[Adenovirus-related acute liver failure treated with intravenous immunoglobulin]. / Insuficiencia hepática aguda por adenovirus tratada con inmunoglobulina intravenos.

BACKGROUND: Acute liver failure in pediatric age is a serious multisystem disease, characterized by a failure of the synthesis and detoxification function of the liver. Among the etiologies, viral infection should be investigated. Treatment is supportive and some cases require liver transplantation. CASE REPORT: A 2-year-old girl was admitted for acute liver failure. The PCR viral panel was positive for Adenovirus 41 and IgG antibodies to SARS-CoV-2 were also found. Supportive treatment was started without improvement, so intravenous immunoglobulin was administered, with resolution of the liver failure. CONCLUSIONS: Immunoglobulin has immunomodulatory mechanisms in children with severe acute hepatitis of infectious etiology, so in some cases, its administration can be considered as adjuvant therapy.

ANTECEDENTES: La insuficiencia hepática aguda en pacientes pediátricos es una enfermedad multisistémica grave, caracterizada por falla de la función de síntesis y detoxificación del hígado. Dentro de su origen debe investigarse alguna infección viral. El tratamiento es de soporte y algunos casos requieren trasplante hepático. REPORTE DE CASO: Paciente pediátrica de 2 años, que ingresó al servicio médico por insuficiencia hepática aguda. El panel viral por PCR fue positivo para adenovirus 41 y anticuerpos IgG para SARS-CoV-2. Se inicio tratamiento de soporte sin reacción satisfactoria, por lo que se administró inmunoglobulina intravenosa, con resultados adecuados y curación de la insuficiencia hepática. CONCLUSIONES: La inmunoglobulina tiene mecanismos inmunomoduladores en pacientes pediátricos con hepatitis aguda grave de origen infeccioso, por lo que en algunos casos puede considerase su administración como terapia adyuvante.

Longitudinal Monitoring of the Effects of Anti-Adenoviral Treatment Regimens in a Permissive In Vivo Model.

Adenovirus infections of immunocompromised patients can cause life-threatening disseminated disease. While there are presently no drugs specifically approved to treat these infections, there are several compounds that showed efficacy against adenovirus in preclinical studies. For any such compound, low toxicity is an essential requirement. As cumulative drug effects can accentuate pathology, especially in patients with other morbidities, it is important to limit antiviral exposure to what is absolutely necessary. This is achievable by monitoring the virus burden of the patients and administering antivirals to suppress virus replication to a non-pathogenic level. We modeled such a system using Syrian hamsters infected with a replication-competent adenovirus vector, in which luciferase expression is coupled to virus replication. We found that virus replication could be followed in vivo in the same animal by repeated measurement of luciferase expression. To test the utility of an interrupted treatment regimen, we used NPP-669 and valganciclovir, two antiviral compounds with high and moderate anti-adenoviral efficacy, respectively. We found that short-term treatment of adenovirus-infected hamsters at times of peak virus replication can prevent virus-associated pathology. Thus, we believe that this animal model can be used to model different treatment regimens for anti-adenoviral compounds.

PD-1 blockade immunotherapy as a successful rescue treatment for disseminated adenovirus infection after allogeneic hematopoietic stem cell transplantation.

Disseminated adenovirus infection is a complication with a relatively high mortality rate among patients undergoing hematopoietic stem cell transplantation. The low efficacy and poor availability of current treatment options are of major concern. Programmed cell death 1 (PD-1) blockade has been used to treat several chronic viral infections. Herein, we report a case of disseminated adenovirus infection in the early posttransplant period. The patient was diagnosed with diffuse large B-cell lymphoma at first and underwent 8 cycles of chemotherapy, including rituximab. She was subsequently diagnosed with acute myeloid leukemia and received haploidentical transplantation. She was diagnosed with Epstein‒Barr virus (EBV)-positive posttransplant lymphoproliferative disorder (PTLD) 2 months after the transplant, and 3 doses of rituximab were administered. The patient was diagnosed with disseminated adenovirus infection with upper respiratory tract, gastrointestinal tract and blood involved at 3 months after transplantation. She was first treated with a reduction in immunosuppression, cidofovir and ribavirin. Then, the patient received salvage treatment with the PD-1 inhibitor sintilimab (200 mg) after achieving no response to conventional therapy. The adenovirus was cleared 3 weeks later, and concomitant EBV was also cleared. Although the patient developed graft-versus-host disease of the liver after the administration of the PD-1 inhibitor, she was cured with steroid-free therapy. Therefore, PD-1 blockade immunotherapy can be considered a promising treatment option for patients with disseminated adenovirus infection after transplantation, with fully weighing the hazards of infection and the side effects of this therapy.

Determinants of antibiotic prescription in children with adenovirus respiratory tract infections.

We performed this study to evaluate factors associated with antibiotic prescriptions in children with adenovirus infection, since no studies have attempted to address this aspect in the pediatric population. Retrospective study of children younger than 18 years of age tested positive for adenovirus on a syndromic nasopharyngeal test from 2018 to 2023. We compared the need of pediatric intensive care unit (PICU), invasive ventilation, and other respiratory support, viral etiologies, clinical presentations, imaging, and laboratory results in the precovid (2018-2019) and covid (2020-2022) period. The use of antibiotics was studied with multivariable logistic regression including demographic as well as clinical data as covariates. Two hundred fifty-eight patients were enrolled. One hundred fifty-eight patients received an antibiotic (mean duration 6.2 (±2.7) days (median 4; IQR: 4-7)). Presence of seizures and C-reactive protein values as predictors for antibiotic prescription (OR for seizures: 12.17; 95% CI: 1.42-103.91; p = 0.022; OR for CrP: 1.03; 95% CI: 1.01-1.04; p = 0.001). Seventy-four patients received intravenous antibiotics (74/156, 47.4%). Risk factors for intravenous antibiotic were the presence of decay (OR: 3.74; 95% CI: 1.25-11.71; p = 0.018), CrP values (OR: 1.02; 95% CI: 1.00-1.03; p = 0.001), and presence of seizures (OR: 16.34; 95% CI: 2.65-100.83; p = 0.003). Duration of intravenous antibiotics correlated with the presence of seizures (Coeff: 1.6; 95% CI: 0.41-2.89; p = 0.009) even when adjusted for CrP values.    Conclusion: The clinical presentation of adenovirus infection in children is non-specific, leading to frequent antibiotic prescription despite bacterial co-infections was rare. Higher CrP values and presenting with seizures are significantly associated with a higher risk of receiving antibiotics. Rapid microbiological tests and newer biomarkers can help clinicians to improve antibiotic prescription in this cohort of children. What is Known: • Adenovirus infection is a common cause of fever and respiratory tract infections in children. • Children with adenovirus infections frequently receive antibiotics, but determinants of this practice are poorly established. What is New: • Higher C-reactive protein values and presenting with seizures are significantly associated with antibiotic prescription. • Since the beginning of COVID-19 and implementation of rapid diagnostics, less children with adenovirus infection received antibiotics.

A Fulminant Case of Adenovirus Genotype C108 Infection in a Pediatric Stem Cell Transplant Recipient with x-Linked Lymphoproliferative Syndrome Type 1.

A 3-year-old male with X-linked lymphoproliferative syndrome type 1 underwent an unrelated umbilical cord blood transplant (UUCBT). The week prior to transplant the patient tested positive for adenovirus (HAdV) with a viral load of <190 copies/mL and was started on cidofovir. UUCBT proceeded as scheduled, and the patient engrafted on day +19. The patient's HAdV load in serum continued to rise with resulting hepatic dysfunction, despite ongoing therapy with cidofovir and HAdV specific T-cell infusions. The patient died 6 months after transplantation having never cleared the virus. Next generation whole genome sequencing and sequence data analyses identified an intertypic recombinant HAdV-C P1H2F2 closely related (99.6% similarity) to genotype C108 in the isolates from three blood specimens obtained during the last week of life. Incidentally, the de novo assembly strategy enabled the detection of an adeno-associated virus type 2 (AAV2) genome in the DNA purified from the plasma isolates. Proteotyping analysis revealed minor differences in the predicted amino acid sequences for E1A, E1B 19K, E1B 55K, DNA polymerase, penton base, and fiber. None of the mutations previously described for HAdV-C5 variants resistant to cidofovir were identified. In silico restriction enzyme analysis revealed a distinct Sac I profile for the identified virus, supporting its designation as a C108 variant.

Oral USC-093, a novel homoserinamide analogue of the tyrosinamide (S)-HPMPA prodrug USC-087 has decreased nephrotoxicity while maintaining antiviral efficacy against human adenovirus infection of Syrian hamsters.

Adenovirus infections of immunocompromised humans are a significant source of morbidity and mortality. Presently, there is no drug specifically approved for the treatment of adenovirus infections by the FDA. The state-of-the-art treatment of such infections is the off-label use of cidofovir, an acyclic nucleotide phosphonate. While cidofovir inhibits adenovirus replication, it has dose-limiting kidney toxicity. There is an apparent need for a better compound to treat adenovirus infections. To this end, we have been developing acyclic nucleotide phosphonate prodrugs that utilize an amino acid scaffold equipped with a lipophilic modifier. Here, we compare the antiviral potential of two prodrugs of HPMPA that differ only in the amino acid-based promoiety: USC-087, based on an N-hexadecyl tyrosinamide, and USC-093, based on an N-hexadecyl serinamide. Oral administration of both compounds was very efficacious against disseminated HAdV-C6 infection in immunosuppressed Syrian hamsters, suppressing virus replication and mitigating pathology even when treatment was withheld until 4 days after challenge. We saw only marginal efficacy after respiratory infection of hamsters, which may reflect suboptimal distribution to the lung. Importantly, neither compound induced intestinal toxicity, which was observed as the major adverse effect in clinical trials of brincidofovir, a prodrug of cidofovir which also contains a C-16 modifier. Notably, we found that there was a significant difference in the nephrotoxicity of the two compounds: USC-087 caused significant kidney toxicity while USC-093 did not, at effective doses. These findings will be valuable guidepoints in the future evolution of this new class of potential prodrugs to treat adenovirus infections.

Safety of Cidofovir Treatment for Suspected or Confirmed Adenovirus Infection in Immunocompetent Pediatric Population.

BACKGROUND: Cidofovir (CDV), a nucleoside phosphonate analogue, exhibits activity against severe cytomegalovirus and adenoviral (ADV) infection. Nevertheless, reports of elevated nephrotoxicity rates limited its use to highly vulnerable cases, mainly immunocompromised children with fulminant infection. Limited data exists regarding CDV safety in immunocompetent children. OBJECTIVE: To evaluate CDV-related toxicity, mainly nephrotoxicity, in immunocompetent children with severe ADV/cytomegalovirus infection. METHODS: We conducted a retrospective review of medical records for all immunocompetent children under 18 years of age treated with intravenous CDV from January 2005 to December 2019. RESULTS: Among the 23 patients identified, 21 were diagnosed with severe ADV infection. Median age was 15 months. Twenty-one (91%) children were admitted to the pediatric intensive care unit. Eighteen patients (78%) received standard CDV protocol (5 mg/kg CDV weekly for 2 weeks), 4 (17%) according to nephroprotective low-dose protocol and 1 patient transitioned. The median duration of CDV treatment was 14 days (range: 1-21 days). All patients received hyperhydration and probenecid with each infusion. Acute kidney injury was recorded in 1 patient (with concurrent septic shock) during CDV treatment. Two children exhibited acute kidney injury before CDV initiation, but renal function normalized during CDV treatment. One patient developed transient neutropenia (600 cells/L), apparently as a result of sepsis. No other major adverse effects were noted. Mortality rate was 3/23 (13%), unrelated to CDV toxicity. CONCLUSIONS: Our findings suggest that CDV-related nephrotoxicity rate in immunocompetent children may be lower than previously reported, perhaps lower than in the severely immunocompromised population.

Adenovirus infection in allogeneic hematopoietic cell transplantation.

Adenovirus (AdV) infection occurs in 0-20% of patients in the first 3-4 months after allogeneic hematopoietic cell transplantation (HCT), being higher in pediatric than in adult patients. About 50% of AdV infections involve the blood, which in turn, correlates with an increased risk developing AdV diseases, end-organ damage, and 6-month overall mortality. The main risk factors for AdV infection are T-cell depletion of the graft by ex vivo selection procedures or in vivo use of alemtuzumab or antithymocyte serum, development of graft versus host disease (GVHD) grade III-IV, donor type (haploidentical or human leucocyte antigen mismatched related donor > cord blood> unrelated matched donor) and severe lymphopenia (<0.2 × 109 /L). The prevention of AdV disease relies on early diagnosis of increasing viral replication in blood or stool and the pre-emptive start of cidofovir as viral load exceeds the threshold of ≥102-3 copies/mL in blood and/or 106 copies/g stool in the stool. Cidofovir (CDV), a cytosine monophosphate nucleotide analog, is currently the only antiviral recommended for AdV infection despite limited efficacy and moderate risk of nephrotoxicity. Brincidofovir, a lipid derivative of CDV with more favorable pharmacokinetics properties and superior efficacy, is not available and currently is being investigated for other viral infections. The enhancement of virus-specific T-cell immunity in the first few months post-HCT by the administration of donor-derived or third-party-donor-derived virus-specific T-cells represents an innovative and promising modality of intervention and data of efficacy and safety of the ongoing prospective randomized studies are eagerly awaited.

Immunity in the balance: Fatal disseminated adenovirus infection in a patient undergoing plasma exchange and immunosuppressive chemotherapy for anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (anti-GBM) disease (formerly known as Goodpasture's syndrome) is a rare autoinflammatory condition that affects the renal and/or pulmonary capillaries. The standard therapeutic regimen for anti-GBM disease involves therapeutic plasma exchange (TPE), cyclophosphamide, and corticosteroids to rapidly remove and inhibit autoantibody production and reduce organ inflammation. Herein we report an 82-year-old female who developed anti-GBM disease but expired despite therapy, secondary to multi-organ failure in the setting of disseminated adenovirus disease. We discuss the utility and potential adverse effect of daily TPE for a protracted course (ie, 10-14 days), the recommended TPE intensity in the 2023 American Society for Apheresis guidelines, updated from every-other-day TPE in the 2019 guidelines, despite no new data. We also highlight the potential for unusual infections to occur in these patients due to the profound immunosuppression, and discuss the importance of balancing immunosuppression to treat the disease with close surveillance of any potential opportunistic infections.

Cyclopentenylcytosine (CPE-C): In Vitro and In Vivo Evaluation as an Antiviral against Adenoviral Ocular Infections.

Adenoviruses are the major cause of ocular viral infections worldwide. Currently, there is no approved antiviral treatment for these eye infections. Cyclopentenylcytosine (CPE-C) is an antiviral that has demonstrated activity against more than 20 viruses. The goals of the current study were to determine the in vitro and in vivo antiviral activity of CPE-C as well as its ocular toxicity. Antiviral activity was evaluated in vitro using standard plaque reduction assays to determine the 50% effective concentrations (EC50s) and in vivo in the Ad5/NZW rabbit ocular replication model. Ocular toxicity was determined in uninfected rabbit eyes following topical ocular application. The in vitro EC50s for CPE-C ranged from 0.03 to 0.059 µg/mL for nine adenovirus types that commonly infect the eye. Ocular toxicity testing determined CPE-C to be non-irritating or practically non-irritating by Draize scoring. In vivo, 3% CPE-C topically administered 4X or 2X daily for 7 days to adenovirus-infected eyes demonstrated effective antiviral activity compared with the negative control and comparable antiviral activity to the positive control, 0.5% cidofovir, topically administered twice daily for 7 days. We conclude CPE-C was relatively non-toxic to rabbit eyes and demonstrated potent anti-adenoviral activity in vitro and in vivo.

[Establishment of a risk model for severe adenovirus pneumonia and prospective study of the timing of intravenous immunoglobulin therapy in children]. / å„¿ç«¥é‡ç—‡è ºç— æ¯’æ€§è‚ºç‚Žé£Žé™©æ¨¡åž‹çš„æž„å»ºåŠé™è„‰æ³¨å°„å ç–«çƒè›‹ç™½æ²»ç–—æ—¶æœºçš„å‰çž»æ€§ç ”ç©¶.

OBJECTIVES: To develop a risk prediction model for severe adenovirus pneumonia (AVP) in children, and to explore the appropriate timing for intravenous immunoglobulin (IVIG) therapy for severe AVP. METHODS: Medical data of 1 046 children with AVP were retrospectively analyzed, and a risk prediction model for severe AVP was established using multivariate logistic regression. The model was validated with 102 children with AVP. Then, 75 children aged ≤14 years who were considered at risk of developing severe AVP by the model were prospectively enrolled and divided into three groups (A, B and C) in order of visit, with 25 children in each group. Group A received symptomatic supportive therapy only. With the exception of symptomatic supportive therapy, group B received IVIG treatment at a dose of 1g/(kg·d) for 2 consecutive days, before progressing to severe AVP. With the exception of symptomatic supportive therapy, group C received IVIG treatment at a dose of 1 g/(kg·d) for 2 consecutive days after progressing to severe AVP. Efficacy and related laboratory indicators were compared among the three groups after treatment. RESULTS: Age<18.5 months, underlying diseases, fever duration >6.5 days, hemoglobin level <84.5 g/L, alanine transaminase level >113.5 U/L, and co-infection with bacteria were the six variables that entered into the risk prediction model for severe AVP. The model had an area under the receiver operating characteristic curve of 0.862, sensitivity of 0.878, and specificity of 0.848. The Hosmer-Lemeshow test showed good consistency between the predicted values and the actual observations (P>0.05). After treatment, group B had the shortest fever duration and hospital stay, the lowest hospitalization costs, the highest effective rate of treatment, the lowest incidence of complications, the lowest white blood cell count and interleukin (IL)-1, IL-2, IL-6, IL-8, IL-10 levels, and the highest level of tumor necrosis factor alpha (P<0.05). CONCLUSIONS: The risk model for severe AVP established in this study has good value in predicting the development of severe AVP. IVIG therapy before progression to severe AVP is more effective in treating AVP in children.

Adenovirus infection diagnosed by metagenomic next-generation sequencing after haploidentical hematopoietic stem cell transplantation: A multicenter study in China.

OBJECTIVE: This study aims to observe and analyze the clinical characteristics and prognosis of adenovirus (ADV) infection diagnosed by metagenomic next-generation sequencing (mNGS) after haploidentical hematopoietic stem cell transplantation (Haplo-HSCT), which was performed following Beijing Protocol. METHODS: The clinical data of patients who developed ADV infection diagnosed by mNGS after Haplo-HSCT between January 2019 and March 2021, recorded in three transplantation centers, were retrospectively analyzed. Potential risk factors for infection and the clinical manifestations of ADV involvement in different end-organs were also studied. Additionally, the patient prognosis regarding the available treatment was observed. RESULTS: A total of seven patients were diagnosed with ADV infection by the mNGS technique after Haplo-HSCT of 976 patients enrolled. The risk factors for infection included antithymocyte globulin steroid-refractory graft-versus-host disease (GVHD) history, CD25 monoclonal antibody or ruxolitinib treatment history and <300 cells/µL of CD3+ T cells count in peripheral blood. The clinical manifestations of ADV infection included encephalitis, hepatitis, cystitis, and pneumonia. Six patients were treated with cidofovir (CDV) and intravenous immunoglobulin (IVIg), and one with CDV, ribavirin, IVIg, thymosin Alpha-1 for injection and low-dose donor lymphocyte infusion. One case showed negative ADV DNA results with improved conditions; however, the patient died of the relapse of the primary disease in the later stage. The remaining six died of ADV infection. CONCLUSION: mNGS can provide screening for ADV and information on ADV subtypes, helpful to understand tissue tropism. This technique could be useful in diagnosing patients at high risk for ADV infection. ADV infection can involve multiple organs, has difficulty in early diagnosis, and has a poor prognosis. Currently, effective treatments are inadequate.

In Vitro efficacy of cyclosporine a and various antiseptics and antiviral drugs on adenovirus genotype 8, a common cause of epidemic keratoconjunctivitis.

PURPOSE: To evaluate the in vitro efficacy of cidofovir, ganciclovir, povidone-iodine, chlorhexidine, and cyclosporine A on adenovirus genotype 8. METHODS: Conjunctival samples were collected from patients with adenoviral conjunctivitis and cultured in A549 cells. Adenovirus diagnosis was confirmed by RT-PCR. For each drug, the 50% cytotoxic concentration (CC 50 ) was determined. Subsequently, the antiviral activity was tested at concentrations below CC 50, and the 50% inhibitor concentration (IC 50 ) of drugs was determined RESULTS: While the IC 50 of cidofovir against adenovirus genotype 8 was 3.07 ± 0.8 µM, ganciclovir, povidone-iodine, chlorhexidine, and cyclosporine A were not found to be effective against adenovirus genotype 8 at concentrations below the CC 50 value. CONCLUSIONS: Cidofovir was found effective and the IC 50 value was within the ranges in the literature. Ganciclovir and cyclosporine A were found to be ineffective at doses below the cytotoxic dose, povidone-iodine and chlorhexidine was found to be highly cytotoxic.

Allograft adenovirus nephritis accompanied by Crohn's disease in a kidney transplant recipient: a novel case report.

Excessive immunosuppression after kidney transplantation (KT) is often encountered in patients undergoing therapy for anti-rejection or autoimmune disease that requires further treatment using immunosuppressive medications (IMs), including biologic agents. We report a novel case wherein a kidney transplant recipient developed severe acute allograft injury and hemorrhagic cystitis at 4.5 years after KT due to adenovirus nephritis after treatment with infliximab for Crohn's disease. The diagnosis was made based on adenovirus immunohistochemistry staining and urine polymerase chain reaction tests. The patient was successfully treated by reducing IMs and administration of immunoglobulin even though allograft function was eventually partially recovered. When new immunosuppressive agents, particularly biologic agents, are initiated for other diseases in addition to maintenance IMs, the following points need to be regarded: (1) pay attention to opportunistic infections even in the late phase of KT, and (2) maintain communication with other specialists who prescribe biologics to ensure appropriate administration of IMs.

[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.

Adenovirus-Related Fulminant Liver Failure After Kidney Transplantation.

BACKGROUND Human adenovirus is a well-known pathogen that can potentially lead to severe infection in immunocompromised patients. Adenovirus infections in solid-organ transplant recipients can range from asymptomatic to severe, prolonged, disseminated disease, and have a significant impact on morbidity, mortality, and graft survival. The clinical manifestations vary from asymptomatic and flu-like illness to severe life-threatening viremia with multi-organ failure. Post-transplant adenovirus infection is well described in kidney recipients, but in adult liver transplant recipients the impact of the virus is not well described. In this report, a case of disseminated adenovirus infection with subsequent fatal acute liver failure in a post-kidney transplant patient is presented. CASE REPORT A 51-year-old man underwent a deceased kidney transplantation for focal segmental glomerulosclerosis. Shortly after the kidney transplantation, he received multiple plasmapheresis with additional steroid treatments for cellular rejection and reoccurrence of his primary kidney disease. Three weeks after the kidney transplant, he developed a disseminated adenovirus infection with subsequent acute liver failure. Despite the early diagnosis and aggressive treatment, the patient died. CONCLUSIONS Patients with organ transplantation with autoimmune background etiology are usually over-immunosuppressed to avoid early rejection. In this population, opportunistic infections are not rare. Fever, general malaise, and transplant organ dysfunction are the first signs of bacterial or viral infection. Early infectious diseases work-up, including tissue biopsy, is fundamental to establish a diagnosis. Broad antibiotic and possible antiviral aggressive treatment are mandatory.

Hsp70 Inhibits the Replication of Fowl Adenovirus Serotype 4 by Suppressing Viral Hexon with the Assistance of DnaJC7.

Fowl adenovirus serotype 4 (FAdV-4) infection results in serious hepatitis-hydropericardium syndrome (HHS) in broilers, which has caused great economic losses to the poultry industry; however, the specific host responses to FAdV-4 remain unknown. In this study, we identified 141 high-confidence protein-protein interactions (PPIs) between the main viral proteins (Hexon, Fiber 1, Fiber 2, and Penton bases) and host proteins via a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. We found that heat shock protein 70 (Hsp70), the protein with the highest score, and its cofactor DnaJ heat shock protein 40 family member C7 (DnaJC7) could negatively regulate the replication of FAdV-4. Furthermore, the nucleotide binding domain (NBD) of Hsp70 and the J domain of DnaJC7 were necessary for inhibiting FAdV-4 replication. We verified that DnaJC7 as a bridge could bind to Hsp70 and Hexon, assisting the indirect interaction between Hsp70 and Hexon. In addition, we found that FAdV-4 infection strongly induced the expression of autophagy proteins and cellular Hsp70 in a dose-dependent manner. Blockage of Hexon by Hsp70 overexpression was significantly reduced when the autophagy pathway was blocked by the specific inhibitor chloroquine (CQ). Our results showed that Hsp70 was co-opted by DnaJC7 to interact with viral Hexon and inhibited Hexon through the autophagy pathway, leading to a considerable restriction of FAdV-4 replication. IMPORTANCE FAdV-4, as the main cause of HHS, has quickly spread all over the world in recent years, seriously threatening the poultry industry. The aim of this study was to identify the important host proteins that have the potential to regulate the life cycle of FAdV-4. We found that Hsp70 and DnaJC7 played crucial roles in regulating the amount of viral Hexon and extracellular viral titers. Moreover, we demonstrated that Hsp70 interacted with viral Hexon with the assistance of DnaJC7, followed by suppressing Hexon protein through the autophagy pathway. These results provide new insight into the role of the molecular chaperone complex Hsp70-DnaJC7 in FAdV-4 infection and suggest a novel strategy for anti-FAdV-4 drug development by targeting the specific interactions among Hsp70, DnaJC7 and Hexon.

Evaluation of knowledge, attitude, and behaviour of ophthalmologists about adenoviral conjunctivitis transmission and treatment : An online survey for Turkish ophthalmologists.

PURPOSE: To determine the prevalence of adenoviral conjunctivitis in Turkish ophthalmologists, to provide an overview of the treatment and prophylaxis of adenoviral conjunctivitis, and to analyze the data in the context of evidence-based treatment recommendations. METHODS: An online questionnaire consisting of 20 multiple-choice questions about the characteristics of the respondents, the individual adenoviral conjunctivitis history of the ophthalmologists, their practice's approaches, and prescription preferences were emailed to Turkish ophthalmologists. RESULTS: The survey was emailed to 500 ophthalmologists; 45% of them returned the questionnaire. According to the responses, the history of adenoviral conjunctivitis infections was positive in 46.7% (n: 120), recurrent attack prevalence was 16.2% in ophthalmologists. Lubricants (67.6%) are the most preferred first-line treatment options for adenoviral conjunctivitis, followed by povidone-iodine (59.6%), topical antibiotics (51.1%), topical antivirals (29.3%), topical corticosteroids (26.7%), and topical nonsteroidal anti-inflammatory agents (19.6%). A total of 98.2% preferred to dismiss infected patients. The preferred prophylaxis options were frequent hand washing/use of gloves (97.8%), disinfection of medical devices (95.1%), isolation of infected patients (79.1%), hand hygiene with gemicides (58.7%). The percentage of single-dose eye drop selection was 46.2. CONCLUSIONS: The findings of this survey showed that most Turkish ophthalmologists generally follow international guidelines for the treatment of adenoviral conjunctivitis. The treatment algorithm is still controversial, so ophthalmologists should be aware of treatment guideline updates in line with evidence-based recommendations. Having sufficient knowledge of the basic characteristics of viruses is important to control the spread of the disease.

Identification of Inhibitors and Drug Targets for Human Adenovirus Infections.

Adenoviruses can cause infections in people of all ages at all seasons of the year. Adenovirus infections cause mild to severe illnesses. Children, immunocompromised patients, or those with existing respiratory or cardiac disease are at higher risk. Unfortunately, there are no commercial drugs or vaccines available on the market for adenovirus infections. Therefore, there is an urgent need to discover new antiviral drugs or drug targets for adenovirus infections. To identify potential antiviral agents for adenovirus infections, we screened a drug library containing 2138 compounds, most of which are drugs with known targets and past phase I clinical trials. On a cell-based assay, we identified 131 hits that inhibit adenoviruses type 3 and 5. A secondary screen confirmed the antiviral effects of 59 inhibitors that inhibit the replication of adenoviruses type 3 or 5. Most of the inhibitors target heat shock protein, protein tyrosine kinase, the mTOR signaling pathway, and other host factors, suggesting that these host factors may be essential for replicating adenoviruses. Through this study, the newly identified adenovirus inhibitors may provide a start point for developing new antiviral drugs to treat adenovirus infections. Further validation of the identified drug targets can help the development of new therapeutics against adenovirus infections.

Antiviral and Virucidal Activities of Camptothecin on Fowl Adenovirus Serotype 4 by Blocking Virus Replication.

Fowl adenovirus serotype 4 (FAdV-4) caused hepatitis-hydropericardium syndrome in poultry and caused huge economic losses to the poultry industry. At present, antiviral drugs have not been reported to be effective against this virus, and new treatment methods are urgently needed to treat FAdV-4. Camptothecin has been shown to have antiviral activity against various viruses; however, whether it can inhibit FAdV-4 infection remains unclear. This study aimed to explore the anti-FAdV-4 effects and mechanisms of camptothecin in vitro and in vivo. Several camptothecin treatments were used to study the antiviral activity of camptothecin on FAdV-4-infected Leghorn male hepatocellular (LMH) cells. The FAdV-4 titers of mock and camptothecin-treated infected cell cultures were determined using tissue culture infective dose assay, and the FAdV-4 copy number was determined using quantitative real-time polymerase chain reaction. In addition, the therapeutic effect of camptothecin on FAdV-4-infected chickens was also evaluated. The results showed that camptothecin significantly reduced the viral replication in LMH cells in a dose-dependent manner, resulting in a reduction in viral titer, viral copy number, and viral Hexon protein expression. Camptothecin was also found to have a significant inhibitory effect on the viral replication step. Finally, camptothecin showed anti-FAdV-4 efficacy in the chicken infection model, and the survival rate was improved. This study was novel in proving that camptothecin had a protective effect against FAdV-4, indicating its potential as an antiviral drug against FAdV-4 infection.