H1N1 Update: CDC Releases 'Quick Facts' for Providers on Antiviral Drug Use

H1N1 Update: CDC Releases 'Quick Facts' for Providers on Antiviral Drug Use

At Friday's CDC press briefing on 2009 H1N1 flu, Dr. Anne Schuchat stressed the importance of antiviral drugs for severe illness and directed clinicians to a fact sheet on "some of the myths and misconceptions about antivirals."

Among the CDC's "Quick Facts for Clinicians on Antiviral Treatments for 2009 H1N1":

• Although initiating treatment within 48 hours of symptom onset is preferable, many patients (including those hospitalized or at high risk for severe illness) may still benefit if treatment is started later.

• While antivirals are advised for patients with heightened risk, even those without risk factors might benefit, making clinical judgment "essential."
• If flu is suspected and treatment seems warranted, antivirals should be started before laboratory confirmation of illness.

CDC fact sheet

CDC press briefing transcript

CDC: 2009 H1N1 Flu: Situation Update 30 October 2009

2009 H1N1 Flu: Situation Update

October 30, 2009, 1:30 PM ET

U.S. Situation Update

Weekly Flu Activity Estimates

U.S. Patient Visits Reported for Influenza-like Illness (ILI)

U.S. Influenza-like Illness (ILI) Reported by Regions

U.S. Influenza and Pneumonia-Associated Hospitalizations and Deaths from August 30 to October 24, 2009

International
Situation Update

Map of International
Activity Estimates
(Including 2009 H1N1 Flu)

Key Flu Indicators

October 30, 2009, 1:30 PM

Each week CDC analyzes information about influenza disease activity in the United States and publishes findings of key flu indicators in a report called FluView. During the week of October 18-24, 2009, a review of the key indictors found that influenza activity continued to increase in the United States from the previous week. Below is a summary of the most recent key indicators:

• Visits to doctors for influenza-like illness (ILI) increased steeply since last week in the United States, and overall, are much higher than what is expected for this time of the year. ILI activity now is higher than what is seen during the peak of many regular flu seasons.
•  
• Total influenza hospitalization rates for laboratory-confirmed flu are climbing and are higher than expected for this time of year. Hospitalization rates continue to be highest is younger populations with the highest hospitalization rate reported in children 0-4 years old. 
•  
• The proportion of deaths attributed to pneumonia and influenza (P&I) based on the 122 Cities Report has increased and has been higher than what is expected at this time of year for four weeks now. In addition, 22 flu-related pediatric deaths were reported this week; 19 of these deaths were confirmed 2009 H1N1, and three were influenza A viruses, but were not subtyped. Since April 2009, CDC has received reports of 114 laboratory-confirmed pediatric 2009 H1N1 deaths and another 12 pediatric deaths that were laboratory confirmed as influenza, but where the flu virus subtype was not determined.
•  
• Forty-eight states are reporting widespread influenza activity at this time. They are: Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia, Wisconsin, and Wyoming. This many reports of widespread activity are unprecedented during seasonal flu.
•  
• Almost all of the influenza viruses identified so far are 2009 H1N1 influenza A viruses. These viruses remain similar to the virus chosen for the 2009 H1N1 vaccine, and remain susceptible to the antiviral drugs oseltamivir and zanamivir with rare exception.

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.

Revised US CDC Recommendations for Use of Antiviral Drugs

Revised US CDC Recommendations for the Use of Influenza Antiviral Drugs

September 8, 2009 2:00 PM ET

Background

On September 8, 2009 CDC updated its recommendations for the use of influenza antiviral medicines to provide additional guidance for clinicians in prescribing antiviral medicines for treatment and prevention (chemoprophylaxis) of influenza during the upcoming 2009-2010 flu season.

These recommendations are intended to help clinicians prioritize use of antiviral drugs for treatment and prevention of influenza. In general, the priority for the use of antiviral medications this season continues to be in persons at increased risk of influenza-related complications as outlined in the antiviral recommendations posted on May 6, 2009.

How is the new guidance different from the guidance that was issued on May 6, 2009?

The priority use for antiviral medications during the upcoming influenza season remains the same as outlined in the antiviral recommendations posted on May 6, 2009; that is to prioritize use of these drugs for those patients who are severely ill (hospitalized) and those patients who are ill with influenza-like illness and who are at high risk for influenza related complications.

The updated guidance provides additional context and guidance for clinicians in an effort to ensure that antiviral drugs are prescribed appropriately this season and that they reach those in greatest need quickly. This includes actions that clinicians may consider taking to reduce possible delays between illness onset in high risk patients and treatment, including a suggestion that clinicians consider providing prescriptions for antiviral medications ahead of time for such patients.

In addition, the updated guidance provides more information about the appropriate (and limited) situations in which antiviral medications should be used for chemoprophylaxis (prevention) this season. The updated guidance states that antiviral drugs should not be used for prevention in healthy persons based on community exposures.

In addition, the guidance places an emphasis on the use of antiviral drugs for early treatment (versus preventatively). The updated recommendations seek a balance between providing clinicians the information and guidance needed to reach those at greatest risk with appropriate and timely treatment; to reduce the chances of antiviral-resistance through inappropriate or unnecessary chemoprophylaxis; and yet to still recognize the overarching importance of clinical judgment in making treatment and chemoprophylaxis decisions.

What are influenza antiviral drugs?

Influenza antiviral drugs are prescription drugs (pills, liquid, or inhaler) that decrease the ability of flu viruses to reproduce. While getting a flu vaccine each year is the first and most important step in protecting against flu, antiviral drugs are a second line of defense in the prevention and treatment of flu.

Who is prioritized for treatment with influenza antiviral drugs?

Most people ill with influenza will recover without complications. 
Some people are at increased risk of influenza complications and are prioritized for treatment with influenza antiviral drugs this season. They include:

• People hospitalized with suspected or confirmed influenza
• People with suspected or confirmed influenza who are at higher risk for complications
• Children younger than 5 years old (children under 2 years old are at higher risk for complications than older children)
• Adults 65 years and older
• Pregnant women
• People with certain chronic medical or immunosuppressive conditions
• People younger than 19 years of age who are receiving long-term aspirin therapy

Physicians may also decide not to treat some people in these groups and/or treat people who are not in these groups based on their clinical judgment.

Who is lower priority for treatment with influenza antiviral drugs?

Treatment with influenza antiviral drugs is generally not needed for people who are not at higher risk for complications or do not have severe influenza, such as those requiring hospitalization. However, any suspected influenza patient who presents with emergency warning signs (for example, difficulty breathing or shortness of breath) or signs of lower respiratory tract illness should promptly receive antiviral therapy.

Doctors may treat some people who are not in a high risk group based on their clinical judgment. In addition, doctors also may decide that treatment is not needed for some who are in a high risk group based on their clinical judgment.

Which influenza antiviral drugs should be used for treatment this season?

At this time, treatment with oseltamivir (trade name Tamiflu®) or zanamivir (trade name Relenza®) is recommended for all people with suspected or confirmed influenza who require hospitalization.

What are the treatment benefits of influenza antiviral drugs?

For treatment, antiviral drugs should be started within 2 days after becoming sick. When used this way, these drugs can reduce the severity of flu symptoms and shorten the time you are sick by 1 or 2 days. They may also prevent serious flu complications.

Antiviral drugs may be especially important for people who are very sick (hospitalized) or people who are sick with the flu and who are at increased risk of serious flu complications, such as pregnant women, young children and those with chronic health conditions.

How effective are antiviral drugs at preventing the flu?

When used to prevent the flu, antiviral drugs are about 70% to 90% effective against susceptible viruses (i.e., viruses that are not resistant to the antiviral medication). It’s important to remember that flu antiviral drugs are not a substitute for getting a flu vaccine.

When should health care providers start treatment with antiviral drugs? 

Once the decision to administer antiviral treatment is made, treatment with zanamivir or oseltamivir should be initiated as soon as possible after the onset of symptoms. Evidence for benefits from antiviral treatment in studies of seasonal influenza is strongest when treatment is started within 48 hours of illness onset.

However, some studies of oseltamivir treatment of hospitalized patients with seasonal influenza have indicated benefit, including reductions in mortality or duration of hospitalization even for patients whose treatment was started more than 48 hours after illness onset.

When treatment is indicated, health care providers generally should not wait for laboratory confirmation of influenza to begin treatment with antiviral drugs because laboratory testing can delay treatment and because a negative rapid test for influenza does not rule out influenza. The sensitivity of rapid influenza diagnostic tests can range from 10-70% for 2009 H1N1 virus.

What can health care providers do to reduce delays in antiviral treatment?

Clinicians can take several actions to reduce delays in antiviral treatment initiation. These include:

1. Informing people at higher risk for influenza complications of the signs and symptoms of influenza and the need for them to get treated early.
2. Ensuring quick access to telephone consultation and clinical evaluation for these patients as well as patients who report severe illness.
3. Considering empiric treatment of patients at higher risk for influenza complications based on telephone contact if hospitalization is not indicated and if this will substantially reduce delay before treatment is initiated.

What are the symptoms of seasonal influenza or 2009 H1N1 influenza?

The symptoms of seasonal and 2009 H1N1 influenza include fever, cough, sore throat, runny or stuffy nose, body aches, headache, chills and fatigue. Some people may also have vomiting and diarrhea. Some people may be infected with the flu, including 2009 H1N1, and have respiratory symptoms without a fever.

Who is at higher risk of influenza related complications?

Groups at higher risk for influenza related complications are similar to those at higher risk for seasonal influenza complications and include: children younger than 5 years old; adults 65 years of age and older, pregnant women, people of any age with certain chronic medical conditions (for example, asthma, diabetes, lung disease, people with weakened immune systems, etc.) and people younger than 19 years of age who are receiving long-term aspirin therapy.

For children younger than 5 years of age, note that the risk for severe complications from seasonal influenza is highest among children younger than 2 years old.

What actions should health care providers take when waiting for influenza test results?

When treatment is indicated, health care providers should consider empiric treatment while influenza test results are pending, if the clinicians decided to test, especially if there will be a significant delay before testing can be performed. Once the decision to administer antiviral treatment is made, treatment with oseltamivir or zanamivir should be initiated as soon as possible after the onset of symptoms.

How long should patients receive treatment with antiviral drugs?

The recommended duration of treatment is five days. However, hospitalized patients with severe infections might require longer treatment courses.

When should clinicians prescribe antiviral drugs for prevention of influenza?

Pre-exposure antiviral chemoprophylaxis should only be used in limited circumstances, and in consultation with local medical or public health authorities. Certain people at ongoing occupational risk for exposure (health care personnel, public health workers, or first responders who are working in communities with influenza A H1N1 outbreak), especially those at higher risk for complications of influenza, should carefully follow guidelines for appropriate personal protective equipment to prevent influenza exposure to influenza. Health care workers at high risk of influenza-related complications who cannot minimize exposure may consider temporary reassignment.

Who should receive antiviral drugs for prevention of influenza?

Antiviral chemoprophylaxis generally should be reserved for people at higher risk for influenza-related complications who have had contact with someone likely to have been infected with influenza. As an alternative to chemoprophylaxis, clinicians can also choose to counsel people at higher risk for influenza-related complications about the early signs and symptoms of influenza and advise them to immediately contact a health care provider for evaluation and possible early treatment if clinical signs or symptoms develop.

Post-exposure antiviral chemoprophylaxis with either oseltamivir or zanamivir can be considered for health care personnel, public health workers, or first responders who have had a recognized, unprotected close contact exposure to a person with confirmed, probable, or suspected 2009 H1N1 or seasonal influenza during that person’s infectious period.

However, use of recommended PPE and other administrative controls (e.g. having health care personnel stay home from work when ill, and triaging for identification of potentially infectious patients) should be used to reduce the need for post-exposure chemoprophylaxis among health care workers.

As an alternative to chemoprophylaxis, health care personnel who have occupational exposures, can also be counseled about the early signs and symptoms of influenza, and advised to immediately contact their healthcare provider for evaluation and possible early treatment if clinical signs or symptoms develop.  

Should antiviral agents be used for post exposure chemoprophylaxis in healthy individuals?

Antiviral agents are discouraged for prevention of illness in healthy children or adults based on potential exposure in community, school, camp or other settings. In addition, there are no safety data regarding long term or frequent use of antiviral agents in children, and limited data for healthy adults.

Which antiviral drugs should health care providers prescribe for chemophrophylaxis of 2009 H1N1?

For antiviral chemoprophylaxis of 2009 H1N1 influenza virus infection, either oseltamivir or zanamivir are recommended. Currently, circulating 2009 H1N1 viruses are susceptible to oseltamivir and zanamivir, but resistant to amantadine

What is the recommended duration for antiviral chemoprophylaxis if used following exposure to someone with influenza?

Duration of antiviral chemoprophylaxis post-exposure is 10 days after the last known exposure.

What is the treatment of choice for pregnant women with suspected or confirmed 2009 H1N1 infection?

Oseltamivir and zanamivir are "Pregnancy Category C" medications, indicating that no clinical studies have been conducted to assess the safety of these medications for pregnant women. Pregnancy should not be considered a contraindication to oseltamivir or zanamivir use. Because of its systemic activity, oseltamivir is preferred for treatment of pregnant women.

What side effects can occur with influenza antiviral drugs?

Side effects differ for each drug. If an antiviral drug has been prescribed for you, ask your doctor to explain how to use the drug and any possible side effects. Health care professionals prescribing flu antiviral drugs should alert patients about adverse events that can occur. For more information about side effects, see Antiviral Drugs: Summary of Side Effects.

Can antiviral drugs be helpful for people unable to take the flu vaccine?

Yes. CDC and ACIP recommend use of antiviral drugs for people allergic to eggs (which can cause them to have an allergic reaction to the vaccine) or for people who previously have encountered complications from Guillain-Barre syndrome (GBS) associated with influenza vaccination. In addition, taking antiviral drugs may be recommended among persons that may not have a good immune response to the flu vaccine.

Should people use antiviral drugs before or after receiving the live attenuated influenza vaccine (LAIV) called FluMist®

LAIV is one of two types of flu vaccine. It is given as a nasal spray and contains weakened, live virus. Flu antiviral drugs taken from 48 hours before through 2 weeks after getting LAIV can lower or prevent the vaccinated person from responding to the vaccine and the person may not get immune protection from the vaccine.

Antiviral drugs can be taken with the inactivated (i.e. killed) flu vaccine.

Singapore braces for second H1N1 wave

Singapore hospitals brace for new H1N1 wave

A recent Singapore press statement (The Straits Time, September 4, 2009) noted that hospitals in the tiny island republic, have been asked to brace for a possible second wave of Influenza A (H1N1), even as the number of cases decline recently.

So although some among our citizens and doctors have felt that this A(H1N1) flu is just another flu, 'hyped up' to be worse that it really is, such sentiments should be considered as outside conventional wisdom.

While we welcome contrarian viewpoints, we should still be prudent when it comes to public health initiatves and direction.


Infectious disease experts in Sinagpore estimated that the first wave had infected about 700,000 people there, which means that some four-fifths of the population have still not been exposed to the virus.

As of Aug 31, 1,181 people with H1N1 had been hospitalised, with 77 needing intensive care. To date, 17 have died: four had no pre-existing conditions.

Associate Professor Paul Ananth Tambyah, head of the National University Hospital’s infectious diseases division, said the numbers were in line with those from other countries and validated Singapore’s approach to have pandemic-preparedness clinics look after the vast majority of patients with flu.

The WHO predicts that two billion people will likely be infected worldwide by this new virus, with a “second wave” expected during winter in the northern hemisphere, the traditional flu season. But as the virus has not changed much so far, the outbreak is likely to be mild and not drawn out, said doctors.

The Singapore health ministry is taking no chances, and will have two million courses of the anti-viral drug Tamiflu by the end of this year, almost double the original stockpile. Another 200,000 courses of Relenza will be added to the current 550,000 in the national stockpile. Singapore has a contract with Australian drug maker CSL for a pandemic vaccine, enough for the population.

CDC: Updated Interim Recommendations for the Use of Antiviral Medications

September 8, 2009 2:00 PM ET

Objective

To provide updated guidance on the use of antiviral agents for treatment and chemoprophylaxis of influenza including 2009 H1N1 influenza infection and seasonal influenza, and assist clinicians in prioritizing use of antiviral medications for treatment or chemoprophylaxis for patients at higher risk for influenza-related complications. Additional revisions to these recommendations should be expected as the epidemiology and clinical presentation of 2009 H1N1 influenza is better understood. This guidance can be adapted according to local epidemiologic data, antiviral susceptibility patterns, and antiviral supply considerations. Clinical judgment is always an important part of treatment decisions.

Summary

• Treatment with oseltamivir or zanamivir is recommended for all persons with suspected or confirmed influenza requiring hospitalization.
• Treatment with oseltamivir or zanamivir generally is recommended for persons with suspected or confirmed  influenza who are at higher risk for complications (children younger than 5 years old, adults 65 years and older, pregnant women, persons with certain chronic medical or immunosuppressive conditions, and persons younger than 19 years of age who are receiving long-term aspirin therapy.
• Persons who are not at higher risk for complications or do not have severe influenza requiring hospitalization generally do not require antiviral medications for treatment or prophylaxis. However, any suspected influenza patient presenting with warning symptoms (e.g., dyspnea) or signs (e.g., tachypnea, unexplained oxygen desaturation) for lower respiratory tract illness should promptly receive empiric antiviral therapy.
• Clinical judgment is an important factor in antiviral treatment decisions for all patients presenting for medical care who have illnesses consistent with influenza.
• Treatment should be initiated as early as possible because studies show that treatment initiated early (i.e., within 48 hours of illness onset) is more likely to provide benefit.
• Treatment should not wait for laboratory confirmation of influenza because laboratory testing can delay treatment and because a negative rapid test for influenza does not rule out influenza. The sensitivity of rapid tests can range from 10 % to 70%. View information on the use of rapid influenza diagnostic tests (RIDTs).
• Testing for 2009 H1N1 influenza infection with real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) should be prioritized for persons with suspected or confirmed influenza requiring hospitalization and based on guidelines from local and state health departments.
• Groups at higher risk for 2009 H1N1 influenza complications are similar to those at higher risk for seasonal influenza complications.
• Actions that should be taken to reduce delays in treatment initiation include:
• Informing persons at higher risk for influenza complications of signs and symptoms of influenza and need for early treatment after onset of symptoms of influenza (i.e., fever, respiratory symptoms);
• Ensuring rapid access to telephone consultation and clinical evaluation for these patients as well as patients who report severe illness;
• Considering empiric treatment of patients at higher risk for influenza complications based on telephone contact if hospitalization is not indicated and if this will substantially reduce delay before treatment is initiated.
• In selected circumstances, providers might also choose to provide selected patients at higher risk for influenza-related complications (e.g., patients with neuromuscular disease) with prescriptions that can be filled at the onset of symptoms after telephone consultation with the provider.
• Antiviral chemoprophylaxis generally should be reserved for persons at higher risk for influenza-related complications who have had contact with someone likely to have been infected with influenza.
• Based on global experience to date, 2009 H1N1 influenza viruses likely will be the most common influenza viruses among those circulating in the coming season, particularly those causing influenza among younger age groups.  Circulation of seasonal influenza viruses during the 2009-10 season is also expected. Influenza seasons are unpredictable, however, and the timing and intensity of seasonal influenza virus activity versus 2009 H1N1 circulation cannot be predicted in advance.
• Persons with suspected 2009 H1N1 influenza or seasonal influenza who present with an uncomplicated febrile illness typically do not require treatment.  However, some groups appear to be at higher risk for influenza-related complications.
• Currently circulating 2009 H1N1 viruses are susceptible to oseltamivir and zanamivir, but resistant to amantadine and rimantadine; however, antiviral treatment regimens might change according to new antiviral resistance or viral surveillance information.
• Information on the dose and dosing schedule for oseltamivir and zanamivir is provided in this document. An April 2009 Emergency Use Authorization authorizes the emergency use of oseltamivir in children younger than 1 year old, subject to the terms and conditions of the EUA

Background

As of August, 2009, more than 98% of circulating influenza viruses in the United States were 2009 H1N1 influenza (previously referred to as novel influenza A (H1N1). Among people who become infected with 2009 H1N1, certain groups appear to be at increased risk of complications and may benefit most from early treatment with antiviral medications. Approximately 70% of persons hospitalized from 2009 H1N1 influenza have had a recognized high risk condition (approximately 60% of children and approximately 80% among adults). These high risk conditions are the same conditions that increase the risk of complications from seasonal influenza infection.

• Children younger than 5 years old. However, the risk for severe complications from seasonal influenza is highest among children younger than 2 years old.
• Adults 65 years of age or older
• Pregnant women
• Persons with the following conditions:
• Chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, hematological (including sickle cell disease), neurologic, neuromuscular, or metabolic disorders (including diabetes mellitus);
• Immunosuppression, including that caused by medications or by HIV;
• Persons younger than 19 years of age who are receiving long-term aspirin therapy, because of an increased risk for Reye syndrome.

Among children, rates of influenza hospitalization from 2009 H1N1 have varied by age group with the highest rates of hospitalization in children younger than 2 years of age. Updated information on hospitalization rates by age group can be found at www.cdc.gov/flu/weekly.

People 65 and older are at lower risk of infection from 2009 H1N1 compared to younger age groups. However, as with seasonal influenza, people 65 or older who develop 2009 H1N1 influenza infection are at increased risk of influenza-related complications compared to younger adults.

Preliminary studies suggest that people who are morbidly obese (body mass index equal to or greater than 40) and perhaps people who are obese (body mass index 30 to 39) may be at increased risk of hospitalization and death due to 2009 H1N1 influenza infection. Additional studies to determine the risk of morbid obesity and /or obesity for these complications of 2009 H1N1 virus infection are underway. Patients with morbid obesity, and perhaps obesity, often have underlying conditions that put them at increased risk for complications due to 2009 H1N1 influenza infection, such as diabetes, asthma, chronic respiratory illness or liver disease. Patients with obesity or morbid obesity should be carefully evaluated for the presence of underlying medical conditions that are known to increase the risk for influenza complications, and receive empiric treatment when these conditions are present, or if signs of lower respiratory tract infection are present.
Transmission of 2009 H1N1 influenza is being studied as part of the ongoing epidemiologic investigation, but data available indicate that this virus appears to be transmitted in ways similar to other influenza viruses. All respiratory secretions and bodily fluids (including diarrheal stool) of 2009 H1N1 cases should be considered potentially infectious.
Close contact, for the purposes of this document, is defined as having cared for or lived with a person who is a confirmed, probable, or suspected case of influenza, or having been in a setting where there was a high likelihood of contact with respiratory droplets and/or body fluids of such a person. Examples of close contact include sharing eating or drinking utensils, physical examination, or any other contact between persons likely to result in exposure to respiratory droplets. Close contact typically does not include activities such as walking by an infected person or sitting across from a symptomatic patient in a waiting room or office.

Special Considerations for Children

Aspirin or aspirin-containing products (e.g. bismuth subsalicylate – Pepto Bismol) should not be administered to any confirmed or suspected ill case of influenza aged 18 years old and younger due to the risk of Reye syndrome. For relief of fever, other anti-pyretic medications such as acetaminophen or non-steroidal anti-inflammatory drugs are recommended.
Children younger than 4 years of age should not be given over-the-counter cold medications without first speaking with a healthcare provider.

Antiviral Treatment

Recommendations for use of antiviral medications may change as data on antiviral effectiveness, clinical spectrum of illness, adverse events from antiviral use, or resistance among circulating viruses become available. As of August 2009, more than 98% of circulating influenza viruses were 2009 H1N1 viruses susceptible to both oseltamivir and zanamivir. These treatment guidelines therefore focus on use of antiviral medications effective against 2009 H1N1 viruses. For antiviral treatment of 2009 H1N1 virus infection, either oseltamivir or zanamivir are recommended (Table 1).
Clinical judgment is an important factor in treatment decisions. Most patients who have had 2009 H1N1 virus infection have had a self-limited respiratory illness similar to typical seasonal influenza. Persons with suspected 2009 H1N1 influenza or seasonal influenza who present with an uncomplicated febrile illness generally do not require treatment. However, some groups appear to be at increased risk of influenza-related complications. Local public health authorities might provide additional guidance about prioritizing treatment within groups at higher risk for severe infection.

1. Treatment is recommended for all hospitalized patients with confirmed, probable or suspected 2009 H1N1 or seasonal influenza.
2. Treatment generally is recommended for patients who are at higher risk for influenza-related complications (see above).
3. Treatment should be initiated empirically when the decision is made to treat patients who have illnesses that are clinically compatible with influenza. Treatment should not await laboratory confirmation because laboratory testing can sometimes delay treatment and because a negative rapid test does not rule out influenza. (See “Evaluation of Rapid Influenza Diagnostic Tests for Detection of Novel Influenza A (H1N1) Virus --- United States, 2009” for more information about the sensitivity of rapid tests.)

These recommendations should be used together with clinical judgment in making treatment decisions for both patients who are at higher risk for influenza-related complications and patients who are not at higher risk. When evaluating previously healthy children with possible influenza, clinicians should be aware that, similar to seasonal influenza, the risk for severe disease is likely to be highest among infants and younger children. Once the decision to administer antiviral treatment is made by the health care provider, treatment with zanamivir or oseltamivir should be initiated as soon as possible after the onset of symptoms.

Evidence for benefits from antiviral treatment in studies of uncomplicated seasonal influenza is strongest when treatment is started within 48 hours of illness onset. Initiating treatment as soon as possible after illness onset is also thought likely to reduce the risk of severe outcomes including severe illness or death. However, some studies of hospitalized patients with seasonal influenza treated with oseltamivir have suggested benefit, including reductions in mortality or duration of hospitalization, even for patients whose treatment was started more than 48 hours after illness onset. The recommended duration of treatment is five days. Hospitalized patients with severe infections (such as those with prolonged infection or who require intensive unit care admission) might require longer treatment courses. Antiviral doses recommended for treatment of 2009 H1N1 influenza virus infection in adults or children 1 year of age or older are the same as those recommended for seasonal influenza (Table 1). Some experts have advocated use of increased (doubled) doses of oseltamivir for some severely ill patients, although there are no published data demonstrating that higher doses are more effective. Oseltamivir use for children younger than 1 year old was recently authorized by the U.S. Food and Drug Administration (FDA) under an Emergency Use Authorization (EUA). These EUA provisions apply only when the product is provided in accordance with the local public health authority's response plans. Dosing for children younger than 1 year old is age-based in the EUA guidance. However, some experts who are currently conducting studies on oseltamivir use in this age group prefer weight based dosing for this age group, particularly for premature or underweight infants. (Table 2) (See Emergency Use Authorization of Tamiflu (oseltamivir) ).

Persons at higher risk for complications from influenza or who have already developed severe illness should be treated as quickly as possible after signs or symptoms develop. To reduce delays in starting treatment, health care providers should:

1. Provide information for patients at higher risk for influenza complications about signs and symptoms of influenza and need for early treatment after symptom onset when ill with influenza;
2. Ensure rapid access to telephone consultation and clinical evaluation for these patients as well as patients who report severe illness;
3. Consider empiric treatment of patients at higher risk for influenza complications based on telephone contact if hospitalization is not indicated and if this will substantially reduce delay before treatment is initiated;
4. Request that patients at higher risk for influenza complications contact the provider if signs or symptoms of influenza develop, obtain the medication as quickly as possible and initiate treatment. In selected circumstances, providers may consider giving a prescription for an influenza antiviral to selected patients who are higher risk for influenza complications. When considering providing a prescription to patients for future use, providers might take into account patient reliability, ability to understand the information about symptoms of influenza, and access to a pharmacy. Providers might prefer to provide a prescription that requires a telephone consultation with the provider before it can be filled.
5. Counsel patients about influenza antiviral benefits and adverse effects, the potential for continued susceptibility to influenza virus infection after treatment is completed (because of other circulating influenza viruses or if illness was due to another cause), and the need to again seek early access to health care consultation if symptoms recur.

State prescribing and dispensing laws and requirements might differ. Clinicians should take applicable state prescribing and dispensing laws and requirements into account in considering these recommendations.
Patients receiving treatment should be advised that they remain potentially infectious to others while on treatment. Despite treatment with antiviral agents, including treatment with the neuraminidase inhibitors, patients may continue to shed influenza virus for up to four or more days after beginning therapy. Therefore, patients should continue good hand washing and respiratory hygiene practices during the entire period on therapy to prevent the transmission of virus to close contacts. View information about homecare of ill persons for providers and patients is available at: Taking Care of a Sick Person in Your Home and Physician Directions to Patient/Parent.

Treatment of influenza when oseltamivir-resistant viruses are circulating

Oseltamivir resistance is common among seasonal influenza A (H1N1) viruses. These viruses typically remain susceptible to rimantadine and amantadine. However, since April 2009, very few seasonal H1N1 viruses have circulated in the United States. Therefore, treatment, when indicated, with either oseltamivir or zanamivir is appropriate. However, if viral surveillance data indicate that oseltamivir-resistant seasonal H1N1 viruses have become more common or are associated with identified community outbreaks, zanamivir or a combination of oseltamivir and rimantadine or amantadine should be considered for use as empiric treatment for patients who might have oseltamivir-resistant seasonal human influenza A (H1N1) virus infection. National surveillance data on influenza viruses circulating in the United States is available and is updated weekly. State and local health departments are also a source of viral surveillance data in some areas. Guidance on empiric treatment recommendations when multiple influenza strains are circulating is available at http://www2a.cdc.gov/HAN/ArchiveSys/ViewMsgV.asp?AlertNum=00279.

Antiviral Chemoprophylaxis

The infectious period for persons infected with the 2009 H1N1 virus appears to be similar to that observed in studies of seasonal influenza. Infected persons may shed influenza virus, and potentially be infectious to others, beginning one day before they develop symptoms to up to 7 days after they become ill. Children, especially younger children, can shed influenza virus for longer periods. However, for this guidance, the infectious period for influenza is defined as one day before until 24 hours after fever ends.

• Post exposure antiviral chemoprophylaxis with either oseltamivir or zanamivir can be considered for the following:
• Persons who are at higher risk for complications of influenza and are a close contact of a person with confirmed, probable, or suspected 2009 H1N1 or seasonal influenza during that person’s infectious period.
• Health care personnel, public health workers, or first responders who have had a recognized, unprotected close contact exposure to a person with confirmed, probable, or suspected 2009 H1N1 or seasonal influenza during that person’s infectious period. Information on appropriate personal protective equipment is available at: Infection Control for Patients in a Healthcare Setting and might be updated frequently as additional information on transmission becomes available.
• Antiviral agents should not be used for post exposure chemoprophylaxis in healthy children or adults based on potential exposures in the community, school, camp or other settings.
• Chemoprophylaxis generally is not recommended if more than 48 hours have elapsed since the last contact with an infectious person.
• Chemoprophylaxis is not indicated when contact occurred before or after, but not during, the ill person’s infectious period as defined above.

Patients given post-exposure chemoprophylaxis should be informed that the chemoprophylaxis lowers but does not eliminate the risk of influenza and that protection stops when the medication course is stopped. Patients receiving chemoprophylaxis should be encouraged to seek medical evaluation as soon as they develop a febrile respiratory illness that might indicate influenza. For antiviral chemoprophylaxis of 2009 H1N1 influenza virus infection, either oseltamivir or zanamivir is recommended (Table 1). Duration of post-exposure chemoprophylaxis is 10 days after the last known exposure to 2009 H1N1 influenza.

Oseltamivir was authorized for use for chemoprophylaxis under the EUA for children younger than 1 year of age, subject to the terms and conditions of the EUA. (See Treatment and Chemoprophylaxis for Children Younger than 1 Year of Age, below.) Age-based dosing recommendations are provided in the fact sheets included with the EUA letter of authorization, however weight-based dosing is an alternative preferred by some experts who are currently conducting studies of oseltamivir use in this age group.

An emphasis on early treatment is an alternative to chemoprophylaxis after a suspected exposure for some persons. Persons with risk factors for influenza complications who are household or close contacts of confirmed or suspected cases, and health care personnel who have occupational exposures, can be counseled about the early signs and symptoms of influenza, and advised to immediately contact their health care provider for evaluation and possible early treatment if clinical signs or symptoms develop. Health care providers should use clinical judgment regarding situations where early recognition of illness and treatment might be an appropriate alternative. In some exposure circumstances (e.g., person exposed is at higher risk for complications), health care providers might choose to give the exposed patient a prescription for an influenza antiviral. Providers can request that the patient contact the provider if signs or symptoms of influenza develop, obtain antiviral medications as quickly as possible, and initiate treatment. These patients should also be counseled about influenza antiviral medication side effects, and informed that they remain susceptible to influenza after treatment is completed.

Persons at ongoing occupational risk for exposure (e.g., health care personnel, public health workers, or first responders who are working in communities with influenza outbreaks) should carefully follow guidelines for appropriate personal protective equipment. Appropriate administrative controls (e.g. having health care personnel stay home from work when ill, and triaging for identification of potentially infectious patients) and personal protective equipment should be used to reduce the need for post-exposure chemoprophylaxis among health care workers.

Antiviral Resistance

2009 H1N1 influenza viruses are susceptible to the neuraminidase inhibitor antiviral medications, oseltamivir and zanamivir, but are resistant to the adamantane antiviral medications, amantadine and rimantadine. This susceptibility pattern is the same as that observed among seasonal influenza A (H3N2) and B viruses in recent years. Oseltamivir resistance appears to be rare at this time. However, oseltamivir-resistant 2009 H1N1 viruses have been identified, typically among persons who develop illness while receiving oseltamivir for chemoprophylaxis or immunocompromised patients with influenza who are being treated. These findings underscore the importance of careful and limited use of antiviral medications for chemoprophylaxis and the need for persons taking antiviral medications to continue to follow recommendations for hand and respiratory hygiene to prevent the spread of antiviral resistant viruses. Additional information on oseltamivir resistance among 2009 H1N1 viruses is available at http://www.cdc.gov/h1n1flu/HAN/070909.htm. Monitoring for antiviral resistance is ongoing and clinicians and state health departments should continue to follow state and national guidance for submission and testing of clinical specimens from persons with suspected 2009 H1N1 virus infection, particularly from those who develop influenza while taking chemoprophylaxis or who have prolonged viral shedding while on treatment.

Antiviral Use for Control of 2009 H1N1 Influenza Outbreaks

Use of antiviral drugs for treatment and chemoprophylaxis of influenza has been a cornerstone for the control of seasonal influenza outbreaks in nursing homes and other long-term care facilities that house large numbers of patients at higher risk for influenza complications. (See MMWR: Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008). At this time, no outbreaks of 2009 H1N1 have been reported in such settings. This may be the result of some level of immunity among persons 65 years and older and/or possibly fewer exposures of such persons to 2009 H1N1 thus far. However, if such outbreaks were to occur, it is recommended that ill patients be treated with oseltamivir or zanamivir and that chemoprophylaxis with either oseltamivir or zanamivir be started as early as possible to reduce the spread of the virus as is recommended for seasonal influenza outbreaks in such settings. Additional guidance for infection control measures in long-term care facilities can be found at: Using Antiviral Medications to Control Influenza Outbreaks in Institutions.
In addition to use in nursing homes, antiviral chemoprophylaxis also can be considered for controlling influenza outbreaks in other closed or semi-closed settings (e.g., correctional facilities, or other settings in which persons live in close proximity) where persons at higher risk for influenza complications are housed. For more information about influenza outbreaks in facilities see:

1. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009
2.  Seasonal Influenza in Adults and Children—Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management: Clinical Practice Guidelines of the Infectious Diseases Society of America (available at: http://www.journals.uchicago.edu/doi/pdf/10.1086/598513).
3. Interim Guidance for Correctional and Detention Facilities on Novel Influenza A (H1N1) Virus
4. Interim Guidance for Homeless and Emergency Shelters on the Novel Influenza A (H1N1) Virus

Outbreaks in schools, camps, workplaces and other group settings should not be managed by providing chemoprophylaxis to all persons potentially exposed to influenza viruses. The healthy populations typically present in these settings should be educated about the signs and symptoms of influenza, and urged to consult their health care provider if severe illness develops. Post-exposure chemoprophylaxis can be considered for those who meet the above criteria for exposure and who have a medical condition that confers a higher risk for influenza complications. An emphasis on early evaluation and treatment, as described above, is an alternative. Persons in these settings also should be educated about hygiene and infection control measures that can reduce transmission of influenza viruses.

Table 1.Antiviral medication dosing recommendations for treatment or chemoprophylaxis of 2009 H1N1 infection. (Table extracted from IDSA guidelines for seasonal influenza.)

Agent, group		Treatment (5 days)	Chemoprophylaxis (10 days)
Oseltamivir
Adults		75-mg capsule twice per day	75-mg capsule once per day
Children ≥ 12 months	15 kg or less	60 mg per day divided into 2 doses	30 mg once per day
	16-23 kg	90 mg per day divided into 2 doses	45 mg once per day
	24-40 kg	120 mg per day divided into 2 doses	60 mg once per day
	>40 kg	150 mg per day divided into 2 doses	75 mg once per day
Zanamivir
Adults		Two 5-mg inhalations (10 mg total) twice per day	Two 5-mg inhalations (10 mg total) once per day
Children		Two 5-mg inhalations (10 mg total) twice per day (age, 7 years or older)	Two 5-mg inhalations (10 mg total) once per day (age, 5 years or older)

 

Treatment and Chemoprophylaxis for Children younger than 1 Year of Age

Children younger than 1 year of age are at higher risk for influenza-related complications and have a higher rate of hospitalization compared to older children. Oseltamivir is not approved for use in children younger than 1 year of age. However, limited safety data on oseltamivir treatment of seasonal influenza in children younger than 1 year of age suggest that severe adverse events are rare. Oseltamivir is authorized for emergency use in children younger than 1 year of age under an EUA issued by FDA, subject to the terms and conditions of the EUA.
Because infants experience high rates of morbidity and mortality from influenza, infants with 2009 H1N1 influenza virus infections may benefit from treatment using oseltamivir. (Table 2 and Emergency Use Authorization of Tamiflu (oseltamivir)).

Table 2. Dosing recommendations for antiviral treatment or chemoprophylaxis of children younger than 1 year using oseltamivir.

Age	Recommended treatment dose for 5 days	Recommended prophylaxis dose for 10 days
Younger than 3 months	12 mg twice daily	Not recommended unless situation judged critical due to limited data on use in this age group
3-5 months	20 mg twice daily	20 mg once daily
6-11 months	25 mg twice daily	25 mg once daily

Some experts prefer weight-based dosing for children aged younger than 1 year, particularly for very young or premature infants based on preliminary data from a National Institutes of Health- funded Collaborative Antiviral Study Group (CASG).  When using weight-based dosing for infants aged younger than 1 year for treatment, those 9 months or older should receive 3.5 mg/kg/dose BID, and those aged younger than 9 months should receive 3.0 mg/kg/dose BID. When using weight-based dosing for infants aged younger than 1 year for chemoprophylaxis, those 9 months or older should receive 3.5 mg/kg/dose QD, and those aged younger than 9 months should receive 3.0 mg/kg/dose QD (Source: D Kimberlin et al. Oseltamivir (OST) and OST Carboxylate (CBX) Pharmacokinetics (PK) in Infants: Interim Results from a Multicenter Trial. Abstract accepted to Infectious Diseases Society of America meeting, October 2009). Health care providers should be aware of the lack of data on safety and dosing when considering oseltamivir use in a seriously ill young infant with confirmed 2009 H1N1 influenza virus infection or who has been exposed to a confirmed 2009 H1N1 influenza case, and carefully monitor infants for adverse events when oseltamivir is used. Additional information on oseltamivir for this age group can be found at: http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM153547.pdf 

Pregnant Women

Pregnant women are known to be at higher risk for complications from infection with seasonal influenza viruses, and severe disease among pregnant women was reported during past pandemics. Hospitalizations and deaths have been reported among pregnant women with 2009 H1N1 influenza virus infection, and one study estimated that the risk for hospitalization for 2009 H1N1 influenza was four times higher for pregnant women than for the general population. While oseltamivir and zanamivir are "Pregnancy Category C" medications, indicating that no clinical studies have been conducted to assess the safety of these medications for pregnant women, the available risk-benefit data indicate pregnant women with suspected or confirmed influenza should receive prompt antiviral therapy. Pregnancy should not be considered a contraindication to oseltamivir or zanamivir use. Because of its systemic activity, oseltamivir is preferred for treatment of pregnant women. The drug of choice for chemoprophylaxis is less clear. Zanamivir may be preferable because of its limited systemic absorption; however, respiratory complications that may be associated with zanamivir because of its inhaled route of administration need to be considered, especially in women at risk for respiratory problems.

Adverse Events and Contraindications

For further information about influenza and antiviral medications, including contraindications and adverse effects, please see the following:

• Antiviral Agents for Seasonal Influenza: Side Effects and Adverse Reactions.
• Harper SA, Bradley JS, Englund JA, et al. Infectious Diseases Society of America Guidelines. Seasonal Influenza in Adults and Children—Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management: Clinical Practice Guidelines of the Infectious Diseases Society of America.
• Jamieson DJ, et al. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet 2009;374:451-8.
• CDC. Intensive-Care Patients With Severe Novel Influenza A (H1N1) Virus Infection --- Michigan, June 2009. 2009:58:749-52.
• Rasmussen SA. Pandemic Influenza and Pregnant Women: Summary of a Meeting of Experts. Am J Public Health 2009 (epub ahead of print).

Adverse events from influenza antiviral medications should be reported through the U.S. FDA Medwatch website.

Antivirals Slightly Shorten Duration of Seasonal Flu in Children

Treatment was well tolerated and slightly reduced transmission to household contacts. 

Children may shed influenza virus longer than adults and are a main source of spread to household contacts. To examine the effect of antiviral treatment in children, researchers performed a meta-analysis of seven randomized controlled trials of neuraminidase inhibitors for outpatient treatment of seasonal influenza and postexposure prophylaxis in children aged 12 years or younger.

Two trials evaluated outpatient treatment with oseltamivir and two with zanamivir within 36 or 48 hours of onset of influenza-like symptoms.

• In a total of 1766 children (1243 with confirmed and 523 with suspected influenza), 
• treatment reduced median time to symptom resolution, return to normal activities, or both by 0.5 to 1.5 days; 
• reductions were statistically significant in one oseltamivir trial and one zanamivir trial. 
• Recovery was significantly faster in children with confirmed influenza than in those with suspected influenza.

Three trials evaluated 10-day courses of oseltamivir (1 trial) or zanamivir (2 trials) for postexposure prophylaxis in 863 children.

• Treatment was associated with an 8% decrease in the incidence of symptomatic influenza (number needed to treat to prevent 1 additional case, 13). 
• Compliance was high — 97% of children took more than 8 of the 10 doses of zanamivir and 90% took all 10 doses of oseltamivir. 
• Both drugs were well tolerated; however, the incidence of vomiting was 5% higher with oseltamivir than with placebo. 
• No deaths were reported.

Comment:
This meta-analysis suggests that neuraminidase inhibitors are well tolerated in children and that they slightly reduce symptom duration and household transmission of seasonal influenza. Whether these data apply to the 2009 influenza A (H1N1) virus pandemic is not clear.

Given that H1N1 disease has been mild so far in otherwise healthy children older than age 5 years, neuraminidase inhibitors cannot be recommended for routine outpatient treatment in low-risk children older than 5 years with uncomplicated suspected 2009 H1N1 influenza 

(JW Pediatr Adolesc Med Aug 21 2009).

— Kristi L. Koenig, MD, FACEP
Published in Journal Watch Emergency Medicine September 4, 2009

Influenza A(H1N1) hits record high with 569 cases (Update)

By LESTER KONG

The Star, 20 August 2009

KUALA LUMPUR: Malaysia recorded its highest number of influenza A(H1N1) cases in a day with 569 infections.

There was also one death, bringing the total number of fatalities to 68.

Health Minister Datuk Seri Liow Tiong Lai said this indicated that the number of detected cases was still on the rise.

“That’s why our surveillance teams are working hard to detect areas that are persistent in local transmission so we can take measures to cut down on it,” he told reporters on Thursday after attending a campaign on prevention and treating A(H1N1).

He added there were 1,533 patients with influenza-like illness (ILI) who were admitted to 104 hospitals included four private establishments.

From this, 195 tested positive for the virus while 35 patients are in the intensive care unit.

A total of 188 people have been discharged from hospital.

Liow also said that private hospitals could not refuse treatment to patients with ILI.

He added the ministry would probe fatalities caused by late treatment of the patients at private hospitals.

According to a press statement from Health director-general Tan Sri Dr Ismail Merican, the death involved a 33-year old woman who was in the 34th week of her pregnancy.

The patient was treated and admitted into a private hospital in Johor Baru on Aug 8 after developing fever and cough for a day.

She was subsequently, referred and admitted to the intensive care unit of the Sultanah Aminah Hospital in Johor Baru for breathing difficulties five days later.

Tamiflu was administered.

“However, she died the following day because of severe pneumonia and respiratory failure,” he said.

She confirmed positive for the virus on Aug 14.

Earlier, Liow said government clinics in urban areas would now be opened on weekends to treat flu patients.

He said this was to reduce congestions and long queues at public hospitals.

The move takes effect immediately and the hours would differ from state to state, he added.

“In terms of hours, it will be the same as weekdays from 8am to 8pm for selangor,” he told reporters on Thursday after the launch of a seminar of stem cell research and therapy at Ampang Hospital.

“It is up to the state directors to decide on the exact number of hours to open in their respective areas depending on the number of patients.”

He added the doctors from public hospitals will be deployed to the clinics whenever necessary to assist the staff there.

Liow added insurance companies should include cause of death due to complications as a result of contracting influenza A (H1N1) in policies for their clients, regardless of whether they were new or old policy holders.

“I am confident that the demand for insurance will go up because of this health sit due to H1N1,” he added.

H1N1 update: Conflicting reports on use of other vaccines...

Pneumonia vaccine may help limit swine flu deaths

The H1N1 virus seen under a microscope (Centers for Disease Control and Prevention / April 28, 2009)

In view of the growing sense of hopelessness and frustration among many, as we grapple with the growing menace of the H1N1 pandemic, there has been differing reports and suggestions that perhaps we can do more, by adopting measures which are unproven, although perhaps appearing rather sensible.


Pneumococal Vaccine for more people?
In an article in the LA Times by Thomas H. Maugh, on 4 August, 2009, it was reported that some scientists have advocated that perhaps the pneumococcal vaccine may be another weapon to use earlier to help reduce the severity and lethality of the H1N1 complications,

"there may yet be something that can be done to reduce hospitalizations and deaths associated with the virus, commonly known as swine flu", to quote certain public health authorities.

"Most of the serious consequences linked to the virus are the result of pneumonia, and an underused vaccine called Pneumovax can prevent, or at least limit, such complications in many patients.

The vaccine, made by Merck & Co., stimulates the body's ability to neutralize the bacteria responsible for many cases of pneumonia, and it has the potential to prevent an estimated one-third of pneumonia deaths linked to swine flu."

"We would certainly like to see the vaccine used more extensively," said Dr. William Schaffner, chairman of the preventive medicine department at Vanderbilt University School of Medicine and president-elect of the National Foundation for Infectious Diseases. Schaffner was a member of the Centers for Disease Control and Prevention advisory committee on vaccines that in early June strongly affirmed current recommendations for who should receive the vaccine.

Further, the vaccine provides protection against pneumonia for up to 10 years, meaning one vaccination provides at least some safeguard not just this year but for future flu seasons as well.

The CDC has issued an Interim guidance for use of 23-valent pneumococcal
polysaccharide vaccine during novel influenza A (H1N1) outbreak















However, not everyone shares the enthusiasm for this penumococcal vaccination initiative:
Some physicians are more skeptical about the pneumococcal vaccine's potential to limit flu deaths. "I think that the pneumococcal vaccine is a very important vaccine that should be taken by all for whom it is appropriate," said Dr. Aaron Glatt, president and chief executive of New Island Hospital in Bethpage, N.Y., and a spokesman for the Infectious Diseases Society of America. "Whether it could play a role in preventing complications from swine flu . . . I don't think that is known."


Not sure how many of H1N1 flu patients would develop bacterial pneumonia... The problem is that there are many causes of pneumonia, an inflammation of the lungs that interferes with breathing and can be fatal. The influenza virus itself can cause pneumonia, as can many others. Or the lungs can be invaded by a bacterium such as Streptococcus pneumoniae or Staphylococcus aureus when the patient is weakened by a viral infection.


Pneumovax protects against 23 strains of S. pneumoniae. It is not yet clear what proportion of swine-flu-related pneumonia is caused by S. pneumoniae and thus could be prevented or ameliorated by immunization.


But preliminary results presented to the CDC vaccine committee in June by Dr. Matthew R. Moore, a CDC medical epidemiologist, indicated that about 40% of swine-flu-related pneumonia had an unknown cause -- and that about 30% were caused by S. pneumoniae. This suggests that at least a third of flu-related pneumonia deaths could be prevented by vaccination.


How many would need to be additionally vaccinated? Is it worth it?
At least 70 million Americans are in groups that the CDC recommends receive the vaccine, according to Moore. That includes about 22 million people ages 2 to 64 with chronic underlying conditions, such as diabetes and heart disease; about 3.5 million with asthma; about 30 million smokers; and all people over the age of 65, about 15 million.


About two-thirds of the elderly have been vaccinated, Moore said, but fewer than a third of the other groups have. The committee has not recommended the vaccine for pregnant women, who are about six times as likely to die from complications of swine flu as the population at large.


The vaccine is relatively inexpensive. Merck charges $33 for the necessary one dose, and physicians who administer it typically charge the patient $50 to $75, which is covered by Medicare and private insurance. The side effects "are mostly local, including swelling and tenderness," Horovitz said.


"Significant side effects are rare unless you are dealing with someone who has a problem with vaccines in general."

---------------------oooooooooo---------------------

Local Scenario, not many with secondary infections to date...
Yet the reality may be less clear, at least for us here in Malaysia.

In our conversations with Dr Christopher Lee, chief of infectious disease at the Sungei Buloh Hospital, there appears to be few patients who develop secondary bacterial pneumonia, although in view of the very severe complications, cultures for bacteria had been performed (with few positive results) and even prophylactic antibiotics had been prescribed.

Still all these difficult cases are now being re-examined and scrutinised to see if some sense could be made to tease out why some patients do so badly, so rapidly...

NEJM Reports on Mexican H1N1 Experience
Recent reports from the Mexican Experience, reported in the New England Journal of Medicine, has also painted a predominantly viral pneumonitis, with few secondary bacterial infections as the cause of death or complications.

















Example of Chest X-ray & Pathology of Lung Tissue










































Treatment

• No patients had received oseltamivir before admission;
• 14 received it in hospital, at a dose of 75 mg twice a day for a minimum of 5 days;
  
• 11 began receiving it at admission (a mean of 8 days after the onset of symptoms) and
  
• 3 between 2 and 10 days after admission.
  
• Four patients who survived did not receive oseltamivir.
  
• After admission, 17 patients received ceftriaxone and 10 received clarithromycin. (thus, antibiotics were given)
  
• Additional antibiotics were prescribed in several patients, on the basis of their clinical course: three were given levofloxacin; seven, vancomycin; five, cefepime; five, imipenem; and two, dicloxacillin.
  

Clinical Course during Hospital Stay

• Respiratory distress requiring intubation and mechanical ventilation developed in 10 patients within the first 24 hours after admission.
• Two additional patients required mechanical ventilation during stay in the hospital
  
• Mechanical ventilation needed for 7 to 30 days in patients who survived and from 4 to 17 days in patients who died.
  
• Norepinephrine infusion was begun in 9 of 18 patients (50%) during the period of hospitalization, and 5 patients received corticosteroids (hydrocortisone at a dose of 300 mg per day or methylprednisolone at a dose of 60 mg per day). (this refers to hemodynamic or blood pressure support, and anti-stress hormone treatment)
  
• Of the 6 patients in whom renal failure developed, five died.
  
• 7 patients had multiorgan system failure.
  
• No patients had disseminated intravascular coagulation or neurologic complications.
  
• Four patients had ventilator-associated pneumonia, each case with a different cause: Acinetobacter baumannii, Achromobacter xylosoxidans, methicillin-resistant Staphylococcus aureus, or Escherichia coli.

• Of 18 patients, 7 died, and 11 recovered and were discharged from the hospital.
  
• Patients died within 10 to 23 days (mean, 14) after the onset of illness and between 4 and 18 days (mean, 9 days) after admission.
  
• Pathological evaluation of the lung showed diffuse alveolar damage, thick hyaline membranes, and prominent fibroblast proliferation.

Mortality

• Mortality among the patients requiring mechanical ventilation was 58%,
  
• four patients had nosocomial pneumonia,
  
• in most patients, lung damage was most likely due to the primary effect of infection with influenza virus.
  
• Possible mechanisms of damage include direct injury to the respiratory epithelium with a secondary cytokine storm.
  
• We do not currently know whether our patients, especially those who died, had viremia, as was reported in association with H5N1 infection, a very aggressive variety of influenza.
  
• Coinfection with other respiratory viruses could also explain the increased pathogenicity among our patients;
  
• however, no other common respiratory viruses were found in our patients.
• Only three of the patients had received influenza vaccine in fall 2009, since most patients were within the age groups for which vaccine was not recommended in Mexico.
• It is currently unknown whether seasonal vaccination offered any protection against Swine-Origin Influenza Virus infection, however.

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Note that no pneumococcus infection was detected in these group of patients from Mexico.

A few had what is commonly known as hospital acquired (nosocomial) infections due to long-standing use of mechanical ventilation or assisted respiration. Thus the verdict is still out...

More than half of those who required breathing support (mechanical ventilation) died

Once kidney or other multi-organ failure takes place the prognosis (outcome) is quite poor.

It is uncertain if seasonal flu vaccination helps to ameliorate the pandemic H1N1 flu severity, although few (only 3) patients with complications had such prior vaccination.

It suggests however, that the H1N1 virus is the main cause of severe penumonia in these patients who did very badly or who died...

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