Dr. Orenstein has been a consultant to Chiron, has received research funds from the Chiron Foundation and has previously received research funds from Medimmune.
Few infectious disease burdens can compare with the impact of global influenza pandemics. During the past century, the United States was affected by three pandemics, 1918-19, 1957-58, and 1968-69 which accounted for approximately 500,000, 70,000, and 34,000 deaths, respectively. In addition, pandemic influenza can be associated with severe strains on the nation's health care delivery capacity as well as substantial economic disruptions. The Department of Health and Human Services has estimated (Table 1) the health burden of a moderate and a severe pandemic in the United States.
|Characteristic||Moderate (1958/68-like)||Severe (1918-like)|
|Illness||90 million (30%)||90 million (30%)|
|Outpatient medical care||45 million (50%)||45 million (50%)|
Source: www.pandemicflu.gov, p18.
Overall, approximately 30% of the population would develop clinical disease, approximately 50% of these persons would seek medical care and up to 1.9 million would die of their illness. Reports of human cases of an avian influenza virus, H5N1, in at least seven countries since 2003, raise concerns that a new pandemic may be at hand. While most influenza experts believe a pandemic of influenza is inevitable, it is not clear when the pandemic will strike, which virus will be its cause and how severe the health burden will be. However, it is important to enhance our preparedness now to be ready for the next pandemic, whenever it should occur.
There are two sugar-based proteins (glycoproteins), the hemagglutinin (H) and the neuraminidase (N), which project from the virus surface and play a critical role in the disease process. The hemagglutinin attaches to receptors on the host cell surface thus allowing the virus to enter5 The neuraminidase is important in final packaging and release of virus from infected cells and may be important in disease severity.
There are two major types of viruses associated with human disease, influenza A and influenza B. Influenza B viruses are stable, that is, their mutations are usually small, they don't mutate into completely new versions, and are not associated with pandemics. Influenza B viruses tend to cause epidemics of influenza which vary in magnitude, severity and interval in years from prior epidemics.
Influenza A viruses are associated with both annual epidemics and global pandemics. There are 16 known hemagglutinins of the influenza A virus, H1 - H16 and nine neuraminidases, N1-N9. Water fowl, particularly ducks and geese, are the natural hosts for the virus. Only three hemagglutinins are known to have circulated in humans — H1, H2 and H3. The H1N1 virus circulated from 1918-19 until 1957 when it was replaced by the A/Asian, H2N2 virus. This virus continued to circulate until 1968 when an H3N2 virus became predominant. In 1977, an H1 virus returned, which was similar to earlier strains of H1N1. This latter strain primarily affects young persons since persons born prior to 1957 were likely exposed to a similar virus and are usually immune. At the present time, three types of influenza viruses circulate in humans, A/H3N2 which tends to be responsible for the most severe of the annual epidemics, A/H1N1 and B. The strains that predominate in a given year vary.
There are two major types of viruses associated with human disease, influenza A and influenza B.
Antigenic drift occurs when the entire hemagglutinin is replaced by a completely new type of hemagglutinin to which virtually the entire population is susceptible. The new hemagglutinins are believed to originate in avian species. For example, the replacement of H1 viruses by H2 viruses in 1957 represented an antigenic shift. There are three criteria which must be met for a pandemic to occur:
- an antigenic shift takes place creating a virus against which almost the entire population lacks immunity,
- the virus causes serious human disease and
- the virus is transmitted efficiently from human to human.
The second mechanism involves mutation of avian viruses which make them efficient in both infecting humans and being transmitted from human to human. Such mutations account for the adaptation of the 1918-19 A/H1N1 virus to humans.
Antigenic drift occurs when the entire hemagglutinin is replaced by a completely new type of hemagglutinin to which virtually the entire population is susceptible.
Between 1998 and 2002, there were a few isolated poultry outbreaks in Hong Kong. However, by late 2003, H5N1 viruses had become responsible for a massive infection of avian influenza in East Asia fowl. Furthermore, the virus had mutated and whereas it had previously caused mild illnesses in chickens, it was now causing severe disease and death.
As of February 13, 2006, the H5N1 virus had spread through migratory birds throughout East Asia, into West Asia, Eastern and Western Europe, and several countries of Africa. There was concern because of bird migration during the winter that the virus would be introduced into Africa. Indeed, WHO is now reporting poultry cases in northern Nigeria (www.who.int/csr/don/2006_02_08/en/). The greater the dissemination of virus, the greater is the chance for mutation and reassortment, which could result in a human-adapted pandemic strain.
The major risk factor is exposure to sick poultry, although, because the virus can cause infection in birds without any symptoms, some persons will not have such exposures. Persons of all ages can develop severe disease but most cases reported to date have been young. In contrast, annual influenza epidemics, which may cause substantial disease particularly in school-aged children, tend to cause their greatest mortality in the elderly.
A major epidemiologic study in Vietnam reported that persons with direct contact with sick or dead poultry in households were 1.73 times as likely to develop a flu-like illness as persons living in households without such contact.
Individuals will usually develop the disease 2-4 days after exposure, although intervals can range up to eight days. Most patients with influenza are shedding virus up to a day before onset of symptoms and are most contagious during the first 1-3 days of illness.
Some small outbreaks suggest person to person transmission may have occurred. The best documented of these occurred in Thailand where an 11-year-old girl apparently infected a 26-year-old mother and a 32-year-old aunt without known chicken exposure. Both secondary cases had provided extensive unprotected nursing care to the 11-year-old girl. However, to date, the vast majority of cases can be linked to poultry exposure as the source rather than transmission from an infected person.
|Median or Mean Range on % of Patients|
|Age (yrs)||13.7 - 22 years|
|Time from illness onset to presentation at hospital||6 - 8 days (3/4 studies)|
|% Fever >38°C||100%|
|Myalgia||0 - 53% (3/4 studies)|
|Diarrhea||41 - 70%|
|Abdominal pain||24 - 50% (2/4 studies)|
|Vomiting||0 - 24% (3/4 studies)|
|Cough||94 - 100%|
|Rhinorrhea||0 - 53% (3/4 studies)|
Pulmonary complications were common including shortness of breath, pulmonary infiltrates, and respiratory failure (Table 3).
|Median or Mean Range on % of Patients|
|Shortness of breath||76 - 100% (3/4 studies)|
|Lymphopenia||33 - 80% (3/4 studies)|
|Thrombocytopenia||33 - 50% (3/4 studies)|
|Increased aminotransferase||67 - 83% (3/4 studies)|
|Respiratory failure||70 - 100%|
|Renal dysfunction||10 - 24% (3/4 studies)|
A decrease in infection-fighting white cells, platelets (which help clotting), inflammation of the liver and problems with kidney funtion were frequently reported with avian flu.
Most cases tended to have prolonged courses prior to hospitalization, which usually occurred 6-8 days after onset.
Initial human isolates of H5N1 viruses have been susceptible to the neuraminidase inhibitors. However, their effectiveness, the dosages required and the length of treatment needed are not known at this time. Based on experience with treatment and prevention with human-adapted influenza strains, it is reasonable to provide equivalent treatment courses.
Oseltamivir, which is administered orally, has led to reductions in length of illness of 1-2 days in healthy adults and 1.5 days in children 1-12 years.18 Middle ear infections were reduced in children by 44%. Treatment should start within 48 hours of onset of illness and ideally the earlier that doses can be administered the better. Adults should be treated with 75 mg twice a day for five days. Doses for children one year of age or older are weight adjusted. Doses need to be reduced for patients in kidney failure.
Zanamivir is administered intranasally, 10 mg (two inhalations) twice a day for five days. In contrast to oseltamivir, which is licensed for treatment of persons one year of age or older, zanamivir is not licensed for persons less than seven years of age.
Treatment should start within 48 hours of onset of illness and ideally the earlier that doses can be administered the better.
Recent reports raise concerns about the effectiveness of oseltamivir against H5N1 influenza viruses. Two persons were reported from Vietnam who developed resistance while on therapy and died still virus positive after the usual course of treatment had ended. Resistance to oseltamivir has been reported in Japan among children, many of whom received less than the recommended doses. However, there has not been evidence to date of transmission from human to human of resistant viruses. Experiments in mice suggest that recent H5N1 viruses are more infective than earlier viruses isolated from Hong Kong and that an eight-day regimen of oseltamivir provided significantly more benefit than the standard five-day course.
Some authorities have recommended that zanamivir be considered as an important alternative to oseltamivir.18 Resistance to this drug has not been a problem to date and from a molecular perspective changes to the virus that would be needed to make it zanamivir resistant would likely decrease its infectivity for humans. However, other experts are concerned that because H5N1 viruses may invade other tissues besides the lungs, zanamivir, as administered intranasally, may not achieve the blood levels needed to treat a body-wide virus when it has already been established but may be useful in preventing infection in the first place.
For the present, your doctor should treat a suspected case of avian influenza with a five-day course of oseltamivir, ideally starting the drug within 48 hours of onset. The WHO website (www.who.int/csr/disease/avian_influenza/en/) and the CDC website (www.cdc.gov/flu/avian/) should be monitored for potential changes to the treatment recommendations.
Exposed health care workers should monitor their temperature twice a day. If fever develops, they should be evaluated and, if no alternative cause is identified, should be placed on a neuraminidase inhibitor. Health care workers exposed to potentially infectious aerosols as a result of a lapse in technique should be considered for a 7-10 day course of prophylactic treatment with neuraminidase inhibitor (75 mg per day).
Household contacts of avian influenza cases should also be monitored for fever and, if febrile, should be treated with a neuraminidase inhibitor.
The major problems with vaccines against pandemic strains are:
- the time interval needed from detection of the virus to production of the first doses (generally at least four months);
- limited production capacity within the United States (only one manufacturer produces vaccine solely within the US and only about five million standard potency doses would be expected weekly after the minimum four-month production time);
- a two-dose schedule, one month apart, is likely to be needed;
- the quantity of antigen needed in each dose may be up to six times the standard dose (90 mcg versus 15 mcg) and
- virus mutations mean vaccines produced against today's strains may be ineffective against strains that actually cause the epidemic.
- moving production from the current manufacture in embryonated chicken eggs to cell-based production to be in a better position to meet surge demands and decrease production time;
- testing of adjuvants to decrease the amount of antigen needed per dose and potentially reduce the number of doses needed;
- evaluating alternative forms of delivery, such as intradermal vaccination, to decrease the amount of antigen needed per dose; and
- assuring that there is year-round egg supply to quicken reaction time when new strains are detected.
Because vaccine supply may be short of demand, the Advisory Committee on Immunization Practices (ACIP) and the National Vaccine Advisory Committee (NVAC) have developed a list, in priority order, of persons for whom vaccines would be targeted. This list is based on maintaining the critical infrastructure, especially of the health care delivery system, as well as protecting those persons thought to be most vulnerable to complications. The actual priorities would have to be adjusted based on the epidemiology of the pandemic strain. The list of priorities is shown in Table 4.
|Element and Tier||Personnel (1000's)||Cumulative Total (1000's)|
|1A. Health care involved in direct patient contact + essential support||9,000||9,000|
|Vaccine and antivirals manufacturing personnel||40||9,040|
|1B. Highest risk group||25,840||34,880|
|1D. Key government leaders + critical public health pandemic responders||151||45,731|
|2. Rest of high risk||59,100||104,831|
|Most CI and other PH emergency responders||8,500||113,331|
|3. Other key government health decision makers + mortuary services||500||113,831|
|4. Healthy 2-64 years not in other groups||179,260||293,091|
|Target Group||Estimated Population (millions)||Strategy||Target Group||Cumulative|
|# Courses (in millions)|
|Patients admitted to hospital||10.0||T||8.0||8.0|
|HCWs with direct patient contact||9.2||T||2.4||10.4|
|Highest risk outpatients||2.5||T||0.7||11.1|
|Pandemic health responders, pub safety & key gov decision makers||3.3||T||0.9||12.0|
|Increased risk outpatients||85.5||T||22.4||34.4|
|HCWs in ER, ICU, EMS, dialysis||1.2||P||4.8||41.2|
|Pandemic societal responders & other HCWs||10.2||T||2.7||43.9|
|Highest risk outpatients||2.5||P||10.0||101.2|
|Other HCWs w/ patient contact||8.0||P||32.0||133.2|
Effectiveness of non-pharmaceutical measures will also depend upon the stage of the pandemic. If transmission is already widespread, internationally and nationally, isolation and quarantine are less likely to have an impact compared to earlier stages. Such measures may be most important to implement when the pandemic is first detected, transmission is limited and new introductions of the virus from outside would be unlikely.
Isolation is designed to prevent transmitting cases from coming in contact with susceptible individuals. Quarantine applies to isolating the exposed but well contacts of cases, potentially in the incubation period, to prevent their contact with other persons. While isolation of cases early in a pandemic seems reasonable, mandatory quarantine of contacts may be difficult to enforce and carries with it obligations to provide food and shelter. It is not clear whether such a strategy given the short incubation period and doubling time of cases would be effective.
On the other hand, it appears reasonable to call for voluntary social distancing. With a severe pandemic, it is likely that the population will stop venturing out from their homes except for necessities, such as food and medical care, and voluntary calls for stopping social gatherings, such as sporting events, will be heeded. School closures may be more effective in rural than urban settings because of the greater potential for urban children to have contact outside of the school system but may be important in both settings if children are primary transmitters.
Wearing of masks in public needs further evaluation since its effectiveness is not clear. Handwashing and cough etiquette seem reasonable but their effectiveness for influenza are not known.
Since vaccine is the best means of preventing influenza, actions that would enhance the vaccine production and delivery infrastructure should be undertaken. For example, influenza vaccine is recommended annually for approximately 180 million Americans, yet the greatest number of doses ever distributed has been only 83 million. Efforts should be made to vaccinate a greater proportion of persons for whom influenza vaccine is already recommended (Table 6). This will encourage manufacturers to enhance capacity and be in a better position to make large quantities of vaccines more rapidly. In addition, the capacity to deliver vaccines to large populations rapidly will be increased. A focus on improving routine influenza vaccination has immediate benefits, regardless of whether or not a pandemic occurs in the near future.
- 65 and older
- Adults and children with a chronic health condition
- Children 6-23 months old
- Women who will be pregnant during the flu season
- Residents of long-term care facilities
- Persons with disorders that compromise respiratory function, handling respiratory secretions or increase aspiration
People who can give the flu to those at high risk
- Household member or caregiver of someone at high risk
- Health care workers
- Household member or caregiver of a child under two years old
Development and refinement of state, local and institutional plans can be useful to address issues such as staffing, security and minimization of economic disruptions.
Preparedness starts with improving surveillance to detect potential pandemic strains as quickly as possible to provide lead time for development of vaccines and implementation of other measures. Clinical suspicion of avian influenza should be raised when someone with unexplained acute respiratory illness is evaluated with a history of recent travel to an area where there are avian or human cases. Obtaining laboratory confirmation is critical and physicians should contact local health authorities immediately when they suspect a case. Vaccines are the best means of reducing influenza and its complications but may not be available early in a pandemic. The initial viruses isolated to date have been susceptible to neuraminidase inhibitors (oseltamivir and zanamivir) and although oseltamivir resistance has been reported, it is reasonable to consider both drugs for treatment and prophylaxis. Other measures such as isolation, social distancing, use of masks and respiratory hygiene may be of some benefit in slowing the epidemic and in buying time for vaccine production and delivery. An important step in preparing for a pandemic is to increase the vaccine production capacity and delivery infrastructure for annual influenza vaccination since it is this capacity that will be needed to produce and deliver pandemic vaccines. Less than 50% of Americans, for whom influenza vaccine is recommended annually, are vaccinated.