Influenza-Related Mortality: Title and subTitle BreakConsiderations for Practice and Public Health

In this issue of THE JOURNAL, the article by Thompson and colleagues¹ estimates the burden of annual influenza mortality and provides much new and challenging information. The basic mortality question under consideration is what causes excess deaths during annual winter influenza "seasons"? Such mortality excesses can be estimated reasonably well from available data, but it is another problem entirely to determine what proportion is actually due to influenza. Traffic deaths, fire deaths, and other death categories can also increase during the same months.

Cause-of-death data are not very helpful because death certificate recordings are inaccurate for many conditions and probably more so for elderly persons, for institutionalized individuals, and for those who succumb to the combined effects of different medical conditions. Population mortality data cannot determine who did and did not have influenza. Traditional influenza mortality accounting is therefore insensitive (ie, unable to detect all influenza deaths that occur).

However, national mortality calculations and "real-time" calculations of combined influenza-plus-pneumonia mortality (so-called P & I mortality)—generated by the Centers for Disease Control and Prevention's weekly 122-city mortality surveillance system² —depend on such imperfect data. Reduced sensitivity may be acceptable for the 122-city system, the principal aim of which is to detect mortality excesses quickly enough to institute public health measures, but it seriously impairs quantifying total influenza mortality. This shortcoming impacts the direction of effort and allocation of resources to deal with whatever mortality excesses occur. To compound the problem, traditional P & I mortality detection may be not only insensitive but also nonspecific, subsuming deaths caused by other viruses and by primary bacterial pneumonias. Although it has long been clear that too many people die during influenza seasons, it is difficult to be sure just who is dying from what.

Thompson et al¹ approach this fundamental problem by constructing more refined statistical models that incorporate national mortality data, and data on isolation or detection of influenza virus types and of respiratory syncytial virus (RSV), a cause of adult mortality not fully appreciated until recently.^{3 - 4} In addition, Thompson et al¹ go beyond P & I mortality to measure excess respiratory and circulatory disease (R & CD) mortality. This provides a range of influenza mortality estimates, from the familiar P & I data (probably underestimates), to the intermediate R & CD data, to the all-cause mortality data (probably overestimates).

The results most immediately apparent from these still-speculative but improved efforts are depressingly familiar. As has been known since the late 1800s, influenza is a major cause of mortality, its greatest burden falling on elderly persons, with a lesser but significant mortality peak in infancy. More surprising is the apparent magnitude of the problem—as many as 50 000 to 70 000 annual influenza deaths are estimated to occur in the United States. By comparison, this range may approach or exceed each year the total number of US lives lost during the entire decade-long Vietnam War, surely placing influenza in the forefront of public health priorities.

Worse is the revelation that annual influenza deaths have been and still are increasing dramatically. Thompson et al¹ speculate reasonably that the approximate doubling in excess influenza season deaths during the past 2 decades resulted from aging of the population. In support of this belief, the authors note that age-specific death rates (ie, deaths per 100 000 persons within specific 5-year age-ranges) have not changed significantly from 1976. It is to be hoped that influenza-specific death rates in the older age groups have in fact declined during the past few decades of increasing influenza vaccination rates,⁵ but such an effect, if present, might not be easy to detect in mortality models.

Thompson et al¹ also draw attention to a lesser-appreciated problem, that a significant component of excess mortality during influenza seasons (25% P & I mortality, 23% R & CD mortality) may be due to RSV and not to influenza. Adding to its well-deserved reputation as a significant cause of childhood illness and mortality, RSV seems also to mimic influenza in predominantly accounting for deaths in older adults. Influenza season mortality is thus a result of at least 2 important causes, each of which will require its own specific responses.

Another important finding by Thompson et al,¹ infrequently discussed but long apparent to some observers,⁶ is the extraordinary burden of influenza mortality in the "elderly elderly," including the demonstration that persons 85 years or older are 32 times more likely than persons 65 to 69 years to die of (probable) influenza. Although it used to be whispered that influenza is "the old man's friend," it is hard to imagine anyone of any age choosing to "befriend" it. The average life expectancy for men and women reaching age 65 years in the United States now exceeds 81 and 84 years, respectively,⁷ and is still increasing steadily.

What then should be done with such troubling information about extreme risk to elderly persons? The data of Thompson et al¹ suggest the need to rethink influenza prevention strategies. These strategies have traditionally grouped all persons older than 65 years into a one-size-fits-all risk group. In recent years, the targeted risk groups have laudably expanded from elderly and chronically ill persons to also include those with lesser but significant risks, such as persons aged 50 to 64 years, pregnant women, and infants and toddlers.^{8 - 9} However, these newer strategies also should probably reflect stronger consideration of the substantial influenza risk to the oldest individuals, the "litmus test" group for new vaccines and for drugs used in treatment and prevention.

The findings of Thompson et al¹ thus mix good news with bad. The results provide a clearer picture of the nature and burden of influenza-associated mortality but a bigger and much different problem than imagined. The challenge seems especially daunting in the face of 50 years of mixed evidence that influenza-prevention approaches, aimed more at personal protection than community control, have been sufficient. Annual influenza vaccination is and must remain among the most important public health priorities. However, current vaccines are not highly immunogenic in the very target groups (the "elderly elderly" and those with serious chronic conditions) that need them most.^{2 ,8}

Nearly 40 years ago, Centers for Disease Control and Prevention luminaries Alexander Langmuir, D.A. Henderson, and Robert Serfling¹⁰ lamented that influenza vaccines were insufficiently protective to constitute a sound basis for national prevention policy. Today's vaccines may be somewhat better, but they still pose the difficulty of trying to reduce influenza deaths by relying primarily on imperfect preventive agents, never fully embraced by the public. Now the medical and public health communities must also face the looming confrontation between an unstoppable force and an immovable object, the aging of the baby boom generation and the predictability of annual influenza. Simple demographics practically ensure an impending public health disaster of great proportion.

Hope lies in the realization that until better influenza and RSV vaccines become available, there still remains much good to be performed in clinical practice. This includes ending the many missed opportunities in the community, the office, and the institution to prevent influenza-associated death and severe illness.¹¹ Endorsement by health care professionals appears to be the strongest determinant of a patient's acceptance of influenza vaccine.¹² Active and organized approaches to prevention strategies (eg, patient calls and mailings) may also help to optimize patient vaccination rates.¹³

An important related role for clinicians is educating patients about the benefits and risks of annual influenza vaccination. Decades of misinformation need to be overcome, especially for older individuals who remember the reactogenic vaccines of 1957-1958 and the "swine flu affair" of 1976-1977, and who commonly hold to a tenacious belief that flu shots can cause the flu.¹⁴ Clinicians must be able to convey the well-documented reality that despite imperfect immunogenicity (not very good at preventing infection, fairly good at preventing severe disease and death² ) influenza vaccines offer a substantial benefit-to-risk ratio and, for those at risk, represent the chief means of significantly reducing the chance of influenza death, hospitalization, and illness.^{5 ,15 - 17} Even an imperfect vaccine, used optimally, can prevent many thousands of deaths. The enormous additional opportunity to prevent hospitalization and severe morbidity,^{8 ,15 - 16} although not addressed by Thompson et al,¹ strengthens the case.

Physicians and other health care professionals can do even more to protect patients by receiving annual influenza vaccinations. Clinician vaccination prevents transmission to patients (a significant risk factor in many patient care situations^{6 ,18} ), prevents the temporary loss of their services, sets a powerful example, and might even make a small contribution to community "herd immunity."

The article by Thompson et al¹ presents a fresh look at influenza mortality. Now may be the time to take a fresh look at what can be done about it. While awaiting better vaccines and revitalized policies, the best immediate means of reducing the enormous burden of influenza mortality appears to be the focused attention of physicians and other health care professionals, who can play a uniquely life-saving role.