Dataset: 11.1K articles from the COVID-19 Open Research Dataset (PMC Open Access subset)
All articles are made available under a Creative Commons or similar license. Specific licensing information for individual articles can be found in the PMC source and CORD-19 metadata.
More datasets: Wikipedia | CORD-19
Deep Learning Technology: Sebastian Arnold, Betty van Aken, Paul Grundmann, Felix A. Gers and Alexander Löser. Learning Contextualized Document Representations for Healthcare Answer Retrieval. The Web Conference 2020 (WWW'20)
Funded by The Federal Ministry for Economic Affairs and Energy; Grant: 01MD19013D, Smart-MD Project, Digital Technologies
Mumps typically begins with a prodrome of low-grade fever, myalgias, anorexia, malaise and headache. Over the next 1–3 days, the patient develops earache and tenderness over the parotid gland, which becomes noticeably enlarged and painful (Figure 1). Parotitis is typically seen in 31–65% (with some authoritative texts citing 60–70%) of cases of mumps infection. In about three quarters of patients, the other parotid gland becomes involved.12,13 The parotitis is nonsuppurative and typically progresses for about three days and lasts for approximately one week.13 Patients often have trismus and have difficulty chewing and speaking. In about 10% of cases, other salivary glands, especially the submandibular gland, can become involved and can mimic anterior cervical lymphadenopathy.
In post-pubertal males, the most common complication of mumps infection is orchitis. In the era prior to the advent of the MMR vaccine, orchitis occurred in between 12% to 66% of post-pubertal males with mumps. In the post-vaccination era, orchitis has been reported in 15% to 40% of post-pubertal males.12 Orchitis typically occurs about 10 days after the onset of parotitis, although it can be seen up to six weeks later. Orchitis is typically unilateral, but bilateral orchitis manifests in 15–30% of cases.13 Orchitis may be accompanied by epididymitis up to 85% of the time.17
Mumps orchitis can lead to a range of testicular complications. True infertility following mumps orchitis is rare but subfertility has been seen in up to 13% of patients. Subfertility can occur even without accompanying testicular atrophy.7, 18–20 Testicular atrophy (any reduction in testicular size) occurs in 30–50% of patients with orchitis.6 Abnormalities of spermatogenesis have been observed to occur in up to half of patients for up to three months after recovery from the acute illness.20 Mumps orchitis and subsequent testicular atrophy have been weakly associated with the development of testicular tumors, including cancer, with an incidence of 0.5%.7, 21, 22
Other complications of mumps infection include meningitis, which may occur in up to 10% of cases. When meningitis does occur, it is typically seen 3–4 days after the onset of parotitis.6 Acute encephalitis and encephalomyelitis are rare. When acute encephalitis due to mumps occurs, it is typically self-limiting. Acute encephalomyelitis, on the other hand, tends to be much more severe. Case fatality rates for acute encephalomyelitis due to mumps virus are up to 10%, while the overall case fatality rate due to CNS complications from mumps virus has been reported to be about 1%.23
Sensorineural hearing loss is another CNS complication of mumps infection. Permanent unilateral hearing loss has been reported to occur in 1 of every 20,000 cases. Bilateral hearing loss is much less frequent. Other rare CNS complications include Guillain Barre Syndrome, transverse myelitis, facial palsy, cerebellar ataxia and flaccid paralysis.7
Oophoritis (ovarian inflammation) has been reported to occur in 5% of post-pubertal females. Symptoms of oophoritis may include lower abdominal pain, vomiting and fever. Long-term sequelae of oophoritis, while rare, may include infertility or premature menopause. Mastitis (breast inflammation) has also been reported as a complication of mumps infection in post-pubertal females.7 In some studies, mumps infection in early pregnancy has been linked with spontaneous abortion, with one study identifying a 27% rate of fetal death after first trimester mumps infection compared with 13% in a control group.7, 24 A second, more recent study has not shown the same association between spontaneous abortion and mumps infection in early pregnancy.25 As of early 2016, there is no reported association between perinatal mumps infection and significant congenital malformations.7
Other rare complications associated with mumps infection include pancreatitis (with rare reported cases of severe hemorrhagic pancreatitis), ECG abnormalities (depressed ST segments, prolonged PR intervals and inverted T waves), myocarditis, polyarthritis, abnormal renal function (with rare reports of severe or fatal nephritis), hepatitis, acalculous cholecystitis, kerato-uveitis, hemophagocytic syndrome and thrombocytopenia.7 (Table)
Vaccines remain one of the greatest accomplishments of human ingenuity, scientific endeavor, and the combined global efforts of the public health community. The rates of incidence and mortality associated with infection by RNA viruses such as polio, measles, mumps and rubella have declined by greater than 95% compared to pre-vaccination rates. Though highly successful in the past, conventional approaches to RNA virus vaccine development, such as live-attenuation through passaging (forward genetics) or inactivation, may be less efficient for generating good candidates than rational targeted mutagenesis (reverse genetics). Advancements in recombinant DNA technology and virus reverse genetics have provided key critical insights into the replication and pathogenesis of RNA viruses and facilitate vaccine development through targeted modifications and directed attenuation. The advent of reverse genetics and molecular engineering of viruses has transformed the field of virology by permitting study of targeted genetic changes in virus genomes. In 1981, the first infectious RNA virus clone was isolated from cDNA to generate poliovirus. Since then, reverse genetics technology and recombinant virus design has been employed to generate reverse genetic clones representing all major virus families. In addition, these techniques and approaches have now become the focus of new efforts to design vaccines that incorporate specific changes in either component-based or virus-based systems to induce lasting immunity in the host without health risks or deleterious effects.
Since the development of effective live-attenuated vaccines, new vaccine preparations utilizing well-established vectors, expression of specific viral proteins or components (subunit vaccines), and development of virus-like particles (VLPs), have continued to shape the domain of vaccine discovery and development. The challenge of establishing a safe, immunogenic platform, which induces lasting immunity in the context of a wide variety of viral systems, has resulted in remarkable creativity and variability in the approaches employed. Use of replicating viruses in vaccines, such as live-attenuated or chimeric vector-based platforms, have the benefits of high immunogenicity, lower costs, and ease to transport and administer. Yet, these viruses have the potential to revert to more pathogenic phenotypes and may be under-attenuated in immunocompromised hosts. Conversely, component, subunit, or killed pathogen vaccines have the benefits of generally being safer and can be used to display the most immunogenic antigens. However, the costs, time of development, and weaker induced immune responses present their own challenges to design and implementation. In this review, we describe RNA virus reverse genetics systems and provide an overview of current efforts to use reverse genetics technology in the development of safe and effective vaccines.
Coronavirus 2019-nCoV infection commonly presents with signs and symptoms of pneumonia or as a nonspecific lower respiratory illness, with coughing or difficulty breathing accompanied by fever.5,19,20 Fever and cough constitute the most common presentations. However, patients may have other respiratory symptoms, sore throat, nasal congestion, malaise, myalgia, and headache. Bilateral infiltrates may be seen on chest X-ray. Severe cases may present with sepsis and even shock. Conversely, some patients may present as only mildly ill or asymptomatic altogether.21 To date, patients with underlying medical conditions and the elderly are more likely to become severely ill, require hospitalization, and ultimately die.22 Early predictions for incubation time are between 2 and 14 days, based on data from similar coronaviruses. The 14-day criterion for epidemiological risk assumes the longest estimated incubation time.23 In addition, the World Health Organization (WHO) has created its own interim case definition.24
Bats are considered a reservoir of severe emerging infectious diseases. Severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), Nipah virus, Hendra virus, and Ebola virus are all thought to be bat-borne viruses1,2.
Notably, bats also host major mammalian paramyxoviruses from the family Paramyxoviridae, order Monone-gavirales3,4. While Henipaviruses (Nipah and Hendra viruses) in South East Asia and Australia are associated with fruit bats5, other paramyxoviruses have been detected not only in fruit bats but in insectivorous bats worldwide6–9. A potential pathway for Nipah virus transmission from bats to humans was found to be associated with a human-bat interface, specifically date palm sap shared by bats and humans10. In addition, serological evidence of possible human infection with a bat-originated paramyxovirus, Tioman virus11, reinforces the epidemiological role of bats in the emergence of pathogens such as paramyxoviruses in humans.
In addition to these bat paramyxoviruses with zoonotic potential, other new paramyxoviruses have been reported. These include several new mammalian paramyxoviruses such as Beilong virus and J virus, which remain unassigned under the family Paramyxoviridae12. Recent bat-associated paramyxoviruses were proposed to be grouped in a separate phylogenetic clade within a potentially separate genus such as Shaanvirus13 which was distantly related to Jeilongvirus14. In addition, novel strains of bat paramyxoviruses in diverse genera have been reported continuously15–17. Based on the recent papers, bat paramyxoviruses found worldwide to date have belonged to the genera Rubulavirus, Morbillivirus, Henipavirus and the unclassified proposed genera Shaanvirus. Expanded classifications for grouping newly identified viruses in bats can be accomplished by further studying the biological characteristics of novel paramyxoviruses as well as genome characterization18.
In this study, active surveillance was performed to reveal paramyxoviruses circulating in Korean bats. A total of 232 bat samples were collected at 48 sites in natural bat habitats and tested for the possible existence of paramyxoviruses.
Ohio led the United States in measles cases in 2014, ostensibly and directly related to unvaccinated international air travelers (Ohio Department of Health, 2015). Researchers have validated concerns that Ohio scored lower than 43 other states in being prepared for infectious disease outbreaks (Trust in America's Health, Robert Wood Johnson Foundation, news release, Dec. 17, 2015). These researchers have urged efforts to protect Americans from “new threats such as Middle East respiratory syndrome coronavirus (MERS-CoV) and antibiotic-resistant superbugs, along with resurging diseases such as tuberculosis, whooping cough and gonorrhea.” These concerns over emergent diseases led us to review the literature of infectious diseases with adequate travel histories and to conduct a retrospective cohort study of the risk to Ohio's population including a nested case control study to explore the association between infectious disease risk and air travel. The methodological reasons for selecting malaria, seasonal influenza hospitalizations (IH), and hepatitis A (HA) among the diseases reviewed will be discussed. HA virus is highly contagious and can affect liver function. HA is transmitted frequently through contaminated food and water. The World Health Organization (WHO) estimates that there are over 1.3 million cases of acute HA every year. Influenza disease is caused by a virus that attacks the respiratory system. Symptoms include sudden onset of fever, body aches, fatigue, and cough. Pneumonia can be a complication of influenza, especially in the persons with weakened immune systems. WHO estimates that over 3 million persons are hospitalized and over 250,000 persons die each year from influenza.
Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder of the central nervous system, which typically follows acute viral or bacterial infection or vaccination. ADEM is characterized by widespread demyelination that predominantly involves the white matter of the brain and spinal cord. Numerous infectious agents, mostly nonspecific upper respiratory tract infections, have been linked to ADEM. Hepatitis virus is a rare cause of ADEM. One case of hepatitis C virus (HCV) and two cases of hepatitis A virus with ADEM have been reported.1-3
We report a case of ADEM associated with HCV infection. This is the first case of ADEM with anti-HCV antibody in the cerebrospinal fluid (CSF).
Viruses, which consist of nucleic acid encased in a protein shell, are parasites of host organisms. The term ‘virus’ comes from the Latin word ‘venom’, which means poison, because a virus is generally considered to be a causative agent like a poison that causes infectious diseases. These tiny, living entities have considerable import, because they can cause substantial damage to humans and non‐human animals and other living organisms. The relationship between humankind and viruses has a long history. For example, the earliest evidence of smallpox was found in 3000‐year‐old Egyptian mummies, who had smallpox‐like eruptions on their skins.1 The overall mortality rate of smallpox was around 30%,2 making it one of the most feared infectious diseases. In 1918–1919, during World War I, influenza A virus caused the Spanish flu pandemic, resulting in infection of approximately 500 million people and more than 20–40 million death worldwide.3
Since the initial isolation of viruses in the 19th century, scientists have identified and characterised a wide variety of viruses, and the field of virology has progressed remarkably since then, enabling us to combat the frequently deadly effects of these viruses. One of the greatest achievements is the complete eradication of smallpox. Although smallpox was once rampant in the world, vaccination of the entire population has eradicated this disease.1 Similarly, the poliovirus vaccine has significantly reduced the incidence of poliomyelitis.4 Despite the progress of virology, we still have many unconquered viral diseases and we are confronted with the problem of emerging infectious diseases, which are caused by newly identified species or strains. For example, Ebola virus disease and acquired immunodeficiency syndrome emerged in 1976 and 1981, respectively,5, 6, 7, 8, 9 and more recently, severe acute respiratory syndrome (SARS), highly pathogenic avian influenza viruses and Middle East respiratory syndrome (MERS) have appeared in human society.10, 11, 12, 13, 14, 15 Therefore, it is important to continue studying the mechanisms of viral replication and pathogenicity.
Yet, these negative aspects of viruses do not tell the whole story since the relationships between hosts and viruses are multitudinous, and virus infections do not necessarily lead to disease symptoms in hosts. Rather, recent studies suggest that there are viruses that are beneficial to the biological functions and/or evolution of their hosts. Recently, we established a research consortium, designated as ‘Neo‐virology’, which is supported by Grants‐in‐Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Science, Sports, and Technology (MEXT) of Japan. In this consortium, we define a virus as a component of the global ecosystem. Our aim was to elucidate the roles of viruses in host organisms and the global ecosystem, in contrast to traditional virology research, which tends to focus on pathogenic viruses that cause diseases in their hosts. This research project is expected to develop into an important scientific field that examines the interactions between the global ecosystem and viruses. In this brief review, we give some insights into the positive side of viruses.
We performed metagenomic sequencing and enterovirus genome assembly using methods developed and validated by our group [1, 2]. Full methods are described in the Supplementary Appendix.
In the article titled “A Rare Cause of Childhood Cerebellitis-Influenza Infection: A Case Report and Systematic Review of Literature”, Dr. Candan Çiçek was missing from the authors' list. The corrected authors' list is shown above.
Additionally, there were errors in the Case Representation section which should be corrected as follows:“CSF cultures were bacteriologically sterile. Polymerase chain reaction [PCR] assays of CSF for influenza virus, herpes simplex virus 1 and 2, adenovirus, enterovirus, cytomegalovirus, human herpesvirus- 6, epstein-barr virus, and varicella zoster virus were all negative” should be corrected to “Multiplex polymerase chain reaction [PCR] assays of CSF for herpes simplex virus 1 and 2, adenovirus, enterovirus, cytomegalovirus, human herpesvirus-6 and -7, Epstein-Barr virus, varicella zoster virus, parechovirus, parvovirus B19 (Neuro 9 Detection, Fast Track Diagnostic, Malta) and influenza virus type A and B, parainfluenza virus, adenovirus, respiratory syncytial virus, human metapneumovirus, human bocavirus, human coronavirus, enterovirus, and rhinovirus (Allplex Respiratory Panel Assays, Seegene, South Korea) were all negative.”“Serologic tests of his blood showed negative results for epstein-barr virus, herpes simplex virus, varicella-zoster virus, cytomegalovirus, measles, mumps, rubella, and mycoplasma pneumoniae. Respiratory viruses such as adenovirus, rhinovirus, respiratory syncytial virus, parainfluenza virus, human bocavirus, human metapneumovirus, and coronavirus were not detected in the nasopharyngeal swab specimen by multiplex PCR. However, we identified influenza A H1N1 virus on the third day of the onset of the symptoms, which was when we started treatment with oseltamivir as 4 mg/kg orally twice a day. The patient was diagnosed with influenza-associated cerebellitis based on the clinical findings” should be corrected to “Serologic tests of his blood showed negative results for Epstein-Barr virus, herpes simplex virus, varicella zoster virus, cytomegalovirus (Vidas®, bioMerieux, France), measles, mumps, rubella, and mycoplasma pneumoniae (Diesse Chorus ELISA, Italy). Respiratory viruses including adenovirus, rhinovirus, respiratory syncytial virus, parainfluenza virus, human bocavirus, human metapneumovirus, and coronavirus were not detected in the nasopharyngeal swab specimen by multiplex PCR (Allplex Respiratory Panel Assays, Seegene, South Korea).”
Seasonal trends, possibly related to epidemic infections, have been described in the diagnosis or relapse of Graves' disease with higher rates in spring and summer. Geographical differences have also been described in England in the incidence of Grave's disease which could be an indirect sign of environmental factors.
More surprinsigly, month of birth was studied in 664 patients with Hashimoto's hypothyroidism and in 359 patients with Graves' hyperthyroidism. Patients had a distinct pattern of distribution for month of birth compared with the general population. These differences point towards a a seasonal viral infection as the initial trigger in the perinatal period, the clinical disease resulting from further specific damage over time.
Rubella virus (RV) is an enveloped, single-stranded, positive-sense RNA virus in the Rubivirus genus, which has been recently moved from the Togaviridae to a new family, Matonaviridae. A total of 13 RV genotypes, which represent 2 clades, have been recognized, but 2 genotypes, 1E and 2B, are currently the most common worldwide. RV replicates at low levels and produces little cytopathology both in vitro and in vivo. A distinct feature of RV is the ability to persist in the placenta and fetus and in immune privileged body sites of immunologically competent individuals [2, 3]. Persistent RV infection is associated with a congenital rubella syndrome (CRS) and a number of less common pathologies such as rubella encephalitis and Fuchs uveitis [4, 5]. The live attenuated vaccine strain, RA27/3 (a virus from the likely extinct 1a genotype and a part of the MMR vaccine), is currently used in the US and globally. It has high immunogenicity, generates long-term immunity after a single dose, is effective in preventing clinical disease, and has a very low rate of adverse events. Worldwide, implementation of rubella vaccination programs has resulted in elimination of rubella and CRS from the Americas and significant reduction in the burden of disease in some developed countries. Similar to wild type RV, RA27/3 can persist in immunologically competent individuals for a limited time causing mild complications, such as transient arthralgia or arthritis in adult women. The vaccine virus involvement in the pathology of Fuchs uveitis is also suspected [5, 9]. The vaccine virus has not been associated with congenital defects, but asymptomatic persistent infections of the fetus have been reported after inadvertent vaccination of unknowingly pregnant women.
Primary immunodeficiency diseases (PID) are a group of hereditary disorders affecting different arms of the immune system. PID patients usually have increased susceptibility to infections and have difficulties eliminating pathogens. Live vaccines, including rubella vaccine, are contraindicated for individuals with severe antibody deficiency, T-cell deficiencies or innate immune defects because they may cause severe or chronic disease. Unfortunately, PID diagnosis often occurs after vaccination with MMR (usually given at the age of 12–15 months). Nevertheless, adverse outcomes related to MMR vaccination of children who are diagnosed with PID are thought to be rare.
Granuloma formation, a well-recognized disease in PID patients, is an accumulation of histiocytes and other immune cells near sites of chronic infection, which may persist for years sometimes resulting in significant pathology. The estimated granuloma prevalence in PID patients is 1–4% and thus ~4,000 individuals in the US are expected to be affected. RV antigen and RNA have been recently found in association with granulomas at various body sites (skin, liver, kidney, spleen, lung and bone periosteum) in children with a broad spectrum of PIDs [16–19]. RV positive cutaneous granulomas have been reported to develop 2–152 weeks (average 48 weeks) after MMR vaccination typically near the vaccination site, but can also appear at other body sites, e.g., face or legs, and then slowly spread. Prominent T cell deficiencies, often with concurrent antibody deficiencies, are common characteristics of PID patients with RV positive granulomas [17, 19]. Immunohistochemical analysis of granulomatous lesions revealed that M2 macrophages in the center of granulomas most commonly harbored RV antigen. Previously, mutated RA27/3 RNA was detected in a few cases but sequencing data were limited [16, 17]. As a result, little was known about the evolution of the vaccine virus during persistent infection in PID patients.
Our initial attempt to isolate infectious virus from the RV-positive skin granuloma of a single PID patient failed. Accumulated deleterious mutations in the vaccine virus after a 22-year-long persistence in this case may have caused loss of infectivity of that virus. However, it was unclear whether loss of infectivity is a common feature of RA27/3-derived viruses within PID patients or a characteristic of vaccine virus evolution within that particular patient.
Here we report the isolation of infectious immunodeficiency-related vaccine-derived rubella viruses (iVDRV) from the skin biopsies of four PID patients collected at different times after vaccination. We have determined full genomic sequences of these iVDRV and characterized the changes relative to the parental RA27/3 virus with the objective of characterizing the RA27/3 evolution during persistent infection in PID patients. The replicative and persistence properties of the recovered iVDRV were compared with those of RA27/3 and wild type RV (wtRV) in WI-38, the primary human fibroblasts used to culture RA27/3 during attenuation. This study also documents iVDRV detection in nasopharyngeal secretions raising the possibility of transmission of iVDRV strains to susceptible non-immune contacts.
Following on from the discovery of tobacco mosaic virus in 1892 and foot-and-mouth disease virus in 1898, the first ‘filterable agent’ to be discovered in humans was yellow fever virus in 1901. New species of human virus are still being identified, at a rate of three or four per year (see below), and viruses make up over two-thirds of all new human pathogens, a highly significant over-representation given that most human pathogen species are bacteria, fungi or helminths. These new viruses differ wildly in their importance, ranging from the rare and mild illness due to Menangle virus to the devastating public health impact of HIV-1.
In this paper, we take an ecological approach to studying the diversity of human viruses (defined as viruses for which there is evidence of natural infection of humans). First, we describe and analyse temporal, geographical and taxonomic patterns in the discovery of human viruses (§2). We then consider the processes by which new human viruses emerge (§3). There are a number of definitions of ‘emergence’; here, we are interested in all stages of the process by which a virus shifts from not infecting humans at all to becoming a major human pathogen. As experiences with HIV-1 and new variants of influenza A (and also with novel animal pathogens such as canine parvovirus) show, this shift can occur rapidly, over time scales of decades, years or even months.
Of course, not all newly identified human virus species are ‘new’ in the sense that they have only recently started to infect humans; many of them have been present in humans for a considerable time but have only recently been recognized (see for a more detailed discussion). Moreover, we recognize that ‘species’ itself is an imprecise designation, especially for viruses such as influenza A where different serotypes can have very different epidemiologies and health impacts. Indeed, the demarcation between genus, species complex, species and serotype (or other designations of sub-specific variation) can be somewhat arbitrary. Nonetheless, a study of currently recognized ‘species’ is a natural starting point for attempts to characterize and interpret patterns of virus diversity.
A 47-year-old woman was admitted to our hospital for dysarthria and left-sided hypesthesia. She had no history of recent febrile illness or vaccination. Two weeks after the first symptoms, she developed right-sided weakness. On admission, she had no fever and normal blood pressure. Electrocardiography and chest X-ray were normal. Laboratory tests showed that anti-HCV antibody was positive and HCV RNA titer was highly elevated (1,660,000 IU/mL). AST and ALT were also mildly elevated (34/44 IU/L). Her medical history revealed that she had blood transfusion during Cesarean section about twenty years ago. She had no symptoms of hepatitis. Serologic tests, including viral markers, showed nothing significant. Levels of anti-cardiolipin antibody, anti-nuclear antibody, and anti-neutrophil cytoplasmic antibody were also normal. Cancer antigen 19-9, was mildly elevated (27.7 U/mL; normal range, 0.8-24.0 U/mL). The CSF examination showed three white blood cells with mildly increased protein (53 mg/dL; normal range, 15-45 mg/dL), normal IgG index, and no IgG oligoclonal bands. CSF anti-HCV antibody was positive. Magnetic resonance imaging (MRI) of the brain and spine revealed multifocal high signal intensity lesions on fluid attenuated inversion recovery and T2-weighted images in the brainstem, thalamus, and cervical and thoracic spinal cord (Fig. 1). Some lesions showed enhancement after gadolinium administration.
Treatment with intravenous methylprednisolone, 1 g daily for 5 days, was instituted. The intravenous methylprednisolone was changed to oral prednisone, 60 mg for 1 week, and then reduced to 10 mg per week. Two weeks after steroid treatment, neurologic symptoms and spine MRI improved further. However, brain MRI had no significant interval change. Follow-up HCV RNA titer increased about three-folds (4,900,000 IU/mL). Liver biopsy demonstrated stage 2 of fibrosis. It was reasonable for chronic C viral hepatitis. At discharge two months after admission, neurologic symptoms and spine and brain MRI (Fig. 2) improved. Her neurologic examination was nearly normal except left side limb ataxia.
A previously healthy man in his 20s developed unilateral testicular pain and swelling. Four days later, he developed headache and fever. He presented to our institution, where he was febrile to 102.7°F with mild meningismus; testicular swelling and tenderness had resolved. The combination of symptoms raised concern for mumps in the setting of a local outbreak, although parotitis was absent. Cerebrospinal fluid (CSF) analysis showed 17 total nucleated cells/µL (79% neutrophils, 12% monocytes, 9% lymphocytes), glucose of 65 mg/dL (serum glucose of 109 mg/dL), and total protein of 31 mg/dL. He was treated empirically with vancomycin, ceftriaxone, and acyclovir. Cerebrospinal fluid enterovirus polymerase chain reaction (PCR) was positive, antimicrobials were discontinued, and the patient recovered fully. Mumps serology was positive for immunoglobulin (Ig)G and negative for IgM, consistent with his reported history of vaccination. A urine culture for mumps performed by the Massachusetts Department of Health State Laboratory was negative. Cerebrospinal fluid Gram stain and culture were negative, as were CSF herpes simplex virus 1 and 2 PCR, Lyme PCR, and testing for syphilis via the Venereal Disease Research Laboratory test. Given the relatively unusual presentation of orchitis and meningitis, we performed metagenomic sequencing to obtain additional genomic information about the particular strain of enterovirus and to identify any potential copathogens including mumps virus.
Neurologic symptoms of ADEM commonly appear 4 to 13 days after the infection or vaccination1-3). Fever, headache, vomiting, and meningismus are often seen at the time of initial presentation and may persist during hospitalization2,18). Encephalopathy is a characteristic feature and may progress rapidly in association with multifocal neurologic deficits4). Progression of initial neurologic signs to maximum deficits usually occurs within 4 to 7 days1,3). The level of consciousness ranges from subtle lethargy to frank coma. The altered mental status often raises concern regarding the risk of seizures, although these occur in only one-third of patients3,19).
In addition to encephalopathy, the most common neurologic features of ADEM include long tract (pyramidal tract) signs, acute hemiparesis, cerebellar ataxia, cranial neuropathies, including optic neuritis, and spinal cord dysfunction (transverse myelitis)2-4,18,19). Symptoms of optic neuritis include vision loss, pain with eye movement, and an afferent pupillary defect. Inflammation of the optic disc may be seen by direct funduscopic examination if there is extensive involvement of the optic nerve. The imaging of the optic nerve with a gadolinium-enhanced MRI of the brain and orbits is a more sensitive means to diagnose optic neuritis in these patients. Symptoms of transverse myelitis include flaccid paralysis of the legs with a change in sensory level on examination. Bowel and bladder involvement secondary to spinal cord disease results in constipation and urinary retention. The arms can be involved if the demyelinating lesion affects the cervical cord. Respiratory failure may appear with high cervical lesions that extend into the brainstem. Aphasia, movement disorders, and sensory deficits are unusual. The severe phase of ADEM generally lasts from 2 to 4 weeks. Children may show deterioration in their condition after hospital admission, and most of them develop new neurologic signs. Patients usually recover completely from the acute illness, although some have neurologic sequelae.
MS is a clinical diagnosis and is characterized by spatially and temporally distinct recurrent episodes of demyelination in the CNS. Acute inflammation and demyelination in a critical area of the brain, optic nerves, or spinal cord can induce a corresponding neurologic deficit. There are no clinical signs that are unique to this disorder, but some are highly characteristic (Table 1)20). Common symptoms of MS are listed in Table 220). A European observational study of 394 children with pediatric-onset MS and 1,775 patients with adult-onset MS showed that children were more likely than adults to present with isolated optic neuritis, an isolated brainstem syndrome, or symptoms of encephalopathy17).
A clinically isolated syndrome (CIS) is defined as a single monosymptomatic attack compatible with MS, such as optic neuritis. An episode of CIS can produce diagnostic and therapeutic dilemmas (Fig. 1), since the vast majority of children will not have a recurrence after a single demyelinating event of the CNS. The value of examinations, including brain MRI, cerebrospinal fluid (CSF) analyses, and other laboratory studies to identify those at high risk of recurrence, is unclear21).
Fetuses and neonates are susceptible to a wide variety of viral infections most commonly involving the central nervous system (CNS) in greater frequency than adults (81). Infections of the CNS are a very common worldwide health problem in childhood with significant morbidity and mortality. In children, viruses are the most common cause of CNS infections, followed by bacteria, and less frequently by fungi and other causes. Advances in the prenatal and perinatal care together with technological advent of imaging modalities have enabled timely detection and detailed exploration of symptoms and signs in the neonatal population starting from the fetal life. Although imaging is practically unable to set the diagnosis of viral infection in the fetuses and neonates, moreover to reveal the pathogens, it has, however, the potential to accurately suggest this scenario, map the extent of involvement and direct the investigation and the consultation accordingly. Additionally, it may reveal complications from viral infections that may cause confusion and usually require special treatment (81).
Some imaging findings are highly suggestive of CNS viral infections in fetuses and neonates (82). Familiarity with the clinical course, the route of transmission and the imaging appearances usually proves helpful in reaching the correct diagnosis and in prompting timely treatment. In general, sequelae of an intrauterine infection reflect a combination of the pathogens and the stage of fetal development at which the exposure occurred (83). Congenital infections, occurring during the second and third trimester, may persist in the neonate affecting its general and neurologic status (83). However, as a rule of thumb, the later the diagnosis of congenital infections is made, the more difficult it is to identify the agent. Additionally, the imaging findings may become non-specific and less conspicuous as incomplete white matter myelination may interfere (83).
If maternal viral infection is suspected, combining prenatal ultrasound and fetal magnetic resonance imaging (MRI) may document the extent of tissue damage and therefore contribute to treatment and counselling (84). Neonatal head ultrasound, sometimes computed tomography (CT), but mainly MRI (Figs. 1 and 2) may reveal sequelae from congenital viral infections (i.e., microcephaly, dystrophic periventricular calcifications, brain atrophy), which may even suggest the causative virus, such as cytomegalovirus (CMV) (85). In previously healthy neonates with viral infection, the imaging investigation of CNS begins with head ultrasound and if further imaging investigation is required, MRI is the modality of choice, even in an emergency setting (86). Non-complicated meningitis is easier to be recognised clinically; however, since complications of meningitis, such as abscesses, infarcts, venous thrombosis, or extra-axial empyemas are difficult to diagnose clinically, imaging plays a crucial role (87).
Viral neonatal and paediatric infections are characterised by a great heterogeneity of clinical manifestations and are considered as major causes of neonatal and paediatric morbidity and mortality (1). Almost 50 years ago, Paediatric Virology was not considered an isolated discipline and was included in the Paediatric Infectious Diseases section of the scientific field of Paediatrics (2,3). However, during the past two decades, new advances in the field of Clinical Virology and Molecular Medicine have expanded the level of knowledge on the prevention, diagnosis and treatment of viral infections occurring in infancy and childhood (4,5). These developments and changes highlight the demand for undergraduate and postgraduate medical education in Paediatric Virology, which combines Paediatrics with Virology, Epidemiology, Molecular Medicine, Evidence-based Medicine, Clinical Governance, Quality Improvement, and Pharmacology and Immunology (5).
The 3rd Workshop on Paediatric Virology was entitled ‘Paediatric Virology: Interaction between basic science and clinical practice’. It was held on October 7th, 2017 in Athens, Greece, as an official session of the 22nd World Congress on Advances in Oncology and the 20th International Symposium on Molecular Medicine. Its aim was to bring together virologists and paediatric health professionals and encourage them to collaborate as an international network to promote paediatric health. Moreover, during the workshop, Nobelist laureate Professor Harald zur Hausen, Emeritus Professor of Virology at the University of Freiburg in Germany, who received the 2008 Nobel Prize in Physiology or Medicine for his discovery of human papilloma viruses (HPVs) causing cervical cancer and Professor Anne Greenough, Professor of Neonatology and Clinical Respiratory Physiology at King’s College London, UK and Vice President of Science and Research at the Royal College of Paediatrics and Child Health (RCPCH), were honoured by the Paediatric Virology Study Group (PVSG) for their indisputable academic, research and publishing contribution to Paediatric Virology.
The present review provides an overview on the wealth of new material from different areas of neonatal and paediatric viral infections presented and discussed during the workshop. Interestingly, 7 out of the 10 top key messages (Table I) of our meeting, as well as both statements of Nobelist laureate Professor Harald zur Hausen, on the occasion of this workshop (Table II), included recommendations on specific prevention strategies against viral infections. Along with the significant role of human breast milk and respiratory syncytial virus (RSV) prophylaxis, these issues included the necessity of the vaccination policy in relation to the migration crisis, prevention of hepatitis in newborns, recent advances on influenza vaccines, male vaccination against HPVs and the the preventative role of probiotics in the management of viral infections in children.
The first descriptions showed a tendency for the disease to follow upper respiratory tract infections or sore throats, which explained why a viral infection has most often been implicated as the cause. Clusters of the disease have been reported during outbreaks of viral infection. Onset of the disease are observed between June and September and this seasonal distribution is almost identical to that of established infections due to some enteroviruses (Echovirus, Coxsackievirus A and B), suggesting that enterovirus infections might be responsible for a large proportion of cases.
An association between subacute thyroiditis and HLA B35 is noted in all ethnic groups tested and two-thirds of patients manifest HLA-B35. Familial occurrence of subacute thyroiditis and recurrence during the course of time are associated with HLA B35. Thus, the onset of subacute thyroiditis is genetically influenced and it appears that subacute thyroiditis might occur through a susceptibility to viral infection in genetically predisposed individuals. HLA-B35 has been reported to be correlated with chronic active hepatitis, with hepatitis B, with rapid progression of AIDS and with the T lymphocyte responses against human parvovirus B19. Recently, the medical records of 852 patients with subacute thyroiditis have been studied. The significant seasonal clusters of subacute thyroiditis during summer to early autumn was confirmed. According to the authors, "the history of patients showed no obvious association with virus infection". Unfortunately, no data on infections are available in the paper.
Bats are the source of multiple zoonotic viruses including severe acute respiratory syndrome (SARS) coronavirus, Hendra virus, Nipah virus, and Marburg virus. In fact, evidence suggests that bats host a greater proportion of zoonotic viruses than any other mammalian order, highlighting the importance of identifying novel viruses in bats. Australian pteropid bats are becoming more urbanized and fewer bats are migrating, resulting in a greater chance of contact between bats and humans or domestic animals. This increased potential for exposure of non-reservoir hosts to bat-borne viruses leads to the increased probability of infection spillovers occurring.
Isolation and phenotypic characterization should be critical components of virus discovery programs because the analysis of novel viral sequences is not currently enough to predict the likelihood of that virus causing a zoonotic disease event. The likelihood of viral emergence and sustained human-human transmission is influenced by many factors. In addition to environmental factors and host behaviors, specific viral traits and host-pathogen interactions play important roles. For example, low viral pathogenicity resulting in low host mortality influences opportunities for sustained viral transmission; viral tissue tropism and host immune responses determine shedding at sites relevant to transmission; and the establishment of chronic or latent infection may allow for sustained or recurrent viral shedding.
Paramyxoviridae is a family of negative strand RNA viruses currently comprising seven genera—Rubulavirus, Henipavirus, Respirovirus, Morbillivirus, Ferlavirus, Aquaparamyxovirus and Avulavirus. PCR and virus isolation have been used to identify many paramyxoviruses in bats globally, in particular, henipaviruses and rubulaviruses. The genus Rubulavirus contains the human pathogens parainfluenza virus 2 (hPIV2) and mumps virus (MuV), as well as bat-borne viruses such as Mapuera and Menangle viruses (MapV and MenPV). Viruses within this genus have a cell attachment glycoprotein with neuraminidase and haemagglutinin capability. In addition to the cell attachment glycoprotein (HN), the rubulavirus genome also encodes a nucleoprotein (N), phosphoprotein (P), V protein, matrix (M) protein, fusion (F) protein and a large polymerase subunit (L). The unedited P gene transcript encodes the V protein, whereas the addition of two non-templated G residues by co-transcriptional stuttering of the RNA-dependent RNA polymerase is required for the expression of the phosphoprotein. MuV and parainfluenza virus 5 (PIV5) also express a short hydrophobic (SH) protein that has been associated with blockage of the TNFα-mediated apoptosis pathway.
PIV5 is most well known as one of the causative agents of Canine Infectious Respiratory Disease Complex (CIRDC), where infection results in self-limiting tracheobronchitis that resolves in 6–14 days when in the absence of any co-infections. Since the discovery of PIV5 in monkey kidney-cell culture in 1954, it has been isolated from a wide range of host species including pigs and cattle.
Here we describe the isolation of a novel rubulavirus that we have called Alston virus (AlsPV). AlsPV is closely related to PIV5 and was isolated from pteropid bat urine collected in Alstonville, New South Wales in 2011. This is the first isolation of this novel virus. This paper describes the characterisation of this virus in order to confirm its classification as a rubulavirus, as well as to determine its pathogenic potential.
Acute disseminated encephalomyelitis (ADEM) is an immune mediated disease of the central nervous system (CNS) that produces multiple inflammatory lesions in the brain and spinal cord, particularly in the white matter. ADEM should be distinguished from other central inflammatory demyelinating disorders of children, including multiple sclerosis (MS) and clinically isolated syndromes that include optic neuritis, transverse myelitis, and neuromyelitis optica (Devic's disease). Most of these disorders are thought to be caused by immune system dysregulation triggered by an infectious or other environmental agent in a genetically susceptible host.
ADEM is often preceded by a viral or bacterial infection, usually in the form of a nonspecific upper respiratory infection. In 3 previous studies, an antecedent infection was identified in 72 to 77 percent of ADEM patients1-3). In general, patients will present within 1 month of this initial illness. Numerous causative pathogens have been identified to date. Viruses that have been implicated include coronavirus, coxsackie virus, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, hepatitis A virus, human immunodeficiency virus, influenza virus, measles virus, rubella virus, varicella zoster virus, and West Nile virus4-11). Other organisms associated include Borrelia burgdorferi, Chlamydia, Leptospira, Mycoplasma pneumoniae, Rickettsia , and beta-hemolytic Streptococcus4,12).
Less than 5 percent of all ADEM cases follow immunization. Postvaccinal ADEM has been associated with immunization for rabies, hepatitis B, influenza, Japanese B encephalitis, diphtheria/ pertussis/tetanus, measles, mumps, rubella, pneumococcus, polio, smallpox, and varicella12). No infectious agent is isolated in most cases. Currently, measles, mumps, and rubella vaccination are most often associated with postvaccination ADEM. It is important to recognize the significant difference between the incidence of ADEM associated with the live measles vaccination (1 to 2 per million) and the incidence of ADEM previously associated with the measles virus infection (1 in 1,000)13).
The pathogenesis of ADEM is incompletely understood. The proposed mechanism of ADEM is that myelin autoantigens, such as myelin basic protein, proteolipid protein, and myelin oligodendrocyte protein, share antigenic determinants with those of an infecting pathogen12). This model is supported by studies of lymphocytes in children with ADEM. In 1 report, the frequency of T cell reactivity to myelin basic protein was 10 times higher in patients with ADEM than in those with encephalitis or normal controls5).
MS is usually thought to be a disease of young adults. However, pediatric MS, defined as onset of MS before the age of 16, is being increasingly recognized. MS presents before the age of 16 in approximately 5 percent of patients14,15). In less than 1 percent of patients, the onset of MS occurs before the age of 10 years16). In addition, pediatric MS affects girls more than boys, with a female to male ratio of 2.817). Since pediatric MS is rare, a child with recurrent episodes of acute neurologic symptoms and white matter lesions on magnetic resonance imaging (MRI) might be originally misdiagnosed with one of several other disorders, including leukodystrophies, vasculopathies, lymphoma, mitochondrial defects, and other metabolic disorders, rather than MS.
Clinicians working with local public health departments must arrange to have specimens from patients under investigation (PUIs) sent to the CDC laboratory. At this time, the CDC has the only laboratory that can definitively test for 2019-nCoV, though laboratory testing capacity is being rapidly expanded. Polymerase chain reaction (PCR) assays conducted on samples from a patient’s upper and lower respiratory tracts will be used to confirm potential cases. In addition, serum antibody titers can be analyzed for confirmation of infection or evidence of immunity. Up-to-date information about the needed specimens and handling requirements to test for 2019-nCoV are available on the CDC website.35
The estimated low effectiveness of malaria vaccine and dengue vaccine in the field 1,2 have disappointed a certain fraction of vaccine enthusiasts. Both vaccines offered some hope in advance of the field studies, but clinical protection in infants and other groups appears to be lower than the earlier expectation based on laboratory experiments and smaller-scale clinical studies among older individuals. As part of lessons to be learnt from these unfavorable outcomes (and from success in earlier vaccines), there is a growing need to clarify what risk factors determine successful and unsuccessful vaccines 3.
Understanding common biological features among the existing (recommended) childhood vaccines, in contrast to recent unsuccessful vaccines, would be useful for designing optimal avenues for future vaccine development. Here we report the results from a simple epidemiological analysis which aimed to identify virological, pathophysiological and eco-evolutionary factors that may lead to a successful vaccine.
Acute cerebellitis which is an inflammatory process of the cerebellum is a rare, clinically isolated syndrome with varied clinical and radiological features. This neurological disorder has uncertain etiology and heterogeneous pathogenesis. However, AC is mostly considered in association with viral and bacterial infections. To our knowledge, there are few previous reports of acute cerebellitis associated with influenza, but it must be considered in patients who show acute cerebellar features during the influenza season.
When 6-week-old female C57BL/6 mice were inoculated via the intranasal and intragastric routes with 105 Tissue Culture Infectious Dose (TCID)50/mL or 102.5 TCID50/mL of bat paramyxovirus B16-40, we found no evidence of infection, i.e. no viral shedding, histopathological findings, or seroconversion.