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.

»» Read More

PLoS One: Viremia In The 2009 H1N1 Pandemic Influenza

 

 

# 5868

 

 

Today, a fascinating study  that associates viremia, and a specific mutation (D222G/N) in the 2009 H1N1 virus, to more severe disease presentation.

 

Viremia simply refers to the presence of viruses in the blood stream.

 

While many viruses cause viremia (ie. Dengue, Chikungunya, WNV) – seasonal influenza, being primarily a respiratory disease, isn’t usually one of them.

 

But as we’ve seen demonstrated over the past several years, the pathogenesis of the 2009 H1N1 virus sometimes deviated from what one normally sees with seasonal flu.

 

Recently, in mBio: Lethal Synergism of H1N1 Pandemic Influenza & Bacterial Pneumonia we saw how novel H1N1 infection exacerbated lung damage due to bacterial co-infection, when seasonal flu did not.

 

In April of 2010, in There’s No Flu Like A New Flu, I listed many of the other differences observed between seasonal flu and the novel H1N1 virus, including:

 

• The Age shift to under-65s seeing the greatest number of fatalities (see Study: Years Of Life Lost Due To 2009 Pandemic).

 

• Research out of Hong Kong that discovered that the novel H1N1 virus – unlike seasonal flu – easily infect and replicate in the conjunctival tissues of the eye  (see I Only Have Eyes For Flu).

 

• Novel H1N1’s unusually high rate of gastro-intestinal symptoms (see The Lancet study Clinical characteristics of paediatric H1N1 admissions in Birmingham, UK).

 

• And reports of patients that presented with neurological symptoms including unexplained seizures and altered mental status (see Japan: Influenza Related Encephalopathy).

 

 

Although the H1N1 pandemic virus of 2009 proved to be relatively mild for the vast majority of those infected, for a very small percentage, it produced serious and sometimes life-threatening illness.

 

Add to this the fact that this flu, unlike seasonal flu, was also frequently detected in companion animals, and it certainly appears that something was inherently different about the 2009 H1N1 virus.

 

Today, a new study appears in PLoS One that adds more weight to that argument. The open access study is called:

 

 

Clinical and Virological Factors Associated with Viremia in Pandemic Influenza A/H1N1/2009 Virus Infection

 

Herman Tse, Kelvin K. W. To, Xi Wen, Honglin Chen, Kwok-Hung Chan, Hoi-Wah Tsoi, Iris W. S. Li, Kwok-Yung Yuen

Positive detection of viral RNA in blood and other non-respiratory specimens occurs in severe human influenza A/H5N1 viral infection but is not known to occur commonly in seasonal human influenza infection.

Recently, viral RNA was detected in the blood of patients suffering from severe pandemic influenza A/H1N1/2009 viral infection, although the significance of viremia had not been previously studied. Our study aims to explore the clinical and virological factors associated with pandemic influenza A/H1N1/2009 viremia and to determine its clinical significance.

Methodology/Principal Findings

Clinical data of patients admitted to hospitals in Hong Kong between May 2009 and April 2010 and tested positive for pandemic influenza A/H1N1/2009 was collected. Viral RNA was detected by reverse-transcription polymerase chain reactions (RT-PCR) targeting the matrix (M) and HA genes of pandemic influenza A/H1N1/2009 virus from the following specimens: nasopharyngeal aspirate (NPA), endotracheal aspirate (ETA), blood, stool and rectal swab.

Stool and/ or rectal swab was obtained only if the patient complained of any gastrointestinal symptoms. A total of 139 patients were included in the study, with viral RNA being detected in the blood of 14 patients by RT-PCR.

The occurrence of viremia was strongly associated with a severe clinical presentation and a higher mortality rate, although the latter association was not statistically significant. D222G/N quasispecies were observed in 90% of the blood samples.

Conclusion

Presence of pandemic influenza A/H1N1/2009 viremia is an indicator of disease severity and strongly associated with D222G/N mutation in the viral hemagglutinin protein.

 

The authors propose several theories as to why the virus was detected in the bloodstream, and gastrointestinal tract.

 

The detected viral RNA in blood could either reflect extensive pulmonary damage with phagocytic uptake of virus-infected cells or true infection of monocyte-derived dendritic cells and macrophages [26].

On the contrary, viruses in the stool may originate from swallowed respiratory secretions, although viral replication in the epithelial tissue along the gastrointestinal tract cannot be ruled out entirely.

 

 

The significance of the H222G/N mutation in the 2009 H1N1 virus has been vigorously debated for nearly two years.

 

The `Norway’ or D222G/N (D225G/N in influenza H3 Numbering) mutation cited in this study was first linked to more severe disease by Norwegian Scientists in November 2009, although patients carrying these strains can have mild illness as well. 

 

While we’ve covered this territory a number of times over the past year, a brief (and hopefully simple) review is in order. If you are up to speed on receptor binding, and the history of the D222G/N variant, feel free to skip the next section.

 

This mutation involves a single amino acid change in the HA1 gene at position 222 from aspartic acid (D) to glycine (G) (or asparagine (N)).

 

The pdmH1N1 virus carrying this mutation appears to bind more readily to receptor cells (α2-3) found deeper in the lungs, whereas unmutated seasonal flu strains bind preferentially to the (α2-6) receptor cells found in the upper airway.

 

A virus’s ability to bind to specific cells is controlled by its RBD or Receptor Binding Domain; an area of its genetic code that allows it to attach to, and infect, specific types of host cells.

(A Very Simplified Illustration of RBDs)

Like a key into a padlock, the RBD must `fit’ in order to open the cell to infection.

 

The evidence for the D222G/N  amino acid substitution driving increased virulence has been mixed, with the World Health Organization, the CDC, and the HPA continuing to investigate. 

 

Complicating matters - viruses can have multiple amino acid changes – and it may be the combination of these changes can unpredictably (at least for now) alter the virus’s behavior. 

 

Since the D222G/N mutation has been found in patients showing mild disease, it may be that a second (or third) mutation elsewhere in the virus – in concert with D222G/N – is required to produce greater virulence.

 

There is simply a lot we don’t know yet.

 

During the first week of January, Eurosurveillance  printed a study looking at fatal and non-fatal cases of influenza in the UK (see Eurosurveillance: Analysis Of Fatal H1N1 Cases In The UK). 

 

Ellis et al. reported that almost all of the virus samples tested in fatal and non-fatal cases during the early wave of the 2010/11 influenza season showed aspartic acid (D) at position 222.

 

In other words, no `Norway’ mutation.

Towards the end of January 2011, Eurosurveillance published a letter from an Italian researcher who had found a high percentage of D222G/N mutations in severely ill patients (43%)  – particularly when taking virus samples from the lower respiratory tract (lungs).

 

In a reply, the authors of the original study concede that in many cases, only upper respiratory swabs were available for this analysis, and that when possible, samples from the lower respiratory system would be useful.

 

This scholarly debate wasn’t over, as Ellis et al. state in their reply:

 

The selection and emergence of the D222G mutation as a cause or consequence of more severe lower respiratory tract infection is still to be resolved.

 

Emergence of this mutant is likely to exacerbate severity of disease, but by itself, may be neither necessary nor sufficient to account for a severe disease outcome, which is invariably a balance between virus virulence factors and host immune response capability.

 

And so the debate has continued, with some scientists believing the `Norway’ mutation causes more severe illness, while others are less certain.

 

It will take more samples, more research, and more time to determine the truth in the matter.

 

Still, this study is another step forward in our understanding of the unusual pathogenesis, and genetic evolution, of the pandemic H1N1 virus.

 

And since we’ve seen similar severe lung damage, and scattered reports of viremia, among the small number of H5N1 `bird flu’ cases that have been examined, what we can learn about the 2009 H1N1 virus may provide clues on how to tackle a more severe pandemic in the future.

»» Read More

mBio: Lethal Synergism of H1N1 Pandemic Influenza & Bacterial Pneumonia

 

 

 

CDC PHIL - Photomicrograph of Streptococcus (Diplococcus) pneumoniae bacteria

 

# 5856

 

 

While the vast majority of people who contracted the H1N1 pandemic flu of 2009 recovered without incident, a very small minority saw severe – sometimes fatal – illness. 

 

Often during 2009 we saw reports of severe lung damage. Damage that in some cases was compared to what has been seen in H5N1 bird flu and during the great pandemic of pandemic of 1918.

 

A few of the stories from back then include:

 

In early September of 2009, in Pathology Of Fatal H1N1 Lung Infections, we looked at a report by Helen Branswell that looked early autopsy results.

 

 

Lung damage in fatal swine flu cases more bird flu than seasonal flu: expert

By Helen Branswell Medical Reporter (CP) 

TORONTO — The lungs of people who have died from swine flu look more like those of the victims of H5N1 avian influenza than those of people who succumb to regular flu, the chief of infectious diseases pathology at the U.S. Centers for Disease Control says.

 

Study of about 70 fatal H1N1 cases so far also reveals there may be more incidences of co-infections with bacteria than was earlier thought, Dr. Sherif Zaki told The Canadian Press in an interview.

 

A couple of weeks later in More On The Pathology Of Novel H1N1, we saw a report by Maggie Fox, then Health and Science Editor for Reuters, who brought us more details of this  story, including comments by Dr. Sherif Zaki of the U.S. CDC who  stated that "This is almost exactly what we see with avian flu. This looks like avian flu on steroids."

 

That same month, I wrote about the use of ECMO (Extracorporeal Membrane Oxygenation) in the treatment of severe lung injury in H1N1 victims in The ECMO Option.

 

In early December (see NIH: Post Mortem Studies Of H1N1) the NIH announced the results of a series of autopsies conducted on H1N1 victims in New York City over the summer, which are chronicled in the Archives of Pathology & Laboratory Medicine.

 

The NIH put together a press release, which provided highlights of the study.

 

FOR IMMEDIATE RELEASE
Monday, Dec. 7, 2009

Media Contact: Anne A. Oplinger
(301) 402-1663
niaidnews@niaid.nih.gov

New York Autopsies Show 2009 H1N1 Influenza Virus Damages Entire Airway

In fatal cases of 2009 H1N1 influenza, the virus can damage cells throughout the respiratory airway, much like the viruses that caused the 1918 and 1957 influenza pandemics, report researchers from the National Institutes of Health (NIH) and the New York City Office of Chief Medical Examiner. The scientists reviewed autopsy reports, hospital records and other clinical data from 34 people who died of 2009 H1N1 influenza infection between May 15 and July 9, 2009. All but two of the deaths occurred in New York City. A microscopic examination of tissues throughout the airways revealed that the virus caused damage primarily to the upper airway—the trachea and bronchial tubes—but tissue damage in the lower airway, including deep in the lungs, was present as well. Evidence of secondary bacterial infection was seen in more than half of the victims.

 

The team was led by James R. Gill, M.D., of the New York City Office of Chief Medical Examiner and New York University School of Medicine, and Jeffery K. Taubenberger, M.D., Ph.D., of the National Institute of Allergy and Infectious Diseases (NIAID) at NIH. The findings are reported in the Archives of Pathology & Laboratory Medicine, now available online and scheduled to appear in the February 2010 print issue.

<SNIP>

“This pattern of pathology in the airway tissues is similar to that reported in autopsy findings of victims of both the 1918 and 1957 influenza pandemics,” notes Dr. Taubenberger.

 

While many people continued to insist that swine flu was no worse than seasonal flu, obviously something was different in the way it produced severe lung damage.  

 

A year into the pandemic, I summarized many of the ways that the 2009 H1N1 virus differed from seasonal flu in There’s No Flu Like A New Flu.

 

While the overall incidence of these complications was relatively low, those who suffered from them often experienced extremely severe illness.

 

 

All of which serves as prelude to an open access study, published today in mBio, called:

 

Lethal Synergism of 2009 Pandemic H1N1 Influenza Virus and Streptococcus pneumoniae Coinfection Is Associated with Loss of Murine Lung Repair Responses

John C. Kash^a, Kathie-Anne Walters^b, A. Sally Davis^a, Aline Sandouk^a, Louis M. Schwartzman^a, Brett W. Jagger^a, Daniel S. Chertow^a, Qi Li^a, Rolf E. Kuestner^b, Adrian Ozinsky^b, and Jeffery K. Taubenberger^a

 

 

The entire study is available, and is well worth reading, but briefly:

 

Scientists at NIAID and the Institute for Systems Biology (ISB) infected experimental mice with both seasonal flu and the 2009 H1N1 pandemic flu, and after 48 hours exposed some of them to Streptococcus pneumoniae, one of the main causes of pneumonia.

 

Mice that were exposed only to the two flu strains showed expected flu symptoms, but all survived.

Mice that were exposed to seasonal flu and S. pneumoniae experienced minor lung damage, but once again, all survived.

 

But all of the mice infected with the pandemic H1N1 virus, and S. pneumoniae showed severe weight loss, lung damage, and 100% mortality

 

Excerpts from the press release below explain what else they found:

 

American Society for Microbiology

 

2009 H1N1 pandemic flu more damaging to lungs, opens opportunities for bacterial infection

(EXCERPT)

The lung tissues of the dead mice revealed that the alveoli were severely inflamed and the surfaces of the bronchioles were wiped clean of the protective layer of cells called the epithelium. There was also increased bacterial replication in the lungs of the co-infected mice, a sign that the bacteria were thriving there.

 

Looking at the mouse genes that were expressed during infection revealed more details about how the pandemic influenza virus sets the stage for lethal bacterial infections. Mice infected with the pandemic flu virus and S. pneumoniae had a similar inflammatory response as the other mice, but they lack responses that would repair and regenerate their damaged epithelial cells, those protective tissues that would otherwise keep bacteria from penetrating to deeper layers of tissue.

 

All these factors add up to big problems in the lung: as compared with seasonal flu, infection with the pandemic strain of flu was associated with more extensive damage to the epithelium that requires more extensive tissue repair. This opens the body up to attack from bacterial invaders, including Streptococcus pneumoniae.

(Continue . . . )

 

So not only did this duel infection lead to greater lung damage, and increased bacterial replication, it also disabled the lung’s ability to repair itself.

 

Since it can take 6 months or longer to develop a vaccine for a novel influenza virus, these results may suggest a bigger role for the 23-valent Pneumonia vaccine (PPVSV) during a future pandemic. 

 

More than a year after the end of the 2009 pandemic, scientists are still uncovering basic information about how pandemic flu differs from seasonal flu. 

 

With luck, work like this will provide better ways for us to deal with an outbreak, when the next one arrives.

»» Read More

H1N1 & The Non-Protective Antibody Response

 

 

 

# 5117

 

 

Normally, with seasonal influenza, it is the elderly and frail that make up 90% of the hospitalizations and deaths each year. The average age of death from seasonal flu in the US has been estimated to be about 76.

 

The mean age of death from the 2009 H1N1 virus,  has been calculated to be half that, or 37.4 years (see Study: Years Of Life Lost Due To 2009 Pandemic).

 

Although the 2009 pandemic was `mild’ in terms of the total number of people killed, it was anything but mild in the way it attacked a small percentage of – mostly young adult – patients.

 

A few blogs from the past year on how novel H1N1 presented differently than seasonal flu:

 

Canada: H1N1 Sent More To ICU Than Seasonal Flu

NIH: Post Mortem Studies Of H1N1

Pathology Of Fatal H1N1 Lung Infections

 

While the reasons why were not clear, it was apparent that in a small subset of patients, H1N1 produced severe – sometimes fatal – lung damage.

 

We’ve an intriguing study published today in the journal Nature Medicine that theorizes why those between the ages of 20 and 50 saw more severe illness from the pandemic than those who were either younger or older.

 

The culprit, researchers suggest, was a non-protective antibody response, that they believe attacked the patient instead of the virus.

 

First a link to the study (which is behind a pay wall) & abstract, followed by a few short excerpts from a press release describing some of the findings.  After that, a link to a sciencemag.org story on the study, and lastly, a link to a Nature News feature story about this study.

 

 

Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes

Ana Clara Monsalvo,Juan P Batalle,M Florencia Lopez,Jens C Krause,Jennifer Klemenc,Johanna Zea Hernandez,Bernardo Maskin,Jimena Bugna,Carlos Rubinstein,Leandro Aguilar,Liliana Dalurzo, Romina Libster, Vilma Savy,Elsa Baumeister,Liliana Aguilar, Graciela Cabral,Julia Font,Liliana Solari,Kevin P Weller,Joyce Johnson,Marcela Echavarria,Kathryn M Edwards,James D Chappell,James E Crowe Jr,John V Williams,Guillermina A Melendi& Fernando P Polack et al.

 

The press release (which I’ve only excerpted), comes from Vanderbilt University Medical Center.

 

Over-reactive immune system kills young adults during pandemic flu

(Excerpts)

In a paper published Dec. 5 in Nature Medicine, Fernando Polack, M.D., the Cesar Milstein Associate Professor of Pediatrics at Vanderbilt, and colleagues in Argentina and Nashville provide a possible explanation for this alarming phenomenon of pandemic flu. The study's findings suggest people are made critically ill, or even killed, by their own immune response.

 

"Every time there is an influenza pandemic there is a large proportion of younger, or middle-aged adults who die. We have always explained these deaths, based on presumed virulence of virus, or getting bacterial infection at the same time. We now have vaccines and antibiotics, but still we see middle-aged individuals who die," Polack said.

 

<SNIP>

 

"We have seen this before. Where non-protective antibody responses are associated with an immune-based disease in the lung," Polack said.

 

Polack has previously published evidence that a first-line immune response, primed by an imperfect antibody, can overreact in a violent and uncontrolled fashion. Patients die from lung damage inflicted by their own immune system. A molecule called C4d, a product of this biochemical cascade (the complement system), is a marker for the strength of the response.

 

In adults who died during the 2009 H1N1 pandemic, high levels of C4d in lung tissues suggest a massive, potentially fatal activation of the complement system.

(Continue . . . )

 

 

You can find a pretty good overview of this study in an article that appears today in Science Magazine.

 

How Swine Flu Killed the Healthy

by Kristen Minogue on 5 December 2010, 1:00 PM

But perhaps the most complete summary can be found in this Nature News story, which also contains an interesting caveat about what all of this could mean for the development of `universal’ flu vaccines. 

Exposure to seasonal flu weakened armour against H1N1

Faulty antibodies from previous infections boosted severity of swine flu in the middle-aged.

»» Read More

Study: Receptor Binding Changes With H1N1 D222G Mutation

 

 

 

# 4909

 

 

Although it’s nestled behind a pay wall at the Journal of Virology, the abstract from a study published ahead of print this week in the Journal of Virology gives us a tantalizing glimpse at research conducted on the D222G mutation that has been found in some isolates of the pandemic H1N1 (pdmH1N1) virus.

 

While we’ve discussed the D222G mutation before, this is an obscure enough subject as to make a review helpful.  I’ll keep it simple (essential so that I can follow, as well), so real scientists may wish to skim or skip ahead.

 

The `Norway’ or D222G (D225G in influenza H3 Numbering) mutation first announced by Norwegian Scientists last November has sparked repeated speculation that it might be associated with increased virulence.

 

This mutation had actually been detected months earlier, and in many other countries, but Norway was the first country to announce a possible link between that mutation and greater virulence.

 

This mutation involves a single amino acid change in the HA1 gene at position 222 from aspartic acid (D) to glycine (G).

 

The World Health Organization’s take on this mutation has been pretty consistent.  It is worth following, and studying, but there is no evidence (as yet) that it poses a substantial public health hazard.

 

In January, in a blog entitled WER Review: D222G Mutation In H1N1, I quoted the latest WHO report that stated:

 

`Based on currently available virological, epidemiological and clinical information, the D222G substitution does not appear to pose a major public health issue.’

 

This view is not universally held, however. There are some who have maintained that that the WHO is underestimating the impact of this mutation.

 

In March of this year, researchers from the Norwegian Institute of Public Health in Oslo reported that they found the mutation in 11 of 61 severe illness cases that they analyzed, but that it was not found in any of the 205 mild cases they looked at  (see CIDRAP Report On The H1N1 Mutation Debate).

 

The WHO WER Review reported that the overall prevalence of D222G was <1.8% (52 detections among >2755 HA sequences) in contrast to a rate of 7.1% in fatal cases. The WHO paper also reported on the occurrence of  two other mutations at this amino acid position, D222E and D222N, although their significance is unclear.

 

While this may sound like fairly damning evidence, it should be noted that mild cases have been detected with this D222G mutation in other studies, and most of the severe and fatal cases of pandemic H1N1 that have been examined did not have this mutation.

 

Which brings us to today’s study, which features an impressive pedigree and some very familiar names including Ab Osterhaus and  Ron Fouchier of the Erasmus Medical Center in Rotterdam.

 

This study was also supported by researchers from the Mt. Sinai School of Medicine in New York, the NIH, the University of Cambridge, the University of Maryland . . . among others.

 

First the abstract (hat tip Tetano on FluTrackers) slightly reformatted for readability, then a little discussion.

 

Virulence-associated substitution D222G in hemagglutinin of 2009 pandemic influenza A(H1N1) virus affects receptor binding.

Chutinimitkul S, Herfst S, Steel J, Lowen AC, Ye J, van Riel D, Schrauwen EJ, Bestebroer TM, Koel B, Burke DF, Sutherland-Cash KH, Whittleston CS, Russell CA, Wales DJ, Smith DJ, Jonges M, Meijer A, Koopmans M, Rimmelzwaan GF, Kuiken T, Osterhaus AD, Garcia-Sastre A, Perez DR, Fouchier RA.

Abstract

The clinical impact of the 2009 pandemic influenza A(H1N1) virus (pdmH1N1) has been relatively low. However, amino acid substitution D222G in the hemagglutinin of pdmH1N1 has been associated with cases of severe disease and fatalities.

 

Here, D222G was introduced in a prototype pdmH1N1 by reverse genetics, and the effect on virus receptor binding, replication, antigenic properties, and pathogenesis and transmission in animal models was investigated.

 

pdmH1N1 with D222G caused ocular disease in mice without further indications of enhanced virulence in mice and ferrets. pdmH1N1 with D222G retained transmissibility via aerosols or respiratory droplets in ferrets and guinea pigs.

 

The virus displayed changes in attachment to human respiratory tissues in vitro, in particular increased binding to macrophages and type II pneumocytes in the alveoli and to tracheal and bronchial submucosal glands.

 

Virus attachment studies further indicated that pdmH1N1 with D222G acquired dual receptor specificity for complex α2,3- and α2,6-linked sialic acids. Molecular dynamics modeling of the hemagglutinin structure provided an explanation for the retention of α2,6 binding.

 

Altered receptor specificity of the virus with D222G thus affected interaction with cells of the human lower respiratory tract, possibly explaining the observed association with enhanced disease in humans.

 

 

Testing here was done on mice, ferrets, guinea pigs, and on human cells in vitro, and each demonstrated (sometimes small) pathogenic differences between the D222G-engineered and regular pdmH1N1 virus.

 

In mice and ferrets, the D222G virus showed no increase in virulence with the exception of `ocular disease’ in mice (I’m guessing conjunctivitis, but without access to the full article, I can’t be certain).

 

Given the low incidence of the D222G mutation in the wild (less than 1.8%), it has been suggested that this mutation might render the virus less contagious, but ferret and guinea pig studies showed it retained transmissibility via aerosols and respiratory droplets.

 

The increased binding to type II pneumocytes in the alveoli (in vitro) is a particularly interesting finding, given that this was also observed in the Baskin Study of H5N1 vs human H1N1 viruses.

 

Seasonal H1N1 viruses, when they invade the lungs, are more likely to attack type I pneumocytes which handle the gas exchange (02 and C02) between the lungs and the blood stream.  

 

Type II pneumocytes are responsible for the production of surfactant with antimicrobial, immunomodulatory, and anti-inflammatory properties, and are the lung’s primary mechanism for repairing damaged cells.

 

Damaging them can significantly degrade the lung’s ability to recover from injury.

 

Which brings us to the last major finding, that D222G acquired dual receptor specificity for complex α2,3- and α2,6-linked sialic acids.

 

Familiar territory to regular readers of this blog, but at the risk of repeating myself:

 

A virus’s ability to bind to specific cells is controlled by its RBD or Receptor Binding Domain; an area of its genetic code that allows it to attach to, and infect, specific types of host cells.

 

(Very Simplified Illustration of RBDs)

 

Like a key into a padlock, the RBD must `fit’ in order to open the cell to infection.

 

Avian adapted influenza viruses bind preferentially to Alpha 2,3 receptor cells, which are commonly found in the digestive tract of birds.

 

Human adapted viruses have an affinity for the alpha 2,6 receptor cell, which populate the upper airway and lungs.

 

Humans have some avian-like alpha 2,3 receptor cells, particularly deep in the lungs. 

 

This has been suggested as the reason that when humans contract H5N1, it is usually a deep lung infection.  It has also been postulated that H5N1’s deeper lung infections may reduce human-to-human transmission, as sneezing is a less common symptom.   

 

This duel receptor affinity with the D222G mutation may help explain why some patients that contract it also develop more serious lung infections.

 

The operative word here being `may’. 

 

The bottom line here is that so far, whatever pathogenic differences this mutation may spark, it has had a relatively small effect on the overall mortality and morbidity of this virus. 

 

That could change, of course, if this mutation were to become more common, or if complementary concurrent changes to the genetic structure of the virus were to further enhance its virulence.

 

All in all, a fascinating piece of research, and one that advances our knowledge of this mutation considerably.  No, it doesn’t answer the `big question’, of whether this mutation will end up becoming a significant public health threat.

 

But scientific knowledge is gained incrementally. 

 

So stay tuned.

 

 

For more on the Baskin Study (Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus by Carole Baskin et. al.  that appeared PNAS), which looked at the comparative pathogenesis of seasonal H1N1, a 1918-like H1N1, and the H5N1 virus, you may enjoy my 3-part series available at the following links:

 

 

Dissecting the Influenza Pathogenesis Study Pt. 1

Dissecting the Influenza Pathogenesis Study Pt. 2

Dissecting the Influenza Pathogenesis Study Pt. 3

»» Read More

Study: What Makes Avian Flu So Deadly

 

 

 

# 4830

 

 

Avian flu, particularly H5N1, has our attention because unlike regular influenza, it has a very high mortality rate.  Among those we know to have been infected, roughly 60% have died.

 

A rate well over 100 times higher than with regular flu.

 

Roughly 18 months ago we got a look at a study that compared the pathogenesis (disease progression) of non-human primates (macaques) infected with the H5N1 virus, seasonal flu, and with two altered viruses carrying genetic material from the 1918 Spanish Flu.

 

The study, entitled Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus by Carole Baskin et. al.  appeared PNAS (The Proceedings of the National Academy of Science).

 

At the time, I wrote a 3-part essay which attempted to put this complex study into layman’s terms. 

 

For those interested in learning more about the human immune system, cytokine production, and the pathogenesis of influenza the Baskin study and these three blogs may be of value:

 

Dissecting the Influenza Pathogenesis Study Pt. 1 (link fixed)

Dissecting the Influenza Pathogenesis Study Pt. 2

Dissecting the Influenza Pathogenesis Study Pt. 3

 

While the Baskin study is fascinating, and gives us considerable insight into what avian flu does to primates, it really doesn’t explain how or why.

 

To help us with those questions, researchers at Baylor College of Medicine and The University of Texas at Austin have studied the molecular structure of the avian flu virus, and have found 4 tiny amino acids dangling from the tip of a protein called NS1 that they believe at least partially explains this virulence.

Their research appears in the latest issue of the Journal of Virology.  You can access the abstract at the link below.

 

J. Virol. doi:10.1128/JVI.01278-10

The ESEV PDZ Binding-Motif of the Avian Influenza A Virus NS1 Protein Protects Infected Cells from Apoptosis through Directly Targeting Scribble

 

Hongbing Liu, Lisa Golebiewski, Eugene C. Dow, Robert M. Krug, Ronald T. Javier, and Andrew P. Rice

 

Admittedly, to non-scientists, this title is more than a little imposing.  

 

Apoptosis is programmed cellular death, while Scribble is a protein the body’s immune system uses to promote the early death (apoptosis) of virally infected cells. 

 

In this way, the immune system can help limit viral replication while it develops defenses (antibodies, cytokines, etc.) against the invader.

 

In the case of H5N1, the virus’s PDZ binding-motif works to  deactivates the host’s apoptosis defense mechanism, giving the virus a decided advantage.

 

Fortunately, for us mere mortals without a virology degree, we have a less technical background piece from the BCM news site which is well worth following the link and reading in its entirety. 

 

 

Avian flu virus protein turns off cell defense

HOUSTON -- (August 23, 2010) -- As the avian influenza A virus seeks to infect its bird hosts, it brings a special weapon to the fray – four tiny amino acids that hang off the end of a viral protein called NS1, said researchers from Baylor College of Medicine (www.bcm.edu) and The University of Texas at Austin in a report that appears in the current Journal of Virology.

 

This collection of molecules known as the PDZ binding-motif help make the avian virus – known to experts at H5N1 – particularly virulent and a threat to human populations everywhere.

(Continue . . . )

»» Read More

Study: Clinical Course Of H5N1 In 22 Patients

 

 

# 4615

 

 

On of the great mysteries surrounding human H5N1 infections has been the abysmal survival rate, particularly in Indonesia and parts of South East Asia.   

 

Worldwide (among confirmed cases), 294 of 498 victims have died.  That’s roughly a 59% fatality rate.  The rate varies, however, with 82% of H5N1 cases dying in Indonesia while less than 32% have succumbed in Egypt.

 

Sobering numbers, particularly when compared to the 2.5%-5% fatality rate experienced during the 1918 pandemic.  Fortunately, the number of cases remains low, and the virus has yet to adapt well enough to human hosts to become a pandemic.

Although human cases have been detected and treated for more than a decade, we rarely get detailed information regarding their course of illness, treatment, or outcome.  

 

In August of 2008 we did get a review of 26 cases out of China, which shed some light on the pathogenesis of the virus (see Clinical Case Review Of 26 Chinese H5N1 Patients)

 

Today a glimpse, via an abstract for a study (subscription req.) in The Journal CHEST, that outlines the clinical course of 22 patients at one hospital in Indonesia. 

 

A hat tip to Dutchy at FluTrackers for this link.

 

 

Clinical course of H5N1 avian influenza in patients at the Persahabatan Hospital, Jakarta, Indonesia, 2005-2008.

Priyanti Z Soepandi, Erlina Burhan, Hadiarto Mangunnegoro, Arifin Nawas, Tjandra Yoga Aditama, Lia Partakusuma, Fathiyah Isbaniah, Suhud Malik, Rachel Benamore, J Kevin Baird, Walter RJ Taylor, and the H5N1 clinical team

Abstract

Background: Limited understanding of the presentation and course of influenza A/H5N1 infection in humans hinders evidence-based management.

Methods: Review of case records of patients with real time, PCR confirmed H5N1 influenza admitted to the Persahabatan Hospital (RSP), Jakarta, Indonesia.

Results: 22 previously well patients, age 3 to 47 years (median 24.5), were identified. All attended a clinic or hospital after a median of 2 days of illness (range 0-7). Times to first dose of oseltamivir (3 died before receiving oseltamivir) were 2 to 12 days (median 7), administered mostly (n=15) at RSP. 19 patients required mechanical ventilation. Deaths numbered 18 (case fatality=82%) occurring within hours to 6 days of RSP admission, corresponding to 6 to 16 days of illness.

Admission hyperglycemia (≥ 140 mg/dL), unrelated to steroids or known underlying diabetes mellitus, and raised d-dimers (0.81 – 5.2 mg/L, ULN < 0.5 mg/L) were present in 14/21 (67%) and 20/21 (95%) patients, respectively.

Fibrinogen concentrations were mostly low/normal 129.9-517.9 mg/dL (median 241.1, normal 200-400 mg/dL) whilst CRP (9/11) and ferritin (6/8) were raised. Risk factors for death (univariate analysis) included: (i) raised d-dimers, (ii) hyperglycemia, (iii) raised urea, (iv) more extensive chest X ray shadowing, and (v) lower admission oxygen saturation.

Conclusions: Early diagnosis and effective treatment of human H5N1 infection remains challenging. Most patients were referred late with advanced disease. Oseltamivir had limited clinical impact. Raised d-dimers, consistent with fibrinolysis, and hyperglycemia warrant more research to determine their underlying mechanisms and optimal treatment.

 

 

A little interpretation for non-medical readers may be helpful here, particularly regarding the elevated d-dimers readings. 

 

D-dimer is a protein fragment left behind in the blood after a fibrin clot has been degraded.  The test is normally used to diagnose thrombosis, but is also diagnostic for DIC (disseminated intravascular coagulation).

 

DIC (which can present as widespread internal bleeding, hemorrhagic shock, and renal failure) is a condition sometimes seen in severe cases of sepsis  and ARDS (Acute Respiratory Distress Syndrome).

 

Unlike Egypt, which has reported favorably on the efficacy of oseltamivir (Tamiflu) in the treatment of H5N1, this report states that oseltamivir had limited clinical impact.

 

Whether this has something to do with the clade of virus being encountered in Indonesia, or the delay in starting treatment, or some other unknown variable, isn’t clear.

 

The d-dimer readings, and hyperglycemia upon admission - which both appear linked to bad outcomes - add new and tantalizing clues to the  pathogenesis of this virus in humans. 

 

In February of 2009 we got a look at a study that compared the pathogenesis (disease progression) of non-human primates (macaques) infected with the H5N1 virus, seasonal flu, and with two altered viruses carrying genetic material from the 1918 Spanish Flu.

 

The study, entitled Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus by Carole Baskin et. al.  appeared PNAS (The Proceedings of the National Academy of Science).

 

At the time, I wrote a 3-part essay dissecting this study for the layperson, which some might still find useful.

 

Dissecting the Influenza Pathogenesis Study Pt. 1

Dissecting the Influenza Pathogenesis Study Pt. 2

Dissecting the Influenza Pathogenesis Study Pt. 3

 

Despite all we’ve learned from human cases, and lab research, there are plenty of  unanswered questions surrounding the virulence of H5N1.   

Questions that we would dearly love to have the answers to now, before the virus becomes a graver threat.

»» Read More

There’s No Flu Like A New Flu

 

 

# 4488

 

 

It has now been a year since the first cases of novel H1N1 emerged, and while the pandemic of 2009 turned out to be less devastating than some feared, this new influenza virus continues to surprise doctors and scientists by its unusual characteristics.

 

Since novel H1N1 has (at least for now) apparently supplanted the previously circulating influenza A strains (H3N2 and seasonal H1H1), we need to recognize, respect, and learn to deal with its differences.

 

Over the past year we’ve seen a number of studies highlighting ways in which novel H1N1 differs from flu strains of the recent past. 

 

Today, a brief review of some of those studies.

 

Influenza A viruses are notorious for their ability to mutate and adapt, and so the characteristics observed in this new virus may change over time. 

 

The most obvious difference between novel H1N1 and seasonal influenzas of the past has been the age shift in infections, hospitalizations, and deaths.

 

Unlike seasonal influenza, novel H1N1 has taken its biggest toll on those under the age of 65. 

 

While the total number of flu-related fatalities may prove to be less during this pandemic than in previous years, In terms of years of life lost, novel H1N1 was anything but benign (see Study: Years Of Life Lost Due To 2009 Pandemic).

 

The following chart comes from:

Preliminary Estimates of Mortality and Years of Life Lost Associated with the 2009 A/H1N1 Pandemic in the US and Comparison with Past Influenza Seasons

 

By Cecile Viboud, Mark Miller, Don Olson, Michael Osterholm et al (5 authors)

 

 

And here we have a breakdown of estimated infections, hospitalizations, and deaths by age groups from the CDC.

 

 

Both sources demonstrate the burden shift to a younger population with this virus.   The median age of death from novel H1N1 related illness (37.4 years)  has been half of that from seasonal flu.

 

In terms of years of life lost (YLL), the average pandemic flu death has a many fold greater impact than the average seasonal flu fatality.   

 

Should novel H1N1 drift antigenically enough over time to evade the pre-existing immunity demonstrated by those over the age of 50, these trends could change.

 

Novel H1N1 also appears to differ from seasonal flu in how it is transmitted, at least according to researchers in Hong Kong who discovered that the novel H1N1 virus – unlike seasonal flu – easily infects and replicates in the conjunctival tissues of the eye  (see I Only Have Eyes For Flu).

 

The study  appears in The American Journal of Pathology is entitled:

 

Tropism and Innate Host Responses of the 2009 Pandemic H1N1 Influenza Virus in ex Vivo and in Vitro Cultures of Human Conjunctiva and Respiratory Tract

Michael C.W. Chan^*@, Renee W.Y. Chan^*, Wendy C.L. Yu^*, Carol C.C. Ho^*, Kit M. Yuen^*, Joanne H.M. Fong^*, Lynsia L.S. Tang^*, Wico W. Lai, Amy C.Y. Lo, W. H. Chui, Alan D.L. Sihoe, Dora L.W. Kwong^¶, David S.H. Wong, George S.W. Tsao, Leo L.M. Poon^*, Yi Guan^*, John M. Nicholls, and Joseph S.M. Peiris^**@

 

Conjunctivitis is sometimes associated with mild avian flu infections in humans, and in tests conducted on baby piglets in Thailand last May (see Casting Viruses Before Swine), conjunctivitis was one of the commonly observed symptoms with the novel H1N1 virus.

 

Another difference observed with novel H1N1 has been its unusually high rate of gastro-intestinal symptoms.  

 

Diarrhea and vomiting have both been commonly reported with H1N1 pandemic influenza, symptoms that occur far less often with seasonal influenza. 

 

Last August The Lancet published a study entitled:

 

Clinical characteristics of paediatric H1N1 admissions in Birmingham, UK

S Hackett a, L Hill a, J Patel a, N Ratnaraja b, A Ifeyinwa b, M Farooqi b, U Nusgen c, P Debenham c, D Gandhi c, N Makwana b, E Smit a d, S Welch a

 

Included in this study was a chart showing the incidence of symptoms observed in pediatric H1N1 admissions. I’ve modified it slightly to highlight the gastrointestinal symptoms.

 

 

Repeatedly we’ve seen nausea, vomiting, and diarrhea listed as atypical symptoms with novel H1N1, as in this report by Maggie Fox of Reuters.

 

US flu study confirms H1N1 more serious in youth

Thu Oct 8, 2009 10:41pm BST

* 45 percent of those hospitalized were under 18

* Diarrhea, vomiting in 42 percent of children with H1N1

* Quick drug treatment may save lives

By Maggie Fox, Health and Science Editor

WASHINGTON, Oct 8 (Reuters) - A study of people who became seriously ill and died with the new pandemic swine flu confirms it is hitting a younger population than the seasonal flu and causes often different symptoms.

 

 

It should be noted that there is some research that suggests that seasonal flu (A & B) may replicate in the G.I. tract of children as well (see Influenza’s Gastrointestinal Connection).

 

The incidence of G.I. involvement with novel H1N1 appears higher than with seasonal flu, however.

 

Beyond the gastrointestinal component, a number of other studies indicate that the novel H1N1 virus – in some small subset of victims – can produce profound lung damage.  

 

In a study that appeared earlier this year in The Journal of Infectious Diseases  researchers ast the Department of Virology, Erasmus Medical Centre and ViroClinics Biosciences BV, Rotterdam used a ferret model to test the pathogenicity of the novel H1N1 virus against seasonal and bird flu.

 

Severity of Pneumonia Due to New H1N1 Influenza Virus in Ferrets Is Intermediate between That Due to Seasonal H1N1 Virus and Highly Pathogenic Avian Influenza H5N1 Virus

Judith M. A. van den Brand,Koert J. Stittelaar, Geert van Amerongen,Guus F. Rimmelzwaan, James Simon, Emmie de Wit, Vincent Munster,Theo Bestebroer, Ron A. M. Fouchier, Thijs Kuiken, and Albert D. M. E. Osterhaus

Results.

Our results showed that the new H1N1 virus causes pneumonia in ferrets intermediate in severity between that caused by seasonal H1N1 virus and by HPAI H5N1 virus. The new H1N1 virus replicated well throughout the lower respiratory tract and more extensively than did both seasonal H1N1 virus (which replicated mainly in the bronchi) and HPAI H5N1 virus (which replicated mainly in the alveoli). High loads of new H1N1 virus in lung tissue were associated with diffuse alveolar damage and mortality.

Conclusions.

The new H1N1 virus may be intrinsically more pathogenic for humans than is seasonal H1N1 virus.

 

In December the NIH released information regarding autopsies performed on H1N1 victims, that showed severe pulmonary damage.  A brief excerpt follows:

 

 

FOR IMMEDIATE RELEASE
Monday, Dec. 7, 2009

Media Contact: Anne A. Oplinger
(301) 402-1663
niaidnews@niaid.nih.gov

New York Autopsies Show 2009 H1N1 Influenza Virus Damages Entire Airway

In fatal cases of 2009 H1N1 influenza, the virus can damage cells throughout the respiratory airway, much like the viruses that caused the 1918 and 1957 influenza pandemics, report researchers from the National Institutes of Health (NIH) and the New York City Office of Chief Medical Examiner. The scientists reviewed autopsy reports, hospital records and other clinical data from 34 people who died of 2009 H1N1 influenza infection between May 15 and July 9, 2009. All but two of the deaths occurred in New York City. A microscopic examination of tissues throughout the airways revealed that the virus caused damage primarily to the upper airway—the trachea and bronchial tubes—but tissue damage in the lower airway, including deep in the lungs, was present as well. Evidence of secondary bacterial infection was seen in more than half of of the victims.

 

And as far back as September, pathologists were talking about the remarkably severe lung damage they were seeing from novel H1N1.

Once again, Maggie Fox of Reuters reported:

 

Swine flu deaths show this flu is different – experts

Tue Sep 15, 2009 10:40pm BST

By Maggie Fox, Health and Science Editor

WASHINGTON (Reuters) - Autopsies on people who have died from the new pandemic H1N1 flu show this virus is different from seasonal influenza, even if it has not yet caused more deaths, experts told a meeting on Tuesday.

 

Americans who died from swine flu had infections deep in their lungs, Dr. Sherif Zaki of the U.S. Centres for Disease Control and Prevention told a meeting of flu experts, including damage to the alveoli -- the structures in the lung that deliver oxygen to the blood.

 

 

Beyond the gastro-intestinal and pulmonary symptoms, we’ve also seen a number of neurological complications, particularly in children.

 

These sorts of complications have been seen in seasonal flu as well.

 

The first hint of this came last summer when the CDC’s MMWR (July 23rd issue) reported on 4 pediatric patients with the novel H1N1 virus who presented with neurological symptoms including unexplained seizures and altered mental status.

 

Neurologic Complications Associated with Novel Influenza A (H1N1) Virus Infection in Children --- Dallas, Texas, May 2009

. . .  On May 28, 2009, the Dallas County Department of Health and Human Services (DCHHS) notified CDC of four children with neurologic complications associated with novel influenza A (H1N1) virus infection admitted to hospitals in Dallas County, Texas, during May 18--28.

 

In November, in a blog entitled Japan: Influenza Related Encephalopathy we looked at this report in the Yomiuri Shimbun.

 

132 flu patients hit with brain disorders since July

The Yomiuri Shimbun

A total of 132 influenza patients in Tokyo and 27 prefectures have developed encephalopathy, or swelling of the brain, since July, according to the National Institute of Infectious Diseases.

Normally, only about 40 to 50 seasonal flu sufferers develop encephalopathy each year, meaning the latest figure has already more than doubled in four months since the new strain of flu began spreading.

 

And in February of this year, we saw an expedited letter that appeared in the CDC’s Journal of Emerging Infectious Diseases .

 

DOI: 10.3201/eid1603.091699

Kitcharoen S, Pattapongsin M, Sawanyawisuth K, Angela V, Tiamkao S. Neurologic manifestations of pandemic (H1N1) 2009 virus infection [letter]. Emerg Infect Dis. 2010 Mar; [Epub ahead of print]

 

Neurologic Manifestations of Pandemic (H1N1) 2009 Virus Infection

This four page letter goes on to describe the presentation, testing, and course of illness of a 34-year-old man, previously healthy, who was admitted to Chaiyaphum Hospital in Chaiyaphum, Thailand, back in August with flu-like symptoms.

 

 

Novel H1N1 is obviously a somewhat different brand of influenza from that which we’ve dealt with over the past few decades. In terms of absolute mortality, it may have spared lives, but in terms of years of life lost (YLL), it has had a serious impact.

 

 

It also presents in some patients differently than ordinary flu, and may differ somewhat in modes of transmission.

 

Since novel H1N1 appears poised to be the dominant flu strain for the immediate future, it is important that we recognize and accept the ways that this flu is different.  

 

Brushing it off as `no worse than regular flu’, as some are inclined to do, invites complacency. 

 

Something that could end up costing lives in the long run.

 

While the pandemic of 2009 could have been a lot worse, there is little comfort to be gained by being felled by a `mild’ virus.  And of course, the whole H1N1 story has yet to be written.

 

It is still worthwhile to get the H1N1 vaccine if you have not done so, and of course, the seasonal shot this fall.  Hand hygiene, staying home when you are sick, and cough and sneeze etiquette are healthy habits year round, not just during flu season.

 

Meanwhile, a year downrange, the pandemic of 2009 is proving to be a fascinating and informative real-life laboratory experiment conducted on a global scale. 

 

One that, thankfully, hasn’t produced more carnage than it has.

 

The knowledge we gain from observing this pathogen, unraveling its secrets, and dissecting our response to it will hopefully pay big dividends when the next pandemic virus threatens humanity.

»» Read More

I Only Have Eyes For Flu

 

 

# 4312

 

 

The study which was conducted in Hong Kong and which appears in The American Journal of Pathology is entitled:

 

Tropism and Innate Host Responses of the 2009 Pandemic H1N1 Influenza Virus in ex Vivo and in Vitro Cultures of Human Conjunctiva and Respiratory Tract

Michael C.W. Chan^*@, Renee W.Y. Chan^*, Wendy C.L. Yu^*, Carol C.C. Ho^*, Kit M. Yuen^*, Joanne H.M. Fong^*, Lynsia L.S. Tang^*, Wico W. Lai, Amy C.Y. Lo, W. H. Chui, Alan D.L. Sihoe, Dora L.W. Kwong^¶, David S.H. Wong, George S.W. Tsao, Leo L.M. Poon^*, Yi Guan^*, John M. Nicholls, and Joseph S.M. Peiris^**@

 

A mouthful to be sure, but one of the major findings is that the novel H1N1 virus – unlike seasonal flu – easily infects and replicates in the conjunctival tissues of the eye.

 

You’ll probably also note some well known names among the authors of this study, including Guan Yi and Malik Peiris.

 

 

Conjunctivitis is sometimes associated with mild avian flu infections in humans, and in tests conducted on baby piglets in Thailand last May (see Casting Viruses Before Swine), conjunctivitis was one of the commonly observed symptoms with the novel H1N1 virus.

 

Anecdotal accounts have come in as well associating conjunctivitis and the novel H1N1 virus.  Indigo Girl on the allnurses pandemic forum  started a thread on that very subject in late July of last year.  

 

But today’s study is the first I’ve seen that directly addresses the virus’s ability to infect a host through the membranes of the eye.

This study also seems to indicate that – unlike the highly virulent H5N1 virus – novel H1N1 is no more likely to produce a cytokine disruption than is seasonal influenza.

 

First the abstract from the Journal Article, then a Hong Kong newspaper story on the findings.

 

     Abstract

The novel pandemic influenza H1N1 (H1N1pdm) virus of swine origin causes mild disease but occasionally leads to acute respiratory distress syndrome and death. It is important to understand the pathogenesis of this new disease in humans.

 

We compared the virus tropism and host-responses elicited by pandemic H1N1pdm and seasonal H1N1 influenza viruses in ex vivo cultures of human conjunctiva, nasopharynx, bronchus, and lung, as well as in vitro cultures of human nasopharyngeal, bronchial, and alveolar epithelial cells.

 

We found comparable replication and host-responses in seasonal and pandemic H1N1 viruses. However, pandemic H1N1pdm virus differs from seasonal H1N1 influenza virus in its ability to replicate in human conjunctiva, suggesting subtle differences in its receptor-binding profile and highlighting the potential role of the conjunctiva as an additional route of infection with H1N1pdm.

 

A greater viral replication competence in bronchial epithelium at 33°C may also contribute to the slight increase in virulence of the pandemic influenza virus. In contrast with highly pathogenic influenza H5N1 virus, pandemic H1N1pdm does not differ from seasonal influenza virus in its intrinsic capacity for cytokine dysregulation.

 

Collectively, these results suggest that pandemic H1N1pdm virus differs in modest but subtle ways from seasonal H1N1 virus in its intrinsic virulence for humans, which is in accord with the epidemiology of the pandemic to date. These findings are therefore relevant for understanding transmission and therapy.

 

The following is an excerpt from a Hong Kong Standard story on this research.  Follow the link to read it in its entirety. 

 

New swine flu in eyes fear

MaryAnnBenitez
Tuesday, February 02, 2010

 

New research has revealed that the swine flu virus can be spread through the eyes, underscoring the importance of personal hygiene to avoid the disease.

 

University of Hong Kong researchers compared the ability of swine flu H1N1 and the seasonal H1N1 and H3N2 flu viruses to replicate in cells and tissue samples from the human upper and lower respiratory tract and in the cells lining the surface of the eye.

 

It found that swine flu is more efficient than seasonal flu in infecting the eyes.

 

The study by the HKU departments of microbiology and pathology was published in the American Journal of Pathology.

 

"We found that pandemic H1N1 flu can actually infect and replicate in conjunctiva [the eyes] while the seasonal flu cannot," said Michael Chan Chi-wai, research assistant professor of the department of microbiology.

 

"The public should be made more aware to wash their hands before rubbing their eyes. It is an important route for pandemic flu."

 

The research also found that unlike bird flu H5N1, swine flu did not lead to a hyper-activation of the human cell cytokine response, a mechanism believed to contribute to the severity of bird flu H5N1 infection.

(Continue . . . )

»» Read More