Human adenovirus causes infections with a very heterogeneous clinical picture, and children are often the most frequently affected group. Interest in adenovirus has increased with the 2022 outbreak of severe acute hepatitis of unknown etiology as human adenovirus was considered as one of the possible etiological agents. We conducted a retrospective study over a 5-year period in two major tertiary hospitals in the Romanian capital with the aim to characterize the clinical picture and the dynamics of liver function tests in children with confirmed adenovirus infection. The study included 1416 children with a median age of 1.1 years (IQR: 0.3, 2.3 years). Digestive symptoms were predominant in 95.2% of children, mainly diarrhea (90.5%) and vomiting (50.5%), and 38.0% had respiratory symptoms. Increased transaminases were identified in 21.5% of patients. Age over 1 year, lethargy, vomiting and dehydration significantly increased the odds of liver cytolysis independent of other risk factors such as chronic conditions or co-infections. Aspartate aminotransferase (AST) was more commonly increased compared to alanine aminotransferase (ALT). Only six children had transaminase increases above 500 U/L, three of which had co-infections with rotavirus, Epstein-Barr virus (EBV), or respiratory syncytial virus (RSV). Liver function tests should be part of routine monitoring for pediatric patients with adenovirus infection. The current study fills a gap in current knowledge related to the frequency and the extent of liver involvement in human adenovirus infection among pediatric patients.

Respiratory syncytial virus (RSV) predominantly affects children and typically manifests as an upper respiratory tract infection. Primary RSV infection in immunosuppressed adults may increase risks of disseminated infection manifesting as RSV hepatitis. A 29-year-old pregnant woman of 10 weeks gestation presented with mild right upper quadrant abdominal pain, intractable nausea, and vomiting, requiring hospitalization. Due to initial lab work showing significantly elevated liver transaminases, she underwent a thorough workup to evaluate for causes of hepatitis. Common viral and autoimmune etiologies of hepatitis were excluded with appropriate serologies. A respiratory viral molecular panel (RVP) was obtained to evaluate for SARS-CoV-2/coronavirus disease 2019 (COVID-19) infection, despite lack of typical respiratory symptoms. No structural pathologies were detected on abdominal imaging with ultrasound and magnetic resonance imaging. No other etiologies for the patient's hepatitis were detected other than RSV infection detected on RVP. The patient's care required close coordination between multiple different subspecialties. Her condition improved due to the early detection of RSV infection and prompt initiation of supportive care. This case highlights the need for providers to consider obtaining an RVP early in workup of hepatitis to evaluate for RSV infection, even when patients have minimal respiratory symptoms. A high index of suspicion is required for early identification of RSV hepatitis as timely supportive care may prevent progression to acute liver failure.

Respiratory syncytial virus (RSV) is a prevalent cause of lower respiratory tract infections. It may be associated with hepatocellular involvement, as indicated by increased liver enzymes aspartate aminotransferase and alanine transaminase (ALT).

To evaluate the rate of increased liver enzyme levels in children with acute bronchiolitis and correlate them with clinical, laboratory, and radiological variables.

The study was a retrospective review of the medical records of children who presented with acute bronchiolitis when admitted to the Pediatric Department, Salmaniya Medical Complex, the Kingdom of Bahrain, between 2019 and 2020. We collected the demographic data, the clinical presentation, the laboratory and radiological findings, and the clinical outcomes. We compared the patients with elevated liver enzymes to those with normal levels at the time of presentation and at follow-up.

We included 166 (57.8%) of 287 patients with acute bronchiolitis who fulfilled the inclusion criteria. Ninety-three (56%) patients were males. The median age at presentation was 3.4 (interquartile range 1.1 to 12.4) mo. Fifty-four (28%) patients tested positive for RSV, which was confirmed in 15 of them (28%) by PCR. Laboratory findings of 161 patients tested at presentation showed high ALT levels in 14 (8.7%) patients and normal ALT in 147 (91.3%). Coagulation profiles were measured in 46 (27.7%) of 166 patients. High prothrombin time was present in 15 (32.6%), a high international normalized ratio was present in 13 (28.3%), and high activated partial thromboplastin time was present in three (6.5%). Thrombin time was elevated in nine (27.3%) of 33 patients. Five (21.7%) of 23 patients with available radiological data had hepatomegaly; one of them had findings suggestive of fatty infiltration. High ALT had a significant association with lengthy hospital stays (P < 0.05) and positive urine culture (P < 0.05). Seventy (42.2%) patients had documented follow-up with liver function tests over a median follow-up period of 10.2 (IQR, 2.4-23.3) mo. Total serum protein and serum globulin levels were normalized at the follow-up time, with a significant P value of < 0.05.

This study showed a low prevalence of liver function involvement in patients with acute bronchiolitis with a benign course. However, there was a rising trend in ALT during follow-up. Prolonged hospital stay and positive urine cultures were associated with elevated liver enzymes.

Since April 5, 2022, an increase in cases of severe acute hepatitis of unknown etiology among children with no underlying conditions was first reported in the United Kingdom (UK). Testing excluded viral hepatitis types A, B, C, D, and E and other known common and uncommon infectious and non-infectious causes of acute hepatitis. As of May 26, 2022, 650 cases of acute hepatitis of unknown etiology in children have been reported in at least 33 countries worldwide, with 99 additional cases pending classification. Here, the current prevalence of this condition around the world, a hazard analysis, possible causes, the risk of an outbreak in China, and advice on prevention have been briefly reviewed.

Considerable evidence supports that cytokines are important mediators of pathophysiologic processes within the central nervous system (CNS). Numerous studies have documented the increased production of various cytokines in the human CNS in various neurological and neuropsychiatric disorders. Deciphering cytokine actions in the intact CNS has important implications for our understanding of the pathogenesis and treatment of these disorders. The purpose of this study is to discuss the recent research on treating cytokine storm and amyloids, including stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's condition, Multi-sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS). Neuroinflammation observed in neurological disorders has a pivotal role in exacerbating Aβ burden and tau hyperphosphorylation, suggesting that stimulating cytokines in response to an undesirable external response could be a checkpoint for treating neurological disorders. Furthermore, the pro-inflammatory cytokines help our immune system through a neuroprotective mechanism in clearing viral infection by recruiting mononuclear cells. This study reveals that cytokine applications may play a vital role in providing novel regulation and methods for the therapeutic approach to neurological disorders and the causes of the deregulation, which is responsible for neuroinflammation and viral infection. However, it needs to be further investigated to clarify better the mechanisms of cytokine release in response to various stimuli, which could be the central point for treating neurological disorders.

In April 2022, the United Kingdom notified the World Health Organization (WHO) of an unexpected increase of acute hepatitis of unknown origin in children. Subsequent investigations have found more than 400 cases in more than 20 countries and regions around the world. Although the potential role of adenovirus type 41 in the pathogenesis of these cases is one hypothesis, but it is probably not the only pathogenic factor, and other infectious and non-infectious causes cannot be completely ruled out. For hepatitis caused by non-hepatitis A, B, C, D and E viruses, there is a lack of systematic monitoring and research, and many unknowns still exist. According to the current etiology speculation and epidemiological characteristics of adenovirus in China, cases of acute hepatitis with unknown origin may be found in China in the future. There is also a risk of imported cases. This article systematically sorts out the reports and studies on child acute hepatitis of unknown origin, hoping to attract the attention of pediatric clinicians in China, raise awareness and vigilance, and calmly prepare for possible abnormal situations.

The olfactory mucosa, where the first step of odor detection occurs, is a privileged pathway for environmental toxicants and pathogens toward the central nervous system. Indeed, some pathogens can infect olfactory sensory neurons including their axons projecting to the olfactory bulb allowing them to bypass the blood-brain barrier and reach the central nervous system (CNS) through the so-called olfactory pathway. The respiratory syncytial virus (RSV) is a major respiratory tract pathogen but there is growing evidence that RSV may lead to CNS impairments. However, the mechanisms involved in RSV entering into the CNS have been poorly described. In this study, we wanted to explore the capacity of RSV to reach the CNS via the olfactory pathway and to better characterize RSV cellular tropism in the nasal cavity. We first explored the distribution of RSV infectious sites in the nasal cavity by in vivo bioluminescence imaging and a tissue clearing protocol combined with deep-tissue imaging and 3D image analyses. This whole tissue characterization was confirmed with immunohistochemistry and molecular biology approaches. Together, our results provide a novel 3D atlas of mouse nasal cavity anatomy and show that RSV can infect olfactory sensory neurons giving access to the central nervous system by entering the olfactory bulb. Cover Image for this issue: doi: 10.1111/jnc.14765.

Central Nervous System (CNS) infections are one of the most critical problems in public health, as frequently patients exhibit neurologic sequelae. Usually, CNS pathologies are caused by known neurotropic viruses such as measles virus (MV), herpes virus and human immunodeficiency virus (HIV), among others. However, nowadays respiratory viruses have placed themselves as relevant agents responsible for CNS pathologies. Among these neuropathological viruses are the human respiratory syncytial virus (hRSV), the influenza virus (IV), the coronavirus (CoV) and the human metapneumovirus (hMPV). These viral agents are leading causes of acute respiratory infections every year affecting mainly children under 5 years old and also the elderly. Up to date, several reports have described the association between respiratory viral infections with neurological symptoms. The most frequent clinical manifestations described in these patients are febrile or afebrile seizures, status epilepticus, encephalopathies and encephalitis. All these viruses have been found in cerebrospinal fluid (CSF), which suggests that all these pathogens, once in the lungs, can spread throughout the body and eventually reach the CNS. The current knowledge about the mechanisms and routes used by these neuro-invasive viruses remains scarce. In this review article, we describe the most recent findings associated to neurologic complications, along with data about the possible invasion routes of these viruses in humans and their various effects on the CNS, as studied in animal models.

A 1-month-old child was admitted at our pediatric intensive care unit (PICU) in a very critical state with generalized cyanosis, grunting, high fever, tachypnea, tachycardia, severe hypotension with capillary refill time > 5 seconds, and no palpable pulse. The child was apparently doing well until a few hours before admission. On admission to PICU, his clinical diagnosis was consistent with severe sepsis with his sequential organ failure assessment scores of 7 to 8 points. We started rapid restoration of circulation with aggressive volume replacement and empiric antimicrobial therapy. Despite optimal supportive therapy, the patient showed severe liver injury leading to liver failure, making the treatment more challenging. His simplex real-time reverse transcriptase polymerase chain reaction assay and enzyme linked immune sorbent assay documented respiratory syncytial virus (RSV) infection. Through our case report we would like to highlight the extrapulmonary manifestations of RSV infections and the importance of liver dysfunction during sepsis.

Deferesirox (DFX), an oral chelating agent, is used to treat chronic iron overload in several hematological diseases such as β-thalassemia, sickle cell disease, and myelodysplastic anemia. DFX is generally well tolerated with the exception of gastrointestinal disturbances and rash, although cases of renal toxicity, as well as acute and chronic liver failure, have been reported in adults and children. Here we describe a 3-year-old girl with β-thalassemia undergoing treatment with DFX who presented with acute liver failure and Fanconi's syndrome. It is important for pediatric gastroenterologists, hepatologists, and hematologists to be aware that the commonly used drug DFX can lead to acute liver failure in children, and liver function should be monitored closely in all patients taking DFX.

The human respiratory syncytial virus (hRSV) is the causative agent for high rates of hospitalizations due to viral bronchiolitis and pneumonia worldwide. Such a disease is characterized by an infection of epithelial cells of the distal airways that leads to inflammation and subsequently to respiratory failure. Upon infection, different pattern recognition receptors recognize the virus and trigger the innate immune response against the hRSV. Further, T cell immunity plays an important role for virus clearance. Based on animal studies, it is thought that the host immune response to hRSV is based on a biased T helper (Th)-2 and Th17 T cell responses with the recruitment of T cells, neutrophils and eosinophils to the lung, causing inflammation and tissue damage. In contrast, human immunity against RSV has been shown to be more complex with no definitive T cell polarization profile. Nowadays, only a humanized monoclonal antibody, known as palivizumab, is available to protect against hRSV infection in high-risk infants. However, such treatment involves several injections at a significantly high cost. For these reasons, intense research has been focused on finding novel vaccines or therapies to prevent hRSV infection in the population. Here, we comprehensively review the recent literature relative to the immunological features during hRSV infection, as well as the new insights into preventing the disease caused by this virus.

Maternal viral infections can have pathological effects on the developing fetus which last long after birth. Recently, maternal-fetal transmission of respiratory syncytial virus (RSV) was shown to cause postnatal airway hyperreactivity (AHR) during primary early-life reinfection; however, the influence of prenatal exposure to RSV on offspring airway immunity and smooth muscle contractility during recurrent postnatal reinfections remains unknown. Therefore, we sought to determine whether maternal RSV infection impairs specific aspects of cell-mediated offspring immunity during early-life reinfections and the mechanisms leading to AHR. Red fluorescent protein-expressing recombinant RSV (rrRSV) was inoculated into pregnant rat dams at midterm, followed by primary and secondary postnatal rrRSV inoculations of their offspring at early-life time points. Pups and weanlings were tested for specific lower airway leukocyte populations by flow cytometry; serum cytokine/chemokine concentrations by multiplex ELISA and neurotrophins concentrations by standard ELISA; and ex vivo lower airway smooth muscle (ASM) contraction by physiological tissue bath. Pups born to RSV-infected mothers displayed elevated total CD3+ T cells largely lacking CD4+ and CD8+ surface expression after both primary and secondary postnatal rrRSV infection. Cytokine/chemokine analyses revealed reduced IFN-γ, IL-2, IL-12, IL-17A, IL-18, and TNF-α, as well as elevated nerve growth factor (NGF) expression. Prenatal exposure to RSV also increased ASM reactivity and contractility during early-life rrRSV infection compared to non-exposed controls. We conclude that maternal RSV infection can predispose offspring to postnatal lower airways dysfunction by altering immunity development, NGF signaling, and ASM contraction during early-life RSV reinfections.

The respiratory syncytial virus (RSV) usually causes a lower respiratory tract infection in affected patients. RSV has also been infrequently linked to extrapulmonary diseases in children. We report four children who had unusually severe clinical manifestations of RSV infections requiring critical care admission. These patients presented to the Royal Hospital, Muscat, Oman, in December 2013 with acute necrotising encephalopathy (ANE), acute fulminant hepatic failure with encephalopathy, pneumatoceles and croup. A unique presentation of ANE has not previously been reported in association with an RSV infection. All patients had a positive outcome and recovered fully with supportive management.

Despite fundamental advances in the research on respiratory syncytial virus (RSV) since its initial identification almost 60 years ago, recurring failures in developing vaccines and pharmacologic strategies effective in controlling the infection have allowed RSV to become a leading cause of global infant morbidity and mortality. Indeed, the burden of this infection on families and health care organizations worldwide continues to escalate and its financial costs are growing. Furthermore, strong epidemiologic evidence indicates that early-life lower respiratory tract infections caused by RSV lead to the development of recurrent wheezing and childhood asthma. While some progress has been made in the identification of reliable biomarkers for RSV bronchiolitis, a "one size fits all" biomarker capable of accurately and consistently predicting disease severity and post-acute outcomes has yet to be discovered. Therefore, it is of great importance on a global scale to identify useful biomarkers for this infection that will allow pediatricians to cost-effectively predict the clinical course of the disease, as well as monitor the efficacy of new therapeutic strategies.

Worldwide, the human respiratory syncytial virus (hRSV) is the leading cause of infant hospitalization because of acute respiratory tract infections, including severe bronchiolitis and pneumonia. Despite intense research, to date there is neither vaccine nor treatment available to control hRSV disease burden globally. After infection, an incubation period of 3-5 days is usually followed by symptoms, such as cough and low-grade fever. However, hRSV infection can also produce a larger variety of symptoms, some of which relate to the individual's age at infection. Indeed, infants can display severe symptoms, such as dyspnea and chest wall retractions. Upon examination, crackles and wheezes are also common features that suggest infection by hRSV. Additionally, infection in infants younger than 1 year is associated with several non-specific symptoms, such as failure to thrive, periodic breathing or apnea, and feeding difficulties that usually require hospitalization. Recently, neurological symptoms have also been associated with hRSV respiratory infection and include seizures, central apnea, lethargy, feeding or swallowing difficulties, abnormalities in muscle tone, strabismus, abnormalities in the CSF, and encephalopathy. Here, we discuss recent findings linking the neurological, extrapulmonary effects of hRSV with infection and functional impairment of the CNS.