The Immune System-A Double-Edged Sword for Adenovirus-Based Therapies.

Pathogenic adenovirus (Ad) infections are widespread but typically mild and transient, except in the immunocompromised. As vectors for gene therapy, vaccine, and oncology applications, Ad-based platforms offer advantages, including ease of genetic manipulation, scale of production, and well-established safety profiles, making them attractive tools for therapeutic development. However, the immune system often poses a significant challenge that must be overcome for adenovirus-based therapies to be truly efficacious. Both pre-existing anti-Ad immunity in the population as well as the rapid development of an immune response against engineered adenoviral vectors can have detrimental effects on the downstream impact of an adenovirus-based therapeutic. This review focuses on the different challenges posed, including pre-existing natural immunity and anti-vector immunity induced by a therapeutic, in the context of innate and adaptive immune responses. We summarise different approaches developed with the aim of tackling these problems, as well as their outcomes and potential future applications.

[Diagnosis and treatment of 26 cases of adenovirus infection after allogeneic hematopoietic stem cell transplantation].

Objective: To analyze the clinical characteristics and prognosis of adenovirus infection after allogeneic hematopoietic stem cell transplantation. Methods: A total of 26 patients with adenovirus infection admitted to the posttransplant ward of the First Affiliated Hospital of Soochow University from 2018 to 2022 were enrolled. Their data on baseline and clinical characteristics, treatment, and follow-up were analyzed. Results: The median patient age was 30 (22, 44) years. Twenty-two patients received related haploid stem cell transplantation, three received unrelated stem cell transplantation, and one received umbilical cord stem cell transplantation. Antithymocyte globulin was included in the conditioning regimen in 25 patients. The median time of adenovirus infection was +95 (+44, +152) days. The median peripheral blood lymphocyte count was 0.30 (0.11, 0.69) × 10(9)/L. Twelve patients had acute graft-versus-host disease. Twenty-four patients received antirejection therapies at diagnosis. Sixteen cases had combined infection with other pathogens with adenovirus infection. Eight cases were diagnosed as asymptomatic infection, and 18 were diagnosed as adenovirus disease, including pneumonia (38.89% ) , gastrointestinal disease (38.89% ) , encephalitis (33.33% ) , hepatitis (5.56% ) , and urinary tract inflammation (5.56% ) . The age of >30 years was a risk factor for adenovirus disease (P=0.03) . Eighteen patients received tapering of immunosuppression, and all 26 patients received at least one antiviral drug. Other treatments included high-dose gamma globulin and donor lymphocyte infusion. Adenovirus infection improved in 10 cases and progressed in 16 cases. The median follow-up time was 30 (7, 237) days. Twenty-two patients died. The all-cause mortality rate was (88.5±7.1) % , and the attributable mortality rate was 45.5% . There was no significant difference in the 100 d survival rate between asymptomatic infected patients and patients diagnosed with adenovirus disease (37.5% vs 22.2% , HR=1.83, 95% CI 0.66-5.04, P=0.24) . Conclusion: The age of >30 years was a risk factor for adenovirus disease. Mortality was high in patients with adenovirus infection after allogeneic hematopoietic stem cell transplantation.

[Diagnosis and treatment of adenoviral keratoconjunctivitis]. / Diagnostika i lechenie adenovirusnogo keratokon"yunktivita.

PURPOSE: To improve the treatment of adenoviral lesions of the eye based on express diagnostics by the fluorescent antibody technique (FAT) and the use of modern drugs. MATERIAL AND METHODS: The study included 184 patients (333 eyes) with various manifestations of adenoviral lesions of the ocular surface, who were divided into two groups: group 1 (149 patients, 196 eyes) - acute form, and group 2 (76 patients, 137 eyes) - long lasting form. Effectiveness of the proposed treatment was evaluated against separate group 3 (controls) consisting of 28 people (46 eyes) with completed acute adenovirus infection, who had previously received antibiotic and corticosteroid therapy in other clinics. Conjunctival scrapings of study patients were examined with FAT in our proposed modification. Study patients received local therapy with modern drugs (Okomistin, Aktipol). RESULTS: FAT detected the adenovirus antigen in 169 cases in group 1 (86%) and in 99 cases in group 2 (72%). Treatment duration amounted to 12±6 days in group 1, 18±8 days in group 2, and 29±7 days in controls. In both study groups, the duration of treatment was significantly reduced in comparison with the controls (p<0.01). Stable clinical effect and complete restoration of visual acuity have been achieved in most cases. There were no allergic and side effects from the therapy. CONCLUSION: Fluorescent antibody technique is a fast and effective way to diagnose adenovirus infection in ophthalmology. In terms of therapy, the use of an antiseptic, an antiviral drug and diluted corticosteroids is the most rational approach.

Influence of the timing of bronchoscopic alveolar lavage on children with adenovirus pneumonia: a comparative study.

BACKGROUND: Adenovirus pneumonia is prone to severe clinical and imaging manifestations in children. Bronchoscopic alveolar lavage (BAL) is an important adjunctive therapy for patients with severe imaging findings. The study aimed to evaluate the effect of the timing on the efficacy of bronchoalveolar lavage in children with adenovirus pneumonia. METHODS: This study included 134 patients with adenovirus pneumonia treated with BAL at Guangzhou Women and Children's Medical Center from January 2019 to January 2020.They were classified into the severe and mild groups. Based on the timing of BAL, each group was divided into the early BAL layer (received BAL within 1-9 days of the illness course) and the late BAL layer (received BAL within 10-14 days of the illness course). The clinical data of patients with different BAL timings were analyzed in two groups. RESULTS: Among the 134 patients, 70 were categorized into the mild group and 64 were categorized into the severe group. Of the 134 patients, 42 patients received BAL early (mild group: n = 21 and severe group: n = 21) and 92 patients received BAL later (mild group: n = 49 and severe group: n = 43). In the mild group, the fever and hospital duration were shorter in patients who received BAL early than in those who received BAL later (p < 0.05). However, in the severe group, there were no statistically significant differences in the fever and hospital duration between patients who received BAL early and those who received BAL later. However, the need for mechanical ventilation and the incidence of BAL complications, such as new need for oxygen, were higher in patients who received BAL early than in those who received BAL later in the severe group (p < 0.05). CONCLUSION: For mild adenovirus pneumonia, early BAL may shorten the fever and hospital duration. However, early BAL in severe cases might not shorten the course of the disease or improve prognosis and may even increase the risks of mechanical ventilation and BAL complications.

Virus-specific T cells for adenovirus infection after stem cell transplantation are highly effective and class II HLA restricted.

Infection with adenoviruses is a common and significant complication in pediatric patients after allogeneic hematopoietic stem cell transplantation. Treatment options with traditional antivirals are limited by poor efficacy and significant toxicities. T-cell reconstitution is critical for the management of adenoviral infections, but it generally takes place months after transplantation. Ex vivo-generated virus-specific T cells (VSTs) are an alternative approach for viral control and can be rapidly generated from either a stem cell donor or a healthy third-party donor. In the context of a single-center phase 1/2 clinical trial, we treated 30 patients with a total of 43 infusions of VSTs for adenoviremia and/or adenoviral disease. Seven patients received donor-derived VSTs, 21 patients received third-party VSTs, and 2 received VSTs from both donor sources. Clinical responses were observed in 81% of patients, with a complete response in 58%. Epitope prediction and potential epitope identification for common HLA molecules helped elucidate HLA restriction in a subset of patients receiving third-party products. Intracellular interferon-γ expression in T cells in response to single peptides and response to cell lines stably transfected with a single HLA molecule demonstrated HLA-restricted CD4+ T-cell response, and these results correlated with clinical outcomes. Taken together, these data suggest that VSTs are a highly safe and effective therapy for the management of adenoviral infection in immunocompromised hosts. The trials were registered at www.clinicaltrials.gov as #NCT02048332 and #NCT02532452.

A new insight into aggregation of oncolytic adenovirus Ad5-delta-24-RGD during CsCl gradient ultracentrifugation.

Two-cycle cesium chloride (2 × CsCl) gradient ultracentrifugation is a conventional approach for purifying recombinant adenoviruses (rAds) for research purposes (gene therapy, vaccines, and oncolytic vectors). However, rAds containing the RGD-4C peptide in the HI loop of the fiber knob domain tend to aggregate during 2 × CsCl gradient ultracentrifugation resulting in a low infectious titer yield or even purification failure. An iodixanol-based purification method preventing aggregation of the RGD4C-modified rAds has been proposed. However, the reason explaining aggregation of the RGD4C-modified rAds during 2 × CsCl but not iodixanol gradient ultracentrifugation has not been revealed. In the present study, we showed that rAds with the RGD-4C peptide in the HI loop but not at the C-terminus of the fiber knob domain were prone to aggregate during 2 × CsCl but not iodixanol gradient ultracentrifugation. The cysteine residues with free thiol groups after the RGD motif within the inserted RGD-4C peptide were responsible for formation of the interparticle disulfide bonds under atmospheric oxygen and aggregation of Ad5-delta-24-RGD4C-based rAds during 2 × CsCl gradient ultracentrifugation, which could be prevented using iodixanol gradient ultracentrifugation, most likely due to antioxidant properties of iodixanol. A cysteine-to-glycine substitution of the cysteine residues with free thiol groups (RGD-2C2G) prevented aggregation during 2 × CsCl gradient purification but in coxsackie and adenovirus receptor (CAR)-low/negative cancer cell lines of human and rodent origin, this reduced cytolytic efficacy to the levels observed for a fiber non-modified control vector. However, both Ad5-delta-24-RGD4C and Ad5-delta-24-RGD2C2G were equally effective in the murine immunocompetent CT-2A glioma model due to a primary role of antitumor immune responses in the therapeutic efficacy of oncolytic virotherapy.

Gravedad de infecciones respiratorias agudas bajas por adenovirus en los años 2015 y 2016 en el hospital de niños Roberto del Rio / Severity of acute lower respiratory infections due to adenovirus in the years 2015 and 2016 at the Roberto del Rio children's hospital

OBJETIVO. Comparar la gravedad de las infecciones respiratorias agudas bajas (IRAb) producidas por Adenovirus (ADV) entre los años 2015 y 2016, en el Hospital de Niños Roberto del Río. MÉTODOS. Se identificó a pacientes hospitalizados por IRAb por ADV, y se registró edad, sexo, días de hospitalización, ingreso a unidad de paciente crítico (UPC), necesidad de ventilación mecánica (VM), entre otros. Se comparó la evolución de los pacientes, y se analizó la relación entre gravedad y presencia de infecciones asociadas a atención de salud (IAAS). RESULTADOS. Se identificó 158 pacientes hospitalizados por IRAb por ADV. La relación hombre: mujer fue 6:4, con una edad promedio de 17.4 meses. La media de días de hospitalización fue de 9.88 el 2015 y 16.06 el 2016 (p=0.01). El promedio de días de oxigenoterapia fue de 5.86 el 2015 y 8.76 el 2016. Un 22.8% (n:36) de los pacientes ingresó a UPC, y el 20.25% (n:32) requirió VM. Un 41.8% de los casos (n:66) correspondió a IAAS. 3 pacientes fallecieron. CONCLUSIONES. Durante el 2016 hubo hospitalizaciones más prolongadas en comparación al 2015, sin diferencias estadísticamente significativas en relación a requerimientos de oxigenoterapia, VM y fallecimiento. La prolongación de la hospitalización se podría asociar a mayor presencia de IAAS.

OBJETIVE. To compare the severity of lower respiratory infections produced by Adenovirus between 2015 and 2016 at the Hospital de Niños Roberto del Río. METHODS. We identified patients hospitalized for lower respiratory tract infection for ADV and we recorded age, sex, days of hospitalization, admission to Intensive Care Unit (ICU), need for mechanical ventilation (MV), among others. The evolution of the patients between the two years were compared. The relationship between severity and the presence of nosocomial infections was also analyzed. RESULTS. We identified 158 hospitalized patients for ADV. The male:female ratio was 6:4, with an average age of 17.4 months. The mean of hospitalization days was 9.88 days in 2015 and 16.06 days in 2016 (p = 0.01). The average number of oxygen therapy days was 5.86 in 2015 and 8.76 in 2016. The 22.8% (n: 36) of cases required admission in the ICU, and 20.25% (n: 32) required MV. The 41.8% (n: 66) of cases corresponded to nosocomial infections. 3 patients died. CONCLUSIONS. During 2016, there were longer hospitalizations for adenovirus infections compared to 2015, without significant differences in relation to oxygen therapy, MV requirements and death. The prolongation of the hospitalization could be associated by the greater presence of nosocomial infections.

Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.

A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.

Detection of adenovirus hepatitis and acute liver failure in allogeneic hematopoietic stem cell transplant patients.

Human adenovirus (HAdV) is an important cause of the common cold and epidemic keratoconjunctivitis in immunocompetent individuals. In immunocompromised patients, HAdV can sometimes cause severe infection such as cystitis, gastroenteritis, pneumonia, encephalitis, hepatitis, or disseminated disease, resulting in significant morbidity and also mortality. In particular, severe cases have been reported in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Indeed HAdV has been recognized as a pathogen that requires careful monitoring in allo-HSCT patients. While HAdV hepatitis leading to severe acute liver failure is rare, such liver failure progresses rapidly and is often fatal. Unfortunately, HAdV hepatitis has few characteristic symptoms and physical findings, which makes it difficult to promptly confirm and start treatment. We report here four cases of HAdV hepatitis after allo-HSCT and their autopsy findings.

Use of cidofovir with extracorporeal membrane oxygenation to treat adenovirus-associated acute respiratory distress syndrome in paediatric patients- a case series.

WHAT IS KNOWN AND OBJECTIVE: Reports of cidofovir dosing with extracorporeal membrane oxygenation (ECMO) support are limited. This case series describes our clinical experience and provides a literature review regarding cidofovir dosing in paediatric patients requiring ECMO support. CASE SUMMARY: Three patients with adenovirus-associated acute respiratory distress syndrome (ARDS) were treated with cidofovir while requiring ECMO support. A 27-month-old patient was treated with cidofovir 1 mg/kg/dose three times weekly, and a 19-month-old patient and an 18-year-old patient were treated with cidofovir 5 mg/kg/dose weekly. WHAT IS NEW AND CONCLUSION: This case series describes the dosing and positive clinical response of cidofovir in paediatric patients with adenovirus-associated ARDS requiring ECMO support.

4-month-old boy coinfected with COVID-19 and adenovirus.

A 4-month-old boy with a history of muscular ventricular septal defect and atopic dermatitis presented with decreased oral intake, loose stools, stuffy nose, mild cough and diaphoresis. The patient had an in-home exposure to COVID-19. The initial respiratory pathogen panel was positive for adenovirus, consistent with his symptoms. The following day, the COVID-19 PCR was also positive. The patient was treated with supportive care, isolation precautions were implemented and the patient was discharged on day 4. This case demonstrates the importance of testing for COVID-19 even if a patient tests positive for another virus due to the possibility of coinfection, especially in children, in order to limit spread of COVID-19 to others.

Viral and bacterial coinfection of the respiratory tract in a 10-month-old child.

A 10-month-old child, immunised appropriately for age, presented with a history of cough, vomiting, diarrhoea, increased work of breathing and eye redness for 1 week. She was treated for suspected bronchiolitis with supportive oxygen and hypertonic saline nebulisation. In view of continuing fever spikes and persistent oxygen requirement, she was evaluated further. Her inflammatory markers were raised, blood film showed neutrophils left shift with toxic granulations and chest X-ray was suggestive of the right upper lobe segmental atelectasis suggestive of a bacterial infection. Her nasopharyngeal aspirate for multiplex tandem PCR was positive for adenovirus, respiratory syncytial virus and Bordetella species. She was treated with oral clarithromycin for 5 days which improved her symptoms. She was discharged with further follow-up. Coinfection with bacteria or atypical bacteria in children with acute respiratory tract infection is common and this coinfection can induce serious illness.

Adenoviruses - Infection, pathogenesis and therapy.

Both well-known and emerging viruses increasingly affect humans and cause disease, sometimes with devastating impact on society. The viruses present in the biosphere are the top predators in the life chain, virtually without enemies, except perhaps the immune system, and harsh environmental physicochemical conditions restricting their dissemination. We know a lot about viruses, but do we know enough? This series of reviews is dedicated to adenoviruses (AdVs), a family of nonenveloped DNA viruses occurring in vertebrates, including humans. AdVs have been the focus of intense research for more than 67 years. Besides causing disease, they have immensely contributed to the advance of life sciences and medicine over the past decades. Recently, AdVs have been widely used as vehicles in gene therapy and vaccination. They continue to provide fundamental insights into virus-host interactions in cells, tissues and organisms, as well as systems and metabolic networks. This special issue of FEBS Letters presents a unique collection of 23 state-of-the-art review articles by leading adenovirologists. In this prelude, I present the chapters, which provide a solid basis for further exploring the rich heritage in adenovirus molecular cell biology, structural biology, genetics, immunology, gene therapy and epidemiology. I conclude with an essential discussion of six blind spots in adenovirology.

Clinical and epidemiological study of acute lower respiratory tract infections caused by adenovirus in hospitalized children. Nineteen years of active epidemiological surveillance. / Estudio clínico-epidemiológico de las infecciones respiratorias agudas bajas causadas por adenovirus en niños hospitalizados. Diecinueve años de vigilancia epidemiológica activa.

INTRODUCTION: Acute lower respiratory tract infection (ALRTI) caused by adenovirus is a major cause of morbidity and mortality in children. OBJECTIVES: To describe the clinical and epidemiological pattern and associated factors in hospitalized children. METHODS: Cross-sectional study in children admitted due to ALRTI to Hospital de Niños "Ricardo Gutiérrez," in the Autonomous City of Buenos Aires, between 2000 and 2018. Viral diagnosis was done by indirect immunofluorescence in nasopharyngeal secretions. The clinical and epidemiological characteristics of adenovirus infection were compared to other respiratory viruses (respiratory syncytial virus, influenza, and parainfluenza). A multiple logistic regression was done to identify independent predictors of infection. RESULTS: Out of 16 018 patients with ALRTI, 13 545 were tested for respiratory viruses; 6047 (45 %) had a positive result. Adenovirus was the least common agent (4.4 % [265] of cases); it tended towards a reduction over the study period (peak in 2003) and circulated throughout the year (peak in July). In total, 63.8 % of patients were males; median age: 11 months (interquartile range: 6-20). The most common clinical presentation was pneumonia (63 %). Prior admissions due to respiratory conditions were seen in 50 %; 15.6 % were readmissions; 58.3 % had comorbidities. Ventilatory support was required by 19.2 % and complications were recorded in 44 %. The fatality rate was 7.7 %. Adenovirus infection was associated with age ≥ 12 months, male sex, clinical presentation of pneumonia, prior admissions due to respiratory conditions, and readmissions. CONCLUSIONS: Adenoviruses were less common than other respiratory viruses, although their morbidity and mortality were important.

Introducción. La infección respiratoria aguda baja por adenovirus es una importante causa de morbimortalidad en niños. Objetivos: Describir el patrón clínicoepidemiológico y los factores asociados en niños hospitalizados. Métodos. Estudio transversal en niños ingresados por infección respiratoria aguda baja al Hospital de Niños Ricardo Gutiérrez, Buenos Aires, en 2000-2018. El diagnóstico viral se realizó mediante inmunofluorescencia indirecta en secreciones nasofaríngeas. Se compararon características clínico-epidemiológicas de infección por adenovirus con otros virus respiratorios (virus sincicial respiratorio, influenza y parainfluenza). Se utilizó regresión logística múltiple para identificar predictores independientes de infección. Resultados. De 16018 pacientes con infección respiratoria aguda baja, 13545 fueron testeados para virus respiratorios y 6047 (el 45 %) fueron positivos. Adenovirus fue el agente menos frecuente [el 4,4 % (265) de los casos]; presentó una tendencia en descenso durante todo el período estudiado (pico en 2003) y circuló durante todo el año (pico en julio). El 63,8 % eran varones; mediana de edad: 11 meses (rango intercuartílico: 6-20). La presentación clínica más frecuente fue neumonía (el 63 %). El 50 % tenía internaciones previas por causa respiratoria; el 15,6 % eran reingresos; el 58,3 % tenía comorbilidades. El 19,2 % requirió asistencia ventilatoria; el 44 % registró complicaciones. La letalidad fue del 7,7 %. La infección por adenovirus se asoció a edad ≥ 12 meses, sexo masculino, presentación clínica de neumonía, internaciones previas por causas respiratorias y reinternaciones. Conclusiones. Los adenovirus fueron detectados con menor frecuencia que los otros virus respiratorios, aunque presentaron un importante perfil de morbimortalidad.

Synergistic antitumor effect of ING4/PTEN double tumor suppressors mediated by adenovirus modified with arginine-glycine-aspartate on glioma.

BACKGROUND: Gene therapy is regarded as a new and promising therapeutic modality for cancers, and adenovirus is one of the most frequently used vectors. However, because of low or absent coxsackievirus and adenovirus receptor levels on the surface of many kinds of tumor cells, the efficiency of adenovirus infection of target tumor cells may be low. Meanwhile, gene therapy by a single vector carrying two or more antioncogenes can improve treatment effects and reduce side effects from vectors. In this research, we aimed to detect the antitumor effect of ING4/PTEN double tumor suppressors mediated by adenovirus modified with arginine(R)-glycine(G)-aspartate(D) (RGD) on glioma cells. METHODS: We treated U87 glioma cells with PBS, blank adenovirus or adenovirus carrying RGD, ING4, PTEN, or both ING4 and PTEN, then we detected and compared the U87 cells' growth, apoptosis, and invasion. Moreover, we established a U87 glioma transplantation tumor model to study the antitumor effect in vivo by measuring the volume and weight of tumor masses in each condition. In addition, we analyzed the transcription of related genes by fluorescent quantitative PCR and detected their expression by immunohistochemistry staining to reveal the underlying mechanisms. RESULTS: The double tumor suppressors ING4/PTEN could inhibit the growth of U87 glioma cells with a synergistic antitumor effect, and the RGD modification also acted as an antioncogene to inhibit U87 cell invasion and tumor angiogenesis. CONCLUSIONS: The ING4/PTEN double tumor suppressors mediated by adenovirus modified with RGD had a significantly synergistic antitumor effect on glioma.

The oncolytic adenovirus VCN-01 promotes anti-tumor effect in primitive neuroectodermal tumor models.

Last advances in the treatment of pediatric tumors has led to an increase of survival rates of children affected by primitive neuroectodermal tumors, however, still a significant amount of the patients do not overcome the disease. In addition, the survivors might suffer from severe side effects caused by the current standard treatments. Oncolytic virotherapy has emerged in the last years as a promising alternative for the treatment of solid tumors. In this work, we study the anti-tumor effect mediated by the oncolytic adenovirus VCN-01 in CNS-PNET models. VCN-01 is able to infect and replicate in PNET cell cultures, leading to a cytotoxicity and immunogenic cell death. In vivo, VCN-01 increased significantly the median survival of mice and led to long-term survivors in two orthotopic models of PNETs. In summary, these results underscore the therapeutic effect of VCN-01 for rare pediatric cancers such as PNETs, and warrants further exploration on the use of this virus to treat them.

Adenovirus infection and disease in recipients of hematopoietic cell transplantation.

PURPOSE OF REVIEW: To provide an update on risk factors associated with adenovirus (ADV) infection in patients after hematopoietic cell transplant (HCT) and on options for ADV monitoring and treatment in the setting of HCT. RECENT FINDINGS: Among patients undergoing HCT, ADV infection continues to be more common amongst those receiving a T-cell-depleted or graft other than from a matched-related donor. Among children undergoing HCT, reactivation in the gastrointestinal tract appears to be the most common source, and the virus is detectable by quantitative PCR in the stool before it is detectable in the blood. Thus, screening for the virus in the stool of these children may allow for preemptive therapy to reduce mortality. Brincidofovir, although still not approved by any regulatory agency, remains a potential agent for preemptive therapy and for salvage in cases not responding to cidofovir. Rapidly generated off-the-shelf virus-specific T cells may facilitate adoptive cell therapy in populations with a special need and previously not eligible for adoptive cell therapy, such as cord blood recipients. SUMMARY: ADV infection continues to adversely affect survival in HCT recipients. Screening stool in children and preemptive therapy may reduce mortality. Brincidofovir and adoptive T-cell therapy remain potential options for treatment.

Extracorporeal Membrane Oxygenation for Severe Adenoviral Pneumonia in Neonatal, Pediatric, and Adult Patients.

OBJECTIVES: We examined data on patients with severe adenoviral pneumonia from the international registry of the Extracorporeal Life Support Organization to identify risk factors for mortality in patients receiving extracorporeal membrane oxygenation. DESIGN: Retrospective analysis. SETTING: International Registry of Extracorporeal Life Support Organization. PATIENTS: We collected de-identified data on all patients with adenoviral pneumonia who needed extracorporeal membrane oxygenation from 1992 to 2016 using International Classification of Diseases, 9th Edition, criteria. INTERVENTIONS: Our primary outcome measure was in-hospital mortality. We also collected data on demographics, preextracorporeal membrane oxygenation ventilator settings, biochemical variables, extracorporeal membrane oxygenation mode, duration, and complications. Initial bivariate analysis assessed potential associations between mortality and various preextracorporeal membrane oxygenation variables as well as extracorporeal membrane oxygenation factors. Variables with p values of less than 0.1 were considered for logistic regression analysis that identified predictors of mortality. MEASUREMENTS AND RESULTS: There were 542 patients with adenoviral pneumonia who were supported with extracorporeal membrane oxygenation. Overall mortality was 58% (307/529 patients) (neonates 86.4% [108/125 patients], children 49% [158/327 patients], and adults 49% [41/83 patients]). Multivariate regression identified hypercapnia (PCO2 > 45.7; odds ratio > 3.2; p < 0.001), immunosuppression (odds ratio, 4.44; 95% CI, 1.69-11.61; p = 0.002] and lack of pharmacologic paralysis (odds ratio, 0.30; 95% CI, 0.16-0.57; p < 0.001] as significant preextracorporeal membrane oxygenation factors for mortality. Neonatal patients had significantly higher mortality than pediatric or adult patients (odds ratio, 10.9; 95% CI, 3.2-37.3; p < 0.001). The presence of renal (odds ratio, 4.4; 95% CI, 2.5-7.7; p < 0.001), neurologic (odds ratio, 2.5; 95% CI, 1.2-5.1; p = 0.014), hemorrhagic (odds ratio, 2.2; 95% CI, 1.2-4.0; p = 0.014), or cardiovascular complications (odds ratio, 2.4; 95% CI, 1.3-4.6; p = 0.006) was associated with higher mortality on extracorporeal membrane oxygenation. CONCLUSIONS: Patients with adenoviral pneumonia supported on extracorporeal membrane oxygenation had mortality of 58% over a 25-year-old period. We identified risk factors both before and during extracorporeal membrane oxygenation which were associated with higher mortality. Mortality in neonatal patients was particularly high.