Treatment Of Adenovirus Infection Research Articles

Characteristics of the Tongue Coating Microbiome in Patients Infected With Adenovirus

Background: Adenovirus(AdV) infection, which distributes globally when regional epidemics are reported throughout the year, has no specific treatment yet. As the significance of the oral microbiome has been increasingly recognized in virus infection, this study aims to explore the characteristics of the tongue coating microbiome in AdV infected patients for the first time. Methods: 26 patients with AdV infection and 34 matched healthy controls were enrolled to collect tongue coating samples for 16S rRNA gene sequencing. Information on the tongue coating microbiome was annotated by the Human Oral Microbiome Database(HOMD). Results: The characteristics of AdV infection include decreased abundance and evenness of microbiome among individuals (p<0.001) and significant differences in the relative abundance at different levels (phylum, class, order, family, genus) (p<0.05), compared with the control group. It should be noted that the combination of 3 genera, including Neisseria, Fusobacterium and Haemophilus, can be used as potential biomarkers to accurately distinguish AdV infection from controls (AUC:0.9714). In addition, Neisseria and Haemophilus were also associated with platelet, AST and CRE. Fifteen KEGG pathways were found associated with AdV infection which was closely related to three biomarkers, with transporters the most important functional module. Conclusions: This study described the characteristics of tongue coating microbiome of ADV infection, provided not only new evidence for the biomarkers and pathways associated with AdV infection, but also novel insights into pathogenesis, prevention and treatment of AdV infections as well. Funding Statement: This work was supported by the National Natural Science Foundation of China (nos. 81673806), Emergency Scientific Research Project of Beijing administration of traditional Chinese medicine(nos.YJ2020-03), Emergency Research Project (nos.BWS20J006), Medical Research Program(CX19015) and Bio-safety Construction Plan (nos.A3704041902-02). Declaration of Interests: The authors report no conflict of interest, and no commercial or other association that might pose a conflict of interest (e.g., pharmaceutical stock ownership, consultancy, advisory board membership, relevant patents, or research funding). Ethics Approval Statement: The study complied with the Ethical Principles of the World Medical Association Declaration of Helsinki and experimental protocols were approved by the committee on ethics of the 5th Medical Centre of Chinese PLA General Hospital (formerly the 302 Military Hospital).

Orphan designation: Brincidofovir, Treatment of adenovirus infection in immunocompromised patients

Orphan designation: Brincidofovir, Treatment of adenovirus infection in immunocompromised patients

Orphan designation: Adenovirus-specific T-cells derived from allogeneic donor leukocytes, expanded ex vivo, Treatment of adenovirus infection in allogeneic haematopoietic stem cell transplant recipients

Orphan designation: Adenovirus-specific T-cells derived from allogeneic donor leukocytes, expanded ex vivo, Treatment of adenovirus infection in allogeneic haematopoietic stem cell transplant recipients

Orphan designation: Adenovirus-specific T-cells derived from allogeneic donor leukocytes, expanded ex vivo, Treatment of adenovirus infection in allogeneic haematopoietic stem cell transplant recipients

Orphan designation: Adenovirus-specific T-cells derived from allogeneic donor leukocytes, expanded ex vivo, Treatment of adenovirus infection in allogeneic haematopoietic stem cell transplant recipients

Screening and Treatment of Adenovirus Infection in Pediatric and Adult Allogeneic Hematopoietic Cell Transplant Recipients: Multicenter Survey of Transplant Centers in the United States

Introduction Allogeneic hematopoietic cell transplant (allo-HCT) recipients are at risk of life-threatening viral infections. Objective The objective of the AdVance US practice patterns survey was to characterize current practices in screening and treatment of adenovirus (AdV) infection in the United States (US). Methods Physicians at participating centers were provided with a link to access an online survey. The survey questions addressed current practices around management of AdV infections in allo-HCT recipients at their center, and classified patients with regard to known risks for AdV infection (e.g., T-cell depletion, cord blood, haploidentical, mismatched, GVHD). When necessary, respondents consulted with other physicians in their center to ensure consensus before submitting responses. Results 62 centers were approached, of which 15 (24%) agreed to participate in this survey prior to the first deadline for response. 11 of the participating centers treat pediatric patients and 4 treat adult patients (Figure). According to CIBMTR data and physician interview responses, the pediatric and adult centers conduct an average of 36 and 142 allo HCTs per year, respectively. Almost all (91%) pediatric centers conduct weekly routine screening for AdV after allo-HCT among higher-risk patients, and around half (55%) conduct routine screening for AdV among lower-risk patients. Routine AdV screening is conducted by 25% of adult centers for higher-risk patients, and none routinely screen lower-risk patients. Among those screening higher-risk patients for AdV, all pediatric and adult centers screen blood samples at least once weekly and the majority (90%) of pediatric centers screen blood for at least 3 months post allo-HCT; the one adult center that screens blood does so weekly for up to 6 months post-HCT. Most pediatric centers have a pre-emptive AdV treatment approach for higher-risk patients (91%) and lower-risk patients (82%), using positive blood PCR as the treatment trigger. All adult centers that screen higher-risk patients use a pre-emptive approach. The pre-emptive AdV treatment most frequently reported by pediatric and adult centers is off-label IV cidofovir in spite of well-known toxicity concerns including renal injury. Conclusions The AdVance US practice patterns survey suggests that pediatric centers are more likely than adult centers to screen for AdV, and are also more likely to have a pre-emptive AdV treatment approach compared to adult centers. Perceived risk of AdV infection is a determining factor for whether routine screening and pre-emptive treatment are implemented. For both pediatric and adult centers, AdV viremia was the most common pre-emptive treatment trigger, with off-label IV cidofovir commonly utilized for treatment in spite of toxicity concerns. Treatment practices in the centers surveyed are generally consistent with ASBMT guidelines.

A survey on incidence and management of adenovirus infection after allogeneic HSCT.

To determine the current practices on the management of Adenovirus (ADV) infection after allogenic stem cell transplantation, a survey was undertook among EBMT centres. The response rate was 20% (91/446): 46% were adult, 44% were paediatric and 10% were mixed centres, respectively. The overall incidence of ADV infection was 7.1%: 4.1% in adult, 15.4% in paediatric, and 3.6% in mixed population. The determination of ADV-DNA in biological samples was used in 96% of centres; 58% of them monitored asymptomatic patients with a frequency of twice a week in 9%, once a week in 45%, every two weeks in 4% of centres. The treatment of ADV infection was mainly based on the administration of cidofovir (87%), being the schedule of 5 mg/kg/week with probenecid the most used, and the reduction of immunosuppression (84%). The threshold of ADV-DNAemia to start cidofovir in high-risk patients was most frequently >1000 copies/ml. Innovative treatments, such as brincidofovir and adoptive ADV-cytotoxic-T-lymphocytes, were used in 27% and 20% of centres, respectively. Almost all responding centres consider ADV infection serious enough to deserve testing asymptomatic or symptomatic patients. Cidofovir and reduction of immunosuppression represent the main therapeutic options but one fourth of responding centres experimented novel therapies.

Management of Adenovirus in Children after Allogeneic Hematopoietic Stem Cell Transplantation

Adenovirus (ADV) can cause significant morbidity and mortality in children following haematopoietic stem cell transplantation (HSCT), with an incidence of up to 27% and notable associated morbidity and mortality. T-cell depleted grafts and severe lymphopenia are major risk factors for the development of adenovirus disease after HSCT. Current antiviral treatments are at best virostatic and may have significant side effects. Adoptive transfer of donor-derived virus-specific T cells has been shown to be an effective strategy for the prevention and treatment of ADV infection after HSCT. Here we review progress in the field and present a pathway for the management of adenovirus in the posttransplant setting.

European guidelines for diagnosis and treatment of adenovirus infection in leukemia and stem cell transplantation: summary of ECIL‐4 (2011)

Human adenovirus (HAdV) infections are increasingly recognized as important pathogens in immunocompromised hosts, especially in patients with severely suppressed T-cell function. The 4th European Conference of Infections in Leukemia (ECIL-4) has developed evidence-based guidelines for diagnosis and management of HAdV infections. The risk for HAdV-associated disease is increased in children, and risk factors for HAdV disease are T-cell depletion, unrelated and cord blood hematopoietic stem cell transplantation, graft-versus-host disease grades III-IV, and lymphopenia. The recommended technique for monitoring of high-risk patients is quantitative polymerase chain reaction. Cidofovir is the most used antiviral therapy, although no controlled study has been performed. HAdV-specific T-cell therapy is in development.

Sequential adenovirus infection of type 14 hemorrhagic cystitis and type 35 generalized infection after cord blood transplantation

We report a case of a 29-year-old male patient with a generalized adenovirus (AdV) infection after cord blood transplantation (CBT) for acute myelocytic leukemia with maturation at 2nd complete remission. Before engraftment, hemorrhagic cystitis was caused by AdV, which resulted in hydronephrosis, renal failure, and adenoviremia on day 34. Forced diuresis, hemodialysis, withdrawal of cyclosporin A, and administration of gamma-globulin or vidarabine were not effective and the patient died of pulmonary alveolar hemorrhage on day 67. At autopsy, old inflammatory change only was observed in the bladder section. In the lungs and kidneys, granular deposits in the nucleus and a high copy number of AdV-DNA were observed. Molecular diagnosis using PCR-restriction fragment length polymorphism analysis demonstrated that AdV with the serotype 14 caused the cystitis. However, retrospective genome typing using PCR sequencing revealed the infection of AdV serotype 35 in the kidneys, lungs, and serum. The present case suggested that Adv infection could not be always caused by a single AdV serotype, and suggested that multiple serotype infection was very difficult to treat. It is desired that a consensus regarding the treatment of AdV infections is established.

Clinical features and treatment of adenovirus infections

Adenoviruses (Ads) are common opportunistic pathogens that are rarely associated with severe clinical symptoms in healthy individuals. In contrast, in patients with compromised immunity, Ad infections often result in disseminated and potentially life-threatening disease. Among these are AIDS patients, individuals with hereditary immunodeficiencies and recipients of solid organ or haematopoietic stem cell transplants (HSCT) who receive immunosuppressive therapy. The latter account for the largest number of severe Ad infections. There is currently no formally approved antiviral therapy for the treatment of severe Ad keratoconjunctivitis and life-threatening Ad infections in immunocompromised patients. Here we update current knowledge on Ad biology, the clinical features observed in different patient groups and specific immune responses towards Ad infections. In addition, we review current and future treatment options, including: (i) the antiviral drugs cidofovir, ribavirin and new investigational compounds, as evaluated in the clinic or in relevant animal models, as well as (ii) novel immunotherapeutic strategies.

Clinical Grade Generation of Hexon-specific T Cells for Adoptive T-cell Transfer as a Treatment of Adenovirus Infection After Allogeneic Stem Cell Transplantation

Adenovirus infection after allogeneic hematopoietic stem cell transplantation is still causing significant morbidity and mortality, especially in children. It has been demonstrated that a sufficient host T-cell response is essential to clear the virus. Adoptive transfer of specific T-cell immunity from the donor to the recipient has become a new treatment option for patients with systemic adenoviral infection who lack specific T-cell responses. The adenoviral hexon protein was shown to be an immunodominant T-cell target. We describe here a Good Manufacturing Practice-compatible generation of hexon-specific T cells developed by isolating interferon-gamma-secreting T cells after stimulation of mononuclear cells ex vivo with hexon protein. Phenotypical and functional characterization of the generated, specific T-cell product resulted in a mixed population of CD4 and CD8-positive T cells with an intermediate effector memory phenotype. Isolated hexon-specific T cells showed high expansion potential in vitro and specific cytotoxicity. T-cell lines, directed against type 5 hexon protein showed good crossreactivity against viral strains from other adenovirus species. The availability for isolation of hexon-specific T cells among 76 hematopoietic stem cell transplantation donors showed in > 72% a sufficient T-cell response (0.05% of T cells). In conclusion, Good Manufacturing Practice-grade selection of adenovirus-specific T cells for adoptive immunotherapy by hexon-induced secretion of interferon-gamma has been established. Adoptive T-cell transfer could potentially restore T-cell immunity against adenovirus after allogeneic stem cell transplantation.

Hexon Specific T-Cells for Adoptive T-Cell Transfer as a Treatment of Adenovirus Infection after Allogeneic Stem Cell Transplantation.

Adenovirus infection (ADV) after allogeneic hematopoietic stem cell transplantation (HSCT) is an emerging pathogen causing relevant morbidity and mortality, with preponderance in children. Since a sufficient host T-cell response has been shown essential to clear the virus, diagnostic procedures for detection of virus-specific T-cells have recently developed to asses the specific cellular immune response. Furthermore adoptive immunotherapy is a new treatment option for patients with absent specific T-cell response and present systemic adenoviral infection. The possibility of an adoptive T-cell transfer depends on the availability of GMP compatible protocols and reagents. The adenoviral hexon protein was shown a immunodominant T-cell target within the viral capsid. In the present study we investigate the presence of Hexon-specific T-cell responses in HSCT donors, i.e. the availability of donors for an adoptive T-cell transfer. Secondly, the emergence of Hexon-specific T-cells in recipients post HSCT was analyzed. Thirdly, a protocol was established under GMP-conditions for adoptive T-cell immunotherapy through isolation of IFN-γ secreting T-cells after ex-vivo stimulation with the adenoviral Hexon protein. This procedure resulted in a mixed population of CD4 and CD8 positive T-cells with an effector memory phenotype and Th1 cytokine pattern (n=8). Isolated Hexon-specific T-cells show a strong expansion potential in vitro as well as specific cytotoxic activity. The availability of a donor was evaluated in 76 HSCT donors. Only 17.1% of donors had no ADV-specific T-cell response and 72.4% of donors were eligible for an adoptive T-cell transfer using the presented approach. The Hexon protein was responsible for almost the complete response to ADV, since no significant difference was seen against ADV lysate and the Hexon protein. In 76% HSCT recipients Hexon directed T-cell responses were evaluated and were shown to be responsible for clearance of the viral infection. In conclusion feasibility of an adoptive T-cell transfer for the treatment of ADV infection post HSCT is shown in accordance to current GMP regulations.

Treatment of Adenovirus Infection by Adoptive Immunotherapy: Adenovirus Capsid Hexon Is the Main Target Protein of Adenovirus-Specific Cellular Immunity.

Introduction: Adenovirus (AdV) infection is a severe complication after hematopoietic stem cell transplantation, particularly in paediatric patients. Control of AdV infection particularly seems to be dependent on CD4+ T-cells but their main AdV antigenic targets have remained unknown so far. In order to design protocols for targeted adoptive immunotherapy the identification of the main AdV antigenic targets is a fundamental prerequisite.Methods: We here adapted a novel technique to directly assess the entire repertoire of CD4+ T-cells specific AdV antigens according to antigen-induced CD154 expression after short-term ex vivo stimulation. AdV-lysate-specific and AdV-hexon-specific CD4+ T-cells were isolated, expanded in vitro and further assessed for their fine specificities using recombinant AdV-proteins and AdV-lysates from various AdV-serogroups. The cytokine profile of AdV-lysate- and AdV-hexon-specific CD4+ T-cells were assessed by intracellular analysis of AdV-induced CD154+ CD4+ T-cells.Results: AdV-lysate-specific CD4+ T-cells reacted predominantly with AdV-hexon capsid protein. Furthermore, AdV-hexon (serogroup B) specific CD4+ T-cells crossreacted with recombinant hexon protein derived from various other AdV-serotypes and were characterized by a Th1-like cytokine profile.Conclusion: Our results prove the effectiveness of antigen-induced CD154-expression for assessment of the entire repertoire of CD4+ T-cells specific for pathogens, for the identification of immunodominant target antigen from pathogens. We demonstrate that adenovirus hexon protein is a suitable candidate antigen for the ex vivo generation of adenovirus-specific, serogroup cross-reactive CD4+ T-cells with a Th1-like cytokine profile for adoptive T-cell therapies.

Treatment of adenovirus infections in patients undergoing allogeneic hematopoietic stem cell transplantation.

Retrospective analysis of 303 patients who underwent allogeneic hematopoietic stem cell transplantation identified 35 (11.5%) with adenovirus infection. Among them, 22 received specific therapy. As first-line therapy, 18 were treated with intravenous ribavirin, 3 with cidofovir, and 1 with vidarabine. Moreover, 2 received donor leukocyte infusion in combination with ribavirin, and 1 received it after failing to respond to other therapies. Seven survived (31.8%; 3 of 13 who received ribavirin alone and 2 of 3 who received cidofovir). Among the 5 patients treated with combined strategies, 2 who received donor leukocyte infusions showed clearance of all symptoms. Acute graft-versus-host disease grade > or = 3 (P = .01) and a long delay between infection and treatment (P = .05) correlated with a greater risk of treatment failure. In conclusion, ribavirin and vidarabine are ineffective options, particularly for patients at who are high risk of acquiring disseminated adenovirus disease. Conversely, cidofovir or donor leukocyte infusions seem to be encouraging approaches if initiated early.