JID: Early Observational Study On Ribavirin & Interferon Treatment of MERS-CoV

 

 

# 8133

 

Last September, in Nature: Animal Testing Of Drug Combo Shows Potential For Treating MERS, we looked at the the potential role of Interferon-α2b & ribavirin in the treatment of MERS-CoV infection, based on a NIAID led study conducted on rhesus macaques. At the time I cautioned that, while encouraging, the following caveats should be kept in mind:

 

• First, the macaque model is not a perfect substitute for humans, as they tend not to be as severely impacted by the MERS virus. 
• Second, treatment was initiated 8 hours post infection, which is an earlier pharmacological intervention than most humans could hope to see. 
• And third, most severe human infections have been seen in people with co-morbidities like COPD, cancer, diabetes, asthma . . . variables this study does not attempt to replicate.

 

Today we get a  study, appearing in the Journal of Infectious Diseases (h/t @ironorehopper on FluTrackers), that looks at an early attempt at using this drug combo in treating critically ill MERS-CoV cases in Saudi Arabia last spring. First a link to the study and some excerpts from the abstract, after which I’ll return with more.

 

 

Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study

Jaffar A. Al-Tawfiq, Hisham Momattin, Jean Dib, Ziad A. Memish

Summary

Results

All patients were critically ill with acute respiratory distress syndrome treated with adjunctive corticosteroids and were on mechanical ventilation at the time of initiation of therapy. The median time from admission to therapy with ribavirin and interferon was 19 (range 10–22) days. None of the patients responded to the supportive or therapeutic interventions and all died of their illness.

Conclusions

While ribavirin and interferon may be effective in some patients, our practical experience suggests that critically ill patients with multiple comorbidities who are diagnosed late in the course of their illness may not benefit from combination antiviral therapy as preclinical data suggest. There is clearly an urgent need for a novel effective antiviral therapy for this emerging global threat.

 

Not exactly a rousing success, but then these were critically ill patients (all on ventilators) with profound comorbidities (4 on maintenance dialysis), and treatment was begun (on average) 19 days into their illness. 

 

Essentially, at that stage of their illness, attempts to use this, or any other antiviral therapy, was pretty much a long shot.

 

During the SARS epidemic a decade ago, the early administration of Ribavirin was associated with a better outcome (see CMAJ Ribavirin in the treatment of SARS: A new trick for an old drug?), but the number of patients treated in this way was fairly small and the results far from conclusive.

 

Of note, of the 5 patients in this observational study, 3 developed adverse side effects from the Interferon-α2b & ribavirin combo therapy, including  pancreatic enzyme elevation (n=2) and significant hemolysis (destruction of red blood cells)  (n=1),  both known side effects of ribavirin.

 

None of which knocks this drug combo out of contention as a potential MERS treatment, as it may eventually prove beneficial if administered early enough in the illness. Despite the potential for side effects, the Ribavirin and Interferon combination has previously found success as a treatment for chronic hepatitis C.

 

While we still lack an effective antiviral to treat the MERS coronavirus, another avenue of investigation is in the use of convalescent plasma from patients who have recovered from the virus (see my 2011 blog Plasma Therapy For Severe H1N1 for a broader discussion of this type of therapy). 

 

This from the World Health Organization Novel coronavirus summary and literature update – as of 8 May 2013.

An international network of clinical experts has been convened to discuss therapeutic options. It concluded that in the absence of clinical evidence for disease-specific interventions, convalescent plasma is the most promising therapy. A memo containing advice for setting up international or regional serum centers, to obtain and share convalescent plasma, has been circulated by WHO to ministries of health in affected countries. WHO and the International Severe Acute Respiratory and Emerging Infection Consortium have developed and shared a set of research protocols and case report forms to help clinical investigators establish studies of pathogenesis and pharmacology. These are available at http://www.prognosis.org/isaric/.

 

This does highlight the need, however, for rapid diagnosis and early intervention, regardless of what treatment is eventually found to be effective.

JID: A Pair Of H7N9 Studies

# 7617

 

The IDSA’s Journal of Infectious Diseases published a pair of new studies on the H7N9 virus yesterday that don’t exactly break new ground, but do add to what we’ve learned from earlier studies.

 

While full access to these studies requires a subscription, we can glean the basics from their abstracts.

 

The first looks at the transmissibility and pathogenicity of the H7N9 virus in ferrets, and finds (as we’ve seen previously in Nature: Limited Airborne Transmission Of H7N9 Between Ferrets & Science: H7N9 Transmissibility Study In Ferrets) that this emerging avian flu virus could be transmitted between ferrets (albeit at low levels) via respiratory droplets.

 

The Novel Avian-Origin Human A (H7N9) Influenza Virus Could be Transmitted between Ferrets via Respiratory Droplets

Lili Xu1,†, Linlin Bao1,†, Wei Deng1,†, Libo Dong3,†, Hua Zhu1, Ting Chen1, Qi Lv1, Fengdi Li1, Jing Yuan1, Zhiguang Xiang1, Kai Gao1, Yanfeng Xu1, Lan Huang1, Yanhong Li1, Jiangning Liu1, Yanfeng Yao1, Pin Yu1, Xiyan Li2, Weijuan Huang2, Xiang Zhao2, Yu Lan2, Junfeng Guo2, Weidong Yong1, Qiang Wei1, Honglin Chen3, Lianfeng Zhang1 and Chuan Qin1,*

Abstract

The outbreak of human infections caused by the novel avian-origin H7N9 subtype influenza viruses in China since March 2013 underscores the need to better understand the pathogenicity and transmissibility of these viruses in mammals.

 

In a ferret model, the H7N9 influenza virus was found to be less pathogenic than a H5N1 virus but was comparable with the 2009 pandemic H1N1 virus, based on the clinical signs, mortality, virus dissemination, and histopathological analyses. The H7N9 virus could replicate in the upper and lower respiratory tract, heart, liver, and olfactory bulb.

 

It is worth noting that the H7N9 virus exhibited low level of transmission between ferrets via respiratory droplets. There were four mutations in the virus isolated from the contact ferret which were D678Y in PB2, R157 K in HA(H3 numbering), I109T in NP, and T10I in NA. These data emphasized that the avian-origin H7N9 subtype influenza virus has the ability to transmit between mammals, highlighting the potential of human-to-human transmissibility.

 

The second study looks for the source of human infection with the H7N9 virus, and finds – as we’ve seen suggested before (see OIE Statement On Live Markets And H7N9) – that live market birds appear to be the major contributing factor.

 

 

Relationship between domestic and wild birds in live poultry market and a novel human H7N9 virus in China

Chengmin Wang1,*, Jing Wang2,*, Wen Su1, Shanshan Gao1, Jing Luo1, Min Zhang1, Li Xie2,*, Shelan Liu3, Xiaodong Liu4, Yu Chen4, Yaxiong Jia4, Hong Zhang1, Hua Ding2 and Hongxuan He1,#†

Abstract

To trace the source of the avian H7N9 viruses, we collected 99 samples from 4 live poultry markets and the family farms of 3 patients in Hangzhou city of Zhejiang province, China.

 

We found almost all positive samples came from chickens and ducks in live poultry markets. These results strongly suggest that the live poultry markets are the major source of recent human infections with H7N9 in Hangzhou city, Zhejiang province of China.

 

Therefore, control measures are needed, not only in the domestic bird population, but also in the live poultry markets to reduce human H7N9 infection risk.

Although the vast majority of positive H7N9 bird and environmental samples have come from live bird markets - not poultry farms - there remain many questions over how this virus could have spread so rapidly and across such a wide swath of China, only via live market birds.

 

Many observers still believe we are missing pieces to this epidemiological puzzle.

 

If the virus makes a return visit this fall, nailing down (and hopefully, interrupting) the source of transmission will be the top priority for public health authorities.

Study: The Benefits Of Antiviral Therapy During the 2009 Pandemic

 

Photo Credit – Wikipedia

 

# 6758

 

While the British press continues to excoriate Roche Pharmaceuticals for their refusal to release all of the testing data on their antiviral drug Tamiflu © – and through innuendo, suggest that the drug is ineffective, or worse, even dangerous – we continue to get third party confirmation that oseltamivir does, in fact, have beneficial effects for severe influenza.

 

A quote from an article yesterday in the Daily Mail reads:

 

“And yet for all we know, Tamiflu might be no better than paracetamol: because Roche, the company making it, still withholds vital information on the risks and benefits from researchers, doctors and patients.”

 

Compelling rhetoric, I suppose. And not wrong in its stated goal, which is the full release of all drug testing data.

 

But then again, not precisely true. 

 

We’ve seen many observational studies conducted over the past few years that show pretty clear evidence that the use of oseltamivir in severe influenza reduces morbidity and mortality.

 

The evidence for its benefits for mild, seasonal flu in healthy patients  . . . well, not so much.

 

Although falling short of the `gold standard’ Randomized Controlled Trials (RCTs) preferred by most scientists, we’ve seen a number of observational studies that suggest significant benefits from the drug.

 

In 2010 we saw an observational study that appeared in JAMA  (see Study: Antivirals Saved Lives Of Pregnant Women) that strongly suggested that Tamiflu was life saving for some patients with pandemic flu.

 

And again in 2010, in BMJ: Efficacy of Oseltamivir In Mild H1N1, we saw a study which suggested that the administration of oseltamivir may have significantly reduced the incidence of pneumonia among otherwise healthy pandemic H1N1 patients.

 

And in Study: Antiviral Therapy For H5N1, we saw the largest study to date on the outcomes of H5N1 patients. The bottom line is essentially out of 308 cases studied, the overall survival rate was a dismal 43.5%.

 

But . . . of those who received at least one dose of Tamiflu . . .  60% survived . . .  as opposed to only 24% who received no antivirals.

 

On the safety side of the equation, while all drugs can have adverse effects (AEs), a recent study (see Study: Adverse Events Associated With Oseltamivir Outpatient Treatment) found `no evidence was identified for an increased risk of neuropsychiatric or other AEs following oseltamivir treatment.’

 

We’ve another study published last week in the Journal of Infectious Diseases that conducted a meta-analysis of 90 observational studies during the 2009 H1N1 flu pandemic. Included were nearly 35,000 patients, 85% of whom has laboratory confirmed H1N1.

 

Impact of neuraminidase inhibitor treatment on outcomes of public health importance during the 2009-10 influenza A(H1N1) pandemic: a systematic review and meta-analysis in hospitalized patients

Stella G. Muthuri*, Puja R. Myles*,Sudhir Venkatesan, Jo Leonardi-Bee and Jonathan S. Nguyen-Van-Tam1

Abstract

Background. The impact of neuraminidase inhibitors (NAI) treatment on clinical outcomes of public health importance during the 2009-10 pandemic has not been firmly established.

<SNIP>

Results. Regarding mortality we observed a non-significant reduction associated with NAI treatment (at any time) vs none (OR, 0.72 [95% CI, 0.51 - 1.01]). However we observed significant reductions for early treatment (≤48h after symptom onset) vs late (OR, 0.38 [95% CI, 0.27 - 0.53]); and for early treatment vs none (OR, 0.35 [95% CI, 0.18 - 0.71]). NAI treatment (at any time) vs none was associated with an elevated risk of severe outcome (OR, 1.76 [95% CI, 1.22 - 2.54]); but early treatment vs. late reduced the likelihood (OR, 0.41 [95% CI, 0.30 - 0.56]).

Conclusions. During the 2009-10 influenza A(H1N1) pandemic, early initiation of NAI treatment reduced the likelihood of severe outcomes compared with late or no treatment.

 

The full text of the article is available online.

 

For those adverse to navigating the 23-page study, a summary can be found in an accompanying commentary by Fred Y. Aoki, MD, and Frederick G. Hayden, MD.  Although based on observational, often retrospective, studies - Aoki and Hayden praised the large number of studies and patients, and the `methodologic rigor’ of their analysis.

The bottom line?

 

. . . antiviral therapy, principally oseltamivir, initiated within 48 hours of onset, reduced the likelihood of severe outcomes, namely admission to a critical care unit or death, by 49 to 65%.

 

They did find that patients who received oseltamivir were more likely to develop pneumonia, but this is a bit of a red herring, as the most seriously ill patients are more apt to receive antiviral therapy.

 

No, oseltamivir isn’t a panacea against influenza.  It isn’t perfect by any means.

 

But once again we get pretty good data to suggest that it does have significant therapeutic value.  Particularly when administered within the first 48 hours of illness.

 

Last January, in The Tamiflu Controversy Continues  we looked at the debate over the effectiveness of oseltamivir (Tamiflu ®) in the wake of the release of a new Cochrane group analysis that found insufficient evidence to show whether the drug reduces influenza complications and transmission.

Several weeks later in The CDC Responds To The Cochrane Group’s Tamiflu Study we saw that agency’s reaffirmation of their support for the drug.

 

Hopefully, in time we’ll see better antivirals developed.

 

Whether we approve of the data release policy of the parent company or not, oseltamivir remains one of the few pharmacological options we have available to treat severe influenza. 

Study: Influenza And Heart Attacks

# 6624

 

Each year during the winter months we see an increase in the rate of heart attacks and coronary related deaths.

 

During the middle-to-late 1990’s a study looked at more than 250,000 AMI’s (acute myocardial infarctions) and found that the rate of heart attacks in the winter ran 53% higher than during the summer.

 

Seasonal distribution of acute myocardial infarction in the second National Registry of Myocardial Infarction.

Spencer FA, Goldberg RJ, Becker RC, Gore JM.

 

 

Over the years this spike in `winter mortality’ has been blamed on a variety of factors.

 

Colder temperatures, increased respiratory infections (including influenza & Pneumonia), over indulgence in food and alcohol, diminished activity levels, forgetting to take prescription medicines, and holiday stress.

 

While cold weather combined with strenuous physical activity (like clearing snow from sidewalks) have often been blamed for this spike, even in balmy Southern California, studies have shown a 33% increase in heart attacks over the holidays.

 

When Throughout the Year Is Coronary Death Most Likely to Occur?

A 12-Year Population-Based Analysis of More Than 220 000 Cases

Robert A. Kloner, MD, PhD; W. Kenneth Poole, PhD; Rebecca L. Perritt, MS

 

Increasingly, inflammation is being seen as a contributor to Cardiovascular disease (CVD), and studies (like this one from the NIH) to `to determine whether a common anti-inflammatory drug can reduce heart attacks, strokes, and deaths’ are underway around the world.

 

One of the hallmarks of an infection is the body’s inflammatory response, which has led some researchers to suppose that some infections might increase one’s risk of having a heart attack.

 

Which brings us to a new study appearing in the Journal of Infectious Diseases that suggest Influenza - and other acute respiratory infections - can act as a trigger for heart attacks.

 

Influenza Infection and Risk of Acute Myocardial Infarction in England and Wales: A CALIBER Self-Controlled Case Series Study

Charlotte Warren-Gash, Andrew C. Hayward1, Harry Hemingway2, Spiros Denaxas2, Sara L. Thomas3, Adam D. Timmis5, Heather Whitaker6 and Liam Smeeth4

ABSTRACT (Excerpt)

Results. Of 22 024 patients with acute coronary syndrome, 11 208 met the criterion of having had their first AMI at the age of ≥40 years, and 3927 had also consulted for acute respiratory infection. AMI risks were significantly raised during days 1–3 after acute respiratory infection (incidence ratio, 4.19 [95% confidence interval, 3.18–5.53], with the effect tapering over time. The effect was greatest in those aged ≥80 years (P = .023). Infections occurring when influenza was circulating and those coded as influenza-like illness were associated with consistently higher incidence ratios for AMI (P = .012).

Conclusions. Influenza and other acute respiratory infections can act as a trigger for AMI. This effect may be stronger for influenza than for other infections.

 

In the same issue of J Infect Disease is an editorial called Increasing Evidence That Influenza Is a Trigger for Cardiovascular Disease.

 

Although both articles are behind a pay wall, CIDRAP NEWS has a brief summary of the study’s findings:

 

Study: Flu can trigger myocardial infarction

A couple of years ago we saw a study in the CMAJ: Flu Vaccinations Reduce Heart Attack Risk that found that those over the age of 40 who get a seasonal flu vaccine each year may reduce their risk of a heart attack by as much as 19%.

 

Almost immediately questions were raised over the way this study was conducted (see Vaccine/Heart Attack Study Questioned), and so the results are in dispute.

 

But today’s study adds to growing evidence that influenza may be a significant contributor to the number of heart attacks each year.

 

While more study will be needed to confirm this link, it does add another good reason to get that flu shot every year. Particularly for those of us over the age of 40, who are at greater risk of cardiovascular disease.

Norovirus: The Gift That Keeps On Giving

 

 

 

# 6319

 

 

The hallmark of a Norovirus infection is that during the first 12 hours of vomiting and diarrhea you are afraid you might die, and during the second 12 hours you begin to fear you won’t.

 

While the vast majority afflicted recover, among the elderly and frail this illness can induce serious dehydration and on rare occasions can be fatal.

 

According to the CDC, each year the norovirus:

 

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

 

 

The CDC maintains an extensive Norovirus webpage where they describe the illness, how it is spread, and how to avoid infection. Among known causes of foodborne illness, norovirus is the largest culprit.

 

Source CDC

 

From the Journal of Infectious Diseases today we’ve an epidemiological investigation that examined a norovirus outbreak among a girl’s soccer team and found a common denominator (a reusable grocery bag) and evidence suggestive of aerosol contamination.

 

In today’s IDSA journal report (and accompanying commentary) we get a fascinating look what may be the `perfect human pathogen’, and how it was easily spread among 17 girls at a soccer tournament in 2010.

 

First, the press release, then the study:

Public release date: 9-May-2012

Investigators trace of role reusable grocery bag in norovirus outbreak

Oregon investigators recently mapped the trail of an outbreak of a nasty stomach bug among participants in a girls' soccer tournament to a reusable open top grocery bag stored in a hotel bathroom. Their findings, which illustrate the role that inanimate objects can play in spreading norovirus infection, appear in The Journal of Infectious Diseases.

 

Noroviruses are a leading cause of gastroenteritis worldwide and the most common cause of foodborne outbreaks in the United States. Highly contagious, even in low concentrations, the viruses spread efficiently from feces and vomit by direct contact or by indirect transmission from viral contamination of surfaces. In October 2010, a cluster of gastroenteritis that appeared in a group of people with no apparent direct physical contact with a pathogen challenged investigators to find the cause and take appropriate control measures.

 

In the study, Kimberly K. Repp, PhD, MPH, of Oregon Health and Sciences University, and William E. Keene, PhD, MPH, of the Oregon Public Health Division in Portland, investigated an outbreak in a group of 17 Oregon girls, 13-14 years old, and their four adult chaperones attending a soccer tournament in Washington state. All had traveled in private automobiles, shared hotel rooms, and eaten at local restaurants. Eight cases were identified, including the index patient who was presumably infected prior to the trip. There was no direct contact between the original patient and her teammates after her symptoms began; before her overt symptoms began she left her room and moved in with a chaperone. The girl subsequently began vomiting and having diarrhea in the chaperone's bathroom. The outbreak affecting the rest of the team began several days later; they were exposed by handling a bag of snacks that unfortunately had been stored in the hotel bathroom. Virus aerosolized within the bathroom likely settled onto the grocery bag and its contents. Matching viruses were found on the reusable shopping bag two weeks later.

(Continue . . . )

 

A Point-Source Norovirus Outbreak Caused by Exposure to Fomites

1. Kimberly K. Repp1, and William E. Keene2

The authors describe the route of infection by saying:

 

Aerosolization of vomit and feces has been demonstrated to be of major importance in norovirus outbreaks [13]. Even viruses aerosolized from flushing a toilet can contaminate surfaces throughout a bathroom [14]. Once a fomes is contaminated, transfer to hands and other animate objects can readily occur [15]. The more confined the space (eg, most bathrooms), the more intense would be the “fallout” [13].

 

The authors also take notice of some of the lesser known hazards of reusable grocery bags (see my earlier blog It’s In The Bag).

 

Accompanying this research letter is an informative editorial by Aron J. Hall called:

 

Noroviruses: The Perfect Human Pathogens?

1. Aron J. Hall

 

 

The role of direct aerosolized human-to-human transmission of norovirus remains a bit murky, although there are numerous anecdotal reports that suggest that it happens.

 

The CDC – in a an MMWR report from 2011 called Updated Norovirus Outbreak Management and Disease Prevention Guidelines describes transmission thusly:

 

Transmission

Norovirus is extremely contagious, with an estimated infectious dose as low as 18 viral particles (41), suggesting that approximately 5 billion infectious doses might be contained in each gram of feces during peak shedding. Humans are the only known reservoir for human norovirus infections, and transmission occurs by three general routes: person-to-person, foodborne, and waterborne.

Person-to-person transmission might occur directly through the fecal-oral route, by ingestion of aerosolized vomitus, or by indirect exposure via fomites or contaminated environmental surfaces.

Study: Statins, Influenza, & Mortality

 

 

 

# 6008

 

We’ve a study today that lends additional weight to the argument that statins – a class of cholesterol lowering drugs – may have a role to play in the treatment of influenza.

 

This would be of particular value during a severe pandemic, when the world would need a cheap (preferably generic) medication that is shelf stable, easy to dispense, has a low incidence of side effects, and can reduce influenza morbidity and mortality.

 

That’s a tall order, but there are some researchers who believe that statins might fit the bill.

 

Over the years we’ve seen a number of studies that have suggested that taking statins can improve survival rates among those with influenza and/or pneumonia.

 

The idea of using them in a pandemic has been largely championed by Dr. David Fedson – former Professor of Medicine at the University of Virginia School of Medicine and formerly Director of Medical Affairs, Aventis Pasteur MSD who has urged that scientists look seriously at statins, which he believes may help modulate the immune response.

 

A couple of his papers on the subject include:

 

Pandemic Influenza: A Potential Role for Statins in Treatment and Prophylaxis

David S. Fedson

New Approaches to Confronting an Imminent Influenza Pandemic

Dr. Fedson and Peter Dunnill, DSc,FREng

 

While we’ve seen a number of studies (see here, here, and here) supporting the notion that statins might reduce mortality due to pneumonia and/or influenza, not every study has been positive.

 

In July of 2009 there was a report that found no evidence of benefit among pneumonia patients (see Another Take On Statins And Pneumonia) taking statins.

 

Today, from the IDSA’s Journal of Infectious Disease we have a new study that looked at the 30 day survival rates of hospitalized influenza patients either taking, or not taking, statins. 

 

They found, after adjusting for:

• age;
• race;
• cardiovascular, pulmonary, and renal disease;
• influenza vaccination and antiviral administration

 

Those not already on statins, or placed on statins during their hospital stay, were nearly twice as likely to die within 30 days of hospitalization as those who received statins.

 

A cautionary note: This was an observational study, not a Randomized Controlled Trial – and so there may have been confounding factors not adjusted for by the authors. Additionally, this study did not attempt to track the amount of statins used by patients during their hospitalization.

 

First a link to the study’s abstract, followed by a few excerpts to the press release, and then a link to an accompanying editorial.

 

 

Association Between Use of Statins and Mortality Among Patients Hospitalized With Laboratory-Confirmed Influenza Virus Infections: A Multistate Study

J Infect Dis. jir695 first published online December 13, 2011 doi:10.1093/infdis/jir695

Meredith L. Vandermeer, Ann R. Thomas, Laurie Kamimoto, Arthur Reingold, Ken Gershman, James Meek, Monica M. Farley, Patricia Ryan, Ruth Lynfield, Joan Baumbach, William Schaffner, Nancy Bennett and Shelley Zansky

 

Since the bulk of this study is behind a pay wall, the press release from the IDSA provides some valuable details.

 

Infectious Diseases Society of America

Statins may reduce mortality in patients hospitalized with influenza

[EMBARGOED FOR DEC. 14, 2011] The two main ways to prevent and control influenza today are annual immunization and antiviral drugs. A team of investigators has found that statins, cholesterol-lowering drugs, may offer an additional treatment to complement these approaches and reduce mortality among patients hospitalized with influenza. The findings are published in The Journal of Infectious Diseases and are now available online.

 

In an observational study led by Meredith L. Vandermeer, MPH, then with the Oregon Public Health Division in Portland, researchers used data for hospitalized adults during the 2007-2008 influenza season to evaluate the association between patients prescribed statins and influenza-related deaths. The data were drawn from the Centers for Disease Control and Prevention's Emerging Infections Program, which conducts active surveillance for patients hospitalized with confirmed influenza in 59 counties in 10 states.

 

Among 3,043 hospitalized patients with laboratory-confirmed influenza, 33 percent were given statin medications prior to or during hospitalization. After adjusting for various factors, patients not receiving statins were almost twice as likely to die from influenza as those who did receive the medication.

 

"Our study found that statins were associated with a decrease in odds of dying among cases hospitalized with laboratory-confirmed influenza, when adjusted for age, race, cardiovascular disease, chronic lung disease, renal disease, influenza vaccine receipt, and initiation of antivirals within 48 hours of admission," the study authors wrote.

(Continue . . .)

 

You’ll find an accompanying editorial, also published today, titled:

 

Statins and Influenza: Can We Move Forward?

Edward E. Walsh

 

More than 2 years ago, the Reveres at the now shuttered Effect Measure Blog took an in depth look at the statin controversy, and why we still don’t know if they are effective against influenza.

 

While the Revere’s are greatly missed in Flublogia, that archive is still online, and very much worth revisiting.

 

Statins for influenza. Why don't we know if it works yet?

Category: Infectious disease • Influenza treatment

Statins for influenza are in the news again, this time because of a paper given at the Annual Meeting of the Infectious Disease Society of America (IDSA). We'll get to it in a moment, but first a little background.

Read on »

 

 

For more on the potential utilization of statins during a pandemic, or for seasonal influenza and pneumonia, you may wish to revisit these earlier blogs:

 

Statins & Pneumonia: Revisited

Statins Revisited

First Statins, Now Fibrates

Nature: Special Influenza Supplement

 

 

 

# 5995

 

 

The journal Nature has released a special, freely accessible, influenza-centric supplement on their website today. 

 

 

You’ll find articles on antiviral drugs, vaccines, epidemiology, and viral evolution. While I’ve only just quickly scanned a couple of the articles, it looks very much worth perusing.

 

Follow the link below to read:

 

Influenza

 

Vol. 480, No. 7376 (08 December 2011)

Produced with support from Sanofi Pasteur, Crucell and Baxter.

 

Our centuries-old battle against influenza occasionally erupts into mass death – the 1918 pandemic alone killed at least 50 million people. What makes this virus such a tough foe is its ability to mutate so that vaccines and drugs quickly become obsolete. Can new research offer hope for defeating this pathogen for good?

PPEs & Transocular Influenza Transmission

 

 

 

 

Photo Credit PHIL (Public Health Image Library)

 

 

# 5633

 

Constant readers of this blog are aware that over the past several years we’ve seen many differing studies on the  effectiveness of different types of  PPEs (Personal Protective Equipment) in protecting against influenza.

 

 

Ideally, the well-protected HCW (Health Care Worker) working in an infectious environment would be wearing an N95 mask, gloves, gown and eye protection.

 

But during the opening months of the 2009 pandemic, it became glaringly obvious that our world faced a shortage of PPEs, and so strategies were adopted to maximize their use.

 

In some cases nurses were issued only one N95 mask to be used for an entire 8 hour shift, and told to don it only when in direct contact with a potentially infected patient.

 

In other venues, HCWs were issued surgical masks in lieu of N95s, despite the recommendation at the time from the CDC that N95 masks were the preferred level of protection.

 

This, as you might imagine, raised concerns among health care workers and sparked protests across the country.

 

Nurses Protest Lack Of PPE’s

Report: Nurses File Complaint Over Lack Of PPE

California Nurses Association Statement On Lack Of PPE

 

 

Fortunately, the virulence of the novel 2009 H1N1 virus was less than originally feared. Had the pandemic carried a higher mortality and morbidity rate, the lack of PPEs would have become a much bigger issue.

 

 

For decades, the assumption was that only properly fitted N95 masks protected the wearer, and that surgical masks were only worn by HCWs to protect the patient during invasive procedures.

 

N-95 Respirator         Surgical Facemask

 

But over the past two years we’ve seen dueling studies that alternately show surgical masks to be a reasonable protective barrier against respiratory viruses  . . . or pretty much useless.

 

Take your pick.

 

A few highlights of these conflicting reports include:

 

In October of 2009 the NEJM published a perspective article (see NEJM Perspective: Respiratory Protection For HCWs) based on a 2009 IOM evaluation of surgical masks vs. respirators, and came out in favor of the N95.

 

A few days later JAMA (Journal of the American Medical Association) published a study which reported that HCWs using surgical masks experienced `noninferior rates of laboratory-confirmed influenza’.

 

In March of 2010, we saw the following study (see Study: Efficacy of Facemasks Vs. Respirators) in Clinical Infectious Diseases, that suggested that surgical masks are just as effective as respirators in protecting HCWs.

 

In guidance, updated as late as March of 2010, the CDC continued to recommend N95 respirators for HCWs who came in close contact with suspected or confirmed influenza patients.

 

But in June of 2010, the CDC proposed new guidance that relaxed those recommendations to using surgical masks for routine care, and reserving N95 masks for aerosol producing procedures (intubation, suctioning, etc).

 

Still, the controversy remains. 

 

Adding to the confusion, we’ve seen recent studies that give more credence to the notion that influenza may be spread in aerosolized form (see Study: Aerosolized Transmission Of Influenza), as opposed to primarily by large droplets. 

 

But the truth is, our knowledge of how influenza spreads, and what barriers work well to protect HCWs, is severely limited.

 

Which is why a few months back the IOM (Institute of Medicine) released, through the National Academies Press, an extensive, 200+ page update on the use of PPEs  that essentially calls for better science on which to base our decisions regarding the right kind of protection for HCWs.

 

While the requisite knowledge won’t come overnight, today we have an ingenious piece of research that appears in the current issue of the IDSA’s  Journal of Infectious Diseases. 

 

Not only does it compare the efficacy of surgical masks verses N95s, it  gives us important new perspectives on the importance of eye protection against the influenza virus.

 

First the link, then I’ll return with a brief summary of what they found.

 

Transocular Entry of Seasonal Influenza–Attenuated Virus Aerosols and the Efficacy of N95 Respirators, Surgical Masks, and Eye Protection in Humans

Werner E. Bischoff, Tanya Reid, Gregory B. Russell and Timothy R. Peters

 

 

Finding safe and ethical ways to test the effectiveness of PPEs against influenza – when exposing test subjects to a virus could endanger their health – has always been a challenge.

Instead, researchers at Wake Forrest chose to expose 28 volunteers (divided into six groups) for 20 minutes to an aerosolized LAIV (Live Attenuated Influenza Vaccine) in a special air-tight chamber.

The six groups were:

 

1. No protective equipment
2. Ocular exposure only
3. Surgical mask only
4. Surgical mask plus eye protection
5. Fit-tested N-95 only
6. Fit-tested N-95 plus eye protection

 

 

While the study size was small, and the type of virus limited to 2 influenza A strains and 1 influenza B strain (MedImmune’s 2009/10 seasonal Flumist), the study yielded some very interesting results.

 

Researchers detected flu virus in all 4 subjects in Group 1 (unprotected), and in 3 of 4 in Group 2 (Ocular Exposure only).

 

Somewhat surprisingly, nasal washes of subjects with ocular exposure only were positive for flu virus within 30 minutes, suggesting the virus made its way rapidly to the nasopharynx by way of the nasolacrimal duct.

 

Flu virus was detected in all 10 volunteers who wore surgical masks (groups 3 & 4), regardless of eye protection.

 

N95 wearers (group 5) fared somewhat better, with 3 of 5 testing positive for the virus.

 

The best result came from the wearing of eye protection and an N95 (group 6). 

 

Only 1 in 5 subjects wearing that combination of protection showed detectable levels of virus.

 

 

The authors conclude:

 

"The eyes could be an entry route for influenza, allowing viral particles easy and fast access to the upper respiratory tract.

The type of surgical mask tested was inferior to a fit-tested N95 respirator in preventing aerosol delivery; however, none of the tested barrier precautions provided complete protection, including a CDC-recommended fit-tested N95 respirator and the addition of eye protection.”

 

This study – like all laboratory research – is subject to certain limitations. The results, while compelling, aren’t definitive.

 

The size of the study – 28 test subjects –was fairly small, and the substitution of a live influenza virus with an LAIV could have potentially skewed the results.

 

More research will be needed to confirm these findings.

 

Meanwhile, conflicting opinions regarding the efficacy of various types of respiratory PPEs will likely continue while we await further studies.

Measles: Forgotten, But Not Gone

 

 

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Measles, which was once almost a youth’s `rite of passage’ in the United States, has been all but eliminated in recent years after the introduction of the first measles vaccine in 1963.

 

The chart below (source: CDC) shows the remarkable effectiveness of the vaccination campaign.

 

 

While many parents today think of measles as a relatively benign childhood illness, it actually produced significant morbidity and mortality with respiratory, ocular, and neurological complications - sometimes resulting in death.

 

During the 1950s – before the introduction of the measles vaccine – in the United States the disease infected roughly 4 million, hospitalized nearly 50,000,  and contributed to the deaths of several hundred every year.  

 

Admittedly, a vast improvement over the mortality rates from earlier in the century, when the disease was far deadlier (for reasons that quite frankly, remain hard to explain – Ian York explored this fascinating mystery in Measles week, part I: Introduction ).

 

But in recent years lower uptake of the vaccine – its reputation tainted by (disproven) claims of a possible link to autism (popularized by Dr. Andrew Wakefield and promoted by various anti-vaccination groups) – and the continual importation of the disease from countries where it remains endemic - have allowed the virus to keep a toehold in developed nations.

 

In developing countries, the incidence – and mortality rate – of measles remains high.   These statistics from the World Health Organization:

 

 

Measles

Fact sheet N°286

Key facts

• Measles is one of the leading causes of death among young children even though a safe and cost-effective vaccine is available.
• In 2008, there were 164 000 measles deaths globally – nearly 450 deaths every day or 18 deaths every hour.
• More than 95% of measles deaths occur in low-income countries with weak health infrastructures.
• Measles vaccination resulted in a 78% drop in measles deaths between 2000 and 2008 worldwide.
• In 2008, about 83% of the world's children received one dose of measles vaccine by their first birthday through routine health services – up from 72% in 2000.

 

Today news on measles from several fronts. 

 

First, the WHO’s  WER (Weekly Epidemiological Record) brings us details on an ongoing measles outbreak in Europe, that has infected more than 6,500 people in 33 nations.

 

Measles outbreaks in Europe

As of 18 April 2011, 33 countries in Europe had reported  6500 measles cases. Epidemiological investigations and genotyping have confirmed transmission of measles virus among several countries in the Region and in the Americas.

<SNIP>

In all these outbreaks, except for the second out-
break in Spain and the outbreak in Turkey, the D4
genotype of measles virus has been confirmed.
The B3 genotype of measles virus was isolated
from cases in the second measles outbreak in
Spain, while the D9 genotype, originating from
and common in south-east Asia (e.g. Malaysia and
Indonesia) was confirmed to have caused the out-
break in Istanbul (Turkey) in January 2011.

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As you can see, there are a number of different strains or genotypes of measles.  New ones emerge, or are detected, every so often.  As of mid-2010, the World Health Organization (WHO) maintained reference strains representing 23 recognized genotypes.

 

From Eurosurveillance this week, a report on a novel strain of (an existing genotype:G3) of measles which has spread across Europe over a 2 month period.

 

Eurosurveillance, Volume 16, Issue 17, 28 April 2011

Rapid communications

Appearance of a novel measles G3 strain in multiple European countries within a two month period, 2010

K E Brown, M N Mulders, F Freymuth, S Santibanez, M M Mosquera, S Cordey, J Beirnes, S Shulga, R Myers, D Featherstone

During late 2010, a previously unrecognised strain of measles genotype G3 virus was identified in five different European countries by the World Health Organization Measles and Rubella Laboratory Network. Apart from one, none had a travel history to south-east Asia, the usual source of G3 viruses, although epidemiological links could be established between some of the cases. This case series illustrates the value of genotyping and sequencing in tracking measles infections, and identifying otherwise unrecognised chains of transmission.

(Continue . . . )

 

And next, from the Journal of Infectious Diseases a report on the impact of an outbreak of measles in Tucson, Arizona in 2008 that affected two healthcare facilities. 

 

 

Health Care–Associated Measles Outbreak in the United States After an Importation: Challenges and Economic Impact

 

J Infect Dis. (2011) jir115 first published online April 28, 2011 doi:10.1093/infdis/jir115

Sanny Y. Chen,

Shoana Anderson, Preeta K. Kutty, Francelli Lugo, Michelle McDonald, Paul A. Rota, Ismael R. Ortega-Sanchez, Ken Komatsu, Gregory L. Armstrong, Rebecca Sunenshine, and Jane F. Seward

 

You can follow the above link to read the entire article, or for the short version, you can read the press release from the IDSA.

 

Infectious Diseases Society of America

Measles outbreak underscores need for continued vigilance in health care settings

[EMBARGOED FOR APRIL 29, 2011] The U.S. measles vaccination program has been successful in eliminating endemic measles in the United States; yet this success has provided challenges that require ongoing vigilance for the rapid identification and response to measles cases in health care settings. In 2008, the largest reported health care-associated measles outbreak in the United States since 1989 occurred in Tucson, Arizona, costing approximately $800,000 in response and containment efforts. In a report published in The Journal of Infectious Diseases and available online, researchers identify preventive measures hospitals and health care facilities can implement to reduce the likelihood and decrease the economic impact of a future measles outbreak in these settings.

 

Due to a highly effective vaccine and high vaccine coverage, measles was declared eliminated in the United States in 2000; however, the potential for measles infection still exists in this country. Non-adherence to U.S. vaccination recommendations and infection among unvaccinated travelers coming into the United States continue to pose potential threats to the public and to health care personnel. In the 2008 Tucson outbreak, an unvaccinated, infected Swiss traveler visited a hospital emergency department on February 12. The traveler was admitted to the hospital the next day, but a measles diagnosis was not confirmed until February 20. This ignited an intense and lengthy public health investigation and response to persons with suspected and confirmed measles as well as contacts of those persons.

(Continue . . . )

 

And again from the Journal of Infectious diseases, an editorial comment on the above study by Stephen M. Ostroff.  

The full text of both articles is freely available.

 

EDITORIAL COMMENTARY:

Stephen M. Ostroff

Measles: Going, Going, But Not Gone

J Infect Dis. (2011) jir125 first published online April 28, 2011 doi:10.1093/infdis/jir125

 

 

While not the scourge of the early 20th century in the United States, measles remains a serious public health threat in much of the world, and is only held at bay in developed countries by relatively high vaccination rates.

 

There is a lot more to the measles story, and I highly recommend reading the entire Mystery Rays blog series on the disease by Ian York from 2010.

 

Measles week, part I: Introduction

Measles week, part II: Emerging disease

Measles week, Part III: Not the answers

Measles week, part IV: Some of the answers

Measles week, Part V: What about the vaccine?

 

 

Priming Numbers

 

 

# 5303

 

 

Photo Credit PHIL 

 

After the abrupt reappearance of bird flu in 2003, the United States, along with a number of other countries around the world decided to create a vaccine against the-then-dominant clade 1 `Vietnam’  strain of the H5N1 virus.

 

The United States produced and stockpiled roughly 20 million doses of vaccine. 

 

The feared pandemic did not break out, but the virus continued to spread across Asia and Europe in wild birds and domesticated poultry, and as it did, it drifted and mutated into several new clades.

 

As Vietnam got better control of their bird flu problem, detections of clade 1 viruses declined, while in 2006 a new and dangerous strain – clade 2.1 emerged in Indonesia.

 

Elsewhere in Asia, and Europe, clade 2.2 (`Qinghai’) viruses spread widely and caused outbreaks in dozens of countries, including human infections in Egypt, Azerbaijan, Iraq, China, and Turkey.   

 

And since the middle of the last decade sub-clades 2.3.2 (`Fujian’) and 2.3.4 have emerged and continue to circulate across much of Asia.

 

We now have more than a half dozen active clades of the virus circulating, and further changes to the virus are anticipated over time.

 

Making the H5N1 bird flu virus a moving target, and very difficult to create a vaccine against in advance.

 

With our current technology, it takes roughly 6 months from the detection of an emerging pandemic strain, to having any quantity of vaccine available.

 

And current studies indicate that it will likely take two vaccinations – several weeks apart – to convey immunity against a novel bird flu virus.

 

An unforgiving timeline that would be trampled by a fast moving pandemic.

 

To get around these difficulties, the suggestion has been made that we should consider `priming’ essential workers with an H5N1 vaccination now (or at the start of an outbreak) – in hopes that even a slightly `mismatched’ vaccine would provide some protection until a second `strain specific’ vaccine could be distributed.

 

Furthermore, it was hoped that those who received an  H5N1 shot now might only require a single booster shot during a pandemic.

 

In May of 2010, Dr. Klaus Stohr, former head of the World Health Organization's global influenza program, wrote in an opinion piece for Nature that the world should consider pre-vaccinating their populations against strains likely to emerge in the future (see The Prime Of Our Lives).

 

And in 2008, Japan – faced with expiring stockpiles of H5N1 vaccines - began a pilot program to pre-vaccinate essential workers in a `use-it or lose-it’ strategy (see Japan Begins Pre-Pandemic Inoculation Of Health Care Workers.)

 

Other countries, including the UK, have considered similar strategies (see UK: Considering A `Prime Directive').

 

The idea of pre-vaccination isn’t farfetched.

 

In the summer of 2008 we saw a study, published in the August edition of The Journal of Infectious Diseases,  which showed that people who received an experimental H5N1 vaccine in Hong Kong 8 years before developed a strong immune response after receiving a single booster shot of a clade 1 H5N1 vaccine. 

 

All of which serves as prelude to a new study, which appears in the March edition of The Journal of Infectious Diseases:

 

Safety and Immunogenicity of Influenza A H5 Subunit Vaccines: Effect of Vaccine Schedule and Antigenic Variant

Robert B. Belshe, Sharon E. Frey, Irene Graham, Mark J. Mulligan, Srilatha Edupuganti, Lisa A. Jackson, Anna Wald, Gregory Poland, Robert Jacobson, Harry L. Keyserling, Paul Spearman, Heather Hill, Mark Wolff

Abstract

Background. The current US national stockpile of influenza H5 vaccine was produced using the antigen from the strain A/Vietnam/1203/2004 (a clade 1 H5 virus). Recent H5 disease has been caused by antigenically divergent H5 viruses, including A/Indonesia/05/2005 (a clade 2 H5 virus).

 

Methods. The influence of schedule on the antibody response to 2 doses of H5 vaccines (one a clade 1 hemagglutinin protein [HA] vaccine and one a clade 2 HA vaccine) containing 90 μg of antigen was evaluated in healthy adults 18–49 years of age.

 

Results. Two doses of vaccine were required to induce antibody titers ≥1:10 in most subjects. Accelerated schedules were immunogenic, and antibody developed after vaccinations on days 0 and 7, 0 and 14, and 0 and 28, with the day 0 and 7 schedule inducing lower titers than those induced with the other schedules. With mixed vaccine schedules of clade 1 followed by clade 2 vaccine administration, the first vaccination primed for a heterologous boost. The heterologous response was improved when the second vaccination was given 6 months after the first, compared with the response when the second vaccination was given after an interval of 1 month.

 

Conclusions. An accelerated vaccine schedule of injections administered at days 0 and 14 was as immunogenic as a vaccine schedule of injections at days 0 and 28, but both schedules were inferior to a vaccine schedule of injections administered at 0 and 6 months for priming for heterologous vaccine boosting.

 

 

A somewhat less daunting press release (see Don't Pitch Stockpiled Avian Flu Vaccine) is available from the Saint Louis University Medical Center.   

 

This study (details are available here) made a number of discoveries, which tend to support the notion of pre-pandemic vaccination.

 

Researchers confirmed that – as expected - a single non-adjuvanted (90 μg antigen) vaccination did not produce an adequate antibody response.  Two shots are required.

 

They also discovered that two doses of clade 1 vaccine did not produce cross-reactive antibodies to the clade 2 virus, and vice-versa.

 

But, administering one dose of a clade 1 vaccine, followed 7 to 180 days later by 1 dose of the clade 2 vaccine, produced cross reactive antibodies against both clades.

 

Subjects who received the two shots 14 or 28 days apart developed a better antibody response than those who received the shots 7 days apart, or on the same day.

 

Somewhat unexpectedly, subjects who received the two shots 6 months apart developed an even stronger antibody response.

 

Not really an option during a pandemic, but an added bonus if you are priming a population in advance.

 

• According to this study, adverse reactions were largely local (mostly injection site tenderness, swelling or redness) and generally occurred on the day of vaccination.
• Less common systemic reactions (primarily malaise, myalgia, & headache) were mostly mild or moderate, and generally subsided over 24-48 hours.

 

 

While the global stockpile of existing H5N1 vaccine is relatively small, it would allow us to prime millions of essential workers in advance of - or at the start of - an H5N1 pandemic. 

 

The authors wrap up by saying that despite changes in the H5N1 virus over time, their study confirms the usefulness of pre-vaccination with an antigenically out-of-date H5N1 vaccine.

 

While we hope we’ll never need it, that is definitely good to know.

JID: Emerging Influenza Resistance Threats

 

 

 

 

# 5125

 

 

The old adage - `if you make a better mouse trap, nature will begin to work on a better mouse’ - is well illustrated by the continual evolution of bacteria and viruses to evade our arsenal of antibiotic and antiviral agents.

Between MRSA and the growing number of emerging carbapenemases  - antibiotic resistance (rightfully) has most of our attention because it directly impacts tens of thousands of patients every year.   

 

Antiviral resistance – for now – is viewed with somewhat less alarm simply because we are not currently in an influenza pandemic, and it is rare that we encounter an influenza virus that is resistant to our entire arsenal of antiviral drugs.

 

But scientists worry that could change.

 

A few short years ago Amantadine (an M2 ion channel blocker) was the preferred influenza antiviral.  It was cheap, plentiful, and worked pretty well.

 

But by the mid 2000s Amantadine began to lose its effectiveness against the H3N2 seasonal flu virus and some strains of the H5N1 bird flu.

 

It has been suggested that the prophylactic use of Amantadine by Chinese poultry farmers (who supposedly included it in their chicken feed for several years) may have contributed to this sudden resistance.

 

But whatever the cause, by January of 2006 the CDC had issued a warning to doctors not to rely on Amantadine (or Rimantadine) to treat influenza.

 

Oseltamivir (Tamiflu) – a newer neuraminidase (NA) inhibitor drug  introduced in 1999 - while far more expensive, became the new treatment standard.

 

But within two years seasonal H1N1 began to show growing resistance to Oseltamivir as well (although H3N2 remained sensitive).

 

By the spring of 2009, - in the space of just about a  year – seasonal H1N1 had gone from almost 100% sensitive to the drug to nearly 100% resistant.

 

The arrival of a novel H1N1 pandemic virus was a game changer, in that it – unlike seasonal H1N1 – was still sensitive to oseltamivir (but not Amantadine).

 

In short order novel H1N1 supplanted the seasonal strain, breathing new life – at least for now – into the neuraminidase (NA) inhibitor class of antivirals.

 

But over the past 18 months we have seen a small number (less than 2% of samples tested) of Oseltamivir resistant novel H1N1 viruses – along with some evidence of transmissibility. 

 

So the concern lingers.  If seasonal H1N1 could go from nearly completely susceptible to completely resistant to oseltamivir in a year’s time – could it happen again with the new H1N1 strain?

 

And if that happens, what antiviral alternatives do we have in the pipeline?

 

These issues are addressed in the January issue of IDSA’s Journal of Infectious Diseases in a pair of articles and an editorial.

 

First, links to the three JID items, followed by excerpts from the IDSA’s press release.

 

“Dual Resistance to Adamantanes and Oseltamivir Among Seasonal Influenza A (H1N1) Viruses: 2008-2010” 
 

“Evidence of Person to Person Transmission of Oseltamivir Resistant Pandemic Influenza A (H1N1) 2009 Virus in a Hematology Unit”

 

“Emerging Influenza Antiviral Resistance Threats”

 

 

A few excerpts from the accompanying press release:

 

 

Influenza Virus Strains Show Increasing Drug Resistance and Ability to Spread

 

Studies Highlight Need for New Antiviral Treatment Options and Strategies

Two new studies raise public health concerns about increasing antiviral resistance among certain influenza viruses, their ability to spread, and a lack of alternative antiviral treatment options. The findings are published in the January 1 issue of The Journal of Infectious Diseases.

 

(Please see below (above) for links to these articles online.)

 

Influenza viruses are treated with two classes of drugs: M2 blockers (adamantanes) and neuraminidase inhibitors (NAIs), including oseltamivir and zanamivir.  While the spread of influenza strains with resistance to one class of drugs has been well documented in recent years, a new report from Larisa Gubareva, MD, PhD and colleagues at the Centers for Disease Control and Prevention (CDC) and at health agencies in West Virginia, Texas, and Canada, confirms that dual resistance can emerge in several ways and has been on the rise during the past three years.

 

<SNIP>

 

Although dual resistant viruses are still rare, the investigators noted an increase in the number of tested viruses with this resistance, from 0.06 percent (2007-2008) to 1.5 percent (2008-2009) to 28 percent (2009-2010); however, during the 2009-2010 season the number of circulating seasonal H1N1 viruses was low, and only 25 viruses were tested.  “Because only two classes of antiviral agents are approved, the detection of viruses with resistance to drugs in both classes is concerning,” said Dr. Gubareva. “If circulation of viruses with dual resistance becomes more widespread among any of the predominant circulating influenza A viruses, treatment options will be extremely limited. New antiviral agents and strategies for antiviral therapy are likely to be necessary in the future.”

 

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