Influenza virus causes outbreaks during the cooler months of the year and thus has a mirror-image season in the antipodes compared with that in the Northern Hemisphere. The circulation of strains in the Southern Hemisphere has some predictive value for vaccine composition in the Northern Hemisphere, and vice versa. This information is important as the degree of antigenic drift is one determinate of vaccine efficacy. Vaccine composition typically must change in at least one component yearly in anticipation of the predicted circulating strains.
A typical outbreak begins in early winter and lasts 4–5 weeks in a given community, although its impact on the country as a whole will be of considerably longer duration. When excess mortality occurs, an influenza outbreak is classified as an epidemic. Influenza’s impact is reflected in increased school and work absenteeism, increased visits to emergency rooms and primary care physicians, and increased hospitalizations, particularly of elderly patients and individuals with underlying cardiopulmonary disease. The impact often is most easily recognized in the pediatric population, whose school absenteeism quickly peaks. Despite efforts to limit influenza spread through vaccination, cohorting, use of masks, and hand washing, long-term-care facilities house another sentinel population, including many elderly patients who are at increased risk of complicated disease.
Influenza is largely spread by small- and large-particle droplets; spread is undoubtedly facilitated by the coughing and sneezing that accompany the illness. Within families, the illness is often introduced by a preschool or school-aged child.
Influenza’s global spread and causative strain(s) in a given year are well documented by the surveillance networks of the World Health Organization (WHO) and the CDC. The severity of an epidemic depends on the transmissibility and virulence of the viral strain, the susceptibility of the population, the adaptation of the virus to its human host, and the degree of antigenic match to the recommended vaccine. None of these parameters is totally predictable for influenza A.
When a major shift in the hemagglutinin and/or the neuraminidase occurs, with introduction of a new serotype from an animal or avian reservoir, an influenza A strain has the potential to cause a pandemic. In modern influenza history, such shifts occurred in 1918 (H1N1), 1957 (H2N2), 1968 (H3N2), 1977 (H1N1), and 2009 (H1N1pdm) (Table 195-1). On the basis of seroarchaeology (the analysis of serum antibody profiles in the elderly), epidemics that took place in the 1890s have been attributed to H3N2 and H2N2 viruses. Epidemics typical of influenza have been documented throughout recorded history.
TABLE 195-1Emergence of Antigenic Subtypes of Influenza A Virus Associated with Pandemic or Epidemic Disease ||Download (.pdf) TABLE 195-1 Emergence of Antigenic Subtypes of Influenza A Virus Associated with Pandemic or Epidemic Disease
|Years ||Subtype ||Extent of Outbreak |
|1889–1890 ||H2N8a ||Severe pandemic |
|1900–1903 ||H3N8a ||? Moderate epidemic |
|1918–1919 ||H1N1b (formerly HswN1) ||Severe pandemic |
|1933–1935 ||H1N1b (formerly H0N1) ||Mild epidemic |
|1946–1947 ||H1N1 ||Mild epidemic |
|1957–1958 ||H2N2 ||Severe pandemic |
|1968–1969 ||H3N2 ||Moderate pandemic |
|1977–1978c ||H1N1 ||Mild pandemic |
|2009–2010d ||H1N1 ||Pandemic |
In some epidemics, a younger age group proves especially susceptible. This is the case with current H1N1 epidemics, where individuals born before 1968 had likely been exposed to related viral strains and thus were relatively protected against the current strain. The 1918 epidemic was striking in this regard: the most severely infected individuals were infants and previously healthy young adults—the latter being a group not typically found to have high influenza mortality (Fig. 195-2). The 1918 epidemic increased all-cause mortality and led to more deaths than all military losses in World War I. In spite of the attention paid to the risk and impact of pandemic disease, it is generally appreciated that—with the exception of 1918—cumulatively more illness occurs during yearly epidemics combined than in pandemics.
Excess pneumonia/influenza deaths in 1900–1953, demonstrating the dramatic peaks of deaths among young infants and young adults (25–34 years of age). (Data are from public health records collated by the author.)
All of the annual influenza A epidemics in the past 50 years have been caused by H1N1 and/or H3N2 strains. H2N2 strains circulated between 1957 and 1968, and H1N1 strains circulated prior to that, including in 1918. However, potentially pandemic viruses continue to emerge, mostly in Asia, with higher-numbered hemagglutinins (e.g., H5, H6, H7, H9) reflecting some of the 16 distinct H and 9 distinct N subtypes in avian reservoirs. Most cases of these potentially pandemic illnesses have occurred in individuals who have had direct contact with domesticated birds or who have visited live-bird markets, which are common in Asia. In addition to the global aeronautic movement of infected people, bird migration is one mechanism for rapid global spread. It is not clear why higher-numbered avian hemagglutinin strains have not acquired the degree of transmissibility necessary to cause pandemic disease.
Avian and Swine Influenza Viruses
The full panoply of influenza viruses is found in domestic and migratory wild birds. It is postulated that epithelial cells in the swine respiratory tract may play a specific role as a “mixing vessel,” allowing the reassortment of genes from avian and human sources and thereby permitting the transition of avian viruses to humans. The nature of the sialic acid receptors for influenza virus hemagglutinin partially accounts for host preference. Humans have largely α-2,6-galactose receptors, while birds have α-2,3-galactose receptors. Swine have both types of receptors on their respiratory epithelial cells—hence their postulated role in facilitating reassortment and host adaptation of avian strains to growth in humans. Strains such as 2009 H1N1pdm (pandemic) had genes of avian, swine, and human origin. Some avian strains—notably H5 strains—are highly pathogenic in humans, as was the 1918 strain. The reasons for the high pathogenicity of certain strains are not entirely clear. Virulence and transmissibility often appear to be separate genetic traits.
After the sequencing of the 1918 virus recovered from the lungs of bodies buried in the Arctic permafrost, the virus was genetically reconstructed under carefully controlled isolation conditions. In animal studies of this viable 1918 virus, both the hemagglutinin and the ribonucleoprotein contributed to high levels of replication accompanied by an abnormally enhanced innate immune response characterized by proinflammatory cytokines. Perhaps this “cytokine storm” is the best explanation for the enhanced illness occurring in young, immunologically vigorous individuals in the 1918 pandemic. Sequencing demonstrated that the 1918 virus was of avian origin. Although the 1918 virus was first identified in military camps in the United States, its impact cannot be attributed to the disruption of war: the illness was well documented in countries such as Iceland that were not directly involved in World War I.
The same concerns about a “cytokine storm” have been raised with regard to the H5N1 viruses that first emerged in Hong Kong in 1996. These viruses exhibited high pathogenicity in individuals who had direct contact with domestic fowl, with mortality rates close to 50%, but also displayed poor human-to-human transmissibility. Pathogenicity appears to be a function not just of the viruses’ surface proteins, but also of an optimal gene constellation including all eight segmented influenza genes. However, unlike the 1918 strain, the H5N1 viruses have, to date, caused only sporadic disease, as have other limited clusters of a highly pathogenic H7N9 virus.
Influenza B and C Viruses
The influenza B viruses are more genetically stable than the influenza A viruses and have no animal reservoirs. Two lineages of influenza B have circulated for the past 40 years (B/Yamagata-like and B/Victoria-like viruses), and it has proven very difficult to predict which strain will be dominant in a given year. This issue has led to the incorporation of representatives of both influenza B lineages plus influenza A/H1N1 and H3N2 viruses into a quadrivalent vaccine.
Influenza C viruses cause intermittent mild disease and have attracted little attention. These viruses have been the subject of fewer than 10 publications annually since the year 2000.
Influenza-Associated Morbidity and Mortality
Although epidemics vary in severity and in the age groups most affected, certain high-risk groups are seen in all epidemics (Table 195-2). These groups are assigned the highest priority for vaccination and other preventive and therapeutic measures. Their caregivers and close contacts are also prioritized targets of interventions. A generalization is that the relative impact of an epidemic is seen in the youngest age group with the least prior exposure—and therefore the least immunity—to influenza. The impact of influenza can be depicted as a pyramid of illnesses, medical visits, hospitalizations, and deaths (Fig. 195-3).
TABLE 195-2High-Risk Groups Who Should be Assigned a High Priority for Influenza Immunization and Treatmenta ||Download (.pdf) TABLE 195-2 High-Risk Groups Who Should be Assigned a High Priority for Influenza Immunization and Treatmenta
|High-Risk Group |
Children 6–59 months of age
Adults ≥50 years of age
Persons with chronic pulmonary (including asthma), cardiovascular (except isolated hypertension), renal, hepatic, neurologic, hematologic, or metabolic disorders (including diabetes mellitus)
Persons who are immunocompromised (any cause, including medications or HIV infection)
Women who are or plan to be pregnant during the influenza season
Children and adolescents (6 months through 18 years of age) who are receiving aspirin- or salicylate-containing medications and who might be at risk for Reye syndrome
Residents of nursing homes and other long-term-care facilities
Native Americans, including Alaska Natives
Persons who are extremely obese (BMI ≥40)
|Contacts and Caregivers |
Caregivers and contacts of those at risk: health care personnel in inpatient and outpatient care settings, medical emergency-response workers, employees of nursing home and long-term-care facilities who have contact with patients or residents, and students in these professions who have contact with patients
Household contacts and caregivers of children ≤59 months (i.e., <5 years) of age (particularly contacts of infants <6 months old) and adults ≥50 years of age
Household contacts and caregivers of persons who are in a high-risk group
Pneumonia and influenza mortality, reported as excess over the anticipated sine-wave curve of deaths during the year, is seen in the CDC’s data for 2012–2017 (Fig. 195-4). In addition to excess respiratory deaths directly attributed to influenza, an increase in circulatory deaths also occurs during an influenza epidemic.