CDC: Norovirus Now Leading Cause Of Gastroenteritis In Children

 

Norovirus – Credit HPA

 

# 7020

 

Prior to the introduction of a pair of live, attenuated  Rotavirus vaccines in the middle of the last decade (RotaTeq and Rotarix), nearly all children in the United States were infected by one of the Rotaviruses before their 5th birthday (cite). 

 

The CDC estimated the pre-vaccine disease burden in the United States each year as:

 

• more than 400,000 doctor visits,
• more than 200,000 emergency room visits,
• 55,000 to 70,000 hospitalizations, and
• 20-60 deaths

 

With the introduction of the Rotavirus vaccine in 2006, the number youngsters needing emergency department care or hospitalization due to the Rotavirus had dropped by about 85% by 2010 (cite).

 

As the number of Rotavirus cases begins to go down, it is not terribly surprising to find a new king of the stomach virus hill among children.

 

From a study just published in the New England Journal of Medicine, we learn that Norovirus has now taken the lead as the number one cause of gastroenteritis in children in the United States.

 

Special Article

Norovirus and Medically Attended Gastroenteritis in U.S. Children

Daniel C. Payne, Ph.D., M.S.P.H., Jan Vinjé, Ph.D., Peter G. Szilagyi, M.D., M.P.H., Kathryn M. Edwards, M.D., Mary Allen Staat, M.D., M.P.H., Geoffrey A. Weinberg, M.D., Caroline B. Hall, M.D., James Chappell, M.D., Ph.D., David I. Bernstein, M.D., Aaron T. Curns, M.P.H., Mary Wikswo, M.P.H., S. Hannah Shirley, B.S. , Aron J. Hall, D.V.M., M.S.P.H., Benjamin Lopman, Ph.D., M.P.H., and Umesh D. Parashar, M.B., B.S., M.P.H.

N Engl J Med 2013; 368:1121-1130

March 21, 2013 DOI: 10.1056/NEJMsa1206589

<SNIP>

Conclusions

Since the introduction of rotavirus vaccines, norovirus has become the leading cause of medically attended acute gastroenteritis in U.S. children and is associated with nearly 1 million health care visits annually. (Funded by the Centers for Disease Control and Prevention.)

 

For some more background on this CDC-funded study, we go to the CDC Newsroom.

 

Norovirus is now the leading cause of severe gastroenteritis in US children

Norovirus is now the leading cause of acute gastroenteritis among children less than 5 years of age who seek medical care, according to a new study published in the New England Journal of Medicine.  Norovirus was responsible for nearly 1 million pediatric medical care visits for 2009 and 2010 in the United States, amounting to hundreds of millions of dollars in treatment costs each year.

 

“Infants and young children are very susceptible to norovirus infections, which often result in a high risk of getting dehydrated from the sudden onset of intense vomiting and severe diarrhea,” said Dr. Daniel Payne, an epidemiologist in the Division of Viral Diseases at the Centers for Disease Control and Prevention. “Our study estimates that 1 in 278 U.S. children will be hospitalized for norovirus illness by the time they turn 5 years of age. It is also estimated that about 1 in 14 children will visit an emergency room and 1 in 6 will receive outpatient care for norovirus infections.”

<SNIP>

 

“Our study confirmed that medical visits for rotavirus illness have decreased,” said Dr. Payne. “Also, our study reinforces the success of the U.S. rotavirus vaccination program and also emphasize the value of specific interventions to protect against norovirus illness.” Norovirus vaccines are currently being developed, which may be especially important for young children and elderly people who are high risk.

 

(Continue . . .)

 

 

 

Noroviruses, which are often mistakenly called `stomach flu’, are single-stranded RNA viruses that are able to evolve rapidly, so we typically see a new dominant norovirus strain emerge every two or three years. 

 

After exposure and a short incubation period (12-24 hours), the victim usually experiences nausea, frequent vomiting & diarrhea, and stomach pain – and may also experience headache, fever, and body aches.

 

The illness generally runs its course in 1 to 3 (very long) days, and most people recover. But among those who are aged or infirmed, the virus can take a heavy toll. According to the CDC, each year the norovirus:

 

• causes about 21 million cases of acute gastroenteritis (inflammation of the stomach or intestines or both)
• contributes to about 70,000 hospitalizations and 800 deaths, mostly among young children and the elderly

 

There are five genogroups (GI, GII, GIII, GIV, and GV) of noroviruses that can infect a variety of species, but  most human infections stem from genogroups GI and GII. GII noroviruses have at least 19 subtypes.

 

The most common cause of human illness is from Genogroup II, genotype 4 (abbreviated as GII.4).

 

In 2009, we saw the emergence of the New Orleans strain of GII.4, which had been the dominant strain for the past three years.

 

That is, until a new strain discovered a year ago by Professor Peter White and his team in the School of Biotechnology and Biomolecular Sciences in Australia (see UNSW: Sydney 2012 Norovirus Rising) - began to spread globally last fall.

 

In short order it was being reported in Japan, Taiwan, Europe, the UK, and North America (see Eurosurveillance: Emergence & Spread Of GII.4 Variant Norovirus).

 

According to a recent MMWR Report On New Norovirus GII.4 Sydney Strain, by December of 2012, the new Sydney strain was the cause of 58% of the norovirus outbreaks across the United States.

 

While reportedly `no worse’ than previous strains (which admittedly isn’t much comfort for those afflicted), levels of immunity to this emerging strain are exceedingly low, and it spreads like wildfire (see Vomiting Larry And His Aerosolized Norovirus).

 

Without a vaccine (yet) against Norovirus, prevention is key. 

 

One of the best preventatives is good hand hygiene, unfortunately, unlike with many other bacteria and viruses, alcohol gel doesn’t do a particularly good job of killing the virus (see CMAJ: Hand Sanitizers May Be `Suboptimal’ For Preventing Norovirus).

 

The CDC offers this advice to help prevent the spread of this virus.

Gastrointestinal Bird Flu Infection In Cats

 

 

 

# 5969  

 

 

An intriguing study from the Journal of Virology this morning that looks at an unusual route of infection  - and resultant pathogenesis – of the H5N1 virus in cats (My thanks to Tetano on FluTrackers for posting this link).

 

The study is called:

 

Marked endotheliotropism of highly pathogenic avian influenza virus H5N1 following intestinal inoculation in cats.

November 2011, doi: 10.1128/​JVI.06375-11

Reperant LA, van de Bildt MW, van Amerongen G, Leijten LM, Watson S, Palser A, Kellam P, Eissens AC, Frijlink HW, Osterhaus AD, Kuiken T.

 

 

Endotheliotropism is simply a 12-dollar word meaning an affinity for endothelial cells which are the cells that line the interior surface of blood vessels throughout the body.

 

 

Photo Credit – Wikipedia

 

From the abstract (the entire study is behind a pay wall), we learn that researchers gave cats enteric coated capsules containing H5N1 infected chicken liver in order to deliver the virus directly to the intestine.

 

(EXCERPT)

Intestinal inoculation of HPAIV H5N1 resulted in fatal systemic disease. The spread of HPAIV H5N1 from the lumen of the intestine to other organs took place via the blood and lymphatic vascular systems but not via neuronal transmission.

 

Remarkably, the systemic spread of the virus via the vascular system was associated with massive infection of endothelial and lymphendothelial cells, resulting in widespread hemorrhages.

 

As the abstract points out, this resulted in a disease process similar to what is seen in terrestrial poultry, and differs greatly from the pathogenesis normally seen from respiratory tract infection.

 

The authors conclude that:

 

The marked endotheliotropism of the virus following intestinal inoculation indicates that the pathogenesis of systemic influenza virus infection in mammals may differ according to the portal of entry.

 

 

The surprise here isn’t that cats (and other mammals) can acquire the H5N1 virus via a non-respiratory route (we’ve known that for some time), it is the discovery of the manner in which the virus spread systemically; via massive infection of endothelial and lymph endothelial cells.

 

While anything that betters our understanding of the H5N1 virus is a good thing, this discovery may eventually have practical applications as well. 

 

Should an outbreak occur, gastrointestinal H5N1 infection (with its atypical pathogenesis) may require a different treatment regimen than is currently used with a respiratory infections.

 

An oral route of infection from the H5N1 virus has been suggested over the years, with several human cases being linked to the consumption of infected poultry.

 

One of the earliest indications that H5N1 could bind and flourish in the human gastrointestinal tract comes from this study involving the deaths of a brother and sister in Vietnam in 2004.

 

Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma.

de Jong MD, Bach VC, Phan TQ, Vo MH, Tran TT, Nguyen BH, Beld M, Le TP, Truong HK, Nguyen VV, Tran TH, Do QH, Farrar J.

 

 

In June of 2007, we got a report (see Atypical Presentations of H5N1)  out of Indonesia, of a child infected with H5N1 but that presented without respiratory symptoms.

 

A year later, in a large review of Chinese bird flu patients (see Clinical Case Review Of 26 Chinese H5N1 Patients), we find several mentions of gastrointestinal involvement as well.

 

Diarrhea was present in only two H5N1 cases at admission, but developed in a quarter of cases during hospitalization. Diarrhea was a common presenting symptom among H5N1 cases in Vietnam  and Thailand , but was reported infrequently among cases in Hong Kong SAR, China and Indonesia.

 

H5N1 virus and viral RNA have been detected in feces and intestines of human H5N1 cases. Whether the gastrointestinal tract is a primary site for H5N1 virus infection is currently unknown.

 

In 2010, we saw a study (see H5N1 Can Replicate In Human Gut) that provided even more evidence that the bird flu virus can thrive in the human gastrointestinal system.

 

We’ve also seen numerous reports over the years of cats infected with the H5N1 virus after consuming infected birds.  The following comes from a World Health Organization GAR report from 2006.

 

 

H5N1 avian influenza in domestic cats

28 February 2006

(EXCERPTS)

Several published studies have demonstrated H5N1 infection in large cats kept in captivity. In December 2003, two tigers and two leopards, fed on fresh chicken carcasses, died unexpectedly at a zoo in Thailand. Subsequent investigation identified H5N1 in tissue samples.

 

In February 2004, the virus was detected in a clouded leopard that died at a zoo near Bangkok. A white tiger died from infection with the virus at the same zoo in March 2004.

 

In October 2004, captive tigers fed on fresh chicken carcasses began dying in large numbers at a zoo in Thailand. Altogether 147 tigers out of 441 died of infection or were euthanized. Subsequent investigation determined that at least some tiger-to-tiger transmission of the virus occurred.

 

In 2006, Dr. C.A. Nidom demonstrated that of 500 cats he tested in and around Jakarta, 20% had antibodies for the bird flu virus.  

 

In 2007 the FAO warned that:

 

Avian influenza in cats should be closely monitored

So far no sustained virus transmission in cats or from cats to humans

 

For an overview of a number of other cases involving cats, see Apparently They Didn't Get The Memo.

 

And it isn’t just the H5N1 virus which as shown some propensity for gastrointestinal involvement.

 

Seasonal A & B Influenza viruses, along with the 2009 H1N1 virus, have been looked at for exhibiting unusual gastrointestinal symptoms, albeit nowhere near as severe as described in today’s study.   

 

In January of 2010, in Influenza’s Gastrointestinal Connection, I wrote about a study that appeared in BMC Infectious Diseases, that looked at seasonal flu in pediatric patients. 

 

 

Influenza virus infection among pediatric patients reporting diarrhea and influenza-like illness

The detection of influenza viral RNA and viable influenza virus from stool suggests that influenza virus may be localized in the gastrointestinal tract of children, may be associated with pediatric diarrhea and may serve as a potential mode of transmission during seasonal and epidemic influenza outbreaks.

 

And lastly, during the 2009 pandemic, the CDC’s Interim guidance on Infection Control for the pandemic H1N1 Virus, warned:

 

Transmission of influenza through the air over longer distances, such as from one patient room to another, is thought not to occur. All respiratory secretions and bodily fluids, including diarrheal stools, of patients with 2009 H1N1 influenza are considered to be potentially infectious.

 

 

More evidence (as if we needed it) to show that influenza is a far more complex, and fascinating, virus than most people give it credit for.

Study: H5N1 Can Replicate In Human Gut

 

 

# 4417

 

 

This morning a brief, but fascinating tidbit from The Journal of Infectious Diseases where scientists have demonstrated that the H5N1 bird flu virus can replicate ex vivo in the human gut.

 

A hat tip to Tetano on FluTrackers for posting this item. First the abstract, then a bit of discussion.

 

 

DOI: 10.1086/651457
BRIEF REPORT

Avian Influenza A(H5N1) Viruses Can Directly Infect and Replicate in Human Gut Tissues

Yuelong Shu, Chris Ka‐fai Li, Zi Li, Rongbao Gao, Qian Liang, Ye Zhang, Libo Dong, Jiangfang Zhou, Jie Dong, Dayan Wang, Leying Wen, Ming Wang, Tian Bai, Dexin Li, Xiaoping Dong, Hongjie Yu, Weizhong Yang, Yu Wang,Zijian Feng,  Andrew J. McMichael,3 and Xiao‐Ning Xu3

 

The human respiratory tract is a major site of avian influenza A(H5N1) infection. However, many humans infected with H5N1 present with gastrointestinal tract symptoms, suggesting that this may also be a target for the virus.

 

In this study, we demonstrated that the human gut expresses abundant avian H5N1 receptors, is readily infected ex vivo by the H5N1 virus, and produces infectious viral particles in organ culture.

An autopsy colonic sample from an H5N1infected patient showed evidence of viral antigen expression in the gut epithelium. Our results provide the first evidence, to our knowledge, that H5N1 can directly target human gut tissues.

 

 

If you’ve followed the H5N1 story closely over the past five years, then the findings of this study shouldn’t come as a complete surprise.  

 

We’ve had more than a few hints along the way. 

 

Influenza in humans (and in most mammals) is primarily seen as a respiratory disease.  Human adapted influenza viruses have an affinity to bind to the α2-6 receptor cells that line the upper airway and lungs in humans. 

 

Avian influenza viruses, however, preferentially bind to the α2-3 receptor cells that are commonly found in the gastrointestinal tract of aquatic birds, the virus’s natural host.   

 

Influenza in birds is a mostly a gastrointestinal illness, and the virus is often spread via feces deposited in lakes and ponds.

 

In order for an avian flu virus, like H5N1, to successfully `jump the species barrier’ and become easily transmissible among humans, it is believed that it must adapt its RBD (receptor binding domain) to match the  α2-6 receptor cells found in the more easily accessible upper respiratory system.

 

(Very Simplified Illustration of RBDs)

 

For a layman’s explanation of the science of RBDs, you might want to have a look at a couple of essays I’ve written in the past.

 

RBD: Looking For The Sweet Spot

Study: H1N1 Receptor Binding

 

Humans do have α2-3 receptor cells, however.  Just not in abundance in their upper airways, where influenza viruses can most easily bind.

 

These α2-3 receptor cells can be found deep in the lungs and in some human epithelial tissues, although their prevalence in the human digestive tract has been a bit of an open question.

 

We’ve seen rare instances of human avian flu infections that were primarily gastrointestinal in nature, raising the intriguing possibility that avian viruses can replicate outside of the human respiratory system.

 

One of the earliest indications that H5N1 could bind and flourish in the human gastrointestinal tract comes from this study involving the deaths of a brother and sister in Vietnam in 2004.

 

Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma.

de Jong MD, Bach VC, Phan TQ, Vo MH, Tran TT, Nguyen BH, Beld M, Le TP, Truong HK, Nguyen VV, Tran TH, Do QH, Farrar J.

Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.

 

In southern Vietnam, a four-year-old boy presented with severe diarrhea, followed by seizures, coma, and death. The cerebrospinal fluid contained 1 white cell per cubic millimeter, normal glucose levels, and increased levels of protein (0.81 g per liter).

 

The diagnosis of avian influenza A (H5N1) was established by isolation of the virus from cerebrospinal fluid, fecal, throat, and serum specimens. The patient's nine-year-old sister had died from a similar syndrome two weeks earlier. In both siblings, the clinical diagnosis was acute encephalitis.

 

Neither patient had respiratory symptoms at presentation. These cases suggest that the spectrum of influenza H5N1 is wider than previously thought.

 

 

In June of 2007, we got a report (see Atypical Presentations of H5N1)  out of Indonesia, of a child infected with H5N1 but that presented without respiratory symptoms.

 

A year later, in a large review of Chinese bird flu patients (see Clinical Case Review Of 26 Chinese H5N1 Patients), we find several mentions of gastrointestinal involvement as well.

 

Diarrhea was present in only two H5N1 cases at admission, but developed in a quarter of cases during hospitalization. Diarrhea was a common presenting symptom among H5N1 cases in Vietnam [11], [12] and Thailand [13], but was reported infrequently among cases in Hong Kong SAR, China [9], [10], and Indonesia [4], [16].

 

H5N1 virus and viral RNA have been detected in feces and intestines of human H5N1 cases [12], [17], [30], [33]. Whether the gastrointestinal tract is a primary site for H5N1 virus infection is currently unknown.

 

And even novel H1N1 (and perhaps Influenza B) are being looked at for exhibiting unusual gastrointestinal symptoms.   Last January, in Influenza’s Gastrointestinal Connection, I wrote about a study that appeared in BMC Infectious Diseases.

 

Influenza virus infection among pediatric patients reporting diarrhea and influenza-like illness

The detection of influenza viral RNA and viable influenza virus from stool suggests that influenza virus may be localized in the gastrointestinal tract of children, may be associated with pediatric diarrhea and may serve as a potential mode of transmission during seasonal and epidemic influenza outbreaks.

 

 

And for my final exhibit, in the CDC’s Interim guidance on Infection Control for the pandemic H1N1 Virus, they state:

 

Transmission of influenza through the air over longer distances, such as from one patient room to another, is thought not to occur. All respiratory secretions and bodily fluids, including diarrheal stools, of patients with 2009 H1N1 influenza are considered to be potentially infectious.

 

With today’s study, another piece has been added to the influenza jigsaw puzzle.  One that may help answer a nagging question about the atypical presentation of influenza infections.