Q&A: New findings about the influenza A (H1N1) 2009 pandemic virus?

Q&A: what have we found out about the influenza A (H1N1) 2009 pandemic virus?

Stephen J Turner¹ Lorena E Brown¹  Peter C Doherty^1,2 and Anne Kelso³

¹Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria 3010, Australia
²Department of Immunology, St Jude Childrens Research Hospital, 332 Nth Lauderdale, Memphis, TN 38105, USA
³WHO Collaborating Centre for Reference and Research on Influenza, 10 Wreckyn Street, North Melbourne, Victoria 3051, Australia

Journal of Biology 2009, 8:69doi:10.1186/jbiol179

http://jbiol.com/content/8/8/69

18 September 2009

© 2009 Biomed Central Ltd

The 1918 pandemic influenza virus is said to have started by causing relatively mild disease in the summer but to have become more severe in the winter. Do we know why, and might influenza A (H1N1) 2009 do the same?

It is not clear precisely what changes resulted in the increased severity of infection during the second wave of the 1918 Spanish influenza pandemic. Certainly the occurrence of multiple waves of influenza infection in the same year is unusual and one possibility is progressive adaptation of the 1918 Spanish influenza virus to its new human host [1].

Molecular analysis, for example, suggests that the virus that emerged during the second wave in the Northern hemisphere had undergone changes in the hemagglutinin (HA) binding site that increased binding specificity for human receptors [2]. This is presumed to have affected the replicative capacity and, therefore, the pathogenicity of the virus.

The 1918 Spanish influenza virus also encoded a non-structural 1 (NS1) protein capable of blocking interferon production and thus prevention of viral replication by the host [3]. Changes in the NS1 protein may also have contributed to host adaptation and increased virulence [1].

Importantly, however, two of the features that account for the virulence of the highly pathogenic avian influenza A (H5N1) viruses are not present either in the Spanish influenza virus or in the current pandemic influenza A (H1N1) 2009 virus [4].

These are a lysine at position 627 of the polymerase basic subunit 2, and glutamic acid in position 92 of NS1 that, at least in animal models of infection, increase the replicative capacity of the virus and block host inhibition of viral replication, respectively [5,6].

As the (H1N1) 2009 pandemic virus continues to spread, the opportunities for adaptation that increases virulence in the human host also increase, but the changes required for such adaptation and for increased virulence are difficult to predict and by no means inevitable [7].

What about the possibility that influenza A (H1N1) might recombine with other more virulent viruses?

There is some concern that co-circulation with seasonal influenza A viruses during the winter, or with highly pathogenic H5N1 viruses in countries where those viruses are endemic, might lead to the emergence of more virulent reassortant viruses [8].

But although occasional dual infections with pandemic and seasonal viruses have been detected during the 2009 Southern hemisphere winter, there have been no reports of emergence of such reassortants.

Might immunity built up in the course of the Northern hemisphere summer lessen the impact of the pandemic in the winter?

Those people who have already been infected with influenza A (H1N1) 2009 are likely to have generated antibody and T cell responses that will provide some level of protection against this virus for the coming Northern hemisphere winter, even if immune escape ('antigenic drift') variants begin to emerge.

There is no evidence so far for such mutants - that is, mutants in which the antibody binding sites in the HA have changed to escape recognition by specific antibody.

The likely explanation for the absence of antigenic drift to date is that the proportion of immune individuals in the community is still too low to drive the selection of such mutants.

This suggests that, despite the large number of people who have been infected, and serological and epidemiological evidence that older people are relatively protected [9,10], the number of susceptible individuals remains very high. 

Use of influenza A (H1N1) 2009 vaccines will be the most important approach to lessening the impact of the pandemic this coming winter in those countries that have access to them. Clinicians will also be able to draw on early international experience in the management of severe cases to reduce morbidity and mortality.

Animal experiments indicate that influenza A (H1N1) 2009 causes relatively severe disease, yet the human disease has been reported as generally relatively mild. How can this discrepancy be explained?

First of all, although initial reports suggest that most human cases of influenza A (H1N1) 2009 infection are mild, particularly in the developed world, this is somewhat misleading as the symptoms are generally reminiscent of those observed with seasonal influenza infection (fever associated with upper respiratory tract illness) and even seasonal influenza is estimated to cause 250,000 to 500,000 deaths worldwide each year.

Second, up to 40% of infected individuals present with vomiting and gastrointestinal (GI) symptoms, which is higher than for seasonal influenza, and while there is no evidence as yet, this may be indicative of more extensive viral replication.

This is actually consistent with three recent studies on the pathogenesis and transmission of influenza A (H1N1) 2009 in ferret models of infection [8,11,12]. All three studies showed that the pandemic strains exhibit more extensive replication in the respiratory tract, particularly the lower respiratory tract, of infected ferrets, as well as in mice [11,12], non-human primates and pigs [11].

Moreover, Maines and colleagues were able to isolate virus from the GI tract of infected ferrets, suggesting an explanation for the increased incidence of GI distress in infected people [12], although no virus has yet been detected in the GI tract of human cases.

All three studies also showed that influenza A (H1N1) 2009 caused more tissue damage in the lower respiratory tract than do typical seasonal influenza strains.

So are you saying the human disease actually isn't mild?

In some cases, certainly it isn't.

It is important to note that the (H1N1) 2009 virus does cause severe infection in some people, including those who are otherwise healthy. 

While some fatal cases have been attributed to secondary bacterial infections or exacerbation of other health conditions, as is commonly seen in fatal cases of seasonal influenza in the elderly, an unusual feature of influenza A (H1N1) 2009 infection is severe viral pneumonitis, leading to acute respiratory distress syndrome, prolonged stays in intensive care units and extended use of mechanical ventilation or extracorporeal membrane oxygenation (ECMO) [13,14]. It is unclear what predisposes some people to mild versus severe complications.

And the tissue damage shown in the animal experiments? Isn't that also indicative of severity?

That is not clear for humans. Although the animal experiments show that influenza A (H1N1) 2009 infection causes more extensive tissue damage than seasonal influenza infection, this could be relatively minor in humans, possibly because of the relatively low binding affinity of the influenza A (H1N1) 2009 viral HA for human receptors.

Human influenza viruses bind their target cells through recognition by the viral HA of cell surface glycoproteins that have sialic acid moieties linked to galactose in a α2,6 configuration.

When Maines and colleagues used a glycan array to compare glycan binding of HAs from influenza A (H1N1) 2009 and 1918 Spanish influenza [12], both showed the same binding specificity and pattern, but the influenza A (H1N1) 2009 HA bound with lower affinity than did the 1918 virus HA.

This was attributed to amino acid differences in the HA binding site. Lower binding affinity could affect the degree of inflammation and pathology caused by (H1N1) 2009 infection, so that although the virus seems to cause more tissue damage, the pathology may not be as extensive as that seen in infection with the more virulent 1918 Spanish influenza virus or highly pathogenic H5N1 viruses.

Could the severe cases be caused by distinct variants of the virus?

It seems not: to date, viruses isolated from such patients have been indistinguishable from those isolated from mild cases.

There are, however, two recent findings that may help explain the increased pathogenesis in experimental animal models and the severe complications in a small number of infected people.

The first is that in non-human primates influenza A (H1N1) 2009 can infect and replicate in type II pneumocytes, a cell type that is found in the lower respiratory tract, where the cells, as well as expressing α2,6-linked sialic acid sequences, also express small amounts of α2,3-linked sialic acid in humans [15].

Second, it has recently emerged that influenza A (H1N1) 2009 HA has dual specificity for α2,6-linked and a range of α2,3-linked sialic acid sequences [16]. These findings suggest that the increased virulence of the influenza A (H1N1) 2009 virus, relative to seasonal influenza, and its capacity to cause severe disease in a small number of individuals, may be linked to an increased likelihood of replication within the lower respiratory tract.

What do we know about the transmissibility of influenza A (H1N1) 2009?

Modeling based on known global spread of influenza A (H1N1) 2009 from Mexico suggests the virus is more transmissible than seasonal influenza and has equivalent transmissibility to that estimated for previous pandemics [17].

Of particular interest is the rapid export of infections from Mexico due to international travel. There was a high correlation between international travel out of Mexico and reported cases of (H1N1) 2009 infection in other countries [17] until community transmission in other countries, such as the USA and Australia, led to spread from those sites.

Animal models, however, have produced conflicting data on the efficiency of aerosol transmission. Using an influenza A (H1N1) 2009 strain isolated in The Netherlands, Munster and colleagues demonstrated efficient aerosol transmission between infected ferrets and contact ferrets [8], whereas Maines and colleagues, using strains from the Mexican and Californian outbreaks, demonstrated inefficient aerosol transmission [12]. Itoh and colleagues on the other hand, using the same Californian strain, were able to demonstrate aerosol transmission [11].

While the reasons for this discrepancy are unclear, it is notable that infection with the Dutch virus induced sneezing in the ferrets, whereas Maines and colleagues did not report sneezing after infection with the Mexican and Californian strains.

Certainly evidence of transmission in both the Dutch and Japanese studies correlates with modeling that suggests the pandemic (H1N1) 2009 virus is efficiently transmitted [17].

Are there indications that mutants of influenza A (H1N1) 2009 are emerging that may affect immunity, transmissibility or sensitivity to antiviral drugs?

At this stage, little variation has been reported among any of the (H1N1) 2009 strains isolated since April 2009. No mutations have been identified in the HA that would be expected to affect binding to antibodies or affinity for α2,6 sialic acid receptors.

As noted above, this is likely to reflect the absence of sufficient population immunity to drive the selection of variants. Given how easily the influenza virus mutates, it is only a matter of time before this happens.


The antiviral drug zanamivir (Relenza) has been used in only a limited way for the control of (H1N1) 2009 and resistance to this drug has not yet been detected among pandemic viruses.

By contrast, oseltamivir (Tamiflu) has been used for treatment and prophylaxis on an unprecedented scale since the beginning of the outbreak.

To date, 22 oseltamivir-resistant pandemic viruses have been reported, mostly from individuals who had received the lower prophylactic dose of the drug.

All of these viruses contain the His275Tyr mutation in the neuraminidase protein that is known to confer oseltamivir resistance. Fortunately, there is no direct evidence as yet for transmission of resistant viruses to untreated contacts.

This differs from the situation among seasonal A (H1N1) influenza viruses in which a strain with the His275Tyr mutation began to spread among untreated individuals in or before late 2007 [18] and has since become the dominant variant of that subtype circulating worldwide.

The fact that an oseltamivir-resistant strain could acquire the ability to out-compete sensitive viruses, even if this does not usually occur, has raised concern that such a variant could also emerge among pandemic H1N1 viruses.

Malaysiakini: Prognosis: Flu to last for a year, mostly mild

Prognosis: Flu to last for a year, mostly mild

Aug 22, 09 3:30pm

Malaysian Medical Association (MMA) president Dr David Quek estimates that the current H1N1 pandemic plaguing the world is expected to run for another year or two.

Quek, however was quick to say that the majority of cases would be mild and it was those in the high risk group that needed to be cautious.

Speaking to Malaysiakini, he said "Every doctor has to be more proactive and practice more responsible and cautious medical professionalism during this trying period, which is expected to run into at least one to two years."

Doctors, he said have to be acutely aware that the initial symptoms could deteriorate into something more serious.

"Doctors must assiduously look out for lung complications, quickly identify high-risk profiles and refer these patients promptly for further more specialised care."

When asked if the medical profession's governing body was not doing enough, the MMA president said "Most of our doctors are actively engaged in looking after many flu-like illness patients. But they find many constraints due to lack of access to specific treatment modalities."

He said that the lack of available and reliable testing and difficulty in confirming such illness as A(H1N1) flu compounds the situation.

Many patients demand to know for sure if they have the flu but the doctors are thus left quite alone to fire fight angry and worried patients with very few resources or reassurances or specific therapies.

He said that it was the Ministry of Health, (MOH) that takes the lead in such matters but it needed the cooperation of all sectors to handle this situation.

While the MOH comes out with the guidelines and policies, implementing it on the ground required all parties to come together.

"The main 'leader' is of course the Ministry of Health (MOH) but the rest of us have to join forces with them to come up with a contingency plan. It is becoming increasingly clear that this is no easy task, and translating policies down to proper and appropriate practical responses and ground-level implementation can be challenging, and would be less than clockwork precision," he said.

Keeping abreast critical

Quek also advised doctors in the private sector to keep themselves updated and not just depend on official handouts as these may be late filtering down to the ground.

"It would be good if every doctor keeps a constant and close tab on the H1N1 pandemic and remains fully aware of the developments and changes, which are evolving daily. Every doctor has to be learning on the trot, so to speak, to keep up with the progress of this outbreak and its management, so that we can serve our patients better.

He said that "logging to the Internet regularly for more updated information will certainly help, instead of lamenting that not enough is being disseminated via the media thus far. Every doctor has to be more proactive and practice more responsible and cautious medical professionalism during this trying period."

Doctors he said "must assiduously look out for lung complications, quickly identify high-risk profiles and refer these patients promptly for more specialised care.

Quek called for an easier access to antiviral drugs and their responsible use and monitoring to help allay public fears of delayed treatment.

But, he warned that this should be tampered with care and not with over-exuberance "in dishing out to one and all."

"There is genuine fear that the precious antiviral drug might be used indiscriminately, just for prevention - this would be a very bad move, which could inadvertently create a worse outcome of drug resistant bugs," Quek said.

Self-qurantine and common sense

He said that in the light of the very quick deterioration of some young patients who have died, it might be prudent to use antiviral treatment earlier and more aggressively.

While there is no specific H1N1 vaccine as such, he expects one to be available by the end of the year.

"We look forward to the specific H1N1 vaccine, when it does come our way, probably towards the end of the year. In the meantime, encouraging those in the front line, heart or lung patents and frequent travelers to have the seasonal flu vaccination is a useful adjunct to help stem the usual problems from other flu types", he said.

In a wide ranging interview, Quek said that most of the affected cases would be mild ones and strongly advised those exhibiting flu symptoms to self-quarantine to help curb the spread of the disease.

As a cardiologist, he said that he had a patient who came to see him and was coughing. When he asked her to take a weeks's quarantine, she was reluctant despite him giving her a medical certificate.

"I informed a young coughing patient who came to my heart clinic that she should probably come back later when she was better because her complaint was not serious. But she was incensed and was upset when I told her to self-quarantine for at least one week. She flatly refused although I was willing to give her MC (medical certificate) for the week."

The patient, he said, was actually exposing the others who were in the high risk group with heart ailments.

Quek concluded by said that the people should join forces with the authorities and medical personal to help in curbing the current pandemic by looking out for the tell-tale signs in both themselves and their loved ones.

Taking proper and commons sense measures, could go a long way, he says, in helping curb the H1N1 spread.

Below is the full text of a question-and-answer session with Malaysian Medical Association president David Quek, who has been keeping a close eye on the H1N1 pandemic.

Tamiflu-resistant H1N1 may have spread in Singapore

Tamiflu-resistant H1N1 may have spread in Singapore

SINGAPORE, Aug 22 — Resistance to Tamiflu has been detected in a patient in Singapore who was down with the pandemic Influenza A (H1N1) bug. Similar cases have also emerged in Hong Kong, China, Japan, Canada, the United States and Denmark.

When the novel strain first appeared in April, the antiviral worked well against it. The World Health Organisation (WHO) feels that these instances of it not working are isolated cases of resistance that have developed because Tamiflu had been used at lower, prophylactic doses in people who might have been exposed to the bug.

Because these so-called contacts were, in fact, already infected, the lower doses turned out to be suboptimal, which allowed resistance to emerge. There is no proof that resistance is circulating in the community at large, the WHO asserts.

Yet there is at least one documented case of a 16-year-old girl who fell ill while travelling from San Francisco to Hong Kong on June 11. Though she declined Tamiflu, an isolate from her was found to carry the H274Y mutation, which signals Tamiflu-resistance.

She was, however, not the world’s first case of such resistance, an honour belonging to a woman seen in Denmark in late June. When she got home from Britain, she was given Tamiflu prophylaxis. Yet she still fell ill on the fifth day of taking Tamiflu. H274Y was detected in her isolate.

Could she have been infected in Britain by someone carrying mainly Tamiflu-sensitive bugs but also a small population of resistant bugs? In that case, suboptimal Tamiflu dosage might have suppressed enough of the sensitive bugs to prevent any clinical symptoms. Over the five days, however, the resistant bugs could have replicated enough to predominate and thus cause clinical illness.

But if this is so, then the mutation must already have been circulating in Britain — which, however, has not reported any cases of Tamiflu resistance yet. Alternatively, she might have caught the resistant bug in Denmark itself, during the five days when she was well and ambulant.

One reason for suspecting community circulation of the resistant bug is that 98 per cent of all seasonal H1N1 bugs now carry H274Y. If patients are infected with both strains, that mutation could jump from seasonal flu to pandemic flu. But the WHO insists there is no evidence this has occurred, so all resistant cases must have emerged because of suboptimal Tamiflu dosages.

There are signs of community circulation in the US, at least. First, the genomics of the Hong Kong isolate where no Tamiflu was used suggests that the infection originated in the US.

Second, it was revealed only this month that a May 30 isolate taken from a young American woman returning to Singapore from Honolulu carried H274Y.

Flying on May 26, she fell ill on board the plane, was hospitalised here on May 27, was confirmed to be a H1N1 case on May 28, but was discharged on May 31 feeling well.

Although her May 28 sample was Tamiflu-sensitive, her May 30 sample had H274Y. Two days is probably too short an interval for resistance to develop from any suboptimal dosages of Tamiflu. At any rate, as a confirmed case, she would have been given the full dosage.

Thus it is entirely possible that she was infected in the US with both the sensitive and resistant strains, which her immune defences could have cleared quickly, so she was discharged fairly quickly.

Third, on Aug 15, the US authorities sent out an urgent report to physicians that two intensive care patients in Washington state who had been infected last month and treated aggressively with Tamiflu were found to have bugs with H274Y.

These four cases suggest that H274Y may already be circulating in the US. It is possible we are seeing relatively few of these isolates for a technical reason: All published genomes are consensus sequences of DNA. That is, the base that is considered to occupy a specific position on the genome is the one that occurs most frequently. But it needs do so 100 per cent of the time.

If a base occurs in only 10 per cent of viral particles, it isn’t likely to show up in the published sequence. It is only when a base occurs in, say, half the cases that it might appear in the consensus sequence.

If H274Y were found in, say, 10 per cent of viral particles, it won’t appear in the consensus sequence of samples taken from a patient prior to Tamiflu being used. Once Tamiflu is employed, the population of sensitive bugs would be drastically reduced. However, those with H274Y would flourish.

Thus, although it was already around prior to Tamiflu being used, the resistant bug would not be detected. After the drug is employed, however, the resistant bugs can grow to greater numbers than the sensitive ones, rendering them detectable.

Of course, if more samples are taken before Tamiflu is used, H274Y might be detected more often. Such comprehensive surveillance, however, would consume too much resources.

History suggests it was limited testing that enabled Tamiflu-resistance in seasonal Influenza A (H1N1) to creep up on the world unawares. The first instance of that was detected in Norway in spring last year.

By the 2008/2009 season, however, it was found in 98 per cent of bugs worldwide. Yet a re-testing of old samples showed that H274Y was already widespread by the autumn of 2007. This means it was circulating in the community before it was first detected in Norway last year.

Is history repeating itself? If so, Singapore should be stocking up on Relenza, the other antiviral that still works. — Straits Times

Healthy people with swine flu do not need Tamiflu, says WHO

Healthy people with swine flu do not need Tamiflu, says WHO

LONDON, Aug 22 — Healthy people who catch swine flu need not be given Tamiflu, the World Health Organisation (WHO) has announced. The advice appears to contradict the UK’s policy of making the antiviral drug readily available to those who call the national pandemic helpline or approach their GPs.

Hundreds of thousands of doses have been given to British patients although the majority have not been severely ill. Fears have been voiced that mass use of Tamiflu will make the virus resistant to it.

The latest advice from the WHO said: “Worldwide, most patients infected with the pandemic virus continue to experience typical influenza symptoms and fully recover within a week, even without any form of medical treatment. Healthy patients with uncomplicated illness need not be treated with antivirals.”

Previously the WHO had said antivirals should be given to patients with “serious progressive illness”. The new guidance is the first time it has specifically advised against otherwise healthy individuals being given the drug.

The recommendation is based on the conclusion of an international panel of experts that includes representatives from the UK. The advice added that Tamiflu, also called oseltamivir, and the similar drug Relenza, also called zanamivir, should be given quickly to seriously ill or deteriorating patients.

The WHO guidance said at-risk groups should receive the drugs. “For patients with underlying medical conditions that increase the risk of more severe disease, WHO recommends treatment with either oseltamivir or zanamivir.

“These patients should also receive treatment as soon as possible after symptom onset, without waiting for the results of laboratory tests. As pregnant women are included among groups at increased risk, WHO recommends that they receive antiviral treatment as soon as possible after symptom onset.”

Some medical researchers have expressed concern about the side-effects of Tamiflu, particularly sickness, nightmares and insomnia in children. A team from Oxford University said this month that children with mild symptoms should not be given Tamiflu and urged the Department of Health (DoH) to urgently rethink its policy.

Figures released by the DoH show that 45,986 courses of antivirals were given to patients in England in the week ending 18 August. In the previous week 90,363 courses of antivirals were given out. The data relates to people collecting the drugs after an assessment via the National Pandemic Flu Service. Many more have collected antivirals via their GP.

The DoH said the new WHO guidance was not too different from its own position that people with mild symptoms could recover without antiviral drugs.

The new WHO statement said: “Worldwide, around 40 per cent of severe cases are now occurring in previously healthy children and adults, usually under the age of 50 years. Some of these patients experience a sudden and very rapid deterioration in their clinical condition, usually on day five or six following the onset of symptoms.”

The first deaths of patients in Wales and Northern Ireland with swine flu has been announced, bringing the number of UK deaths to 61. In Wales, a 55-year-old woman was admitted to the Royal Gwent hospital in Newport on 2 August and given antiviral drugs. She developed cardiac problems and died on Saturday.

In Northern Ireland, a female patient who was said to have had an underlying health condition died last night in hospital. No further details were released.

The Department of Health has hinted that accumulating evidence about the degree of severity of the outbreak might lead to a change in policy. A spokesman said: “We believe a safety-first approach of offering antivirals, when required, to everyone remains a sensible and responsible way forward. However we will keep this policy under review as we learn more about the virus and its effects.”

“The WHO recommendations are in fact in line with UK policy on antivirals. We have consistently said that many people with swine flu only get mild symptoms and they may find bed rest and over-the-counter flu remedies work for them.

“WHO state that 40 per cent of severe cases worldwide have been in previously healthy children and adults and that serious cases should be treated immediately. This emphasises the need not to become complacent about the mildness of the illness and the reasoning behind a precautionary policy.

“People with underlying health conditions, pregnant women and parents with children under the age of one should speak to their GP if they have symptoms. If people have any doubts about taking antivirals they should contact their GP.” — Guardian

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My Comments:

A(H1N1) flu as a novel disease has no precedent on what is the absolutely correct approach.... Just another potentially confusing conflicting situation, which shows up the shifting uncertainties of handling this pandemic H1N1 flu, even by the WHO...

Malaysians should not be too ready to confer blame on authorities and doctors when most of these approaches/directives are also changing/modifying from the world's highest authorities...

However, many Malaysians are now so suspicious and cynical as to anything smacking of governmental conspiracy and obfuscation, that we seem to have lost the art of rational discourse (sigh!), someone or everyone who collaborates, must be blamed! Including the harbinger of news or information, no matter how apolitical, so sad...

BMJ Editorial: Pandemic flu: will there be a second wave?

Pandemic flu: will there be a second wave?

Fiona Godlee, editor, BMJ

fgodlee@bmj.com

Rates of swine flu are levelling off in the northern hemisphere as summer progresses. The question now is whether we’ll have a second wave this winter, and if so how bad it will be.

Two evolutionary virologists writing in JAMA are cautiously reassuring (JAMA 2009;302:679-80). Looking back over the 14 or so pandemics since 1510, they say that pandemic flu has never been able to infect the entire population at once, and although it tends to recur after a first wave, it eventually adopts the familiar seasonal flu pattern.

As for A/H1N1, they say its modest transmission efficiency and its arrival in the northern hemisphere's early summer, as well as the degree of pre-existing population immunity from previous flu viruses and vaccines, all give reason to hope for a more indolent pandemic course and fewer deaths than in past pandemics. They don't think it's inevitable that the virus will mutate into a more virulent or contagious strain.

A second wave of A/H1N1 during the northern hemisphere's winter would coincide with its regular bout of seasonal flu, something the southern hemisphere is experiencing at the moment.

Melissa Sweet asks what lessons we can learn from Australia (doi:10.1136/bmj.b3317), and finds contradictory views among experts there. Some think the final death toll of A/H1N1 will be lower than for seasonal flu, noting that the big difference between now and 1918 is the availability of effective antibiotics. But others warn against being too dismissive. They are seeing respiratory failure of an unprecedented severity in young people, sparking concerns about how well intensive care will cope.

For me the wisest voice is that of Robert Booy. "We had both more severe disease and a huge amount of very mild disease, and people either played it one way or the other, and in doing so they either underplayed it or overplayed it, and the truth was somewhere in the middle." This fits with Heath Kelly's advice among a list of top tips for the northern hemisphere: "Be aware of the pandemic paradox: a high proportion of asymptomatic and mild cases but serious disease in the overweight and pregnant women."

If swine flu does come back with a vengeance, the UK may already have shot one of its bolts. Despite WHO advice to the contrary, in England the government opted for relatively indiscriminate use of antivirals after self diagnosis.

Could the government really not have provided more balanced information on the likely benefits and harms of antivirals and been more parsimonious?

Matthew Shun-Shin and colleagues updated and expanded an earlier Cochrane review on the effectiveness, safety, and tolerability of oseltamivir and zanamivir in seasonal influenza in children (doi:10.1136/bmj.b3172), information that must have been available to ministers when they were making their plans.

The evidence suggests that these two agents are of limited efficacy in children and are associated with a significant risk of side effects, mainly vomiting. Coupled with the risk of resistance and the financial cost of widespread use, these findings have led to calls to cut back the use of antivirals in mild flu and flu-like illness.

These calls are hard to ignore. Indeed, Hugh Pennington, emeritus professor of bacteriology at the University of Aberdeen, has told the media that Tamiflu may be useless by the autumn because of current indiscriminate use (http://tinyurl.com/qnsm4s).

According to news reports, ministers thought it would be publicly unacceptable to withhold antiviral drugs, even after it became clear that swine flu was generally a mild illness. Yet we know it's possible to educate patients and the public about the need to avoid unnecessary use of drugs, as last week's BMJ showed (BMJ 2009;339:b2885).

A(H1N1): Tamiflu-resistant flu cases found in USA, China, Hong Kong, Singapore, Canada, Denmark, Japan, so far...

A(H1N1): Two Tamiflu-resistant flu cases in US

HOUSTON: The Seattle health department said on Friday that two immuno-suppressed patients being treated for A (H1N) flu had been identified as resistant to Tamiflu, China’s Xinhua news agency reported.

One case involved a male teenager with leukaemia who received a stem cell transplant in early May, according to local health experts. While recovering in hospital in a single room he contracted A(H1N1) flu, they said, adding the boy has recovered.

The second case involved a woman in her 40s, who also has leukaemia and had a stem cell transplant late last year, the health experts said. That woman remains in hospital and is being treated with an intravenous form of the only other flu drug available, Relenza, and another antiviral drug, ribavirin, they disclosed, saying the two patients have no links to each other.

Local health officials also said that there is no evidence indicating that people who came in contact with the two patients became infected with a Tamiflu-resistant virus.

Since the pandemic began, 11 cases of Tamiflu resistance have been reported. Three of those were reported Friday - two in Seattle and a new case in Hong Kong.

Japan and China have each reported three. In the case of China, one case occurred in Hunan province on the mainland and two in Hong Kong. Canada, Denmark and Singapore have each found one.

Most of these cases have occurred in people who took the drug as treatment for the flu or to prevent infection with the flu.

The sole exception so far is the case of the California teenager who travelled to Hong Kong. She had not previously taken Tamiflu, suggesting she was infected from the start with a resistant virus. The source of her infection was not found and no other cases of resistance have been reported from the San Francisco area, where she lives.

“Viruses can develop drug resistance over time. It’s important that antiviral treatments only be used as recommended by a health care provider, to minimise drug resistance and preserve an important tool against the illness for those who need it,” said Dr David Fleming, Director and Health Officer for Public Health of Seattle & King County.

“The vast majority of people with H1N1 virus continue to be treatable with Tamiflu, and in cases where it becomes ineffective, other options are available,” Dr. Fleming said. -- Bernama