Human Norovirus Infection: Identification, Epidemics and Treatment

Human Noroviruses (HuNoVs) are important enteric pathogens, which affect the stomach and intestines, leading to gastroenteritis or more commonly called the "stomach flu" or “winter vomiting bug". HuNoVs are mainly transmitted by the fecal-oral route, either by directly infected person-to-person contact or directly via contaminated foods, water and surface areas. The virus is highly contagious as 10-100 virus particles are sufficient to cause diseases. HuNoVs can spread easily and cause prolonged outbreaks. This is due to their environmental persistence, high infectivity, being resistance to disinfection and difficulty in preventing transmission. HuNoVs are the most common causative agent leading to acute gastroenteritis among infectious diseases worldwide and poses a serious public health problem, especially among children being the most susceptible. In developing countries, the highest cost of medical care after respiratory infections is listed for acute gastroenteritis. In this study, Norovirus outbreaks, precautions, its identification and struggles were informed and some suggestions were made about this case.


INTRODUCTION
HuNoVs are non-enveloped, a single-stranded RNA viruses, belong to the genus Norovirus, in the Caliciviridae family. Norovirus strains have been divided into seven genogroups (GI-GVII), which can be further classified into at least thirty genotypes. GI, GII, and GIV infect humans whereas GII,GIV, GV, GVI and GVII NoVs (Noroviruses) have been determined in animals (da Silva Poló et al., 2017).
In recent years, viruses are defined as important factors in foodborne diseases. Although viruses cannot reproduce in food and environmental surfaces, they serve as vectors which allow them to easily penetrate humans. Primary factors in the transmission of viral agents are: contamination of drinking water with sewage water, use of underground waters mixed with sewage water for vegetable growing, washing of raw vegetables with contaminated water, preparation of food by infected personnel, and catching of shellfish from contaminated areas. Additionally, secondary contamination factors are contamination of foodstuffs during processing, storage, distribution or final preparation (Dreyfuss, 2009; A. . One of the foodborne viruses is HuNoV (Human norovirus), which causes digestive system infections in humans. HuNoVs are accepted as the worldwide reason for 60-80% of acute gastroenteritis outbreaks which affect the individuals of all age groups (R L Fankhauser et al., 1998; B. A. Lopman et al., 2003). The infections caused by HuNoVs are mainly transmitted by the faecal-oral route. The main factors in the spread of HuNoVs in the population and their outbreaks are: Low infective dose (10-100 viral particles) High viral load (up to 1012 genomic copies) in the vomit and feces of infected individuals Resistance of the agent to environmental conditions (R L Atmar et al., 2008) HuNoV is one of the most common causes of outbreaks in environments where individuals coexist such as schools, passenger ships, restaurants, hospitals, nursing homes, camps and dormitories. HuNoV outbreaks are associated with contamination by contaminated food makers to a considerable extent. On the other hand, although the first source is contaminant food or water as well as the spreading fecal-oral route or aerosol exposure, the contamination directly from the person through the surface / bodies of contaminants also plays a major role.
Laboratory studies with HuNoV have shown that virus can be easily transferred between food, food contact surfaces, hands and the environment. Workers working in the food industry often go back to work and continue to work in the same department, even after treatment, after complaints of gastroenteritis. However, in many cases, even if there are no clinical signs of disease, still the virus spread continues. For this reason, it is important to prevent the transfer of virus from infected food personnel. It has been shown that HuNoV is one of the most important factors of acute gastroenteritis outbreaks and if it is not prevented it could spread to large populations in a short time and threaten public health (R L Fankhauser et al., 1998;Widdowson et al., 2005).
water, and 18% of them cannot be detected (Parashar et al., 2001). In a study conducted in the USA between 2000 and 2004, it was determined that contagion occurs mostly because of human to human transmission, secondly due to contaminated foods (Blanton et al., 2006).
While it is reported that HuNoV-originated food outbreaks in the US are 15,000 hospital cases per year and 1,500 deaths, It is estimated that more than 600,000 HuNoV-infected cases are reported each year in the UK, especially in the winter months. In the surveillance studies of acute gastroenteritis (AGE) outbreaks in the US and European countries between 1995 and 2000 ,it is found that 43% to 95% of outbreaks were caused by HuNoVs (Scallan, Griffin, Angulo, Tauxe, & Hoekstra, 2011).
Surveillance studies of acute gastroenteritis (AGE) outbreaks in the US and European countries between 1995 and 2000 found that 43% to 95% of outbreaks were caused by HuNoVs. People are rarely receiving medical help because of the illness, which is mostly mildly observed, and only part of the HuNoV cases around the world are officially reported.
For a disease that is mostly mild, people rarely receive medical treatment for it, and therefore only some of the HuNoV cases in the world are reported to the public. The rates of HuNoV in AGE outbreaks seen worldwide in 1996-2000 are over 95% in the US, UK, Denmark, Sweden, Finland, the Netherlands and France, 84% in Holland, 57% in Spain and 43% (B. A. Lopman et al., 2003). In 2005, a case of Noroviruses (GGII) in Denmark was found to have originated from frozen raspberries imported from Poland. There was a Norovirus outbreak affecting 652 people in 6 hospitals (31.4%) and 11 nursing homes In 2008, the outbreak of NoV in Aksaray was determined. This epidemic occurred when 25 students who were studying in a high school went to the hospital with complaints of nausea, vomiting, abdominal pain and diarrhea. In addition, similar incidents were observed simultaneously in the districts of Gülağaç, Ortaköy and Sarıyahşi and in neighboring provinces Şereflikoçhisar / Ankara and Konya (Uyar, Carhan, Ozkaya, & Ertek, 2008). GI and GII were found to be the most common genogroups among NoVs diagnosed by PCR in stool specimens examined. In a study conducted to reveal the frequency of HuNoV presence in Turkey, HuNoV GI and GII species in tomatoes, parsley, green onions, lettuce, mixed salad and bulgur prepared foods, were the pathogens reported in humans (Yılmaz et al., 2011).
Uyar and colleagues (2008) assessed a total of 50 stool specimens taken from the cases of "diarrhea and nausea-vomiting" in Aksaray, Şereflikoçhisar, Kırşehir and Adana, where possible bacterial, viral and parasitic factors could not be detected in terms of HuNoV. ELISA and RT-PCR methods were used for HuNoV laboratory diagnosis, where 26% (13/50) of the stool specimens were positive for antigen, and 33% (13/40) were positive for nucleic acid.

Laboratory Diagnosis
The laboratory diagnosis is especially important for the detection of outbreaks. Immunoelectron microscopy was used to show some viruses that could not be produced in cultures in stool specimens, but due to the inadequacy of routine use, new methods had to be ELISA is a valuable method that it is highly sensitive and it can be used to examine many samples in a short time. The antigen can be searched in feces by ELISA for a rapid diagnosis of HuNoV (Rabenau et al., 2003). The recently-described Tulane virus (TV) is a typical calicivirus. The in vitro cultured Tulane Virus (TV) recognizes human tissue-blood group antigens (HBGA). The TV known as the monkey calicivirus has been isolated from the National Primate Research Center's rhesus monkey faeces. In vitro, rhesus monkey replicates in kidney cells and causes typical cytopathic effects in cells. Unlike MNV and FCV, TV recognizes Type B HBGA receptors for infecting (Farkas et al., 2010).
In 2017, Scientists at Baylor College of Medicine have, for the first time grown NoV in human intestinal epithelial cells. This will allow for promising developments in diagnosis, prevention and treatment (Graciela Gutierrez, n.d.).

Treatment and Prevention
Norovirus gastroenteritis usually heals spontaneously without requiring any treatment. Difficulties about cell culture studies has been a barrier to the development of antiviral drugs for HuNoV. Until now there is no specific licensed vaccination for HuNOV. Mechanisms of immunity to HuNoVs are unclear. It appears that immunity may be strain-specific and lasts only a few months; therefore, given the genetic variability of noroviruses, individuals are likely to be repeatedly infected throughout their lifetimes. The main principle in treatment is the prevention of dehydration by replacement of isotonic fluids. Approximately 10% of people with Norovirus gastroenteritis may require oral or intravenous fluid therapy for dehydration. In addition, analgesics, antiemetics and symptomatic drug treatment are applied to clinical findings such as muscle aches, headache and vomiting (Hall et  It is difficult to control the outbreak of norovirus infection by food, water, personal contact and environmental surfaces. Since outbreaks are usually caused by water and food, it is important to protect these sources from being contaminated. Because the virus is highly resistant to environmental conditions, foodstuffs must be subjected to adequate heat treatment and sewage contact should be prevented to the water resources to be used in the production of food. Foodborne contamination is associated with a greater risk of contamination of all kinds of food, especially marine products such as mussels, oysters, fresh vegetables and fruits (Gallimore et al., 2004;Patel et al., 2009;Westrell et al., 2010). Sodium hypochlorite, the most effective disinfectant in surface disinfection should be used. 5

No Precautions
Clothes should be changed and washed immediately after contamination from vomit or feces. 6 Avoiding direct contact with infected individuals, and contaminated vectors such as food, water or other objects. 7 Patients should be allowed to return to work after the symptoms have completely disappeared. 8 Patients should be informed that they will be the source of virus outbreaks for a long time after healing. Table 1: General precautions to be taken to prevent Norovirus infections (Uyar et al., 2008). If contamination is detected in water sources, chlorination must be done at a high level (≥10 mg / l) for Noroviruses. Contaminated areas should be cleaned with disinfectants, 10% sodium hypochlorite with germicides and contaminant bed covers should be washed with detergents containing bleach and at least 70 ° C (Öztürk, 2008). Contaminated areas should be cleaned with hypochloritecontaining disinfectants (10% sodium hypochlorite solution) or appropriate germicides (Rebecca L . Fankhauser et al., 2002).

HuNoV Durability and Inactivation in Environmental Surfaces and Hands
Detection of the agent from environmental surfaces during gastroenteritis outbreaks in HuNoV indicates that HuNoV may be infectively found on environmental surfaces for extended periods of time. HuNoV is often infected with the fecal contents of infected persons and the surrounding surfaces and clothing through hands and the infected foods. Studies on the presence of HuNoV in the hands were mainly carried out using viruses (MNV, FCV etc.) or similar viruses such as Hepatitis A (Todd, Greig, Bartleson, & Michaels, 2009).
In these studies, it has been shown that enteric viruses can survive for several hours in human hands. In the investigation of outbreaks, the swine from the patient's food handler showed that the detection of HuNoV RNA showed the virus remained long-term in the hands (Boxman et al., 2009). In 2009, Liu and his colleagues showed in their study that HuNoV RNA can still survive in the hands for more than two-hours.

Inactivation Methods of HuNoVs on Surfaces and Hands
As long as there are HuNoVs that are resistant to the environment, HuNoVs will cause major problems in both the food chain and the healthcare industry (B. Lopman et al., 2012). In general, measures for food hygiene are designed to control the reproduction of harmful bacteria in food production (such as protecting the cold chain) (Gary P Richards, 2012). HuNoVs cannot reproduce in the human body for a long time and can maintain their durability in environmental conditions, so cool and humid conditions keep them alive instead of inactivating them. As a result, there is a need for food hygiene solutions specifically designed for the inactivation of enteric viruses, as well as for the control of bacteria in the prevention of foodborne outbreaks. In the health sector, strict hygiene measures are needed to prevent and control the spread of HuNoVs. Several chemical and physical inactivation methods have been developed for the control of infections caused by HuNoV. Chlorine, is the most frequently used disinfector because of its ease of application, reliability, cost effectiveness, residual biocide effect and superior effect against bacteria and viruses. Ethanol, sodium bicarbonate, ozone and quaternary ammonium compounds are some of the chemicals used for the inactivation of FCV and MNV (Rockx et al., 2002;Wobus et al., 2004).However, there is a need for more precise information on the effectiveness of HuNoV inactivation methods.
According to European disinfection standards (Sıckbertbennett et al., 2005), inactivation of viral contaminants requires quantitative suspension and environmental surface testing at a maximum of 60 min above 20 ° C and at least 4 log reduction in all test groups. Chemical and physical disinfection methods including sodium hypochlorite, heat and UV methods are used against HuNoV and other enteric viruses (Marion . HuNoV infectivity cannot be done in the laboratory, except for voluntary work. Inactivation assays are based on genomic detection methods using resistant HuNoV virus-like particles (VLP) containing viruses or RNA representing HuNoV (G P Richards, 1999).
Chemical disinfection is the most common approach to break the chain of contact with food and other environmental surfaces of HuNoVs. Centers for Disease Control and Prevention recommend the use of a sodium hypochlorite solution in the disinfection of environmental surfaces that are potentially contaminated with HuNoV (Maccannell et al., 2011). However, although sodium hypochlorite is effective against HuNoV-representing viruses, HuNoV RNA cannot be completely destroyed (Barker, Vipond, & Bloomfield, 2004; Sıckbertbennett et al., 2005). There are various contradictions in the efficacy of alcohols against HuNoV. It has been shown that 55-60% ethanol solution inactivates MNV at 6 log10 levels over 5 minutes (Magulski et al., 2009). In 2010 Girard and colleagues showed that 2-1-(Butoxy) -praponol and ethoxyl alcohols had no effect on HuNoV and MNV.
The most important method of preventing the spread of HuNoV infections through the hand and controlling the transmission of viruses, is through proper hand hygiene. Ethanol-based hand sanitizers are frequently used for the inactivation of bacterial and respiratory viruses (Maccannell et al., 2011). However, the effectiveness of various ethanol-based chemistries on HuNoVs is still unclear. It has been observed by the FDA in a 2010, food safety survey, that washing hands at home using water and soap before food preparation has reduced the incidence of foodborne illnesses (Ali, Verrill, & Zhang, 2014).
Outbreaks from HuNoV in hospitals and other health care facilities can sometimes last for months . Infection may be more severe in inpatients leading to death than healthy individuals Young children and geriatrics have a higher incidence of infection.
Foods can be contaminated with fecal contamination by non-hygienic applications from food personnel. The food staff can easily infect food and surrounding surfaces from their hands. Especially in the food production line, there is a high possibility that contaminants from surfaces such as refrigerators, door handles and work benches, are found in foods. It is not a surprise that foodborne poisoning and outbreaks are caused by sandwiches and salads that are processed by hand or that are not re-heat treated after preparation. Increasing consumption of these types of ready-to-eat food in modern life increases the rate of food-borne HuNoV infections that the virus uses as a means of such food.
When assessed from the food industry point of view, avoiding secondary contaminations caused by food workers is an important preventive measure to be taken in the fight against this disease. As well as the prevention of contamination sources, another point to be