A Case Series of Children with Acute Hepatitis and Human Adenovirus Infection.

BACKGROUND: Human adenoviruses typically cause self-limited respiratory, gastrointestinal, and conjunctival infections in healthy children. In late 2021 and early 2022, several previously healthy children were identified with acute hepatitis and human adenovirus viremia. METHODS: We used International Classification of Diseases, 10th Revision, codes to identify all children (<18 years of age) with hepatitis who were admitted to Children's of Alabama hospital between October 1, 2021, and February 28, 2022; those with acute hepatitis who also tested positive for human adenovirus by whole-blood quantitative polymerase chain reaction (PCR) were included in our case series. Demographic, clinical, laboratory, and treatment data were obtained from medical records. Residual blood specimens were sent for diagnostic confirmation and human adenovirus typing. RESULTS: A total of 15 children were identified with acute hepatitis - 6 (40%) who had hepatitis with an identified cause and 9 (60%) who had hepatitis without a known cause. Eight (89%) of the patients with hepatitis of unknown cause tested positive for human adenovirus. These 8 patients plus 1 additional patient referred to this facility for follow-up were included in this case series (median age, 2 years 11 months; age range, 1 year 1 month to 6 years 5 months). Liver biopsies indicated mild-to-moderate active hepatitis in 6 children, some with and some without cholestasis, but did not show evidence of human adenovirus on immunohistochemical examination or electron microscopy. PCR testing of liver tissue for human adenovirus was positive in 3 children (50%). Sequencing of specimens from 5 children showed three distinct human adenovirus type 41 hexon variants. Two children underwent liver transplantation; all the others recovered with supportive care. CONCLUSIONS: Human adenovirus viremia was present in the majority of children with acute hepatitis of unknown cause admitted to Children's of Alabama from October 1, 2021, to February 28, 2022, but whether human adenovirus was causative remains unclear. Sequencing results suggest that if human adenovirus was causative, this was not an outbreak driven by a single strain. (Funded in part by the Centers for Disease Control and Prevention.).

A fatal case of viral sepsis and encephalitis in a child caused by human adenovirus type 7 infection.

Adenoviruses are highly prevalent pathogens responsible for a wide range of clinical diseases, including respiratory tract infection, acute gastroenteritis, and conjunctivitis. However, adenovirus infection is rarely associated with central nervous system involvement. Here, we report a fatal viral sepsis and encephalitis in a child caused by a human adenovirus type 7 infection. We detected human adenovirus type 7 in the patient's nasopharyngeal swab, blood, and cerebrospinal fluid. Our findings indicate clinicians should be aware of the possible central nervous system involvement in adenovirus infection.

An outbreak of adenovirus D8 keratoconjunctivitis in Leicester, United Kingdom, from March to August 2019.

We report a large epidemic (n = 126) of keratoconjunctivitis predominantly with two lineages of adenovirus (AdV) type D8 in patients seen in eye casualty between march and August 2019. Other AdV species identified by viral sequencing included B, C, and E. Despite various features of more severe eye disease being present, these were not significantly different between the different AdV species, with similar rates of pseudomembrane formation and keratitis observed in patients with AdV species B as for those with AdV species D.

Epidemiological characteristics, clinical characteristics, and prognostic factors of children with atopy hospitalised with adenovirus pneumonia.

BACKGROUND: Atopy may be associated with disease severity and a poor prognosis of human adenovirus (HAdV) pneumonia in children. Our aim was to observe the clinical characteristics and pulmonary radiological changes in children with atopy and HAdV pneumonia in China. METHODS: Children hospitalised with HAdV pneumonia from June 2018 to December 2019 were analysed. All children were divided into atopic with HAdV, non-atopic with HAdV, and atopic without HAdV infection group. Each group was further divided into the mild and severe pneumonia groups according to disease severity. Standard treatment was initiated after admission, and regular follow-up evaluations were conducted at 1 month after discharge. Baseline and clinical characteristics and pulmonary radiological changes in children with and without atopy were evaluated. Risk factors associated with small airway lesions in patients with HAdV pneumonia were analysed. RESULTS: The eosinophil count in the atopic group was significantly higher than that in the non-atopic group (P < 0.05). Severe coughing, wheezing, and small airway lesions on chest high-resolution computed tomography (HRCT) upon admission, after discharge and 1 month after discharge were significantly higher in the atopic group (with or without HAdV infection) than in the non-atopic group (P < 0.05). There were significant differences in the number of patients with wheezing and small airway lesions during hospitalisation and after discharge among the three groups (P < 0.05). The risks of small airway lesions in children with a family or personal history of asthma, severe infection, atopy, and HAdV infection were 2.1-, 2.7-, 1.9-, 2.1-, and 1.4-times higher than those in children without these characteristics, respectively. CONCLUSIONS: Children with atopy and HAdV pneumonia may experience severe coughing in mild cases and wheezing in mild and severe cases. Children with atopy are more susceptible to the development of small airway lesions, recurrent wheezing after discharge and slower recovery of small airway lesions as observed on pulmonary imaging than non-atopic children after HAdV infection. A family or personal history of asthma, atopy, severe infection, and HAdV infection are independent risk factors associated with the development of small airway lesion as observed on chest HRCT.

Adenovirus Infection in Children with Down Syndrome.

BACKGROUND: Adenovirus infections are prevalent in children. They usually cause a mild self-limited disease. However, this infection can be associated with considerable morbidity and mortality in specific populations, especially among immunocompromised children. Children with Down syndrome are susceptible to a higher frequency and increased severity of viral infections. Little is known about the severity and clinical course of adenovirus infections in children with Down syndrome. OBJECTIVES: To characterize hospitalized children diagnosed with Down syndrome and presenting with adenovirus infection. METHODS: We performed a retrospective review of children admitted with adenovirus from January 2005 to August 2014 from a single tertiary pediatric medical center in Israel. Data were compared between patients with and without Down syndrome. RESULTS: Among the 486 hospitalized children with adenoviral infection, 11 (2.28%) were diagnosed with Down syndrome. We found that children with Down syndrome were more likely to experience a higher incidence of complications (18.2% vs. 2.4%, P = 0.008), a higher rate of admissions to the intensive care unit (36.4% vs. 2.4%, P < 0.001), and more prolonged hospitalizations (17 ± 15.9 days compared to 4.46 ± 3.16, P = 0.025). CONCLUSIONS: Children with Down syndrome who were hospitalized with adenovirus infection represent a high-risk group and warrant close monitoring. If a vaccine for adenovirus becomes available, children with Down syndrome should be considered as candidates.

Two cases of epidemic keratoconjunctivitis-associated dacryocystitis.

This report presents two cases of epidemic keratoconjunctivitis (EKC)-associated dacryocystitis. Both patients presented with preseptal edema. Orbital computed tomography (CT) scans were performed out of concern for orbital cellulitis and revealed soft tissue edema involving the preseptal aspect of the eyelids and also the lacrimal sac. Both patients were initially diagnosed with bacterial preseptal cellulitis with dacryocystitis and admitted for treatment with intravenous antibiotics. After no improvement on antibiotics, both patients were noted to have exam findings consistent with viral conjunctivitis, and one patient had a positive conjunctival swab for adenovirus. Both patients were subsequently treated with topical steroids, and symptoms improved. EKC has previously been identified as a cause of acquired nasolacrimal duct obstruction and canalicular stenosis, and acute inflammation of the lacrimal apparatus may explain this link. Dacryocystitis may also be contributory to the copious tearing seen in patients with epidemic keratoconjunctivitis.

Epidemiology of human adenovirus infection in children hospitalized with lower respiratory tract infections in Hunan, China.

To investigate the current genotypes of circulating human adenovirus (HAdV) strains, we molecularly genotyped HAdV in the nasopharyngeal aspirates (NPAs) of patients with acute lower respiratory tract infections (ALRTIs) and attempted to determine their associations with clinical symptoms. A total of 4751 NPA samples were collected from 4751 patients admitted to Hunan Provincial People's Hospital from September 2007 to March 2014, of which 447 (9.4%) samples were HAdV positive. Fourteen different HAdV types were identified; HAdV types 1 to 7 (HAdV 1-7) were identified in 95.7% of the 447 NPA samples with HAdV-7 and HAdV-3 being the most prevalent. In addition, 93.3% (417 of 447) of patients were younger than 5 years. The incidence of HAdV infection peaked in summer. Different HAdV types showed a predilection for different age groups and different seasonal distribution patterns. Coinfection of HAdVs and other respiratory viruses was detected in 63.3% (283 of 447) of the HAdV-positive samples. The most common clinical diagnosis was pneumonia and the most common symptoms were fever and cough. In comparison with children infected with HAdV-3 alone, those infected with HAdV-7 alone had an increased frequency of severe pneumonia involvement (11.6% vs 32.4%; P = 0.031), higher intensive care unit admission rates (7.0% vs 26.5%; P = 0.019), and a longer length of hospital stay (P = 0.03). Mixed infections in younger children were associated with a longer hospital stay (P = 0.023). Our results demonstrate the recent changes in the trends of circulating HAdV genotypes associated with ALRTIs in Hunan China.

Outcomes of human adenovirus infection and disease in a retrospective cohort of pediatric solid organ transplant recipients.

Information about HAdV infection in SOT recipients is limited. We aimed to describe HAdV infection epidemiology and outcomes in a single-center retrospective cohort during the era of PCR availability. SOT recipients transplanted at the CHOP 2004-2013 were followed up for 180 days post-transplant. HAdV infection was defined as a positive HAdV PCR from a clinical specimen. HAdV disease was defined by organ-specific radiologic and/or laboratory abnormalities. No HAdV surveillance protocols were employed during the study period; testing was solely per clinician discretion. Progression of HAdV infection was defined as HAdV disease or ≥1-log viral load increase since a corresponding site's first positive specimen. Of the assembled 425 SOT recipients, 227 (52.6%) had ≥1 HAdV PCR. Twenty-four (10.6%) had ≥1 HAdV-positive PCR. HAdV-positive subjects were younger than uninfected subjects (2.0 years vs 6.5, P = 0.001). Infection incidence rates were highest in liver recipients (15.3%), followed by heart (8.6%), kidney (8.3%), and lung (4.2%). Four subjects (16.7%) met HAdV disease criteria at virus detection. Five subjects (20.8%) had progression of HAdV infection. All-cause mortality rates in positive and negative subjects were 0% and 3.9%, respectively. HAdV infection was infrequently detected in SOT recipients. Over one-third of HAdV-positive patients met disease criteria at detection or had infection progression, but none died. This low all-cause mortality raises questions about benefits of HAdV surveillance. Larger multicenter studies are needed to assess incidence variance by center and comparative effectiveness of therapeutic interventions.

Human adenoviral type 54 keratoconjunctivitis accompanied by stellate keratitis and keratic precipitates: two cases.

BACKGROUND: Of the 10 patients with adenoviral type 54 keratoconjunctivitis examined at Nojima Hospital, 2 developed stellate keratitis and mutton-fat keratic precipitates (KPs) following acute symptoms. CASE PRESENTATION: We encountered 10 cases of epidemic keratoconjunctivitis from August to October 2017. All patients were adults with a mean age of 60.9 ± 10.0 years. The species D human adenovirus (HAdV)-54 was detected in the conjunctival scrapings of these patients. Fluorometholone instillation was administered during the first week for acute symptomatic relief. Case 1: A 64-year-old female was prescribed with fluorometholone instillation, which was discontinued after 1 week when her symptoms alleviated. One week after discontinuation of the instillation, she presented with blurred vision in her left eye with KPs and multiple stellate keratitis. The anterior chamber had no apparent cells. Her symptoms disappeared after 1 week of betamethasone instillation. Case 2: A 66-year-old female was prescribed with 0.1% fluorometholone instillation, which was discontinued within10 days. Three months after the appearance of initial symptoms, multiple subepithelial corneal infiltrates (MSI) appeared in her eyes. Stellate keratitis and dark-brown pigmentation were observed in the centres of MSI, with several cells in the anterior chamber. Betamethasone was prescribed, and MSI and stellate keratitis improved within 1 week. However, KPs were observed in the left eye. The instillation was continued for 3 more weeks until symptoms improved. CONCLUSIONS: MSI is an immune reaction that occurs after the disappearance of acute symptoms. Here, corneal findings and KPs were observed after improvement in eye redness and discontinuation of steroids. These symptoms were presumed to be secondary inflammation due to immune response to the adenoviral antigen. The clinical features of HAdV-54 keratoconjunctivitis on the ocular surface are initially moderate, but become active in the subacute to chronic phases. This may develop atypical findings, including stellate keratitis with KPs. Although early steroid administration can relieve acute symptoms, it may facilitate chronic corneal immunological reaction.

Co-infection with human polyomavirus BK enhances gene expression and replication of human adenovirus.

Immunocompromised patients are susceptible to multiple viral infections. Relevant interactions between co-infecting viruses might result from viral regulatory genes which trans-activate or repress the expression of host cell genes as well as the genes of any co-infecting virus. The aim of the current study was to show that the replication of human adenovirus 5 is enhanced by co-infection with BK polyomavirus and is associated with increased expression of proteins including early region 4 open reading frame 1 and both the large tumor antigen and small tumor antigen. Clinical samples of whole blood and urine from 156 hematopoietic stem cell transplant recipients were tested. We also inoculated adenocarcinomic human alveolar basal epithelial cells with both human adenovirus 5 and BK polyomavirus to evaluate if co-infection of viruses affected their replication. Data showed that adenovirus load was significantly higher in the plasma (mean 7.5 x 103 ± 8.5 x 102 copies/ml) and urine (mean 1.9 x 103 ± 8.0 x 102 copies/ml) of samples from patients with co-infections, in comparison to samples from patients with isolated adenovirus infection. In vitro co-infection led to an increased (8.6 times) expression of the adenovirus early region 4 open reading frame gene 48 hours post-inoculation. The expression of the early region 4 open reading frame gene positively correlated with the expression of BK polyomavirus large tumor antigen (r = 0.90, p < 0.0001) and small tumor antigen (r = 0.83, p < 0.001) genes. The enhanced expression of the early region 4 open reading frame gene due to co-infection with BK polyomavirus was associated with enhanced adenovirus, but not BK polyomavirus, replication. The current study provides evidence that co-infection of adenovirus and BK polyomavirus contributes to enhanced adenovirus replication. Data obtained from this study may have significant importance in the clinical setting.

Adenovirus associated with acute diarrhea: a case-control study.

BACKGROUND: Diarrhea is a major source of morbidity and mortality among young children in low-income and middle-income countries. Human adenoviruses (HAdV), particular HAdV species F (40, 41) has been recognized as important causal pathogens, however limited data exist on molecular epidemiology of other HAdV associated with acute gastroenteritis. METHODS: In the present preliminary study, we performed a case-control study involving 273 children who presented diarrheal disease and 361 healthy children matched control in Children's hospital of Hebei Province (China) to investigate the relationship between non-enteric HAdV and diarrhea. HAdV were detected and quantified using quantitative real-time PCR (qPCR) and serotyped by sequencing and phylogenetic analysis. Odds ratio (OR) was used to assess the risk factor of HAdV. RESULTS: HAdV were detected in 79 (28.94%) of 273 children with diarrhea including 7 different serotypes (HAdV 40, 41, 3, 2,1,5 and 57) with serotypes 40, 41 and 3 being the most dominant and in 26 (7.20%) of 361 healthy children containing 9 serotypes (HAdV 40, 41, 3, 2,1,5,57,6 and 31). A majority (91.14%) of HAdV positives occurred in diarrhea children and 65.38% in controls< 3 years of age. No significant difference in the viral load was found between case and control groups or between Ad41-positive patients and healthy controls. In addition to HAdV 40 and 41, HAdV 3 was also associated with diarrhea (OR = 17.301, adjusted OR = 9.205, p < 0.001). CONCLUSIONS: Our results demonstrate a high diversity of HAdV present among diarrhea and healthy children and implicate that non-enteric HAdV3 may lead to diarrhea.

Adenovirus-associated acute conjunctivitis in Beijing, China, 2011-2013.

BACKGROUND: Human adenovirus (HAdV)-associated acute conjunctivitis is a common infectious disease and causes significant morbidity among residents in Beijing, China. However, little is known about the epidemiology and type distribution of acute adenoviral conjunctivitis in Beijing. METHODS: Acute conjunctivitis surveillance was conducted in 18 hospitals in Beijing from July through October during 2011-2013. HAdVs were detected by PCR from eye swab and types were determined by partial hexon and fiber gene sequencing. Risk factors associated with adenoviral conjunctivitis were analyzed. RESULTS: Of 876 conjunctivitis cases, 349 (39.8%) were HAdV positive. HAdV detection was most common in conjunctivitis patients aged 18-40 years; patients with contact history with a conjunctivitis case; patients with specimen collected on days 4-6 post symptom onset and patients who worked in food service as catering attendants. Fifteen types were identified among adenoviral conjunctivitis cases. Five HAdV types (HAdV-4, - 37, - 53, - 64 and - 8) accounted for 81.1% of all adenoviral conjunctivitis cases. HAdV-37, - 4 and - 53 were the most common types associated with adenoviral conjunctivitis in 2011, 2012 and 2013, respectively. CONCLUSION: Multiple HAdV types were associated with acute conjunctivitis in Beijing. Predominant types associated with adenoviral conjunctivitis circulating in Beijing varied from year to year.

Case report: a fatal case of disseminated adenovirus infection in a non-transplant adult haematology patient.

BACKGROUND: We report a fatal case of disseminated adenovirus infection in a non-transplant haematology adult patient with chronic lymphocytic leukaemia who had completed combination chemoimmunotherapy a few months before developing respiratory symptoms. In such non-transplant patients, monitoring for adenovirus in the blood is not routine. However, with adenoviruses, when there is a more peripheral (i.e. non-blood) site of infection such as the chest, serial adenovirus monitoring in blood for the duration of that illness may be warranted. CASE PRESENTATION: This case started with an initial bacterial chest infection that responded to treatment, followed by an adenovirus pneumonitis that disseminated to his blood a week later with levels of up to 92 million adenovirus DNA copies/ml. Despite prompt treatment with cidofovir, his respiratory function continued to deteriorate over the next two weeks and he was moved to intensive care. Intravenous immunoglobulin and ribavirin were subsequently added to his treatment. However, he died soon after this with a final adenovirus load of 20 million copies/ml in his blood. CONCLUSIONS: We recommend that even in non-transplant haematology patients, where such patients present with an acute respiratory adenovirus infection, teams should consider checking the blood for adenovirus to check for signs of disseminated infection. The earlier this can be tested, the earlier treatment can be initiated (if adenovirus positive), which may produce more successful clinical outcomes.

Evaluation of Adenovirus-36 (Ad-36) antibody seropositivity and adipokine levels in obese children.

Adenovirus 36 (Ad-36) has recently been suggested as a possible contributor to the current obesity epidemic. The aim of this study was to investigate the prevalence of Ad-36 antibodies in obese children, as well as investigate the role of serum leptin and lipid levels in Ad-36-obesity. Seventy-one obese children and 62 non-obese children were included as the patient group (PG), including the healthy control group (HCG), respectively. Simultaneously, Ad-36 antibodies and adipokine levels were assessed with serum neutralization assays (SNA) and ELISA. Ad-36 antibody was detected in 9 patients (12.7%) and 1 patient (1.6%) in both the PG and HCG, respectively, while a significant difference was detected between groups (p < 0.05). Although serum LDL, total cholesterol, triglycerides and leptin levels were detected significantly higher, adiponectin level was detected paradoxically lower in the PG. However, a significant difference was not detected for lipids and leptin levels; adiponectin levels were found to be significantly lower in Ad-36 antibody-positive PG (p < 0.05). In conclusion, we suggest there is an association between Ad-36 and obesity in children, including IL-6 levels increasing in obese children with Ad-36 seropositivity. Conversely, adiponectin levels in obese children with Ad-36 seropositivity were higher. As such, there is a need for studies to understand the mechanisms underlying this observation.

Clinical features of community acquired adenovirus pneumonia during the 2011 community outbreak in Southern Taiwan: role of host immune response.

BACKGROUND: Human adenovirus 7 (HAdV-7) was responsible for a significant number of fatalities during the 2011 community outbreak in Taiwan. The mechanisms underlying the pathogenesis of severe adenovirus infections in non-immunocompromised individuals remain unclear. Adenovirus pneumonia was associated with pleural effusion in a number of patients from the 2011 outbreak suggesting that similar to bacterial pneumonia, patients diagnosed with adenovirus pneumonia who have pleural effusion are more severely and systemically infected, and may have a more protracted disease course. We hypothesized that the host immunological response determines the severity of adenoviral infection. METHODS: This retrospective case series study included patients diagnosed with severe lower respiratory tract infections at the National Cheng Kung University Hospital in southern Taiwan between December 2010 and October 2011. The main inclusion criteria were 1) presence of multifocal patchy infiltrates, lobar consolidation or reticular interstitial opacities in chest X-rays, and 2) presence of adenovirus isolated from respiratory specimens. All patients had adenovirus isolated from respiratory specimens, and were negative for other viruses. Pleural effusion was confirmed in all patients using chest echography. Clinical features and laboratory data were compared in patients with (n = 12) and without (n = 15) parapneumonic effusion. RESULTS: Presence of parapneumonic effusion was significantly associated with a longer febrile duration, more complicated clinical management, and a greater risk of extrapulmonary involvement, notably hepatitis. Patients without pleural effusion had significantly higher numbers of WBCs, platelets, and absolute segment cell counts (ASCs) compared to patients with pleural effusion (all p < 0.05). Patients without pleural effusion had significantly higher counts of CD4+, CD8+, and CD20+ T cells (all p < 0.05) compared to patients with pleural effusion. CONCLUSION: Our data indicated that presence of parapneumonic effusion in adenoviral pneumonia was associated with longer febrile duration, more complicated clinical management, a greater risk of hepatitis, and suppression of host cellular immunity. Further prospective, large-scale studies are needed to validate our results.

Treatment of Adenoviral Acute Respiratory Distress Syndrome Using Cidofovir With Extracorporeal Membrane Oxygenation.

Adenovirus infections are associated with respiratory (especially upper respiratory) infection and gastrointestinal disease and occur primarily in infants and children. Although rare in adults, severe lower respiratory adenovirus infections including pneumonia are reported in specific populations, such as military recruits and immunocompromised patients. Antiviral treatment is challenging due to limited clinical experience and lack of well-controlled randomized trials. Several previously reported cases of adenoviral pneumonia showed promising efficacy of cidofovir. However, few reports discussed the efficacy of cidofovir in acute respiratory distress syndrome (ARDS). We experienced 3 cases of adenoviral pneumonia associated with ARDS and treated with cidofovir and respiratory support, including extracorporeal membrane oxygenation (ECMO). All 3 patients showed a positive clinical response to cidofovir and survival at 28 days. Cidofovir with early ECMO therapy may be a therapeutic option in adenoviral ARDS. A literature review identified 15 cases of adenovirus pneumonia associated with ARDS.