January 30, 2014 | 3
Muddled about all the new flu viruses?
It’s hard to keep up with the changing names in the news. H1Nwhat? Bird flu. Pig flu. MERS. SARS. Here is a quick overview of this dizzying, dyslexia inducing array, with what you need to worry about, even if some aren’t yet in your backyard.
I explained a bit about regular, or seasonal flu in a recent post. There are three main types of flu, A, B, and C, named after core proteins. Most of the seasonal flu outbreaks each year are from influenza A. Influenza B strikes every 2-4 years, and is a less serious problem. C is milder and hasn’t caused epidemics.
The different strains of influenza A are named for surface proteins, HA (hemagglutinin) and NA (neuraminidase). Three subtypes of H (H1, H2, H3) and two of NA (N1 and N2) generally cause the annual epidemics. This year’s strain, pH1N1, caused a large worldwide outbreak in 2009, infecting an estimated 24% of the world’s population (and almost half of kids age 5-19) and killing ~200,000. In contrast, the 1918 H1N1 pandemic killed 50 million.
Again, the best illustration I’ve seen for the relationship between different flu strains in people and animals is that by David McCandless.
Reassortment occurs when two different flu strains infect a cell simultaneously, and RNA from each recombine, forming a new combination with different surface proteins and to which there is little immunity. Such new strains produced by reassortment are often seen initially in China and Southeast Asia because people, birds, and pigs live in close, often crowded conditions.
There have been four pandemics (worldwide epidemics) in past 100 years:
1918 H1N1, from seasonal human and avian (bird) flu
1957 H2N2, from human and avian reassortment
1968 H3N2 human and avian components
2009 novel H1N1 contains genes from a combination of human, swine, and avian reassortment.
When these viruses cross different species, that creates conditions ripe for another pandemic, as people lack immunity to these new strains. So what are the new strains that are emerging from animals, threatening explosive epidemics?
To help me keep these confusing sound-alikes straight, I made a table, like I have done for studying seemingly forever. (Click to enlarge the image). These are ordered by my worry level.
Further details follow, below.
The 1918 H1N1 flu was originally from an avian strain that adapted to be able to infect people. While initially thought to have originated in battle-torn Europe, new evidence suggests the “Spanish” flu actually originated in China. Because there was no pre-existing immunity, this virus fueled a widespread pandemic and vast number of deaths. This is why there is concern that H5N1 will similarly make the jump from birds to people.
The H1N1 that emerged in 2009 is now designated as “novel H1N1” or pH1N1, to identify it as being different from the human origin H1N1. The pH1N1 has genetic material from birds and swine (and was previously called “swine flu”).
The most striking difference between H1N1 and the seasonal flu is that typically in seasonal flu, the elderly are the group dying. In 2009, however, deaths were conspicuously in young adults, especially in pregnant women, and that pattern appears to be recurring this year. One of the theories about the high death rate in young adults is that this is due to a “cytokine storm,” where a robust immune system produces an excessive inflammatory response to the infection, damaging the lungs and leading to death. This is believed to have caused many of the deaths in 1918. And many elderly appear to have some protective cross-immunity from previous infections, resulting in their lower death rate in the 2009 outbreak. Curiously, with H1N1, mortality has been highest in pregnancy, obesity, young adults, and indigenous peoples.
The incubation period is generally 1.5-3 days, but can go up to 7 days. Viral shedding begins before symptoms, so people can spread infection before they know they are ill. Shedding typically lasts 5-7 days, but may be much longer, especially in immunocompromised people.
One of the problems with pH1N1 is that the rapid diagnostic tests available are very inaccurate, often missing the flu. Specimens from suspected patients then have to be sent to a CDC-affiliated lab for RT-PCR (reverse transcription-polymerase chain reaction) rather than being done locally. Treatment decisions therefore have to be made based on clinical symptoms and epidemiology.
Treatment options are limited, largely due to the rapid emergence of resistance to oseltamivir (Tamiflu).
There is a recent disturbing article from Matt Memoli showing that patients who are immunocompromised may initially show fewer symptoms than normal hosts, though they have a much higher respiratory failure and death rate. They also can shed virus for prolonged periods—a mean of 19 days. A few shed virus for months, some multi-resistant, meaning these patients could become an important source for spreading drug resistant strains throughout a community.
H3N2 is a seasonal variant of influenza A, and is one of the strains used in the flu vaccine. The problem again comes from a reassortant strain, H3N2v, which is a combination of swine flu and pandemic H1N1, which emerged in 2012.
Infections with H3N2v have been seen mostly in children less than 10 years old, who have no protective immunity, and are associated with exposure to pigs at agricultural fairs. Curiously, while cases have been reported globally, they are more prominent in the Americas. There have only been 300+ cases reported so far. Symptoms are typical flu-like, with fever, cough, runny nose, and myalgias (muscle aches), and mortality is low, as with seasonal flu (<1%).
H7N9 and other new Chinese strains
First reported in 1999, infections with H9N2 have been seen mostly in China, and associated with poultry exposure. There have been less than 20 cases to date, generally mild, and more often in younger children. H9N2 can also infect cats and dogs, who then can further serve as hosts, spreading infection.
There is evidence that H9N2 coexists with H7N9 in live poultry markets, raising heightened concern that reassortment will occur, resulting in a more virulent strain.
Just last month, another new influenza A was identified in China. The first H10N8 infection was found in a 73 year old, immunocompromised woman.
H7N9, another bird flu first reported in China in March, 2013, has produced only mild illness in poultry, making surveillance and detection more difficult. About 220 people have been infected to date, but they have been much more ill than the other strains discussed. Unlike the other strains, which primarily cause illness in the young, H7N9 affects older adults (mean 60 yo), and mostly (70%) men. It is believed to be transmitted through live poultry markets; more than 75% of affected patients had had contact with domestic poultry. Given this, widespread culling of poultry has begun in some areas, as well as closures of live markets. There have been few family clusters and only 2 cases in health care workers (HCW), suggesting little person-to-person transmission.
But H7N9 causes severe pneumonia, ARDS, multi-organ failure, and has a fatality rate of 25-33%. The high death rate appears linked to high cytokine levels. Interestingly, there also appears to be a genetic predisposition to the worse illness. [Widely varying death rates were seen in the 2009 H1N1 pandemic as well, with particularly high mortality in Mexico].
A new study shows that H7N9 can be transmitted to songbirds—finches and parakeets, as well as to sparrows—via water troughs. Because domesticated chickens and game birds also interact with the songbirds, this may facilitate interspecies spread. Song birds are quite popular as pets in China, particularly among elderly men, which might help explain the different epidemiologic pattern of illness.
H5N1, aka Bird flu
Here things start to get even more interesting and a lot more worrisome. This avian flu was first detected in 1997 in Hong Kong. Since 2003, there have been epidemics in infected birds, with spread of the infection from Asia to Europe by migrating birds. In China and Southeast Asia, millions of birds have been killed in an attempt to quell outbreaks.
While only ~650 cases have been reported from 16 countries so far, this strain, like H7N9, causes respiratory failure, and 60% of victims died. Only H5N1 is again killing a younger population, with 79% of deaths occurring in those under 30. Earlier in January, the first case of H5N1 was reported in North America, in a young woman who died after a 3-week visit to Beijing, China. She reportedly had no contact with live markets or farms. Also atypically, she died of meningoencephalitis, rather than pneumonia.
While there have been outbreaks of highly pathogenic H5N1 in poultry and wild birds in India, there have been no human reports yet. A new study looking at antibodies to H5 and H7 in 466 high risk poultry workers in Pune, India found zero antibodies to either strain. This suggests that huge populations there are at risk for outbreaks from these more pathogenic strains.
H5N1 outbreaks have raised two other particular issues. The first is that of “dual-use research of concern” (DURC), which is research that could be misused for harm. With H5N1, the question came to a head over whether data regarding transmission of a mutated H5N1 virus to ferrets or people should be prohibited from publication as a national security issue.
The other issue relates to global economic disparities. Indonesia, the country most affected by H5N1, decided to stop sending viral isolates to WHO in 2007, seriously hampering efforts to study the newly emerging virus. Indonesia’s argument was that the samples they freely provided would be exploited by wealthy countries to develop a vaccine that would be too costly for developing countries. Similarly, concerns have also justifiably been raised that, in the event of a pandemic, vaccines or medicines would be stockpiled by wealthy countries and not be shared with those in need. A pact was reached in 2011, stipulating that at least 10% of antivirals and vaccines would be reserved for WHO donations and tiered pricing.
So why worry about these new flu strains?
A big immediate source of concern is that there are relatively novel flu strains circulating in China, ready to wantonly exchange genetic information, producing a new, lethal flu, to which people have no immunity. Doomsday scenarios have this being spread throughout the world by migrating birds as well as people’s travel.
There are problems with surveillance and with responses to such threats. For example, last fall’s short-sighted Congressional budget slowdown caused the CDC to have to stop monitoring for flu. Similarly, NIH’s funding for influenza research was cut 7% in 2012.
Lack of rapid, accurate diagnostic tests fuels the overuse of antibiotics, particularly levofloxacin (Levaquin), a major contributor to the rise in antibiotic resistance, MRSA, and C. difficile infections. Antibiotics are not necessary or helpful for viral infections!
Vaccine production often falls short and most of the supply has been produced in wealthy countries, causing both logistical problems in fulfilling needs, as well as ethical concerns over the disparities in access.
I’ll have more on vaccine development and on the other threatening respiratory viruses in an upcoming post.
It appears that we have been fortunate that no influenza to rival the deadly 1918 “Spanish flu” has yet appeared. Given the pool of viruses circulating in birds, people and other mammals, especially in China, the ease with which viruses reassort themselves, and the ease of transmission by migratory birds and travelers, many knowledgeable people are wondering just how long our good fortune can last.
Suggested reading/resources for this rapidly changing news:
CIDRAP, Center for Infectious Disease Research and Policy
Crawford Killian Crof’s blog
Michael Costen Avian Flu Diary
H1N1 age distribution - BMJ 2009;339:b5213
Influ-venn-za by David McCandless
H7N9 map, projected growth graph, and age distribution courtesy Laidback Al, Novel Infectious Diseases
Photos by Judy Stone CC BY-NC-SA 3.0
“Molecules to Medicine” banner © Michele Banks