Latin America and the Caribbean. This document represents the second delivery by a group of experts in the region inside the Latin-American Society of Pediatric Infectious Diseases (SLIPE), presenting a up-to-date look into the management of congenital infectious diseases and give a tool to detect possible strategic sceneries and a change in the management of congenital infections in our region.

Adoptive therapy with cytomegalovirus-specific cytotoxic T lymphocytes for refractory cytomegalovirus DNAemia and disease after allogeneic haematopoietic stem cell transplantation.

Cytomegalovirus (CMV) DNAemia and disease are common complications in patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT). Few studies have compared the efficacy and safety of the HSCT donor and third-party CMV-specific cytotoxic T lymphocytes (CMV-CTLs) in the treatment of CMV DNAemia and disease. In this study, we retrospectively compared the efficacy and safety of HSCT donor and third-party CMV-CTLs in patients with refractory CMV DNAemia or disease after allo-HSCT at our centre from January 2017 to September 2021. Fifty-three patients who received CMV-CTL therapy were enrolled, including 40 in the donor group and 13 in the third-party group, and they were adults aged 18 years or older. Within 6 weeks of treatment, 26 (65.0%) and 9 (69.2%) patients achieved complete response in the donor and third-party groups (p = 1.000). The 2-year overall survival was 59.6% (95% CI 46.1%-77.1%) and 53.8% (32.6%-89.1%) in the donor and third-party groups (p = 0.860). Four (10.0%) patients in the donor group and two (15.4%) patients in the third-party group developed acute graft-versus-host disease within 3 months after CMV-CTL infusions. In conclusion, our data suggest that donor and third-party CMV-CTLs have comparable efficacy and safety for refractory CMV DNAemia and disease.

Adoptive transfer of CMV-specific TCR-T cells for the treatment of CMV infection after haploidentical hematopoietic stem cell transplantation.

BACKGROUND: Cytomegalovirus (CMV) reactivation after unmanipulated haploidentical stem cell transplantation (SCT) frequently occurs, causing life-threatening morbidities and transplantation failure. Pre-emptive therapy upon the detection of CMV viremia using antiviral agents is currently the standard of care but it was associated with significant toxicity. The CMV antigen-specific cytotoxic T lymphocyte therapy was limited by the time-consuming manufacture process and relatively low success rate. More effective and safer approaches for the treatment of CMV reactivation after haploidentical SCT are in urgent need. METHODS: A single-arm, open-label, phase I clinical trial evaluating the safety and efficacy of CMV-targeting T cell receptor-engineered T (CMV-TCR-T) cell therapy as the first-line pre-emptive therapy for patients with CMV reactivation after haploidentical peripheral blood SCT (PBSCT) was conducted in the Chinese PLA General Hospital. Six patients with CMV reactivation after haploidentical SCT were adoptively transferred by one to three doses of SCT donors-derived CMV-TCR-T cells. This trial was a dose-escalation study with doses ranging from 1×103 CMV-TCR-T cells/kg body weight per dose to 5×105 CMV-TCR-T cells/kg per dose. RESULTS: Except for the grade 1 cytokine release syndrome observed in one patient and mild fever in two patients, no other adverse events were observed. Four patients had response within a month after CMV-TCR-T cell infusion without the administration of any antiviral agents. The other two patients who initially did not respond to CMV-TCR-T cell therapy had salvage ganciclovir and foscarnet administration and then had rapid CMV clearance. The CMV-TCR-T cells displayed overall robust expansion and persistence in the peripheral blood after infusion. The CMV-TCR-T cells were first detected in the peripheral blood of these patients 3-7 days after the first dose of CMV-TCR-T infusion, rapidly expanded and persisted for at least 1-4 months, providing long-term protection against CMV reactivation. In one patient, the CMV-TCR-T cells started to expand even when the anti-graft-versus-host disease reagents were still being used, further indicating the proliferation potential of CMV-TCR-T cells. CONCLUSIONS: Our study first showed CMV-TCR-T cell as a highly feasible, safe and effective first-line pre-emptive treatment for CMV reactivation after haploidentical PBSCT. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05140187).

Development of a highly cytotoxic, clinical-grade virus-specific T cell product for adoptive T cell therapy.

At present, recipients of allogeneic hematopoietic stem-cells are still suffering from recurrent infections after transplantation. Infusion of virus-specific T cells (VST) post-transplant reportedly fights several viruses without increasing the risk of de novo graft-versus-host disease. This study targeted cytomegalovirus (CMV) for the development of an innovative approach for generating a very specific VST product following Good Manufacturing Practices (GMP) guidelines. We used a sterile disposable compartment named the Leukoreduction System Chamber (LRS-chamber) from the apheresis platelet donation kit as the starting material, which has demonstrated high levels of T cells. Using a combination of IL-2 and IL-7 we could improve expansion of CMV-specific T cells. Moreover, by developing and establishing a new product protocol, we were able to stimulate VST proliferation and favors T cell effector memory profile. The expanded VST were enriched in a closed automated system, creating a highly pure anti-CMV product, which was pre-clinically tested for specificity in vitro and for persistence, biodistribution, and toxicity in vivo using NOD scid mice. Our results demonstrated very specific VST, able to secrete high amounts of interferon only in the presence of cells infected by the human CMV strain (AD169), and innocuous to cells partially HLA compatible without viral infection.

Recomendaciones para el diagnóstico y el manejo de la infección por citomegalovirus en la mujer embarazada y el recién nacido / Recommendations for the diagnosis and management of cytomegalovirus infection in pregnant women and newborns

Resumen La Sociedad Chilena de Infectología, a través de su Comité de Infecciones Neonatales, en conjunto con la Sociedad Chilena de Obstetricia y Ginecología, proponen un documento de diagnóstico y manejo de la infección por citomegalovirus (CMV) en la mujer embarazada y el recién nacido. Esta guía aborda el manejo de la infección en el binomio, su enfrentamiento diagnóstico y terapéutico, orientado al equipo de salud que atiende a mujeres embarazadas y recién nacidos con infección por CMV en Chile. Considera la situación epidemiológica global y latinoamericana, con recomendaciones para la evaluación clínica y de laboratorio; establece criterios de diagnóstico, propone enfoques terapéuticos de acuerdo a la situación clínica, analiza las medidas de prevención y establece una propuesta nacional para el seguimiento de esta enfermedad. Se ha puesto especial énfasis en entregar, de forma práctica, y con la mayor evidencia posible, las recomendaciones para el manejo del binomio con infección por CMV.

Abstract The Chilean Society of Infectology, through its Neonatal Infections Committee in conjunction with the Chilean Society of Obstetrics and Gynecology, propose a document for the Diagnosis and Management of Cytomegalovirus Infection in Pregnancy and Newborn. This guideline suggests the management of mother and child infection, its diagnostic and therapeutic options. Considers the global and Latin American epidemiology, with recommendations for clinical and laboratory evaluation, diagnostic criteria, therapeutic approaches according to the clinical situation, analyzes prevention measures and establishes a national proposal for monitoring this disease.

Manifestaciones clínicas asociadas al síndrome de TORCH / Clinical manifestations associated to the TORCH syndrome

Las infecciones neonatales se adquieren comúnmente por la vía intrauterina o durante el parto. El acrónimo TORCH fue designado para un grupo de infecciones comunes, y se utiliza de forma universal para caracterizar el cuadro clínico que presenta el feto o el recién nacido compatible con una infección congénita que incluye rash, hepatoesplenomegalia, hidrocefalia o microcefalia, alteraciones cardiovasculares, auditivas y oculares. Las siglas TORCH comprenden toxoplasmosis, otros (sífilis y HIV), rubeola, citomagalovirus y herpes simple. Lo más importante de este término es que dota al médico de las herramientas para hacer un enfrentamiento racional, tanto diagnóstico como terapéutico, y establecer un plan de acción para minimizar los daños producidos por estas infecciones. Con esta revisión nos proponemos destacar las manifestaciones clínicas más importantes asociadas al síndrome de TORCH, así como sus vías de transmisión, diagnóstico y tratamiento de las infecciones que lo comprenden, teniendo en cuenta que con relativa frecuencia en nuestra institución son interconsultados estos pacientes y que de su evaluación correcta y oportuna puede depender un diagnóstico certero, con un tratamiento adecuado, y una mejor evolución de estos(AU)

Neonatal infections are often acquired during pregnancy or childbirth. The acronym TORCH refers to a group of common infections, and is universally used to characterize a clinical status of fetuses or newborns which is compatible with a congenital infection, including rash, hepatosplenomegaly, hydrocephalus or microcephaly, as well as cardiovascular, hearing or sight disorders. The initials TORCH stand for Toxoplasmosis, Other infections (such as syphilis or HIV), Rubella, Cytomegalovirus and Herpes simplex. The term is especially useful because it provides doctors with the tools required for a rational diagnostic and therapeutic response and the development of an action plan aimed at minimizing the damage caused by these infections. The purpose of this review is to present the most important clinical manifestations of the TORCH syndrome, as well as its routes of transmission, diagnosis and treatment of the infections making it up(AU)

Síndrome de TORCH: enfoque racional del diagnóstico y tratamiento pre y post natal. Recomendaciones del Comité Consultivo de Infecciones Neonatales Sociedad Chilena de Infectología, 2016 / TORCH syndrome: Rational approach of pre and post natal diagnosis and treatment. Recommendations of the Advisory Committee on Neonatal Infections Sociedad Chilena de Infectología, 2016

There is a lot of bacterial, viral or parasite infections who are able to be transmitted vertically from the mother to the fetus or newborn which implicates an enormous risk for it. The TORCH acronym is used universally to refer to a fetus or newborn which presents clinical features compatible with a vertically acquired infection and allows a rational diagnostic and therapeutic approach. The traditional "TORCH test" is nowadays considered not appropriate and it has been replaced for specific test for specific pathogens under well defined circumstances. The present document reviews the general characteristics, epidemiology, pathogenesis, diagnostic and therapeutic options for the most frequently involved pathogens in the fetus or newborn with TORCH suspicion.

Existen numerosas infecciones bacterianas, virales y parasitarias que pueden transmitirse desde la madre al feto o recién nacido (RN) y que significan un riesgo para él. El acrónimo TORCH se utiliza en forma universal para caracterizar a aquel feto o RN que presenta un cuadro clínico compatible con una infección congénita y que permite un enfrentamiento racional, tanto diagnóstico como terapéutico. El concepto tradicional de realizar un "test de TORCH" sin consideraciones específicas a cada paciente, hoy en día se considera no adecuado y ha sido reemplazado por exámenes específicos para patógenos específicos bajo circunstancias bien definidas. El presente documento revisa las características generales, epidemiológicas, patogénicas, diagnósticas y terapéuticas de los patógenos más frecuentemente involucrados en el estudio de pacientes con sospecha de TORCH.

Cytomegalovirus infection in transplant recipients

Cytomegalovirus infection is a frequent complication after transplantation. This infection occurs due to transmission from the transplanted organ, due to reactivation of latent infection, or after a primary infection in seronegative patients and can be defined as follows: latent infection, active infection, viral syndrome or invasive disease. This condition occurs mainly between 30 and 90 days after transplantation. In hematopoietic stem cell transplantation in particular, infection usually occurs within the first 30 days after transplantation and in the presence of graft-versus-host disease. The major risk factors are when the recipient is cytomegalovirus seronegative and the donor is seropositive as well as when lymphocyte-depleting antibodies are used. There are two methods for the diagnosis of cytomegalovirus infection: the pp65 antigenemia assay and polymerase chain reaction. Serology has no value for the diagnosis of active disease, whereas histology of the affected tissue and bronchoalveolar lavage analysis are useful in the diagnosis of invasive disease. Cytomegalovirus disease can be prevented by prophylaxis (the administration of antiviral drugs to all or to a subgroup of patients who are at higher risk of viral replication) or by preemptive therapy (the early diagnosis of viral replication before development of the disease and prescription of antiviral treatment to prevent the appearance of clinical disease). The drug used is intravenous or oral ganciclovir; oral valganciclovir; or, less frequently, valacyclovir. Prophylaxis should continue for 90 to 180 days. Treatment is always indicated in cytomegalovirus disease, and the gold-standard drug is intravenous ganciclovir. Treatment should be given for 2 to 3 weeks and should be continued for an additional 7 days after the first negative result for viremia. .

Late cytomegalovirus infection after hematopoietic stem cell transplantation: case reports

Cytomegalovirus is related to high rates of morbidity and mortality after hematopoietic stem cell transplantation. This report highlights the importance of adequate monitoring and management of this infection. We report on two cases of patients with late subclinical cytomegalovirus infection. These patients were monitored for antigenemia by indirect immunofluorescence assay. Active cytomegalovirus infection is most common in the first three months after transplantation however the cases reported herein show the importance of monitoring for active infection after Day +100 post-transplantation. Early detection of active infection enables quick preemptive therapy. In conclusion, we emphasize that patients with risk factors for developing severe or late cytomegalovirus disease should be monitored for more than 100 post-transplant days as late active infection is a reality.

Infecção pelo citomegalovírus na gestação:uma visão atual / Cytomegalovirus infection in pregnancy: a current view

A infecção pelo citomegalovírus representa a mais prevalente infecção correlacionada com deficiência neurológica congênita. Apesar da ocorrência da transmissão vertical em taxas consideravelmente elevadas, nem sempre o feto é atingido. O risco de danos ao concepto é maior quando a infecção materna se desenvolve no primeiro trimestre ou no início do segundo trimestre. O recente desenvolvimento de testes sorológicos que visam a detecção de IgM e IgG específico, além do teste de avidez pelo IgG, representam os métodos mais confiáveis de diagnóstico da infecção materna, enquanto a amniocentese (PCR no líquido amniótico), em conjunto com exames de imagem possuem um papel significativo na detecção da infecção fetal. Apesar dos promissores estudos envolvendo novas técnicas de tratamento, a prevenção da doença continua sendo fundamental, por meio dos bons hábitos de higiene pessoal. O presente artigo busca revisar os aspectos mais atuais da infecção congênita pelo citomegalovírus, assim como técnicas de diagnóstico, tratamento e prevenção.

Cytomegalovirus infection represents the most prevalent infection correlated with congenital neurological deficit. Despite the high occurrence of vertical transmission rates, the fetus is not always committed. The risk of fetal damage is higher when maternal infection develops in the first trimester or early second trimester. The recent development of serological tests to detect specific IgM and IgG, as well as by IgG avidity testing, represents the most reliable methods for diagnosis of maternal infection, whereas amniocentesis (amniotic fluid PCR) associated with imaging methods have significant role in the detection of fetal infection. Despite the promising new techniques for studies involving treatment, prevention remains crucial through the good personal hygiene habits. The aim of this article is to review the most current aspects about the cytomegalovirus congenital infection, as well as techniques for diagnosis, treatment and prevention.

Citomegaloviroses: clínica, diagnóstico e tratamento / Cytomegalovirosis: clinical, diagnosis and treatment

Este artigo tem como objetivo discutir as manifestações da citomegalovirose, enfocando aspectos etiopatogênicos, epidemiológicos, manifestações clínicas, diagnóstico laboratorial, tratamento e profilaxia.

Infecçäo por citomegalovírus em paciente com HIV / Cytomegalovirus infection in patients with HIV

O citomegalovírus é um agente oportunista responsavel por manifestaçoes clínicas em pacientes imunodeprimidos (ex.: aidéticos). Dentre os órgaos afetados, estao o pulmao, esofago, trato gastrointestinal, adrenal e sistema nervoso e retina. O diagnóstico pode ser feito através de níveis de linfócitos CD4 ou técnicas de reaçao em cadeia de polimerase, devendo-se fazer o diagnóstico diferencial com toxoplasmose, necroses retinianas e candidíase. No tratamento, sao usadas drogas como o Ganciclovir e Foscamet, associados ou nao à Zidovudine.