New Chinese Bird Flu Still Pandemic Threat

Throughout April and early May 2013, news headlines focused on a bird flu virus that was sickening people in China’s urban centers. Chinese influenza experts isolated the avian (bird) flu virus and determined it was an influenza A (H7N9) subtype, which had never been identified in humans before. As new cases and fatalities were reported almost daily, media headlines focused on the pandemic potential of the virus.

But human infections virtually stopped in early May — and so did public interest. No longer bombarded by bird flu information, most people have shelved concern about the H7N9 avian influenza virus. The few news headlines that appeared focused mostly on the cost to the poultry industry of bird flu containment measures — and how well the Chinese government has purportedly handled this latest avian flu outbreak. At present, China’s H7N9 avian flu outbreak seems to have turned into nothing more than another blip in public health history textbooks.

But it might be too soon to assume that the world has escaped a devastating influenza pandemc. There are still more questions than answers about the latest flu outbreak in China. Should you worry about the new Chinese bird flu? Does the slowdown in infections mean that H7N9 avian flu virus is not a threat to most humans? Or is the H7N9 avian influenza virus just temporarily stalled, mutating until it causes a horrific global outbreak of disease?

Experts are still concerned – and you should be, too. Here’s a brief primer on the avian flu (influenza A(H7N9) virus) outbreak in China and how it could affect you, no matter where you live.

The Emergence of Influenza A (H7N9)

On March 31, 2013, Chinese health officials reported to the World Health Organization (WHO) that a new bird flu virus, influenza A(H7N9), had begun infecting people in February, causing severe illness and death. The count of confirmed cases and deaths in China’s avian flu outbreak spiraled upward throughout April, reaching 126 cases and 24 deaths on April 29.

The first human cases of H7N9 infection occurred in Shanghai. By early May, the H7N9 “bird flu” virus, officially dubbed influenza A(H7N9), had spread to cities and provinces through large swaths of China, starting in the south and spreading to the north and west. A 53-year-old Taiwanese man who traveled to China returned home with the infection, the first case outside China.

Faced with the potential threat of pandemic influenza, global health officials responded quickly. Public health experts from the World Health Organization (WHO), the U.S. Centers for Disease Control and Prevention (CDC), and laboratories around the world joined the Chinese CDC in trying to stem the outbreak.

In China, open poultry markets were closed and chickens slaughtered in an attempt to control the spread of the virus. New diagnostic tests were developed, the genomic sequence of the virus posted and analyzed, and surveillance increased in China and elsewhere. On May 8, the U.S. declared that the new bird flu virus “poses a significant potential for a public health emergency” and gave emergency use authorization for diagnostic kits – clearing the fast track for rapid approval of tests for the H7N9 virus.

The response seemed to work. The outbreak tapered off in early May, finally stabilizing at 131 cases and 36 deaths in mid-May, with the last confirmed case reported on May 8. Another case (in a six-year ol boy) and death (in an unidentified patient) were reported on May 28.

Health officials, including well-known virologist Robert Webster of St. Jude Children’s Research Hospital in Memphis, praised China’s rapid response in closing poultry markets and sharing information with the international health community.  Webster noted that the international health community had little idea what was going on in China during the height of H5N1 outbreaks in birds and humans and contrasted the response to H7N9. “It’s like the difference between night and day,” Webster said.

Yet the threat posed by H7N9 remains serious. Officials at the U.S. Centers for Disease Control and Prevention (CDC) warned that lack of new cases may be the result of a seasonal shift in the virus. How the virus spreads – that is, the epidemiology of the virus – CDC officials cautioned, has not changed significantly. About three out of four infections have been linked directly to infected poultry and environments.

Two family clusters have been identified in which limited human-to-human transmission may have occurred. That, along with genetic changes in the H7N9 virus that suggest it has at least partly adapted to mammals, still has scientists concerned that the virus has the potential to travel easily between people in a manner called “sustained human-to-human transmission.”

Seasonal flu viruses have this trait. If the influenza A(H7N9) virus mutates so it can infect people like seasonal flu viruses, the results would be catastrophic. Because H7 viruses have never been known to infect humans before, no one has immunity to the virus. This, experts believe, is why the majority of people who have contracted the new bird flu have become extremely ill – and why it is so lethal.

What is Bird Flu? What is Influenza Type A?

Avian Influenza A(H7N9) is a type of influenza “A” virus – in common parlance, “bird flu.” There are many types of avian influenza viruses. Avian influenza is infectious – that is, it spreads easily between birds – and widespread. Fifteen subtypes of type-A influenza viruses are known to infect birds. Infected birds show a wide range of symptoms, which vary from slight illness to severe, quickly-spreading, fatal disease.

What Do the H’s and N’s Mean?

The “H” and “N” in influenza A viruses’ names are shorthand for two proteins found on the surface of those viruses. The “H” stands for hemigglutinin (HA), and the “N” for neuraminidase (NA). Together, these proteins help to determine the, including which species it can infect and . Their structure determines whether the virus can attach to cells in the human respiratory tract, which is necessary for rapid human-to-human transmission.

There are 16 HA subtypes and 9 NA subtypes of influenza A viruses. In addition, HA and NA proteins can combine in many different ways. Many different types and combinations of the proteins, only some of which have the correct sequence (“key”)

Birds can carry all known subtypes of influenza A viruses, but only some types and subtypes occur with any regularity in humans. The chief “human flu viruses” are H1N1, H1N2, and H3N2.

Why is Avian Influenza A(H7N9) and Why is H7N9 Different?

Unlike “high pathogenic” influenza A viruses like H5N1, which is easy to detect because it makes birds very sick and often kills them, H7N9 is a “low pathogenic” avian influenza. That means most birds infected with the influenza A(H7N9) virus don’t become sick (low pathogeneity has nothing to do with the level of illness it causes in humans).

While that may be good news for birds, it’s not good news for controlling the virus’ spread. Because H7N9 doesn’t make chickens sick, it is nearly impossible for farmers to detect, said Juan Lubroth, chief veterinary officer at the UN’s Food and Agriculture Organization (FAO). Undetected, the virus can spread widely in birds.

H7N9 is also unique in its apparently urban origins. Historically, most influenza A viruses that have caused a pandemic have originated in agricultural settings. Such was the case with the 2009 H1N1 virus, which appears to have started in pigs – hence the “swine flu” designation. And the devastating 1918 “Spanish” flu is thought to have originated on a farm in Topeka, Kansas.

In contrast, H7N9 appears to be mostly an urban phenomenon, with few cases identified in rural areas. It does appear to be linked to live poultry markets in China’s largest cities. Public health experts have long expressed concern about poor sanitation, close proximity of many people to lots of animals, and open integration of wild and domestic birds in these markets, making them a breeding reservoir for influenza and other viruses.

Is H7N9 going to cause a pandemic?

CDC director Tom Friedan told Reuters News on May 8: “This particular virus is not going to cause a pandemic because it doesn’t spread person-to-person,” Frieden said. “But all it takes is a bit of mutation for it be able to go person-to-person.”

“I cannot say with certainty whether that will happen tomorrow, within 10 years or never.”

Friedan’s statement (misconstrued by a very bad headline from Reuters, “Current China bird flu virus can’t cause pandemic”), sums up why experts are still so nervous: The influenza A(H7N9) virus, in its current form, cannot travel from person to person easily enough to cause an influenza pandemic. But that doesn’t mean it couldn’t develop the ability to travel human to human. And if it does, the results could be unimaginably catastrophic.

Friedan and other health officials are concerned about the pandemic potential of H7N9 for several reasons, but two stand out: 1) a very high case fatality rate and 2) the potential for the virus to mutate and spread easily among humans.

Epidemiologists measure the severity of a disease using a calculation called the “case fatality rate,” abbreviated “CFR.” It’s a simple ratio: Out of the people who have the disease, how many have died?

At first blush, that would seem easy to determine for H7N9. Of the 132 confirmed cases, 37 people have died. That’s a CFR of 37/132, or more than one out of four people.

But the true CFR won’t be known until epidemiologists know about how many people truly have the disease. And with influenza, that may be difficult to determine. Many respiratory infections share common symptoms, including a stuffy nose, sore throat, sneezes, and fever. Many people may develop mild disease and never seek medical help.

Epidemiologists refer to this as “the denominator problem:” Because we only hear about the worst cases of disease, it may appear to be far more lethal than it is. It’s possible that the virus is very widespread and causing only mild illness in most people.

At least that’s what flu experts such as Laurie Garrett have pointed out. But results published May 8 by Chinese public health experts and the CDC suggest that the prevalence of H7N9 may indeed be very low – and that 24% CFR may be frighteningly close to accurate. For comparison, the Great Flu (aka “Spanish Flu) of 1918-1919 had a 1% CFR.

To come up with that estimated CFR, researchers tested more than 20,000 people with flu-like illness during March and April. They found only 6 cases of H7N9. Four of the cases had been exposed to poultry, providing further evidence that transmission is still largely confined to poultry-to-human.

Health officials are concerned that the virus may develop the ability to easily infect humans. Avian influenza A H7 viruses usually infect birds, although  a few H7 subtypes have been known to infect humans. In the past, they’ve caused only mild illness and haven’t spread from person to person.

But H7N9 has caused serious illness and death in the people it has infected. Although it has not spread person to person yet, this particular form of the virus seems to have started well on its way to that viral goal. Unlike the influenza A(H5N1) strain, which still retains primarily avian traits, the H7N9 strain that has infected humans appears to have adapted to mammals. For example, this H7N9 flu virus has genetically adapted to be able to thrive at human body temperature, which is much lower than birds’ body temperatures.  

And then there are the ferrets. On May 23, a group of Chinese and U.S. scientists published results of a study of transmission of Influenza A H7N9 in ferrets and pigs. Influenza researchers often use ferrets to study the spread of influenza viruses in mammals, including humans. Likewise, pigs have served as a “mixing bowl” for avian and mammalian influenza strains.

When researchers purposefully infected ferrets and pigs, two troublesome trends emerged. The ferrets not only became infected, they passed the virus to uninfected ferrets. And they passed the virus on before they showed signs or symptoms of disease. That suggests that the behavior of the virus in humans may be similar.

A mutable opponent

Thus far, the influenza A (H7N9) virus has not shown that it can easily and rapidly be transmitted between humans. Although two family clusters have been identified, it’s unclear whether individuals in those families contracted the disease because they were all exposed to the H7N9 virus in the environment, or if they got it from each other. If the transmission is human-to-human, it appears to be limited.

In other words, there’s no evidence of sustained human-to-human transmission, which is what the virus needs to, well, go viral. Experts estimate the H7N9 virus would need to undergo at least two more significant mutations for that to happen.

So why are flu experts still holding their breath? The answer to that question has to do with flu virus’s ability to mutate – i.e. change its genetic material – very rapidly: Two more mutations, especially in a virus that is already infecting humans, might not be that hard a goal for the mutable flu virus to achieve. A study reported in The Lancet on May 6 by Chinese researchers gives an idea of the complexity and speed of the mutation process that the H7N9 virus has undergone up till now.

The team took isolates from people and infected birds, then compared them to H7N9 viruses found in wild birds. The matching process showed that the “H” gene in H7N9 seems to have come from avian influenza viruses in ducks. The reservoir for the “N” gene in H7N9 seems to be wild migratory birds along the east Asian flyway.

The virus also contains six internal genes, which, the researchers determined, seem to have come from two groups of H9N2 avian influenza viruses found in chickens. Ducks and chickens appear to have acted as intermediate hosts, leading to human infections with the virus.

The research team concluded that the novel H7N9 virus could have at least four origins, and it appears to have evolved into at least two different lineages since then.

That’s a whole lot of recombining and interacting, in multiple species. And it hasn’t stopped, even if the virus has gone underground for the moment.

What’s going to happen to H7N9?

The H7N9 virus has pandemic potential. That’s why public health experts are encouraging people to shift from a “wait and see” attitude to a “prepare and see” approach.

But saying a virus has pandemic potential is very different from saying it’s going to cause a pandemic. As Michael Osterholm of the University of Minnesota and colleagues wrote in the Journal of the American Medical Association, the virus could go three ways:

“Three primary scenarios exist for how this A(H7N9) virus outbreak will unfold. First, the virus could disappear in the animal reservoir, ending new human cases. Second, the virus could persist in the animal reservoir, resulting in sporadic human infections. Third, the virus could, through mutation or reassortment, become readily transmissible between humans, resulting in a global pandemic.”

In other words, all the attention to the H7N9 virus outbreak could turn out to be much ado about nothing (unless you happen to be one of those 131 people affected by the virus or their loved ones). Or it could lead to a global outbreak of influenza that could leave millions dead in its wake, destroy economic and political systems and infrastructure, and wreak havoc with humankind. We just don’t know.

What is the Treatment for H7N9 Bird Flu?

Treatment for H7N9, like treatment for any flu, is mostly supportive. Almost all of the people in whom the virus has been identified have required hospitalization, where they were given oxygen, fluids, and anti-viral drugs. People who have fallen ill with H7N9 have needed help with breathing and other body functions.

Antiviral medications have helped some – but not all – people who have been sickened by H7N9. For any of antiviral drugs to be effective in slowing the virus, they need to be administered early in the course of the disease – often before the person realizes how sick she or he is. Antibiotics may be used to help prevent secondary bacterial infections, but they are not effective in stopping the virus.

Based on the initial genetic analyses of the virus, experts expected it to be sensitive to the neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza), but resistant to the antiviral drugs amantadine (Symmetrel) and rimantadine (Flumadine). But on May 28, a group of Chinese researchers reported  signs that resistance to oseltamivir may develop after people start taking the drug.

The team, led by Zhenghong Yuang, PhD, Shanghai Medical College of Fudan University in China, tracked the level of virus in throat swabs of 14 H7N9 patients who were being treated with antiviral medications. The medications led to lower viral load in 11 patients. But three patents became severely ill and required additional extracorporeal membrane oxygenation (ECMO); two of those three died. The researchers isolated a viral mutation associated with drug resistance from two of the patients, but not from others.

Yuang and colleagues wrote in The Lancet, they wrote, “the apparent ease with which antiviral resistance emerges … is concerning; it needs to be closely monitored and considered in future pandemic response plans.”

Will there be a H7N9 vaccine?

Although it’s too early for a vaccine to go into global production, vaccine manufacturers have stepped up preparation. On May 1, Greffex announce that it had created a comprehensive vaccine for influenza A(H7N9). On May 14, Novavax announced that it had completed purification of one lot of H7N9 vaccine and begun animal studies. Every major flu vaccine manufacturer has begun work on a vaccine.

The question, though, is not whether a vaccine can be developed. We know how to develop flu vaccines. The question is whether we have the knowledge, technology, capacity, and political willpower to develop an effective H7N9 flu vaccine, manufacture and distribute that vaccine quickly and equitably in a way that can stem the spread of the virus, should it spread widely.

Political and economic barriers stand in the way of you rolling up your sleeve for the needle. As Deborach MacKenzie observes in New Scientist, investment into research and development for flu vaccine technologies is sorely lacking. We do not currently have the technology and capacity to quickly produce enough vaccine, should H7N9 acquire those last two mutations it needs to spread quickly from human to human. And should the need for flu vaccine arise, political barriers mean that vaccine is likely to be distributed unevenly, with richer countries protecting their own first – leaving people in developing countries most vulnerable.

Vaccine makers are scurrying to avoid a repeat of 2009, when H1N1 influenza A vaccines arrived too late to make a difference for those caught in the second wave of disease. But that may be difficult. Global vaccine manufacturing capacity has increased little since then. As Mackenzie observes:

“Most vaccine is still made by growing flu virus laboriously in chicken eggs, which takes six months – if you’re lucky. A few new factories that grow virus in cell cultures instead can expand production more readily, but are no quicker. And commercial factories won’t switch from ordinary flu vaccine to H7N9 until a pandemic is imminent. By then it will be too late.”

Influenza A flu viruses mutate rapidly – which is why you’re urged to get a new seasonal flu shot every year (and if you were wondering, no, the seasonal flu shot will not protect you from H7N9).

Among the many obstacles to getting an effective vaccine to market, one challenge is intrinsic to this virus: As Deborah Mackenzie wrote in New Scientist on May 8, it takes a lot of this virus to make someone sick: “Virologists at the European Flu Summit in Brussels last week told New Scientist that early results show 13 times more H7N9 virus is needed to elicit a protective immune response than is needed for ordinary flu. That’s bad news: the more virus a vaccine requires, the fewer doses that can be grown in a given time.”

That means it takes more time to grow the vaccine. While the vaccine is growing slowly in the lab, on its way to becoming a vaccine, the virus can spread.

Nor is a vaccine a fix-all for pandemic influenza. Although a vaccine might offer the best available protection, that protection wouldn’t be stellar. As Osterholm and colleagues remind us, the 2009 H1N1 vaccine was only 72% effective when adjuvanted (i.e. things were added to make it more effective) and 56% when unadjuvanted.

Flu vaccines are far less effective in older adults – and thus far, the average age of those affected by H7N9 is 60 years. So, Osterholm writes, “If a pandemic occurs and this epidemiologic pattern persists, a pandemic A(H7N9) vaccine, even if it includes an adjuvant, will likely have limited to modest effects on the overall morbidity and mortality from the novel strain.”

Is travel to and from China safe?

Health officials have not implemented any travel bans to or from China, as the virus does not appear to spread easily from person to person. But anyone travelling to or living in China should take extra precautions. Avoid touching open poultry markets. Do not touch live birds, their feces, or their saliva. Eat only well-cooked chicken or other bird flesh.

How can I protect myself and my loved ones from H7N9 avian influenza?  

If you are in an area where people have become ill, avoid live poultry markets. Well-cooked chicken is safe to eat, but live birds, feces, and secretions pose a risk. If you or a loved one develops flu-like symptoms, seek evaluation immediately.

At the moment, unless you live in China and are regularly exposed to poultry, you’re probably not at risk of H7N9. But the moment may change – and it’s a very, very good time to develop a personal pandemic preparedness plan in place for your family.

• Follow the news. Pay attention to new information coming out almost daily about Influenza A (H7N9). Set up a news feed on a site that you like so you’re in the know, and prepare back-up plans for how you would get news should normal news sources not be available.
• Plan for a disruption in services. Water, gas, electricity, and other utilities may be disrupted. Stores may not be fully stocked, restaurants may close, and government services may be shut down or minimized. 
• Plan for closures of work and school. Can you work from home? What would you do if your children’s school were to close?
• Stock up on non-perishable food, water, and other essentials. Include foods that require little water or time to cook.
• Review your first-aid kit, and make sure it contains the things you would need to care for family members should they fall ill – and the items you would need to protect yourself:
  • A pain reliever/fever reducer such as acetaminophen (Tylenol) or ibuprofren (Motrin)
  • Nasal saline spray 
  • Tissues
  • Personal protection equipment (PPE): Your kit should include gloves, masks, and goggles, as well as infection control supplies.
• Stay healthy
  • Practice good hygiene. Wash hands carefully and frequently with soap and water (antibacterial soap is not necessary)
  • Cover your mouth and nose with a tissue when you sneeze or cough, then clean your hands. Use an alcohol-based hand sanitizer if you don’t have easy access to soap and water.
  • Eat a healthful diet that emphasizes vegetables, fruits, and whole grains. Included lean sources of meat such as poultry and fish, low-fat dairy products, and minimize fat and sugar.
  • Drink adequate water. Dehydration makes your respiratory tract more susceptible to flu viruses.
  • Exercise at least 20 minutes, 3-4 times a week. Exercise can help to bolster the immune system and ward of infections.

Further Reading

The following resources provide more information about avian influenza (bird flu) and the latest news about the influenza A (H7N9) virus:

• Center for Infection Disease Response and Preparedness (CIDRAP) www.cidrap.umn.edu
• The bird flu report: Daily News about Avian Influenza http://h7n9flunews.com/
• Avian Flu Diary http://afludiary.blogspot.com/
• The H7N9 section of Virology Down Under: http://www.uq.edu.au/vdu/VDUInfluenza_H7N9.htm
• Centers for Disease Control and Prevention
• World Health Organization (WHO) H7N9 Information: http://www.who.int/influenza/human_animal_interface/influenza_h7n9/en/
• ProMED, The Program for Monitoring Emerging Diseases http://www.promedmail.org/
• CrofsBlogs by the excellent Crawford Kilian http://crofsblogs.typepad.com/h5n1/

Some of the most useful recent journal articles:

• Osterholm MT, Ballering KS, Kelley NS. Major Challenges in Providing an Effective and Timely Pandemic Vaccine for Influenza A(H7N9). JAMA. 2013;():1-2. doi:10.1001/jama.2013.6589. http://jama.jamanetwork.com/article.aspx?articleid=1686871
• Morens, D.M., Taubenberger, J.K., Fauci, A.S. (2013). Pandemic influenza viruses — Hoping for the road not taken. http://www.nejm.org/doi/full/10.1056/NEJMp1307009

 

Photo Credits

Slider/Top of page: Devan Hsu via Flickr Creative Commons

Other images: U.S. Centers for Disease Control and Prevention