Norovirus

Etiology

Norovirus Genotypes

Noroviruses have 10 known genogroups and 49 genotypes. The classification into genogroups and genotypes is based on amino acid diversity in VP1 and ORF1 proteins. Human infections are predominantly due to genogroups GI, GII, and GIV, with GII being the most common cause of gastroenteritis. A minimal number of cases are attributed to GIV. While both genogroups I and II are clinically relevant, a specific strain from genogroup II, norovirus GII.4, has been responsible for the majority of human outbreaks over the preceding 12 years. However, a different GII variant appears to be contributing to recent outbreaks.[4]

As of December 2024, United States surveillance data has identified a significant increase in norovirus-associated gastroenteritis compared with a similar period from previous years.[CDC NoroSTAT Data] The surge in gastroenteritis cases is likely partly due to the emergence of the norovirus strain variant, GII.17.[5] In addition, social distancing during the early years of the COVID-19 pandemic may have decreased exposure to norovirus and thereby reduced background immunity.[6] Studies have shown that waterborne outbreaks tend to be associated with genogroup I strains, while healthcare-related and winter outbreaks are more likely to have genogroup II strains as a causative agent.

The primary mode of transmission of norovirus is fecal-oral. Sources include ingesting contaminated water or food or direct transmission from a contaminated surface or infected person. The virus is resistant and can stay on surfaces even after disinfecting. Norovirus also has a low viral inoculum that causes infection. As few as 10 viral particles are needed to cause infection.[7]

Gastroenteritis Outbreaks

Norovirus outbreaks are common in several different settings. Norovirus is known to cause gastroenteritis outbreaks in hospitals and other healthcare facilities. In addition to healthcare settings, outbreaks may occur in schools, military barracks, cruise ships, and resorts.[8] Person-to-person transmission is the most common mode, but contaminated surfaces also contribute to disease propagation.

Surfaces may be contaminated with viral particles by splashing of emesis or stool or by aerosolized viral particles. Outbreak incidence of norovirus gastroenteritis tends to occur during winter months. Good hand hygiene and effective surface cleaning should be stressed during norovirus outbreaks. Studies suggest that washing hands with soap and running water for at least 20 seconds is the most effective form of hand hygiene for eliminating norovirus. Studies on the effectiveness of alcohol-based hand rubs are inconclusive. Some studies suggest that high-concentration ethanol-based hand sanitizers decrease viral concentration on the hands, but these types of cleaners should be used as a supplement to hand-washing with soap and water. Surfaces such as sinks, toilets, tables, chairs, and beds should be cleaned with a hypochlorite (bleach) solution, and adequate contact time should be ensured. Furthermore, items contaminated with infected emesis or stool that cannot be properly disinfected should be discarded.

Epidemiology

Worldwide, norovirus is responsible for an estimated 685 million cases of gastroenteritis, 150,000 adult deaths, and 50,000 child deaths annually. While lower-income countries bear the greatest disease burden, norovirus infection outbreaks occur worldwide.[9][3] In the United States, approximately 21 million cases of norovirus gastrointestinal illness are diagnosed each year. Because patients with mild disease may not seek medical treatment, the number of cases likely exceeds the estimate. Norovirus is believed to cause approximately 60% of cases of acute gastroenteritis in the United States, and the CDC attributes 400,000 emergency department visits and 71,000 hospitalizations each year to norovirus infection. In a review of reported norovirus outbreaks, food-related transmission was the most common source of widespread disease. Food-related transmission may be due to the ingestion of food that is contaminated during production or the ingestion of food that food service workers contaminated during preparation. High-risk food for norovirus contamination includes foods that are served raw, like fruits and vegetables, as well as oysters and fish.

Although people of all age groups are at risk of contracting norovirus, those at the extremes of age and the immunocompromised are at the highest risk of poor outcomes. Older adults are at increased risk of fatal outcomes, with some studies showing a 30-day mortality rate of 7% for patients with community-acquired norovirus infection. Similarly, neonates have an increased rate of serious complications, eg, necrotizing enterocolitis. Of all age groups, young children have the highest incidence of norovirus. Estimates suggest an annual incidence of norovirus to be 21,400 per 100,000 for children younger than 5. Norovirus infections are also more prevalent in developing nations. Nguyen et al estimated that 17% of reported gastroenteritis cases in developing countries are due to norovirus. Also notable is norovirus’s effects on immunocompromised patients. Patients with compromised immune systems have a higher risk of norovirus infection, higher rates of complications, and increased potential for prolonged asymptomatic viral shedding.[10][11]

Pathophysiology

Noroviruses are difficult to culture in a lab setting, making it difficult to predict how they infect and replicate in humans. Studies suggest that infection is multifaceted and involves multiple cell types in the human gut. The predominant cell type lining the human gut is a single layer of intestinal epithelial cells called enterocytes. Lying deep to the enterocytes are numerous immune cells. Several studies have confirmed that norovirus infects and replicates in immune cells, including macrophages, dendritic cells, and B cells.

Authors have postulated that noroviruses have a way of bypassing enterocytes to enter the human hosts. Proposed mechanisms include entering through M cells, a specialized type of cell in the gut that overlies the Peyer patches and lymphoid follicles in the gut. M cells lack microvilli and do not secrete mucus, making it easier for the norovirus to enter the host and invade immune cells. However, although definitive data are lacking, other studies suggest noroviruses may directly invade enterocytes lining the gut lumen. Furthermore, the role of the host’s preexisting gut microflora in norovirus infection is being investigated. Experts have proposed that norovirus interacts with bacteria in the gut to enhance infection and replication.

The average period from inoculation with the virus until clinical symptoms develop is 1.2 days, and norovirus symptoms usually resolve within 1 to 3 days. Although symptoms may resolve, humans can continue to shed the virus in their stool for extended periods, up to 60 days in some cases. Immunocompromised patients can continue to shed the virus for months or years.[12] The immunologic interaction between humans and norovirus is complex and not well understood.

Host genetic factors appear to play a role in the susceptibility to norovirus, and specific IgG and IgA antibodies develop after infection. The immunologic role of norovirus antigenic diversity remains uncertain, and conflicting data on the duration of immunity has been reported, ranging from a few weeks to several years.[13][14]

History and Physical

Clinical History

The history and physical exam are essential in evaluating all patients with abdominal pain and gastrointestinal symptoms. Patients infected with norovirus typically have symptoms consistent with gastroenteritis. Common symptoms include nausea, vomiting, abdominal pain and cramping, diarrhea, myalgias, headache, and chills. Some patients report a predominance of diarrhea, while others report nausea and vomiting as primary symptoms. Symptoms may develop with or without prodrome and typically persist for 1 to 3 days.

Essential historical elements to elicit include the patient’s living quarters (eg, nursing home, military barracks), the source of water (eg, river, city, well), recent travel, recent antibiotic use, ingestions of undercooked or raw food, or recent sick contacts (eg, school). Screening for immunocompromised states, which could predict a longer course of symptoms and a greater risk for morbidity and mortality, is also critical.

Physical Examination

Physical exam findings are usually consistent with gastroenteritis. The abdominal exam may reveal nonspecific, nonfocal tenderness, but significant tenderness or peritoneal signs on the abdominal exam should prompt further investigation for other pathology. Likewise, the grossly bloody stool is inconsistent with norovirus infection and warrants further investigation. Patients may show signs of dehydration, eg, tachycardia, orthostatic hypotension, decreased skin turgor, and dry mucous membranes depending on their hydration status. Rarely, patients may present with significant neurologic symptoms such as a seizure or encephalopathy.

Evaluation

Norovirus Evaluation

Many cases of norovirus go undiagnosed, as many patients do not seek medical attention for treatment. For patients seeking evaluation by a clinician, the diagnostic evaluation will be similar to most patients with gastroenteritis. Usually, diagnostic testing is not indicated. A metabolic panel may be warranted for certain patients to assess for electrolyte abnormalities and hydration status. Stool studies such as stool culture, Clostridium difficile toxin, and ova and parasite testing are not usually indicated unless symptoms are prolonged or an alternative pathogen is suspected.

In cases where norovirus is suspected, several enzyme immunoassays and reverse transcription polymerase chain reaction (RT-PCR) are available for the detection of norovirus. Although not usually indicated for individual cases of gastroenteritis, these assays may be useful in detecting norovirus outbreaks. While enzyme immunoassays are the most readily available test, RT-PCR remains the gold standard for detection. Both types of tests use stool or emesis samples to detect GI and GII noroviruses. However, limitations do exist for norovirus testing. Many healthcare facilities do not have access to enzyme immunoassays or RT-PCR, and the sensitivity and specificity of testing are variable. The accuracy of results depends upon the number of samples tested, the timing of stool collection, and proper handling of the sample. Because laboratory testing for norovirus is not uniformly available, clinical evaluation can be useful in detecting norovirus outbreaks. The Kaplan clinical and epidemiological criteria for norovirus were developed before the development of laboratory testing and are still considered useful when definitive testing is unavailable.[15][16][17]

The Kaplan Criteria

If all of the following Kaplan criteria are positive, a norovirus outbreak is highly probable:

1. Vomiting in more than half of symptomatic cases
2. Mean (or median) incubation period of 24 to 48 hours
3. Mean (or median) duration of illness of 12 to 60 hours
4. No bacterial pathogen isolated on stool culture

Treatment / Management

The management of norovirus infection involves treating the patient’s symptoms and mitigating the risk of an outbreak. The primary clinical focus should be on the patient’s hydration status, with an emphasis on infection control to prevent the spread of disease to healthcare workers and patient contacts.

Norovirus Management

The mainstay of treatment is oral rehydration therapy. The World Health Organization and the American Academy of Pediatrics recommend oral rehydration solutions with electrolytes and glucose. Oral rehydration solutions are preferred over sports drinks and juices for pediatric patients because the latter contains a high carbohydrate and osmotic load that may exacerbate diarrhea.

Patients with intractable vomiting or severe dehydration require intravenous hydration and, possibly, hospital admission. Antibiotics generally are not indicated unless a concern for bacterial infection is present. Antimotility agents have been beneficial in adults, and antiemetics may provide symptomatic relief. Studies support the use of ondansetron in vomiting children, but antimotility agents are not recommended for pediatric patients.

Infection Control Measures

Infection control is a priority in preventing norovirus outbreaks. While efforts at vaccine development are underway, hand hygiene, surface cleaning, and prevention of body fluid exposure are the mainstays of infection control. Currently, hand hygiene is the primary preventive method for outbreaks.[18] Additionally, inpatients should be placed in single occupancy rooms when possible, with contact precautions maintained for at least 48 hours after symptom resolution. If isolation is not feasible, symptomatic and asymptomatic individuals should be separated. Cleaning protocols recommend using bleach-based disinfectants, prioritizing frequently touched surfaces, and moving from less to more contaminated areas.[18] (Please refer to the Etiology section for more information on the prevention of norovirus spread).(B3)

Norovirus Vaccines

Norovirus vaccine development remains a priority for both the perceived public health and economic benefits. Developing a vaccine has been difficult because of the complex nature of norovirus, human immune responses, difficulty culturing the virus, and limited animal models for vaccine testing. Several vaccines are currently in pre-clinical development; one has completed phase 2 adult clinical trials. Due to viral evolution, development efforts have focused on multivalent vaccines similar to influenza vaccines.[19][20][21](B3)

Differential Diagnosis

The differential diagnosis of norovirus includes rotavirus, cholera, Clostridium difficile, Salmonella, Cryptosporidium, Enterovirus, Escherichia coli, Shigella, Campylobacter, and Vibrio infections. Patients presenting with abdominal pain should have the following differentials considered: mesenteric ischemia, abdominal aortic aneurysm, bowel perforation, ectopic pregnancy, appendicitis, cholecystitis, bowel obstruction, diverticulitis, pancreatitis, pyelonephritis, urinary tract infection testicular or ovarian torsion, myocardial infarction, and pelvic inflammatory disease.

Prognosis

While the vast majority of patients experience no significant complications from norovirus infection, over 70,000 hospitalizations and 800 deaths in the United States are attributed to the effects of norovirus each year. Patients at the extremes of age and immunocompromised patients are at the highest risk of adverse outcomes, including death. Specifically, neonatal patients with norovirus infection are at risk for necrotizing enterocolitis, and studies show increased mortality in older adults with norovirus infection. Furthermore, immunocompromised patients are at risk for increased severity and a prolonged clinical course of the illness, with diarrhea lasting months to years in some patients.

Complications

Complications of norovirus include:

• Hypokalemia
• Dehydration
• Hyponatremia
• Metabolic alkalosis
• Renal failure
• Hemolytic uremic syndrome
• Neonatal necrotizing entercolitis