[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.

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.

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.

TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination.

Adenovirus has enormous potential as a gene-therapy vector, but preexisting immunity limits its widespread application. What is responsible for this immune block is unclear because antibodies potently inhibit transgene expression without impeding gene transfer into target cells. Here we show that antibody prevention of adenoviral gene delivery in vivo is mediated by the cytosolic antibody receptor TRIM21. Genetic KO of TRIM21 or a single-antibody point mutation is sufficient to restore transgene expression to near-naïve immune levels. TRIM21 is also responsible for blocking cytotoxic T cell induction by vaccine vectors, preventing a protective response against subsequent influenza infection and an engrafted tumor. Furthermore, adenoviral preexisting immunity can lead to an augmented immune response upon i.v. administration of the vector. Transcriptomic analysis of vector-transduced tissue reveals that TRIM21 is responsible for the specific up-regulation of hundreds of immune genes, the majority of which are components of the intrinsic or innate response. Together, these data define a major mechanism underlying the preimmune block to adenovirus gene therapy and demonstrate that TRIM21 efficiently blocks gene delivery in vivo while simultaneously inducing a rapid program of immune transcription.

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.

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.

Approach to infection and disease due to adenoviruses in solid organ transplantation.

PURPOSE OF REVIEW: Adenoviruses are an important cause of morbidity and mortality of solid organ transplant patients and remain a clinical challenge with regard to diagnosis and treatment. In this review, we provide an approach to identification and classification of adenovirus infection and disease, highlight risk factors, and outline management options for adenovirus disease in solid organ transplant patients. RECENT FINDINGS: Additional clinical data and pathologic findings of adenovirus disease in different organs and transplant recipients are known. Unlike hematopoietic cell transplant recipients, adenovirus blood PCR surveillance and preemptive therapy is not supported in solid organ transplantation. Strategies for management of adenovirus disease continue to evolve with newer antivirals, such as brincidofovir and adjunctive immunotherapies, but more studies are needed to support their use. SUMMARY: Distinguishing between adenovirus infection and disease is an important aspect in adenovirus management as treatment is warranted only in symptomatic solid organ transplant patients. Supportive care and decreasing immunosuppression remain the mainstays of management. Cidofovir remains the antiviral of choice for severe or disseminated disease. Given its significant nephrotoxic effect, administration of probenecid and isotonic saline precidofovir and postcidofovir infusion is recommended.

Current practices in the management of adenovirus infection in allogeneic hematopoietic stem cell transplant recipients in Europe: The AdVance study.

OBJECTIVE: Adenovirus (AdV) infections are potentially life-threatening for allogeneic hematopoietic stem cell transplant (allo-HCT) recipients. The AdVance study aimed to evaluate the incidence, management, and outcomes of AdV infections in European allo-HCT recipients. METHODS: As part of the study, physician surveys were conducted to determine current AdV screening and treatment practices at their center. RESULTS: All of the 28 respondents who treat pediatric patients reported routine AdV screening practices, with 93% screening all allo-HCT recipients and others screening those with transplant-related risk factors. Nearly all centers take a pre-emptive approach to AdV treatment in both high- (89%) and low-risk patients (75%). Among the 14 respondents who treat adult patients, 5 (36%) reported routine screening practices and few (21%) screen all allo-HCT recipients unless risk factors are present. In adults, pre-emptive AdV treatment is uncommon and quantitative AdV thresholds are rare. Typical treatment for all patients with symptomatic AdV infection is off-label intravenous cidofovir. CONCLUSIONS: Our findings confirm that screening for AdV is more common in pediatric patients. Antiviral treatment is employed in both pediatric and adult patients, although adults are generally treated when AdV disease is diagnosed. The approach to AdV screening and treatment is risk-based and consistent with clinical guidelines.

Management of adenovirus infection in patients after haematopoietic stem cell transplantation: State-of-the-art and real-life current approach: A position statement on behalf of the Infectious Diseases Working Party of the European Society of Blood and Marrow Transplantation.

The important insights gained over the past years in diagnosis and treatment of invasive adenoviral infections provide new paradigms for the monitoring and clinical management of these life-threatening complications. A meeting was held to discuss and subsequently disseminate the current advances in our understanding of the aetiology/pathogenesis and future treatment options facilitating effective control or prevention of adenovirus-related diseases in the allogeneic haematopoietic stem cell transplant setting. Invited experts in the field discussed recent progress with leading members of the Infectious Diseases Working Party of the European Society of Blood and Marrow Transplantation at the "State-of-the-art" Meeting in Poznan, Poland, in October 2017. In this review article, the panel of experts presents a concise summary of the current evidence based on published data from the last 15 years and on recent achievements resulting from real-life practice. The present position statement reflects an expert opinion on current approaches to clinical management of adenovirus infections in patients undergoing allogeneic haematopoietic stem cell transplant and provides graded recommendations of the panel for diagnostic approaches and preemptive therapy reflecting the present state of knowledge.

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.

Adenovirus-specific T-lymphocyte efficacy in the presence of methylprednisolone: An in vitro study.

Virus-specific T-cell (VST) infusion becomes a promising alternative treatment for refractory viral infections after hematopoietic stem cell transplantation (HSCT). However, VSTs are often infused during an immunosuppressive treatment course, especially corticosteroids, which are a first-line curative treatment of graft-versus-host disease (GVHD). We were interested in whether corticosteroids could affect adenovirus (ADV)-VST functions. After interferon (IFN)-γ based immunomagnetic selection, ADV-VSTs were in vitro expanded according to three different culture conditions: without methylprednisolone (MP; n = 7), with a final concentration of MP 1 µg/mL (n = 7) or MP 2 µg/mL (n = 7) during 28 ± 11 days. Efficacy and alloreactivity of expanded ADV-VSTs was controlled in vitro. MP transitorily inhibited ADV-VST early expansion. No impairment of specific IFN-γ secretion capacity and cytotoxicity of ADV-VSTs was observed in the presence of MP. However, specific proliferation and alloreactivity of ADV-VSTs were decreased in the presence of MP. Altogether, these results and the preliminary encouraging clinical experiences of co-administration of MP 1 mg/kg and ADV-VSTs will contribute to safe and efficient use of anti-viral immunotherapy.

Adenovirus Ocular Infections: Prevalence, Pathology, Pitfalls, and Practical Pointers.

Adenoviral conjunctivitis comprises a large number of physician office visits in the United States and places a great financial burden on health care. It is estimated that the incidence of adenovirus infection to be as high as 20 million cases per year in the United States. There are multiple adenovirus serotypes, each associated with different types and severity of infection. Ocular manifestations of adenovirus include epidemic keratoconjunctivitis, pharyngoconjunctival fever, and nonspecific conjunctivitis. Adenoviral conjunctivitis is primarily a clinical diagnosis. Laboratory diagnosis is available although until recently rarely used. At present, there is no established or approved specific effective drug against adenovirus. Treatment is primarily supportive and includes artificial tears and cool compresses. Topical antibiotics are only indicated if a bacterial coinfection is suspected or in high-risk patients such as children. Prevention against this extremely contagious disease is of utmost importance. Although most cases are self-limited and have a relatively benign course, permanent visual disability can occur. For this reason, it is imperative that all eye care providers are capable of diagnosing and effectively treating these patients, and also preventing the spread of this contagious disease to others.

Manufacture of GMP-compliant functional adenovirus-specific T-cell therapy for treatment of post-transplant infectious complications.

BACKGROUND AIMS: In pediatric patients, adenovirus (ADV) reactivation after allogeneic hematopoietic stem cell transplantation (allo HSCT) is a major cause of morbidity and mortality. For patients who do not respond to antiviral drug therapy, a new treatment approach using ADV-specific T cells can present a promising alternative. Here we describe the clinical scale Good Manufacturing Practice (GMP)-compliant manufacture and characterization of 40 ADV-specific T-cell products, Cytovir ADV, which are currently being tested in a multi-center phase I/IIa clinical trial. This process requires minimal intervention, is high yield, and results in a pure T-cell product that is functional. METHODS: Mononuclear cells (2 × 10(7)) were cultured in a closed system in the presence of GMP-grade ADV peptide pool and cytokines for 10 days. On day 10, the T-cell product was harvested, washed in a closed system, counted and assessed for purity and potency. Additional characterization was carried out where cell numbers allowed. RESULTS: Thirty-eight of 40 products (95%) met all release criteria. Median purity of the cell product was 88.3% CD3+ cells with a median yield of 2.9 × 10(7) CD3+ cells. Potency analyses showed a median ADV-specific interferon (IFN)γ response of 5.9% of CD3+ and 2345 IFNγ spot-forming cells/million. CD4 and CD8 T cells were capable of proliferating in response to ADV (63.3 and 56.3%, respectively). These virus-specific T cells (VST) were heterogenous, containing both effector memory and central memory T cells. In an exemplar patient with ADV viremia treated in the open ASPIRE trial, ADV-specific T-cell response was detected by IFNγ enzyme-linked immunospot from 13 days post-infusion. ADV DNA levels declined following cellular therapy and were below level of detection from day 64 post-infusion onward. CONCLUSIONS: The clinical-scale GMP-compliant One Touch manufacturing system is feasible and yields functional ADV-specific T cells at clinically relevant doses.

The Use of Bandage Contact Lenses in Adenoviral Keratoconjunctivitis.

PURPOSE: To evaluate the safety and efficacy of the use of the bandage contact lenses (BCLs) in adenoviral keratoconjunctivitis-related ocular surface problems. METHODS: Fifteen eyes of 15 consecutive patients presenting at the Ankara University Medical Center, Cornea and Contact Lens Service, and requiring BCL use for adenoviral keratoconjunctivitis-related ocular surface problems were enrolled. Visual acuity, slitlamp examination findings, indication and duration of the BCL use, the total follow-up, and any adjuvant medication were recorded. All patients were followed regarding the success of treatment and adverse effects associated with BCL use. RESULTS: The average age at the time of presentation was 26.8±15.5 years. The major reasons for BCL use included epithelial defect (7 eyes), filamentous keratopathy (5 eyes), epithelial edema (1 eyes), and filamentous keratopathy together with epithelial defect (2 eyes). After the first appearance of conjunctivitis symptoms, the mean time to BCL application was 9.0±3.9 days. The mean duration of contact lens wear was 9.9±6.5 days, and the mean follow-up was 26.4±15.8 days. Preservative-free artificial tears and topical antibiotics were used in all cases. Besides, topical ganciclovir 0.15% gel (8 eyes), topical 0.4% povidone-iodine solution (9 eyes), and topical steroids (11 eyes) were used in various combinations. At the end of the follow-up period, the mean visual acuity improved from 0.23±0.32 logMAR units (∼0.6 Snellen line) to 0.0l±0.04 logMAR units (∼1.0 Snellen line) (P=0.042). No sight-threatening complication related to contact lens wear was encountered. CONCLUSION: Adjuvant use of BCLs seems to be safe and effective in the treatment of adenoviral keratoconjunctivitis-related ocular surface problems. Close follow-up and prophylactic use of topical antibiotics are rationalistic for prevention of secondary infections.

Adenovirus infections in immunocompetent and immunocompromised patients.

Human adenoviruses (HAdVs) are an important cause of infections in both immunocompetent and immunocompromised individuals, and they continue to provide clinical challenges pertaining to diagnostics and treatment. The growing number of HAdV types identified by genomic analysis, as well as the improved understanding of the sites of viral persistence and reactivation, requires continuous adaptions of diagnostic approaches to facilitate timely detection and monitoring of HAdV infections. In view of the clinical relevance of life-threatening HAdV diseases in the immunocompromised setting, there is an urgent need for highly effective treatment modalities lacking major side effects. The present review summarizes the recent progress in the understanding and management of HAdV infections.

Expression of an engineered soluble coxsackievirus and adenovirus receptor by a dimeric AAV9 vector inhibits adenovirus infection in mice.

Immunosuppressed (IS) patients, such as recipients of hematopoietic stem cell transplantation, occasionally develop severe and fatal adenovirus (Ad) infections. Here, we analyzed the potential of a virus receptor trap based on a soluble coxsackievirus and Ad receptor (sCAR) for inhibition of Ad infection. In vitro, a dimeric fusion protein, sCAR-Fc, consisting of the extracellular domain of CAR and the Fc portion of human IgG1 and a monomeric sCAR lacking the Fc domain, were expressed in cell culture. More sCAR was secreted into the cell culture supernatant than sCAR-Fc, but it had lower Ad neutralization activity than sCAR-Fc. Further investigations showed that sCAR-Fc reduced the Ad infection by a 100-fold and Ad-induced cytotoxicity by ~20-fold. Not only was Ad infection inhibited by sCAR-Fc applied prior to infection, it also inhibited infection when used to treat ongoing Ad infection. In vivo, sCAR-Fc was delivered to IS mice by an AAV9 vector, resulting in persistent and high (>40 µg ml(-1)) sCAR-Fc serum levels. The sCAR-Fc serum concentration was sufficient to significantly inhibit hepatic and cardiac wild-type Ad5 infection. Treatment with sCAR-Fc did not induce side effects. Thus, sCAR-Fc virus receptor trap may be a promising novel therapeutic for treatment of Ad infections.

[A case of adenovirus infection complicated by gram-negative polymicrobial sepsis: A clinical and morphological observation].

Among respiratory infections, adenovirus infection (ADVI), in the presence of which there may be severe pneumonia that frequently results in a fatal outcome, occupies particular attention. ADVI in patients without immunodeficiency is usually mild and shows a limited extent of injury. At the same time the disease in immunocompromised individuals may be severe, presenting with viremia, evolving sepsis, and high death rates. The paper gives a characteristic example of severe ADVI and its fatal outcome.

Patient, virus, and treatment-related risk factors in pediatric adenovirus infection after stem cell transplantation: results of a routine monitoring program.

Human adenovirus (HAdV) infection after hematopoietic stem cell transplantation (HSCT) is associated with significant morbidity and mortality in children. The optimal surveillance and treatment strategies are under discussion. Here, we present data from 238 consecutive pediatric allogeneic HSCT recipients who underwent transplantation in a single center who were included in a prospective, weekly HAdV DNAemia monitoring program by quantitative PCR. HAdV loads >1000 copies/mL were detected in 15.5% of all patients. Despite a low mortality directly attributed to HAdV infection (2 patients, 0.84%), blood HAdV loads >10,000 copies/mL (6.7% of all patients) were significant and independent risk factors for poor survival. We searched for patient, virus, and treatment-related risk factors of HAdV DNAemia and disease. Detection of HAdV in blood before day 50 post transplantation was a major independent risk factor for the development of blood HAdV loads >10,000 copies/mL. HAdV typing revealed A31, C1, and C2 as the predominant pathogens among several other HAdV strains with type C species detected in most patients with severe HAdV disease. Stool HAdV loads were prospectively monitored in 111 patients and correlated with but did not significantly precede detection in blood. Treatment with cidofovir led to stable or reduced viral load in 70% of patients with blood HAdV loads >1000 copies/mL. Thus, early occurrence of HAdV-DNA in blood of pediatric HSCT recipients predisposes for development of high viral loads. Control of HAdV infections was attempted by preemptive cidofovir treatment of patients with high blood HAdV loads or with symptomatic organ infections and correlated with low HAdV-attributed mortality.