COCA Conference Call Summaries and Slides:
INFLUENZA IN SENIORS (December 15, 2004)

NOTE: This document is provided for historical purposes only and may not provide our most accurate and up-to-date information. The most current Clinician's information can be found on the Clinician Home Page.

Lisa Rotz, M.D.
Acting Director of the Bioterrorism and Response Program
National Center for Infectious Diseases

Dennis O’Mara
Acting Deputy Director
Immunization Services Division
National Immunization Program

Raymond A. Strikas, M.D.
Associate Director for Adult Immunization
Immunization Services Division
National Immunization Program

Scott Harper, M.D.
Medical Officer
Influenza Branch
National Center for Infectious Diseases

Please note: Data and analysis discussed in these presentations were current when presented. Data collection and analysis are ongoing in many cases; therefore updates may be forthcoming elsewhere on this website, through publications such as CDC's Morbidity and Mortality Weekly Report or other venues. Presentations themselves will not be updated. Please bear this in mind when citing data from these presentations

PART I: Dr. Lisa Rotz:

UPDATE ON INVESTIGATIONAL NEW DRUG AVAILABILITY

The CDC, FDA and HHS have been working with several foreign manufacturers of influenza vaccine for U.S. availability under an Investigational New Drug (IND) designation. The IND vaccine is licensed and has been used safely in other countries, including Europe , which allowed the FDA to review our application to make it available for this year’s flu response.

At this time:

• HHS has committed to purchasing 1.2 million doses of this vaccine to supplement existing licensed vaccine distribution.
• CDC is currently working with state public health officials to identify areas which will use the IND vaccine when it becomes available in January 2005, along with their allotment of licensed vaccine, to reach their risk groups.
• We have the option to purchase additional vaccine should flu activity pick up.

PART II: Mr. Dennis O’Mara

ANNOUNCEMENT OF VACCINE SHORTAGE

• On October 5, 2004 Chiron Corporation announced that they would not be able to deliver their projected production of influenza vaccine to the U.S. market this year. Prior to that date, we had anticipated that their contribution would have made available over 100 million doses, an all-time record and 5 million doses more than was available during the 2002-2003 season.
• We also learned that Aventis Pasteur would eventually produce 58 million doses, slightly more than they had originally anticipated. Meanwhile, MedImmune, which produces live, attenuated vaccine, increased their output from 1 million to 3 million doses, leaving us with a total of 61 million doses available for distribution in 2004-2005.
• Also on October 5 th, Aventis Pasteur voluntarily ceased distribution, having already distributed 33 million vaccine doses, and agreed to collaborate with CDC to develop an allocation plan for the remainder of their production, which would optimize our joint purpose of reaching as many at-risk individuals as possible.

TWO PHASES OF DISTRIBUTION

PHASE ONE: 14 million doses from Aventis Pasteur were distributed as they came off the production line and were used to fill orders from state and local public health officials for Veteran’s Administrations, the Indian Health Service, long-term care facilities, all acute care hospitals, and vaccines for children in both private and military settings.

PHASE TWO: A decision was made to have the Association of State and Territory Health Officials and state health departments guide the distribution of 11 million doses of remaining vaccine:

• 3 million doses would go to public health departments, to be used in their clinics and/or redirected to other providers in their jurisdictions. Because public health entities vary in their operations from state to state, and we did not know which providers in a given state were seeing the preponderance of at-risk people, we believed state public health authority distribution was best.
• We now have 700,000 doses of preservative-containing vaccine remaining which we expect to come out in December; an additional 1.8 million doses will be available in January.
• 1 million doses of preservative-free product are available, which is licensed for children ages 6 through 36 months.
• We expect 1.2 million plus doses of vaccine to be available under IND , as mentioned earlier.

We’re well aware that in many places, providers in both the public and private sectors have vaccine that has not been used. We also know that in some areas, demand has slowed. In these situations, the providers can neither use nor redirect their excess vaccine. We’re trying as best we can to work through that, so that areas of the country where demand and need for vaccine continue will receive substantial quantities.

Finally, the Advisory Committee on Immunization Practices (ACIP) is going to meet on Friday, December 17, 2004 to discuss the pros and cons of widening the range of target groups for vaccination this year.

PART III: Dr. Ray Strikas

RISKS FOR INFLUENZA COMPLICATIONS

The risk for complications, that is hospitalizations and deaths from influenza, are highest among:

• Persons 65 years of age and older
• Young children, particularly those less than 2 years of age
• Persons of any age with certain underlying health conditions

On average, more than 200,000 hospitalizations are estimated to occur in influenza epidemics annually. These hospitalizations, as well as deaths, include both illnesses related to pneumonia and influenza and exacerbations of pulmonary and cardiovascular conditions.

Hospitalization rates for adults are increased:

• Two- to four-fold in high-risk persons between 15 to 44 years of age as compared to persons who don’t have those high-risk conditions
• Ten-fold for those 45 to 65 years of age
• Two- to four-fold for persons 65 years of age and older with a high-risk condition

In adults, rates for hospitalization are highest in older persons:

• Over 60% of influenza-related hospitalizations are estimated to occur in people 65 years of age and older
• 90% of the estimated average 36,000 annual deaths from influenza occur in older persons, 65 years and older

The high-risk conditions that appear to increase the risk for influenza complications, as recommended by the Advisory Committee and Immunization Practices (ACIP), include:

• Chronic disorders of the pulmonary and cardiovascular systems, including asthma
• Conditions that require regular medical follow-up, such as chronic metabolic diseases, diabetes mellitus, renal dysfunction, hemoglobinopathies, and immunosuppression, whether caused by medications or illnesses such as HIV or AIDS
• Pregnancy

In discussing these issues, this leaves a lot of latitude and questions when we present this information on the phone or in meetings. There has been a working convention, though not published or articulated in our recommendations, that end-organ compromise is probably an indicator of increased risk. If end-organ compromise doesn’t exist, then the person may not be at increased risk of complications of influenza. An example that one might use is a person with hypertension who does not have any end-organ damage.

Concerns have also been raised about other conditions, such as neurological problems, stroke and multiple sclerosis. We do not have good data on the risk of complications following influenza infections for these conditions. Ideally, we would like to offer influenza vaccine to everyone, vaccine supply permitting, but at present we cannot. Therefore, we have, this year in particular, restricted to recommending vaccine for these conditions.

Lastly, it is ultimately the decision of the clinician to make a judgment for his or her patient whether that person, in their opinion, is at increased risk for complications of influenza. If they deem that to be the case, even if the person does not have one of the listed conditions, we think it is quite reasonable that the physician or other clinician offer that person influenza vaccine.

PNEUMOCOCCAL VACCINE

The ACIP has for many years recommended vaccination against pneumococcal disease with the pneumococcal polysaccharide vaccine for:

• All adults 65 and older
• People 2 to 64 years who are either immunocompromised or have certain underlying medical conditions

These individuals include most of the same persons listed in the priority groups for this year’s influenza vaccine season.

Pneumococcal polysaccharide vaccine is currently underutilized. Recent estimates of coverage suggest:

• Only about 56% of adults 65 and older have ever received this vaccine
• Coverage is lower among young persons with chronic medical conditions
• As many as 15 million older persons and 32 million people ages 2 to 64 have been recommended to receive this vaccine, but remain unvaccinated

You should be aware that Merck, the sole manufacturer of this polysaccharide vaccine for adults, indicates that it has adequate supplies of this vaccine on hand. As of some weeks ago, they had planned to triple normal production volumes to meet anticipated increase in demand.

PART IV: Dr. Scott Harper

UPDATE ON INFLUENZA ACTIVITY

The influenza activity, thus far, has been typical for an influenza season. Compared with last season, when we had early activity, this season we are seeing pretty much what we expect from year to year. In terms of types of viruses, and this is relevant for purposes of choosing an antiviral agent, both influenza A and influenza B have been isolated in various parts of the country. Of those influenza A viruses isolated, all of the ones that have been characterized have been influenza A (H3N2) viruses.

Geographically, there has been either sporadic or local activity with many states reporting no activity. We are still relatively early in the season, with it typically starting around November, so this is not unexpected. We could still have considerably more activity as the season progresses; but to date, we have not seen a great deal of influenza activity across the country.

ANTIVIRAL AGENTS

There are two main classes of influenza antiviral medications available:

• Adamantanes, which includes amantadine and rimantadine, have been around for a long time; and are active only against influenza A viruses
• Neuraminidases inhibitors, newer agents which include oseltamivir and zanamivir, and are active against both influenza A and influenza B viruses

All four agents are approved for treatment in persons who have diagnosed influenza infection. However, only three are approved for chemoprophylaxis: amantadine, rimantadine, and oseltamivir (more commonly called Tamiflu).

ADAMANTANES

Amantadine and rimantadine are available in both tablets and syrup form. Again, there is no activity against influenza B viruses; but for influenza A viruses, administration:

• Reduces the length of symptoms by one to two days
• Decreases influenza A viral shedding in infected persons

Potential adverse effects of amantadine and rimantadine include:

• Gastrointestinal side effects, such as nausea and vomiting
• Central nervous system side effects (particularly with amantadine) such as difficulty concentrating, nervousness, insomnia, exacerbation of seizures, etc.

These effects have particular relevance when dealing with the aging population. Another important point is that there should be a dosage reduction for persons with kidney disease, and also for persons who are 65 years and older.

There are more specifics on how to reduce dosages and what conditions require reductions in the annual ACIP Influenza Prevention Guidelines, which are available from the CDC web site. This is a good resource for specific indications and adverse events for amantadine and rimantadine.

We know that there is pretty rapid development of antiviral resistance in these two drugs. Depending on the studies looked at, 10% to 30% of persons treated will develop resistance, usually within 2 to 5 days.

These are not viruses that are more easily transmitted or that cause more serious illness, but there are obvious public health implications for transmitting viruses that are resistant to these drugs. These viruses remain susceptible to the neuraminidase inhibitors, even though they are resistant to amantadine and rimantadine.

NEURAMINIDASES INHIBITORS

Oseltamivir and zanamivir are chemically related compounds which are administered either by tablet or suspension (oseltamivir), or by an orally inhaled powder (zanamivir). These drugs:

• Are active against both influenza A and B viruses
• Decrease shedding of both virus strains in infected persons
• Reduce length of symptoms by one to two days

There is also some evidence that these drugs reduce more serious complications, based on a recent compilation of studies that was published by Fred Hayden and his group, but that is early data.

Adverse effects for oseltamivir include gastrointestinal side effects. There does need to be a dosage reduction in persons with kidney disease. Again, I would refer you to the ACIP recommendations for more specifics on that.

Adverse effects with zanamivir include:

• Gastrointestinal side effects
• Headache
• Bronchospasm in persons with a history of bronchospasm

Individuals with a history or bronchospasm should not get zanamivir.

There is much less frequency of resistant viruses produced when neuraminidases inhibitors are used.

CDC GUIDELINES AND RECOMMENDATIONS

CDC encourages the use of amantadine or rimantadine for chemoprophylaxis and the use of oseltamivir or zanamivir for treatment, as supplies allow. There are several reasons, but in part it is to minimize development of the amantadine and rimantadine resistance among circulating influenza viruses.

An overall guiding principle of these guidelines is that people who are at high risk of serious complications from influenza may end up benefiting most from antiviral medications, so they should receive priority for their use.

Treatment

The CDC recommends a tiered treatment system, however, antiviral treatment (not prophylaxis) is recommended for:

• Any person who is experiencing a potentially life-threatening influenza-related illness
• Any person who is at high risk for complications and who is within the first two days of illness

Depending on local supply, persons who are influenza-infected, but do not have conditions placing them at high risk, should also be considered for treatment.

Chemoprophylaxis

Antiviral chemoprophylaxis is recommended in the following situations:

• Any person who lives or works in institutions, caring for people at high risk of complications of influenza infections. These institutions include nursing homes, hospitals and other facilities caring for persons with immunosuppressive conditions such as HIV and AIDS. When vaccine is available, in the setting of an outbreak:

• Staff should receive chemoprophylaxis only during the two week period following their vaccination
• Residents, vaccinated or not, should receive chemoprophylaxis during the entire outbreak.

If staff is unable to be vaccinated, then they should also receive prophylaxis throughout the period of an outbreak at their institution.

For persons and communities where influenza viruses are circulating (which typically lasts about 6 to 8 weeks), chemoprophylaxis should be considered for:

• Persons who are at high risk for complications, and who have not been vaccinated
• Persons who are at high risk who have been vaccinated, but haven’t had time to respond (i.e. within the two weeks immediately following vaccination)
• Persons with immunosuppressive conditions who aren’t expected to mount an adequate antibody response to influenza vaccine should receive antiviral medications for the duration of the community outbreak activity
• Healthcare workers with direct patient care responsibilities who are unable to obtain vaccine

CDC does not recommend use of these drugs for chemoprophylaxis of non-high-risk persons in the community.

QUESTIONS AND ANSWERS

Q&A with Mr. Dennis O’Mara:

Q: What is the late-season availability of vaccine, and when is it too late to vaccinate?

A: If you look back, starting from last year and working backwards over the previous 27 years, you see that the most common month in which influenza peaks, according to the surveillance data, is February. In those last 27 years, influenza peaked in February or later in 16 of those years.

It would appear that, while influenza vaccine is not cooperating with us this year, influenza is, to a degree. While it’s uncertain about how much influenza we’ll see, or when it might peak, it looks like the activity, as Dr. Harper alluded to earlier, is fairly slow. So the opportunity for vaccination continues.

The recommendations generally suggest that vaccination can and should continue for as long as the vaccine supply is available. Even when influenza is occurring in a community, because you can talk about when influenza peaks – even if it has peaked, there is still the downside of the curve and there are still cases occurring.

Unvaccinated, unprotected people can benefit from vaccination, even after the onset of influenza. Obviously, optimal months for vaccination are October and November, according to the ACIP, but that should not prevent continuation of the vaccination effort into December and beyond, because great benefit can still be achieved in many years when influenza activity is delayed.

Q&A with Dr. Strikas:

Q: Is the IND flu vaccine going to be distributed to areas that are known to have a shortage of the approved flu vaccine, or is distribution going to be based on some other criteria? Who is going to make that determination?

A: I’m aware of some of the general discussions. Certainly we have asked states about their vaccine supplies and we’ve asked them about their interest in using IND vaccine, because it does pose an additional demand on resources to have this vaccine used – because of additional requirements of written consent, which is not required for the licensed vaccine, as well as registration of patients, data collection, and monitoring of adverse events.

It is going to be in part a state decision, whether they have a need for vaccine, made jointly with CDC, and whether they’ve got the infrastructure to be able to manage this vaccine, and the resources to set up special clinics for the vaccine. So it is going to be a combination of state and CDC decision-making to try to direct the vaccine where need exists.

Q: Some news organizations are showing a loosening of restrictions. Does CDC have comments about that?

A: About a week ago, CDC and the Association of State and Federal Health Officials did issue guidance saying that we are primarily adhering to the priority groups, as we described on October 5 th, who should receive vaccine, and ask others to defer.

The one exception to that, we stated a week ago, was for practitioners in private medical settings who had extra vaccine and who had vaccinated all the priority groups of the public that they could identify; they could then extend their vaccine use to people 50 to 64 years of age, and to contacts of other high risk persons besides children less than 6 months of age, in an effort to make the best use of the vaccine – if these providers found that they could not identify other providers or health departments or others who could use the vaccine for the interim priority groups I identified. That is where CDC is right now.

As Dennis said, the ACIP is discussing issues around vaccine supply and broadening vaccine recommendations to other groups. They will be discussing this Friday. We hope to disseminate their decision late Friday, if at all possible, and let people know. It is possible to ACIP may change their decision. They may broaden the recommendations somewhat, and they may suggest that the recommendations be broadened at a later time, perhaps in January.

So these are several of the options that the committee will be discussing. But at the present, CDC and ACIP are standing by the priority groups, as identified on October 5 th, again, with the one exceptions of modest amounts of vaccine in private practice offices that have done everything they can to use it, and of course, don’t wish to dispose of it without using it in patients.