Predicting norovirus and rotavirus resurgence in the United States following the COVID-19 pandemic: a mathematical modelling study.

BACKGROUND: To reduce the burden from the COVID-19 pandemic in the United States, federal and state local governments implemented restrictions such as limitations on gatherings, restaurant dining, and travel, and recommended non-pharmaceutical interventions including physical distancing, mask-wearing, surface disinfection, and increased hand hygiene. Resulting behavioral changes impacted other infectious diseases including enteropathogens such as norovirus and rotavirus, which had fairly regular seasonal patterns prior to the COVID-19 pandemic. The study objective was to project future incidence of norovirus and rotavirus gastroenteritis as contacts resumed and other NPIs are relaxed. METHODS: We fitted compartmental mathematical models to pre-pandemic U.S. surveillance data (2012-2019) for norovirus and rotavirus using maximum likelihood estimation. Then, we projected incidence for 2022-2030 under scenarios where the number of contacts a person has per day varies from70%, 80%, 90%, and full resumption (100%) of pre-pandemic levels. RESULTS: We found that the population susceptibility to both viruses increased between March 2020 and November 2021. The 70-90% contact resumption scenarios led to lower incidence than observed pre-pandemic for both viruses. However, we found a greater than two-fold increase in community incidence relative to the pre-pandemic period under the 100% contact scenarios for both viruses. With rotavirus, for which population immunity is driven partially by vaccination, patterns settled into a new steady state quickly in 2022 under the 70-90% scenarios. For norovirus, for which immunity is relatively short-lasting and only acquired through infection, surged under the 100% contact scenario projection. CONCLUSIONS: These results, which quantify the consequences of population susceptibility build-up, can help public health agencies prepare for potential resurgence of enteric viruses.

Childcare and School Acute Gastroenteritis Outbreaks: 2009-2020.

OBJECTIVES: Acute gastroenteritis (AGE) outbreaks commonly occur in congregate settings, including schools and childcare facilities. These outbreaks disrupt institutions, causing absences and temporary facility closures. This study analyzed the epidemiology of school and childcare AGE outbreaks in the United States. METHODS: We analyzed AGE outbreaks occurring in kindergarten to grade 12 schools and childcare facilities reported via the National Outbreak Reporting System in the United States from 2009 to 2019 and compared this information to 2020 data. Outbreak and case characteristics were compared using the Kruskal-Wallis rank sum test, χ2 goodness-of-fit test, and Fisher exact test. RESULTS: From 2009 to 2019, there were 2623 school, 1972 childcare, and 38 school and childcare outbreaks. School outbreaks were larger (median, 29 cases) than childcare outbreaks (median, 10 cases). Childcare outbreaks were longer (median, 15 days) than school outbreaks (median, 9 days). Norovirus (2383 outbreaks; 110 190 illnesses) and Shigella spp. (756 outbreaks; 9123 illnesses) were the most reported etiologies. Norovirus was the leading etiology in schools; norovirus and Shigella spp. were dominant etiologies in childcare centers. Most (85.7%) outbreaks were spread via person-to-person contact. In 2020, 123 outbreaks were reported, 85% in the first quarter. CONCLUSIONS: Schools and childcare centers are common AGE outbreak settings in the United States. Most outbreaks were caused by norovirus and Shigella spp. and spread via person-to-person transmission. Fewer outbreaks were reported in 2020 from the COVID-19 pandemic. Prevention and control efforts should focus on interrupting transmission, including environmental disinfection, proper handwashing, safe diapering, and exclusion of ill persons.

Establishment and application of ERA-LFD method for rapid detection of feline calicivirus.

Feline calicivirus (FCV) has a single-stranded, positive-sense RNA genome, and it is responsible for many infectious respiratory diseases in cats. In addition, more worryingly, highly virulent strains of FCV can cause high mortality in felines. Therefore, a rapid and reliable diagnosis tool plays an important role in controlling the outbreak of FCV. In this study, enzymatic recombinase amplification (ERA) assay combined with lateral flow dipstick (LFD) was developed for the detection of FCV, targeting a relatively conversed position of FCV-ORF1. The results showed that the optimal reaction condition was at 40 °C for 30 min. ERA-LFD method was highly sensitive with the detection limit as low as 3.2 TCID50 of FCV RNA per reaction. The specificity analysis demonstrated no cross-reactivity with feline parvovirus (FPV), feline herpesvirus (FHV) and feline infectious peritonitis virus (FIPV). ERA-LFD was highly repeatable and reproducible, with the intra-assay and inter-assay coefficients of variation for this method both less than 7%. The general test showed that all the recombinant plasmids with known mutant sites and FCV strains with different mutant sites stored in our laboratory were all detected by this method. Of the 23 samples, 14 samples were tested positive for FCV by ERA-LFD and RT-qPCR, respectively. In summary, ERA-LFD assay was a fast, accurate and convenient diagnosis tool for the detection of FCV. KEY POINTS: • The detection principle of ERA-LFD was introduced. • Almost all the currently known FCV strains can be detected. • ERA-LFD is easy to operate and can be used for field detection.

Changes in norovirus incidence in Victoria, Australia, during the COVID-19 pandemic, 2020-2021.

There were 142 norovirus positive outbreaks in Victoria for the 2020-2021 calendar years; however, almost half of these (48.6%) occurred in Q1 (January-March) of 2021. For the two-year period, 69.0% of all norovirus positive outbreaks were in childcare settings, and the predominant genotype was GII.P16/GII.2 (64.9%) followed by GII.P31/GII.4_2012 (20.9%). Norovirus incidence was particularly low in 2020 (n = 26) and close to average in 2021 (n = 116), but genotype diversity was low in both years. With the thought that 2022 will approach a more normal aspect to socialising and travel, norovirus incidence in 2022 may be predicted to increase above typical levels.

Antiviral Effects of Adipose Tissue-Derived Mesenchymal Stem Cells Secretome against Feline Calicivirus and Feline Herpesvirus Type 1.

Mesenchymal stem cells (MSCs) have excellent anti-inflammatory and immunomodulatory capabilities and therapeutic effects in some viral diseases. The therapeutic impact of MSCs mainly relies on the paracrine effects of various secreted substances. Feline calicivirus (FCV) and feline herpesvirus type 1 (FHV1) are common and highly prevalent pathogens causing upper respiratory diseases, and FCV is associated with gingivostomatitis in cats. Recently, feline MSC treatment has been reported to improve the clinical symptoms of feline chronic gingivostomatitis, but the antiviral effects of feline MSCs on FCV and FHV1 are not known. In this study, we evaluated the antiviral efficacy of using feline MSC secretome as a conditioned medium on FCV and FHV1 viral replication in Crandell-Reese feline kidney (CRFK) cells, and RNA sequencing was used to analyze how the CRFK cells were altered by the MSC secretomes. The feline MSC secretome did not inhibit FCV or FHV1 viral entry into the CRFK cells but had antiviral effects on the replication of both FCV and FHV1 in a dose-dependent manner.

Norovirus Intestinal Infection and Lewy Body Disease in an Older Patient with Acute Cognitive Impairment.

We present a case report on an older woman with unspecific symptoms and predominant long-term gastrointestinal disturbances, acute overall health deterioration with loss of autonomy for daily activities, and cognitive impairment. Autopsy revealed the presence of alpha-synuclein deposits spread into intestinal mucosa lesions, enteric plexuses, pelvic and retroperitoneal nerves and ganglia, and other organs as well as Lewy pathology in the central nervous system (CNS). Moreover, we isolated norovirus from the patient, indicating active infection in the colon and detected colocalization of norovirus and alpha-synuclein in different regions of the patient's brain. In view of this, we report a concomitant norovirus infection with synthesis of alpha-synuclein in the gastrointestinal mucosa and Lewy pathology in the CNS, which might support Braak's hypothesis about the pathogenic mechanisms underlying synucleinopathies.

Rotavirus and Norovirus Infections in Children Under 5 Years Old with Acute Gastroenteritis in Southwestern China, 2018-2020.

OBJECTIVE: Rotaviruses and noroviruses are important causes of acute gastroenteritis in children. While previous studies in China have mainly focused on rotavirus, we investigated the incidence of norovirus in addition to rotavirus in Southwestern China. METHODS: From January 2018 to December 2020, cases of rotavirus or norovirus infections among children under five ages with acute gastroenteritis were evaluated retrospectively. RESULTS: The detection rate of rotavirus was 24.5% (27,237/111,070) and norovirus was 26.1% (4649/17,797). Among 17,113 cases submitted for dual testing of both rotavirus and norovirus, mixed rotavirus/norovirus infections were detected in 5.0% (859/17,113) of cases. While there was no difference in norovirus incidence in outpatient compared to hospitalized cases, rotavirus was detected two times more in outpatients compared to hospitalized cases (26.6% vs.13.6%; P < 0.001). Both rotavirus and norovirus infections peaked in children aged 12-18 months seeking medical care with acute gastroenteritis (35.6% rotavirus cases; 8439/23,728 and 32.5% norovirus cases; 1660/5107). Rotavirus infections were frequent between December and March of each year while norovirus was detected earlier from October to December. Our results showed significant correlation between virus detection and environmental factors such as average monthly temperature but not relative humidity. In addition, we observed a reduction in the detection rates of rotavirus and norovirus at the beginning of the SARS-CoV-2 pandemic in 2020. CONCLUSION: Our results indicate that rotavirus and norovirus are still important viral agents in pediatric acute gastroenteritis in Southwestern China.

Potent Protease Inhibitors of Highly Pathogenic Lagoviruses: Rabbit Hemorrhagic Disease Virus and European Brown Hare Syndrome Virus.

Rabbit hemorrhagic disease (RHD) and European brown hare syndrome (EBHS) are highly contagious diseases caused by lagoviruses in the Caliciviridae family. These infectious diseases are associated with high mortality and a serious threat to domesticated and wild rabbits and hares, including endangered species such as riparian brush rabbits (Sylvilagus bachmani riparius). In the United States (U.S.), only isolated cases of RHD had been reported until Spring 2020. However, RHD caused by GI.2/rabbit hemorrhagic disease virus (RHDV)2/b was unexpectedly reported in April 2020 in New Mexico and has subsequently spread to several U.S. states, infecting wild rabbits and hares and making it highly likely that RHD will become endemic in the U.S. Vaccines are available for RHD; however, there is no specific treatment for this disease. Lagoviruses encode a 3C-like protease (3CLpro), which is essential for virus replication and a promising target for antiviral drug development. We have previously generated focused small-molecule libraries of 3CLpro inhibitors and demonstrated the in vitro potency and in vivo efficacy of some protease inhibitors against viruses encoding 3CLpro, including caliciviruses and coronaviruses. Here, we report the development of the enzyme and cell-based assays for the 3CLpro of GI.1c/RHDV, recombinant GI.3P-GI.2 (RHDV2/b), and GII.1/European brown hare syndrome virus (EBHSV) as well as the identification of potent lagovirus 3CLpro inhibitors, including GC376, a protease inhibitor being developed for feline infectious peritonitis. In addition, structure-activity relationship study and homology modeling of the 3CLpro and inhibitors revealed that lagovirus 3CLpro share similar structural requirements for inhibition with other calicivirus 3CLpro. IMPORTANCE Rabbit hemorrhagic disease (RHD) and European brown hare syndrome (EBHS) are viral diseases that affect lagomorphs with significant economic and ecological impacts. RHD vaccines are available, but specific antiviral treatment for these viral infections would be a valuable addition to the current control measures. Lagoviruses encode 3C-like protease (3CLpro), which is essential for virus replication and an attractive target for antiviral drug discovery. We have screened and identified potent small-molecule inhibitors that block lagovirus 3CLpro in the enzyme- and cell-based assays. Our results suggest that these compounds have the potential for further development as antiviral drugs for lagoviruses.

Emerging norovirus GII.4 Sydney[P31] causing acute gastroenteritis outbreak in children in Japan, during COVID-19, 2021.

INTRODUCTION: Norovirus (NoV) is the most common agent causing outbreaks and sporadic cases of acute gastroenteritis among all ages, especially children under 5 years old. During the coronavirus disease 2019 (COVID-19) pandemic, NoV infection has decreased drastically in Japan due to school closures and no outbreak related to NoV infection had been reported. METHOD: In mid-September 2021, NoV outbreak occurred in kindergarten and nursery schools in Maizuru, Kyoto prefecture, Japan. Twenty-six stool samples collected from patients who were diagnosed of NoV gastroenteritis from the outbreak by an immunochromatographic (IC) kit at a pediatric outpatient clinic in Maizuru city during 3 weeks from September 13 to October 8, 2021 were examined for the presence of NoV GII by reverse transcriptase-polymerase chain reaction (RT-PCR), genome sequencing, and phylogenetic analysis. RESULT: All 26 samples were confirmed positive to NoV GII and their genotypes were identified as GII.4 Sydney[P31]. The amino acid substitutions in open reading frame1 (ORF1) and ORF2 genes were found when compared with previously detected sporadic NoV GII.4 Sydney[P31] strains isolated in Japan. The clinical characterization of infected children was described. Most of the children were mild cases and vomiting was the most frequent clinical symptom. CONCLUSION: This study reported a recent emergence of NoV GII.4 Sydney[P31] causing acute gastroenteritis outbreak in children in Japan during the COVID-19 pandemic and suggests a need for further monitoring of NoV GII.4 variants.

Return of Norovirus and Rotavirus Activity in Winter 2020‒21 in City with Strict COVID-19 Control Strategy, China.

A rapid decrease in viral gastroenteritis during winter 2019-20 and a return of norovirus and rotavirus activity during winter 2020-21 were observed while multiple nonpharmaceutical interventions for coronavirus disease were in effect in Hong Kong. The initial collateral benefit of coronavirus disease countermeasures that reduced the viral gastroenteritis burden is not sustainable.

Norovirus outbreak amid COVID-19 in the United Kingdom; priorities for achieving control.

Norovirus, an enteric virus primarily responsible for gastroenteritis outbreaks worldwide, is currently causing outbreaks around the United Kingdom during the COVID-19 pandemic. With an already exhausted health care system, the significant burden norovirus can have on the National Health Service, including economic and social burdens, is immense and cannot be tolerated. Primary challenges and priorities to be focused on due to the increase in norovirus outbreaks include a further depletion of health care services, increase cases in schools, nurseries, and care facilities, underreporting of the cases, and no effective vaccine being available. Therefore, it is essential to increase awareness about norovirus and its transmission in public, take necessary precautions, and increase reporting of cases. This article discusses the impact norovirus has during the COVID-19 pandemic, and the challenges, and recommendations to achieve control before it reaches epidemic levels.

Norovirus: Facts and Reflections from Past, Present, and Future.

Human Norovirus is currently the main viral cause of acute gastroenteritis (AGEs) in most countries worldwide. Nearly 50 years after the discovery of the "Norwalk virus" by Kapikian and colleagues, the scientific and medical community continue to generate new knowledge on the full biological and disease spectrum of Norovirus infection. Nevertheless, several areas remain incompletely understood due to the serious constraints to effectively replicate and propagate the virus. Here, we present a narrated historic perspective and summarize our current knowledge, including insights and reflections on current points of interest for a broad medical community, including clinical and molecular epidemiology, viral-host-microbiota interactions, antivirals, and vaccine prototypes. We also include a reflection on the present and future impacts of the COVID-19 pandemic on Norovirus infection and disease.

Dasabuvir Inhibits Human Norovirus Infection in Human Intestinal Enteroids.

Human noroviruses (HuNoVs) are acute viral gastroenteritis pathogens that affect all age groups, yet no approved vaccines and drugs to treat HuNoV infection are available. In this study, we screened an antiviral compound library to identify compound(s) showing anti-HuNoV activity using a human intestinal enteroid (HIE) culture system in which HuNoVs are able to replicate reproducibly. Dasabuvir (DSB), which has been developed as an anti-hepatitis C virus agent, was found to inhibit HuNoV infection in HIEs at micromolar concentrations. Dasabuvir also inhibited severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human rotavirus A (RVA) infection in HIEs. To our knowledge, this is the first study to screen an antiviral compound library for HuNoV using HIEs, and we successfully identified dasabuvir as a novel anti-HuNoV inhibitor that warrants further investigation. IMPORTANCE Although there is an urgent need to develop effective antiviral therapy directed against HuNoV infection, compound screening to identify anti-HuNoV drug candidates has not been reported so far. Using a human HIE culture system, our compound screening successfully identified dasabuvir as a novel anti-HuNoV inhibitor. Dasabuvir's inhibitory effect was also demonstrated in the cases of SARS-CoV-2 and RVA infection, highlighting the usefulness of the HIE platform for screening antiviral agents against various viruses that target the intestines.

Differential impact of the COVID-19 pandemic on laboratory reporting of norovirus and Campylobacter in England: A modelling approach.

BACKGROUND: The COVID-19 pandemic has impacted surveillance activities for multiple pathogens. Since March 2020, there was a decline in the number of reports of norovirus and Campylobacter recorded by England's national laboratory surveillance system. The aim is to estimate and compare the impact of the COVID-19 pandemic on norovirus and Campylobacter surveillance data in England. METHODS: We utilised two quasi-experimental approaches based on a generalised linear model for sequential count data. The first approach estimates overall impact and the second approach focuses on the impact of specific elements of the pandemic response (COVID-19 diagnostic testing and control measures). The following time series (27, 2015-43, 2020) were used: weekly laboratory-confirmed norovirus and Campylobacter reports, air temperature, conducted Sars-CoV-2 tests and Index of COVID-19 control measures stringency. RESULTS: The period of Sars-CoV-2 emergence and subsequent sustained transmission was associated with persistent reductions in norovirus laboratory reports (p = 0.001), whereas the reductions were more pronounced during pandemic emergence and later recovered for Campylobacter (p = 0.075). The total estimated reduction was 47% - 79% for norovirus (12-43, 2020). The total reduction varied by time for Campylobacter, e.g. 19% - 33% in April, 1% - 7% in August. CONCLUSION: Laboratory reporting of norovirus was more adversely impacted than Campylobacter by the COVID-19 pandemic. This may be partially explained by a comparatively stronger effect of behavioural interventions on norovirus transmission and a relatively greater reduction in norovirus testing capacity. Our study underlines the differential impact a pandemic may have on surveillance of gastrointestinal infectious diseases.

Impact of Nonpharmaceutical Interventions for Severe Acute Respiratory Syndrome Coronavirus 2 on Norovirus Outbreaks: An Analysis of Outbreaks Reported By 9 US States.

In April 2020, the incidence of norovirus outbreaks reported to the National Outbreak Reporting System dramatically declined. We used regression models to determine if this decline was best explained by underreporting, seasonal trends, or reduced exposure due to nonpharmaceutical interventions (NPIs) implemented for severe acute respiratory syndrome coronavirus 2 using data from 9 states from July 2012 to July 2020. The decline in norovirus outbreaks was significant for all 9 states, and underreporting and/or seasonality are unlikely to be the primary explanation for these findings. These patterns were similar across a variety of settings. NPIs appear to have reduced incidence of norovirus, a nonrespiratory pathogen.

A pre- and during Pandemic Survey of Sars-Cov-2 Infection in Stray Colony and Shelter Cats from a High Endemic Area of Northern Italy.

Cats are susceptible to infection with severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). Whilst a number of studies have been performed worldwide on owned cats, limited data are available on stray, colony or shelter cats. We investigated SARS-CoV-2 infection in a stray cat population before and during human outbreaks of SARS-CoV-2 in cities in the Lombardy region in northern Italy, a high endemic region for SARS-CoV-2, using serological and molecular methods. A cohort of different samples were collected from 241 cats, including frozen archived serum samples from 136 cats collected before the 2019 coronavirus disease (COVID-19) pandemic and serum, pharyngeal and rectal swab samples from 105 cats collected during the SARS-CoV-2 outbreak. All pre-pandemic samples tested seronegative for antibodies against the nucleocapsid of SARS-CoV-2 using indirect enzyme linked immunosorbent assay (ELISA) test, while one serum sample collected during the pandemic was seropositive. No serological cross-reactivity was detected between SARS-CoV-2 antibodies and antibodies against feline enteric (FECV) and infectious peritonitis coronavirus (FIPC), Feline Immunodeficiency Virus (FIV), Feline Calicivirus (FCV), Feline Herpesvirus-1 (FHV-1), Feline Parvovirus (FPV), Leishmania infantum, Anaplasma phagocytophilum, Rickettsia spp., Toxoplasma gondii or Chlamydophila felis. No pharyngeal or rectal swab tested positive for SARS-CoV-2 RNA on real time reverse transcription-polymerase chain reaction (rRT-PCR). Our data show that SARS-CoV-2 did infect stray cats in Lombardy during the COVID-19 pandemic, but with lower prevalence than found in owned cats. This should alleviate public concerns about stray cats acting as SARS-CoV-2 carriers.

Norovirus Infections Drop 49% in the United States with Strict COVID-19 Public Health Interventions.

Norovirus is a substantial burden on the U.S. We compared norovirus outbreaks before and during COVID-19. There were fewer norovirus outbreaks during COVID-19 compared to a similar time period in 2019 (326 versus 638, P<0.001). CONCLUSION: COVID-19 public health interventions may be considered to decrease the burden of norovirus. This demonstrates the ability of more restrictive interventions to decrease other outbreaks of known or emerging viruses.