Acute Adenovirus Infection Research Articles

A High Copy Number from a Pharyngeal Swab Is Not Associated with Different Presenting Features in 100 Children with Acute Adenovirus Infection from a Cluster in Italy.

Human mastadenoviruses, frequently denominated adenoviruses (HAdVs), may cause respiratory tract, gastrointestinal or, less frequently, other involvements. Epidemics of HAdV infections occur globally, in communities, and in closed or crowded settings. In our institution, a cluster of infants and children admitted for HAdV infection was recently observed. The aim of this study was to describe the pattern of their presenting features and investigate the possible correlation between the HAdV copy number and the clinical picture. Two main patterns of clinical presentation were observed: 68 patients had mainly respiratory symptoms (pharyngitis n = 67, cough n = 44; tonsillar exudate n = 17; other respiratory signs n = 4) while 26 patients showed prevalent gastrointestinal involvement (diarrhea n = 26, vomiting n = 8). Patients with respiratory symptoms had a significantly higher count of WBC, PMN, and platelets, while CRP level approached statistical significance (p = 0.07) for higher values in the patients with diarrhea. In order to explore the impact of selected presenting features, the possible association between the level of CRP and the presence of pharyngeal exudate, cough, vomiting, diarrhea, duration of fever, number of neutrophils, and administration of antibiotics was analyzed. Patients falling in the tertile with more elevated CRP values had tonsillar exudate and diarrhea significantly more often, while those in the lower tertile had a 4.4-day duration fever vs. ≥5.0 days in the remaining patients. Antibiotic therapy was administered more frequently to patients with higher values of CRP (p = 0.006). The duration of hospitalization was not associated with the CRP level. The median time from the receipt of a positive HAdV PCR test result to patient discharge was 1 day in 73% of cases. The number of copies of HAdV detected via PCR ranged between 47 million and 15/μL. Falling in the highest tertile of copy number was significantly associated with pharyngitis. The 24 patients with evidence of viral coinfection had no difference in the demographics or presenting features, with the only exception being a significantly higher leukocyte count. The rapid turn-around of the results of the molecular testing of the HAdV genome on a pharyngeal swab allowed us to rapidly diagnose HAdV infection, allowing us to stop antibiotic therapy and immediately discharge the patients, with reduced discomfort for the families and more appropriate use of hospital beds. A high copy number of HAdV from a pharyngeal swab should not be taken as an indicator of worse prognosis, thus allowing for the preferential use of qualitative rather than quantitative assay.

Diagnosis and treatment of adenoviral keratoconjunctivitis

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. 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). 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. 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.

Central Nervous System Disease and Adenoviruses

Research Article| March 01 2019 Central Nervous System Disease and Adenoviruses AAP Grand Rounds (2019) 41 (3): 35. https://doi.org/10.1542/gr.41-3-35 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Central Nervous System Disease and Adenoviruses. AAP Grand Rounds March 2019; 41 (3): 35. https://doi.org/10.1542/gr.41-3-35 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: adenoviruses, central nervous system dysfunction, adenovirus infections Source: Schwartz KL, Richardson SE, MacGregor D, et al. Adenovirus-associated central nervous system disease in children. J Pediatr. 2018 6 November [published online ahead of print]; doi: https://doi.org/10.1016/j.jpeds.2018.09.036Google Scholar Investigators from The Hospital for Sick Children (SickKids) in Toronto conducted a retrospective observational study to characterize adenovirus-associated central nervous system (CNS) disease in children. Three data sources were used: the SickKids microbiology and encephalitis databases (which include children who had been admitted to SickKids during 2000–2016 and 1996–2016, respectively) and a literature search. Children in the SickKids databases were eligible for the study if they were previously healthy; were 1 month to 18 years old; had neurologic symptoms; did not have a preexisting neurologic disorder; and had adenovirus detected by direct fluorescent antibody staining, culture, or polymerase chain reaction (PCR). Child cases identified from the literature search were eligible if they had a neurologic diagnosis other than febrile seizures and had microbiologic or serologic evidence of acute adenovirus infection. Clinical and demographic characteristics of identified children were abstracted from each data source. Using SickKids microbiology data, investigators determined the frequency and spectrum of neurologic complications of adenovirus disease. Using SickKids encephalitis data, investigators determined the frequency of adenovirus among children with encephalitis. Cases identified by literature search were then pooled with children identified in the SickKids databases (excluding those with febrile seizures) to characterize the adenovirus-associated CNS disease spectrum further. Multivariable logistic regression was used to identify risk factors associated with death or neurologic impairment. Of the 977 cases of adenovirus infection in the SickKids microbiology database, 32 (3.3%) had neurologic symptoms. Of these, 26 had febrile seizures, 4 had encephalitis, 1 had acute demyelinating encephalomyelitis, and 1 had aseptic meningitis. Of the 431 children in the SickKids encephalitis database, 8 (1.9%) had adenovirus (including the 4 with encephalitis identified in the SickKids microbiology database). There were 16 studies identified by the literature search involving 38 children, resulting in a pooled total of 48 cases. Of these, the median age was 2 years, and 40% were female. The most common prodromal symptoms were upper respiratory illness (48%), vomiting (22%), and diarrhea (19%). Hepatitis developed during hospitalization in 40%. There were 10 (21%) deaths, and 8 (17%) had permanent neurologic impairment. Children who developed seizures during their illness course had greater odds of death or permanent neurologic impairment (adjusted OR, 7.3; 95% CI, 1.69–31.45). The investigators conclude that adenovirus is a rare cause of CNS disease in children but can be fatal. Dr Brady has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. Adenoviruses are common, accounting for at least 5%–10% of respiratory infections in children.1 Vomiting and diarrhea are often present concurrently.2 A specific viral etiology is usually not sought in children with these self-limited symptoms, so the incidence of adenovirus infections is difficult to ascertain. In the current study, the authors reviewed rare CNS manifestations of... You do not currently have access to this content.

Changes in the number of CD31&lt;sup&gt;&amp;minus;&lt;/sup&gt;CD45&lt;sup&gt;&amp;minus;&lt;/sup&gt;Sca-1&lt;sup&gt;+&lt;/sup&gt; cells and Shh signaling pathway involvement in the lungs of mice with emphysema and relevant effects of acute adenovirus infection

BackgroundCOPD is a leading cause of mortality worldwide, and cigarette smoke is a pivotal risk factor. Adenovirus is a common cause of acute exacerbations of COPD and expedites COPD progression. Lung stem/progenitor cells play an important role in the development of COPD, while the relevant mechanism remains elusive. Here, we investigated the number of lung CD31−CD45−Sca-1+ cells and sonic hedgehog (Shh) signaling pathway expression levels in cigarette smoke extract (CSE)-induced emphysema mice, as well as the relevant effects of acute adenovirus infection (AAI).Materials and methodsBALB/c mice were treated with CSE by intraperitoneal injection and/or adenovirus endotracheal instillation at different time points for 28 days. Lung function, lung histomorphology, CD31−CD45−Sca-1+ cell count, and expression levels of major components in the Shh signaling pathway in the lungs were measured.ResultsCSE intraperitoneal injection and adenovirus endotracheal instillation successfully induced emphysema and AAI in mice, respectively. In the lungs of emphysema mice, both the number of CD31−CD45−Sca-1+ cells and expression levels of Shh signaling pathway molecules were reduced. However, AAI increased the number of inhibited CD31−CD45−Sca-1+ cells and activated the suppression of the Shh signaling pathway.ConclusionBoth CD31−CD45−Sca-1+ cell numbers and Shh signaling pathway expression levels were downregulated in the lungs of emphysema mice induced by CSE intraperitoneal injection, which likely contributes to the pathogenesis of emphysema. Additionally, these inhibited lung CD31−CD45−Sca-1+ cells and Shh signaling pathway molecules were upregulated during AAI, indicating that they play a protective role in the epithelial repair process after AAI injury.

Diagnosis of Pediatric Acute Adenovirus Infections

Human adenovirus (HAdV), especially species C (HAdV-C), can be detected incidentally by polymerase chain reaction in nasopharyngeal (NP) samples, making it difficult to interpret clinical significance of a positive result. We classified patients into groups based on HAdV culture positivity from respiratory specimens and the presence of an identified co-pathogen. We hypothesized that HAdV-C would be over-represented and viral burden would be lower in patients most likely to have incidental detection (ie, with a negative viral culture and documented co-pathogen). Immunocompetent children with HAdV + nasopharyngeal specimens were classified into 4 groups: group I (HAdV culture (+) and no co-infection), group II (culture (+) and co-infection), group III (culture (-) and no co-infection) and group IV (culture (-) and co-infection). Viral burden (cycle threshold) and species were compared among groups. Of 483 nasopharyngeal specimens, HAdV was isolated in culture in 252 (52%); co-infection was found in 265 (55%) patients. Group I (most consistent with acute disease) had significantly lower cycle thresholds (median 23.9; interquarile range 22.2-28.1) compared with group IV (most consistent with incidental detection; median 37.3; interquarile range 35.3-38.9; P < 0.0001). HAdV-C accounted for 41% samples of group I and 83% of group IV (P < 0.0001). We identified a subset of 22 patients with bacterial or fungal co-pathogens, 18 of whom had no growth on viral culture (group IV) with a median cycle threshold of 37.4 (interquarile range 33.9-39.2). Species identification and viral burden may assist in interpretation of a positive HAdV result. Low viral burden with HAdV-C may be consistent with incidental detection.

Meningoencephalitis Due to Adenovirus in a Healthy Infant Mimicking Severe Bacterial Sepsis

We present the case of a previously healthy 15-month-old girl with acute adenovirus infection who had features of severe bacterial sepsis and meningitis. Real-time qPCR done on cerebrospinal fluid identified adenovirus as the causative agent allowing stopping antibiotic treatment. The patient subsequently recovered without sequelae. An overview of published and unpublished data on adenovirus central nervous system infection in immunocompetent children is presented.

T-cell Ig and ITIM domain regulates natural killer cell activation in murine acute viral hepatitis

Uncontrolled natural killer (NK) cell activation during the early response to acute viral infection can lead to severe immunopathology, and the mechanisms NK cells use to achieve self-tolerance in such contexts are currently unclear. Here, NK cells up-regulated a coinhibitory receptor, T-cell Ig and ITIM domain (TIGIT), during challenge with the viral double-stranded RNA (dsRNA) analog poly I:C. Blocking TIGIT by antibody treatment in vivo or a genetic deficiency in Tigit enhanced NK cell activation and aggravated liver injury in a poly I:C/D-GalN-induced model of acute fulminant hepatitis, suggesting that TIGIT is normally required for protecting against NK cell-mediated liver injury. Furthermore, adoptively transferring Tigit(-/-) NK cells into NK cell-deficient Nfil3(-/-) mice also resulted in elevated liver injury. Reconstituting Kupffer cell-depleted mice with poliovirus receptor (PVR/CD155, a TIGIT ligand)-silenced Kupffer cells led to aggravated liver injury in a TIGIT-dependent manner. Blocking TIGIT in an NK-Kupffer cell coculture in vitro enhanced NK cell activation and interferon-gamma (IFN-γ) production in a PVR-dependent manner. We also found that TIGIT was up-regulated selectively on NK cells and protected against liver injury in an acute adenovirus infection model in both an NK cell- and Kupffer cell-dependent manner. Knocking down PVR in Kupffer cells resulted in aggravated liver injury in response to adenovirus infection in a TIGIT-dependent manner. TIGIT negatively regulates NK-Kupffer cell crosstalk and alleviates liver injury in response to poly I:C/D-GalN challenge or acute adenovirus infection, suggesting a novel mechanism of NK cell self-tolerance in liver homeostasis during acute viral infection.

Phylogenetic analyses of novel squamate adenovirus sequences in wild-caught Anolis lizards.

Adenovirus infection has emerged as a serious threat to the health of captive snakes and lizards (i.e., squamates), but we know relatively little about this virus' range of possible hosts, pathogenicity, modes of transmission, and sources from nature. We report the first case of adenovirus infection in the Iguanidae, a diverse family of lizards that is widely-studied and popular in captivity. We report adenovirus infections from two closely-related species of Anolis lizards (anoles) that were recently imported from wild populations in the Dominican Republic to a laboratory colony in the United States. We investigate the evolution of adenoviruses in anoles and other squamates using phylogenetic analyses of adenovirus polymerase gene sequences sampled from Anolis and a range of other vertebrate taxa. These phylogenetic analyses reveal that (1) the sequences detected from each species of Anolis are novel, and (2) adenoviruses are not necessarily host-specific and do not always follow a co-speciation model under which host and virus phylogenies are perfectly concordant. Together with the fact that the Anolis adenovirus sequences reported in our study were detected in animals that became ill and subsequently died shortly after importation while exhibiting clinical signs consistent with acute adenovirus infection, our discoveries suggest the need for renewed attention to biosecurity measures intended to prevent the spread of adenovirus both within and among species of snakes and lizards housed in captivity.

Gene Transcript Abundance Profiles Distinguish Kawasaki Disease from Adenovirus Infection

Acute Kawasaki disease (KD) is difficult to distinguish from other illnesses that involve acute rash or fever, in part because the etiologic agent(s) and pathophysiology remain poorly characterized. As a result, diagnosis and critical therapies may be delayed. We used DNA microarrays to identify possible diagnostic features of KD. We compared gene expression patterns in the blood of 23 children with acute KD and 18 age-matched febrile children with 3 illnesses that resemble KD. Genes associated with platelet and neutrophil activation were expressed at higher levels in patients with KD than in patients with acute adenovirus infections or systemic adverse drug reactions, but levels in patients with KD were not higher than those in patients with scarlet fever. Genes associated with B cell activation were also expressed at higher levels in patients with KD than in control subjects. A striking absence of interferon-stimulated gene expression in patients with KD was confirmed in an independent cohort of patients with KD. Using a set of 38 gene transcripts, we successfully predicted the diagnosis for 21 of 23 patients with KD and 7 of 8 patients with adenovirus infection. These findings provide insight into the molecular features that distinguish KD from other febrile illnesses and support the feasibility of developing novel diagnostic reagents for KD based on the host response.

Adenovirus RIDα regulates endosome maturation by mimicking GTP-Rab7

The small guanosine triphosphatase Rab7 regulates late endocytic trafficking. Rab7-interacting lysosomal protein (RILP) and oxysterol-binding protein–related protein 1L (ORP1L) are guanosine triphosphate (GTP)–Rab7 effectors that instigate minus end–directed microtubule transport. We demonstrate that RILP and ORP1L both interact with the group C adenovirus protein known as receptor internalization and degradation α (RIDα), which was previously shown to clear the cell surface of several membrane proteins, including the epidermal growth factor receptor and Fas (Carlin, C.R., A.E. Tollefson, H.A. Brady, B.L. Hoffman, and W.S. Wold. 1989. Cell. 57:135–144; Shisler, J., C. Yang, B. Walter, C.F. Ware, and L.R. Gooding. 1997. J. Virol. 71:8299–8306). RIDα localizes to endocytic vesicles but is not homologous to Rab7 and is not catalytically active. We show that RIDα compensates for reduced Rab7 or dominant-negative (DN) Rab7(T22N) expression. In vitro, Cu2+ binding to RIDα residues His75 and His76 facilitates the RILP interaction. Site-directed mutagenesis of these His residues results in the loss of RIDα–RILP interaction and RIDα activity in cells. Additionally, expression of the RILP DN C-terminal region hinders RIDα activity during an acute adenovirus infection. We conclude that RIDα coordinates recruitment of these GTP-Rab7 effectors to compartments that would ordinarily be perceived as early endosomes, thereby promoting the degradation of selected cargo.

Quantitation of Adenovirus Genome During Acute Infection in Normal Children

Adenovirus infection causes a wide range of clinical illness in normal children. New molecular techniques allow quantitation of viral genome to study the natural history of adenovirus infection and viral load in normal children. Clinical samples were collected from 38 previously healthy, febrile children, and viral cultures were performed. Quantitative polymerase chain reaction (PCR) was used to detect adenovirus genome and to determine viral load. Adenovirus isolates were genotyped with a PCR-based assay. Adenovirus culture was positive in 6 children who were diagnosed with acute adenovirus infection. Throat swabs contained high copy numbers of adenovirus genome (1.6 x 10(6)-6 x 10(7) copies/swab) from 4 of 4 adenovirus culture-positive children. Only 2 of 32 adenovirus culture-negative children had detectable adenovirus genome from throat swabs, but with a lower copy number (8 x 10(2) copies/swab). Adenovirus genome was not detected in blood samples from 5 of 6 adenovirus culture-positive children with uncomplicated upper respiratory tract infection and from all adenovirus culture-negative children. High level viremia (1.8 x 10(8)/ml) was detected in an adenovirus culture-positive 6-month-old infant with fever, pneumonia, conjunctivitis and hepatitis. Subsequent reduction in viral load paralleled her clinical recovery. Adenovirus viruria (1 x 10(9) copies/ml) with normal urinanalysis was detected in another adenovirus culture-positive child. All 6 adenovirus isolates were genotyped as adenovirus type 7h. Viral load assessment in clinical samples determined by quantitative PCR can be useful in the diagnosis of adenovirus infection in immunocompetent, febrile children.

Adenovirus DNA in serum of children hospitalized due to an acute respiratory adenovirus infection.

Serum samples from 68 immunocompetent infants (mean age, 12.6 months) with an acute adenovirus infection of the respiratory tract (39 experiencing their first adenovirus infection) were tested for the presence of adenovirus DNA, to investigate whether viral dissemination via the blood is usually present in the immunocompetent patient. Using a nested polymerase chain reaction assay, adenovirus DNA could be detected in acute-phase serum samples from 28 (41%) children. Adenovirus DNA was never found in follow-up serum samples, indicating a short period ( approximately 1 week) of viral dissemination. In children experiencing their first adenovirus infection, viral DNA could be detected in 72% of the acute-phase serum samples collected within the first week after onset of symptoms. Adenovirus DNA could also be detected in 25% of the acute-phase serum samples from patients with reinfection.

Characterization of Human Proliferative T Cell Responses to Adenovirus

Although cellular immune responses are likely important for recovery from acute adenovirus infection, they have not been studied in humans. As a first step, a sensitive assay for the detection of adenovirus-specific proliferative T cell responses was developed. Peripheral blood mononuclear cells from 29 of 30 healthy adults exhibited specific proliferative responses to adenovirus type 2 antigen. Adenovirus-specific proliferation was found to be mediated by CD4+ T cells. Specific proliferative responses were detected to purified Ad2 virions and by Ad2-infected cell lysates, indicating that adenovirus structural proteins are important targets. In addition, specific proliferative responses to the uncommon adenovirus type 35 were found in persons without serologic evidence of prior Ad35 infection. These data suggest that adenovirus-specific CD4+ T cells recognize conserved antigens among different serotypes and that a majority of persons develop long-lived CD4+ T cell responses to adenovirus.

Immunoassay diagnosis of adenovirus infections in children.

Direct detection of viral antigen in nasopharyngeal secretions and stool specimens by radioimmunoassay and the determination of serum antibody responses by complement fixation and immunoglobulin class-specific enzyme immunoassay against the hexon antigen were compared for diagnostic efficacy in 52 children with acute adenovirus infections. The highest diagnosis rate (85% of the cases) was obtained by antigen detection in nasopharyngeal secretions. Adenovirus antigen was also detected in stools of 72% of the 18 patients tested. The immunoglobulin G (IgG) antibody enzyme immunoassay detected 77% of the cases, being more sensitive than the complement fixation test with a 67% detection rate. The IgM antibody response was variable with no clear correlation with the age of the patient or severity of the clinical symptoms. IgM antibody response was detected in 48% of the patients and had the normal transient course, with a persistence of the IgM antibodies of approximately 2 months. Determination of IgA antibodies gave a diagnostic increase in titer in 37% of the cases and was found less suitable for serological diagnosis. Because of the clinical importance of rapid laboratory diagnosis, the direct detection of viral antigen in nasopharyngeal secretions or stool or both should be used as the primary diagnostic test in adenovirus infections.

Antibody to human adenovirus early antigens during acute adenovirus infections.

The antibody (Ab) response to human adenovirus (AV) early antigens (EA) in acute AV infections was studied by the immunoperoxidase antibody technique for determining virus-specific immunoglobulin G (IPA-IgG). AV-EA-Ab appeared about 5 days after the onset of clinical symptoms, reached a peak 15 to 30 days later, and declined in titer after a few months. The staining pattern in the IPA-IgG reaction was usually nuclear; however, in most primary infections sera obtained 2 to 3 weeks after the onset of infection also showed cytoplasmic staining. According to the recent deoxyribonucleic acid homology classification of human AV in five groups (A, B, C, D, and E), the EA-Ab response in primary human infections was found to be group specific for groups A to D, with consistent cross-reactions with group E. In AV type 4 (group E) infections, EA-Ab appeared to be directed against all groups, although at different titers. Comparable results were obtained using AV type-specific animal antisera. Thus, it was concluded that group E shares EA with all the other groups. Furthermore, in each individual with remote AV infections, the current infection elicited an anamnestic EA-Ab response to all AV groups responsible for previous infections. In diagnostic virology these findings can be applied to the rapid diagnosis of a current for recent) AV infection on a single serum sample and to the rapid group identification of clinical isolates by using type-specific animal antisera containing EA-Ab (one for each group) or sera from patients with primary AV infections.

Bronchiolitis obliterans, bronchiectasis, and other sequelae of adenovirus type 21 infection in young children.

A remarkably high incidence of bronchiectasis and other pulmonary sequelae was observed in young children affected during an epidemic of severe lower respiratory tract infections apparently caused by adenovirus type 21. The histopathological findings are described in four cases in which one or both lungs were obtained for examination at intervals ranging from two months to three years after the acute infections. Widespread bronchiolar obliteration (bronchiolitis obliterans) was a striking finding in all four. The severity of bronchial inflammation and of bronchiectasis was proportional to the time elapsed since the acute infections. Bronchiolar obliteration is a likely sequel of the necrotizing bronchiolitis which may occur during acute adenovirus infections. The role of bronchiolar obliteration in the pathogenesis of bronchiectasis and other chronic lung disease is discussed. Adenoviruses may be a major cause of post-infectious bronchiectasis in childhood.