1503CHAPTER 198 Human Papillomavirus Infections

common. Rates of clearance of genital warts are not as high with

the 3.75% formulation as with the 5% preparation, but the duration

of treatment is shorter (daily application required for a maximum

of 8 weeks) and fewer local and systemic adverse reactions occur.

Imiquimod should not be used to treat vaginal, cervical, or anal

lesions. The safety of imiquimod during pregnancy has not been

established.

Interferon Recombinant interferon α is used for intralesional

treatment of genital warts, including perianal lesions. The recommended dosage is 1.0 × 106

 IU of interferon into each lesion three

times weekly for 3 weeks. Interferon therapy causes clearance of

infected cells by immune-boosting effects. Adverse events include

headache, nausea, vomiting, fatigue, and myalgia. Interferon therapy is costly and should be reserved for severe cases that do not

respond to less expensive treatments. Interferon should not be used

to treat vaginal, cervical, or anal lesions.

Cryotherapy Cryotherapy (liquid nitrogen treatment) for HPVassociated lesions causes cellular death. Genital warts usually disappear after two or three weekly sessions but often recur. Cryotherapy,

which is nontoxic and is not associated with significant adverse

reactions, can also be used for diseased cervical tissue. Local pain

occurs frequently.

Surgical Methods Exophytic lesions can be surgically removed

after intradermal injection of 1% lidocaine. This treatment is well

tolerated but can cause scarring and requires hemostasis. Genital

warts can also be destroyed by electrocautery, in which no additional hemostasis is required.

Laser Therapy Laser treatment affords destruction of exophytic

lesions and other HPV-infected tissue while preserving normal

tissue. Local anesthetics are generally adequate. Efficacy for genital

lesions is at least equal to that of other therapies (60–90%), with low

recurrence rates (5–10%). Complications include local pain, vaginal discharge, periurethral swelling, and penile or vulvar swelling.

Laser therapy has also been used successfully for cervical dysplasia

and anal disease caused by HPV.

Therapeutic Vaccines The innate and adaptive immune systems

are altered in patients with HPV-associated cancers. Antitumor

immune responses are blunted by specific viral mechanisms.

Numerous therapeutic vaccines that are being developed are

designed to enhance the cell-mediated response to the HPV E6 and

E7 oncoproteins, which are expressed in HPV-associated cancers.

Such vaccines would enhance the ability to treat HPV-associated

cancers, conditions that are very difficult to treat with current

modalities. However, while progress has been made, no HPV

vaccine is currently available for treatment of HPV infection or

HPV-associated disease.

Other Therapies Both trichloroacetic acid and bichloroacetic acid

are caustic agents that destroy warts by coagulation of proteins.

Neither of these agents is recommended for treatment. Sinecatechins (15% ointment) and podophyllotoxin (0.05% solution or gel

and 0.15% cream) are occasionally used for external genital warts,

but other modalities listed above are as or more effective and are

better tolerated.

RECOMMENDATIONS FOR TREATMENT

Table 198-1 lists available treatments for genital warts. An optimal

therapy for HPV-related genital tract disease that combines high

efficacy, low toxicity, low cost, and low recurrence is not available.

For genital warts of the penis or vulva, cryotherapy is the safest,

least expensive, and most effective modality. However, all available

modalities for treatment of genital warts carry high rates of recurrence. Guidelines for the treatment of genital warts can be found on

the CDC website (https://www.cdc.gov/std/tg2015/warts.htm).

Women with vaginal lesions should be referred to a gynecologist

experienced in colposcopy and treatment of these lesions. Treatment of cervical disease involves careful inspection, biopsy, and

histopathologic grading to determine the severity and extent of

disease. Women with evidence of HPV-associated cervical disease

should be referred to a gynecologist familiar with HPV and experienced in colposcopy. Optimal follow-up of these patients includes

colposcopic examination of the cervix and vagina on a yearly basis.

Guidelines from the American College of Obstetricians and Gynecologists are available for the treatment of cervical dysplasia and

cancer.

For anal or perianal lesions, cryotherapy or surgical removal is

safest and most effective. Anoscopy and/or sigmoidoscopy should

be performed in patients with perianal lesions, and suspicious

lesions should be biopsied to rule out malignancy.

■ COUNSELING PATIENTS REGARDING

HPV DISEASE

Most sexually active adults will be infected with HPV during their lives.

The only way to avoid acquiring an HPV infection is to abstain from

sexual activity, including intimate touching and oral sex. Practicing

safe sex (partner reduction, use of condoms) may help reduce HPV

transmission. Most HPV infections will be controlled by the immune

system and cause no symptoms or disease. Some infections lead to

genital warts and cervical precancers. Genital warts can be treated for

cosmetic reasons and to prevent spread of infection to others. Even

after resolution of genital warts, latent HPV may persist in normalappearing skin or mucosa and thus theoretically may be transmitted to

uninfected partners. Precancerous cervical lesions should be treated to

prevent progression to cancer.

■ FURTHER READING

Clifford GM et al: Carcinogenicity of human papillomavirus (HPV)

types in HIV-positive women: A meta-analysis from HPV infection

to cervical cancer. Clin Infect Dis 64:1228, 2017.

Curry SJ et al: Screening for cervical cancer: US Preventive Services

Task Force Recommendation Statement. JAMA 320:674, 2018.

De Sanjosé S et al: The natural history of human papillomavirus infection. Best Pract Res Clin Obstet Gynaecol 47:2, 2018.

Garland SM et al: Impact and effectiveness of the quadrivalent

human papillomavirus vaccine: A systematic review of 10 years of

real-world experience. Clin Infect Dis 63:519, 2016.

Giuliano AR et al: Efficacy of quadrivalent HPV vaccine against HPV

infection and disease in males. N Engl J Med 364:401, 2011.

Gravitt PE, Winer RL: Natural history of HPV infection across the

lifespan: Role of viral latency. Viruses 9:265, 2017.

TABLE 198-1 Recommended Treatments for Genital Warts Caused by Human Papillomavirusa

TREATMENT IMIQUIMOD CRYOTHERAPY INTERFERON SURGICAL REMOVAL LASER

Effectiveness Good Good Good Excellent Excellent

Recurrence Frequent Frequent Frequent Frequent Frequent

Adverse effects Frequent, mild to

moderate

Mild, well tolerated Frequent, moderately

severe

Mild, well tolerated Mild to moderate, well

tolerated

Availability Fair Good Fair Good Fair

Cost Expensive Inexpensive Very expensive Moderately expensive Very expensive

a

Imiquimod can be self-administered. All other treatments must be administered by a clinician.

1504 PART 5 Infectious Diseases

Section 13 Infections Due to DNA and

RNA Respiratory Viruses

199

The most common and frequent infections in humans are respiratory

virus infections. Influenza viruses and coronaviruses have been the

agents responsible for the largest infectious disease pandemics. These

viruses are easily transmitted by contact, droplets, and fomites. Furthermore, transmission can occur before the appearance of symptoms.

These viruses are also associated with a large reproductive number (the

number of secondary infections generated from one infected individual to others). Some classical respiratory viruses (e.g., rhinoviruses)

enter the body through the respiratory tract, replicating and causing

disease only in cells of the respiratory epithelium. Other, more systemic

viruses (e.g., measles virus and severe acute respiratory syndrome

[SARS] coronavirus) spread via the bloodstream and cause systemic

disease; however, they also may enter through and cause disease in

the respiratory tract. Although infections with systemic viruses often

induce lifelong immunity against disease, respiratory viruses that do

not cause high-grade viremia usually can reinfect the same host many

times throughout life. Reinfection with the same virus is common

because of incomplete or waning immunity after natural infection.

Hundreds of different viruses cause infection of the respiratory tract,

and within each virus type, there can be a nearly unlimited diversity

of field strains that vary antigenically, geographically, and over time

(e.g., antigenically drifting influenza viruses or coronaviruses). Specific

antiviral treatment options are limited, and only a few licensed vaccines

are available. For further discussion of common respiratory virus

infections, see Chap. 35 and syndrome-specific chapters.

Common viral respiratory infections can be categorized in several

ways, including by site of anatomic involvement, disease syndrome, or

etiologic agent.

ANATOMIC SITES IN THE HUMAN

RESPIRATORY TRACT

The type of respiratory disease that develops during virus infection

is dictated to a large degree by the cell types and tissue organization

in the respiratory tract. The vocal cords mark the transition between

the upper and lower respiratory tracts. The upper respiratory tract is

a complex anatomic system with interconnected structures, including the sinuses, middle-ear spaces, Eustachian tubes, conjunctiva,

Common Viral

Respiratory Infections,

Including COVID-19

James E. Crowe, Jr.

Lopalco PL: Spotlight on the 9-valent HPV vaccine. Drug Des Devel

Ther 11:35, 2016.

Rosenblum HG et al: Declines in prevalence of human papillomavirus vaccine-type infection among females after introduction of

vaccine—United States, 2003-2018. MMWR Morb Mortal Wkly Rep

70:415, 2021.

Schiffman M et al: Carcinogenic human papillomavirus infection.

Nat Rev Dis Primers 2:16086, 2016.

Serrano B et al: Epidemiology and burden of HPV-related disease.

Best Pract Res Clin Obstet Gynaecol 47:14, 2018.

Small W Jr et al: Cervical cancer: A global health crisis. Cancer

123:2404, 2017.

Wentzensen N et al: Eurogin 2016 roadmap: How HPV knowledge is

changing screening practice. Int J Cancer 140:2192, 2017.

nasopharynx, oropharynx, and larynx. The tonsils and the adenoids

are large collections of lymphoid tissue in the pharynx that participate

in immunity but also are susceptible to infections. The lower respiratory tract structures include the trachea, bronchi, bronchioles, alveolar

spaces, and lung tissue, including epithelial cells and blood vessels. The

epithelial cell types that line the respiratory tract are varied in morphology and function, and their susceptibility to different virus infections

varies. The principal types of cells in the major airways are ciliated or

nonciliated epithelial cells, goblet cells, and Clara cells. Smooth-muscle

cells form major tissue structures around the epithelial structures of

the large airways of the lower respiratory tract down to the level of

the bronchioles, and these cells are reactive to intrinsic and extrinsic

signals, including viral infection or exposure to allergens or pollutants.

The pathologic process of wheezing is driven by smooth-muscle contraction and obstruction of airways caused by mucus accumulation and

epithelial sloughing in the lumen. Reactive airways causing wheezing

are most often due to constriction of lumen size at the level of the

bronchioles (which have the narrowest lumen diameter of the airways).

The lung does not have smooth-muscle or ciliated cells but instead

possesses pneumocytes of types I and II. Pneumonia (Chap. 126) is an

infection of the pneumocytes in the lung tissue and the alveolar spaces.

The alveolar spaces also contain cells of the monocyte lineage, such as

macrophages, which patrol the air spaces.

DISEASE SYNDROMES

Since different respiratory viruses tend to have a predilection for replication in differing cells or regions of the respiratory tract, it is possible

for the well-trained clinician with epidemiologic information to understand the most likely associations of viruses with clinical syndromes.

The clinical diagnoses for virus infections in the upper respiratory tract

are rhinitis or the common cold, sinusitis, otitis media, conjunctivitis,

pharyngitis, tonsillitis, and laryngitis. In reality, some upper respiratory

tract infections affect more than one upper respiratory tract anatomic

site during a single infection, such as the classical pattern of pharyngoconjunctival fever during adenovirus infection. Lower respiratory

tract syndromes also can be associated easily with anatomic region,

including tracheitis, bronchitis, bronchiolitis, pneumonia, and exacerbations of reactive airway disease or asthma. Bronchiolitis is a disease

condition characterized by trapping of air in the lungs with difficulty in

expiration (i.e., wheezing); it is caused by inflammation or infection of

the bronchioles, the smallest and most highly resistant airways. Again,

mixed syndromes occur, such as laryngotracheitis, usually termed

croup. Croup, a disease condition characterized by difficulty in inspiration associated with a barky cough, is caused by inflammation or

infection of the larynx, trachea, and bronchi. When respiratory symptoms occur in the context of a respiratory viral illness with significant

systemic signs, infection with particular agents can be suspected (e.g.,

influenza, measles, SARS, SARS-CoV-2, or hantavirus pulmonary syndrome [HPS]), with exposure history taken into account.

ETIOLOGIC AGENTS

■ RESPIRATORY VIRUSES CAUSING DISEASE IN

IMMUNOCOMPETENT HOSTS

Children have more frequent respiratory virus infections than adults;

thus, it was natural that many early discoveries about the viral causes

of respiratory infections came from pediatric studies. The principal

causes of acute viral respiratory infections were determined in large

epidemiologic studies in the 1960s and 1970s, when cell culture of

infectious agents became available. More recently, studies of viral

epidemiology have been conducted in adults, especially in special

populations such as the elderly, nursing home residents, and immunocompromised individuals. Rapid antigen detection tests (based on

immunoassays for detection of viral proteins) became available for

respiratory syncytial virus (RSV) and influenza virus in the 1980s.

With the availability of sensitive and specific molecular tests, such as

reverse transcription combined with the polymerase chain reaction

(RT-PCR), studies in the past several decades have greatly increased

the extent to which we understand the causes of viral respiratory

1505CHAPTER 199 Common Viral Respiratory Infections, Including COVID-19

infections. Multiplex panels of RT-PCR tests capable of detecting a

dozen or more viruses are commonly available for clinical testing of

respiratory secretions. Nested multiplex PCR assays performed in two

stages provide sensitive tests that have been especially helpful in studies

of infection in adults, who often shed much lower concentrations of

virus in secretions than do children. Typically, influenza viruses, RSV,

and human metapneumovirus (hMPV) are the most common causes

of serious lower respiratory tract disease in otherwise healthy subjects;

parainfluenza viruses (PIVs) and adenoviruses also cause substantial

disease. Rhinoviruses (the most common cause of the common cold

syndrome) have been increasingly associated with lower respiratory tract

syndromes. Rhinovirus infection is so common, even in asymptomatic

individuals, that it has been hard to establish clear figures for the role of

rhinovirus in lower respiratory disease. COVID-19 and the associated

public health measures deployed in 2020−2021 altered the epidemiology of respiratory viruses such that conventional viruses were greatly

reduced in incidence. Generally, about two-thirds of cases of respiratory illness in a research setting can be associated with a specific viral

agent. Besides the viruses mentioned above (and discussed below),

several additional viruses identified with molecular tools have been

associated with respiratory illness. Still, it is fair to say that our diagnostic tools remain suboptimal since a specific infectious agent is not

identified in approximately one-third of clinical respiratory illnesses in

large surveillance studies. It is likely that in most of these cases pathogens are not detected because of the very low titers of virus in patient

samples at the time of clinical presentation, which may occur after the

period of peak virus shedding. It is also possible that novel agents are

yet to be identified. As emerging tools for microbiome and “virome”

studies (with sequencing of all nucleic acids in a sample) are applied in

these settings in coming years, new agents and new associations with

disease will probably be discovered.

■ RESPIRATORY VIRUSES CAUSING DISEASE IN

IMMUNOCOMPROMISED HOSTS

Special populations of patients are susceptible not only to the conventional respiratory viruses discussed above but also to agents causing

symptoms during reactivation of latent viruses or new infections with

opportunistic agents. Most prominently, reactivating latent viruses,

such as herpes simplex virus (HSV) and cytomegalovirus (CMV) and

adenoviruses, cause disease in immunocompromised humans. Patients

at most risk are those with hematopoietic stem cell or solid organ

transplantation, leukopenia caused by chemotherapy, or advanced

HIV-AIDS. In immunosuppressed patients with pneumonia, CMV is

the virus recovered most frequently during deep respiratory tract diagnostic procedures such as bronchoalveolar lavage. These patients also

are highly susceptible to more frequent and more severe disease caused

by common respiratory viruses, including RSV, hMPV, PIVs, influenza

viruses, rhinoviruses, and adenoviruses. Conventional acute respiratory viruses can cause chronic and sometimes fatal infections in these

populations. Nosocomial transmission of respiratory viruses occurs

in hematopoietic stem cell transplantation units, and the frequency of

transmission can be high, with entire units affected.

■ SPECIFIC VIRAL CAUSES OF RESPIRATORY

DISEASE

Orthomyxoviridae: Influenza Viruses (See also Chap. 200)

Influenza virus infection and influenza syndrome usually are associated with fever, myalgias, fatigue, sore throat, headache, and cough.

Influenza causes severe and even fatal pneumonia, particularly in

elderly patients, nursing home residents, immunocompromised persons, and very young children. Influenza pneumonia has an unusually

high rate of complication by bacterial superinfection, with staphylococcal and streptococcal bacterial pneumonia occurring in as many as

10% of cases in some clinical series.

Influenza is a single-stranded, segmented, negative-sense, RNA

genome virus of the family Orthomyxoviridae. There are three (sero)

types of influenza viruses: A, B, and C. Influenza A and C viruses infect

multiple species, whereas influenza B virus infects humans almost

exclusively. Type A viruses appear to be the most virulent for humans

and most commonly cause severe disease manifestations, although

type B viruses cause substantial morbidity. On the basis of antibody

response, influenza A viruses can be subdivided into 18 different

hemagglutinin (H) surface protein subtypes and 11 neuraminidase (N)

surface protein subtypes. The subtypes that have caused major pandemics in humans are H1N1, which caused the 1918 pandemic; H2N2,

which caused the 1957 pandemic; H3N2, which caused the 1968 pandemic; and H1N1pdm2009, which caused the 2009 pandemic. Currently, two type A subtypes (H1N1 and H3N2) and two type B lineages

(Yamagata and Victoria) cause annual seasonal epidemics.

Major pandemics caused by new influenza viruses are always possible. Many highly pathogenic influenza viruses circulate in aquatic

birds. Occasionally, avian viruses infect humans directly after close

contact with infected wild birds or poultry. Co-housing of pigs (which

have both avian and human influenza virus receptors) with poultry

may increase the risk of reassortment of human and animal or bird

viruses; reassortment can make the zoonotic viruses more fit for replication in humans. Several outbreaks of avian influenza have occurred

in limited numbers of humans to date, and there is the risk of a worldwide pandemic with avian influenza viruses if a strain acquires the

potential to spread efficiently from human to human. H5N1 influenza

virus infection of humans, predominantly by direct chicken-to-human

transmission, occurred during an epizootic in Hong Kong’s poultry

population in 1997. The disease affected many types of wild and

domestic birds and caused a high rate of systemic disease and death in

infected humans. This virus, carried in the gastrointestinal tract of wild

birds, has spread throughout Asia and beyond and continues to evolve

antigenically. Avian H7N7 and H7N9 viruses also have caused zoonotic outbreaks. A significant outbreak of H7N9 virus infection began

in China in March 2013, with high mortality, and there have been six

outbreaks to date, the largest in 2016−2017 with 766 human infections.

H7N9 is considered to have high potential to cause a future pandemic.

H1N2 virus is endemic in pigs and affects humans with close contact.

An H3N2 variant virus that differs antigenically from seasonal human

viruses is endemic in pigs and occasionally infects children who have

close contact with pigs in the United States. Rare human cases caused

by H6, H9, and H10 subtype viruses have been reported. Type B

influenza viruses co-circulate in humans during seasonal epidemics.

Type B viruses mutate less frequently than type A viruses. The slower

evolution of type B viruses is probably linked to the fact that they

are almost exclusively human pathogens. There is only one B type of

influenza, but these viruses began to diverge into two antigenically distinguishable lineages in the 1970s. The two virus lineages were named

after the initial designated representative strains—B/Victoria/2/87 and

B/Yamagata/16/88—and can be distinguished by serologic or genotyping laboratory tests. The evolution of B viruses over time spurred the

inclusion of two type B virus antigens in seasonal influenza vaccines,

expanding some multivalent vaccines from trivalent (H1N1, H3N2, B)

to a quadrivalent format. During the COVID-19 pandemic, the diversity of influenza in humans has been reduced, as strains in lineage B/

Yamagata and one clade of H3N2 known as 3c3.A were not detected.

Pneumoviridae (the formal species names of family

Pneumoviridae were updated in 2019; Table 199-1) •  RESPIRATORY SYNCYTIAL VIRUS Human RSV (hRSV) is a singlestranded, negative-sense, nonsegmented, RNA genome virus of the

genus Pneumovirus in the family Paramyxoviridae. Infection is ubiquitous, affecting most humans in the first several years of life and causing

reinfections throughout life. RSV is among the most transmissible

viruses of humans. Disease epidemics occur yearly, typically between

October or November and March in temperate regions. RSV is one

of the most common viral causes of severe lower respiratory tract

illness in the elderly and in children; it is among the most important

causes of hospitalization of elderly and infant patients throughout the

world. There is only one serotype of RSV, but antigenic variability does

occur in circulating field strains. In immune serum reciprocal crossneutralization studies, the two antigenic subgroups, A and B, appear

to be ~25% antigenically related; this relatedness may partially explain

1506 PART 5 Infectious Diseases

the susceptibility of humans to reinfection, which is very common and

can be caused by viruses of the same subgroup or even the same strain.

However, reinfection in otherwise healthy adults usually is associated

with mild disease confined to the upper respiratory tract. Severe lower

respiratory tract disease is common in the elderly, especially in frail

institutionalized elderly populations. Immunocompromised patients of

any age also are at risk of severe or prolonged disease, especially recipients of hematopoietic stem cell transplants. Wheezing is common with

primary infection in children (bronchiolitis), and there is a strong association of RSV infection early in life and subsequent asthma, although

it is unclear whether severe childhood RSV causes asthma or is the first

manifestation of reactive airway disease. RSV causes exacerbations of

asthma and is associated with acute exacerbations of chronic obstructive pulmonary disease (COPD), also referred to as acute exacerbations

of chronic bronchitis (AECB).

HUMAN METAPNEUMOVIRUS hMPV was discovered only in 2001

but probably has always been present in human populations. Infection

occurs first in early childhood, and reinfections are common throughout life. This virus is similar in many respects to RSV. It belongs to the

family Paramyxoviridae and is a member of the genus Pneumovirus.

It causes both upper and lower respiratory disease. It appears to be

somewhat less virulent than RSV, causing about half as much severe

lower respiratory tract disease, probably because it does not possess

the nonstructural genes that RSV expresses in infected cells to abrogate

the effect of host innate immune effectors like interferons. The clinical

features of lower respiratory tract infections caused by hMPV are like

those of such infections caused by other paramyxoviruses, most often

including cough, coryza, and wheezing. Like RSV, hMPV plays an

important role in exacerbations of asthma or COPD and causes pneumonia or wheezing in frail and institutionalized elderly individuals and

immunocompromised patients.

Paramyxoviridae (the formal species names of family

Paramyxoviridae were updated in 2019; Table 199-2) •  HUMAN PARAINFLUENZA VIRUSES The human PIVs (hPIV) are

a group of four distinct serotypes (designated 1–4) of single-stranded,

negative-sense RNA viruses belonging to the family Paramyxoviridae.

hPIV3 most commonly causes severe disease, and repeated infection

is common throughout life, although secondary infections often are

mild or asymptomatic. Primary infections in children manifest as

laryngotracheitis (croup), while subsequent infections typically are

limited to the upper respiratory tract. hPIVs are detected with sensitive

RT-PCR tests or, more classically, by cell culture with immunofluorescent microscopy or hemadsorption in reference laboratories.

MEASLES VIRUS (See also Chap. 205) Measles virus is also a paramyxovirus but of the genus Morbillivirus. This virus causes a systemic

infection known as rubeola but also can manifest with respiratory

symptoms. Measles virus probably is the most contagious respiratory

virus infection of humans: it is transmitted efficiently not only by direct

contact with infected persons or fomites (like other respiratory viruses)

but also by small-particle aerosols. Measles virus infection is preventable by vaccination but is so infectious that cases are inevitable—even in

the United States—whenever vaccination rates fall below 90–95% in

a population. The virus causes systemic illness, sometimes including

severe pneumonia, when primary infection occurs in an unvaccinated

adult or an immunocompromised person of any age. Therefore, vigilance in maintaining high vaccination rates is critical. With primary

infection, the illness in children is typically milder; however, mortality

rates in lower-resource countries are high, especially among persons

with underlying risk factors, including malnutrition.

Symptoms of measles include ≥3 days of high fever and a classical

set of upper and lower respiratory tract symptoms sometimes termed

“the 3 Cs”: cough, coryza, and conjunctivitis. Unlike most respiratory

viruses, measles virus circulates in the bloodstream and thus causes

disseminated infection with systemic manifestations. Usually, a characteristic diffuse maculopapular rash appears within days of fever onset.

Koplik’s spots (see Fig. A1-2)—typical mucosal lesions in the mouth

that appear briefly—are considered diagnostic of measles infection in

the setting of the typical rash and fever.

Picornaviridae A wide variety of picornaviruses cause respiratory

disease, including nonpolio enteroviruses, rhinoviruses, and parechoviruses (Chap. 204). The designations of these viruses can be

confusing: the Enterovirus, rhinovirus, and Parechovirus species names

were changed (with the approval of the International Committee on

Taxonomy of Viruses) to remove references to host species names

(such as the formerly used terms human, simian, etc.). These changes

are summarized in Table 199-3. The genus Enterovirus consists of

15 species, including enteroviruses A through L and rhinoviruses A

through C. The genus Parechovirus contains six species, one of which—

Parechovirus A—encompasses 19 types: human parechovirus (HPeV)

1 through 19. These viruses exhibit seasonal patterns that differ from

those of most other acute respiratory viruses. Rhinovirus infections

occur year-round. Enterovirus infections occur most commonly in the

summer months in temperate areas.

RHINOVIRUSES Rhinoviruses have single-stranded, positive-sense

RNA genomes. Rhinoviruses A through C represent species in the

Enterovirus genus of the family Picornaviridae. Rhinoviruses are the

most common viral infective agents in humans and the most frequent

cause of the common cold. Field isolates of rhinovirus are exceptionally

diverse; they can be classified by serotyping into >100 serotypes or,

alternatively, by genotyping into a large number of genotypes that cause

cold symptoms. At the time of writing in 2021, the species Rhinovirus

A contained 80 types, Rhinovirus B had 32 types, and Rhinovirus C had

57 types. The viral particles are icosahedral in structure and are nonenveloped. Rhinoviruses are responsible for at least half of all cases of

the common cold. Rhinovirus-induced common colds may be complicated in children by otitis media and in adults by sinusitis. Most adults,

in fact, have radiographic evidence of sinusitis during the common

cold, which resolves without therapy. Therefore, the primary disease is

probably best termed rhinosinusitis. Rhinovirus infection is associated

with exacerbations of reactive airway disease in children and asthma in

adults. It is not clear whether rhinovirus is restricted to the upper respiratory tract and only indirectly induces inflammatory responses that

affect the lower respiratory tract or whether the viruses spread to the

lower respiratory tract. In the past, it was thought that these viruses did

TABLE 199-1 Family Pneumoviridae, Human Pathogens with Current

Species Names, the International Committee on Taxonomy of Viruses:

2019 Release

GENUS CURRENT SPECIES NAME FORMER SPECIES NAME

Metapneumovirus Human metapneumovirus

(hMPV)

Same

Orthopneumovirus Human orthopneumovirus Human respiratory

syncytial virus (hRSV)

TABLE 199-2 Family Paramyxoviridae Human Pathogens with Current

Species Names, the International Committee on Taxonomy of Viruses:

2019 Release

GENUS CURRENT SPECIES NAME FORMER SPECIES NAME

Respirovirus Human respirovirus 1 Human parainfluenza virus

type 1 (hPIV1)

Human respirovirus 3 Human parainfluenza virus

type 3 (hPIV3)

Orthorubulavirus Mumps orthorubulavirus

Human orthorubulavirus 2

Human orthorubulavirus 4

Human orthorubulavirus 4

Mammalian

orthorubulavirus 5

Mumps virus

Human parainfluenza type 2

(hPIV2)

Human parainfluenza type 4a

(hPIV4a)

Human parainfluenza type 4b

(hPIV4b)

Parainfluenza type 5 (PIV5)

1507CHAPTER 199 Common Viral Respiratory Infections, Including COVID-19

not often replicate or cause disease in the lower respiratory tract. However, recent studies have discerned strong epidemiologic associations of

rhinoviruses with wheezing and asthma exacerbations, including episodes severe enough to require hospitalization. Rhinovirus C has been

associated with more severe disease syndromes, such as pneumonia or

exacerbation of COPD. Rhinoviruses likely can infect the lower airways

to some degree, inducing a local inflammatory response. Another possibility is that significant local infection of the upper respiratory tract

may induce regional elaboration of mediators that causes lower airway

disease. The association of rhinovirus infection with lower respiratory

tract illness is difficult to study because diagnosis by cell culture is not

sensitive. RT-PCR diagnostic tests are difficult to interpret because

they are often positive for prolonged periods and even asymptomatic

individuals may have a positive test. Comprehensive serologic studies

to confirm infection are difficult because of the large number of serotypes. Nevertheless, most experts believe rhinoviruses are a common

cause of serious lower respiratory tract illness.

ENTEROVIRUSES Nonpolio enteroviruses are common and distributed worldwide. Although infection often is asymptomatic, these

viruses cause outbreaks of clinical respiratory disease, sometimes with

fatal consequences. The species Enterovirus A consists of 25 serotypes,

including coxsackieviruses and some nonpolio enteroviruses that cause

respiratory disease. Coxsackieviruses cause oral lesions and often

are associated in children with hand-foot-and-mouth disease. The

pharyngitis associated with this infection characteristically manifests

with herpangina, a clinical syndrome of ulcers or small vesicles on the

palate that often involves the tonsillar fossa and is associated with fever,

difficulty swallowing, and throat pain. Outbreaks commonly occur

in young children during the summer. Enterovirus A71 also causes

large outbreaks of hand-foot-and-mouth disease, especially in Asia,

sometimes leading to neurologic complications and even death. The

species Enterovirus B consists of >90 serotypes, including the echoviruses (echo being an acronym for enteric cytopathic human orphan,

which may be an archaic notion since most echoviruses are associated

with human diseases, most commonly in children). Echoviruses can

be isolated from many children with upper respiratory tract infections

during the summer months. Echovirus 11 has been associated with

laryngotracheitis or croup. Epidemiologic studies also have associated

echoviruses with epidemic pleurodynia, an acute illness characterized

by sharp chest pain and fever. The species Enterovirus C consists of

23 serotypes, including the polioviruses. The species Enterovirus D

consists of five serotypes, including enterovirus D68, which has been

associated with wheezing and a polio-like syndrome in children.

PARECHOVIRUSES The genus Parechovirus comprises six species,

one of which is Parechovirus A, which can affect humans. The most

common member of the genus Parechovirus, HPeV-1, is a frequent

human pathogen. The genus also includes the closely related HPeV-2.

HPeVs usually cause mild respiratory or gastrointestinal illness. Most

infections occur in young children. The seroprevalence of HPeV-1 and

HPeV-2 is high among adults.

Adenoviridae Viruses of the family Adenoviridae infect both

humans and animals. As their designation indicates, adenoviruses

were first isolated in human lymphoid tissues from surgically removed

adenoids. In fact, some serotypes establish persistent asymptomatic

infections in tonsil and adenoid tissues, and virus shedding can occur

for months or years. These double-stranded DNA viruses are <100 nm

in diameter and have nonenveloped icosahedral morphology. The large

double-stranded DNA genome is linear and nonsegmented. The seven

major human adenovirus species (designated A through G) fall into 57

immunologically distinct serotypes. Human respiratory tract infections

are caused mainly by the B and C species. Adenovirus infections can

occur throughout the year. Many serotypes cause sporadic outbreaks,

while others appear to be endemic in particular locations. Respiratory

illnesses include mild disease such as the common cold and lower

respiratory tract illnesses including croup, bronchiolitis, and pneumonia. Conjunctivitis is associated with infection by the B and D species.

A particular constellation of symptoms referred to as pharyngoconjunctival fever is frequently associated with acute adenovirus infection.

In contrast, gastroenteritis has been associated most frequently with

virus serotypes 40 and 41 of species F. Immunocompromised patients

are highly susceptible to severe disease during infection with respiratory adenoviruses. The syndrome of acute respiratory disease (ARD),

especially common in stressful or crowded living conditions, was first

recognized among military recruits during World War II and has continued to be a problem when vaccination has been suspended temporarily because of lapses in vaccine supply. ARD is most often associated

with adenovirus types 4 and 7. Adenovirus vaccine containing live adenovirus types 4 and 7 taken orally as two tablets, which prevents most

illness caused by these two virus types, is only available for U.S. military

personnel 17−50 years of age. It is recommended by the Department of

Defense for military recruits entering basic training or other military

personnel at high risk for adenovirus infection.

Coronaviridae Members of the genus Coronavirus also contribute to

respiratory illness, including severe disease. Dozens of coronaviruses

affect animals. In the twentieth century, only two representative strains

of human coronaviruses were known to cause disease: 229E (HCoV229E) and OC43 (HCoV-OC43). An outbreak of infection with

SARS-associated coronavirus (SARS-CoV) first showed that animal

coronaviruses have the potential to cross from other species to humans,

with devastating effects. The one major SARS-CoV epidemic to date

(2002−2003) encompassed >8000 cases, with mortality rates approaching 10%. SARS-CoV causes a systemic illness with a respiratory route

of entry. In contrast to most other viral pneumonias, SARS lacks upper

respiratory symptoms, although cough and dyspnea occur in most

patients. Typically, patients present with a nonspecific illness manifesting as fever, myalgia, malaise, and chills or rigors; watery diarrhea may

occur as well. Investigators have reported the identification of a fourth

human coronavirus, HCoV-NL63. Evidence is emerging that this new

group 1 coronavirus is a common respiratory pathogen of humans,

causing both upper and lower respiratory tract illness. HCoV-HKU1

was first described in January 2005 after its detection in a patient with

pneumonia. Several cases of respiratory illness have been associated

with this virus, but its infrequent identification suggests that this group

2 coronavirus has caused a low incidence of illness to date. The Middle

TABLE 199-3 Enterovirus, Rhinovirus, and Parechovirus Species

Names, the International Committee on Taxonomy of Viruses: 2019

Release

GENUS

CURRENT SPECIES

NAME FORMER SPECIES NAME

Enterovirus (now 15

species)

Enterovirus A: consists of

25 serotypes, including

coxsackieviruses

and some nonpolio

enteroviruses that cause

respiratory disease

Human enterovirus A

Enterovirus B: consists of

63 serotypes, including

some coxsackieviruses,

echoviruses, and

nonpolio enteroviruses

Human enterovirus B

Enterovirus C: consists of

23 serotypes, including

the polioviruses

Human enterovirus C

Enterovirus D: consists of

5 serotypes and includes

enterovirus D68

Human enterovirus D

Rhinoviruses A–C Human rhinoviruses A–C

Parechovirus (now 6

species)

Parechovirus A: consists

of 19 types (1–19). Human

parechoviruses (HPeVs)

1 and 2 are common

human pathogens.

HPeV-1 and HPeV-2 were

formerly classified in the

genus Enterovirus as

echoviruses 22 and 23,

respectively.