1514 PART 5 Infectious Diseases

bronchoscopy. Such droplets may contain viruses, but their range is

usually limited to about 3 ft. Transmission of large-particle droplets

occurs when they are deposited on the nasal mucosa or conjunctivae.

To prevent transmission in these settings, providers should implement

droplet precautions. They should wear a face mask, such as a surgical

mask, for close contact (within 3 ft of the patient). Patients also should

wear a face mask when exiting the examination room and should avoid

coming into close contact with other patients.

Airborne Precautions Airborne transmission occurs through the

dissemination of airborne droplet nuclei (particles of ≤5 μm) or evaporated droplets containing viruses that can remain suspended in the air

for long periods. Certain viruses that are carried by the airborne route

can be inhaled by a susceptible host in the same room or over a long

distance from the source patient, depending on environmental factors

such as temperature and ventilation. Viruses transmitted by this route

are SARS-CoV, measles virus, and VZV. Patients with these infections

should be managed with personal respiratory protection and special

ventilation and air handling. Providers should wear an N95 respirator

selected with fit-testing, which must be repeated annually. Powered

air-purifying respirators (PAPRs) are used in some cases. The patient

should be housed in an airborne-infection isolation room—a negativepressure room that has a minimum of six air exchanges per hour and

exhausts through high-efficiency particulate air (HEPA) filtration or

directly to the outside.

GLOBAL CONSIDERATIONS

■ HENDRA AND NIPAH VIRUSES

These emerging paramyxoviruses, which are grouped in their own new

genus (Henipavirus), may not be respiratory pathogens in a conventional sense, but they probably infect humans by the respiratory route.

Nipah virus is a newly recognized zoonotic virus, named after the

location in Malaysia where it was first identified in 1999. It has caused

disease in humans who have had contact with infectious animals.

Hendra virus (formerly called equine morbillivirus) is another closely

related zoonotic paramyxovirus and was first isolated in Australia in

1994. The viruses have caused only a few localized outbreaks, but their

wide host range and ability to cause high mortality raise concerns for

the future. The natural host of these viruses is thought to be a certain

species of fruit bat present in Australia and the Pacific. Pigs may be an

intermediate host for transmission to humans in Nipah infection and

horses in Hendra infection. Although the mode of transmission from

animals to humans is not defined, inoculation of infected materials

onto the respiratory tract probably plays a role. The clinical presentation usually appears to be an influenza-like syndrome that progresses

to encephalitis, includes respiratory illness, and causes death in about

half of identified cases.

■ BUNYAVIRIDAE: HANTAVIRUS

Intermittent outbreaks of hantavirus infection occur in South America

and cause a severe lung infection: HPS. In addition, >400 cases of HPS

have been reported in the United States. The disease was first recognized

during an outbreak in 1993. About one-third of recognized cases end

in death. The Four Corners outbreak (at the intersection of the northwestern corner of New Mexico, the northeastern corner of Arizona, the

southeastern corner of Utah, and the southwestern corner of Colorado)

is well known; however, cases now have been reported in a total of

32 states. Patients with HPS usually present with an influenza-like

illness, including fever. Findings on physical examination are nonspecific, often consisting only of fever and elevated respiratory and heart

rates. In addition to respiratory symptoms, abdominal pain is common.

Diagnosis is often delayed until illness becomes severe, at which point

intubation and mechanical ventilation may be required for respiratory

support.

SUMMARY

Viruses are the leading causes of acute lower respiratory tract infection

in most populations. Influenza virus and RSV are the most common

pathogens; hMPV, PIV3, and rhinoviruses account for most other

acute viral respiratory infections. Infection in otherwise healthy adults

generally leads to partial immunity to these pathogens, with protection

against severe lower respiratory disease. However, reinfection, with

upper respiratory tract illness, is common throughout life. Special

populations such as immunocompromised patients, institutionalized

frail elderly patients, and patients with COPD are at highest risk for

severe disease.

■ FURTHER READING

Arons MM et al: Presymptomatic SARS-CoV-2 infections and transmission in a skilled nursing facility. N Engl J Med 382:2081,

2020.

Beard KR et al: Treatment of influenza with neuraminidase inhibitors.

Curr Opin Infect Dis 31:51, 2018.

Centers for Disease Control and Prevention: Infection control

guidance. Available at https://www.cdc.gov/coronavirus/2019-ncov/

hcp/infection-control-recommendations.html. Updated February 23,

2021. Accessed May 9, 2021.

Centers for Disease Control and Prevention: Updated healthcare infection prevention and control recommendations in response to

COVID-19 vaccination. Available at https://www.cdc.gov/coronavirus/

2019-ncov/hcp/infection-control-after-vaccination.html. Updated

April 27, 2021. Accessed May 9, 2021.

Centers for Disease Control and Prevention: Interim clinical

considerations for use of mRNA COVID-19 vaccines currently

authorized in the United States. Available at https://www.cdc.gov/

vaccines/covid-19/info-by-product/clinical-considerations.html.

Accessed January 7, 2021.

Diaz-Decaro JD et al: Critical evaluation of FDA-approved respiratory multiplex assays for public health surveillance. Expert Rev Mol

Diagn 18:631, 2018.

Falsey AR et al: Bacterial complications of respiratory tract viral illness: A comprehensive evaluation. J Infect Dis 208:432, 2013.

Fendrick AM et al: The economic burden of non-influenza-related

viral respiratory tract infection in the United States. Arch Intern Med

163:487, 2013.

Fry AM et al: Seasonal trends of human parainfluenza viral infections:

United States, 1990–2004. Clin Infect Dis 43:1016, 2006.

Infectious Diseases Society of America: Guidelines on the

treatment and management of patients with COVID-19. Available

at https://www.idsociety.org/practice-guideline/covid-19-guidelinetreatment-and-management/. Published April 11, 2020. Updated

April 14, 2021. Accessed May 9, 2021.

Iuliano AD et al: Estimates of global seasonal influenza-associated

respiratory mortality: A modelling study. Lancet 391:1285, 2018.

Johnston SL et al: The relationship between upper respiratory infections and hospital admissions for asthma: A time-trend analysis. Am

J Respir Crit Care Med 154:654, 1996.

McMichael TM et al: COVID-19 in a long-term care facility - King

County, Washington, February 27-March 9, 2020. MMWR Morb

Mortal Wkly Rep 69:339, 2020.

Monto AS, Cavallaro JJ: The Tecumseh study of respiratory illness.

II. Patterns of occurrence of infection with respiratory pathogens,

1965–1969. Am J Epidemiol 94:280, 1971.

National Health Service England: Coronavirus guidance for clinicians and NHS managers. Available at https://www.england.nhs.uk/

coronavirus/. Accessed May 9, 2021.

National Institutes of Health: COVID-19 Treatment Guidelines

Panel. Coronavirus Disease 2019 (COVID-19) treatment guidelines. Available at https://www.covid19treatmentguidelines.nih.gov/.

Updated April 23, 2021. Accessed May 9, 2021.

Segaloff HE et al: The impact of obesity and timely antiviral administration on severe influenza outcomes among hospitalized adults. J

Med Virol 90:212, 2018.

U.S. Food and Drug Administration: Emergency use authorization. Available at https://www.fda.gov/emergency-preparedness-andresponse/mcm-legal-regulatory-and-policy-framework/emergencyuse-authorization#infoMedDev. Accessed May 9, 2021.

1515CHAPTER 200 Influenza

Wang D et al: Clinical characteristics of 138 hospitalized patients

with 2019 novel coronavirus-infected pneumonia in Wuhan, China.

JAMA 323:1061, 2020.

Williams JV et al: Human metapneumovirus infection plays an etiologic role in acute asthma exacerbations requiring hospitalization in

adults. J Infect Dis 192:1149, 2005.

■ 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 respiratory 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 pneumonia 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. 200-1). The hemagglutinin functions as the viral attachment

protein, binding to sialic acid receptors on the cells that line the superficial 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 singlestrand 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. Reassortment takes

place when a single cell is infected with two different strains.

Among the influenza viruses, the A viruses are of paramount importance for several reasons: (1) the plasticity of their genomes, which

200 Influenza

Kathleen M. Neuzil, Peter F. Wright

FIGURE 200-1 An electron micrograph of influenza A virus (×40,000). (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.)

enables them to react to the prevailing immunity in the community

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 ability,

particularly after an antigenic shift, to cause a worldwide epidemic

(pandemic). The most severe influenza A pandemic in modern history

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 2021–22 season, U.S.-licensed influenza vaccines

will contain an influenza A/Victoria/2570/2019 (H1N1)pdm09-like

virus (for egg-based vaccines) or an influenza A/Wisconsin/588/2019

(H1N1)pdm09-like virus (for cell-based and recombinant vaccines); an

influenza A/Cambodia/e0826360/2020 (H3N2)-like virus; influenza B/

Washington/02/2019 (Victoria lineage)-like virus; and an influenza B/

Phuket/3073/2013 (Yamagata 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 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 departments 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.

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;

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. In the United States, influenza

virus circulation in first-quarter 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. In 2020, Southern Hemisphere temperate climates had

virtually no influenza circulation. Influenza activity remained at low

levels at the start of the 2020−2021 Northern Hemisphere season.

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 serotype from an animal or avian reservoir, an influenza A strain has the

potential to cause a pandemic. In modern influenza history, such shifts

1516 PART 5 Infectious Diseases

occurred in 1918 (H1N1), 1957 (H2N2), 1968 (H3N2), 1977 (H1N1),

and 2009 (H1N1pdm) (Table 200-1). 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.

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. 200-2).

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.

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, H8, H9) reflecting some of the 18 distinct H and 11

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 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-2,6-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

2000

<1 Year

65–74 Years

Influenza epidemics with excess pneumonia/influenza

mortality >20/100,000

25–34 Years

1500

Pneumonia/influenza mortality rate per 100,000

1000

500

1900 1905 1910 1915 1920 1925 1930 1935

FIGURE 200-2 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 the PF Wright.)

TABLE 200-1 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

a

As determined by retrospective serologic survey of individuals alive during those

years (“seroarchaeology”). b

Hemagglutinins formerly designated as Hsw and H0

are now classified as variants of H1. c

From this time until 2016–2017, viruses of the

H1N1 and H3N2 subtypes circulated in alternating years or concurrently. d

A 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;

2015:1209.

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 are mainly associated 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 very difficult to predict which strain will be dominant in

1517CHAPTER 200 Influenza

Deaths

12,000–61,000*

Hospitalizations

140,000–810,000*

Illnesses

9,300,000–45,000,000*

FIGURE 200-3 Pyramid of impact of influenza illness. *The top range of these

burden estimates is from the 2017–2018 flu season. These are preliminary and may

change as data are finalized. (From https://www.cdc.gov/flu/about/burden/index

.html.)

TABLE 200-2 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 (BMI ≥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

a

No hierarchy is implied by order of listing.

Source: Centers for Disease Control and Prevention 2020–2021 summary of

recommendations for influenza vaccine (https://www.cdc.gov/mmwr/volumes/69/rr/

rr6908a1.htm#T2_up).

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 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. 200-3). 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 200-2).

Mortality attributable to influenza, reported as excess over the anticipated sine-wave curve of pneumonia and influenza deaths during the

year, has been between 12,000 to 61,000 deaths annually over the past

decade. 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. 200-4).

Influenza-associated pediatric mortality is based on laboratory confirmation rather than modeling estimates. During the 2015−2020 influenza seasons, an estimated 95 to 195 children have died annually from

influenza disease.

■ 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.

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,

largely confined to the globular head of the protein, 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 now 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 immunity is thought to play a role in clearance of an influenza infection that

1518 PART 5 Infectious Diseases

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

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 (Chap. 199). Symptoms of

influenza typically begin within 48–72 h of exposure. The constellation

of symptoms caused by an H3N2 viral strain, A/Port Chalmers 1/73,

was followed prospectively in young seronegative children. Although

these data involve children and a viral strain circulating 45 years ago,

they present a representative picture of influenza today except that

irritability in a young child is more specifically recognized as malaise,

myalgia, and headache in an adult (Table 200-3).

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 and

rheumy, 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 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

30

28

26

24

22

20

18

16

14

12

10

8

6

4

2

0

40 50 10 3020 40 50 10 3020 40 50 10 40 50

MMWR week

3020 40 50

0

2000

4000

6000

8000

10000

12000

Number of deaths

% of all deaths due to PIC

14000

16000

18000

20000

10 3020

2017 2018 2019 2020

Seasonal baseline

Epidemic threshold

Number of influenza coded deaths

Number of COVID-19 coded deaths

% of deaths due to PIC

Baseline

Threshold

Pneumonia, Influenza, and COVID-19 Mortality from the

National Center for Health Statistics Mortality Surveillance System

FIGURE 200-4 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/flu/weekly/index.htm.)

TABLE 200-3 Clinical Observations in 24 Seronegative Children

Examined during Influenza A/Port Chalmers Infection

CONDITION/EVENT NO. OF PATIENTS

Coryza 22

Fever (temperature >38.4°C [>101°F]) 21

Cough 21

Pharyngitis 20

Irritability 20

Fever (temperature >39.5°C [>103°F]) 13

Anorexia 12

Tonsillitis 8

Vomiting 7

Otitis 6

Pneumonia 6

Diarrhea 6

Hoarseness 4

Croup 1