Mouse Adenovirus Type 1 Persistence Exacerbates Inflammation Induced by Allogeneic Bone Marrow Transplantation.

Bone marrow transplantation (BMT) recipients are at risk for substantial morbidity and mortality from human adenovirus infections, often in the setting of reactivation of persistent virus. Human adenovirus persistence in mucosal lymphocytes has been described, but specific cellular reservoirs of persistence and effects of persistence on host responses to unrelated stimuli are not completely understood. We used mouse adenovirus type 1 (MAV-1) to characterize persistence of an adenovirus in its natural host and test the hypothesis that persistence increases complications of BMT. Following intranasal infection of C57BL/6J mice, MAV-1 DNA was detected in lung, mediastinal lymph nodes, and liver during acute infection at 7 days postinfection (dpi), and at lower levels at 28 dpi that remained stable through 150 dpi. Expression of early and late viral transcripts was detected in those organs at 7 dpi but not at later time points. MAV-1 persistence was not affected by deficiency of IFN-γ. We detected no evidence of MAV-1 reactivation in vivo following allogeneic BMT of persistently infected mice. Persistent infection did not substantially affect mortality, weight loss, or pulmonary inflammation following BMT. However, T cell infiltration and increased expression of pro-inflammatory cytokines consistent with graft-versus-host disease (GVHD) were more pronounced in livers of persistently infected BMT mice than in uninfected BMT mice. These results suggest that MAV-1 persists in multiple sites without detectable evidence of ongoing replication. Our results indicate that MAV-1 persistence alters host responses to an unrelated challenge, even in the absence of detectable reactivation. IMPORTANCE Long-term persistence in an infected host is an essential step in the life cycle of DNA viruses. Adenoviruses persist in their host following acute infection, but the nature of adenovirus persistence remains incompletely understood. Following intranasal infection of mice, we found that MAV-1 persists for a prolonged period in multiple organs, although we did not detect evidence of ongoing replication. Because BMT recipients are at risk for substantial morbidity and mortality from human adenovirus infections, often in the setting of reactivation of persistent virus in the recipient, we extended our findings using MAV-1 infection in a mouse model of BMT. MAV-1 persistence exacerbated GVHD-like inflammation following allogeneic BMT, even in the absence of virus reactivation. This novel finding suggests that adenovirus persistence has consequences, and it highlights the potential for a persistent adenovirus to influence host responses to unrelated challenges.

Adenovirus 5 produces obesity and adverse metabolic, morphological, and functional changes in the long term in animals fed a balanced diet or a high-fat diet: a study on hamsters.

Adenovirus 5 (Ad-5) infection is a common cause of acute respiratory infections and the main vector used in gene therapy. There are few studies on the relationship of Ad-5 to obesity. In the present study, we evaluated the chronic effects of Ad-5 infection on golden (Syrian) hamsters fed either a balanced diet (BD) or a high-fat diet (HFD). After a single inoculation with Ad-5 (1 × 107 pfu), the body weight of the animals was measured weekly. Medium-term (22 weeks) serum biochemical analyses and long-term (44 weeks) liver morphology, adiposity, and locomotive functionality (movement velocity) assessments were carried out. In the animals fed the BD, adenovirus infection produced hyperglycemia and hyperlipidemia. In the long term, it produced a 57% increase in epididymal pad fat and a 30% body weight gain compared with uninoculated animals. In addition, morphological changes related to non-alcoholic fatty liver disease (NAFLD) were observed. The animals fed the HFD had similar but more severe changes. In addition, the hamsters presented an obesity paradox: at the end of the study, the animals that had the most morphological and functional changes (significantly reduced movement velocity) had the lowest body weight. Despite the fact that an HFD appears to be a more harmful factor in the long term than adenovirus infection alone, infection could increase the severity of harmful effects in individuals with an HFD. Epidemiological studies are needed to evaluate the effect of adenovirus as a precursor of chronic liver and cardiovascular diseases, including the chronic effects of gene therapy.

Canine adenovirus type 1 causing neurological signs in a 5-week-old puppy.

BACKGROUND: Infectious canine hepatitis is a rarely encountered disease, that is caused by Canine Adenovirus-1. Clinical signs can vary dramatically, and neurological signs are rarely seen. Neurological manifestation of this disease is rarely reported in the veterinary literature. CASE PRESENTATION: A 5-week-old, male entire Husky cross puppy presented for a one-day history of abnormal neurological behaviour (circling, ataxia, vocalization and obtund mentation). The puppy was euthanized shortly after presentation due to rapid deterioration. Histopathology raised concerns for Canine Adenovirus 1 (CAdV-1) based on vasculitis in the brain and intranuclear inclusion bodies in endothelial cell and hepatocytes; immunohistochemistry on brain tissue confirmed CAdV-1 infection. CONCLUSIONS: This report discusses possible routes of infection and manifestations of adenovirus infections causing neurologic signs. It also provides a timely reminder that CAdV-1 should be considered a differential in unvaccinated dogs that present with neurological signs. Further studies are required to better understand the neurotrophic tendencies of this virus.

The effect of different dietary levels of DL-methionine and DL-hydroxy analogue on the antioxidant status of young turkeys infected with the haemorrhagic enteritis virus.

BACKGROUND: The results of experiments involving broiler chickens and turkeys indicate that increased dietary methionine (Met) levels may improve the antioxidant protection of tissues in fast-growing birds. This is an important consideration since viral infections induce oxidative stress. The aim of this study was to verify the hypothesis that turkey diets with increased Met content can suppress oxidation processes induced by infection caused by the haemorrhagic enteritis virus (HEV), and that the noted effect is determined by the chemical form of this amino acid: DL-methionine (DLM) or DL-hydroxy analogue of Met (MHA). RESULTS: Dietary Met content above 40% higher than the level recommended by the NRC (1994) intensified lipid peroxidation in the small intestine, leading to an increase in malondialdehyde (MDA) and lipid peroxide (LOOH) levels, but it also stimulated antioxidant mechanisms in the blood and liver of turkeys infected with HEV. In comparison with DLM, MHA contributed to more severe symptoms of oxidative stress, such as elevated MDA levels in the intestines, and a decrease in glutathione peroxidase (GPx) activity and ferric-reducing ability of plasma (FRAP). CONCLUSIONS: In HEV-infected turkeys, diets with increased Met content did not exert a clear antioxidant effect, which was noted in uninfected birds. The prooxidant activity of Met observed in the small intestinal wall was suppressed in the blood and liver of turkeys, most likely due to intensified synthesis of uric acid and glutathione. In comparison with MHA, DLM had a more beneficial influence on the analysed parameters of the redox status in the small intestine, blood and liver of turkeys.

Longitudinal investigation of adenovirus 36 seropositivity and human obesity: the Cardiovascular Risk in Young Finns Study.

BACKGROUND/OBJECTIVES: Adenovirus-36 (Adv-36) infection is associated with exaggerated adipogenesis in cell culture and the development of obesity in animal models and humans, but a causal relationship remains unproven. Our objective was to determine whether serological evidence of Adv-36 infection in childhood and/or adulthood is associated with adult obesity. SUBJECTS/METHODS: Paired plasma concentrations of Adv-36 antibodies were measured by a novel enzyme-linked immunosorbent assay in a subgroup (n=449) of the Cardiovascular Risk in Young Finns Study in childhood (mean age 11.9 years) and adulthood (mean age 41.3 years). The study group included (1) individuals who had maintained normal-weight status (2) those who became obese adults from a normal-weight status in childhood and (3) those that were overweight/obese as a child and obese as an adult. RESULTS: Mean (s.d.) time between baseline and follow-up was 29.4 (3.2) years (range 21-31 years). A total of 24.4% of individuals who were normal weight throughout life were seropositive for Adv-36 during child and/or adulthood as compared with 32.3% of those who became obese adults (P=0.11). Those who became obese in adulthood were more likely to be Adv-36 seropositive as adults compared with those who maintained normal weight (21.3% vs. 11.6%, P=0.02). This difference was mediated by a decline in Adv-36 seropositivity between child and adulthood in those maintaining normal weight. No differences were observed in body mass index across the life course, nor in waist circumference in adult life, between those who were Adv-36 seronegative or seropositive at any age. CONCLUSIONS: Individuals who gained weight across the life course were more likely to be Adv-36 seropositive in adult life than those who did not gain weight. However, analysis of change in weight status in relation to Adv-36 positivity did not support a causal role for Adv-36 in the development of obesity.

Liver-primed CD8+ T cells suppress antiviral adaptive immunity through galectin-9-independent T-cell immunoglobulin and mucin 3 engagement of high-mobility group box 1 in mice.

UNLABELLED: The liver is a tolerogenic environment exploited by persistent infections, such as hepatitis B (HBV) and C (HCV) viruses. In a murine model of intravenous hepatotropic adenovirus infection, liver-primed antiviral CD8(+) T cells fail to produce proinflammatory cytokines and do not display cytolytic activity characteristic of effector CD8(+) T cells generated by infection at an extrahepatic, that is, subcutaneous, site. Importantly, liver-generated CD8(+) T cells also appear to have a T-regulatory (Treg) cell function exemplified by their ability to limit proliferation of antigen-specific T-effector (Teff ) cells in vitro and in vivo via T-cell immunoglobulin and mucin 3 (Tim-3) expressed by the CD8(+) Treg cells. Regulatory activity did not require recognition of the canonical Tim-3 ligand, galectin-9, but was dependent on CD8(+) Treg cell-surface Tim-3 binding to the alarmin, high-mobility group box 1 (HMGB-1). CONCLUSION: Virus-specific Tim-3(+) CD8(+) T cells operating through HMGB-1 recognition in the setting of acute and chronic viral infections of the liver may act to dampen hepatic T-cell responses in the liver microenvironment and, as a consequence, limit immune-mediated tissue injury or promote the establishment of persistent infections.

Corneal sensitivity may decrease in adenoviral epidemic keratoconjunctivitis--a confocal microscopic study.

OBJECTIVES: To report a new clinical finding, decreased corneal sensitivity, in epidemic keratoconjunctivitis and to evaluate this sign with corneal confocal microscopy. METHODS: Forty-one eyes of 28 patients who developed corneal infiltrates after an outbreak of epidemic keratoconjunctivitis were included in the study. Clinical and confocal microscopic findings are described. RESULTS: In this outbreak of 72 patients, 28 (38.9%) developed corneal infiltrates. The corneal involvement was unilateral in 15 patients (53.6%) and bilateral in 13 patients (46.4%). Corneal sensitivities were measured in 35 eyes of 24 patients and found to be decreased in 26 eyes (74.3%). Decreased corneal sensation was a feature of mainly stage 2 (7 eyes) and stage 3 (11 eyes) keratitis. Corneal sensitivity returned to normal levels in all eyes in a mean of 8.5 days. The main confocal microscopic features during the period of decreased corneal sensitivity were morphologic changes in the infected epithelial cells, extracellular bright microdeposits, infiltration with round inflammatory cells and dendritic cells, increased brightness in the extracellular matrix and the stroma surrounding the corneal nerves, and increased keratocyte activity. The intensity of the inflammatory reaction in the extracellular space and corneal stroma and the reflectivity of the corneal nerves had subsided by the second confocal measurements. CONCLUSION: There may be a transient decrease in the corneal sensitivity during the course of epidemic keratoconjunctivitis. Confocal microscopy can help to evaluate the changes in the cornea during this period. Future studies are needed to understand the nature of this clinical finding.

A comparative study of neural and mesenchymal stem cell-based carriers for oncolytic adenovirus in a model of malignant glioma.

Glioblastoma multiforme is a primary malignancy of the central nervous system that is universally fatal due to its disseminated nature. Recent investigations have focused on the unique tumor-tropic properties of stem cells as a novel platform for targeted delivery of anticancer agents to the brain. Neural stem cells (NSCs) and mesenchymal stem cells (MSCs) both have the potential to function as cell carriers for targeted delivery of a glioma restricted oncolytic virus to disseminated tumor due to their reported tumor tropism. In this study, we evaluated NSCs and MSCs as cellular delivery vehicles for an oncolytic adenovirus in the context of human glioma. We report the first preclinical comparison of the two cell lines and show that, while both stem cell lines are able to support therapeutic adenoviral replication intracellularly, the amount of virus released from NSCs was a log higher than the MSC (p < 0.001). Moreover, only virus loaded NSCs that were administered intracranially in an orthotopic glioma model significantly prolonged the survival of tumor bearing animals (median survival for NSCs 68.5 days vs 44 days for MSCs, p < 0.002). Loading oncolytic adenovirus into NSCs and MSCs also led to expression of both pro- and anti-inflammatory genes and decreased vector-mediated neuroinflammation. Our results indicate that, despite possessing a comparable migratory capacity, NSCs display superior therapeutic efficacy in the context of intracranial tumors. Taken together, these findings argue in favor of NSCs as an effective cell carrier for antiglioma oncolytic virotherapy.

Increased oxidative stress in children with post infectious Bronchiolitis Obliterans.

BACKGROUND: There is increasing evidence that oxidative stress is involved in the development and severity of bronchiolitis obliterans occurring in post-transplant patients. In developing countries, the most common form of bronchiolitis obliterans occurs after severe lung infection, mainly caused by adenovirus. However, the oxidative status in the lungs of children with post infectious bronchiolitis obliterans is unknown. METHODS: The aim of this study was to measure the oxidant (8-isoprostane and protein carbonyls) and antioxidant (catalase and glutathione peroxidase) activity in the bronchoalveolar lavage fluid of 21 children with post-infectious bronchiolitis obliterans, and to correlate oxidant/antioxidant level with lung function. Lung function was assessed by spirometry and plethysmography, one week prior to fiberbronchoscopy. RESULTS: There was a markedly increased oxidative stress (lipid and protein oxidation) in the bronchoalveolar lavage fluid, and a notorious impairment of lung function demonstrating moderate-severe distal airway narrowing. There was not a significant correlation between the level of oxidants or antioxidants and lung function. There was a consistent antioxidants/oxidants pattern characterised by markedly increased 8-isoprostane and carbonyls, increased GPx and normal catalase activity. CONCLUSION: The present study shows for the first time that children with post-infectious bronchiolitis obliterans have a markedly increased oxidative stress in their lungs.

An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor-alpha.

UNLABELLED: Tumor necrosis factor-alpha (TNF) is an inflammatory cytokine that induces context-dependent proliferation, survival, and apoptosis responses in hepatocytes. TNF stimulates and enhances growth factor-mediated hepatocyte proliferation and survival following partial hepatectomy, but also acts in concert with other inflammatory cytokines of the innate immune response during viral infection to induce apoptosis in hepatocytes. In other epithelial cell types, TNF has recently been shown to stimulate autocrine release of transforming growth factor-alpha (TGF-alpha) and interleukin-1 (IL-1) family ligands. Here, we examine the role of these autocrine ligands in modulating TNF-induced proliferation and apoptosis in primary hepatocytes. We show that TNF-induced hepatocyte proliferation is regulated by an inducible, coupled, and self-antagonizing autocrine cascade involving the pro-proliferative TGF-alpha and IL-1 receptor antagonist (IL-1ra) ligands and antiproliferative IL-1alpha/beta ligands. Moreover, cooperative stimulation of hepatocyte proliferation by combined TNF and TGF-alpha treatment is self-limited through antiproliferative autocrine IL-1alpha/beta feedback. We show that TNF potently induces apoptosis of adenovirus-infected hepatocytes in a manner similarly determined through the integrated activity of a coupled TGF-alpha-IL-1alpha/beta-IL-1ra autocrine cascade. Exogenous TGF-alpha can either enhance or diminish apoptosis in adenoviral vector-treated and TNF-treated hepatocytes, in a biphasic relationship also mediated by autocrine IL-1alpha/beta feedback. CONCLUSION: We demonstrate that TNF-induced hepatocyte proliferation and apoptosis are both governed by a self-antagonizing TGF-alpha-IL-1alpha/beta-IL-1ra autocrine cascade in vitro, and thus identify multiple molecular targets for control of TNF-regulated hepatocyte phenotypic responses related to liver regeneration and adenoviral gene therapy.

Distinct cell death pathways triggered by the adenovirus early region 4 ORF 4 protein.

In transformed cells, induction of apoptosis by adenovirus type 2 (Ad2) early region 4 ORF 4 (E4orf4) correlates with accumulation of E4orf4 in the cell membrane-cytoskeleton fraction. However, E4orf4 is largely expressed in nuclear regions before the onset of apoptosis. To determine the relative contribution of nuclear E4orf4 versus membrane-associated E4orf4 to cell death signaling, we engineered green fluorescent fusion proteins to target E4orf4 to specific cell compartments. The targeting of Ad2 E4orf4 to cell membranes through a CAAX-box or a myristylation consensus signal sufficed to mimic the fast Src-dependent apoptotic program induced by wild-type E4orf4. In marked contrast, the nuclear targeting of E4orf4 abolished the early induction of extranuclear apoptosis. However, nuclear E4orf4 still induced a delayed cell death response independent of Src-like activity and of E4orf4 tyrosine phosphorylation. The zVAD.fmk-inhibitable caspases were dispensable for execution of both cell death programs. Nevertheless, both pathways led to caspase activation in some cell types through the mitochondrial pathway. Finally, our data support a critical role for calpains upstream in the death effector pathway triggered by the Src-mediated cytoplasmic death signal. We conclude that Ad2 E4orf4 induces two distinct cell death responses, whose relative contributions to cell killing may be determined by the genetic background.

Siadenovirus infection in two psittacine bird species.

Consensus polymerase chain reaction was used to identify a novel adenovirus from two psittacine birds: a plum-headed parakeet (Psittacula cyanocephala) with lethargy, weight loss, and marked leukocytosis; and an umbrella cockatoo (Cacatua alba) with lethargy, weight loss, and feather abnormalities. Phylogenetic and comparative sequence analysis suggested that this virus is a member of the genus Siadenovirus, and is here termed psittacine adenovirus 2. This extends the characterized adenoviruses of psittacine birds beyond Aviadenovirus to include the genus Siadenovirus. Identification and further study of adenoviral types and species will provide useful diagnostic, prognostic, and epidemiologic information for the clinician. Like other known members of the genus Siadenovirus, Psittacine adenovirus 2 is AT-rich over the region sequenced, and it is hypothesized that this may be associated with shorter host-virus evolutionary association.

Incidence and clinical manifestations of adenoviral infection among children undergoing allogeneic stem cell transplantation.

BACKGROUND: Adenoviral infection in children undergoing stem cell transplantation is associated with significant morbidity and mortality. Identification of adenoviral infection by polymerase chain reaction from blood facilitates accurate and rapid diagnosis and surveillance. The incidence of adenoviral infection among children undergoing SCT in Israel is not known. OBJECTIVE: To estimate the incidence of adenoviral infection in pediatric SCT patients and to characterize the morbidity associated with proven infection. METHODS: Blood samples obtained weekly from children who underwent allogeneic SCT were retrospectively tested for adenovirus using standard PCR. A total of 657 samples collected from 32 patients were examined. Correlation was made between the presence of adenovirus in samples and clinical records. RESULTS: Of the 32 patients 4 had adenoviral infection by PCR (12.5%). Clinical disease was present in all four patients concurrent with positive PCR. Gastrointestinal complaints and abnormal hepatocellular enzymes were uniformly present. One patient died due to disseminated disease. T cell depletion was a significant risk factor for adenoviral infection (P = 0.03). CONCLUSIONS: In the patient population studied, the incidence of adenoviral infection in children undergoing SCT was 12.5%. The combination of gastrointestinal symptoms and abnormal hepatocellular enzymes should raise the suspicion of adenoviral infection, especially when occurring during the first few months after SCT.

Adenovirus IL-13-induced airway disease in mice: a corticosteroid-resistant model of severe asthma.

Interleukin 13 (IL-13) is considered to be a key driver of the development of airway allergic inflammation and remodeling leading to airway hyperresponsiveness (AHR). How precisely IL-13 leads to the development of airway inflammation, AHR, and mucus production is not fully understood. In order to identify key mediators downstream of IL-13, we administered adenovirus IL-13 to specifically induce IL-13-dependent inflammation in the lungs of mice. This approach was shown to induce cardinal features of lung disease, specifically airway inflammation, elevated cytokines, AHR, and mucus secretion. Notably, the model is resistant to corticosteroid treatment and is characterized by marked neutrophilia, two hallmarks of more severe forms of asthma. To identify IL-13-dependent mediators, we performed a limited-scale two-dimensional SDS-PAGE proteomic analysis and identified proteins significantly modulated in this model. Intriguingly, several identified proteins were unique to this model, whereas others correlated with those modulated in a mouse ovalbumin-induced pulmonary inflammation model. We corroborated this approach by illustrating that proteomic analysis can identify known pathways/mediators downstream of IL-13. Thus, we have characterized a murine adenovirus IL-13 lung model that recapitulates specific disease traits observed in human asthma, and have exploited this model to identify effectors downstream of IL-13. Collectively, these findings will enable a broader appreciation of IL-13 and its impact on disease pathways in the lung.

An adenovirus type F41 outbreak in a pediatric bone marrow transplant unit: analysis of clinical impact and preventive strategies.

BACKGROUND: Adenovirus (HAdV) was identified in blood and stool specimens from 6 children on a pediatric bone marrow transplant (BMT) unit within 2 weeks. Two further adenovirus positive patients were identified in other areas of the childrens' hospital. The study aimed to determine the clinical course of different HAdV subtypes and to investigate whether the cluster was caused by nosocomial transmission or by endogenous reactivation. METHODS: Descriptive epidemiologic investigation was performed reviewing patients' charts. Molecular typing of identified adenovirus-DNA was performed by partial sequencing of the hexon gene. RESULTS: In 6 of 8 patients, HAdV-F41 was detected in feces. All but 1 patient presented with vomiting or diarrhea and all were treated with cidofovir. In 4 patients transmissions of HAdV-F41 within the hematological department were probable whereas 2 children on the BMT ward reactivated HAdV-C1 and -C2, respectively. HAdV-F41 was shed in feces for up to 64 days after onset of clinical symptoms. HAdV-F41 DNA in blood reached a maximum of 2 x 10(5) copies/mL. One patient harbored two HAdV types simultaneously, HAdV-F41 in feces and HAdV-C2 in blood samples. HAdV-C2 reached high virus concentrations in blood (4 x 10(9) copies/mL) and led to the only fatal case. Although the HAdV-F41 outbreak involving 6 children led to gastroenteritis and may also have been associated with mild hepatitis, coincidental, endogeneous reactivations of other HAdV types (C1 and C2) led to a more severe course. CONCLUSIONS: HAdV typing is essential both for the prognosis and for distinguishing between transmission or endogenous reactivation. Applying HAdV-specific infection control measures is crucial to prevent transmission.

Adenovirus infections and lung disease.

Adenovirus, particularly its E1A protein, has been investigated in the pathogenesis of chronic obstructive pulmonary disease (COPD). High levels of E1A DNA were found in the lungs of COPD patients, where its expression increased with disease severity. In lung epithelial cells, E1A increased intercellular adhesion molecule-1 and interleukin-8 expression, as well as nuclear factor-kappaB activation, in response to inflammatory stimuli. In addition to regulating the mediators that promote emphysema, E1A upregulates transforming growth factor-beta1 expression in bronchiolar epithelial cells and transforms lung epithelial cells to express mesenchymal markers. These results support its additional role in the airway remodeling process reported in COPD.

Fas activity mediates airway inflammation during mouse adenovirus type 1 respiratory infection.

CD8 T cells play a key role in clearance of mouse adenovirus type 1 (MAV-1) from the lung and contribute to virus-induced airway inflammation. We tested the hypothesis that interactions between Fas ligand (FasL) and Fas mediate the antiviral and proinflammatory effects of CD8 T cells. FasL and Fas expression were increased in the lungs of C57BL/6 (B6) mice during MAV-1 respiratory infection. Viral replication and weight loss were similar in B6 and Fas-deficient (lpr) mice. Histological evidence of pulmonary inflammation was similar in B6 and lpr mice, but lung mRNA levels and airway proinflammatory cytokine concentrations were lower in MAV-1-infected lpr mice compared to infected B6 mice. Virus-induced apoptosis in lungs was not affected by Fas deficiency. Our results suggest that the proinflammatory effects of CD8 T cells during MAV-1 infection are mediated in part by Fas activation and are distinct from CD8 T cell antiviral functions.

Fecal Respiratory Viruses in Acute Viral Respiratory Infection and Nasopharyngeal Diarrheal Viruses in Acute Viral Gastroenteritis: Clinical Impact of Ectopic Viruses Is Questionable.

Our aim was to determine the detection rate of respiratory viruses (RVs) in feces of patients with acute viral respiratory infection (AVRI) and the detection rate of diarrheal viruses (DVs) in nasopharyngeal samples from patients with acute viral gastroenteritis. The relationships between the presence of fecal RVs or nasopharyngeal DVs and their impacts on the clinical severity were also investigated. A total of 144 fecal specimens were collected from AVRI patients and 95 nasopharyngeal specimens were collected from acute viral gastroenteritis patients. Clinical characteristics and laboratory profiles were compared between subgroups on the basis of the presence or absence of virus in the specimens. The detection rate of RVs in feces was 17.4% (25/144), whereas the detection rate for viruses identical to the respiratory pathogen was 10.4% (identical group, 15/144). Within the identical group, adenovirus (86.7%, 13/15) was most commonly found. Patients in the identical group showed statistically higher values for C-reactive protein, mean age, increased frequency of vomiting, and decreased frequency of chest film involvement and cough (p < 0.05). The detection rate of nasopharyngeal DVs among acute viral gastroenteritis patients was 19.0% (18/95), and in the identical group it was 15.8% (15/95). Norovirus group II and enteric adenovirus were the major pathogens detected in the identical group. There were no significant differences in clinical characteristics and laboratory profiles between the subgroups. In conclusion, the major pathogens of fecal RV and nasopharyngeal DV were adenovirus and norovirus group II, respectively. However, their relationship with the clinical symptoms or disease severity is unclear.

Pancreatitis Is an Important Feature of Broilers Suffering from Inclusion Body Hepatitis Leading to Dysmetabolic Conditions with Consequences for Zootechnical Performance.

The aim of the present study was to further unravel the pathophysiologic mechanisms of inclusion body hepatitis (IBH). In a first trial, the susceptibility of specific-pathogen-free (SPF) broilers to fowl aviadenovirus (FAdV) infections was investigated. Regardless of viral dose, route of infection, and susceptibility to disease on day 1, the 3-week-old SPF broilers showed resistance to IBH, with no mortality being recorded throughout the experiment. In a second trial, SPF broilers were orally infected at 3 weeks of age with a FAdV-E strain, and their digestive and metabolic processes were monitored. The birds' performance decreased from 7 days postinfection (dpi) onward, and hepato- and pancreatomegaly were found at necropsy at 4, 7, and 10 dpi and at 7 dpi, respectively. Clinical chemistry revealed transient hyperlipasemia at 4 dpi and hyperglycemia from 4 dpi onwards, with 25% of infected birds showing glycemia levels suggestive of diabetes mellitus. Histopathology findings included typical adenoviral hepatitis in the liver, while in the pancreas, inflammation characterized by multifocal infiltrations of lymphocytes, together with shrinkage of acinar cells, loss of acinar arrangement, and hyperplasia of islet cells, was noticed. Additionally, the pancreatic tissue had tendentiously lower levels of enzyme activity, and in the ileum, the digestibility of fat was significantly impaired. Hence, our data reinforce the concept of age-related resistance to experimentally induced IBH. Additionally, we demonstrated that FAdV-induced pancreatitis in broilers interferes with the digestive process and evolves into a dysmetabolic condition that resembles diabetes, affecting the health and zootechnical performance of birds, and therefore providing an important component of IBH pathogenesis.