Influenza 2004

January 2004

---Philip A. Brunell, MD

This should be an interesting year for influenza. So far we have been told that there have been outbreaks of influenza in the U.S. earlier than in most of the preceding years and that the vaccine does not match the most prevalent circulating H3N2 strain and that supplies of vaccine are short. These portend a bad year for influenza.

Deaths in children have been reported, which has resulted in a rush of people to get immunized, which has consequently depleted vaccine stocks in many areas. There is intense activity to determine whether and where shortages may exist. The government has purchased additional doses of killed vaccine produced by Chiron, as well as live vaccine from Wyeth/Medimmune; the latter at a price significantly below market price. The manufacturer also has offered rebates of $25 for the live vaccine.

The “bad match” is among the most disconcerting news. WHO has a network of laboratories throughout the world that monitors isolates of influenza virus to determine their antigenic make up. This is done months in advance of the influenza season in the United States. Isolates from the Far East, where many new strains have emanated in recent years, and the Southern Hemisphere, where new strains circulate during their winter prior to arrival here, are tested to attempt to predict what we will be experiencing in the United States during coming influenza season. Sufficient lead-time is needed to make a decision about the strains that manufacturers should incorporate into the vaccine for the next influenza season. Influenza vaccines are still produced in embryonated chicken eggs so much needs to be done between the time a recommendation is made until the vaccines appear in your office.

There are two types of changes that can occur in influenza virus. One is an antigenic shift, due to a reassortment of influenza virus RNA in which there is a change in the hemagglutinin and/or neuraminidase (eg, H1N1 to H2N2). When this occurs, a portion of the population will have had no antigenic experience with the new strain resulting in pandemics or major epidemics. This is not what is happening this year. What has occurred is antigen drift. This results from point mutations in the hemagglutinin leading to significant antigenic change from previous strains. As a consequence, individuals who may have been infected with these strains or vaccinated with antigens designed to prevent infections with them may not be well protected against the new stain. The most recent assessment from the CDC is as follows, “The A/Fujian strain predominated in Australia and New Zealand during the recent Southern Hemisphere influenza season and is a drift variant related to the vaccine strain, A/Panama/ 2007/99. Antibodies produced against the vaccine virus cross-react with A/Fujian/411/2002-like viruses, but at a lower level than against A/Panama/ 2007/99 (H3N2). Vaccine effectiveness depends, in part, on the match between vaccine strains and circulating viruses and cannot be determined by laboratory testing. Although vaccine effectiveness against A/Fujian/ 411/2002-like viruses may be less than that against A/Panama/2007/99-like viruses, it is expected that the current U.S. vaccine will offer some cross-protective immunity against the A/Fujian/411/2002-like viruses and reduce the severity of disease.”

It is hard to assess the significance of the fatal cases in children that have been reported. Enhanced surveillance in Michigan during the last influenza season turned up a number of deaths and severe illnesses in otherwise healthy children. Two of the cases of encephalitis ended fatally (Morbidity and Mortality Weekly Report. 2003;52(35):837). Febrile seizures are not uncommon in children with influenza. Cases of encephalitis should be reported to nih9@cdc.gov or (404) 639-2893, including those that are not accompanied by the classical signs of influenza. None of these children had been known to receive salicylates. Parents should be warned about avoidance of salicylates, as there is a strong association of this drug with Reye’s syndrome. Three deaths in otherwise normal children have been associated with community-acquired methicillin-resistant Staphylococcus aureus. If antibiotic treatment is considered, this should be taken into account. It is unclear whether these deaths portend a more lethal strain of influenza.

Virulent strains

Some strains of the virus are known to be more virulent, eg, swine flu. There are genes that affect virulence but these are not well defined. A recent report suggests that a mutation, which allows plasmin to cleave to the hemagglutin, may be a mechanism for this increase.

The new live-attenuated intranasal vaccine (LANIV) contains a gene for attenuation. A new LANIV is licensed for healthy children older than 5 years of age. Previous trials have indicated that these may have broader antigenic protections than the older inactivated vaccine. However, the vaccine is not recommended for children with asthma, immunocompromised children or children under 5 years of age. The prohibition for the latter group is particularly unfortunate as the inactivated vaccine, although recommended, has scant evidence of efficacy in the very young. The prohibition of live vaccines in the immunocompromised is standard although we do bend when it comes to varicella and measles. However, the current caution on the use of LANIV for individuals who may be in contact with high-risk persons may be a bit over the top. It would be unfortunate if the LANIV was withheld because of this concern and no vaccine was given because of the inability to obtain inactivated vaccine. Neither of the influenza vaccines should be given to children with severe egg allergies as the vaccine is produced in embryonated eggs. Measles and mumps are produced in tissue culture derived from chickens and do not carry a similar warning.

The Vaccine for Children program does cover the immunization of children 6 to 23 months of age for whom immunization had been “encouraged where feasible” and their contacts and is now recommended (MMWR. 2003;52(49):1197).

The ACIP has recommended routine immunization of those 6 to 23 months of age starting in the 2004-2005 season in order to allow time for logistics to be worked out. Presumably, one of the reasons for this is that a governmental agency should not make a recommendation for which there is inadequate funding to implement. It is too bad this could not make it into the omnibus bill that contains a lot of items of much lower priority. Influenza vaccine can be given simultaneously with other vaccines. Two doses are required for children being immunized for the first time. Half doses, 0.25 cc, are used for those under 24 months of age. Some vaccine packaged in 0.25 ml is virtually thimerosal free.

The start of influenza epidemics varies from year to year but most do not peak until after the New Year, thus, the directive to continue to immunize beyond the usual fall season when immunization is normally recommended. This year we had very early outbreaks in Texas and Colorado as well as activity in many other parts of the county. Most of the isolates have been H3N2 Fujian rather than Panama, the vaccine strain. There is lesser circulation of the H1N1 and B strains at this time. These are contained in the vaccine.

We have available antiviral agents that can be used for treatment or prophylaxis. These should not be used in lieu of vaccination. There are two types of antiviral agents, neuraminidase inhibitors, eg, oseltamivir (Tamiflu, Roche) and zanamivir (Relenza, GlaxoSmithKline). The M2 inhibitors, amantadine and rimantadine (Flumadine, Forest), although considerably less expensive are useful only in influenza A infections as influenza B viruses do not have an M2 protein. Thus, it is necessary to know which strain is circulating in the community. One also has the option of rapid testing in the office.

Influenza in infants may manifest as severe croup, bronchiolitis, pneumonia or an upper respiratory infection. It is indistinguishable from the other agents causing these illnesses.

At this time, the major means of protection appears to be meticulous infection control. Since cases in children resemble those produced by other viruses including influenza, it probably is a good time to review office procedures.