Respiratory adenovirus infections in children: a focus on Africa.

PURPOSE OF REVIEW: Lower respiratory tract infections (LRTIs) are an important cause of child morbidity and mortality globally, especially in children under the age of 5 years in Africa. Respiratory viruses, including human adenoviruses (HAdVs), are common causes of LRTIs in children. This review aims to shed light on the epidemiology, clinical manifestations, sequelae, and treatment options specific to adenovirus respiratory infections in African children. RECENT FINDINGS: Recent evidence has challenged the perception that adenovirus is a negligible cause of LRTIs. Studies show HAdV emerging as the third most common viral pathogen in fatal pneumonias among under-5 children in low-income and middle-income African countries, contributing to 5.5% of all pneumonia deaths and ranking second in hospital-associated viral pneumonia deaths. Predominant HAdV serotypes associated with disease differ by country and region, and have changed over time. Risk factors for increased disease severity and long-term respiratory sequelae in previously healthy African children with HAdV LRTIs are not well established. SUMMARY: Although respiratory viruses, including HAdV, are recognized contributors to LRTIs, the prevalence and impact of adenovirus infections have been under-recognized and understated. Available data suggests that African children, particularly those under 5 years old, are at risk of severe sequelae from respiratory HAdV infections. Long-term sequelae, including bronchiectasis and postinfectious bronchiolitis obliterans, further underscore the significant impact of HAdV infections. However, the scarcity of comprehensive data hampers our understanding of the extent of the impact of HAdV infections on child lung health in Africa. We recommend scaled-up HAdV surveillance, ensuring its consistent inclusion in population-level LRTI assessments, and expanded and equitable access to diagnostics for early recognition of African children at risk of developing chronic sequelae and death. Enhanced understanding of adenovirus epidemiology and clinical outcomes and the availability of therapeutic options are essential for informed public health strategies and clinical care.

[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.

Potential Diagnostic and Prognostic Biomarkers for Adenovirus Respiratory Infection in Children and Young Adults.

Human Adenoviruses (HAdV) are known to be potentially associated with strong inflammatory responses and morbidity in pediatric patients. Although most of the primary infections are self-limiting, the severity of clinical presentation, the elevation of the white blood cell count and inflammatory markers often mimic a bacterial infection and lead to an inappropriate use of antibiotics. In infections caused by HAdV, rapid antigen detection kits are advisable but not employed routinely; costs and feasibility of rapid syndromic molecular diagnosis may limit its use in the in-hospital setting; lymphocyte cultures and two-sampled serology are time consuming and impractical when considering the use of antibiotics. In this review, we aim to describe the principal diagnostic tools and the immune response in HAdV infections and evaluate whether markers based on the response of the host may help early recognition of HAdV and avoid inappropriate antimicrobial prescriptions in acute airway infections.

Nonenteric Adenoviruses Associated with Gastroenteritis in Hospitalized Children.

The object of this study was to investigate the frequency of human adenovirus (HAdV) infections in hospitalized pediatric patients. Stool samples were collected during a 1-year period (February 2018 to January 2019). HAdV was detected by a broad-range PCR and genotyped by sequencing and phylogenetic analysis. Demographic characteristics and detailed clinical information were analyzed for each patient. HAdV was detected in 7.1% of stool samples (34/476). Among these patients, 23.5% were coinfected with other enteric viral or bacterial pathogens. The majority (85.2%) of HAdV positives were detected in children of <5 years of age. Two HAdV species (B and C) with three types were identified in this study population. HAdV species F was not detected. Genetic analysis shows that the isolates circulating in our region present high diversity and do not exhibit clonal expansion. The presence of nonenteric HAdV in subjects with gastrointestinal symptoms and in immunocompromised patients has already been reported by different studies and underlines the need to develop routine molecular assays that have wide reactivity for most types of adenovirus in order to obtain an optimal tool for their rapid and accurate diagnosis. IMPORTANCE Gastroenteritis is the second leading cause of death among infants and children worldwide. Our study shows that adenovirus types other than 40 and 41 might be related to acute gastroenteritis. Therefore, a novel approach using diagnostic methods able to detect all adenovirus types is desirable in order to overcome the limitations of the current techniques.

Antigenic competition in the generation of multi-virus-specific cell lines for immunotherapy of human cytomegalovirus, polyomavirus BK, Epstein-Barr virus and adenovirus infection in haematopoietic stem cell transplant recipients.

Adoptive transfer of multivirus-specific T cell lines (MVST) is an advanced tool for immunotherapy of virus infections after hematopoietic stem cell transplantation (HSCT). Their preparation includes activation of donor virus-specific T cells by the mixture of oligopeptides derived from immunodominant antigens of several most harmful viruses, i.e. human cytomegalovirus (HCMV), polyomavirus BK (BKV), Epstein-Barr virus (EBV) and adenovirus (ADV). The aim of our study was to find out whether antigenic competition may have an impact on the expansion of virus-specific T cells. MVST from several heathy blood donors were generated using a pulse of overlapping oligopeptides (PepMixes™, derived from the IE1 and pp65 CMV antigens, VP1 and LTAG BKV antigens, BZLF1 and EBNA1 proteins of EBV and hexon protein from ADV) and short time culture in the presence of IL-7 and IL-4. The amount of virus-specific T cells in MVST was measured by ELISPOT and flow cytometry after re-stimulation with individual antigens. To evaluate antigenic competition, MVST were expanded either with a complete set of antigens or with the mixture lacking some of them. MVST expanded with the antigen mixture including CMV antigens contained a lower proportion of the T cells of other antigen specificities. A similar inhibitory effect was not apparent for EBV-derived peptides. The competitive effect of CMV antigens was most pronounced in MVST from CMV-seropositive donors and was mediated by both IE1 and pp65-derived peptides. Antigenic competition did not influence the phenotype of either CMV- or BKV-specific T cells. Both T cell populations had an effector memory phenotype (CD45RO+, CD27-, CCR7-). However, CMV-specific T cells preferentially consist of CD8+ while in BKV-specific T cells, the CD4+ phenotype predominated. Modification of the MVST manufacture protocol to prevent antigenic competition may increase the efficacy of MVST in therapy of BKV infections in HSCT recipients.

Severe adenovirus pneumonia with hemophagocytic syndrome and respiratory failure.

We report the case of an 18-month-old infant with severe serotype 3 adenovirus pneumonia, exceptionally associated with hemophagocytic syndrome. Treatment included cidofovir and mechanical ventilation for 13 days. The child developed chronic respiratory insufficiency due to bronchiectasis and bronchiolitis obliterans.

Bioinformatics analysis reveals four major hexon variants of human adenovirus type-3 (HAdV-3) as the potential strains for development of vaccine and siRNA-based therapeutics against HAdV-3 respiratory infections.

Human adenovirus type 3 (HAdV-3) encompasses 15-87% of all adenoviral respiratory infections. The significant morbidity and mortality, especially among the neonates and immunosuppressed patients, demand the need for a vaccine or a targeted antiviral against this type. However, due to the existence of multiple hexon variants (3Hv-1 to 3Hv-25), the selection of vaccine strains of HAdV-3 is challenging. This study was designed to evaluate HAdV-3 hexon variants for the selection of potential vaccine candidates and the use of hexon gene as a target for designing siRNA that can be used as a therapy. Based on the data of worldwide distribution, duration of circulation, co-circulation and their percentage among all the variants, 3Hv-1 to 3Hv-4 were categorized as the major hexon variants. Phylogenetic analysis and the percentage of homology in the hypervariable regions followed by multi-sequence alignment, zPicture analysis and restriction enzyme analysis were carried out. In the phylogram, the variants were arranged in different clusters. The HVR encoding regions of hexon of 3Hv-1 to 3Hv-4 showed 16 point mutations resulting in 12 amino acids substitutions. The homology in HVRs was 81.81-100%. Therefore, the major hexon variants are substantially different from each other which justifies their inclusion as the potential vaccine candidates. Interestingly, despite the significant differences in the DNA sequence, there were many conserved areas in the HVRs, and we have designed functional siRNAs form those locations. We have also designed immunogenic vaccine peptide epitopes from the hexon protein using bioinformatics prediction tool. We hope that our developed siRNAs and immunogenic vaccine peptide epitopes could be used in the future development of siRNA-based therapy and designing a vaccine against HAdV-3.

Respiratory adenovirus infections in immunocompetent and immunocompromised adult patients.

Adenovirus (AdV) can cause severe respiratory infections in children and immunocompromised patients, but less is known about severe AdV pneumonia in immunocompetent adults. In this retrospective study, we compared respiratory tract infections and pneumonia caused by AdV in immunocompromised and immunocompetent adult patients regarding clinical presentation and severity of infection. The results show that AdV can cause severe infections in both immunocompetent and immunocompromised patients, and the clinical presentation and need for hospitalisation, mechanical ventilation and antiviral treatment were equal in both groups. No underlying risk factors for severe AdV infection in healthy individuals were identified.

Transfer of Hexon- and Penton-selected adenovirus-specific T cells for refractory adenovirus infection after haploidentical stem cell transplantation.

Adenovirus (HAdV) infections confer a high risk of morbidity and mortality for immunocompromised patients after stem cell transplantation (SCT). Treatment with standard antiviral drugs is of limited efficacy and associated with a high rate of adverse effects. HAdV-specific T cells are crucial for sustained viral elimination and the efficacy of adoptive T-cell therapy with donor-derived HAdV-specific T cells has been reported by several investigators. Here, we report our experience with the transfer of HAdV-specific T cells specific for penton, which was recently identified as an immunodominant target of T cells, and hexon in a 14-year-old boy after T-cell-depleted haploidentical SCT for myelodysplastic syndrome (MDS). He developed severe HAdV-associated enteritis complicated by acute graft-versus-host disease (GvHD). The patient received ten infusions of allogeneic HAdV-specific T cells manufactured from the haploidentical stem cell donor using the CliniMacs Interferon-γ (IFN-γ) cytokine capture and immunomagnetic selection. Initially, T cells were generated against the immunodominant target hexon and in subsequent transfers dual antigen-specific T cells against hexon and penton were applied. T-cell transfers were scheduled individually tailored to current immunosuppressive treatment. Each transfer was followed by reduction of HAdV load in peripheral blood and clinical improvement. Importantly, T-cell responses to both penton and hexon pools emerged in patient blood after repetitive transfers. Unfortunately, the patient experienced bacterial sepsis, and in this context, severe GvHD requiring intensive immunosuppression followed by secondary progression of HAdV infection. The patient succumbed to multiorgan failure 283 days after SCT. This case demonstrates the feasibility of HAdV-specific T-cell transfer even in the presence of immunosuppressive treatment. Targeting of multiple immunodominant viral proteins may prove valuable in patients with complicated HAdV infections.

Infección letal por adenovirus: presentación de un caso / Lethal infection for adenovirus: case report

Adenovirus (ADV) can cause serious, localized or disseminated, sometimes lethal disease. There is no specific treatment, only support management according to requirements and severity of disease. Extracorporeal membrane oxygenation (ECMO) has been used in severe ADV infection. Cidofovir has been reported as a therapeutic option. This case reports a lethal case of ADV respiratory infection despite the treatment with cidofovir an ECMO.

El adenovirus (ADV) puede causar infección respiratoria grave, localizada o diseminada y letal en pacientes susceptibles. No existe terapia específica, solo de soporte según requerimientos y gravedad. En este sentido el manejo con oxigenación por membrana extracorpórea (ECMO) ha sido utilizado en niños con infección grave por ADV. Si bien no existe terapia específica actual se ha reportado uso de cidofovir que ha ganado espacio como posibilidad terapéutica en caso de enfermedad grave. Se presenta el caso clínico de un paciente que cursó con infección letal por ADV a pesar del tratamiento de soporte con ECMO y el tratamiento con cidofovir.

Infección respiratoria por adenovirus en pediatría: de ayer a hoy / Adenovirus pediatric respiratory infection: past and present

Acute respiratory infections represent a world pediatric health burden. RSV, influenza and adenoviruses are among the most frequent causative agents. Adenoviruses usually produce upper respiratory infections, but they can be responsible for acute lower respiratory infection in children with severe clinical outcome. It is necessary a special clinical and epidemiological organization to avoid nosocomial adenovirus local outbreaks. Rapid diagnose, done by immunofluorescence assay and PCR, individual case isolation and supportive therapy are necessary for an appropriate management. The increasing immune compromised population represents a challenge for the adenovirus diagnosis with quantitative PCR and for nosocomial infection control and potential antiviral treatment.

Las infecciones respiratorias agudas son un problema prioritario mundial de morbimortalidad infantil y son causadas predominantemente por virus, entre los que destacan el virus respiratorio sincicial (VRS), virus influenza (FLU) y adenovirus (ADV). Los ADV normalmente causan infecciones respiratorias altas, pero pueden provocar infecciones bajas muy graves, que dejan secuelas y tienen alta letalidad. Requieren un manejo clínico y epidemiológico especial para evitar los graves brotes nosocomiales observados en Latinoamérica. Esto incluye un diagnóstico rápido hecho con técnicas de inmunodiagnóstico y reacción en cadena polimerasa (PCR), aislamiento individual del paciente y terapia de soporte. En pacientes inmunocomprometidos, la infección por ADV representa un gran desafío para el diagnóstico, con uso de PCR cuantitativo (qPCR) y eventual tratamiento antiviral. El objetivo de esta revisión es el de actualizar las propiedades, patogenia, epidemiología y diagnóstico del ADV, con énfasis en los cuadros respiratorios de mayor morbimortalidad que se producen en algunos niños.

Strategies of adoptive T -cell transfer to treat refractory viral infections post allogeneic stem cell transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) can expose patients to a transient but marked immunosuppression, during which viral infections are an important cause of morbidity and mortality. Adoptive transfer of virus-specific T cells is an attractive approach to restore protective T -cell immunity in patients with refractory viral infections after allogeneic HSCT. OBJECTIVES: This narrative review summarizes clinical evidence and developments of almost 30 years of adoptive T -cell transfer. The review is based on evidence extracted from PubMed searches and the clinical and experimental work of the authors. CONTENT: Viral infections after HSCT are frequently caused by the endogenous reactivation of persistent pathogens such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus (AdV). Current antiviral medication is not satisfactory and does not treat the underlying pathophysiology which is the lack of specific T -cell immunity. Adoptive transfer of virus-specific T cells could be a potentially curative, pathogen-specific, and non-toxic treatment providing long-term immunity against the virus. The isolation of virus-specific T cells from a healthy donor and infusion into a recipient is known as adoptive T -cell transfer and has been performed in many patients using different treatment protocols. Based on basic research, new isolation protocols aim at a safe and fast availability of cellular products for adoptive T -cell transfer. We summarize preclinical and clinical data on each of the main pathogens and on the technical approaches currently available to target either single antigens or even multiple pathogens. CONCLUSION: Cellular therapy is considered as one of the major recent breakthroughs in medicine. Translation of this individualized treatment into first-line clinical routine is still limited. Main hurdles are availability of the technique, limited compatibility of classical phase III designs with cellular therapy, and regulatory restrictions. Multinational efforts are required to clarify the status of cellular treatment in first-line clinical routine with the overall objective to strengthen evidence-based treatment guidelines for the treatment of refractory viral infections post HSCT.

Clearance of Treatment Refractory Adenoviremia via Adenovirus-specific Donor T-Cell Transfer During Aplasia After αßTCR-CD19-Depleted Stem Cell Transplantation.

Here, we report the case of severe adenoviremia in a 7-year-old boy with highly-resistant, acute leukemia. A combined approach of αßTCR-CD19-depleted stem cell transplantation, enabling immunosuppression-free post-transplant care, and early transfer of adenovirus-specific donor T cells during aplasia resulted in rapid and complete clearance of the treatment-refractory adenoviremia.

Effect of cold atmospheric plasma (CAP) on human adenoviruses is adenovirus type-dependent.

More than 70 human adenovirus types were identified divided into 7 different species (A-G). Diseases caused by human adenoviruses are type-dependent and can range from mild to severe respiratory infections, gastrointestinal infections or eye infections such as epidemic keratoconjunctivitis. Unfortunately there is no specific anti-adenovirus therapy available. Here we addressed the question whether treatment with cold atmospheric plasma (CAP) for anti-adenoviral therapy such as virus-mediated ulcerations may be feasible. CAP has already been explored for the treatment of dermatological diseases such as chronic wounds. To investigate whether CAP is an effective antiviral tool, purified human adenovirus types derived from different human adenovirus species (HAdV -4, -5, -20, -35, -37, -50) tagged with luciferase were treated with defined dosages of plasma. The CAP treatment was varied by incrementally increasing the time span of CAP treatment. After CAP treatment, the virus containing solution was added to eukaryotic cells and the viral load was determined by measurement of luciferase expression levels. Through the plasma treatment the adenovirus driven luciferase expression directly correlating with adenovirus transduction efficiencies could be reduced for HAdV-5 and HAdV-37. Plasma treatment had no influence on adenovirus derived luciferase expression levels for HAdV-4 and HAdV-50 and it even had a positive effect on luciferase expression levels for HAdV-20 and HAdV-35. These results suggest that CAP has a type dependent effect on adenoviruses and that infectivity can be even increased for certain adenovirus types. Further studies should address the mechanisms behind this phenomenon. In summary we demonstrate that CAP may represent an interesting option for antiviral treatment in a virus type dependent manner.

Viral infections directly involved in kidney allograft function.

Modern immunosuppressive therapy has dramatically reduced the incidence of acute rejection and improved graft survival in kidney transplant patients. However, infectious complications remain an important issue. Amongst the various pathogens, viruses such as adenovirus and polyomavirus BK can directly cause acute or chronic graft dysfunction. Adenovirus mainly causes haemorrhagic cystitis and tubulointerstitial nephritis in kidney transplant patients. While patients show apparent clinical symptoms such as fever, dysuria, gross haematuria, frequency and urgency of urination, and most patients show acute graft dysfunction, these symptoms and graft dysfunction are reversible. Polyomavirus BK infection, however, is asymptomatic but graft outcome is poor if the patient develops tissue-invasive nephropathy confirmed by graft biopsy. Recently, an attempt to create a pathological classification for predicting the clinical course has been made by the Banff Working Group on Polyomavirus Nephropathy. With regards to treatment, the basic strategy is a reduction of calcineurin inhibitor and/or antimetabolites, and the effectiveness of several adjunct treatments has been investigated in several clinical trials. There are other unresolved issues, such as the diagnosis of subsequent acute rejection, the definition of remission, methods of resuming immunosuppression and long-term follow-up. Most of all, development of effective vaccines and novel drug discovery are necessary to prevent the development and progression of BKV-associated nephropathy.

Adenoviral keratitis: a review of the epidemiology, pathophysiology, clinical features, diagnosis, and management.

PURPOSE OF REVIEW: Adenoviral keratitis is a common and bothersome ocular infection that produces a lot of burden on healthcare systems and patients. The goal of this article is to provide a review of the topic, with an emphasis on current attempts at advancing strategies in diagnosis and management. RECENT FINDINGS: Sixty-eight articles and one textbook published on adenoviral keratitis were reviewed. The findings on the epidemiology, pathophysiology, clinical features, diagnosis, and management were summarized. Any contradicting opinions for which the literature was unclear were either omitted or recorded as lacking strong evidence. SUMMARY: Although significant effort has been made to develop new methods for diagnosis and management, adenoviral keratitis is predominantly diagnosed clinically with prevention being the mainstay of management. The use of newer DNA analysis techniques and topical anti-inflammatory agents for treatment of corneal infiltrates show promising results, but a better understanding of the pathogenesis and clinical features can lead to more targeted methods of diagnosis and therapy.

Outbreak of influenza and rhinovirus co-circulation among unvaccinated recruits, U.S. Coast Guard Training Center Cape May, NJ, 24 July-21 August 2016.

Military and Coast Guard recruits are particularly susceptible to respiratory infections. Although seasonal influenza vaccinations are mandatory for recruits, the vaccine expires annually in June. On 29 July 2016, the U.S. Coast Guard Training Center Cape May, NJ, identified an increase in febrile respiratory illness (FRI) among recruits. During 24 July-21 August, a total of 115 recruits reported symptoms. A total of 74 recruits tested positive for respiratory infections: influenza A (H3) (n=34), rhinovirus (n=28), influenza/rhinovirus co-infection (n=11), and adenovirus/rhinovirus co-infection (n=1), while 41 recruits had no laboratory-confirmed specimen but were considered suspected cases. Only one recruit reported receiving the seasonal influenza vaccine within the previous 12 months. Influenza predominated during 24 July-6 August, whereas rhinovirus predominated during 7 August-20 August. Most (92.2%) cases were identified in four of 10 recruit companies; incidence rates were highest among recruits in weeks 2-4 of an 8-week training cycle. Key factors for outbreak control included rapid detection through routine FRI surveillance, quick decision-making and streamlined response by using a single chain of command, and employing both nonpharmaceutical and pharmaceutical interventions.

Adenovirus Infection in Children With Acute Myeloid Leukemia: A Report From the Canadian Infection in Acute Myeloid Leukemia Research Group.

BACKGROUND: Children with acute myeloid leukemia (AML) are at high risk of life-threatening bacterial and fungal infection. However, little is known about the prevalence or severity of adenovirus infection in this population. Objective was to describe the characteristics, treatments and outcomes of adenovirus infection in children with newly diagnosed AML. METHODS: We performed a retrospective chart review based upon 2 multicenter cohort studies that focused on identifying risk factors for infection in children with AML. Inclusion criteria were patients with de novo AML who were ≤18 years of age at diagnosis with a clinical specimen positive for adenovirus. RESULTS: Among the 235 patients with AML, 12 (5.1%) had positive adenovirus testing. The most common site of isolation was stool (n = 11, 91.6 %), and the most frequent symptom was diarrhea (n = 11, 91.6 %). Two patients received specific treatment for adenovirus, namely intravenous immunoglobulin only in 1 patient and both intravenous immunoglobulin and inhaled ribavirin in a second patient. In 11 patients, adenovirus resolved uneventfully without recurrence, including 10 that received no adenovirus-specific therapy. However, 1 patient developed sepsis syndrome in the setting of disseminated adenoviral infection and died from multiorgan failure. CONCLUSION: In children with AML, adenovirus infection was rare and typically not associated with severe disease, even without specific treatment. However, disseminated and fatal disease can occur in this population. Further investigations are needed to identify pediatric AML patients at particular risk for severe adenovirus infection and to determine optimal treatment approaches in these patients.

Curative or pre-emptive adenovirus-specific T cell transfer from matched unrelated or third party haploidentical donors after HSCT, including UCB transplantations: a successful phase I/II multicenter clinical trial.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT), the most widely used potentially curable cellular immunotherapeutic approach in the treatment of hematological malignancies, is limited by life-threatening complications: graft versus host disease (GVHD) and infections especially viral infections refractory to antiviral drugs. Adoptive transfer of virus-specific T cells is becoming an alternative treatment for infections following HSCT. We report here the results of a phase I/II multicenter study which includes a series of adenovirus-specific T cell (ADV-VST) infusion either from the HSCT donor or from a third party haploidentical donor for patients transplanted with umbilical cord blood (UCB). METHODS: Fourteen patients were eligible and 11 patients received infusions of ADV-VST generated by interferon (IFN)-γ-based immunomagnetic isolation from a leukapheresis from their original donor (42.9%) or a third party haploidentical donor (57.1%). One patient resolved ADV infection before infusion, and ADV-VST could not reach release or infusion criteria for two patients. Two patients received cellular immunotherapy alone without antiviral drugs as a pre-emptive treatment. RESULTS: One patient with adenovirus infection and ten with adenovirus disease were infused with ADV-VST (mean 5.83 ± 8.23 × 103 CD3+IFN-γ+ cells/kg) up to 9 months after transplantation. The 11 patients showed in vivo expansion of specific T cells up to 60 days post-infusion, associated with adenovirus load clearance in ten of the patients (91%). Neither de novo GVHD nor side effects were observed during the first month post-infusion, but GVHD reactivations occurred in three patients, irrespective of the type of leukapheresis donor. For two of these patients, GVHD reactivation was controlled by immunosuppressive treatment. Four patients died during follow-up, one due to refractory ADV disease. CONCLUSIONS: Adoptive transfer of rapidly isolated ADV-VST is an effective therapeutic option for achieving in vivo expansion of specific T cells and clearance of viral load, even as a pre-emptive treatment. Our study highlights that third party haploidentical donors are of great interest for ADV-VST generation in the context of UCB transplantation. (N° Clinical trial.gov: NCT02851576, retrospectively registered).

Single- and multiple viral respiratory infections in children: disease and management cannot be related to a specific pathogen.

BACKGROUND: The number of viral pathogens associated with pediatric acute respiratory tract infection (ARI) has grown since the introduction of reverse transcription real-time polymerase chain reaction (RT-PCR) assays. Multiple viruses are detected during a single ARI episode in approximately a quarter of all cases. The clinical relevance of these multiple detections is unclear, as is the role of the individual virus. We therefore investigated the correlation between clinical data and RT-PCR results in children with single- and multiple viral ARI. METHODS: Data from children with ARI were prospectively collected during two winter seasons. RT-PCR testing for 15 viruses was performed in 560 ARI episodes. In the patients with a single-viral etiology, clinical data, laboratory findings, patient management- and outcome data were compared between the different viruses. With this information, we compared data from children of whom RT-PCR data were negative, with children with single- and multiple viral positive results. RESULTS: The viral detection rate was 457/560 (81.6%) of which 331/560 (59.1%) were single infections and 126/560 (22.5%) were multiple infections. In single viral infections, some statistically significant differences in demographics, clinical findings, disease severity and outcome were found between children with different viral etiologies. However, no clinically recognizable pattern was established to be virus-specific. In a multivariate analysis, the only variables that were correlated with longer hospital stay were the use of oxygen and nebulizer therapy, irrespective of the viral pathogen. Children with RT-PCR positive test results had a significant higher disease severity, fever, length of hospital stay, days of extra oxygen supply, and days of antibiotic treatment than children with a negative RT-PCR test result. For children with single- versus children with multiple positive RT-PCR test results, these differences were not significant. CONCLUSIONS: Disease (severity), management and outcome in pediatric ARI are not associated with a specific virus. Single- and multiple viral ARI do not significantly differ with regard to clinical outcome and patient management. For general pediatrics, RT-PCR assays should be restricted to pathogens for which therapy is available or otherwise may have clinical consequences. Further research with an extended panel of RT-PCR assays and a larger number of inclusions is necessary to further validate our findings.