# 96 - 206 Influenza

### 206 Influenza

Kathleen M. Neuzil

Influenza
■
■DEFINITION
The term influenza represents both a clinically defined respiratory illness 
accompanied by systemic symptoms of fever, malaise, and myalgia and 
the name of the orthomyxoviruses that cause this syndrome. Although 
this term is sometimes used more generally to denote any viral respi­
ratory illness, many features distinguish influenza from these other 
illnesses, most particularly its systemic symptoms, its propensity to 
cause sharply peaked winter epidemics in temperate climates, and its 
capacity to spread rapidly among close contacts. The morbidity and 
mortality associated with influenza epidemics are documented closely 
in the United States by the Centers for Disease Control and Prevention 
(CDC), which records clinical cases of influenza-like illness, cases of 
virologically documented influenza, and excess deaths due to pneumo­
nia and influenza combined.
■
■ETIOLOGIC AGENTS
Three influenza viruses occur in humans: A, B, and C. These viruses 
are irregularly circular in shape, measure 80–120 nm in diameter, and 
have a lipid envelope and prominent spikes that are formed by the two 
surface glycoproteins, hemagglutinin (H) and neuraminidase (N) 
(Fig. 206-1). The hemagglutinin functions as the viral attachment 
protein, binding to sialic acid receptors on the cells that line the super­
ficial epithelium of the respiratory tract. The neuraminidase cleaves 
the virus from the cell membrane to facilitate its release from the cell 
and prevents self-aggregation of viruses. Influenza A viruses have eight 
single-strand negative-sense RNA segments in their genomes that 
encode hemagglutinin and neuraminidase as well as internal genes, 
including polymerase, matrix, nucleoprotein, and nonstructural genes. 
The segmented nature of the genome allows gene reassortment; an 
analogy for reassortment is the shuffling of a deck of cards. Reassort­
ment takes place when a single cell is infected with two different strains 
of influenza.
PART 5
Infectious Diseases
Among the influenza viruses, the A viruses are of paramount 
importance for several reasons: (1) the plasticity of their genomes, 
which enables them to react to the prevailing immunity in the com­
munity by modifying their immunogenic epitopes, particularly on the 
hemagglutinin surface protein (antigenic drift); (2) the segmentation 
of their genomes, which allows genes coding both surface and internal 
proteins to be reassorted between influenza A variants (antigenic shift); and 
(3) their extensive mammalian and avian reservoirs, in which multiple 
variants with distinct hemagglutinin and neuraminidase genes lie in 
wait. As a result of all of these factors, influenza A virus has the abil­
ity, particularly after an antigenic shift, to cause a worldwide epidemic 
(pandemic). The most severe influenza A pandemic in modern history 
FIGURE 206-1  An electron micrograph of influenza A virus (×40,000). (From YZ 
Cohen, R Dolin: Influenza, in Harrison’s Principles of Internal Medicine, 19th ed. DL 
Kasper et al [eds]. New York: McGraw-Hill, 2015, p 1209.)

took place in 1918; ~50 million deaths were attributed to the culpable 
influenza A H1N1 virus in the years surrounding 1918.
The influenza A viruses are further classified by their surface 
glycoproteins (H and N), the geographic location of their isolation, 
their sequential number among isolated viruses, and their year of 
isolation. Thus, for the 2024–2025 season, U.S.-licensed egg-based 
influenza vaccines will contain hemagglutinin derived from an influ­
enza A/Victoria/4897/2022 (H1N1) pdm09-like virus, an influenza 
A/Thailand/8/2022 (H3N2)-like virus, and an influenza B/Austria/

1359417/2021 (B/Victoria lineage)-like virus. U.S. cell culture–based 
inactivated and recombinant influenza vaccines will contain HA 
derived from an influenza A/Wisconsin/67/2022 (H1N1) pdm09-like 
virus, an influenza A/Massachusetts/18/2022 (H3N2)-like virus, and 
an influenza B/Austria/1359417/2021 (B/Victoria lineage)-like virus.
■
■EPIDEMIOLOGY
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 composi­
tion 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 influenza activity exceeds 
a predetermined baseline, an influenza outbreak is classified as an 
epidemic. Influenza’s impact is reflected in increased school and work 
absenteeism, increased visits to emergency departments and primary 
care physicians, and increased hospitalizations, particularly of older 
persons and individuals with underlying cardiopulmonary disease. 
The impact often is most easily recognized in the pediatric population, 
whose school absenteeism quickly peaks.
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.
Influenza is largely spread by small- and large-particle droplets; 
however, emerging data support a role for aerosol transmission. 
Transmission is likely modulated by temperature and humidity. Spread 
is facilitated by the coughing and sneezing that accompany the ill­
ness. Within families, the illness is often introduced by a preschool 
or school-aged child. In the United States, influenza virus circulation 
in the first quarter of 2020 declined sharply within 2 weeks of the 
COVID-19 emergency declaration and widespread implementation of 
community mitigation measures and travel restrictions. The decline 
occurred in other Northern Hemisphere countries and the tropics, 
and in 2020, Southern Hemisphere temperate climates had virtually no 
influenza circulation. Influenza activity remained at low levels during 
the 2020–2021 Northern Hemisphere season, and increased in seasons 
thereafter. While changes in health care–seeking behavior and testing 
priorities during the pandemic may have contributed, such declines 
in influenza detection were noted even in areas with continued or 
increased testing, implicating community mitigation measures as the 
most likely reason.
Influenza A Viruses 
When a major shift in the hemagglutinin 
and/or the neuraminidase occurs, with introduction of a new sero­
type 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 206-1). On the basis of 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 206-1  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
aAs determined by retrospective serologic survey of individuals alive during those 
years (“seroarchaeology”). bHemagglutinins formerly designated as Hsw and H0 
are now classified as variants of H1. cFrom this time until 2016–2017, viruses of the 
H1N1 and H3N2 subtypes circulated in alternating years or concurrently. dA novel 
influenza A/H1N1 virus emerged to cause this pandemic.
Source: Adapted from YZ Cohen, R Dolin. Influenza. In: Kasper DL, et al, eds. 
Harrison’s Principles of Internal Medicine, 19th ed. New York, McGraw-Hill, 2015, 

p. 1209.
In some epidemics, a younger age group proves especially suscep­
tible. 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 epi­
demic was striking in this regard: the most severely infected individu­
als were infants and previously healthy young adults—the latter being 
a group not typically found to have high influenza mortality (Fig. 206-2). 
The 1918 epidemic increased all-cause mortality and led to more 
deaths than all military losses in World War I. Despite the attention 
paid to the risk and impact of pandemic disease, it is generally appre­
ciated that—with the exception of 1918—cumulatively more illness 
occurs during yearly epidemics combined than in pandemics. All of 

Pneumonia/influenza mortality rate per 100,000
<1 Year

65–74 Years

25–34 Years

Influenza epidemics with excess pneumonia/influenza
mortality >20/100,000
FIGURE 206-2  Excess pneumonia/influenza deaths in 1900–1953, demonstrating the 
dramatic peaks of deaths among young infants and young adults (25–34 years of 
age) in 1918. (Data are from public health records collated by PF Wright.)

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. 

Avian Influenza Viruses 
Wild birds are considered the natural 
hosts for influenza viruses, and potential pandemic viruses continue to 
emerge with higher-numbered hemagglutinins (e.g., H5, H6, H7, H8, 
H9) reflecting some of the 18 distinct H subtypes in avian reservoirs. 
Bird migration contributes to rapid global spread. Highly pathogenic 
influenza H5 and H7, in particular, have been associated with wide­
spread outbreaks in poultry, human infections through contact with 
infected birds, and limited human-to-human transmission. Most 
human infections have occurred in individuals who have had direct 
contact with domesticated birds or who have visited live-bird markets.
Some avian strains—notably H5 strains—are highly pathogenic in 
humans, as was the 1918 strain. The reasons for the high pathogenic­
ity of certain strains are not entirely clear. 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 in young, immunologically vigorous individuals during 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.
CHAPTER 206
The same concerns about a “cytokine storm” have been raised about 
the H5N1 viruses that first emerged in Hong Kong in 1996. These 
viruses exhibited high pathogenicity in individuals who had direct con­
tact with domestic fowl, with mortality rates close to 50%, but also dis­
played 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
Sporadic H5 avian infections have been reported in many mammals, 
including sea lions, sea elephants, foxes, goats, and zoo animals. In 
2024, a multistate outbreak of highly pathogenic H5 avian influenza in 
dairy cows was first reported, with rare human infections from animal 
exposures. It is unclear why higher-numbered avian hemagglutinin 
strains have not acquired the degree of transmissibility necessary to 
cause pandemic disease.
Swine Influenza Viruses 
Swine play an important role in inter­
species transmission of influenza. 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 transmission 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-2,6galactose 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. The swine origin 2009 H1N1pdm 
strain was a reassorted virus with gene segment origins from avian, 
human, and swine hosts.
Influenza B and C Viruses 
The influenza B viruses are more 
genetically stable than the influenza A viruses and are mainly associ­
ated with human infection. Two lineages of influenza B have circulated 
for the past 40 years (B/Yamagata-like and B/Victoria-like viruses), 
and it has proven difficult to predict which strain will be dominant 
in a given year. Co-circulation of both B lineages—Victoria and 
Yamagata—began in 2011. This led to the incorporation of representa­
tives of both influenza A lineages plus influenza A/H1N1 and H3N2

Deaths
4,900–51,000
Hospitalizations
100,000–710,000
Illnesses
9,300,000–41,000,000
FIGURE 206-3  Pyramid of impact of influenza illness. Estimated range of annual 
burden of influenza in the United States from 2010–2023. (From https://www.cdc 
.gov/flu-burden/php/about/index.html?CDC_AAref_Val=https://www.cdc.gov/flu/
about/burden/index.)
viruses into quadrivalent vaccines, first marketed in the United States 
in 2013. However, since March 2020, B/Yamagata influenza viruses 
have not circulated in the population. Thus, influenza vaccines in the 
United States will revert to a trivalent vaccine for the 2024–2025 season, containing only a B/Victoria-like virus.
Influenza C viruses cause intermittent mild disease. The clinical 
information about this virus is limited because of the small number of 
isolated viruses compared to influenza A or B viruses.
Influenza-Associated Morbidity and Mortality 
Influenza 
virus infects people of all ages and causes mild to severe illness, and 
even death in some cases. The impact of influenza is highly variable 
from year to year and can be depicted as a pyramid of illnesses, medical visits, hospitalizations, and deaths (Fig. 206-3). Infection rates are 
highest among children, with complications and hospitalizations from 
seasonal influenza being greatest among certain high-risk groups during most epidemics. 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 (Table 206-2).
PART 5
Infectious Diseases
Mortality attributable to influenza, reported as excess over the 
anticipated sine-wave curve of pneumonia and influenza deaths during 
the year, varied between 4900 and 51,000 deaths annually from 2010 to 
2023. The dramatic effect of the COVID-19 pandemic on excess pneumonia and influenza mortality data is evident from the comparison of 
2020 data with data from the prior three seasons (Fig. 206-4). Due to this 
outsized effect of COVID-19, the method for calculating mortality due 
to influenza changed starting with the 2023–2024 season and is now 
restricted to percentage of deaths with influenza listed on the death 
certificate. In contrast to mortality surveillance in adults, influenzaassociated pediatric mortality is based on laboratory confirmation. 
Upon normalization of influenza circulation after the COVID-19 
pandemic, 184 children died in 2022–2023 and 138 children died in 
2023–2024 from laboratory-confirmed influenza. These numbers are 
undoubtedly underestimates, since all children are not tested for influenza, and even among those who are tested, tests are less sensitive later 
in the illness.
■
■PATHOGENESIS AND IMMUNITY
At a cellular level, influenza virus binds to sialic acid receptors and 
enters the epithelial cell through receptor-mediated endocytosis. The 
virus then enters an endosome, where acidification promotes proteolytic cleavage of the hemagglutinin, exposing a fusion domain. The 
influenza hemagglutinin undergoes a marked structural reorganization 
in this cleavage step. Hemagglutinin cleavage may be one of the factors 
that restrict viral growth to epithelial cells, as a unique protease in the 
respiratory milieu is required for this cleavage to occur. The fusion 
domain allows the viral RNA to enter the cytoplasm. The nucleoprotein 
is transported into the nucleus of the cell, where transcription to a positive-sense RNA and replication take place. Viral proteins then assemble 
on the apical surface of the infected cell and, after incorporation of cellular membrane, bud from the membrane back into the mucosal milieu.

TABLE 206-2  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
American Indians/Alaska Natives
Persons who are extremely obese (body mass index ≥40)
Contacts and Caregivers
Caregivers and contacts of those at risk: health care personnel in inpatient and 
outpatient care settings who have the potential for exposure to patients or to 
infectious materials, medical emergency-response workers, autopsy personnel, 
employees of nursing home and long-term-care facilities who have contact with 
patients or residents, and students and trainees 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 (including children) and caregivers of persons who are in a 
high-risk group
aNo hierarchy is implied by order of listing.
Source: Centers for Disease Control and Prevention 2023–2024 summary of 
recommendations for influenza vaccine (https://www.cdc.gov/mmwr/volumes/72/rr/
rr7202a1.htm).
Influenza infection is initiated in the upper respiratory tract via 
aerosolized virus. The cells infected with influenza virus are primarily 
the ciliated cells of the respiratory tract. Denudation of the superficial 
epithelium probably accounts for much of the symptomatology and 
may predispose to secondary bacterial infections. The onset of symptoms follows an incubation period that, for a viral illness, is very short: 
48–72 h. The infection spreads to the lungs but, even there, remains 
confined to the epithelial layer. Influenza virus is associated with 
systemic symptoms of fever, malaise, and myalgia. These manifestations are presumed to be mediated by cytokines, and excess cytokine 
production has been implicated in the acute toxicity of H5N1 and other 
highly pathogenic influenza viruses.
The immune response to influenza virus occurs at the systemic and 
mucosal levels and involves both T and B cells. The B-cell responses 
are directed primarily toward antigenic epitopes on the two surface 
glycoproteins—i.e., hemagglutinin and neuraminidase. At a structural 
level, the four recognized epitopes on the hemagglutinin are largely 
confined to the globular head of the protein, which collectively constitute the targets for hemagglutination inhibition (HAI) antibodies. 
HAI and neutralizing antibodies are highly correlated; HAI antibody 
levels are used as a measure of susceptibility to clinical infection and 
thus as a measure of vaccine-induced protection. In a child or an adult 
without prior vaccination or with the emergence of a distinctly new 
strain, serum HAI antibody is a surrogate for protection. However, 
in individuals with both vaccine-induced and natural immunity, the 
protective efficacy of a vaccine based on serum HAI antibody is more 
difficult to predict.
There is considerable research interest in the induction and protective role of broadly neutralizing antibodies that recognize less antigenically variable regions on the stalk of the hemagglutinin. The results of 
these studies have led to investments toward research and development 
of a universal influenza vaccine, although no such vaccines are yet 
available in clinical practice.
The role of T-cell immunity, which primarily recognizes internal protein epitopes, remains unclear in humans. However, T-cell

Pneumonia, Influenza, and COVID-19 Mortality from the
National Center for Health Statistics Mortality Surveillance System

Number of influenza coded deaths
Number of COVID-19 coded deaths
% of deaths due to PIC
Baseline
Threshold 

% of all deaths due to PIC

Epidemic threshold

Seasonal baseline

MMWR week

FIGURE 206-4  Pneumonia, influenza, and COVID-19 mortality. MMWR, Morbidity and Mortality Weekly Report; PIC, pneumonia, influenza, COVID-19. Data through the week 
ending January 23, 2021, as of January 28, 2021. (From https://www.cdc.gov/fluview/?CDC_AAref_Val=https://www.cdc.gov/flu/weekly/index)
immunity is thought to play a role in clearance of an influenza infection that quite reproducibly develops 8–10 days after exposure. A role 
for T cells in protection against acquisition of infection has also been 
proposed.
CLINICAL MANIFESTATIONS
Attack rates of clinical influenza vary considerably from year to year. 
With the advent of molecular diagnostic tests, prospective studies 
with regular sampling demonstrate that asymptomatic or minimally 
symptomatic cases of influenza are more common than previously 
recognized. When symptomatic, influenza is primarily a respiratory 
illness causing cough, sore throat, and rhinorrhea or nasal congestion. 
The illness has a sudden onset and is epidemiologically linked to close 
contact with persons who have similar symptoms and often to community-wide respiratory illness. What distinguishes influenza from 
most other respiratory viral illnesses is the degree of accompanying 
fever, chills, fatigue, myalgia, and malaise. SARS-CoV-2 is the exceptional respiratory virus that also has a remarkable systemic component 
(Chaps. 204 and 205). Symptoms of influenza typically begin within 
48–72 h of exposure.
Respiratory symptoms, particularly recurrent cough, persist well 
beyond the 2–5 days of systemic symptoms. There is a postinfectious 
delay in return to normal levels of activity. Pulmonary function is 
persistently decreased after acute influenza. Persons with a regular 
exercise routine (e.g., runners) note a decrease from their prior level 
of performance that typically lasts for a month or more. In the elderly, 
the respiratory presentation may be less prominent, but there is often a 
decline in baseline activity and a loss of appetite.
On physical examination, the patient with influenza appears ill, 
with sweating, coughing, nonpurulent conjunctivitis, and diffuse pharyngeal erythema. With lower respiratory involvement, pulmonary 
examination typically reveals nonlocalizing scattered rales, rhonchi, 
and wheezes. When present, localized pulmonary findings suggest 
relatively complicated pneumonia with a bacterial component. Muscle 

Number of deaths

CHAPTER 206
Influenza
pain may be elicited by pressure, particularly in the calves and thighs. 
There are rare gastrointestinal findings. No rash is associated with 
influenza.
■
■COMPLICATIONS
Most persons who become ill with influenza virus infection recover 
without serious complications or sequelae. Complications of influenza 
occur most commonly in persons ≥65 years of age, young children, 
persons of all ages with underlying cardiopulmonary disease and 
immunosuppression, and women who are in the second or third trimester of pregnancy.
Respiratory Complications 
Pneumonia characterized by progressive air hunger, localized pulmonary findings on physical examination, and radiographic findings of diffuse infiltrates or consolidation is 
the most common complication of influenza. Pneumonia in influenza 
can be primary influenza viral pneumonia, secondary bacterial pneumonia, or mixed viral and bacterial pneumonia. Primary viral pneumonia is characterized by increasing dyspnea, persistent fever, and—in 
more severe cases—cyanosis. Primary influenza pneumonia was typical in the 1918 pandemic and occurs with H5N1 virus, as initially 
described in Hong Kong in 1997. Pathologically, a marked inflammatory reaction in the alveolar septa is characterized by infiltration of 
monocytes, lymphocytes, and macrophages, with variable numbers of 
neutrophils. Destruction and hemorrhage are seen in the respiratory 
epithelium. Large amounts of virus can be recovered from the lungs.
In secondary bacterial pneumonia or mixed viral and bacterial 
pneumonia, illness may be biphasic, with evidence of recovery from 
the primary influenza illness followed by recrudescence of fever and 
pulmonary symptoms. Localizing findings may be detected on pulmonary examination and/or x-ray. The development of secondary 
bacterial infection is not surprising, as influenza de-epithelializes the 
airways and destroys ciliary function, allowing bacterial contamination. Another proposed mechanism for bacterial/viral enhancement is

the production by Staphylococcus and Pseudomonas of proteases that 
enhance cleavage of the influenza hemagglutinin and thereby facilitate 
viral replication. The risk of secondary bacterial disease is greatest in 
elderly patients and those with chronic obstructive pulmonary disease 
(COPD).

Some influenza strains cause laryngotracheobronchitis, bronchiol­
itis, or croup in children. Otitis media—a common accompaniment to 
influenza in children—may also be due to a combination of influenza 
virus and bacteria.
Extrapulmonary Complications 
Although influenza is believed 
to spread only rarely beyond the respiratory epithelial cells, where 
unique endogenous proteases facilitate hemagglutinin cleavage and 
productive infection, this disease causes not only prominent systemic 
complaints but also a variety of extrapulmonary manifestations. The 
most common extrapulmonary manifestation of influenza is myositis, 
which is seen more often in influenza B and is characterized by severe 
muscle pain, elevated creatinine phosphokinase levels, and myoglobin­
uria that can lead to renal failure. The muscles are extremely tender to 
touch. Myo-/pericarditis is seen less frequently. However, a consistent 
epidemiologic link exists between influenza epidemics and excess car­
diovascular hospitalizations.
Neurologic involvement, while rare, does occur following influenza 
infection. Influenza-associated encephalopathy or encephalitis is char­
acterized by rapid progression within a few days of influenza infection. 
Transverse myelitis and parkinsonian symptoms have been reported. 
Postinfectious acute demyelinating encephalomyelitis can follow influ­
enza as well as other viral infections. Neurologic manifestations are 
more frequent in children as compared to adults. Children most com­
monly present with febrile seizures, increased seizure frequency among 
those with seizure disorders, or self-limited encephalopathy. More 
serious manifestations of meningitis, encephalitis, and focal brain 
lesions may occur, particularly in children with preexisting neurologic 
conditions.
PART 5
Infectious Diseases
Guillain-Barré syndrome can develop after influenza and was 
reported after a widespread influenza vaccination effort in the fall of 
1976 that was undertaken in anticipation of a swine influenza epidemic 
(which never materialized). Until aspirin was recognized as a cofactor 
in its precipitation, Reye syndrome, an acute hepatic decompensation, 
was seen commonly in children and adolescents with influenza, par­
ticularly those infected with influenza B virus. Subsequently, the use 
of aspirin for fever control and symptom relief in children with viral 
infections was strongly discouraged, and Reye syndrome has virtually 
disappeared from clinical practice.
■
■LABORATORY FINDINGS AND DIAGNOSIS
There is a strong argument for establishing a microbiologic diagnosis 
from both an individual-patient and a public-health perspective. This 
information is particularly valuable early in the season, when the 
extent of influenza and the precise circulating strain(s) are uncertain; 
in the management of high-risk or hospitalized patients; in settings 
such as long-term-care facilities and hospitals, where the institution of 
specific infection-control measures is appropriate; and in any patient 
with influenza-like illness if the test results will influence clinical 
management.
Influenza virus is most easily recovered from nasal or pharyngeal 
specimens. A number of rapid influenza diagnostic tests (RIDTs) are 
TABLE 206-3  Categories of Vaccines Licensed for Prevention of Seasonal Influenza, United States
 
LIVE ATTENUATED
STANDARD INACTIVATED
HIGH-DOSE INACTIVATED
RECOMBINANT
ADJUVANTED INACTIVATED
Route
Intranasal
Intramuscular
Intramuscular
Intramuscular
Intramuscular
Approved ages
2–49 years
≥6 months
≥65 years
≥18 years
≥65 years
HAa

Substrate
Eggs
Eggs/cell culture
Eggs
Cell culture
Eggs
Number of strains

aHemagglutinin content in micrograms per strain.

available. They work by detecting viral antigens and can provide results 
within 10–15 min. Rapid molecular assays (i.e., nucleic acid amplifica­
tion tests [NAATs]) detect viral genetic material. Several NAATs are 
authorized for home use, including tests that detect and differentiate 
between SARS-CoV-2, influenza A, and influenza B in self-collected 
anterior nasal swab samples. In addition to RIDTs and rapid molecular 
assays, several influenza diagnostic tests are available in specialized 
hospital and public health laboratories, including reverse transcription 
polymerase chain reaction (RT-PCR) and viral culture. Many nucleic 
acid–based tests are multiplex and target a panel of common respira­
tory pathogens— influenza, respiratory syncytial virus, parainfluen­
zavirus, and coronaviruses including SARS-CoV-2—an advantage in 
the ill hospitalized patient and during outbreaks of other respiratory 
pathogens. Clinicians should not use viral culture for initial or primary 
diagnosis of influenza because results will not be available in a timely 
manner to inform clinical management, but viral culture can confirm 
the strain and allow for antiviral sensitivity testing.
Serologic confirmation of infection is also possible but requires paired 
serum samples, with the convalescent-phase sample obtained 2 weeks 
after infection. Other laboratory tests are of limited value. Mild leu­
kopenia is seen in influenza, and a white blood cell count >15,000/μL 
suggests a secondary bacterial component in influenza pneumonia.
■
■DIFFERENTIAL DIAGNOSIS
Influenza may be diagnosed clinically based on an acute presentation 
of a febrile respiratory illness during high periods of influenza circu­
lation. However, less common presentations of influenza and cases 
occurring outside of peak influenza season are frequently misdiag­
nosed on the basis of symptoms alone. Influenza symptoms and signs 
may overlap with symptoms of other respiratory viruses. Respiratory 
syncytial virus often co-circulates with influenza virus; it particularly 
affects the youngest children, causing bronchiolitis, but it can also 
infect the elderly, leading to an influenza-like nonspecific respiratory 
illness and a decline in mobility, nutrition, and pulmonary function, 
with resultant hospitalization.
Persons with COVID-19 have a wide range of symptoms reported, 
ranging from mild to severe illness. Many of these symptoms—fever, 
chills, cough, shortness of breath, fatigue, muscle aches, headaches, 
congestion or runny nose—overlap with the symptoms of influenza. 
While new loss of taste (ageusia) or smell (anosmia) may distinguish 
COVID-19 from influenza, they are reported in the minority of 
infected persons. When SARS-CoV-2 and influenza viruses are cocirculating, clinicians should consider both viruses, as well as co-infection, 
in patients with acute respiratory illness symptoms. The similar clini­
cal presentations reiterate the importance of testing in order to inform 
treatment decisions.
■
■IMMUNIZATION
Vaccination is the best approach to prevent influenza. The vaccines 
currently available in the United States are increasing in number 
and diversity (Table 206-3). These vaccines fall into two broad cat­
egories: parenterally administered inactivated influenza vaccines and 
intranasally administered live-attenuated influenza vaccines. Current 
vaccines are further classified based on production substrate (eggs, 
cell), antigen dose and valence (trivalent or quadrivalent), and the 
presence or absence of adjuvants. Current inactivated influenza vac­
cines are designed with the common goal to induce immunity to the 
NONREPLICATING VACCINES

hemagglutinin surface glycoprotein of the influenza virus. No effort is 
made to standardize the neuraminidase content.
As the viral surface hemagglutinin undergoes frequent antigenic 
drift, the seasonal influenza vaccine is reformulated as often as twice 
annually to match the strains projected to circulate in the following 
influenza season. The decision about vaccine composition must be 
made ~10 months before the seasonal peak in influenza virus circulation; this decision is made by committees at the WHO. Subsequently, 
the U.S. Food and Drug Administration (FDA), which has regulatory 
authority over vaccines in the United States, convenes an advisory 
committee that considers the recommendations of WHO, reviews and 
discusses similar data, and makes a final decision regarding vaccine 
virus composition of influenza vaccines licensed and marketed in the 
United States. This timing can result in a mismatch of vaccine composition with the viral strains that are actually prevalent in the upcoming 
season. Influenza vaccine is unique in being given seasonally in the 
months immediately preceding an outbreak in temperate climates. In 
the United States, vaccine is typically available starting in August or 
September.
The performance of current influenza vaccines varies by year, vaccine formulation, and the underlying age, health condition, and prior 
virus and vaccine exposure of the recipient. Unfortunately, the relative 
contribution of each of these factors has not been well-elucidated, 
given the many variables involved and the complex interplay of infection and host response. Depending on the degree to which vaccine 
strains match circulating strains, seasonal influenza vaccines will confer more or less protection, as antibody against influenza is for the most 
part strain specific. A meta-analysis of randomized controlled trials 
of influenza vaccine efficacy over 12 influenza seasons showed inactivated influenza vaccines had a pooled efficacy of 59% (95% confidence 
interval, 51–67%) among those aged 18–65 years. Since 2004−2005, 
the CDC has estimated the effectiveness of seasonal influenza vaccine 
to prevent laboratory-confirmed influenza associated with medically 
attended respiratory illness. During that period, effectiveness ranged 
from ~40 to 60% across all age groups during seasons when most 
circulating influenza vaccines are antigenically similar to the recommended influenza vaccine components; effectiveness was lower in 
years with strain mismatch. Importantly, studies support that influenza 
vaccine mitigates disease severity. For example, observational studies in 
children support that influenza vaccination reduces intensive care unit 
hospitalizations and deaths by an estimated 74 and 65%, respectively.
Newer technologies have been developed to overcome some of the 
limitations of current vaccines. The first fully recombinant vaccine was 
approved by the FDA in 2017. Both recombinant and cell-based vaccines may overcome the egg adaptation of vaccine strains that may contribute to diminished vaccine effectiveness. Oil-in-water adjuvanted 
vaccines and high-dose vaccines elicit greater immune responses 
than traditional inactivated influenza vaccines and are approved in 
the United States for persons ≥65 years of age. In most head-to-head 
comparisons, high-dose vaccines have shown superior effectiveness to 
standard dose. While evidence is more limited, select comparisons of 
recombinant and adjuvanted vaccines with standard vaccines likewise 
show improved effectiveness.
In head-to-head comparisons in pediatric populations in the 1990s, 
a live, attenuated, intranasally administered vaccine (LAIV) exhibited 
an efficacy exceeding that of injected inactivated vaccines. LAIV is a 
desirable option in children given the ease of intranasal administration and theoretical advantage of stimulating mucosal immunity by 
the topical route. However, in the 2014−2016 influenza seasons, LAIV 
had lower replicative fitness and no demonstrable efficacy assignable 
to the vaccine’s H1N1 component. Consequently, advisory committees 
in the United States and elsewhere suspended the recommendations 
for use of LAIV until manufacturing improvements allowed reinstatement of recommendations for its use in 2018. Since that time LAIV 
has performed comparably to inactivated influenza vaccines in annual 
effectiveness assessments.
Inactivated influenza vaccines have been licensed for >60 years and 
have a robust safety and tolerability profile. While local reactions are 
most common following inactivated influenza vaccines, rare adverse 

events may occur. These include Guillain-Barré syndrome, identified 
in 1976 and less frequently during other years; oculorespiratory syndrome, first recognized in 2000; and febrile seizures first reported in 
young children in Australia in 2010. Adjuvanted vaccines in general 
cause more local pain and erythema than unadjuvanted vaccines. 
LAIVs have been associated with excess wheezing and hospitalizations 
in children younger than 2 years and thus are not licensed for use in 
this age group.

The recommendations for use, the approved age range of each 
product, the route of administration, and the anticipated side effects 
are updated annually by the CDC (https://www.cdc.gov/acip-recs/hcp/
vaccine-specific/flu.html.) In the United States, routine annual influenza vaccination is recommended for all persons 6 months of age and 
older. For persons 65 years of age and over, higher-dose or adjuvanted 
vaccines are preferred. For other age groups, no preferential recommendation is made for one influenza vaccine product over another. 
Two doses of vaccine should be given to children <9 years of age who 
have not received at least two lifetime doses of influenza vaccine prior 
to the start of the season. All other children should receive one dose. 
Groups at special risk of experiencing or transmitting influenza and for 
whom influenza immunization is a particularly high priority are listed 
in Table 206-2.
History of severe allergic reaction (e.g., anaphylaxis) to any vaccine 
component is a contraindication to influenza vaccines. A history of 
Guillain-Barré syndrome within 6 weeks of a previous dose of influenza vaccine is considered a precaution for the use of all influenza 
vaccines. Egg allergy alone necessitates no additional safety measures 
for influenza vaccination beyond those recommended for any vaccine 
recipient, regardless of severity of previous reaction to egg.
CHAPTER 206
TREATMENT
Influenza
Influenza
Antiviral therapy for influenza has been limited by the paucity of 
available drugs, the short duration of symptoms in uncomplicated 
influenza, and the changing patterns of drug resistance in influenza 
viral strains. In the past, influenza A infection could be treated with 
the M-2 channel blockers amantadine and rimantadine. Widespread resistance has currently relegated these compounds to historical interest only.
Neuraminidase inhibitors have been the mainstay for treatment 
of influenza A and B viruses for many years. As their name implies, 
these drugs inhibit the influenza neuraminidase and thus limit 
the egress of influenza virus from an infected cell. They are most 
effective in patients whose influenza illness is recognized early and 
confirmed by rapid diagnostic testing or on the basis of clinical and 
epidemiologic evidence. In experimental trials, these drugs hasten 
the resolution of symptoms if given within 48 h of infection. There 
are indications for their use both prophylactically—either throughout the season or, when a case is recognized in a close contact, in 
the short term—and therapeutically. The anticipated effect of early 
administration is the resolution of symptoms 1–2 days sooner 
than without treatment. The use of neuraminidase inhibitors is 
recommended for complicated influenza infections in hospitalized patients in the absence of formal proof of efficacy and when 
diagnosis may have been delayed. All the available neuraminidase 
inhibitors carry a risk of development of resistance, particularly 
with prolonged administration (e.g., to an immunodeficient individual with persistent recovery of influenza virus). Resistance 
to neuraminidase inhibitors is not widespread among currently 
circulating influenza A or B strains, but its development has been 
demonstrated in the laboratory, and clinical resistance could influence the utility of these drugs.
The defined risk groups who can benefit from neuraminidase 
inhibitors include children <2 years of age, adults >65 years of age, 
patients with chronic conditions, immunosuppressed individuals, 
pregnant women, women who have delivered infants ≤2 weeks previously, patients <19 years old who are receiving long-term aspirin