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In the recipients of allo-HSCT, most viral infections are opportunistic and closely related with immune status. Thus, factors influencing engraftment and immune reconstitution all potentially impact viral infections. Peripheral blood stem cell transplantation is associated with fewer viral infections than bone marrow and cord blood transplantation due to better hematopoietic and immune reconstitution. Compared with HLA-match related transplantation, HLA-mismatch related and unrelated transplantation have an increasing risk of viral infections because immune reconstitution is delayed by the intensified GVHD prophylactic strategy, such as the use of ATG. GVHD may delay immune reconstitution and is considered an independent risk factor of viral infections. In addition, other factors, such as the serologic status of donors and recipients before transplantation as well as the age of recipients, may also affect the incidence of viral infections. For example, CMV-seronegative recipients receiving graft from CMV-seropositive donors are at high risk of CMV diseases. Children are high-risk population of CARVs infections.
In the recipients of allo-HSCT, the difference in the reported incidence is due in part to asymptomatic or subclinical manifestations in most of viral infections and the changing epidemiology of viruses as well as differences in diagnostic methods. Till now, large-sampled epidemiological data on overall incidence of viral infections are absent in the recipients of allo-HSCT. The limited data show that community acquired respiratory viruses (CARVs) and herpesviruses are the most common pathogens. Among the causes of CARVs respiratory tract infections, a preponderance of respiratory syncytial virus (RSV) and parainfluenza virus (PIV) are reported, followed by influenza virus and human metapneumovirus (HMPV). In herpesvirus family, the incidence of herpes simplex virus (HSV) and varicella zoster virus (VZV) infections as well as cytomegalovirus (CMV) diseases have significantly decreased because of the effective prophylaxis. The reports on human herpes virus (HHV)-6 diseases are increasing in allo-HSCT recipients.
Although viruses infecting humans had already been described since 1901 and viruses were suspected to play a role in diarrhea, it lasted until 1972, when the first virus causing gastroenteritis (norovirus) was identified in an outbreak of diarrhea in Norwalk (California, United States). Shortly after the discovery of norovirus several other viruses causing gastroenteritis were discovered: rotavirus in epithelial cells of children with gastroenteritis, astrovirus in infantile diarrhea cases, enteric adenoviruses in the feces of children with acute diarrhea, and sapovirus during an outbreak of gastroenteritis in an orphanage in Sapporo, Japan. All these viruses spread via the fecal-oral route through person-to-person transmission and are described in more detail below.
Noroviruses are part of the family Caliciviridae and outbreaks of norovirus gastroenteritis have been reported in cruise ships, health care settings, schools, and in the military, but norovirus is also responsible for around 60% of all sporadic diarrhea cases (diarrhea cases where an enteropathogen could be found), reviewed in the literature. The pathogenesis of norovirus infection has been tested in vivo. Filtrated norovirus was given to healthy volunteers after which most of them developed diarrhea. Culturing of the virus, however, has been a problem since its discovery, yet one study has recently described the cultivation of norovirus in B cells, and has revealed that co-factors, such as histo-blood antigen expressing enteric bacteria, are probably needed before enteric viruses can be cultured in vitro. Sapoviruses are also members of the Caliciviridae. There are five human genogroups of sapovirus described which account for 2.2%–12.7% of all gastroenteritis cases around the globe. Sapovirus outbreaks occur throughout the year and can be foodborne. For sapoviruses it has been described that the virus was not found before onset of an outbreak, and that it was found in 95% of the patients during an outbreak, while it declined to 50% after an outbreak, indicating that the virus introduces disease in a naturally infected host.
Rotavirus infection is the most common cause of viral gastroenteritis among children; however, parents of infected children also often become ill and as a result rotavirus is the second most common cause of gastroenteritis in adults. Studies in human volunteers have shown that infection with rotavirus causes diarrhea, results in shedding of the virus and a rise in antibody anti-virus titer after infection. Additionally, astroviruses infections are common, accounting for about 10% of all sporadic diarrhea cases. Astrovirus has been isolated from diseased people, filtrated and administered to healthy individuals after which in some of the volunteers diarrheal disease was observed and astrovirus was shed in their stools. The virus can replicate in human embryonic kidney cells and was detected by electron microscopy (EM). Adenoviruses are responsible for around 1.5%–5.4% of the diarrhea cases in children under the age of 2 years, reviewed in the literature. Of the 57 identified adenovirus types, only adenoviruses type 40 and 41 are associated with diarrhea. Next to these two types, adenovirus type 52 can also cause gastroenteritis, although it has been argued whether type 52 is actually a separate type since there is not sufficient distance to adenovirus type 41. Adenoviruses can generally be propagated in cell lines; however, enteric adenovirus 40/41 are difficult to culture, reviewed in the literature.
The majority of emerging infectious diseases that affect humans originate from animal reservoirs, predominantly wild life, including bats, rodents and birds. Norovirus is one of five genera of the family Caliciviridae and the most common non-bacterial cause of foodborne gastroenteritis worldwide. Noroviruses are currently categorized into at least seven genogroups (GI–GVII) that are further divided into more than 40 genotypes. The virus contains three open reading frames (ORFs), ORF1 encoding the polyprotein that includes the viral polymerase, and ORF2 and ORF3 encoding the major- and minor capsid protein (VP1, VP2), respectively. Recombination between ORF1 and ORF2 frequently occurs and therefore a dual nomenclature describing both the polymerase and capsid genotype is used. Viruses from genogroups GI, GII and GIV are known to infect humans. Animal noroviruses including viruses found in pigs, dogs, and cats are closely related to human strains and cluster within GII (porcine norovirus) and GIV (feline and canine norovirus), respectively. Noroviruses belonging to the other genogroups infect a broad range of hosts that includes livestock animals such as cows and sheep but also marine mammals and rodents. In the past years, an increasing number of metagenomic studies have led to the discovery of additional noroviruses in new animal hosts and it seems evident that we lack understanding of the full diversity of noroviruses and their host range. Most human infections and outbreaks are caused by viruses belonging to GI and GII. The GII.4 genotype viruses have been particularly prevalent in the past two decades, and evolve through accumulation of mutations but also by recombination. Such recombinants and other new genotypes emerge regularly but the origin of these new viruses is not well understood. This regular detection of novel strains and the reporting of human-like norovirus genotypes in stool samples of symptomatic and asymptomatic farm animals have sparked interest in the possible role of animals as potential zoonotic reservoir for these emerging strains. Antibodies directed against bovine and canine norovirus have been detected in humans suggesting some level of exposure of humans to animal norovirus. For other viruses of the Caliciviridae family, interspecies transmission has been reported including some case reports of zoonotic events between marine mammals and humans (reviewed in).
This systematic review summarizes the literature on the known animal reservoir for norovirus, the virus diversity, prevalence, and geographic distribution, as well as pathological findings associated with norovirus infections in animals. We will further discuss the existing evidence and probability of interspecies transmission including susceptibility of animals used as models in norovirus research. There are several reviews that focus exclusively on the role of mice in norovirus research; therefore, we will discuss murine norovirus only in context of surveillance of wild animals. Molluscs are an important vehicle of foodborne norovirus transmission, but do not support norovirus replication and have been reviewed elsewhere.
In the 1980s and 1990s some viral agents were identified for which the direct association with disease is less clear. Aichi viruses are members of the Picornaviridae identified in fecal samples of patients with gastroenteritis. Aichi virus infection has been shown to elicit an immune response. Since their discovery, two case-control studies were performed, but, although both studies only found Aichi virus in stools of diarrheic patients, the prevalence of Aichi virus (0.5% and 1.8%) was too low to find a significant association with diarrhea. In immuno-compromised hosts the virus is found in higher quantities and is not associated with diarrhea. Toroviruses, part of the Coronaviridae, were first identified in 1984 in stools of children and adults with gastroenteritis. Torovirus infection is associated with diarrhea and is more frequently observed in immuno-compromised patients and in nosocomial infected individuals. Retrospective analysis of nosocomial viral gastroenteritis in a pediatric hospital revealed that in 67% of the cases torovirus could be detected. However, only a limited number of studies report the detection of torovirus and therefore the true pathogenesis and prevalence of this virus remains elusive. Picobirnaviruses belong to the Picobirnaviridae and were first detected in the feces of children with gastroenteritis. Since the initial discovery, the virus has been detected in fecal samples of several animal species, and it has been shown that the viruses are genetically highly diverse without a clear species clustering, reviewed in the literature. This high sequence diversity has also been observed within particular outbreaks of gastroenteritis, limiting the likelihood that picobirnaviruses are actually causing outbreaks, as no distinct single source of infection can be identified.
Gastrointestinal (GI) symptoms are not an uncommon manifestation of an influenza virus infection. However, little is known about the GI pathogenesis of influenza viruses. It is possible that GI symptoms developed during the clinical course of influenza could either be a part of disease manifestation, due to the side effects of antibiotic treatment, or a co-infection with other diarrheal pathogens. Gastrointestinal manifestation associated with seasonal influenza has been recognised for more than 30 years. During the influenza A epidemic of 1988 in Australia several children developed hemorrhagic gastritis of varying severity after a typical Influenza-like illness (ILI). Similarly, during the two epidemics in 1973 and 1974, influenza virus B was detected in hospitalised children who had abdominal pain, often severe enough to require differentiation from acute appendicitis, as a dominant symptom. Less severe GI symptoms have been reported to occur in 20-30% of children with an influenza B infection. Early epidemiologic study of the pandemic influenza A/H1N1 2009 virus suggested that it produced diarrhea, vomiting, or both, in ≈ 25% of case-patients.
However, fecal excretion of pandemic and seasonal influenza viruses has rarely been studied, and the lack of reports of co-infection among influenza and enteric viruses is probably because of reporting bias. Consequently it remains unknown whether co-infection with influenza pathogens in patients with GI symptoms represents rare events. Previous studies reported the detection of seasonal influenza in the stools of pediatric patients presenting concurrent acute diarrhea (AD) and ILI, and in the stools of hospitalised and outpatients presenting both GI and respiratory symptoms. Influenza viral RNA was also detected in the stools of A/H1N1 2009 positive patients hospitalised due to the progression of acute gastroenteritis. Previous studies showed that the avian influenza A/H5N1 virus can be detected in stools, and the presence of this virus was further demonstrated in the biopsy of the small and large intestines of fatal cases. Other respiratory viruses have been found in stools, such as respiratory syncytial virus, SARS coronavirus, adenovirus and bocavirus. But, to our knowledge, there are no studies reporting the detection of Influenza viruses in the stools of adult patients consulting in general practice for acute diarrhea.
In the present study we aimed to investigate the presence of pandemic and seasonal influenza viruses in the stools of General Practitioners’ (GPs) adult patients presenting exclusively GI symptoms and the proportion of concurrent infections by enteric and influenza viruses by using a case control design.
It has been suggested that annual epidemics of different viral infections can interfere with each other, but clear trends over long time periods and underlying mechanisms are not known.1, 2, 3, 4 A few population‐level studies in Europe were based on observations in one respiratory season only (the 2009 H1N1 pandemic) in which the annually recurring influenza epidemic occurred relatively early. With the occurrence of several early influenza A seasons in recent years, an exploration of longer time trends of different viruses was considered useful to gain more insight in the suggested relationship between circulating viruses. Understanding viral shifts and potential drivers thereof is relevant for further understanding whether certain viruses might promote or inhibit (pandemic) influenza spread and whether influenza vaccination could potentially affect trends in other respiratory viruses.
In Europe, influenza epidemics generally occur in winter, with the official start of the epidemic when influenza‐like illness (ILI) incidence in primary care sentinel surveillance exceeds an epidemic threshold (in combination with influenza A virus detection in clinical specimens collected from a subset of those ILI patients).5 In the Netherlands, the influenza epidemic threshold has been calculated at an ILI incidence of 5·1/10 000 for minimally two consecutive weeks which is usually not exceeded before the turn of the year,5, 6, 7, 8 but the timing of the first exceedance (i.e., start of the epidemic) can vary between November and March (based on data from 1970 to 2006).9 An extremely early influenza season was the 2009/2010 season when the influenza A(H1N1)pdm09 pandemic strain appeared and the ILI epidemic threshold was reached by early October (week 41). Such early occurrence may affect the circulation of other seasonal pathogens, and theories on possible interference between outbreaks of different respiratory viruses have been postulated to be a possible cause of delays in expected seasonal outbreaks of other respiratory viruses.1, 2, 3 While those earlier population‐level studies focused mainly on the possible interaction between influenza A virus and rhinovirus circulation, there may also be a relationship between influenza A and other prevalent viruses. Therefore, we investigated trends in several common viruses for which laboratory data were available from national surveillance in the Netherlands for a longer time period of up to 10 years including both respiratory and enteral viruses.
Various strategies, such as those using vaccines and antibiotics, have been exploited for the prevention and treatment of infectious diseases, but infection control has not yet been achieved at a sufficient level. In addition to avian influenza, severe acute respiratory syndrome, and Ebola hemorrhagic fever, many problematic diseases of tropical origin remain poorly controlled, such as dengue fever and Zika virus infection.
As climate change including global warming and the increased geographical movement of people and goods have emerged, the numbers of pathogenic virus species and affected areas have increased. Therefore, the risk of viral infection has now become a critical issue. A representative pathogenic virus, influenza virus, sometimes undergoes a process of discontinuous mutation. As a result, the efficacy of vaccines against influenza virus may become disrupted, and this phenomenon has sometimes caused pandemics. In Japan, the first case of Zika virus infection was reported in 2016. Some cases infected with dengue virus were reported in 2014 after the virus had been absent for 70 years previously. In addition, influenza and Norovirus infections often occur seasonally.
With the progress of recent immunological research, the innate immune response and the subsequently activated acquired immune response for the recognition and elimination of viruses have been unveiled. It has been reported that the process of viral elimination largely depends on the induction of type 1 interferons (IFNs), and that the regulation of inflammatory cytokines is mediated via pattern recognition receptors such as Toll-like receptors [9, 11] and retinoic-acid-inducible gene I. Studies have begun to elucidate the immunostimulatory effects of lactic acid bacteria and have reported their capacity to contribute to the prevention of viral infections including influenza as well as the treatment of Helicobacter pylori infection. As discussed in the following sections, type 1 IFNs are considered to be pivotal in mediating the protective effect of lactic acid bacteria against these infections.
In this review, we first summarize the recent preventive and therapeutic strategies against infectious diseases with special emphasis on the viral infection and then outline the possible applications of several probiotics and paraprobiotics as prophylactics or therapies against (viral) infectious diseases on the basis of published clinical trial data. Since it is very difficult to cite all studies regarding the effects of paraprobiotics or probiotics on virus infectious disease, we showed representative studies below with two criteria; 1) Single probiotics or paraprobiotics study in human clinical trial (excluded mixture of strains and animal studies), 2) Evaluation of efficacy on (viral) infectious disease.
Finally, we introduce the unique topic of immune defense mechanisms against viral infections that are induced by probiotics and paraprobiotics.
Human enteric viruses constitute a serious public health concern, since they are capable of causing a variety of acute illnesses, including the most commonly reported acute gastrointestinal illness. They are mainly transmitted via the fecal-oral route either by person-to-person contact or by ingestion of contaminated water and food, particularly shellfish, soft fruits and vegetables. Enteric viruses are shed in enormous quantities in feces (109 to 1010/g) and have an infectious dose on the order of tens to hundreds of virions. Enteric viruses are host-specific and are not capable of replicating in the environment, but they survive for long periods of time on food or food contact surfaces or in water (ground, surface, and drinking water). These characteristics enable enteric viruses to play a significant role in food- and waterborne outbreaks. Aside from noroviruses, which have been recognized as the largest cause of outbreaks, the viruses most often implicated in outbreaks include hepatitis viruses (hepatitis A virus and hepatitis E virus), rotavirus, adenovirus (40, 41), astrovirus, enterovirus [2, 3, 4, 5, 6, 7]. Additional viruses of lesser epidemiologic importance include human bocavirus, cosavirus, parvovirus, sapovirus, tick-borne encephalitis virus (TBEV), Aichi virus, and coronavirus [8, 9, 10, 11].
Tools for rapid detection of viral pathogens are important for analyzing clinical, environmental and food samples. Detection of these enteric viruses based on their infectivity is complicated by the absence of a reliable cell culture method and the low levels of contamination of food and environmental samples. To date, real time RT-PCR has been one of the most promising detection methods due to its sensitivity, specificity, and speed. Recently, the ISO/TS 15216–1 and 15216–2 standards covering real time RT-PCR for both quantitative determination and qualitative detection of NoV and HAV in foodstuffs were published [14, 15, 16].
The aim of this study was to develop real time RT-PCR assays for detection of a total of 19 human enteric viruses (including 3 genogroupes of norovirus and 4 coronaviruses) and two control process viruses (mengovirus and murine norovirus) generally used for monitoring the recovery of viral foodstuff extraction methods. Limits of detection of the viral genomes were determined with the conventional RT-qPCR system and with the Fluidigm’s BioMark System by using the qualitative nanofluidic real-time RT-PCR array and the quantitative digital RT-PCR array. The advantages of these new detection techniques were determined by detecting and quantifying pathogenic viruses in clinical samples.
Noroviruses are an evolutionarily diverse group of single-stranded positive-sense RNA viruses without the envelope, belonging to the Caliciviridae family, and are responsible for a substantial part of acute viral gastroenteritis in humans.1,2 Norovirus outbreaks have happened both in developing and industrialized nations.3 Once infected, symptoms are characterized by non-bloody diarrhea, vomiting, nausea, and abdominal cramps, and there has been no specific treatment to accelerate the cure of patients infected with the virus.4 Vaccines have yet to be fully developed and brought into practice,5 and the presence of various genotypes prevents infected human from acquiring sufficient specific immunity.6
Published studies have reported that around 30% of norovirus infection remains asymptomatic,7 while such asymptomatically infected individuals are known to excrete substantial volume of viruses.8,9 Vomit from infectious individuals contains over 107 copies/gram of noroviruses,8,9 and infectious vomitus is known to be sometimes aerosolized,10,11 making it difficult to prevent secondary transmissions. The virus spreads through fecal-oral routes, such as via contaminated water, food, and people’s contaminated hands.12,13 Published studies indicate that infections associated with environmental contaminants are mainly caused by contaminated water or foods (especially oysters),11 accounting for seasonal outbreaks that are frequently observed in winter.14 Given these features, workers who are directly engaged in cooking and handling of foods, such as cooks, food servers, and food factory workers, are considered as one of the key subjects for prevention of secondary transmissions.15–17
One of the notable virological features of noroviruses is genotype variation, which is divided into five genogroups and many genotypes in each genogroup.18 As of 2017, the most prevalent genotype in humans is GII.4,19,20 which accounts for as many as 80% of all reported norovirus infections with virus isolation.21 Some pieces of evidence indicate that this genotype evolves rapidly, escaping from selection pressure.22,23 In Japan, the majority of outbreaks are caused by genogroup II, and a large proportion is caused by GII.4.24 GII.4-associated epidemics in Japan were first observed in 2006, and the genotype has been continuously observed every year since then.25
To decipher the most effective preventive measures against this virus, it is vital to quantitatively clarify the natural history characteristics, including asymptomatic ratio, the risk of infection per exposure, and the probability of virus shedding. Nevertheless, explicit estimates are very scarce, except for rigorous challenge studies that helped quantify the natural history5,26; moreover, it is unclear if the natural history of experimentally infected individuals are similar to those based on natural infection. A small number of mathematical modelling studies estimated a part of the abovementioned values,27–30 but explicit model-based estimates of the asymptomatic ratio have yet to be offered. The present study aims to estimate the asymptomatic ratio of norovirus infection, reanalyzing foodborne outbreak data with laboratory testing in Japan, along with other parameters, including virus shedding frequency and the risk of infection. In addition to estimating the asymptomatic ratio for all noroviruses, the present study also compares the estimate across different genogroups and genotypes.
Transmission via the food- and waterborne route is a common mode of spread of a wide range of viruses. Many commonly recognized food- and waterborne infections are caused by viruses that are transmitted by the fecal-oral route. Particularly caliciviruses (norovirus, sapovirus) can cause diarrhea and vomiting and less commonly astroviruses, rotaviruses, and adenoviruses (Newell et al., 2010). Other viruses cause symptoms resulting from extra-intestinal spread, like hepatitis A (HAV), and hepatitis E (HEV). High levels of viral shedding through stool and vomit lead to dispersal in the environment. Moreover, the stability of many food- and waterborne viruses allows for prolonged persistence in the environment. Food- and water associated transmission is also suspected to enhance the spread and emergence of zoonotic viruses (e.g., Middle East Respiratory Syndrome-coronavirus and Nipah virus) and facilitates the occurrence of zoonotic events though the handling of bushmeat (Ebola virus) (Wolfe et al., 2005; European Food Safety Authority, 2014; Mann et al., 2015).
Challenges of detecting viruses transmitted by the food- and waterborne route are their diversity and the frequent secondary person-to-person transmissions, which may mask an initial food- or waterborne introduction. In addition, there is a lack of awareness among clinicians (Beersma et al., 2012), as the symptoms caused by foodborne viruses are not specific to the viruses causing the illness. Furthermore, there is limited coverage in surveillance of food- and waterborne viral disease, hampering detecting and tracing (Ahmed et al., 2014; Verhoef et al., 2015).
In the past years, high-throughput sequencing technologies have increased the ability to measure genomic material from diverse samples tremendously. These methods will most likely continue to improve in the future (Aarestrup et al., 2012). Specifically, metagenomic analysis using untargeted sequencing has received a lot of attention, because the high throughput of current sequencing technologies has made it possible to obtain multiple high coverage genomes from highly complex samples (Cotten et al., 2014; Smits et al., 2015). Even though it is still a developing field, metagenomics is starting to become mature enough for applications outside of the research environment.
With the development of multiplex real-time polymerase chain reaction (RT-PCR) protocols came the realization that unraveling etiologies of main disease syndromes is more complex than previously recognized. This led to questions about the detection of viruses for which the role as causes of illness remains to be evaluated, the importance of co-infections and recognition of less common disease etiologies (Binnicker, 2015). Similarly, high throughput metagenomic sequencing broadens the scope of detectable viruses, which, apart from making it more complex, make us further understand the role of viruses in health and disease. The biggest promise, however, is that of routine application of metagenomic sequencing in diagnostic context, facilitating viral detection and offering huge potential for tracing of viruses in (foodborne) outbreaks.
General practitioners enrolled 175 adult patients consulting for AD and 101 non diarrheal individuals, but we received stools samples from 138 cases and 93 controls. The two populations (cases and controls) presented similar demographic characteristics: median age of cases was 37 years [28 - 54] versus 39 years [29 - 54] for controls (p = 0.62); the proportion of women in the cases group was 45.9% versus 47.3% in the control group (p = 0.85).
Viruses are infective obligate parasites that can replicate only in the living cells of animals, plants, fungi, or bacteria. Although extremely small in size and simple in structure, viruses cause numerous diseases such as cancer, autoimmune disease, and immunodeficiency as well as organ-specific infectious diseases including the common cold, influenza, diarrhea, hepatitis, etc.,,,.
Recent progress in the formulation of antiviral therapies and vaccines has helped to prevent, shorten the duration, or decrease the severity of viral infection,,. Most antiviral agents are designed to target viral components, but mutations in the viral genome often result in drug resistance and immune evasion, creating a major hurdle for antiviral therapies and vaccine development. In addition, the continuous emergence of new infectious agents such as the Ebola virus and Middle East respiratory syndrome coronavirus (MERS-CoV) necessitate the advancement of novel therapeutic approaches. Accordingly, great attention has recently been drawn to the development of antivirals with broad-spectrum efficacy and immunomodulators which improve host resilience by increasing host resistance to the viral infection.
Korean ginseng (the root of Panax ginseng Meyer) is one of the most popular medicinal plants used in traditional medicine in East Asian countries including Korea. Ginseng contains various pharmacologically active substances such as ginsenosides, polysaccharides, polyacetylenes, phytosterols, and essential oils, and among those, ginsenosides are considered the major bioactive compounds. Korean Red Ginseng (KRG) is a heat-processed ginseng which is prepared by the repeated process of steaming and air-drying fresh ginseng. KRG has been shown to possess enhanced pharmacological activities and stability compared with fresh ginseng because of changes in its chemical constituents such as ginsenosides Rg2, Rg3 Rh1, and Rh2, which occur during the steaming process.
Currently, numerous studies have reported the beneficial effects of KRG on diverse diseases such as cancer, immune system disorder, neuronal disease, and cardiovascular disease,,,. In addition, KRG and its purified components have also been shown to possess protective activities against microbial infections. In this review, we summarize the current knowledge on the effects of KRG and its components on infections with human pathogenic viruses and discuss the therapeutic potential of KRG as an antiviral and vaccine adjuvant.
Noroviruses are members of the RNA virus family Caliciviridae, and are a major cause of human infectious gastroenteritis worldwide. An estimated three million people each year in the UK suffer from ‘winter vomiting disease’ caused by human norovirus. Infection causes the classic symptoms of vomiting, diarrhea and malaise, and outbreaks are common in closed or semi-closed communities such as in hospitals, care homes, schools and cruise ships. In addition to the major burden of noroviruses on human health, noroviruses have also been found associated with intestinal disease in cows, pigs, mice, a lion, cats and dogs. The first canine norovirus (CNV) was reported from a single dog with enteritis in Italy in 2007. Subsequent studies have identified CNV in stools of dogs from Portugal,, Greece and the US. To date there have been no reports of CNV present in the UK.
Significant sequence variation has been found in different CNV strains identified to date. Noroviruses are assigned to six genogroups based on complete capsid sequences, with strains of norovirus assigned to the same genogroup if they share 55–85% amino acid identity. Human noroviruses are grouped together in genogroups I, II and IV whereas CNV strains have been assigned to genogroups IV and VI. Human and canine noroviruses in genogroup IV share <85% amino acid identity, thus are separated into different genotypes, IV.1 and IV.2 respectively. Genetic recombination is believed to occur between different norovirus strains, which may explain the significant heterogeneity between the CNV strains identified.
The prevalence of CNV in dogs with clinical signs of gastroenteritis across Europe has been estimated to be between 2.1% (Italy) and 40% (Portugal). A study in the US identified CNV at a prevalence of 11% in canine diarrhoea samples. CNV has also been detected in healthy dogs, and the association between infection and clinical signs is yet to be formally established. CNV has been identified in dogs also infected with other enteric viral pathogens such as canine parvovirus (CPV) and canine enteric coronavirus (CECoV), thus elucidating the role of CNV infection in disease is difficult.
Serological prevalence of CNV in countries where the virus has been detected has not been reported. A preliminary serological survey in Italy suggested less than 5% dogs were seropositive to a genogroup IV.2 lion norovirus (strain Pistoia/387/06/ITA) but the sample size was small. As with human norovirus, CNV has yet to be cultivated in cell culture thus obtaining sufficient quantities of virus for serological screening is not possible. However, the major capsid protein of noroviruses (VP1) has been shown to spontaneously assemble into virus-like particles (VLPs) when recombinant VP1 is expressed in an appropriate system. Production of lion and canine norovirus VLPs has previously been achieved and proven to be an efficient way of generating antigen for serological analysis,.
The aim of this study was to elucidate the importance of CNV in the UK dog population and evaluate any changes over time. No prior information on CNV prevalence in the UK has been described, so in order to address this our study has sought to determine the prevalence of CNV RNA in canine fecal samples, in conjunction with the prevalence of anti-CNV antibodies in different populations of dogs.
Advances in the enteric microbiology research have improved the understanding of etiology of infectious gastroenteritis, as well as the involvement and transmission modes of enteric pathogens. This has enabled the design of specific control strategies limiting the losses due to consequent severe infections. Although, bacteria and viruses are both responsible for gastroenteritis, the latter have had more impact on public health (Gunn et al., 2015). As of date, non-bacterial acute gastroenteritis, and respiratory infections are the leading causes of global deaths in both humans (mainly children) and animals (Dominguez et al., 2009; Bok and Green, 2012; Dhama et al., 2015). Since the identification of the first enteric virus, Norovirus (Caliciviridae), in 1972 using electron microscopy, a range of viruses, such as Rotavirus (Reoviridae), Picobirnavirus (Picobirnaviridae), Astrovirus (Astroviridae), enteric Adenovirus (Adenoviridae), Sapovirus (Calciviridae), Torovirus (Coronaviridae), Parechovirus, Bocavirus, and Aichivirus (Picornaviridae), and many more, have been found to be associated with gastroenteritis infections (Cheng et al., 2008; Dhama et al., 2009, 2014; Malik et al., 2011, 2014; Ahmed et al., 2014; Yip et al., 2014; Sidoti et al., 2015; Kattoor et al., 2017; Delmas et al., 2018; Kattoor et al., 2019). The enteric viruses known as of now along with their respective advanced diagnostic methods are tallied in Table 1. Although acute viral gastroenteritis is more common in immune-compromised and young individuals (Krones and Högenauer, 2012), it is also seen in the aged individuals, which may be due to changes in physiology and the waning of immunity with time (Estes and Kapikian, 2007).
New viruses are emerging at a faster pace, apparently as a feature of their rapidly changing genetic makeup due to the accumulation of point mutations, reassortments or recombinations (Malik et al., 2016; Kattoor et al., 2017). For an example, a new porcine coronavirus, has emerged through recombination between the transmissible gastroenteritis virus and a porcine epidemic diarrhea virus (Boniotti et al., 2016). Enteric viral diseases are diagnosed by identifying the causative viral agents in feces/body fluids or viral antigens and/or antibodies in the serum of patients. Conventional methods to achieve this, however, are either inefficient, cumbersome or time consuming, because of the pace of change of the virome. There were not much significant approaches available in the past, and in the recent time various techniques have come up offering a modern field for advances in bio-techniques for the easy, quick and reliable diagnosis and discovery of new viruses. In clinical laboratories, polymerase chain reaction (PCR)-based assays are considered as gold-standard for the detection of viruses, but when it comes to multiple detections of similar types of viruses simultaneously, variations in the properties of viral nucleic acids make the amplification difficult (Fout et al., 2003; Fong and Lipp, 2005). Among different techniques used to explore new viruses, such as conventional and next-generation sequencing, metagenomics has been a promising approach to study the unrevealed viral genomes since more than a decade (Garza and Dutilh, 2015; Martinez-Hernandez et al., 2017). This allows researchers to study the genetic material directly from pooled samples and bypass the need for culturing the virus in vitro as well. Virome capture sequencing is another approach for vertebrate viruses, in which several million probes covering the genomes of several viral taxonomies are used to enrich virus targets (Briese et al., 2015). A new metagenomic sequencing method, ViroCap, based on the target nucleic acid capture and enrichment detects viral sequences with up to 58% variation from the references used to select capture probes (Wylie et al., 2015).
Nevertheless, several diagnostic methods have been developed over the last two decades, seeing the constant evolution of viruses, newer, sensitive, efficient, and rapid diagnostics are still warranted for the effective diagnosis (Liu et al., 2007; Saminathan et al., 2016). This paper systematically describes and discusses the features, advantages and limitations primarily of advanced diagnostic tools devised for the sensitive and quick detection of enteric viruses worldwide (Figure 1).
Viral meningoencephalitis due to a prolonged infection with enterovirus is strongly suggestive of a specific class of PIDD. Enteroviruses are the most common cause of viral meningitis in the general population manifesting as acute onset headache with gradual resolution over days to a few weeks. In patients with agammaglobulinemia, manifestations are quite different (124). These children typically present with regression of developmental milestones. Ataxia or clumsiness may be noted by parents or on examination. Features early on are subtle, and the slow progression can lead to efforts at mitigation with physical therapy or behavioral strategies. In a patient with a known humoral immune deficiency, the index of suspicion should be high and a workup should not be delayed if there are clear neurologic signs or symptoms. CNS infection in patients with agammaglobulinemia has a very poor prognosis. There can be other phenotypes associated with enteroviral disease in patients with agammaglobulinemia; however, CNS infection is the most common. Dermatomyositis and hepatitis have been described and have progressed in some cases to CNS infection. Treatment for enteroviral disease includes high dose immunoglobulin and when available, drugs directed at enterovirus.
A unique subset of CNS enteroviral infections occurs in either SCID or agammaglobulinemia with live-attenuated polio vaccine. Wild-type polio, occurring in three serotypes, has been nearly eradicated. Even early on, it was recognized that the live-attenuated vaccine could cause disease (125) and that patients with hypogammaglobulinemia could excrete virus for years (126, 127). Currently, circulating wild-type polio is seen only in Afghanistan and Pakistan although virus can be isolated in sewage from other countries supporting ongoing risk for immunodeficient individuals (128). Vaccine-associated poliomyelitis can be due to infection of an immune deficient individual and spread to the CNS or to revertants of vaccine-strain virus (129, 130). In the latter case, even normal hosts can have overt paralytic disease. Vaccine-associated poliomyelitis can appear as acute flaccid paralysis or with a meningoencephalitis in immunodeficient individuals. The prognosis has generally been poor (131).
Testing for defects related to herpes simplex encephalitis often involves genetic sequencing although functional analyses are available on a research basis. Table 3 lists the currently recognized genetic causes of susceptibility to herpes simplex encephalitis.
The diagnosis of enteroviral meningoencephalitis in PIDD patients requires a specific description. In a patient with agammaglobulinemia detection of enterovirus is surprisingly difficult. PCR analysis of cerebrospinal fluid or stool (less specific) should be performed. However, it is not unusual for children with agammaglobulinemia and suggestive clinical features to require a brain biopsy for diagnosis. The biopsy tissue can be tested for enterovirus by PCR. In a patient who presents with CNS enteroviral disease, identification of an immune deficiency is critical because of the prognostic implications. The strong association of CNS enteroviral disease with agammaglobulinemia supports a strategy that begins with enumeration of peripheral blood B cells by flow cytometry. Only if that is negative and there are no other secondary immune deficiencies should alternatives such as CD40L or CVID be sought. A reasonable secondary screen would be to measure immunoglobulin levels and responses to vaccines.
The search yielded 6702 papers of which a total of 182 were included in the review. An additional nine papers were later included (see methods).
Based on 1,123 observations from ten observational studies, and five observations from one experimental study, we estimate the median incubation period for genogroup I noroviruses to be 1.1 days (95% CI 1.1-1.2 days) with a dispersion of 1.82 (95% CI 1.75-1.90). 5% of genogroup I norovirus cases will become symptomatic 0.4 days (95% CI 0.4-0.5 days) after infection and 95% of cases will develop symptoms by 3.0 days (95% CI 2.8-3.2 days) (Table 3).
Given the number of different viral pathogens potentially associated with food- and waterborne transmission their detection has not been straightforward. Partly because many of these pathogens lack cell culture systems that are sensitive and robust enough for application in routine settings (Amar et al., 2007). The entry point for disease-based surveillance of viruses spreading by food and water is the reporting of patients presenting to a clinician. However, patients only present themselves in case of a severe symptomatic infection, or in case self-help is not sufficient. Mild symptoms are therefore generally not registered creating a bias in surveillance. This phenomenon is captured in the surveillance pyramid (Figure 1), and the full extent of disease can only be captured through epidemiological studies addressing incidence and etiology at community level coupled with severity of a range of enteric pathogens (Sethi et al., 1999; de Wit et al., 2001; Tam et al., 2012). Additionally, it is challenging to distinguish between foodborne outbreaks and outbreaks caused by direct contact between humans. Classic clinical symptoms of foodborne disease vary, ranging from diarrhea and vomiting to abdominal cramps and general malaise, which makes it hard for clinicians to pinpoint the exact causative agent. This leads to misdiagnosis if the diagnostic workup is selective, and if there are no obvious signs of food-related exposure (Beersma et al., 2012). Moreover, heterogeneity in clinical interpretation can be caused by host factors, such as differences in the expression of histo-blood-group antigens that are receptors for rota- and noroviruses (Payne et al., 2015; de Graaf et al., 2016). Susceptibility to fecal-orally transmitted viruses may also be influenced by the established microbiome and virome in the host population, of which the prior is shown to differ between different locations and age groups (Yatsunenko et al., 2012). It is reasonable to think that the differences in the gut environment are more pronounced between countries with larger social and economic differences such as first and third world countries, which often differ in their resident pathogens (Ott et al., 2012; Yatsunenko et al., 2012; Hay et al., 2013). The role of the gut virome, in addition to the gut microbiome, is a relatively new concept and has been described as potentially having influence on gut health and therefore expression of disease (Cadwell, 2015). Because of under and miss-diagnoses, clinical surveillance likely only captures the tip of the iceberg of food- and waterborne viral disease cases.
One of the most affected sites in untreated human immunodeficiency virus (HIV)-infected persons is the gastrointestinal tract. In these patients diarrhoea occurs frequently, especially in HIV-1 patients who are not treated with anti-retroviral therapy. Routine diagnostics in fecal samples often remain negative, despite the sensitive diagnostic assays which are now available. In this study our aim is to identify the cause of diarrhoea for patients in which no enteropathogen could be found. There are several possible explanations why these patients remain negative in routine diagnostics: First, HIV-1 itself might play a role. HIV-1 infected mucosal cells have been observed in HIV-1 infected persons and enterocytes exposed to HIV-1 show altered function and proliferation. However, it has not been demonstrated that HIV-1 causes diarrhoea. Secondly, there are several recent reports describing novel viral agents which are found in stool that could play a role in diarrhoea (see below), and these agents are not yet included in routine diagnostics. Thirdly, an unknown or unexpected virus might be causing diarrhoea.
One of the recently described gastrointestinal viruses is cosavirus, which was identified in 2008 as a member of the Picornaviridae. The virus was originally found in 2 patients with gastrointestinal infections. However, its link with diarrhoea has not been established and a recent study in HIV-infected individuals detected cosavirus in a substantial number of patients without diarrhoea. Aichi virus is another recently described picornavirus which was identified in fecal samples of patients with gastroenteritis. Several manuscripts have since then confirmed that the virus is associated with diarrhoea, although in one study, which included children without diarrhoea, the association with disease could not be established since the amount of positive samples was too low. Human gyrovirus, a member of the Circoviridae, is the most unusual novel virus which is found in gastrointestinal infections. The virus is genetically very closely related to gyroviruses found in chicken meat and therefore it remains uncertain whether human gyrovirus in stool is a sign of gastrointestinal infection or a virus which is digested with food and shed in feces, like many food related viruses.
Identification of unknown and unexpected viruses is performed via virus discovery cDNA-AFLP followed by Roche 454 sequencing (VIDISCA-454). This technique, which can detect single stranded and double stranded RNA and DNA viruses, has been developed in our laboratory and is a sensitive next generation sequencing-based assay which enables detection of known and unknown viruses in a wide range of different sample types, including stool samples.
In the current study, a cohort of 196 HIV-1 infected individuals of whom 29 suffered from severe diarrhoea was investigated. In this patient group we determined how many cases of diarrhoea could be explained by known enteropathogens, recently described viruses and unknown viruses.
Based on ten observations from two experimental studies and 1,417 estimates from ten observational studies, we estimate the median incubation period for genogroup II noroviruses to be 1.2 days (95% CI 1.2-1.3 days) with a dispersion of 1.56 (95% CI 1.49-1.62). 5% of genogroup II norovirus cases will exhibit symptoms 0.6 days (95% CI 0.5-0.6 days) after infection and 95% of cases will become symptomatic by 2.5 days (95% CI 2.4-2.6 days) (Table 3).
We investigated trends in the reporting of common infectious respiratory and enteral viruses for which laboratory data were available for the 10‐year period from 2003 to 2012, or part thereof:
Influenza virus type AInfluenza virus type BRespiratory syncytial virus (RSV)Rhinovirus (2006 onwards)Coronavirus (mid‐2005 onwards)Norovirus (2007 onwards)EnterovirusRotavirus
The data were available from the “Weekly Virological Records System” of the Dutch Working Group on Clinical Virology giving the number of positive laboratory diagnoses by year and week, but not providing data on the denominator nor on age or gender of the patient. Submitting laboratories are associated with either hospitals or regional laboratories to which both GPs and hospitals submit samples. The estimated proportion of all positive diagnostics captured by this national surveillance varies between the monitored pathogens and was estimated between 38% (for rotavirus) and 73% (for influenza virus) in a 2002 study of five pathogens.10 The types of tests used can differ between the submitting laboratories and over time. Respiratory viruses were detected in throat swabs mainly by PCR‐based methods in respiratory specimens from patients with respiratory disease symptoms. Enteric viruses were detected in fecal samples by EIA‐based methods (rotavirus, norovirus) and by PCR‐based methods (norovirus). Enterovirus was detected mainly by PCR and in the early years also by culturing, in throat swabs, CNF, and in fecal specimens collected from patients suspected for an enterovirus infection. Cross‐reaction between rhinovirus and enterovirus PCRs for throat swab samples cannot be excluded completely. When collected from patients suspected for enterovirus infection, typing of enteroviruses indicated that this was a minority. When collected from patients with respiratory symptoms, enteroviruses might be misidentified as rhinovirus, as occurred during enterovirus D68 outbreaks.11
Virus infections are a continuous threat to the human population; e.g. HIV, hepatitis viruses, and influenza viruses constitute a large proportion of morbidity and mortality each year. Apart from infection with well-described viruses, outbreaks with previously undescribed viruses occur regularly (e.g. SARS-CoV, MERS-CoV)–. Furthermore, respiratory tract infections and diarrhoea in young children or immunocompromised persons often test negative for known viruses, and could very well be caused by yet unknown pathogens.
Discovery of new viruses in the last decade has been boosted by large improvements in sequencing technology. These methods form the basis for improved virus discovery processes capable of generating 10e5–10e7 sequence reads directly from a clinical sample. A virus discovery method to amplify RNA and DNA virus sequences directly in patient material (VIDISCA-454) without prior knowledge of the viral genome sequence has been developed. The resulting DNA library is then subjected to Roche-454 next generation sequencing and this method has been successfully used to identify human coronavirus NL63, a novel HIV-1 subtype, and 2 novel parvoviruses in bats.
One limitation of the current technique is that a substantial amount of non-viral RNA and DNA derived from the host or from other agents in the sample can dominate the resulting sequences. Especially in respiratory samples, ribosomal RNA is massively present, over 80% of all sequence reads derived from a clinical sample originate from this material. Sequence reads from fecal samples can be dominated by bacterial or dietary components. A method for focusing sequencing on immunogenic viruses was sought.
Another limitation of the current techniques is that detection of reads derived from a known virus does not necessarily indicate that this virus is a pathogen. Recently, many new viruses have been identified in human samples without clear association with disease, necessitating further detailed investigations to determine the pathogenicity of the virus–.
To facilitate the detection of immunogenic viruses and to reduce the detection of non disease-related viruses (bacteriophages and plant viruses) and host cellular RNA, a technique was developed that uses convalescent serum of the patient to concentrate viruses that have elicited and immune response prior to sequencing. Comparing the sequences derived from input and antibody captured material identifies immunogenic agents and can provide an important first step in identifying a disease-related virus.
Food safety and its related issues are attracting interest worldwide because they are closely related to human lives and health conditions. Pathogens from the environment may contaminate food and food products, thus foodborne pathogens and their detection are directly related to human life and safety. Foodborne viruses, among all other pathogens, are relatively new, gaining more attention due to their emerging contamination events and the small scale of outbreaks.
Global public food safety issues have been increasing in recent years. Foodborne disease outbreaks related to fresh produce have been increasing in North America and European Union 1. In the United States, norovirus is the main pathogen, responsible for 59%, followed by Salmonella, which is responsible for 18% of foodborne diseases related to fresh produce. In European Union, norovirus is responsible for 53%, followed by Salmonella, which is responsible for 20% of foodborne diseases related to fresh produce. In Canada, Salmonella is the main pathogen, responsible for 50%, and hepatitis A virus is responsible for 0.1% of foodborne diseases from fresh produce 2. Although viruses are not the major pathogen in Canadian fresh produce, they are prevalent in farm-level infection such as hepatitis E virus (34%), porcine enteric calicivirus (20%), and rotavirus (7%) in finisher pigs 3. These viruses are hypothesised to infect humans zoonotically through swine and pork exposure.