Infectious Diseases of The Lungs: Viral Infections

SECTION H
INFECTIOUS DISEASES OF THE LUNGS
32 VIRAL INFECTIONS
FRANCES EUN-HYUNG LEE, MD • JOHN J. TREANOR, MD
INTRODUCTION Croup Influenza Virus

Classification Bronchiolitis Measles Virus
Transmission Pneumonia Metapneumoviruses
Pathogenesis of Infection MAJOR VIRAL PATHOGENS Parainfluenza Viruses
CLINICAL SYNDROMES Adenoviruses Respiratory Syncytial Virus
Common Cold Coronaviruses Rhinovirus
Pharyngitis Cytomegalovirus Varicella-Zoster Virus
Acute Bronchitis Hantaviruses
Influenza-like Illness Herpes Simplex Virus
INTRODUCTION the replication of which is generally restricted to the

respiratory tract, and others in which respiratory involve-
Viral infections are important causes of disease of the ment is part of a generalized infection. Virus classification
respiratory tract. The common cold is the most fre- depends in part on the type and configuration of the nucleic
quently encountered infectious syndrome of humans, acid in the viral genome, the characteristics of the viral
while influenza continues to be a major cause of mortality structural proteins, and the presence or absence of an
and serious morbidity worldwide. Respiratory viral infec- envelope surrounding the virus particle. The number of
tions frequently complicate the course of patients with distinct antigenic types within each of the virus families
chronic obstructive pulmonary disease (COPD) and asthma. As also varies.
the number of immunocompromised persons in the popu-
lation has increased, infections due to cytomegalovirus
and other herpes viruses, adenoviruses, and paramyxovi-
ruses have assumed increasing importance in pulmonary TRANSMISSION
medicine. Finally, recent years have seen the emergence of
new viral respiratory pathogens, including hantaviruses, The routes by which the different respiratory viruses spread
human metapneumovirus, avian influenza A viruses, and from person to person are variable and include combina-
the severe acute respiratory syndrome (SARS) and Middle East tions of contact, droplet, and aerosol transmission. For
respiratory syndrome (MERS) coronaviruses. This introduc- example, rhinovirus and respiratory syncytial virus (RSV)
tory section outlines general concepts of respiratory viral are primarily spread by direct contact with contaminated
infections and their associated clinical syndromes. The fol- skin and environmental surfaces followed by self-inoculation
lowing sections then provide a review of the major viral of virus onto the nasal mucosa or conjunctiva. Other
pathogens infecting the respiratory tract. viruses, such as measles and varicella-zoster viruses, spread
as small-particle aerosols. Other viruses may spread by
means of larger-particle aerosols over short distances (1 m).
CLASSIFICATION
The relative importance of the various transmission routes
Viruses of importance in the respiratory tract (Table 32-1) under natural conditions for each virus varies and in many
include those considered to be principal respiratory viruses, cases is unknown.
527
528 PART 3 • Clinical Respiratory Medicine
Table 32-1 Viral Infections of the Respiratory Tract

Group Nucleic Acid Envelope Types Disease/Syndrome*
Adenovirus DNA No 1–47 Common cold; bronchitis; bronchiolitis; pharyngoconjunctival
fever; acute respiratory disease (ARD) in military recruits;
pneumonia
Coronavirus RNA Yes 229E, OC43, Common cold, severe acute respiratory syndrome (SARS), Middle
SARS-CoV, East respiratory syndrome (MERS)
MERS-CoV
Hantavirus RNA Yes Multiple Acute respiratory distress, pneumonitis
Orthomyxovirus RNA Yes
Influenza virus A, B, C Influenza; common cold; pharyngitis; croup; bronchitis;
bronchiolitis; pneumonia
Paramyxoviruses RNA Yes
Measles virus Measles; pneumonia; bronchiectasis
Parainfluenza virus 1–4 Common cold; croup; bronchitis; bronchiolitis; pneumonia
Respiratory syncytial virus A, B Common cold; croup; bronchitis; bronchiolitis; pneumonia
Human metapneumovirus A, B Bronchiolitis, common cold
Picornaviruses RNA No
Enterovirus
Coxsackievirus 1–24 Type A21 colds and ARD; others (types 2, 4, 5, 6, 8, 10);
herpangina
Echovirus 1–34 Common cold (importance uncertain)
Rhinovirus 1–100 Common cold
Herpes viruses DNA Yes
Herpes simplex virus 1, 2 Acute pharyngitis in normal persons; chronic ulcerative
pharyngitis; tracheitis; pneumonia in immunosuppressed
patients
Cytomegalovirus 1 Mononucleosis; acute and chronic pharyngitis; pneumonia in
immunosuppressed patients
Varicella-zoster virus 1 Pneumonia in normal persons and immunosuppressed patients
Epstein-Barr virus 1 Mononucleosis; acute and chronic pharyngitis
Human herpesvirus 6 1 Pneumonia in immunosuppressed patients
Filovirus RNA Yes Marburg; Pharyngitis as an early manifestation of hemorrhagic fever
Ebola 1, 2
Human immunodeficiency RNA Yes 1, 2 Pharyngitis with primary infection; secondary pulmonary
virus infections due to immunodeficiency
Papillomavirus DNA No >60 Laryngeal and tracheobronchial papillomatosis
*Bacterial infections, including sinusitis, otitis media, and pneumonia, complicate respiratory virus infection. Also, infection with the respiratory viruses may
precipitate attacks of asthma and cause exacerbations in patients with chronic obstructive pulmonary disease.
PATHOGENESIS OF INFECTION
CLINICAL SYNDROMES
The initial sites of infection and pathogenesis differ for the
various virus groups. Some, such as rhinovirus, are associ- As shown in Table 32-1, infection by one of the respiratory
ated mainly with upper respiratory tract involvement. viruses may result in more than one clinical syndrome.
Others, such as influenza, commonly invade the lower Similarly, a particular syndrome can result from infection
airways and sometimes pulmonary parenchyma in addi- with different viruses. The poor correlation of agent and
tion to causing upper airway disease. The viruses also syndrome makes specific etiologic diagnosis on clinical
differ in the relative contributions to the clinical manifesta- grounds inaccurate, although knowledge of the seasonal
tions of disease from damage due to direct viral mecha- patterns of infection may be helpful. Moreover, infection
nisms and damage due to host immune responses and with a single virus may cause disease at multiple levels of
inflammation. the respiratory tract.
An additional important feature of respiratory virus
infections is their effect on the resident bacterial flora of the COMMON COLD
upper airways. Respiratory virus infections alter bacterial
colonization patterns, increase bacterial adhesion to respi- There is no universally accepted, standard definition of a
ratory epithelium, and reduce mucociliary clearance and cold, but the term is usually used to refer to acute rhinitis
phagocytosis. These impairments of host defenses by viruses with variable degrees of pharyngitis. Systemic complaints
allow colonization by pathogenic bacteria and invasion of are absent or modest in severity and fever is unusual. Aller-
normally sterile areas, such as the paranasal sinuses, middle gic diseases of the upper airway often have clinical manifes-
ear, and lower respiratory tract, resulting in secondary tations similar to those of colds. Colds are frequently
infection. associated with involvement of the middle ear, likely due to
32 • Viral Infections 529
Table 32-2 Viruses Associated with the Common Cold Sneezing Rhinorrhea
Virus Percentage of Cases*

Rhinovirus 40
Coronavirus 10
Parainfluenza virus 10–15
Respiratory syncytial virus
Influenza virus
Adenovirus
Obstruction Sore throat
Other viruses (enterovirus, rubeola, 5
Symptom severity
rubella, varicella)
Presumed undiscovered viruses 20–30
Group A β-hemolytic streptococci† 5–10
*Estimated percentage of colds annually.

†
Included because differentiation of streptococcal and viral pharyngitis is
not possible by clinical means.
Cough Headache
eustachian tube dysfunction. Colds are associated with

symptomatic otitis media in approximately 2% of cases in
adults and in a higher proportion in young children. Colds
are frequently associated with sinus mucosal thickening or
secretions on computed tomography scans but rarely result
in symptomatic sinusitis. Vertigo associated with viral laby- Day 1 Day 2 Day 3 Day 4 Day 1 Day 2 Day 3 Day 4
rinthitis may also be seen.
The common cold syndrome is caused by any one of a Time point
large number of antigenically distinct viruses found in four Figure 32-1 Some common clinical features of rhinovirus colds (105
principal groups (Table 32-2). Epidemiologic studies have natural infections). Graphs show symptom severity by time point.
(Adapted from Gwaltney JM Jr, Hendley JO, Patrie JT: Symptom severity pat-
indicated that on an annual basis, any one antigenic type terns in experimental common colds and their usefulness in timing onset of
of virus is responsible for less than 1% of all colds. Since illness in natural colds. Clin Infect Dis 36:724–723, 2003, Fig. 2.)
the discovery of the respiratory viruses in the 1960s, rhi-
novirus has emerged as the prototype common cold virus
(Fig. 32-1). Table 32-3 Important Microbial Agents Associated with
The recommended approach to colds is to use individual Acute Pharyngitis
remedies to treat specific symptoms. Nasal sprays contain-
Pharyngitis with colds Rhinovirus
ing decongestants should be used for no more than 3 days, and influenzal illness Influenza virus
to avoid a rebound vasomotor rhinitis. Cough syrups con- (no exudate) Coronavirus
taining expectorants are of unproven value in common Respiratory syncytial virus
colds. Symptoms of sneezing and rhinorrhea can be Exudative pharyngitis Streptococcus pyogenes (group A
alleviated with nonselective antihistamines such as brom- (exudate is not β-hemolytic streptococcus)
pheniramine, chlorpheniramine, or clemastine fumarate,1 present in all cases) Mixed anaerobic infection (Vincent
angina and peritonsillar abscess)
but treatment with selective H1 inhibitors is not effective. Adenovirus
Studies of pseudoephedrine have demonstrated measurable Herpes simplex virus
improvements in nasal air flow consistent with a deconges- Epstein-Barr virus
tant effect.2 Nonsteroidal anti-inflammatory drugs such as Corynebacterium diphtheriae
(pseudomembrane)
naproxen moderate the systemic symptoms of rhinovirus
infection. However, the use of the decongestant phenylpro-
panolamine has been shown to be associated with an
increased risk of hemorrhagic stroke.3 Topical application viruses that cause colds. In some cases, pharyngeal symp-
of ipratropium, a quaternary anticholinergic agent that is toms predominate to a degree that overshadows other com-
minimally absorbed across biologic membranes, reduces plaints. The kinins are potent stimulators of pain nerve
rhinorrhea significantly in naturally occurring colds. This endings, and high levels of bradykinin and lysylbradykinin
agent probably exerts its major effect on the parasympa- are present in nasal secretions of patients with rhinovirus-
thetic regulation of mucous and seromucous glands. induced colds. Intranasal application of bradykinin pro-
Importantly, most over-the-counter cough and cold reme- motes sore throat and nasal symptoms in volunteers,
dies have not been studied in pediatric populations, where supporting a role for these agents in the pathogenesis of
they may be associated with significant side effects.4 cold symptoms.5
The respiratory viruses causing pharyngitis can be
divided into two groups: those associated with a pharyngeal
PHARYNGITIS
or tonsillar exudate and those without such an exudate
Pharyngitis most often presents as part of the common cold (Table 32-3). Pharyngitis is often a prominent complaint
syndrome and thus is usually associated with the same with adenovirus and influenza virus infection. Also, some
viruses are associated with other types of enanthems, as dextromethorphan in suppressing night time coughing,7
meaning lesions on the mucous membranes, such as vesi- but honey should not be administered to infants younger
cles and ulcers. Coxsackie A viruses are associated with the than 1 (due to risk of infant botulism).
condition herpangina, a painful, often febrile pharyngitis of
children and young adults characterized by vesicular lesions INFLUENZA-LIKE ILLNESS
of the soft palate.
Viruses in the herpes family cause a small proportion of The clinical syndrome of influenza is characterized by the
cases of pharyngitis. Primary infection with herpes simplex rapid onset of constitutional symptoms, including fever,
virus manifests as an acute vesiculoulcerative pharyngitis chills, prostration, muscle ache, and headache, concurrent
or gingivostomatitis that may have an exudative character. with or followed by upper and lower respiratory tract symp-
In immunocompromised patients, herpes simplex virus toms. Systemic symptoms tend to dominate for the first
causes large, shallow ulcers of the mucosa that are chronic several days of illness, whereas respiratory complaints,
and progressive if untreated. Epstein-Barr virus mononu- particularly cough, predominate later in the first week
cleosis characteristically has an acute exudative pharyngi- of illness. Photophobia, excess tearing, and pain with eye
tis. Mononucleosis due to cytomegalovirus infection may movement are common early in the illness. Mild conjuncti-
have a nonexudative pharyngitis that is acute or chronic, vitis, clear nasal discharge without obstruction, pharyngeal
and rarely, cytomegalovirus causes oral ulcerations in injection, and small tender cervical lymph nodes are fre-
immunosuppressed patients. Pharyngitis can arise during quently present. Fever may peak at 39° C to 40° C or higher
primary infection with human immunodeficiency virus (HIV). and can last for 1 to 5 days. Persistent nonproductive cough,
Viruses in the hemorrhagic fever group produce an acute easy fatigability, and asthenia are common in the second
pharyngitis early in the disease, before skin lesions appear. week of illness.
Exudative pharyngitis is a common clinical manifestation Influenza type A and B viruses are the most important
in Lassa fever. causes of the influenza syndrome, particularly when the
Typically, sore throat accompanied by nasal symptoms illness presents in an epidemic form. However, the syn-
is more likely to be viral in nature. Infection with mixed drome can also be seen in association with infection by
anaerobic bacteria (Vincent angina) or Corynebacterium other viruses, including adenovirus, parainfluenza, and
diphtheria is also in the differential diagnosis of exudative RSV. The characteristic clinical features of influenza and its
pharyngitis. The treatment of most cases of viral pharyn- epidemic nature usually permit the practitioner to make an
gitis is symptomatic. accurate diagnosis during recognized epidemics of influ-
enza virus infection, particularly if cough and fever are
ACUTE BRONCHITIS present.8 Specific antiviral therapy is effective if given early
in the course of the illness (see the section on influenza
The diagnosis of acute bronchitis is usually applied to cases virus). Symptomatic treatment (bed rest, oral hydration,
of acute respiratory disease with severe and prolonged antipyretics, and antitussives) is also beneficial. Fever
cough that continues after other signs and symptoms of the should be treated in certain clinical situations, such as in
acute infection have subsided. Cough appears during the children with previous febrile convulsions or patients with
first week of illness in 30% of rhinovirus colds in young preexisting cardiac disease. Because of its possible associa-
adults and in 80% or more of cases of influenza A virus tion with Reye’s syndrome, aspirin must be avoided in pedi-
infection, in which it is often prolonged. Adenovirus infec- atric patients.
tions characteristically involve the tracheobronchial tree,
with resultant bronchitis that, in military populations, is CROUP
part of the syndrome of acute respiratory disease.
The mechanisms of cough production in viral infection The croup syndrome of children is characterized by an
are not well understood but may include direct damage to unusual brassy or barking cough (see Audio 30-3) that may
the respiratory mucosa, release of inflammatory substances be accompanied by inspiratory stridor, dyspnea, and
in response to the infection, increased production and/or hoarseness.8a The symptoms are often preceded by several
decreased clearance of respiratory secretions, and stimula- days of upper respiratory illness and are typically worse at
tion of airway irritant receptors. Intranasal application of night. Croup is seen primarily in children younger than 6.
several prostaglandins also produces cough in uninfected The term acute infectious croup or laryngotracheobronchitis is
volunteers.5 Infection may also enhance airway reactivity, applied to a contagious disease that affects otherwise
leading to increased sensitivity to cold air and pollutants healthy children, often associated with a respiratory illness
such as smoke. in the family. The term acute spasmodic croup is applied to a
The differential diagnosis of acute bronchitis includes similar syndrome that is most common in young children
nonviral infections and noninfectious etiologies such as prone to recurrent attacks precipitated by respiratory viral
cough-variant asthma. Bordetella pertussis, Mycoplasma infections and possibly allergic or other factors. In these
pneumoniae, and Chlamydia pneumoniae infections cause pro- children, fever is frequently absent and symptoms often
longed cough. In otherwise healthy persons, workup of abate within several hours.
acute cough should be directed toward determining the Most children with acute laryngotracheobronchitis
presence of pneumonia and, if this is not present, then have symptoms of decreasing intensity over several days
treatment with antibacterial agents is of no benefit.6 Symp- and can be managed at home. However, increasing laryn-
tomatic treatment is directed at the suppression of cough. geal obstruction can be associated with respiratory insuffi-
In children, a single nocturnal dose of honey is as effective ciency. This is manifested by restlessness, air hunger, stridor
A B
Figure 32-2 Laryngotracheobronchitis. Anteroposterior (A) and lateral (B) neck radiographs of a 2-year-old child with croupy cough, inspiratory stridor,
and fever. The anteroposterior view shows subglottic narrowing, referred to as the “steeple” sign (arrow), characteristic of laryngotracheobronchitis. Lateral
view shows ballooning of hypopharynx resulting from laryngeal obstruction. (Courtesy Joan McIlhenny, MD, Department of Radiology, University of Virginia
Medical Center.)
at rest, use of accessory muscles, and intercostal retractions ments in oxygenation. Steroids have been shown to confer
and may be followed by development of exhaustion with significant benefits in the management of mild, moderate,
severe hypoventilation, cyanosis, and cardiovascular col- and severe croup, including more rapid improvement in
lapse. A fluctuating course is typical. symptoms, reduced length of hospital stay, and reduced
Radiologic examination of the upper airway shows glottic rates of intubation. Administration of single-dose steroid
and subglottic edema (Fig. 32-2, eFig. 32-1) and helps to therapy in this setting has not been associated with
differentiate the disorder from acute bacterial epiglottitis. significant side effects and should probably be used in any
However, radiographs are limited in accuracy and, when patient ill enough to require an emergency department or
the diagnosis is uncertain, radiologic and pharyngeal clinic visit.9
examination should be avoided because of the risk of car- Antiviral agents have not been tested for efficacy in this
diorespiratory arrest in acute epiglottitis. Emergency assess- situation, although the potential benefit of antiviral therapy
ment by an otolaryngologist or an anesthesiologist is in the typical self-limited course of croup would likely be
indicated in this situation. limited. Since croup is a viral illness, antibiotic therapy is of
The acute infectious croup syndrome has been associated no benefit.
principally with infection by one of the parainfluenza
viruses, as well as RSV, influenza A and B viruses, adenovi- BRONCHIOLITIS
ruses, and rhinovirus. Measles is an important cause of
severe croup in the developing world, and influenza A epi- Bronchiolitis is an acute inflammatory disorder of the small
demics also are associated with severe croup. The differen- airways characterized by obstruction with “air trapping,”
tial diagnosis of croup includes acute bacterial epiglottitis, hyperinflation of the lungs, and atelectasis typically seen in
diphtheritic croup, asthma, and intrinsic or extrinsic upper children younger than 2. After a several-day prodrome of
airway obstruction related to an aspirated foreign body, mild upper respiratory tract symptoms, patients typically
allergic angioedema, and retropharyngeal abscess. present with inspiratory and expiratory wheezing. The
Because the majority of hospitalized children are hypox- clinical features, which include tachypnea, intercostal
emic, oxygen is the mainstay of treatment for severe disease. and suprasternal retractions, nasal flaring, hyperresonant
Humidified air, or mist therapy, is commonly used, but the chest, wheezing, and inspiratory rales, usually lead to an
value of mist therapy has not been proven, and removal of accurate clinical diagnosis. The infant is often afebrile and,
the child from the parents and placement in a mist tent can in mild cases, symptoms resolve within several days. Chest
be more distressing than beneficial to the child. radiographs show increased lung volumes with flattening of
Administration of nebulized racemic epinephrine is com- the diaphragms, peribronchial thickening (eFig. 32-2), and
monly used for symptomatic relief in croup. It is believed often atelectasis or parenchymal consolidation indicative of
that α-adrenergic stimulation by this drug causes mucosal concurrent bronchopneumonia (Fig. 32-3). Chest computed
vasoconstriction, leading to decreased subglottic edema. tomography (CT) may show bronchial wall thickening and
The onset of action is rapid, often within minutes, but the areas of increased attenuation representing atelectasis
duration of relief is also limited, lasting 2 hours or less. mixed with areas of decreased attenuation due to small
Therefore, treated subjects should be observed closely for airway inflammation and obstruction producing air trap-
clinical deterioration. Although symptomatic relief is con- ping (eFig. 32-3). The white blood cell count and differential
siderable, use of epinephrine is not associated with improve- count are usually within normal limits.
many patients with acute viral infections. Also, because

viral infections may be complicated by secondary bacterial
pneumonias, invasive procedures would be necessary to dif-
ferentiate among pure viral pneumonias, secondary bacte-
rial pneumonias, and mixed viral and bacterial infections.
Normal Host
The relative importance of the different viruses as causes of
pneumonia depends on the season and the age distribution
of the population under study. During outbreaks, influenza
virus accounts for more than 50% of viral pneumonia in
adults. In addition, RSV, adenovirus, parainfluenza virus,
and varicella virus cause pneumonia in normal adults.
Unusual viruses continue to emerge in epidemics of severe
acute pneumonitis, including hantavirus, coronavirus
(SARS), and avian influenza A viruses.
In children, RSV, parainfluenza virus, and adenovirus,
in addition to influenza viruses, are the most important
causes of pneumonia. Measles virus pneumonia affects
children and adults during epidemics in susceptible popula-
Figure 32-3 Respiratory syncytial virus pneumonia. Frontal chest radio- tions. There are reports of cases of pneumonia in adults
graph in an intubated infant shows bilateral peribronchial interstitial and children attributable to rhinovirus, but the evidence
thickening and right upper and left lower lobe consolidation; the right that these viruses are definite causes of pneumonia is
upper lobe opacity is associated with mild volume loss. (Courtesy Michael
Gotway, MD.) circumstantial.
The clinical and radiographic features of sporadic cases
of viral pneumonia are usually not sufficiently characteris-
The majority of cases in which an etiologic agent has tic to permit specific viral diagnosis or differentiation from
been identified are associated with RSV. Other viruses asso- bacterial pneumonias on clinical grounds alone. Exceptions
ciated with bronchiolitis include human metapneumovi- include measles (eFig. 32-4) and varicella pneumonia, in
rus, bocavirus, parainfluenza virus, influenza A and B which the associated rash establishes the diagnosis. There-
viruses, adenovirus, measles, and rhinoviruses. The major fore, attention is first directed at excluding primary or sec-
differential diagnostic consideration is asthma, which is ondary bacterial pneumonia. Tests to detect viral antigens
uncommon in children younger than one year old. or nucleic acid are increasingly available and are rapidly
Correction of hypoxemia is the most important aspect of being adopted as the preferred approaches for establishing
managing lower respiratory tract disease. Studies of corti- the etiologic diagnosis11a,b (see Chapter 17).
costeroid therapies have found no consistent benefit. Studies Treatment of viral pneumonia in the normal host is sup-
of bronchodilators have reached conflicting results, and portive in nature and directed at early antimicrobial therapy
bronchodilating drugs may contribute to increased restless- of secondary bacterial infections, if present. Specific antivi-
ness and cardiovascular stress, so guidelines do not suggest ral therapy may be beneficial and is discussed with the
that bronchodilators be used routinely. One recent random- individual pathogens. Viral pneumonias with extensive
ized trial suggests that “on-demand” use of inhaled racemic involvement of lung tissue may require prolonged ventila-
adrenaline may result in decreased length of stay in infants tory assistance and pulmonary rehabilitation. Some cases
hospitalized with bronchiolitis.10 Because of the dehydrat- of viral pneumonia have a rapid and relentless fatal course,
ing effect of tachypnea and reduced oral intake in some with generalized alveolar and interstitial opacities, develop-
hospitalized infants, parenteral rehydration is often neces- ment of the adult respiratory distress syndrome (ARDS), and
sary, but care must be taken to avoid inducing hypona- progressive respiratory failure.
tremia. Aerosol treatment with the synthetic nucleoside
ribavirin has been associated with reductions in virus titers Immunocompromised Host
but inconsistent clinical benefits. Antibacterial drugs, Viral pneumonia can be an important problem for the
including azithromycin, are of no benefit.11 increasing number of persons in the population who have
deficiencies in immunity as the result of cytotoxic chemo-
therapy, organ transplantation, and the acquired immunode-
PNEUMONIA
ficiency syndrome (AIDS). The major respiratory viruses
Viruses are important causes of pneumonia in both adults that affect normal persons may also cause pneumonia in
and children. They have been associated with up to 40% of impaired hosts; severe and prolonged pneumonias due
radiographically proven pneumonias in hospitalized adults to adenovirus, respiratory syncytial, influenza, measles,
and are estimated to cause 16% of total pneumonias in or parainfluenza virus can develop in such patients. Immu-
pediatric outpatients and up to 49% in hospitalized infants. nocompromised patients can also shed respiratory viruses
These figures may underestimate the importance of viral for prolonged periods and thus be responsible for extensive
infections as a cause of pneumonia, particularly in out transmission of infection to others. In addition, these indi-
patients, because of the insensitivity of viral diagnostic viduals may develop pneumonia due to viruses, such as
methods and because of the lack of chest radiographs in cytomegalovirus, that rarely cause lower respiratory tract
disease in normal hosts. Cytomegalovirus causes severe 1 and 2, routinely infect infants and young children, who
primary viral pneumonia (see eFigs. 91-3, 91-4, and then have prolonged asymptomatic viral shedding from
91-5), as well as predisposing patients to bacterial and the respiratory and gastrointestinal (GI) tracts. Other types,
fungal superinfections because of its immunosuppressive including those that have been most often implicated in
effects.11c,d Varicella-zoster and herpes simplex virus pneu- respiratory disease (e.g., types 3, 4, and 7), are acquired
monias are relatively uncommon but serious infections in later in life, characteristically in epidemic settings. In most
immunosuppressed patients. instances, viral transmission probably takes place by direct
contact with infectious secretions. However, the explosive
nature of adenoviral acute respiratory disease in military
recruits probably reflects airborne spread.
MAJOR VIRAL PATHOGENS Most community adenovirus respiratory disease has
been recognized in the summer months in association with
ADENOVIRUS
outbreaks or sporadic cases of febrile pharyngitis or bron-
Adenovirus is a medium-sized (65 to 80 nm), nonenveloped chitis. Nosocomial outbreaks of adenovirus infection have
virus with a genome composed of linear double-stranded arisen in hospital wards, special care units, and psychiatric
DNA12 (Fig. 32-4). Currently, 47 antigenic types of adeno- facilities. New variants of adenovirus have occasionally
virus are associated with human infection, although not all emerged and have been associated with outbreaks world-
types have been associated with human disease. The protein wide. Since 1996, a specific variant of adenovirus type 7
coat of the virus is composed of 252 hexagonal and pen- (Ad7d2) has been responsible for several civilian outbreaks
tagonal capsomeres in an icosahedral array with long pro- and a large military outbreak.13 More recently, adenovirus
jecting fibers at each vertex. These fibers are thought to be type 14 (Ad14), a previously rare serotype, has been respon-
the site of host cell attachment. Adenoviruses type 2 and 5 sible for outbreaks of disease both in the military and in
and coxsackie B viruses use the same receptor, designated civilian populations.14-16 Most cases have been relatively
the coxsackie virus and adenovirus receptor (CAR), whose mild febrile respiratory illnesses, but some cases have been
usual function is to mediate cell interactions with extracel- seen with severe pneumonia requiring hospitalization.
lular matrix proteins. Some adenoviruses use the comple- Infection with adenovirus type 36 is associated with weight
ment regulatory protein CD46 as a cellular receptor. Virus gain in mice,17 and serologic positivity for this serotype
entry into the cell is also promoted by interaction of the appears to be more common in adults and children with
penton base of the virus with alpha-V integrins. Viral type– obesity.18
specific antigens, which give rise to neutralizing antibody,
are present on the hexons and fibers of the capsid. The Pathogenesis
hexons also contain a complement-fixation antigen with Adenoviruses have been isolated from the upper airway, eye,
cross-reactivity among the mammalian adenoviruses. urine, stool, and rarely, blood. The incubation period for
naturally acquired adenovirus disease of the respiratory
Epidemiology and Transmission tract is usually 4 to 7 days but may be up to 2 weeks.
The adenoviruses that cause human disease do not have Cytopathologic changes have also been observed in
nonhuman reservoirs, although nonhuman adenoviruses bronchial epithelial cells,19 and crystalline arrays of
are found in other species. Some serotypes, especially types virus particles have been found in alveolar lining cells of
infected persons with severe illness.20 The extent of damage
to the respiratory tract in nonfatal adenovirus respiratory
disease is not well defined but may result from a combina-
tion of direct viral mechanisms and host-related inflam-
matory responses to infection. In cases of fatal adenovirus
pneumonia, bronchial epithelial necrosis, bronchial
obstruction, and interstitial pneumonia have been seen.21
Cells containing large basophilic, intranuclear inclusions,
so-called “smudge cells,” appear to be characteristic (Fig.
32-5). In lung transplant recipients, necrotizing broncho-
centric pneumonia with diffuse alveolar damage has been
reported.22
Clinical Illness
Adenovirus Respiratory Disease. The nonpneumonic
respiratory syndromes associated with adenovirus infection
include acute respiratory disease of military recruits and
pharyngoconjunctival fever of civilians, which have similar
characteristics (Fig. 32-6). Adenovirus respiratory disease
Figure 32-4 Photoelectron micrograph showing human adenovirus typically involves the pharynx as a moderate to severe,
type 2. Each virion contains a lobulated group of three adenosomes, sometimes purulent, pharyngitis. Also characteristic of this
which are composed of DNA and protein. Full virion particles contain a
total of 12 adenosomes, each of which is found below one vertex of the
disease is marked tracheitis, bronchitis, or tracheobronchi-
icosahedral capsid. (Courtesy J. Brown and W. Newcomb, University of tis, as well as rhinitis and conjunctivitis. Conjunctivitis is
Virginia.) not a feature of infection with the other major respiratory
populations, both can be seen as sporadic cases. In young

children, adenovirus infection has been associated with
both mild and febrile respiratory illness, with an associated
otitis media in approximately 40% of these cases.
Adenovirus Pneumonia. Adenovirus was first recog-

nized as a cause of viral pneumonia in military recruits and
has since been recognized as a rare cause of pneumonia in
civilian adults (eFig. 32-5) and children. The clinical char-
acteristics of adenovirus pneumonia are similar to those of
other pneumonias, so it is difficult to make an accurate etio-
logic diagnosis on the basis of clinical features. In fatal
cases, there has been extensive pulmonary damage, with
death intervening 2 to 3 weeks into the illness. Intravascu-
lar coagulopathy has also been a late feature of some cases,
Figure 32-5 Adenovirus causing necrotizing pneumonia. Focal necro- and a septic shock picture has been described.23 Adenovi-
sis is apparent; the prominent cell in the center of the field is an adenovirus- ruses cause a particularly aggressive form of pneumonia in
infected “smudge cell,” with an enlarged nucleus with basophilic inclusions neonates, characterized by necrotizing bronchiolitis and
surrounded by a thin rim of cytoplasm (H&E, ×80 original magnification). alveolitis.24 The virus may be acquired from the mother,
(Courtesy William D. Travis, MD, Memorial Sloan Kettering Cancer Center, New
York, NY.) perhaps via the birth canal. Long-term sequelae of adeno-
virus infection may include persistent radiographic abnor-
malities, abnormal pulmonary function tests, bronchiectasis,
Fever and bronchiolitis obliterans.
Myalgia
Headache Adenovirus Infection in Persons with Impaired
Chills
Anorexia Immunity. Adenoviruses can cause fatal pneumonia and
Pharyngitis disseminated infection, with hepatitis, hemorrhagic cysti-
Cough tis, and renal failure, in transplant patients and other
Earache immunodeficient persons.25 Various immunotypes have
Conjunctivitis been recovered from these patients (eTable 32-1), including
Adenopathy
Sputum higher numbered serotypes that are only seen in such
Rhinitis patients. Types seen with particular frequency include 1, 2,
5, 6, 7, 11, 21, 31, 34, and 35. The clinical importance of
0 10 20 30 40 50 60 70 80 90 100 the recovery of an adenovirus from these patients, particu-
% of cases larly from stool samples, is often difficult to determine,
because immunodeficient patients may shed adenoviruses
ARD in military recruits in the absence of overt disease caused by them.
Pharyngoconjunctival fever in civilians
Diagnosis
Figure 32-6 Graph showing comparison of the clinical characteristics of
acute respiratory disease (ARD) of military recruits and pharyngoconjunc- Although diagnosis was traditionally achieved by virus
tival fever of civilians. (Adapted from Dascomb HE, Hilleman MR: Clinical and culture, viral antigens or nucleic acid can be detected
laboratory studies in patients with respiratory disease caused by adenoviruses. directly from appropriate specimens of respiratory secre-
Am J Med 21:161–174, 1956, and Martone WJ, Hierholzer JC, Keenlyside RA, tions, conjunctival swabs, stool, or urine, depending on
et al: An outbreak of adenovirus type 3 disease at a private recreation center
swimming pool. Am J Epidemiol 111:229–237, 1980.)
the clinical syndrome. Rapid detection of viral antigens in
clinical specimens by ELISA or immunofluorescence and of
viral DNA by nucleic acid amplification techniques is
viruses and therefore, when present, is a useful diagnostic increasingly used instead of viral culture because of the
finding in adenovirus respiratory disease. With adenovirus fastidiousness of some serotypes and slow rate of isola-
respiratory disease, the conjunctivitis is typically mild and tion25a (see Chapter 17). Quantitative measurement of ade-
follicular, although some adenovirus types also cause the novirus DNA levels in plasma may be useful for diagnosis
more severe condition, epidemic keratoconjunctivitis. Fever, and response to therapy.26
chills, myalgia, and prostration are prominent features of Frozen specimens (−70° C) are satisfactory for testing
adenovirus infection, so it is often perceived by the patient because of the relative stability of adenoviruses. In cell
as a “flulike” illness or an unusually severe cold. culture, cytopathic effect usually appears in 3 to 7 days but
Cases of acute respiratory disease tend to have more tra- may take several weeks, thus limiting the utility of viral
cheobronchitis, perhaps reflecting acquisition of infection culture in guiding clinical management. The time required
by the airborne route. Conversely, in pharyngoconjunctival to detect virus in cell culture can be shortened to as little
fever, the infrequency of cough and other tracheobronchial as 2 days by employing centrifugation culture systems.
complaints in some outbreaks may reflect infection con- Serodiagnosis has relied primarily on testing for a group-
tracted by pharyngeal and/or conjunctival inoculation specific complement-fixation antibody response, using
with virus from contaminated water. The two syndromes acute and convalescent serum specimens; however, infec-
are associated with the same viral serotypes and, in civilian tion with some adenovirus types is not detected by the
32 • Viral Infections 534.e1
eTable 32-1 Adenoviruses Associated with Respiratory Tract

Disease in Immunocompromised Patients*
PRIMARY IMMUNODEFICIENCIES
Upper Respiratory Tract Infection
Group B Type 34
Bronchitis
Group C Type 1
Bronchiolitis
Group C Type 2
Pneumonia
Group A Type 31
Group B Types 7, 11, 35
Group C Type 2
ORGAN TRANSPLANT RECIPIENTS
Group B Type 7
Group C Type 2
Pneumonia
Group A Type 31
Group B Types 7, 11, 34, 35
Group C Types 1, 2, 5, 6
Group E Type 4
CANCER IMMUNOSUPPRESSION PATIENTS
Group A Type 31
Group B Type 35
Pneumonia
Group B Type 21
Group C Types 1, 2
Group E Type 4
AIDS PATIENTS
Group A Type 31
Group D Type 29
Pneumonia
Group B Types 3, 11, 16, 21, 34, 35
Group C Types 1, 2, 5
Group D Types 8, 22, 29, 30, 37,
43, 44, 45, 46, 47
*Adapted from Hierholzer JC: Adenoviruses in the immunocompromised

host. Clin Microbiol Rev 5:262–274, 1992.
complement-fixation test. In biopsy specimens, the appear- viral replicases and proteinases, particularly the 3C-like
ance of characteristic intranuclear basophilic inclusion proteinase, are also antiviral drug targets.
bodies seen by light microscopy or of crystalline arrays of
virus seen by electron microscopy is useful in histopatho- Epidemiology and Transmission
logic diagnosis. Human coronaviruses OC43 and 229E have been recog-
nized as causes of the common cold for many years and
Treatment and Prevention cause frequent reinfections throughout life. In adults, these
Antiviral treatment of adenovirus infection does not have viruses account for 4% to 15% of acute respiratory disease
proven value. Ganciclovir and cidofovir are active in vitro, annually and up to 35% during peak periods. Annual illness
and an increasing number of reports indicate that intrave- rates in children reach 8%, with peak rates up to 20%.34
nous ganciclovir may be useful in seriously ill patients, When polymerase chain reaction (PCR) techniques were
although at the expense of significant renal toxicity.27 Cido- applied to samples collected over 20 years from children
fovir has also been used for treatment and for presumptive younger than 5, coronaviruses were associated with 11.4
therapy of adenovirus infection in high-risk immunocom- lower respiratory tract episodes and 67.3 upper respiratory
promised patients.28 Although intravenous ribavirin (which tract illnesses per 1000 person-years. 35 The reported fre-
is active for group C adenoviruses in vitro)29 or ribavirin quency of infection in adults for 229E and OC43 viruses
combined with immunoglobulin30 has been used in indi- has ranged from 15 to 25 per 100 persons per year, with
vidual patients, failures are common.31 up to 80% of infections seen in persons with prior antibody
Because of the prominent fever and systemic complaints to the infecting virus.36 Coronaviruses usually circulate
associated with adenovirus respiratory disease, analgesics, during winter and early spring but can be detected
such as aspirin and acetaminophen, are needed more often year-round.37
than with a milder coryzal illness such as a rhinovirus cold. Novel coronaviruses have recently been associated with
Warm saline gargles are helpful for relieving throat pain, severe respiratory disease in outbreaks around the world.
which does not usually require narcotics. The presence of SARS emerged in southern China in 2003 and quickly
pharyngeal exudate may sometimes lead to an incorrect spread globally.38 The causative virus was subsequently
diagnosis of streptococcal pharyngitis, resulting in the ini- named SARS-CoV. Ultimately, at least 8098 probable cases
tiation of antimicrobial therapy. of severe respiratory disease and 774 deaths in all ages were
Effective and safe live oral vaccines for adenovirus types attributable to SARS worldwide before the outbreak termi-
4 and 7 were developed for military use and, when delivered nated in 2004. The source of this outbreak is believed to
in enteric-coated capsules, have controlled acute respira- have been from an animal reservoir, the civet cat. More
tory disease in recruit populations. Use of these vaccines recently, a second outbreak of coronavirus severe respira-
was not associated with replacement by nonvaccine sero- tory illness has been recognized, with cases primarily found
types. When manufacturing of these vaccines was discon- in Middle Eastern countries.39,39a,39b In May 2014, the first
tinued, adenoviruses reemerged as important causes of case of MERS was confirmed in a traveler from Saudi Arabia
acute respiratory disease in this population. A new vaccine to the United States. A second case was identified in a trav-
for Ad4 and Ad7 has subsequently been introduced.32 eler from Saudi Arabia to Florida. The two cases were not
linked.39c The virus responsible for MERS has been named
MERS-CoV. It is genetically closely related to coronaviruses
CORONAVIRUSES
found in bats, and evidence indicates that MERS-CoV also
Coronaviruses are enveloped viruses containing a single- infects camels, but the role of each of these in transmission
stranded, positive-sense ribonucleic acid (RNA) genome of to humans remains to be defined.40,41 Information on MERS-
approximately 29,000 nucleotides. Distinctive club-shaped CoV is actively evolving; current information can be found
projections are present on the virus surface, giving the at http://www.cdc.gov/coronavirus/mers/.
appearance of having a crown or corona, from which it For all coronaviruses, transmission likely involves close
derives its name. Coronaviruses are classified into four contact and inoculation of the respiratory tract with infec-
genera: alpha, beta, gamma, and delta. The beta genus is tious secretions via large droplets as demonstrated in
further subdivided into four lineages, A-D. The human human challenge experiments for OC4342 and animal
coronavirus strains 229E (HCoV 229E) and HCoV NL63 studies for SARS-CoV.43 For SARS-CoV, virus shedding
are members of the alpha genus, while the human strains peaked at day 10 of symptom onset, which was at the
HCoV OC43 and HKU1 are members of the beta genus. height of disease severity.44 This phenomenon accounted
The novel coronaviruses, SARS-CoV and MERS-CoV, are for the preponderance of transmission in hospitals, a feature
also members of the beta genus, in lineages B and C, that allowed the outbreak to be controlled with infection
respectively.33 control procedures. The incubation period for SARS is esti-
The virus contains five structural proteins: spike or S mated from 2 to 10 days, and for conventional human coro-
protein, hemagglutinin-esterase (HE), M (matrix), E (envelope), naviruses 3 to 4 days.
and N (nucleocapsid). The spike protein is the major envelope
glycoprotein and mediates both attachment to cells and Pathogenesis
fusion with the cell membrane; antibodies to the spike Conventional coronavirus antigen has been detected in epi-
protein are thought to be associated with protection and thelial cells shed from the nasopharynx of infected volun-
thus are candidates for therapeutic and vaccine targets. teers45 and, during experimental infection, nasal airway
The second envelope protein, HE, is only found in some resistance, mucosal temperature, and the albumin content
coronavirus strains. Nonstructural proteins such as the of nasal secretions increase.46 However, relatively little is
known about the pathogenesis of the common cold induced effective immunity short-term because rechallenge with
by conventional human coronaviruses. homotypic virus, the 229E serotype, resulted in infection
The hallmark of pulmonary pathology in fatal cases of and illness.57 In addition, under certain circumstances, vac-
SARS was diffuse alveolar damage,47 type II pneumocyte cines against animal coronaviruses have led to enhanced
hyperplasia, squamous metaplasia, and multinucleated disease.58 This is being taken into consideration but is
giant cells. Hemophagocytosis, or the phagocytosis of not deterring efforts to develop an efficacious SARS-CoV
erythrocytes, leukocytes, and platelets by histiocytes, was vaccine.59
reported, potentially as a consequence of cytokine dysregu- There are no currently available antiviral agents with
lation.48 Furthermore, virus was detected within pulmo- demonstrated clinical activity against coronaviruses in
nary epithelial cells.49 From these findings, it is postulated humans. Agents with potential activity against SARS-CoV
that disease pathogenesis involves both direct damage to include chloroquine, protease inhibitors, ribavirin, type I
pulmonary epithelia by the virus in combination with an interferons, niclosamide, and anti-inflammatory agents
excessive or dysregulated host immune response. such as indomethacin.60-62 Ribavirin in combination with
lopinavir/ritonavir (protease inhibitors used in HIV disease)
Clinical Illness was associated with a lower incidence of adverse outcomes
Conventional human coronaviruses produce a typical compared with historical controls of ribavirin alone in one
coryzal illness that is indistinguishable from colds due to study. Nelfinavir, another protease inhibitor, has also dem-
other viruses. Coronaviruses have also been linked with onstrated in vitro antiviral activity. Other targets for con-
acute otitis media, exacerbations of asthma in children, and trolling SARS viral replication have included interferons.
with exacerbations of chronic bronchitis and pneumonia in Although the mechanisms are unknown, chloroquine,
adults. niclosamide, and indomethacin all inhibit SARS-CoV in
In contrast, SARS has a nonspecific presentation that is vitro.63-65
difficult to distinguish from other viral acute respiratory
illnesses, particularly influenza. Common symptoms on
CYTOMEGALOVIRUS
presentation are fever, chills and/or rigors, myalgias, and
occasionally diarrhea. Cough and dyspnea are the predomi- Cytomegalovirus (CMV) is a member of the gammaherpesvi-
nant respiratory symptoms but may not be present initially. rus subfamily of the herpes viruses and has the same struc-
Respiratory disease becomes more severe over 4 to 7 days, tural and biochemical characteristics, which include an
and about 20% of patients require respiratory support. internal core containing linear double-stranded DNA, an
MERS has had a similar presentation, although GI symp- icosadeltahedral capsid containing 162 capsomeres, and
toms may be more prominent.50 SARS fatality rates were an envelope derived from the host-cell nuclear membrane.
9.6% for all ages but higher in older adults,51 and children However, the large size of the CMV virion (200 nm) and
had milder disease.52 Similarly, the majority of recognized larger genome (>200,000 bp) distinguish it from other
cases of MERS to date have been in individuals with comor- human herpes viruses. There is approximately 80% homol-
bidities.53 SARS laboratory abnormalities include elevations ogy between the genomes of various strains of CMV, but
in lactate dehydrogenase, transaminases, and creatine sufficient differences exist to permit strain identification by
kinase, as well as hematologic abnormalities, particularly restriction endonuclease analysis. The CMV genome codes
lymphopenia (depletion of CD4 and CD8 T cells) and for approximately 33 structural proteins, the functions of
thrombocytopenia. many of which are currently unknown. In addition, clinical
isolates often encode multiple gene products not seen in
Diagnosis laboratory strains. Envelope glycoproteins B and H have
Common findings on chest CT include unilateral or bilateral been identified as major antigens eliciting neutralizing anti-
areas of ground-glass opacifications and interlobular septal body. Glycoprotein B may also be a target for cytotoxic T
and intralobular interstitial thickening. In most patients, lymphocyte responses,66 while multiple proteins also serve
peripheral involvement in the lower lung zones has been as targets for T-cell responses. CMV-specific, cytotoxic T-cell
observed. In some cases, after recovery from acute illness, responses are an important host defense mechanism that is
pulmonary fibrosis has developed.54 Clinical features pre- associated with survival from CMV infection in bone
dictive of poor outcomes included the presence of bilateral marrow transplant recipients.67 However, CMV uses multi-
disease at presentation, markedly elevated lactate dehydro- ple mechanisms, including down-regulation of HLA class I
genase, older age, and other comorbid conditions. on the cell surface and interference with antigen process-
The main site of viral replication of SARS-CoV appears ing, to evade recognition by the host.
to be the lower respiratory tract.49 PCR detection is most
reliable in the sputum, but viral RNA can also be detected Epidemiology and Transmission
in the blood and stool.55 Serum antibodies rise within 2 to Infection with CMV, whether symptomatic or not, is fol-
3 weeks of illness, although measurements at 4 weeks have lowed by prolonged excretion of virus in urine, saliva, stool,
become the standard to exclude SARS. tears, breast milk, vaginal secretions, and semen. Thus, the
major reservoir for CMV is asymptomatic infected persons.
Treatment and Prevention Virus shedding persists for years in children with congenital
Immunity against coronaviruses appears to be short-lived. and perinatal CMV infections. The virus is believed to be
Epidemiologic studies of coronavirus infection have demon- transmitted by direct contact, especially under conditions
strated high reinfection rates.56 In human volunteer experi- of intimacy such as found in child care centers68 and the
ments, infection with a 229E-like coronavirus only induced family setting. Thus, the rate of acquisition of infection is
greater in populations with high density, leading to infec- nucleosis. In immunocompromised hosts, there may be a
tion at an early age. In addition to transmission by sexual variety of clinical syndromes, the severity of which is
intercourse, passage through a contaminated birth canal, impacted by whether infection is acquired de novo or repre-
and ingestion of breast milk, CMV infection can be acquired sents reactivation of endogenous virus. The risk of severe
from transfused blood products and from transplanted disease is particularly high in transplant patients when a
organs. No seasonal patterns of CMV infection have been CMV-seronegative recipient receives an organ from a sero-
observed. positive donor.
The pathogenesis of CMV pneumonia is partly related to
Pathogenesis viral replication but also thought to have an immunopatho-
In human fibroblast cell cultures, CMV produces a slowly logic basis.70 The development of CMV pneumonitis reflects
progressive lytic infection. Infected cells contain large irreg- a complex interaction between viral infection and graft-
ular basophilic intranuclear inclusions and also eosino- versus-host disease, particularly in marrow transplant
philic inclusions in paranuclear areas. The intranuclear recipients71,72,72a (see Chapter 91). Two patterns of histopa-
inclusions are a hallmark of CMV infection and have been thology have been described in the lung tissue of bone
found in cells of a number of organs, including kidney, liver, marrow transplant patients with serious pneumonia.73 One
and the GI tract, as well as the lung (Fig. 32-7). In the lung, is a miliary pattern, with multiple focal lesions showing
fibroblasts, epithelial cells, endothelial cells, and smooth extensive cytomegaly with localized necrosis, alveolar hem-
muscle cells are all targets for CMV infection.69 orrhage, fibrin deposition, and neutrophilic response (see
In immunocompetent persons, most infections are sub- Fig. 32-7). The other is an interstitial pattern, with alveolar
clinical. If symptoms arise, the most typical manifestation cell hyperplasia, interstitial edema, lymphoid infiltration,
is that of acute pharyngitis with features similar to mono- and diffusely distributed cytomegalic cells.
Clinical Illness
Cytomegalovirus causes a variety of human diseases,
including congenital and perinatal infections, infectious
mononucleosis, hepatitis, posttransfusion infection, and
invasive infection in patients with impaired immunity. In
transplant populations, CMV infection often involves mul-
tiple organ systems in conjunction with other opportunistic
infectious agents.
Because the virus rarely causes pneumonia in healthy
hosts, the main impact of CMV as a respiratory pathogen is
in immunocompromised patients. In recipients of alloge-
neic bone marrow transplants, CMV is the most common
infectious cause of interstitial pneumonia and, if untreated,
is responsible for the highest fatality rate. The risk of CMV
pneumonia is greatest between 30 and 90 days after bone
marrow transplant. However, late-onset CMV syndromes,
A at more than 180 days posttransplantation, have been
increasingly recognized with effective control of earlier-
onset disease.
Risk factors for the disease include advanced age, the
presence of acute graft-versus-host disease, intensive con-
ditioning regimens, and allografts. CMV infection and
pneumonitis also develop in the majority of lung transplant
recipients who are seronegative and, if infection develops in
a single-lung recipient, disease is especially marked in the
transplanted lung.74 In these patients, CMV pneumonitis
may be a factor in the development of bronchiolitis obliter-
ans. CMV can also be a primary pathogen in persons with
AIDS, although it is more often encountered in conjunction
with other pulmonary pathogens74a (see Chapter 90). Char-
acteristically, patients with CMV pneumonia have sustained
B fever, nonproductive cough, and dyspnea. Rales and tachy-
pnea are often present, and marked hypoxemia is an indica-
Figure 32-7 Cytomegalovirus infection. A, CMV pneumonitis with mild
alveolar wall thickening and hyperplastic type II pneumocytes, some of tor of life-threatening infection. Pneumonitis may be
which are infected, showing cytomegaly, nucleomegaly, thickened accompanied by mild neutropenia, thrombocytopenia, and
basophilic nuclear membranes and nuclear inclusion and small basophilic elevated liver enzymes, which may be helpful in differential
cytoplasmic inclusions (hematoxylin and eosin x80 original magnification). diagnosis.
B, CMV pneumonitis with infected cells highlighted by immunohisto-
chemistry with a brown color (CMV immunohistochemistry, ×40 original
Recently, CMV reactivation has been demonstrated to
magnification). (Images courtesy William D. Travis, MD, Memorial Sloan Ket- play a role in critically ill, previously immunocompetent
tering Cancer Center, New York, NY.) patients. During the critical illness, some evidence suggests
a transient and vulnerable period of “immunoparalysis,” marrow/stem cell transplant recipients. The combination
making reactivation and not exogenous infection of CMV of ganciclovir therapy and intravenous CMV immune glob-
more likely. In these patients, CMV viremia was found in ulin81 can reduce mortality from approximately 90% to
33% and was associated with prolonged hospitalization and 50% or lower in these patients. The effect of the immune
death.75 It is currently unclear whether CMV prophylaxis globulin in this situation may mostly be to ameliorate
would be beneficial in this setting. graft-versus-host disease. Whether combination therapy is
required in solid organ transplant recipients with CMV
Diagnosis pneumonia is uncertain. Cidofovir and foscarnet are other
Cytomegalovirus pneumonia should be in the differential antiviral drugs with activity against CMV. Both have been
diagnosis for any immunosuppressed patient with unex- used successfully to treat CMV retinitis, but their effective-
plained lower respiratory complaints or pulmonary opaci- ness for treating CMV pneumonia has not been established.
ties. However, the clinical assessment of patients with All of the available CMV antivirals have the potential for
suspected CMV pneumonia is complicated because there serious side effects that require close monitoring.
are often simultaneous pulmonary infections with other Guidelines for reducing the risk of CMV disease in stem
microbes76,77 and because the clinical features and radio- cell transplant recipients have been published.82 Transplant
graphic appearance of CMV pneumonia are not sufficiently candidates should be screened for evidence of CMV immu-
characteristic to permit an accurate etiologic diagnosis. In nity, and CMV-seronegative recipients of allogeneic stem
addition, noninfectious pulmonary conditions are also cell transplants from CMV-seronegative donors should
common in the population at risk for CMV pneumonitis, receive only leukocyte-reduced or CMV-seronegative RBCs
including pulmonary malignancy or hemorrhage and post- and/or leukocyte-reduced platelets. In mismatched solid
transplant lymphoproliferative disorder (see eFigs. 91-16 organ transplant recipients (seronegative recipient/
and 91-17). seropositive donor), posttransplant prophylaxis with oral
Chest radiographic changes (see eFig. 91-5A) are usually ganciclovir or its prodrug valganciclovir significantly
bilateral, with diffuse or focal haziness involving the mid reduces the risk of CMV disease, although late-onset disease
and lower lung fields. Both miliary and interstitial radio- still happens.83 Another strategy is preemptive therapy with
graphic patterns have been described. Patients with a ganciclovir or another anti-CMV agent when screening
miliary pattern may have a sudden onset of tachypnea, detects infection, but before clinically detectable disease
severe respiratory distress, and hypoxemia resulting in a develops. This strategy requires the use of rapid, sensitive,
rapidly fatal course,78 whereas patients with an interstitial and specific laboratory tests for diagnosis.
pattern of disease often have an insidious onset of pneumo- No vaccines are available for the prevention of CMV
nia with slowly progressive hypoxemia. In these patients, infection or disease, although several strategies are being
pulmonary opacities may be initially localized, with bilat- actively pursued, including live attenuated and inactivated
eral spread over days or weeks. Often the perihilar distribu- subunit vaccines.
tion of the opacity is suggestive of pulmonary edema.74
Common chest CT scan findings include small nodules HANTAVIRUSES
(see eFigs. 91-3B, 91-4, 91-5), consolidation (see eFig.
91-2), and ground-glass attenuation (see eFigs. 91-3 Hantaviruses are members of the Bunyavirus family and
and 91-5).79 include a number of genetically diverse viruses. The hanta-
In patients with possible CMV pneumonia, the preferred virus responsible for an outbreak of severe pulmonary
approach to diagnosis is quantitative PCR in serum or bron- disease in the southwestern United States, Sin Nombre
choalveolar lavage (BAL) fluid.80 Culture and pathologic virus, is roughly spherical, with a mean diameter of
examination of specimens obtained by BAL and transbron- 112 nm. The virions contain a dense envelope, surrounded
chial biopsy may also be diagnostic, although these speci- by fine surface projections. Filamentous nucleocapsids are
mens are less suitable for making management decisions in present within the virions. The genome consists of negative-
acutely ill patients. The detection of virus in respiratory sense single-stranded RNA arranged in three physically dis-
secretions, urine, or blood does not establish with certainty crete gene segments. The smallest segment (S) encodes the
that CMV is responsible for a particular clinical syndrome. nucleoprotein, the middle-sized segment (M), the two enve-
This is particularly true in patients with AIDS, in whom lope glycoproteins, G1 and G2, and the largest (L), the puta-
detection of CMV in BAL is often not associated with pul- tive polymerase protein.84
monary pathology. However, in transplant recipients, the Viral entry into the cell is mediated by a variety of cell
presence of CMV in blood does increase the risk of subse- surface integrins,85 which may be related to the patterns of
quent development of CMV pneumonia and is used in pathogenicity of the virus. The genome is segmented, and
guiding preemptive therapy. Serologic testing has no role in genetic reassortments in dually infected cells are common.
diagnosis of acute infection and is used only to determine It is believed that new pathogenic strains arise by this
the serologic status of donors and recipients before mechanism.
transplantation.
Epidemiology and Transmission
Treatment and Prevention The hantavirus pulmonary syndrome (HPS) is a zoonosis in
Once CMV pneumonitis is established, particularly in allo- which humans experience severe, often fatal disease. Each
geneic bone marrow transplant patients, poor outcomes are of the individual hantavirus strains appears to be associ-
common. Ganciclovir is highly active against CMV in vitro, ated with a specific rodent host (e.g., Sin Nombre virus with
but monotherapy is not effective in pneumonitis in bone the deer mouse, Bayou virus with the rice rat, Black Creek
Canal virus (BCCV) with the cotton rat, and New York virus period of several days, the patient presents with a mild,
with the white-footed mouse). The rodent hosts experience nonproductive cough and progressive dyspnea resulting
prolonged asymptomatic infection, but the features that are from leakage of high-protein edema fluid into the alveoli.
associated with maintenance of these viruses in rodent On physical examination patients are febrile, with tachy-
populations and with rodent-to-rodent transmission are pnea and tachycardia with mild hypotension. Examination
unclear. Serologic studies suggest that hantaviral infection of the chest may reveal fine crackles but is otherwise
of feral rodents is widespread throughout North America.86 unremarkable.
Transmission to humans is presumed to result from Laboratory studies generally reveal hemoconcentration,
contact with infected rodent excreta. Hantaviruses are mild thrombocytopenia, and mildly elevated liver function
stable and can persist in the environment for 10 to 15 days tests. The triad of thrombocytopenia, left shift with circulat-
without loss of viability.87 Risk factors for acquisition of ing myeloblasts, and circulating immunoblasts is highly
HPS include high densities of rodents in the household, suggestive of HPS.101 Multivariate analysis has identified
cleaning of contaminated environments, agricultural dizziness, nausea, and the absence of cough as clinical
activities, and other forms of occupational exposure to symptoms predictive of HPS, as well as thrombocytopenia,
rodent droppings. In the Four Corners region of the south- elevated hematocrit, and decreased serum bicarbonate as
western United States, El Niño–southern oscillation events features that help distinguish HPS from other causes of
have been linked to increased rainfall, high rodent popula- acute respiratory distress such as pneumococcal pneumo-
tion densities, and increased numbers of cases of HPS.88 nia and influenza.102 Mild renal abnormalities may be
Person-to-person transmission was not seen in the North detected but, unlike the situation with another hantaviral
American outbreaks.89 In contrast, a recent outbreak of illness, hemorrhagic fever with renal syndrome, do not
HPS in South America has suggested that, under certain progress to renal failure. Renal dysfunction may be more
circumstances, person-to-person transmission can take common in HPS associated with the Bayou hantavirus.103
place.90 This feature appears to be unique to the particular Pleural effusions are present in most cases. Early in the
hantavirus implicated in that outbreak (Andes virus) course of HPS, these effusions are transudative, while later
and has not been a major component of other outbreaks. they develop higher fluid protein content and in severe
Currently, approximately 11 to 48 cases of HPS per year cases have the protein characteristics of plasma.104 Cardio-
are reported in the United States,91 with a case fatality rate pulmonary manifestations in severe cases include a shock
of 35%. state with low cardiac index, low stroke volume index, and
high systemic vascular resistance.104 Progression is associ-
Pathogenesis ated with worsening cardiac dysfunction and development
Infection with Sin Nombre virus or other agents of HPS of lactic acidosis. In those patients who survive, exertional
have relatively long incubation periods (median 14 to 17 dyspnea and reduced expiratory flow are common in early
days; range 1 to 51 days),92 and antibody and cellular convalescence and resolve in most patients.105 However,
responses in humans are usually detectable at the time of some patients have manifested long-term pulmonary and
presentation.93 Neutralizing antibody is directed against the cognitive dysfunction.106
surface glycoproteins G1 and G2, and lower titers on pre-
sentation correlate with greater disease severity.94 Viremia Diagnosis
is detectable at presentation and declines promptly after Chest radiographs are typical of pulmonary edema, without
resolution of fever. consolidation. In the absence of immunodeficiency, patients
Pathologic findings in fatal cases include pleural effu- universally have detectable serum immunoglobulin M (IgM)
sions, alveolar edema and fibrin, and interstitial mononu- and IgG antibody at the time of admission, and serologic
clear cell infiltrate95 with little necrosis or neutrophil techniques are the mainstay of diagnosis. In low-prevalence
infiltration. These findings are felt to be most consistent areas, a positive IgM is diagnostic.107 Virus can also be
with a capillary leak syndrome with subsequent noncardio- detected in blood by reverse transcriptase polymerase chain
genic pulmonary edema. Immunopathologic responses reaction (RT-PCR) during the first 10 days of illness.108 In
play a major role in HPS.96 Infection of humans with Sin contrast, hantaviruses are difficult to isolate from clinical
Nombre virus and other hantaviruses results in widespread material in cell culture and grow slowly. Isolation of virus
expression of viral antigens in endothelial cells of pulmo- from tissue is laborious and time consuming and must be
nary and cardiac tissues,97 and CD8 T cell responses peak undertaken in suitable containment facilities, so it is not
at the time of maximal clinical symptoms, implicating these useful for diagnosis.
responses in the pathogenesis of disease.98 Myocardial
depression has also been ascribed to induction of nitric Treatment and Prevention
oxide and locally secreted cytokines in response to infec- Treatment is supportive and requires careful management
tion.99 Another pathogenic mechanism may be antagonism of fluid status to maintain perfusion without exacerbating
of the host innate immune response by the hantavirus pulmonary edema. It has been suggested that high-dose
G1 tail.100 steroid therapy may be useful96 because of the pathogenesis
of the disease and potential utility of steroids in systemic
Clinical Features capillary leak syndrome. In severe cases, extracorporeal
Presentation of HPS begins with a prodrome of fever, chills, membrane oxygenation may be beneficial.109,110 The
and myalgias, occasionally accompanied by abdominal dis- broad-spectrum antiviral agent ribavirin is active against
comfort and GI symptoms, and generalized malaise. Upper hantavirus in vitro and was demonstrated to be effective
respiratory symptoms are usually absent. After a variable against hantavirus-induced hemorrhagic fever with renal
syndrome in Korea.111 However, trials of ribavirin in HPS Latent infection is established in sensory nerve ganglia
have not shown efficacy.112 and is followed by life-long recurrences of virus shedding
and often lesions on skin and mucous membranes of the
involved dermatomes. Cellular immunity is of primary
HERPES SIMPLEX VIRUS
importance in controlling HSV infection; studies in patients
Both herpes simplex virus (HSV) types 1 and 2 belong to the with AIDS and severe mucocutaneous HSV indicate that
alphaherpesvirus subfamily of herpesviruses and share the both CD4 and CD8 T cells contribute to control of viral
same basic structural features. HSV-1 is most commonly replication and spread.115
associated with respiratory infection, whereas HSV-2 is
more commonly associated with genital infection. The two Clinical Illness
HSV types were originally differentiated by neutralization Acute Gingivostomatitis and Pharyngitis. Herpetic
assay and have been found to differ in a number of biologic disease of the oral cavity and pharynx is the most common
and biochemical properties as well. Infection with either overt manifestation of primary infection with HSV-1. Scat-
type results in production of both type-specific and cross- tered or clustered vesicles and ulcers of various sizes (3 to
reactive antibodies, with higher concentrations of antibod- 7 mm) are located on the buccal mucosa, tongue, gingiva,
ies being produced against the homologous type. or floor of the mouth. Individual lesions usually appear as
a shallow, white-based ulcer surrounded by a thin rim of
Epidemiology and Transmission erythema. Pain is prominent in involved areas of the mouth
Humans are the reservoir for HSV-1 and HSV-2 viruses. and pharynx, and regional nodes are tender and enlarged,
With primary infection, infectious virus is produced in the particularly with the pharyngitis. Fever, malaise, and
skin and mucous membranes, being present in vesicle fluid reduced oral intake may add to the overall severity of these
and cellular debris from herpetic ulcers. After establishment illnesses, which last up to 2 weeks.
of latency in nerve ganglia, virus is intermittently shed in
respiratory, vaginal, and urethral secretions in the absence Chronic Ulcerative Pharyngitis and Laryngotrache-
of clinical disease. Asymptomatic respiratory tract shed- itis. In immunocompromised patients, including those
ding can be detected in about 1% to 2% of seropositive with AIDS, both primary and recurrent HSV infection may
children and adults. manifest as a chronic erosive process of the mucous mem-
HSV-1 spreads by means of transfer of virus-containing branes of the oral cavity and upper airway. Characteristi-
respiratory secretions, vesicle fluid, and cell debris under cally, the lesions appear as large (5 to 15 mm) individual
conditions of close personal contact. The portals of entry ulcerations that are slowly progressive and may coalesce
for primary infection are the mucous membranes of the when present in adjacent sites. The base of the ulcer is white
oropharynx and possibly the eye. Virus deposited onto areas or gray. Although shallow, the lesions are usually painful
of burned or abraded skin, and exogenous inoculation or and may reduce oral intake. Herpetic lesions are sometimes
autoinoculation of virus, also lead to clinical lesions. Cases present on the lip and skin of the face. Infection may spread
of HSV-1 arise sporadically throughout the year, occasion- to the esophagus and lower airway, possibly facilitated by
ally in small clusters. HSV-1 infection is usually acquired in instrumentation such as orotracheal intubation or bron-
childhood or adolescence, with epidemiologic surveys choscopy, resulting in the development of similar lesions at
showing a prevalence of antibody to HSV-1 in 30% to 100% these sites. Clinical features of herpetic tracheobronchitis
in adults. include dyspnea, cough, fever, chills, diaphoresis, chest
pain, wheezes, hypotension, and hypoxemia.116 Herpetic
Pathogenesis tracheobronchitis has also been reported in elderly patients
Primary HSV infection has a mean incubation period of presenting with bronchospasm who did not have histories
approximately 1 week. Primary infection begins at a local of chronic lung disease or of immunosuppression.117
site, with viral replication in parabasal and intermediate
epithelial cells and resultant cell destruction and initiation Pneumonia. Herpes simplex virus causes pneumonia in
of host inflammatory responses. Cells containing charac- neonates with congenital and peripartum infections and in
teristic nuclear inclusions and sometimes multinucleation patients with malignancy, burns, organ transplantation,
may be observed in lesions. In immunocompetent individ- and other conditions associated with impaired immunity.
uals, regional lymph nodes may be involved during primary Herpes simplex pneumonia has been reported in neonates
infection, but the disease is usually contained at the between the third and 14th days of life and to be associated
primary site by innate antiviral responses. In neonates and with prominent hila and central interstitial opacity on
others with deficient or impaired immune systems, local chest radiography.118 Other associated findings include
infection may be followed by viremic spread to multiple thrombocytopenia, disseminated intravascular coagula-
organs, including skin, liver, brain, adrenals, and lungs. tion, abnormalities in liver function, vesicular skin lesions,
Disease may also disseminate in such individuals following and deterioration during antimicrobial treatment. The
reactivation of latent infection. Visceral infection is char- pathologic findings in infants, children, and adults suggest
acterized by a highly destructive coagulation necrosis of that the disease may be the result of direct extension of
involved sites.113 In a series of fatal cases of HSV pneumo- infection from the tracheobronchial tree to the lung or
nia, inflammatory infiltrates, parenchymal necrosis, and as the result of hematogenous dissemination of virus
hemorrhage were found at autopsy.114 Patients with associ- from mucocutaneous lesions of the upper airway or genito-
ated herpetic laryngotracheitis have necrotizing lesions in urinary tract. CT scan findings include multifocal segmen-
these areas. tal and subsegmental ground-glass opacities but are not
distinctive.119 In one study, more than one half of the HSV pneumonia depends on obtaining a sample of involved
patients had concomitant pulmonary infection with other lung for viral culture and testing for HSV antigen or nucleic
microorganisms, including bacterial, candidal, and Asper- acid. Limited experience with lung biopsy in patients with
gillus species and cytomegalovirus.114 Histologic evidence of HSV pneumonia suggests that obtaining adequate samples
herpetic esophagitis was present in 10 of 16 patients with for culture and histologic examination may be a problem114
herpes pneumonia in whom esophageal examination was and that, when possible, generous biopsy specimens should
performed. Some cases are nosocomially acquired.120 be obtained.
Herpes simplex virus infection of the lower airway has
also been found in association with ARDS. The relationship Treatment and Prevention
of HSV infection to ARDS is unclear, but the presence of No vaccines of proven value are currently available. Primary
HSV in the lower respiratory tract was associated with the HSV gingivostomatitis in immunocompetent persons
need for prolonged respiratory support and an increased responds to oral acyclovir treatment. Specific therapy of
late mortality. Isolation of HSV from lower respiratory herpes simplex pneumonia has not been evaluated in con-
tract secretions has also been common in mechanically trolled trials, but most clinicians would use intravenous
ventilated patients and may be associated with a poor acyclovir. In immunosuppressed patients with chronic
outcome,121,122 although it is unclear whether this repre- mucocutaneous HSV infection, including pharyngitis and
sents reactivation as a consequence of severe illness or laryngotracheitis, prompt treatment with acyclovir is rec-
whether the virus plays a direct role in mortality.123,124 ommended to control the local infection and prevent pos-
sible dissemination to the lung. Valacyclovir, the valine ester
Diagnosis prodrug of acyclovir, and famciclovir, the prodrug of pen-
The clinical features of herpetic gingivostomatitis are suf- ciclovir, are orally administered drugs that are also effective
ficiently characteristic to permit accurate diagnosis in most for mucocutaneous HSV.
cases. Other conditions with similar oral lesions are limited Antiviral susceptibility testing should be considered
and include herpangina, aphthous stomatitis, Steven- in patients with serious HSV infection who do not respond
Johnson syndrome, and other enanthems resulting from to initial treatment with oral valacyclovir or intravenous
infection and drug sensitivities. In herpangina, the lesions acyclovir. Foscarnet is probably the best available alterna-
are smaller (1 to 3 mm), more often vesicular, and usually tive therapy. Prophylactic intravenous and oral acyclovir
localized to the soft palate. The ulcers in aphthous stomati- regimens have been shown to be effective in preventing
tis are few, relatively deep, and circumscribed. Aphthosis is recurrences of mucocutaneous HSV infection in seroposi-
characterized by periodic recurrence, whereas acute her- tive patients undergoing intense periods of immuno-
petic gingivostomatitis and pharyngitis are limited to a suppression, such as bone marrow transplant recipients
single occurrence. Herpetic pharyngitis, when exudative, or patients receiving combination chemotherapy for
must be distinguished from pharyngitis due to Streptococcus leukemia.
pyogenes, adenovirus, Epstein-Barr virus, and diphtheria.
The diagnosis of acute herpetic disease of the oropharynx INFLUENZA VIRUS
can be confirmed by examination of Giemsa- or Wright-
stained smears of scrapings from the base of a fresh lesion Influenza viruses belong to the family Orthomyxoviridae
(Tzanck test) and by culture of scrapings or swab speci- and are classified into three distinct types: influenza A,
mens. Techniques for the rapid detection of viral antigens influenza B, and influenza C virus. All three viruses share
or DNA are widely available. the presence of a host cell–derived envelope, envelope gly-
Chronic ulcerative pharyngitis due to HSV has a charac- coproteins important for entry and egress from cells, and a
teristic clinical appearance that is highly suggestive of the segmented negative-sense, single-stranded RNA genome.
diagnosis. The white color of the lesions may lead to confu- The standard nomenclature for influenza viruses includes
sion with candidiasis, but the lesion of thrush is an easily the influenza type, place of initial isolation, strain designa-
removable plaque, not an ulcer. Thrush and chronic her- tion, and year of isolation. For example, an influenza A
petic pharyngitis may coexist in the same patient. The virus isolated from a patient in Puerto Rico in 1934 is given
lesions of aphthous stomatitis are not characteristically the strain designation A/Puerto Rico/8/34.
found in the back of the oropharynx and are relatively small The envelope glycoproteins are the hemagglutinin (HA)
(2 to 5 mm) with a fixed diameter. and neuraminidase (NA). HA mediates binding of the virus
The diagnosis of herpetic laryngotracheitis may be diffi- to sialic (also known as neuraminic) acid residues on host
cult because of the inaccessibility of the lesions. The disease cell glycoproteins and glycolipids and is essential for viral
should be suspected in any immunocompromised patient entry. NA cleaves terminal sialic acid (neuraminic acid) resi-
with herpetic lesions of the mouth, upper airway, or skin of dues from host cell molecules, thereby releasing new viral
the face, especially if endotracheal intubation has been per- particles from the cell in which they replicated. At least 16
formed. In such patients, bronchoscopic examination is highly divergent, antigenically distinct HAs (H1 to H16),
indicated for sampling of suspected areas for cytology and and at least 9 distinct NAs (N1 to N9), have been described
viral culture. in influenza A viruses. Influenza A viruses are therefore
The diagnosis of HSV pneumonia should be suspected in further divided into subtypes on the basis of the hemagglu-
any immunocompromised patient with unexplained pul- tinin (H) and neuraminidase (N) (e.g., H1N1 or H3N2). Infec-
monary opacities, especially in the presence of herpetic tion with influenza virus results in long-lived resistance to
laryngotracheitis or herpetic lesions of other mucocutane- reinfection with the homologous virus. Infection induces
ous sites, including the genital area. Definitive diagnosis of both systemic and local antibodies, as well as cellular
responses, each of which plays a role in recovery from infec- that time. Perhaps for this reason, older adults were rela-
tion and resistance to reinfection. tively spared, and the pandemic disease affected mainly
children, adolescents, and adults younger than 50.
Epidemiology and Transmission Although the circulation of multiple antigenic subtypes
Influenza virus infection is acquired by transfer of virus- is confined to influenza A viruses, influenza B viruses
containing respiratory secretions. Both small particle aero- undergo significant antigenic variation as well. Currently,
sols and droplets probably play a role in this transmission, two antigenically distinct lineages of influenza B have
but for infection control purposes influenza is generally con- co-circulated, designated the “Yamagata” and the “Victo-
sidered to be transmitted by droplets. In temperate climates ria” lineages. Because antibodies to viruses in one lineage
in either hemisphere, epidemics are seen almost exclusively do not provide substantial protection against the other,
in the winter months (generally October to April in the recent influenza vaccines have included examples of both
Northern hemisphere and May to September in the South- (see later).
ern hemisphere), whereas in the tropics, influenza may be
seen throughout the year. Pathogenesis
Influenza epidemics are regularly associated with mor- Infection with influenza virus in humans is generally limited
bidity and mortality, usually expressed in the form of excess to the respiratory tract. After inoculation, the incubation
rates of pneumonia and influenza-associated hospitaliza- period is thought to be from 18 to 72 hours depending in
tions and deaths, with as many as 51,000 deaths annually part on the inoculum dose. Virus shedding is maximal at
in the United States.125 Attack rates are generally highest in the onset of illness and may continue for 5 to 7 days or
the young, whereas mortality is generally highest in the longer in children. In immunocompromised patients, espe-
elderly. Excess morbidity and mortality are particularly cially recipients of solid organ or hematopoietic stem cell
high in those with medical conditions including pulmonary transplants, viral shedding can be prolonged for weeks to
conditions such as asthma or COPD. Rates of influenza- months.132
related hospitalizations are particularly high in healthy Bronchoscopy of individuals with influenza typically
children younger than 2, where rates approach those of reveals diffuse inflammation of the larynx, trachea, and
older children with high-risk conditions.126,127 bronchi, as well as a range of histologic findings, from vacu-
A high frequency of antigenic variation is a unique olization of columnar cells with cell loss, to extensive des-
feature of influenza virus that helps explain why this virus quamation of the ciliated columnar epithelium down to the
continues to cause epidemic disease. Antigenic variation basal layer of cells.133,134 Generally, the tissue response
principally involves the two external glycoproteins of the becomes more prominent as one moves distally in the
virus, the HA and NA, and is referred to as antigenic drift airway. Recovery is associated with rapid regeneration of
or antigenic shift, depending on whether the variation is the epithelial cell layer and pseudometaplasia. Fatal influ-
small or great. Antigenic drift refers to relatively minor anti- enza pneumonia exhibits diffuse alveolar damage with
genic changes that result from amino acid changes in one hyaline membranes lining the alveoli, and the alveolar air
or more of the five identified major antigenic sites on the spaces contain edema fluid, strands of fibrin, desquamated
HA molecule.128 Antigenic shift refers to the complete epithelial cells, and inflammatory cells (Fig. 32-8A-D).
replacement of the HA or NA with a novel HA or NA. These Abnormalities of pulmonary function are frequently
viruses are “new” viruses to which the population has no demonstrated in otherwise healthy, nonasthmatic young
specific immunity. When such a new virus is introduced adults with uncomplicated (non-pneumonic) acute influ-
into a population, a severe, worldwide epidemic, or pan- enza. Demonstrated defects include diminished forced expi-
demic, of influenza can result. Influenza pandemics in ratory flow rates, increased total pulmonary resistance, and
the 20th century include the H1N1 pandemic of 1918, decreased density-dependent forced expiratory flow rates
the H2N2 pandemic of 1957, and the H3N2 pandemic of consistent with generalized increased resistance in airways
1968. Extensive surveillance and sequence information less than 2 mm in diameter,135,136 as well as increased
suggests that these new HA and NA genes are introduced responses to bronchoprovocation.135 In addition, abnor-
into viruses circulating in humans from resident popula- malities have been seen in the carbon monoxide diffusing
tions of influenza A viruses in birds.129 capacity137 and the alveolar-arterial oxygen difference.138
Since 1997, sporadic outbreaks of influenza in humans Pulmonary function defects can persist for weeks after clini-
caused by direct transmission of avian viruses from bird to cal recovery. Influenza in asthmatics or patients with
human have been reported. Although sustained human-to- chronic obstructive disease with influenza may result in
human transmission has not been seen, avian subtypes acute declines in forced vital capacity or FEV1. Individuals
such as H5N1130 and H7N9131 continue to pose a potential with acute influenza may be more susceptible to broncho-
pandemic threat. In the spring of 2009, a novel H1N1 virus constriction from air pollutants such as nitrates.139
containing genes from viruses of swine, avian, and human
origin emerged. Importantly, the HA gene of this virus was Clinical Illness
derived from swine influenza virus. Although still an H1N1 Typical uncomplicated influenza often begins with an
virus, the novel, or pandemic H1N1 (pH1N1) was antigeni- abrupt onset of symptoms after an incubation period of 1
cally distinct from the human H1N1 viruses in circulation to 2 days. Systemic symptoms include feverishness, chilli-
since 1977. Instead, the HA was closely related to human ness, or frank shaking chills, headaches, myalgia, malaise,
H1 viruses from the early 20th century that had been intro- and anorexia. Typical respiratory symptoms include dry
duced into pigs in approximately 1918 and had not under- cough, severe pharyngeal pain, and nasal obstruction and
gone significant antigenic evolution in these animals since discharge. Elderly individuals may simply present with
A B C
D2
D3
D1 D4
Figure 32-8 Pulmonary involvement in 2009 H1N1 influenza A. A, Acute necrotizing tracheitis and inflammation of the submucosal tracheal mucous
glands (H&E, ×400 original magnification). Inset: Immunohistochemical stain for influenza. Viral antigen is stained red-brown on a hematoxylin-stained
background, with prominent staining of the respiratory epithelium and underlying mucous glands. B, Postmortem lung section showing diffuse alveolar
damage with hyaline membranes (arrow) lining an alveolar duct and adjacent alveoli. The alveolar air spaces contain edema fluid, strands of fibrin, desq-
uamated epithelial cells, and inflammatory cells (H&E, ×100 original magnification). C, Massive infiltration of neutrophils in the airspaces of alveoli associ-
ated with secondary bacterial bronchopneumonia (H&E, ×100 original magnification). Inset: Brown and Hopps modified tissue Gram stain showing chains
of bacteria morphologically compatible with streptococci or pneumococci (arrow) (×1000 original magnification). D1, Immunohistochemical staining for
influenza in bronchus. Viral antigen is stained red-brown on a hematoxylin and eosin–stained background. Arrow shows influenza antigen–positive cells
in the bronchial epithelium. D2,The section shows an acute necrotizing bronchitis with transmural infiltration of inflammatory cells (×100 original mag-
nification). D3 and 4, Immunohistochemical staining for influenza in a bronchiole. Influenza antigen–positive cells are seen in the bronchiolar epithelium,
including ciliated cells, and in the nuclei of some basilar cells (×400 original magnification). Immunohistochemical staining for influenza in alveolar cells,
both type I (D3) and type II (D4) (×1000 original magnification). (Adapted from Gill JR, Sheng ZM, Ely SF, et al: Pulmonary pathologic findings of fatal 2009
pandemic influenza A/H1N1 viral infections. Arch Pathol Lab Med 134(2):235–243, 2010. Fig 1).
fever, lassitude, and confusion without any of the charac- bilateral abnormalities (Fig. 32-9, eFigs. 32-6 and 32-7),
teristic respiratory complaints. There may be a wide range sometimes suggestive of an acute lung injury pattern
of symptoms, but the presence of fever plus either sore or ARDS (eFig. 32-8). H1N1 (“swine-origin”) influenza
throat or cough is predictive of positive culture results for infection has a relatively nonspecific appearance, ranging
influenza in adults. from normal or nearly normal chest radiography at presen-
The syndrome of primary influenza viral pneumonia was tation to multifocal bilateral opacities resembling multifocal
first well documented in the 1957-1958 outbreak. The pneumonia (eFig. 32-9) or a noninfectious acute lung
illness begins with a typical onset of influenza, followed by injury pattern. Chest CT often shows multifocal areas of
a rapid progression of fever, cough, dyspnea, and cyanosis. ground-glass opacity and consolidation, which may show a
Physical examination and thoracic imaging studies reveal peripheral distribution, resembling organizing pneumonia
Table 32-4 Target Groups for Influenza Immunization*

PERSONS AT INCREASED RISK FOR COMPLICATIONS
■ All children aged 6 through 59 months
■ All persons aged ≥50 years
■ Adults and children who have chronic pulmonary (including
asthma) or cardiovascular (except isolated hypertension), renal,

hepatic, neurologic, hematologic, or metabolic disorders (including
diabetes mellitus)
■ Persons who have immunosuppression (including
immunosuppression caused by medications or by HIV infection)

■ Women who are or will be pregnant during the influenza season
■ Children and adolescents (aged 6 months to 18 years) who are
receiving long-term aspirin therapy and who might be at risk for

experiencing Reye syndrome after influenza virus infection
■ Residents of nursing homes and other long-term care facilities
■ American Indians/Alaska Natives
■ Persons who are morbidly obese (BMI ≥40)
PERSONS WHO CAN TRANSMIT INFLUENZA TO THOSE

AT HIGH RISK
Figure 32-9 Seasonal influenza A. Frontal chest radiograph shows multi- ■ Health care personnel
focal, bilateral, perihilar, and lower lobe predominant bronchovascular ■ Household contacts (including children) and caregivers of children
thickening and somewhat nodular consolidation. (Courtesy Michael aged ≤59 months (i.e., aged <5 years) and adults aged ≥50 years,
Gotway, MD.) with particular emphasis on vaccinating contacts of children aged
<6 months
■ Household contacts (including children) and caregivers of persons
(eFig. 32-9B-E), although other patterns, including small with medical conditions that put them at higher risk for severe
nodules (eFigs. 32-10A and B), ground-glass opacity asso- complications from influenza
ciated with linear and reticular abnormalities without a
clear zonal distribution (eFig. 32-10C), and lobar consolida- *Routine annual influenza vaccination is recommended for all persons aged
≥6 months who do not have contraindications.
tion (eFig. 32-10D), may be observed. Gram stain of the Adapted from Summary Recommendations: Prevention and Control of
sputum fails to reveal significant bacteria, and bacterial Influenza with Vaccines: Recommendations of the Advisory Committee
culture yields sparse growth of normal flora, whereas viral on Immunization Practices—(ACIP)—United States, 2013-14. Influenza
cultures yield high titers of influenza A virus. Such patients Prevention and Control Recommendations http://www.cdc.gov/flu/
professionals/acip/2013-summary-recommendations.htm
do not respond to antibacterial drugs and the mortality
is high.
Secondary bacterial pneumonia is an important compli-
cation of influenza (Fig. 32-8C) (eFig. 32-11). The classic 17). The reported sensitivities of each test in comparison to
description is of an influenza illness followed by a period of cell culture or nucleic acid amplification varies between
improvement, usually lasting 4 to 14 days. Recrudescence 40% and 80% and depends on the nature of the samples
of fever is associated with symptoms and signs of bacterial tested and the viral strain. In general, sensitivities in adults
pneumonia such as cough, sputum production, and an and elderly patients tend to be lower than those reported in
area of consolidation detected on physical examination young children, who shed much larger quantities of virus
and chest radiography. The most common bacteria impli- and higher concentrations of antigen in their samples.148
cated are Streptococcus pneumoniae, with a significantly Similarly, sensitivity is likely to be higher early in the course
increased frequency of Staphylococcus aureus,140,141 includ- of illness, when viral shedding is maximal.
ing methicillin-resistant staphylococcus (MRSA). Patients Molecular diagnostic techniques have recently emerged
may present with mixed viral and bacterial pneumonia. as the diagnostic modality of choice in most laboratories.
Bacterial superinfections of influenza have been postulated Real-time RT-PCR methods have been developed and
as a major cause of death during the pandemic of 1918.142 licensed and are discussed in greater detail in Chapter 17.
Patients with a wide range of preexisting conditions are Many of these tests are designed to detect multiple respira-
well recognized to be at higher risk for the development of tory pathogens simultaneously and are leading to a growing
pneumonia and other complications of influenza leading to recognition of the role of respiratory viruses and coin
hospitalization or death (Table 32-4). In recent years, new fection in diverse respiratory infections.148a Most cases of
conditions leading to increased risk have been recognized, influenza, in otherwise healthy individuals with typical
including the presence of neuromuscular conditions that symptoms during the course of a recognized influenza epi-
compromise respiration143 and, in the 2009 pandemic, the demic, do not need specific viral confirmation. However,
presence of obesity.144,145 In addition, the 2009 pandemic diagnostic testing should be used if the results of the test
reemphasized the known increased risk of hospitalization will influence subsequent clinical management, such as the
or death in women in all stages of pregnancy or in the use of antiviral agents, the need for antibacterial drugs, and
immediate postpartum period.146,147 the use of infection control.149
Virus can also be isolated readily from nasal swab speci-
Diagnosis mens, nasal aspirates, combined nose and throat swabs,
Immunologic detection of influenza antigens in respiratory sputum, or endotracheal aspirate specimens. More than
samples can be used for rapid diagnosis, and a large number 90% of positive influenza cultures can be detected within 3
of such tests are commercially available147a (see Chapter days of inoculation.150
Although vaccine virus can be recovered from vacci-

Treatment and Prevention nated individuals, particularly children, for several days fol-
Vaccines. Two types of vaccine are available for preven- lowing vaccine, transmission is extremely unusual.159 Live
tion of influenza. Inactivated vaccines consist of partially vaccine can be administered safely to health care workers
purified HA and NA preparations derived from virions pro- except for those caring for immunosuppressed individuals
duced in eggs or in cell culture or, in one case, purified requiring barrier precautions.
recombinant HA produced in insect cells. Current vaccines Randomized controlled comparisons of the efficacy of
contain one example of H1N1, one example of H3N2, and inactivated and live attenuated vaccine in children have
either one or both lineages of influenza B. Inactivated vac- consistently shown that live vaccine provides superior effi-
cines are administered intramuscularly or intradermally cacy in this population, with an approximately 50% lower
and are primarily designed to induce systemic antibody, cumulative incidence of influenza in those receiving live
although they also induce cellular immune responses that vaccine.160 Similar comparisons in adults have suggested
may be associated with protection. Inactivated vaccines are slightly superior efficacy of inactivated vaccine,161 and large
well tolerated in all age groups, although hypersensitivity cohort studies are also consistent with the interpretation
to hens’ eggs is a relative contraindication to use of egg- that inactivated vaccine has slightly better efficacy than live
produced vaccines. Generally, if persons can eat eggs or vaccine in adults, particularly in those who have received
egg-containing products, vaccination is safe. If necessary, vaccines in previous years.162
individuals with anaphylaxis can be desensitized and safely Previous strategies for prevention of influenza in the
vaccinated,151 or vaccines free of egg products can be used. United States and other countries have focused on targeting
Increases in hemagglutination-inhibition antibody are vaccines to persons at higher risk for influenza-related com-
seen in about 90% of healthy adult recipients of vaccine. plications (see Table 32-4) and on individuals in close
Only a single dose of vaccine is required in individuals who contact with these high-risk individuals. Such recommen-
have been previously vaccinated or who have experienced dations were complex and in some ways difficult to imple-
prior infection with a related subtype, but a two-dose sched- ment, leading to lower than desired vaccine uptake. In
ule is required in unprimed individuals. This includes chil- addition, it was recognized that more universal vaccination
dren up to age 9 who have not previously been vaccinated strategies, particularly of children, might be able to impact
or who were vaccinated for the first time with only a single the spread of influenza in the community. Currently, the
dose in the previous season.152 Diminished responses and United States and many other countries have adopted a
diminished efficacy are seen in elderly and immunocompro- universal vaccination strategy with annual vaccination of
mised populations. all members of the population. This, of course, includes
The protective efficacy of inactivated influenza vaccine is health care providers, and most institutions have adopted a
estimated to be in the range of 70% to 90% in healthy policy of mandatory vaccination of individuals in contact
adults when there is a good antigenic match between with patients.
vaccine and epidemic viruses.153,154 Few prospective trials of Antibody responses to influenza A virus, whether induced
protective efficacy have been conducted in high-risk popula- by vaccination or natural infection, are predominantly
tions. In one placebo-controlled prospective trial, inacti- directed at the “globular head” domain of the HA protein,
vated vaccine was approximately 58% effective in preventing which is involved in binding host cells. This domain of HA
influenza among adults older than 60 and 29% in those mutates frequently, and amino acid substitutions in this
older than 70.155 However, this study used a serologic defini- domain allow the new viral variant to escape recognition
tion of influenza infection, possibly biasing results in favor by antibodies that developed in response to the original
of vaccine efficacy. virus. Thus, new antigenic variant viruses emerge regu-
Observational studies have suggested that in practice the larly, and this necessitates development and administration
effectiveness of inactivated vaccine in prevention of acute of new influenza vaccines each year. The costly and logisti-
respiratory illness due to influenza ranges between 40% cally complex requirement for a distinct influenza vaccine
and 60%, with even lower effectiveness in older adults and each year has stimulated efforts to develop a vaccine that
in seasons with antigenic mismatch. Attempts to improve targets conserved domains of the influenza virus hemag-
the effectiveness of inactivated vaccines have included the glutinin, rather than the variable globular head domain.
use of higher doses and adjuvants. Although these efforts have revealed evidence for broadly
The live attenuated vaccine, administered intranasally, neutralizing antibodies produced by certain subjects, a
induces a limited, asymptomatic infection of the upper clear strategy for production of a vaccine that induces
respiratory tract and induces a variety of immune responses broadly neutralizing antibodies has not yet emerged.163-165
designed to mimic the protective immunity induced by
natural infection.156,157 The vaccine is well tolerated and Antivirals. Two classes of antiviral agents are currently
highly effective in children but is associated with an available for the treatment and prevention of influenza: the
increased frequency of wheezing in children younger than M2 inhibitors (M2Is) amantadine and rimantadine (ada-
2 years of age. Live vaccine is protective in adults as well, mantanes) and the neuraminidase inhibitors (NAIs) oseltami-
resulting in decreased laboratory-confirmed influenza in vir and zanamivir. The M2 protein is located in the viral
challenge studies and reduced frequencies of influenza-like envelope, where it functions as a proton channel and is
illness in the field.158 Although the vaccine is well tolerated essential for viral escape into the host cell cytoplasm, where
in the elderly and in those with chronic lung disease, viral replication takes place. The M2-inhibiting adaman-
immune responses are less frequent in older recipients and tanes specifically block the ion channel function of the
the vaccine is not licensed for use in those older than 49. influenza A M2 protein and are not active against influenza
B viruses. Resistance to these drugs emerges readily in related complications, with reductions in the use of anti-
treated individuals, particularly children,166 and there may bacterials and in hospitalization.170 Only oseltamivir is
be prolonged shedding of resistant viruses in immunocom- currently licensed for use in children younger than 5 years
promised patients even after therapy is terminated.167 For of age. Administration of oseltamivir liquid at a dose of
reasons that remain unclear, the first decade of this century 3 mg/kg in children 0 to 8 months of age, and 3.5 mg/kg
has seen the emergence and spread of adamantane- in children 9 to 11 months of age, twice daily for 5 days
resistant influenza A (H3N2) viruses,168 and pH1N1 viruses reached target ranges. Earlier studies showed that they were
are also uniformly resistant. Therefore, the adamantane well tolerated and resulted in a 36-hour reduction in the
M2I drugs do not have utility against current influenza duration of symptoms in children with influenza A.170a,171
viruses but might be used if susceptible strains emerge in NAIs have also been used successfully for seasonal or
the future. contact prophylaxis.
NAIs are potent inhibitors of influenza virus in vitro and Initial placebo-controlled trials of NAI therapy conducted
in vivo because neuraminidase activity is essential for viral primarily in otherwise healthy adults did not capture sub-
release, a necessary step for viral spread to other cells. Influ- stantial numbers of influenza complications. However,
enza B viruses are somewhat less sensitive than influenza A pooled analyses of these studies of early therapy with zana-
viruses but are well within clinically achievable concentra- mivir172 and oseltamivir170,173 demonstrated a significant
tions. Avian viruses with all nine known neuraminidase reduction in the rate of influenza complications in treated
subtypes are also sensitive. Although zanamivir and oselta- individuals. Subsequent experience in the emerging epi-
mivir have an identical mechanism of action and similar demic of pH1N1 virus has also suggested a beneficial
profile of antiviral activity, they have differing pharmaco- effect of early therapy on complications. These include
logic properties. Zanamivir is not orally bioavailable and observations in hospitalized patients174,175 and surveillance
is administered as a dry powder for oral inhalation, using data suggesting that therapy as late as 5 days improved
the so-called “diskhaler” device. Oseltamivir phosphate is survival of hospitalized patients.176 Surveillance data have
an orally bioavailable ethyl ester prodrug that is rapidly also suggested that treated children had lower rates of
absorbed from the GI tract and converted in the liver by complications.177
hepatic esterases to the active metabolite, oseltamivir car- Mutations within the catalytic framework of the NA that
boxylate. The metabolite is excreted unchanged in the urine abolish binding of the drugs have been described.178,179
by tubular secretion, with a serum half-life of 6 to 10 hours. Depending on the location of the mutation, these viruses
The major adverse effects reported for oseltamivir have may be specifically resistant to only one of the inhibitors.180
been GI upset in about 10% to 15% of recipients, probably Resistance mutations in the NA may also be associated with
due to irritation caused by rapid release of the drug in the altered characteristics of the enzyme with significantly
stomach. Rates of nausea can be substantially reduced if reduced activity.181,182 Drug-resistant viruses are most com-
the drug is taken with food. Adverse effects reported for monly isolated from treated children.183 Viral fitness appears
zanamivir have been at essentially the same rate as in to be less compromised by oseltamivir resistance mutations
placebo recipients. However, postmarketing surveillance in the N1 neuraminidase,184 and resistance was common
has found that inhaled zanamivir may be uncommonly among seasonal H1N1 viruses before the pH1N1 pandemic.
associated with bronchospasm in influenza patients, par- Currently, the majority of seasonal influenza viruses are
ticularly those with underlying airways disease; this acute susceptible to both drugs, but N1 resistance is being spo-
bronchospasm has sometimes been severe or fatal. radically reported and it is important to continue to monitor
The dose of oseltamivir should be reduced to 75 mg once susceptibility patterns.
daily in individuals with renal impairment (i.e., with creati- Although the benefits of antiviral therapy were initially
nine clearance 15–30 mL/min and 75 mg every other day demonstrated as a shortening of illness duration in healthy
in prophylactic treatment). No data are available regarding adults with uncomplicated influenza, this is generally not
the use of the drug in individuals with more significant considered the priority target group for antiviral therapy.
levels of renal impairment. Likewise, no information is Current recommendations include the use of antivirals in
available regarding the use of oseltamivir in individuals individuals at risk for more severe influenza, or in individ
with hepatic impairment. Clinically significant drug inter- uals with severe disease or requiring hospitalization.149
actions have not been reported. Because the drug is elimi- Treatment should be started as early as possible, but even
nated by tubular secretion, probenecid increases serum delayed therapy can be of benefit in hospitalized patients.
levels of the active metabolite approximately twofold. Treatment of patients requiring mechanical ventilation
However, dosage adjustments are not necessary in individu- can be challenging. Administration of oseltamivir by naso-
als taking probenecid. Coadministration of cimetidine, gastric tube is effective, and intravenous preparations of
amoxicillin, or acetaminophen has no effect on serum levels zanamivir and the experimental NAI peramivir are avail-
of oseltamivir or oseltamivir carboxylate.169 Because zana- able under compassionate use protocols.
mivir has no significant systemic absorption, there are no
recommended dosage reductions. MEASLES VIRUS
Both NAIs are effective in the treatment of influenza due
to either influenza A or B virus if administered within the Measles virus is classified in the Morbillivirus genus of the
first 48 hours of symptom onset, with reduced duration of Paramyxoviridae family and is structurally similar to para-
illness and earlier return to work or normal activities. Meta- influenza virus and RSV. Its surface glycoproteins include a
analysis of results of these trials has also suggested that hemagglutinin responsible for attachment to cells, a fusion
early treatment may reduce the frequency of influenza- (F) protein responsible for cell membrane fusion and virus
penetration of cells, but no neuraminidase. The cell surface The onset of the rash correlates temporally with the
molecule SLAM (Signaling Lymphocyte Activation Molecule) development of host immune responses and subsequent
serves as a receptor for entry of the virus into susceptible termination of virus shedding. Skin rash develops in
cells.185 In addition, the complement regulatory protein agammaglobulinemic patients with measles, whereas
CD46 can also serve as a receptor, particularly for the progressive giant cell (measles virus) pneumonia without
vaccine strain.186 Only one serotype of wild measles virus is rash may develop in those with deficient cell-mediated
recognized, although minor antigenic differences are immune function. The pathologic changes in involved
detectable by monoclonal antibodies. The human is the sole organs include lymphoid hyperplasia, mononuclear cell
natural host for measles virus. infiltration, and the presence of multinucleated giant cells.
Lower respiratory tract involvement may be associated with
Epidemiology and Transmission the destruction of ciliated respiratory epithelium, intersti-
Measles is found worldwide, but epidemic patterns vary tial pneumonia, epithelial cell hyperplasia, and syncytial
depending on population density and levels of acquired cell formation.
immunity. Before vaccine use, measles arose in epidemics of
3 to 4 months in duration every 2 to 5 years in temperate Clinical Illness
regions.187 Except in isolated areas, most people experienced Typical Measles. The typical prodrome of measles lasts 2
infection by 20 years of age, and 90% of reported cases to 8 days and is characterized by fever, malaise, anorexia,
were seen in those younger than 10. Infection confers life- cough, coryza, and conjunctivitis. Koplik spots, which are
long protection against measles, although asymptomatic erythematous macular lesions with central white-yellow
reinfections may develop. or gray puncta, appear on the buccal or labial mucous
Measles virus infection is highly contagious and can membranes toward the end of the prodromal period. The
spread despite high levels of acquired immunity in the pop- maculopapular, erythematous eruption begins about the
ulation. Airborne transmission via small-particle aerosols face and neck and progresses to involve the upper body,
and possible spread by fomites appear to account for its high trunk, and extremities. The rash typically resolves after
communicability. The virus remains infectious in small- 5 to 6 days in the order in which it appeared. The fever
particle aerosols for several hours at low relative humidity abates and symptoms improve several days after the
and has caused secondary infections in the absence of face- appearance of the rash, although persistent cough is
to-face contact with an index case.188 The incubation period common. Leukopenia is common during the prodromal
is usually 9 to 14 days but may be longer in adults. Patients and early exanthematous stages of measles. Pronounced
are most infectious during the late prodrome, when respira- leukopenia (<2000 cells/µL) is associated with a poor prog-
tory involvement contributes to creation of infectious aero- nosis. The development of neutrophilic leukocytosis sug-
sols. The virus may be shed for several days after the onset gests the possibility of bacterial superinfection or other
of rash in normal hosts. complications.
Measles-associated mortality in developed countries is Lower respiratory tract complications develop in 4% to
usually 0.1% or less but approaches 2% of cases in the 50% of patients. These include bronchitis, pneumonia, and,
developing world. Case fatality rates have been as high as less often, croup or bronchiolitis. In young adults, a multi-
25% in some areas. Most deaths result from respiratory lobar reticulonodular opacity is the most common radio-
tract involvement, neurologic complications, or both, and graphic abnormality (see eFig. 32-4).191 In the absence of
are related to various combinations of malnutrition, young bacterial superinfection or atypical measles, pleural effu-
age, and complications of the immunosuppression induced sion or lobar consolidation is uncommon. In patients with
by measles virus infection itself. altered cell-mediated immune function, and rarely in appar-
ently normal persons, infection by wild measles virus can
Pathogenesis cause a lethal giant cell pneumonia with or without rash.192
The respiratory tract and possibly the conjunctival epithe- Severe virus-induced pneumonia has been recognized
lium are the portals of entry and initial sites of replication during measles in pregnant women193 and in those infected
of measles virus, as well as subsequent target organs of with HIV.194 In hospitalized patients, mortality rates are
disease expression. An initial viremic phase leads to infec- approximately 70% in oncology patients and 40% in HIV-
tion of mononuclear phagocytes including dendritic cells, infected patients.192
and a second phase of viremia, corresponding to the pro- Secondary bacterial infection has been found in 30% to
dromal stage of illness, results in dissemination of virus to 50% of young adults with measles-related pneumonia.
the epithelial cells of the skin, respiratory tract, gut, bile Symptoms and signs indicative of bacterial infection usually
duct, and bladder and to lymphoid organs. begin 5 to 10 days after onset of the rash. One study employ-
Measles virus–induced giant cells may be present in the ing transtracheal aspiration found a range of bacterial
tonsils, appendix, other lymphoid organs, and various epi- pathogens in adults, most commonly Haemophilus influen-
thelial surfaces, including those of the respiratory tract. zae, Neisseria meningitidis, and S. pneumoniae.191 Up to 30%
The effects of infection on the lymphoid system include leu- of cases are complicated by otitis media or sinusitis. Acute
kopenia and immune suppression manifested by cutaneous nonrespiratory complications include hepatitis, encephali-
anergy and depressed natural killer cell activity189 for weeks tis, keratitis, mesenteric adenitis, as well as a high rate of
after rash onset. The mechanisms by which measles induces severe diarrheal disease in children in developed countries.
immunosuppression are incompletely understood, but Measles infection or vaccination may be accompanied by
infection of dendritic cells and suppression of IL-12 produc- conversion of the tuberculin skin reaction from positive
tion are thought to play an important role.190 to negative for weeks. Measles may exacerbate active
tuberculosis, but whether measles reactivates dormant mission.199,200 The vaccine is safe, and it has been conclu-
tuberculosis is unresolved.195 sively shown to have no association with autism.201,202
There have been recent outbreaks of measles in undervac-
Atypical Measles. An unusual clinical syndrome has cinated communities in the United States, often introduced
been recognized in adolescents and young adults who by an imported case in an immigrant or traveler.202a
received the inactivated measles vaccine between 1963
and 1968 and who were subsequently re-exposed to METAPNEUMOVIRUSES
the wild virus. The illness begins abruptly, with high
fever, headache, myalgia, vomiting, abdominal pain, and The human metapneumoviruses (hMPVs) are pleomorphic
nonproductive cough. Respiratory symptoms, including particles with short envelope projections, resembling other
dyspnea, coryza, sore throat, and pleuritic chest pain, are paramyxoviruses.203 These viruses are closely related to the
common. A polymorphous eruption, which may include pneumoviruses (of which RSV is the human example), dif-
vesicles, petechiae, purpura, and urticarial lesions, begins fering only by the absence of two nonstructural proteins
typically on the distal extremities and spreads proximally and a slightly different arrangement of gene order on the
over 3 to 5 days. Although Koplik spots are absent, con- negative-sense, single-stranded RNA genome. The basic
junctivitis and glossitis with strawberry tongue have been virology of these viruses closely resembles that of RSV.
described. Envelope glycoproteins include the SH (sulfhydryl), F (fusion),
Pulmonary abnormalities are found in most cases, and and G (attachment), although there is little sequence homol-
acute respiratory failure has been described. Chest radio- ogy in these genes between RSV and hMPV.204 By analogy,
graphic changes include patchy, diffuse, or dense lobar it is expected that antibody to the F and G proteins of hMPV
opacities, pleural effusions, and hilar lymphadenopathy.196 would play a role in protection against reinfection. At least
Residual nodular pulmonary opacities may persist for years two major genetic groups have been identified, roughly cor-
and lead to diagnostic confusion. The fever and other symp- responding to subgroups A and B of RSV.205 Sequential
toms usually resolve in 1 to 3 weeks. The pulmonary func- infections of the same individual tend to involve different
tion changes in atypical measles include transient genogroups. The role of cell-mediated immunity in this
hypoxemia and significantly reduced lung volumes. infection is largely unexplored.
Diagnosis Epidemiology and Transmission
The diagnosis of measles is most readily confirmed in hMPV infections are distributed worldwide and have been
immunocompetent patients by detecting measles virus– documented in both the outpatient206 and inpatient
specific IgM by ELISA. In immunodeficient patients, detec- setting.207 Recent estimates of disease burden based on PCR
tion of measles virus by nucleic acid amplification of urine diagnostics suggest that hMPV results in 1 to 1.2 hospital-
or of samples obtained by throat or nasopharyngeal swab izations, 13 emergency department visits, and 55 outpa-
is sensitive and specific; samples can be sent to the U.S. tient visits per 1000 children younger than 5.208,209 Children
Centers for Disease Control (http://www.cdc.gov/measles/ younger than 6 months are at the highest risk. As with
lab-tools/rt-pcr.html). Measles virus may also be isolated many other respiratory viruses, infection is linked to day
from the blood, urine, or respiratory secretions during the care attendance.210 Serologic studies suggest that essen-
prodrome and up to several days after the exanthem tially all children have been infected by age 5.203
appears. Isolation of virus from clinical specimens has been Similar to the case with RSV, disease has also been docu-
performed in several types of human and monkey cell cul- mented in adults and in the elderly,211 although asymptom-
tures but is slow and inefficient. Respiratory and conjuncti- atic infection is also common in adults. Outbreaks of severe
val secretions or urine sediment stained by various disease have been documented in residential care facilities
techniques reveals multinucleated giant cells in most cases. in older adults.212,213 Severe disease may also be seen in
Immunofluorescent staining of skin biopsy specimens, cells immunocompromised subjects such as hematopoietic stem
from combined nasopharyngeal and throat swab samples, cell transplant recipients (see eFig. 91-6).214,215 The mode
and, less often, exfoliated cells in the urine demonstrates of transmission has not been documented but is likely to be
measles virus antigens early in the disease. via droplet spread as with RSV. There is a clear seasonal
variation in incidence, with the majority of cases appearing
Treatment and Prevention during the winter months.206
The treatment of measles involves supportive care and spe- An interesting feature of the epidemiology of these
cific therapy for bacterial complications. No antiviral agents viruses is that children with hMPV are often coinfected with
have proven clinical value, but aerosol and intravenous other respiratory viral pathogens, especially RSV.216 Dual
ribavirin and immunoglobulin have been used in treating infections with both viruses may result in more intense
measles pneumonia.193,197 Vitamin A therapy reduces mor- bronchiolitis in some infants.217 hMPV was also detected in
bidity and mortality in severe measles in children.198 many cases of SARS but did not appear to exacerbate this
Patients suspected of having measles should be placed in illness.218
respiratory isolation.
The live attenuated measles vaccine currently used in Clinical Features
the United States provides durable immunity in more than Human metapneumoviruses appear to be responsible for a
90% of recipients. Recent outbreaks have seen cases in ado- spectrum of acute respiratory illnesses ranging from mild
lescent and adult recipients of two doses of measles vaccine, or asymptomatic infection to severe bronchiolitis and pneu-
but the illness has been mild and not associated with trans- monitis. The clinical picture most closely resembles that
of RSV, and bronchiolitis is the major manifestation in chil- infected cells after viral replication. The F glycoprotein has
dren.206,219 Clinical features in hospitalized children include membrane-fusing activity and is responsible for viral pen-
wheezing and hypoxia.220 A variety of other lower and etration into cells and for the formation of multinucleated
upper respiratory tract syndromes are also associated with syncytial cells. Antibodies against the HN and F are involved
hMPV infection, including croup and pneumonitis.206,207 in protective immunity.
There are no clinical features that can distinguish between
disease caused by hMPV and RSV, although RSV may be Epidemiology and Transmission
more severe. Parainfluenza viruses have a worldwide distribution, and
Symptomatic infection in adults and in the elderly has almost all persons are infected initially during childhood.
also been described.211 hMPV infections of young adults Parainfluenza type 3 virus may cause infection in infancy,
had features of the common cold, with nasal congestion, whereas infections by type 1 and 2 viruses appear to be
rhinorrhea, cough, and hoarseness predominating. Frail prevented by maternal antibody and usually arise later.
elderly and high-risk adults had lower rates of hMPV infec- National surveillance has demonstrated distinct seasonality
tion but more severe clinical symptoms, with significantly for type 1 viruses, with biennial outbreaks in the fall of odd-
higher frequencies of dyspnea and wheezing, and more numbered years. In contrast, yearly outbreaks of type 3
prolonged illness.211 Elderly patients with hMPV infection virus take place in the spring, with smaller autumn out-
were hospitalized with diagnoses of COPD, bronchitis, and breaks in those years without type 1 outbreaks. Type 2
pneumonia. hMPV appears to be a leading cause of respi- viruses are detected much less frequently but appear to be
ratory tract infection in lung transplantation patients.221 more prevalent in the autumn; type 4 does not exhibit
In one study, hMPV was the most commonly detected notable seasonality.227
RNA virus in BAL samples from immunocompromised Parainfluenza viruses appear to be transmitted from
patients.222 person to person by direct contact with infectious respira-
tory secretions or by large-particle aerosols. The incubation
Pathogenesis period is approximately 3 to 6 days. Virus is transmitted
Relatively little is known regarding the pathogenesis of this readily in families. Outbreaks of infection have been seen in
disease. In hospitalized children with hMPV, levels of nasal closed populations, such as nurseries, day care centers, and
secretion RANTES have been reported to be suppressed, hospitals, in which susceptible populations have high attack
while levels of nasal IL-8 were increased.223 The immune rates (40% to 80%).
responses elicited by hMPV are similar to those of RSV but Parainfluenza virus infections, most commonly type 1
often not as vigorous.224 virus, are associated with approximately 40% of croup
cases and up to 75% of those with a documented viral
Diagnosis cause, with smaller proportions of pneumonia or bronchi-
Viral culture is slow and has low sensitivity. Most infections olitis cases in children. The incidence of croup and lower
have been detected by nucleic acid amplification techniques, respiratory tract disease due to type 1 or 2 infections is
which are available in panels to detect and identify respira- highest between 6 months and 3 years of age, whereas
tory viruses224a-d (see Chapter 17). parainfluenza type 3 is an important cause of bronchiolitis
or pneumonia in infants younger than 6 months. Reinfec-
Prevention and Treatment tions with parainfluenza viruses are common and, in young
Treatment is supportive. No antiviral agents or vaccines are children, may arise within several months of each other.
currently licensed for treatment or prevention of hMPV Recent population-based disease burden estimates suggest
infections, and this is unlikely to change in the near future. that 1 in 1000 children younger than 5 experience parain-
Ribavirin is as active in vitro against hMPV as it is against fluenza virus–related hospitalization, and that about 6.8%
hRSV,225 but there are no data to support the therapeutic of hospitalizations for fever or respiratory illness in this age
efficacy of this drug. There are no specific monoclonal anti- group can be attributed to parainfluenza virus.228
bodies available for clinical use, although intravenous
immunoglobulin has been suggested as a possible therapeu- Pathogenesis
tic agent in immunocompromised hosts.226 Although viremia has been described, replication of the
virus is generally restricted to the respiratory tract mucosa.
The quantity of virus shed in respiratory secretions tends
PARAINFLUENZA VIRUSES
to parallel the severity of illness.229 Virus shedding com-
Parainfluenza viruses belong to the Paramyxovirus genus of monly continues for periods of 8 to 10 days in initial infec-
the Paramyxoviridae family, which includes mumps virus tions but may last for 3 weeks or longer. Prolonged shedding
and important veterinary pathogens. This group of (months) of parainfluenza virus type 1 or 3 has been
medium-sized (150 to 200 nm), pleomorphic, enveloped reported in apparently normal hosts,230 as well as in immu-
viruses has a nonsegmented, single-stranded RNA genome nodeficient children.231
contained in a helical nucleocapsid. The human parainflu- The pathologic findings in fatal cases are typical of other
enza viruses are separated into types 1 to 4, and type 4 is viral pneumonias and include peribronchiolar and alveolar
further divided into subtypes A and B, on the basis of anti- lymphocytic infiltration.232 Infection of the tracheal epithe-
genic differences. One envelope glycoprotein (HN) has both lium with localized edema and fibrinous exudate contrib-
hemagglutinin and neuraminidase activity and mediates utes to airway narrowing in croup. The mechanisms that
adsorption of virus to host cell receptors for entry into host account for the laryngotracheal localization of parainflu-
cells, as well as subsequent release of new virions from enza virus–induced disease are unresolved. Virus-host cell
interactions (specifically cleavage of the F protein) and not associated with improved survival in bone marrow
other host factors, including the nature of the immune transplant recipients.238 The combination of aerosolized
response, are postulated to play contributory roles in the ribavirin and intravenous immunoglobulin is frequently
pathogenesis of croup. The nasopharyngeal secretion con- used in immunocompromised patients,239 but there is no
centrations of parainfluenza virus–specific IgE and of his- direct evidence of efficacy. The sialidase DAS-181 is active
tamine and leukotriene C4, as well as cellular responses to in vitro and in small clinical studies240,240a but is not cur-
viral antigen, are higher in patients with wheezing than in rently available for clinical use.
those with upper respiratory tract illness alone.233 Initial attempts to develop vaccines for the prevention of
parainfluenza viruses involved use of formalin-inactivated
Clinical Illness virus. However, these vaccines failed to provide protection
Primary infections are usually symptomatic and are associ- in field trials carried out in the 1960s, despite being mod-
ated with the most severe forms of illness. Initial infections estly immunogenic. In contrast to RSV vaccines, the use
with parainfluenza virus types 1 to 3 cause febrile rhinitis, of formalin-inactivated parainfluenza vaccine was not
pharyngitis, laryngitis, and bronchitis in children. Depend- associated with enhanced disease on subsequent infection.
ing on the serotype causing infection, 50% to 80% of Several approaches have been explored subsequently,
primary infections are associated with fever, and up to one including use of live attenuated viruses and recombinant
third of children have evidence of lower respiratory tract subunit vaccines. Clinical trials of these are ongoing.
involvement. In parainfluenza virus type 1 and 2 infections,
lower respiratory disease is principally manifested as croup, RESPIRATORY SYNCYTIAL VIRUS
whereas type 3 infection has been associated with croup,
bronchiolitis, and pneumonia. RSV is classified in the Pneumovirus genus of the Paramyxo-
In adults and older children, reinfections are frequently viridae family. Similar in structure to parainfluenza viruses,
asymptomatic. Symptomatic infections are manifested as RSV is a pleomorphic (150 to 300 nm), enveloped virus
common colds, usually without fever, and less often phar- with a single-stranded, nonsegmented RNA genome. The
yngitis, tracheobronchitis, or influenza-like illness. Pneu- surface proteins include the F protein responsible for fusion
monia and exacerbations of chronic airway disease have of the viral envelope with the host cell membranes and
been described following parainfluenza virus infection in formation of syncytium, and the G protein, a heavily glyco-
adults and in the elderly.234 sylated protein responsible for attachment to cells. Antibod-
Although uncommon, parainfluenza viruses can cause ies against the F and G protein neutralize RSV in vitro, but
serious lower respiratory tract disease, including fatal antibodies against the G do not prevent syncytium forma-
pneumonia with or without giant cells, in children with tion. Two major antigenic groups (designated A and B)241
immunodeficiency or leukemia, and in pediatric and adult are distinguished primarily by differences in the G glycopro-
stem cell transplant recipients.235 Nosocomial outbreaks tein. The clinical and epidemiologic importance of strain
in immunosuppressed patients have been reported.236 variation are under study, but infections by group A strains
Because upper respiratory illness may be absent and naso- appear to be more severe.242 Further antigenic subgroups
pharyngeal cultures negative, BAL is often required for and genomic heterogeneity are recognized among circulat-
diagnosis. ing RSV strains.
Diagnosis Epidemiology and Transmission
Rapid diagnosis of parainfluenza infection can be made by RSV is worldwide in distribution and, in temperate climates,
detection of viral antigen or RNA in respiratory secretions causes annual outbreaks of infection in the late fall, winter,
obtained using throat or nasopharyngeal swabs. Detection or spring. Epidemics are associated with increases in pedi-
of parainfluenza RNA is performed in multiplex nucleic acid atric hospitalizations and deaths due to lower respiratory
amplification panels for respiratory viruses224a-d (see Chapter tract illness in infants and young children.243 Nearly 50%
17), which may be more readily available than rapid antigen of children are infected within the first year of life, and
detection assays. Respiratory secretions contain the virus at almost all have been infected by 3 years of age. Reinfections
the time of symptom onset. Viral culture is also sensitive, in children and adults are quite common even with the
and parainfluenza viruses can be isolated as early as 3 days same strain,244 suggesting immunity is only partial. Epide-
and usually within 10 days after inoculation of cell culture miologic factors related to serious illness in infected infants
with specimens from infants and children. Virus replication include low socioeconomic status, crowding, maternal
in cell culture is usually detected by hemadsorption of smoking, lack of breast feeding, day care center attendance,
guinea pig erythrocytes or immunofluorescence. and history of allergic disease. RSV is also recognized as a
cause of severe disease in older adults245 and may result in
Treatment and Prevention a greater total burden of mortality in the elderly than in
There are currently no available antiviral agents of proven infants.125
effectiveness against parainfluenza virus. Ribavirin is active RSV spreads by large-particle aerosols during close per-
against parainfluenza viruses in vitro and would theoreti- sonal contact and by hand contamination with infectious
cally be expected to be active in vivo as well. Anecdotal secretions and subsequent self-inoculation of the eye or
reports in immunodeficient children with severe parainflu- nose. RSV is a major nosocomial pathogen on pediatric
enza virus infections suggest that aerosolized ribavirin may wards, and there can be high attack rates during outbreaks
be associated with antiviral effects and clinical benefit,237 in hospitals, transplantation units, day care centers, and
although delayed treatment with aerosol ribavirin was geriatric homes. Attack rates in children have approached
100% during outbreaks in day care centers and are com- infants born prematurely are also at risk for severe disease,
monly 20% to 50% in hospital staff and patients during perhaps because they lack maternal antibody. Mortality is
epidemic periods. In the family setting, secondary infection usually 0.5% to 1.5% in previously healthy infants hospital-
develops in approximately one half of infants and up to one ized with RSV disease but is 15% to 40% in those with
third of adult contacts after introduction of virus by an primary immunodeficiency, cancer chemotherapy, or pul-
older sibling.246 monary and heart disease. Pulmonary hypertension is
associated with a particularly high frequency of poor out-
Pathogenesis comes. Severe disease has also been associated in children
Viral replication generally begins in the upper respiratory with a family history of asthma and those exposed to ciga-
tract with gradual (4- to 5-day) progression to involve the rette smoke in the household.253 However, it is important to
lower respiratory tract. In children with normal immunity, recognize that the majority of those hospitalized with RSV
the duration of viral shedding ranges from 1 to 3 weeks. are previously healthy young children.243
Clinical signs of bronchiolitis include airway trapping and Chest radiographic findings in lower respiratory tract
wheezing. Pathologic findings in RSV bronchiolitis include disease include bronchial wall thickening, peribronchial
necrosis of bronchiolar epithelium, loss of ciliated epithelial shadowing, air-trapping (eFig. 32-12A), and, in pneumo-
cells, and marked peribronchiolar mononuclear inflamma- nia, multilobar patchy shadowing or poorly defined nodu-
tion.247 Virus-induced cytopathology and associated sub- larity (Fig. 32-3, eFig. 32-12B). Although no radiographic
mucosal edema lead to obstruction of smaller bronchioles, pattern is specific, air trapping, alone or with other abnor-
particularly in infants, with distal collapse or air trapping. malities, is highly associated with RSV infection in hospital-
Both serum and mucosal antibody responses are seen but ized children.254 Chest CT findings (eFig. 32-13) are
are associated with limited protection. The magnitude of relatively nonspecific, often resembling other viral pulmo-
the antibody response is related to the age at primary infec- nary infections, including multifocal areas of ground-glass
tion, with infants younger than 8 months having approxi- opacity, consolidation, and small nodules, which may show
mately 10-fold lower antibody levels than older ones.248 branching configurations (“tree-in-bud” opacity).
Reinfection may take place within weeks after primary The most common physiologic abnormality is hypoxemia
infection.244 Circulating and mucosal antibody levels that may persist for weeks after apparent recovery.255
increase with each successive infection and appear to be Prolonged pulmonary function abnormalities, including
associated with milder illness. High titers of serum neutral- increased airway resistance, peripheral airway obstruction,
izing antibody are generally associated with a lower risk of and decreased arterial oxygen saturation, have been
severe illness in infants and children.249 detected in children years after bouts of bronchiolitis.256
Cell-mediated immunity appears to be important in viral Bronchiolitis in infancy has also been associated with an
clearance and may also be involved in pathogenesis. For increased risk of subsequent recurrent wheezing and cough
example, adult bone marrow transplant patients are at high and airway hyperreactivity.
risk of severe lower respiratory disease from RSV which is In adults, one half or more of recurrent infections are
likely due to prolonged periods of decreased cellular immu- associated with upper respiratory tract illness. Adults typi-
nity.250,251 In contrast, AIDS patients with decreased cellular cally experience coryza, pharyngitis, and cough, sometimes
immunity may suffer only mild disease, but viral shedding accompanied by low-grade fever. Bronchitis, influenza-like
can continue for up to 6 months.252 illness, pneumonia, and exacerbations of asthma and
Studies investigating the association of severe RSV chronic bronchitis have also been described in adults with
disease in infants with genetic polymorphisms have impli- RSV infection. In the United States, approximately 170,000
cated several candidate innate and adaptive immune genes hospitalizations and more than 10,000 deaths are associ-
including surfactants, TLR4, and several cytokine and che- ated with RSV annually in adults older than 65.125 In elderly
mokine genes as modulating the severity of RSV disease. adults, the clinical features of RSV infection can mimic
those of influenza, although fever is less frequent and
Clinical Illness wheezing is more frequent.257 In one study, RSV infection
The clinical manifestations of infection depend on both the was seen in 3% to 7% of healthy elderly and 4% to 10% of
age and immunologic state of the host. In infants and high-risk adults annually. Compared with influenza, ICU
young children, upper respiratory illness accompanied by admissions were higher, and mortality was similar, at 7% to
fever and otitis media is common. RSV is the major cause 8%.245 RSV also contributes to 5% to 10% of COPD exacer-
of lower respiratory tract illness in infants and young chil- bations.258 Older patients with severe RSV infection had a
dren and accounts for 45% to 90% of bronchiolitis, up to longer period of viral shedding, higher levels of mucosal
40% of pneumonia, and smaller proportions of croup and IL-6, and a higher frequency of circulating activated T cells
bronchitis cases in this age group. Most severe infections are compared with young patients with mild disease,259 sug-
seen in infants younger than 6 months, and almost all gesting viral loads and inflammation may play a role in
primary infections are symptomatic, with 40% or more disease severity.
associated with bronchiolitis or pneumonia. Approximately In immunosuppressed children and adults, RSV, often
1% to 2% of infections result in hospitalization, and about nosocomially acquired, causes severe lower respiratory
one in ten hospitalized infants require mechanical ventila- tract disease. Upper respiratory tract illness usually pre-
tory support. cedes the development of pneumonia, and complicating
The risk of hospitalization and severe bronchiolitis is par- sinusitis and otitis media are common. Two thirds or more
ticularly high in infants with congenital heart disease, of the bone marrow transplant recipients that develop RSV
chronic lung disease, or immunodeficiency. In addition, pneumonia will die of the infection.
In contrast to the earlier vaccine experience, passive

Diagnosis transfer of antibody to the RSV F protein has been shown
The most rapidly and readily available approach to estab- to be a highly effective means to prevent RSV morbidity in
lishing RSV infection is by rapid antigen detection. The sen- high-risk children. The currently commercially available
sitivity of such techniques is dependent on the quality of product, palivizumab, is a humanized monoclonal antibody
the nasopharyngeal specimen, with nasopharyngeal aspi- to the F protein.272 Administration of palivizumab to infants
rates superior to brushings or swabs.260 In addition, sensi- with prematurity or bronchopulmonary dysplasia resulted
tivity is related to the amount of antigen being shed, so it is in a 55% reduction in RSV-related hospitalizations and a
generally greater in children than adults. In transplant lower incidence of ICU admissions.273 In a second trial,
patients with suspected RSV pneumonia, samples of the administration of palivizumab to infants and children with
lower respiratory tract by BAL are more sensitive than hemodynamically significant congenital heart disease was
throat swabs for detection of RSV antigens.261 PCR-based well tolerated and resulted in a 45% decrease in RSV-
respiratory viral multiplex assays for detection of RSV and associated hospitalizations.274
other respiratory viruses have also been approved by the Prophylaxis with palivizumab should be considered for
U.S. Food and Drug Administration and are becoming infants younger than 24 months with chronic lung disease
widely available224a-d (see Chapter 17). RSV grows well in severe enough to require medical therapy within 6 months
several human cell lines, in which it causes formation of of the anticipated start of the RSV season.275 Prophylaxis
characteristic syncytia. Virus can be detected as early as 2 with palivizumab (and not RSV-IVIG) should be given to
days and usually within 7 days on primary isolation from infants with hemodynamically significant congenital heart
specimens collected from children. disease and infants born before 32 weeks of gestation. Pro-
phylaxis for infants between 32 and 35 weeks of gestation
Treatment and Prevention depends on the presence of other RSV risk factors, such as
Correction of hypoxemia is the most important aspect of exposure to tobacco smoke, attendance at day care, school-
managing RSV lower respiratory tract disease. Ribavirin is aged siblings in the household, and congenital airway
highly active against RSV in vitro, and aerosolized ribavirin abnormalities. Palivizumab has not been shown to be effec-
has been shown to reduce viral shedding and shorten the tive in the therapy of established RSV disease.
course of illness in some but not all studies. Aerosolized Recommendations for interruption of nosocomial trans-
ribavirin is currently recommended for use only in selected mission include handwashing, decontamination of sur-
infants and young children who are at high risk for serious faces and inanimate objects, and isolation of infected
RSV disease.262 patients. Use of disposable eye-nose goggles by pediatric
In immunosuppressed patients, particularly hematopoi- staff reduces the risk of nosocomial RSV infection in both
etic stem cell transplant recipients, both aerosolized ribavi- staff and patients.276 Regular use of gowns, gloves, and pos-
rin and high-dose oral ribavirin have been used for early sibly masks by hospital staff caring for infected children
treatment to prevent progression to pneumonia.263 Recent may also reduce the risk of nosocomial RSV spread. Protec-
studies suggest that intermittent aerosolized ribavirin is tive isolation of high-risk infants or deferring their elective
as effective as continuous aerosolized ribavirin in these admission has been recommended during institutional out-
patients.264 Once RSV pneumonia has developed, intrave- breaks of RSV.
nous ribavirin alone is ineffective but, if treatment is initi-
ated before the onset of respiratory failure, combinations of
RHINOVIRUS
aerosolized ribavirin with intravenous immunoglobulin,
and particularly paluvizumab (see later) may be benefi- Rhinoviruses (RVs) are species in the Enterovirus genus in the
cial.265,266 In adults, short courses of systemic corticoste- Picornaviridae family. The RV virion is a nonenveloped par-
roids for RSV-related wheezing did not affect viral loads or ticle 30 nm in diameter with four major structural proteins.
shedding and only mildly diminished antibody responses.267 The genome of RV consists of single-stranded RNA of
An effective vaccine for prevention of RSV has not yet approximately 2.5 × 106 daltons and codes for a 240 kD
been developed. In a study of formalin-inactivated RSV protein that is cleaved into the structural units of the virion.
vaccine conducted in the 1960s, vaccinated infants devel- RV genomes have been found to have 45% to 62% homol-
oped more severe disease compared with unvaccinated chil- ogy with poliovirus genomes. Poliovirus and RV differ,
dren.268 The mechanisms of this enhancement remain however, in the construction of their protein shells: that of
uncertain, although studies in those vaccine recipients and RV being loosely packed with a resultant sensitivity to inac-
in rodent models have implicated low levels or low affinity tivation at low pH and that of poliovirus being tightly
of the antibodies induced by the formalin-inactivated packed, providing the virion with resistance to acid inacti-
vaccine, which permitted excessive cytolytic T-cell responses vation. The acid sensitivity of RV and its optimum growth
to develop and cause tissue damage. Low-affinity antibod- at 32° C to 34° C are thought to account for its replication
ies may also have contributed to immune complex forma- in the nasal passages (and possibly large airways) but not
tion and deposition, leading to local inflammation.269,270 in the GI tract.
Formalin-inactivated RSV also primes a T helper 2 response, On the basis of sequence data, rhinovirus are grouped
with high levels of interleukin 4 and interleukin 5, which into three genogroups: A, B, and C.277 In addition, three of
can promote inflammation of small airways.271 Although the four proteins in the RV shell (VP1, VP2, and VP3) react
this adverse experience has prompted extra caution, current with neutralizing antibody, forming the basis on which
RSV vaccine development efforts are ongoing and focus on more than 100 antigenic types have been numbered. The
live attenuated and recombinant subunit vaccines. presence of neutralizing antibody in serum and nasal
introduce it into their homes, infecting other family

members. Studies of experimental RV colds in volunteers
have shown that RV is most efficiently spread by contami-
nated fingers accidentally depositing virus into the nose or
eye. Experimental RV transmission has also been achieved
by the airborne route, presumably by large-particle aerosol.
The relative importance of these two routes of RV transmis-
sion under natural conditions has not been determined.
Pathogenesis
Approximately two thirds of both natural and experimental
RV infections result in overt illness. The incubation period
of RV colds is usually 2 days but may be up to a week.
Symptoms begin within 1 day following experimental infec-
tion. Small doses of RV instilled into the nose or eye of
susceptible volunteers regularly lead to infection, indicating
that mucociliary clearance is not effective against the virus.
VP1 During the period of illness, sloughed ciliated epithelial cells
containing viral antigen are present in nasal secretions.281
VP3 VP2 In general, the number of RV-infected cells in the naso-
pharynx appears to be limited,282 and infection does not
lead to detectable damage to the epithelium of the nasal
Figure 32-10 View of one side of rhinovirus shell drawn to scale with passages. These results have suggested that virus-induced
attached antibody molecule. Top, The protein shell is built of 12 pentam-
ers, one of which is shown (white). Each of the five wedge-shaped subunits cellular injury is not the direct cause of symptoms in RV
of the pentamer (white) is called a “protomer.” The antibody binding site colds and that inflammatory mediators play an important
(brown) bridges protomers of two adjacent pentamers. Bottom, Surface role. Nasal secretions during the initial response to RV infec-
organization of the protomer. Three of the polypeptide chains (VP1, VP2, tion are predominantly the result of increased vascular per-
VP3) making up each protomer are exposed on the virus surface, while the
smallest polypeptide (VP4) is buried at the bottom of the protomer. The
meability, as demonstrated by elevated levels of plasma
host-cell receptor is thought to bind near the base of the cleft formed by proteins in nasal secretions.283 Glandular secretions (lacto-
antigenic plateaus forming VP1, VP2, and VP3. The blunt-nosed binding ferrin, lysozyme, and secretory IgA) predominate late in
site of the antibody is too wide to fit into the base of the cleft. (Courtesy colds.283 In contrast to the situation in allergic rhinitis, his-
Dr. Roland Rueckert, University of Wisconsin.) tamine does not appear to play a role in the induction of
symptoms in colds. Nasal secretion kinin levels correlate
with symptoms in natural and experimental colds, and
secretions correlates with protection from infection. X-ray intranasal administration of bradykinin causes increased
diffraction studies of RV have disclosed the presence of a nasal vascular permeability, rhinitis, and sore throat.284
large depression on the surface of the virus shell at a junc- Interleukin (IL)-1, IL-6, and IL-8 concentrations also increase
tion between the plateaus of the three proteins (Fig. in experimental RV colds and correlate well with symptom
32-10).278 This depression contains the recognition site severity.285 Enhanced synthesis of proinflammatory cyto-
for the host cell receptor, intercellular adhesion molecule-1 kines and cell adhesion molecules in the middle ear may
(ICAM-1), which binds 91 of the 102 known rhinovirus also contribute to the pathogenesis of otitis media associ-
serotypes.279 RV serotypes that do not bind to ICAM-1 are ated with colds.286 Polymorphisms in the IL-6 gene affect
referred to as the minor receptor group viruses and appear to the symptomatic response to experimental RV challenge in
utilize the low-density lipoprotein receptor.280 Manipulation adults.287
of these receptor proteins has been explored as a potential
control measure for rhinovirus infection. Clinical Illness
RV colds vary in severity from mild episodes characterized
Epidemiology and Transmission by 1 to 2 days of coryza or scratchy throat to full-blown
RVs are worldwide in distribution. In the United States, RV illnesses with profuse and prolonged rhinorrhea, pharyngi-
has been observed to cause 0.74 to 0.77 infections per tis, and bronchitis. The profile of a typical RV cold, based on
person per year in adults. RV is believed to produce even composite results from young adults with natural infection,
higher infection rates in children, leading to acquisition of is shown in Figure 32-1. The median length of illness is 1
antibody to the different RV types throughout childhood week, with symptoms lasting up to 2 weeks in one quarter
and adolescence, with peak antibody prevalence in young of cases. Peak symptoms are usually seen on the second and
adults. Immunity to RV is type specific and confers long- third days of illness. The characteristics of RV illness are not
lived protection following infection, although there may be distinctive enough to permit their differentiation from colds
second infections with the same virus type. The different due to other respiratory viruses. RV is among the respira-
immunotypes circulate in a given population in an appar- tory viruses implicated in the development of acute sinusitis
ently random manner. In the United States, RV infections and represents about half of all viruses recovered from
are most prevalent in the early fall and late spring. middle ear effusions in children with acute otitis media.288
The major reservoir for RV is school children, who trans- Recently, a clinical presentation indistinguishable from that
mit RV infection among their peers in the classroom and of influenza has also been reported in healthy adults.289
RV alone or in combination with bacteria has been recov- a highly contagious, childhood disease that typically causes
ered from aspirates obtained by direct puncture of the max- community outbreaks in late winter and early spring
illary sinuses of patients with acute sinusitis.290 Mucosal months in temperate regions. Varicella spreads rapidly to
thickening and/or sinus exudates have been observed in up household contacts, with an attack rate of nearly 90%
to 77% of subjects with acute colds.291 These abnormalities within 2 weeks. Consequently, most adults in temperate
are transient, and in uncomplicated cases they resolve areas have experienced infection during childhood, but a
within 21 days. However, clinically manifest acute bacterial high proportion of adults in semitropical and tropical areas
sinusitis is seen in a small (0.5% to 5%) proportion of indi- remain susceptible to primary infection.300 Herpes zoster is
viduals with naturally occurring colds. It is presumed that nonseasonal and is seen in persons of all ages, although its
the RV infection impairs mucociliary clearance and other incidence increases almost linearly after 30 years of age.
local defenses in the sinus cavity, allowing secondary bacte- About 10% to 20% of adults experience zoster, typically as
rial invasion. a single episode after the fifth decade of life. Clinically appar-
There is increasing evidence for an important role of rhi- ent reinfections can be seen with VZV.
noviruses in lower respiratory tract disease in adults and Although the virus has been infrequently recovered from
children.292 RV is the second most frequently recognized respiratory secretions of varicella patients, epidemiologic
agent associated with pneumonia and bronchiolitis in evidence indicates that the virus is spread from person to
infants and young children and commonly causes exacer- person through airborne transmission. Cutaneous lesions
bations of preexisting airways disease in those with COPD may also be the source of infectious virus. Susceptible
or cystic fibrosis.293 Colds are generally more severe in atopic persons have been infected after contact with patients with
individuals and rhinoviruses are major causes of asthma varicella, or, less often, with herpes zoster. Before the imple-
exacerbation.294 Children with a history of wheezing/ mentation of vaccination, VZV was an important cause of
asthma had significantly more RV-associated hospitaliza- nosocomial outbreaks on pediatric wards, with spread by
tions than those without a history.295 small-particle aerosols.
RV infections may also be associated with severe lower
respiratory tract disease in transplant patients296 and in Pathogenesis
some cases can be associated with prolonged shedding.297 The incubation period of varicella averages 2 weeks,
These viruses can also be detected in lower respiratory tract and almost all cases of varicella develop within 11 to 20
disease in individuals with hematologic malignancy, often days after exposure. The initial portal of infection is the
in conjunction with other pathogens.298 respiratory tract, with viremic dissemination leading to the
extensive cutaneous and mucous membrane lesions. Fol-
Diagnosis lowing infection, VZV establishes latency in the posterior
Rapid tests for detecting RV nucleic acid are available in dorsal root ganglia. Reactivation of virus replication and
respiratory virus panels (see Chapter 17); they generally do centrifugal spread along sensory nerves lead to the unique
not distinguish rhinoviruses from other enteroviruses. RVs dermatomal distribution of shingles (zoster). In immuno-
can be isolated in cell culture, usually within 2 to 7 days compromised hosts with zoster, virus may disseminate to
after inoculation. Virus is present in nasopharyngeal secre- other sites.
tions in highest concentrations during the first and second
days of illness but may be shed for as long as 3 weeks. When Clinical Illness
indicated, identification of the specific serotype of a rhino- Varicella. In children with normal immunity, varicella is
virus isolate is made by neutralization test. usually not associated with significant systemic or respira-
tory manifestations. The exanthem typically begins around
Treatment and Prevention the scalp and head, with subsequent involvement of the
The only effective therapy for RV colds currently available trunk and extremities. Lesions progress through various
is symptomatic treatment of individual complaints. Reme- stages (erythematous macules, vesicles, pustules, crusts), so
dies recommended for such treatment are described in the an area will have lesions in different stages of evolution. In
section on common cold in this chapter. Although hand contrast, in smallpox, a disease with which varicella was
washing is undoubtedly important in preventing transmis- often confused, lesions begin on the face and spread out-
sion, a recent study could show no benefit to routine hand wardly to the extremities, and adjacent lesions are at the
disinfection in the prevention of RV colds.299 As mentioned same stage of development.
earlier, the plethora of rhinovirus serotypes suggests that In children and susceptible adults who are immunocom-
an effective vaccine will not be forthcoming in the foresee- promised, particularly those with defects in cell mediated
able future. Advances in understanding of the structural immunity, including HIV infection,301 varicella follows a
and molecular biology of the rhinoviruses has led to devel- more severe course. Continued lesion development, particu-
opment of a number of strategies for antiviral intervention, larly involving the extremities; high fever; and visceral
including receptor blockade and capsid-binding agents. involvement with pneumonia, meningoencephalitis, and
However, none of these agents has reached approval for hepatitis are common. During pregnancy, severe pneumo-
clinical use. nia can develop in approximately 10% of varicella cases.
Viral pneumonia is the major complication of varicella
in normal adults, in whom the frequency is estimated to be
VARICELLA-ZOSTER VIRUS
25-fold higher than in children.302 Smoking is a significant
Varicella-zoster virus (VZV) is an enveloped double-stranded risk factor. Pneumonia associated with varicella is usually
DNA virus with a large genome (≈125,000 bp). Varicella is apparent 1 to 6 days after the onset of rash. Symptoms
affected. Mortality depends on the degree of immunosup-

pression and ranges from zero to 10%.
Diagnosis
A rapid diagnosis of herpes group infection can be estab-
lished by cytologic examination of lesion scrapings (Tzank
smear and others), which has a sensitivity of 70% to 85%
when lesions are in the vesicular stage. Direct immunofluo-
rescence for VZV antigen in lesions is the most sensitive
rapid laboratory test. The virus is labile but can be isolated
from vesicular fluid during the first 3 days of varicella in
normal hosts and for up to 10 days in immunocompro-
mised hosts or patients with disseminated zoster. Direct
inoculation of vesicular fluid onto monolayers of cell
culture (human embryonic lung fibroblasts) at the bedside
increases the likelihood of isolation.
Treatment and Prevention
Live, attenuated varicella vaccine generates neutralizing
antibody in more than 95% of recipients and also generates
Figure 32-11 Acute varicella pneumonia. Frontal chest radiograph long-lived CD8+ cytotoxic T-cell responses against varicella
shows multifocal, bilateral, poorly defined nodular opacities in a predomi-
nantly perihilar and lower lobe distribution. No pleural effusion is present. virus.304 Vaccination of immunosuppressed children,
(Courtesy Michael Gotway, MD.) including those with leukemia, is safe, although a small
proportion of children will experience a mild, varicella-like
clinical syndrome approximately 1 month after vaccina-
include cough, dyspnea, pleuritic chest pain, and hemopty- tion.305 In both healthy and immunosuppressed children,
sis. Physical findings other than fever and tachypnea are the vaccine is highly effective at preventing varicella, with
often modest. The intensity of the rash does not necessarily efficacy rates of 50% to 90%. Two doses of varicella vaccine
correlate with the severity of pneumonia. The characteris- administered subcutaneously are recommended for chil-
tic chest radiographic pattern is that of diffuse nodular (1 dren 12 months and older, adolescents, and adults without
to 10 mm) opacities (Fig. 32-11, eFig. 32-14), which may evidence of prior immunity.306 Second-dose catch-up vac-
resolve with miliary calcified nodules (eFig. 32-15).303 Hilar cination is recommended for those who previously received
lymphadenopathy, pleural effusions, and peribronchial only a single dose of vaccine.
opacities are frequently present. Pulmonary infarction may A higher-dose live vaccine effectively re-stimulates virus-
complicate the clinical picture. Chest CT in patients with specific cellular immunity in adults and can reduce the fre-
varicella pneumonia typically shows multifocal or diffuse, quency of reactivation, as well as the clinical severity of
variably sized nodules (1 to 10 mm), which may be circum- zoster.307 The high-dose live vaccine is recommended as a
scribed or poorly defined (eFig. 32-16). Ground-glass single dose in all healthy individuals 60 and older.308
opacity halos may be seen around some of the nodules. Although uncomplicated varicella in children usually
Pulmonary function studies have found normal expiratory requires no specific treatment, oral acyclovir initiated
flow values but decreased carbon monoxide diffusing within 24 hours of rash onset reduces the number of
capacity, which may persist for months. However, many lesions, duration of fever, and healing time compared with
individuals with radiographic changes are relatively placebo in children, adolescents, and adults.309 Sequential
asymptomatic. intravenous and oral acyclovir has been used in therapy of
varicella in immunocompromised children.310 In immuno-
Herpes Zoster. Zoster represents reactivation of latent compromised patients with localized zoster, intravenous
virus along one to three dermatomes and, in adults, is acyclovir has been found to halt dissemination. In addition,
usually associated with pain. The thoracic dermatomes are oral acyclovir, valacyclovir, and famciclovir are effective for
involved in about one half of cases. Prolonged severe pain, the treatment of zoster and may reduce the duration of
or postherpetic neuralgia, can be a serious complication, postherpetic neuralgia in healthy adults.311 Intravenous
with increased frequency in those older than 50. acyclovir (10 mg/kg every 8 hours for 5 to 7 days) appears
Zoster presents more often in those receiving immuno- efficacious in varicella pneumonia in previously healthy
suppressive therapy or chemotherapy for malignancies and adults if started early.312
at anatomic sites irradiated for treatment of malignancies.
Depending on the degree of immunosuppression, herpes
zoster may develop in 30% or more of patients. Cutaneous Key Points
dissemination (defined as more than 20 lesions outside the ■ Viral infections, important causes of disease of the
primary dermatome) develops in 25% to 50% of immuno- respiratory tract, are associated with substantial mor-
suppressed patients and in up to 2% of apparently normal bidity and mortality in all age groups.
patients with zoster. It is associated with visceral involve- ■ Clinical syndromes such as the common cold, pharyn-
ment including pneumonitis, as well as hepatitis, meningo- gitis, acute bronchitis, influenza-like illness, croup,
encephalitis, and uveitis in approximately one half of those
Burton DR, Poignard P, Stanfield RL, et al: Broadly neutralizing antibodies

bronchiolitis, and pneumonia—may be caused by present new prospects to counter highly antigenically diverse viruses.
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eFIGURE IMAGE GALLERY
A B
eFigure 32-1 Radiographic appearance of croup: the “steeple” sign. A, Detail frontal chest radiograph in a child with croup shows smooth, superiorly
tapered narrowing of the subglottic tissues (arrows) due to edema. B, Normal appearance of the subglottic trachea—note the less tapered appearance.
(Courtesy Michael Gotway, MD.)
eFigure 32-3 Chest CT: infectious bronchiolitis. Axial chest CT displayed

in lung windows shows patchy areas of increased attenuation due to atel-
ectasis (arrow) associated with areas of decreased attenuation caused by
“air trapping” (single arrowheads), in some areas with a clearly lobular con-
figuration (double arrowheads). (Courtesy Michael Gotway, MD.)
eFigure 32-2 Chest radiography: infectious bronchiolitis. Frontal chest
radiograph in a pediatric patient with bronchiolitis shows patchy, bilateral
perihilar linear opacities with slight depression of the left diaphragm due
to left lower lobe air trapping. (Courtesy Michael Gotway, MD.)
556.e2 PART 3 • Clinical Respiratory Medicine
eFigure 32-4 Chest radiography: measles pneumonia. Frontal chest

radiograph in a child with a typical measles rash shows patchy, bilateral
faintly nodular bronchovascular thickening with a predominantly perihilar
distribution. The imaging features are consistent with viral infection but
nonspecific as regards potential etiologic agents. (Courtesy Michael
Gotway, MD.)
B D
A C E
eFigure 32-5 Adenovirus pneumonia: imaging findings. A, Frontal chest radiograph shows bilateral areas of ground-glass opacity and consolidation
without pleural effusion. B–E, Axial chest CT displayed in lung windows shows multifocal ground-glass opacity with areas of consolidation with air bron-
chograms formation (arrow). Small nodules (arrowheads) are also present. The imaging features are suggestive of pulmonary infection but nonspecific as
regards etiology. (Courtesy Michael Gotway, MD.)
A B
C D
eFigure 32-6 Seasonal influenza A infection: imaging findings. A, Frontal chest radiograph shows patchy, bilateral linear interstitial thickening in a
perihilar distribution, some of which represents bronchial thickening. Abnormalities are slightly more nodular appearing in the right upper lobe (arrows),
and consolidation is developing in the left upper lobe (arrowhead). B–D, Axial chest CT displayed in lung windows shows multifocal, bilateral, upper lobe
predominant ground-glass opacity associated with linear abnormalities consistent with mild, smooth interlobular septal thickening and intralobular
interstitial thickening. The cystic appearance is due to centrilobular emphysema outlined and contrasted with the surrounding infiltrative lung abnormali-
ties. (Courtesy Michael Gotway, MD.)
eFigure 32-7 Seasonal influenza A infection: variable chest radio-

graphic findings. Frontal chest radiograph shows predominantly left peri-
hilar peribronchovascular thickening and nodularity. The imaging findings
are nonspecific and could be the result of a number of causes of bronchop-
neumonia. (Courtesy Michael Gotway, MD.)
B D
A C E
eFigure 32-8 Seasonal influenza A infection progressing to respiratory failure with diffuse alveolar damage. A, Frontal chest radiograph in a previ-
ously healthy 51-year-old woman with no significant previous medical history presenting to the emergency department with fever, cough, and nasal
congestion shows multifocal, perihilar predominantly linear opacity and bronchovascular thickening and hazy opacities. The patient had been seen as an
outpatient and treated with several broad-spectrum antibiotics with no improvement. At the time the chest radiograph was performed, the patient was
mildly leukopenic with an oxygen saturation of 82% on room air. B–E, Axial chest CT displayed in lung windows shows multifocal, bilateral, nonsegmental
areas of ground-glass opacity, in some areas peripherally and peribronchially distributed, associated with intralobular interstitial thickening, mild inter-
lobular septal thickening, and a few areas of consolidation. The imaging findings are nonspecific and can be seen with numerous causes of noninfectious
acute lung injury and other pulmonary infections including severe acute respiratory syndrome (SARS). Surgical lung biopsy showed diffuse alveolar
damage with some intrabronchiolar and alveolar inflammatory cells suggesting the possibility of an infectious insult, and bronchoscopy before the surgical
biopsy recovered influenza A. The patient suffered hypoxic respiratory failure requiring mechanical ventilation but subsequently recovered. (Courtesy
Michael Gotway, MD.)
B D
A C E
F G H
eFigure 32-9 H1N1 (“swine-origin”) influenza A infection: imaging findings. A, Frontal chest radiograph in a patient subsequently diagnosed with
H1N1 influenza during the 2009 pandemic shows multifocal basal predominant consolidation, consistent with bronchopneumonia, but nonspecific.
B–E, Axial chest CT displayed in lung windows shows nonspecific bilateral areas of ground-glass opacity, nodular subpleural consolidation (arrows) and
other foci of patchy, peripheral, increased lung attenuation, and small nodules (arrowheads), some of which appear centrilobular. F–H, Serial frontal chest
radiograph obtained during the course of the disease shows worsening of bilateral opacities associated with hypoxemic respiratory failure (F and G) but
subsequent clearing of bilateral lung opacity following recovery (H). (Courtesy Michael Gotway, MD.)
A C
B D
eFigure 32-10 H1N1 (“swine-origin”) influenza A infection: variable imaging findings at chest CT. A and B, Axial chest CT displayed in lung windows
shows patchy areas of upper lobe predominant ground-glass opacity (arrows) and small, solid, centrilobular nodules (arrowheads). The opacity in the left
lower lobe (B) appears somewhat segmental, suggestive of bronchopneumonia. C, Axial chest CT shows multifocal, bilateral areas of ground-glass opacity
associated with interlobular septal thickening and intralobular interstitial thickening, but no clear zonal distribution; these findings are nonspecific and
can be observed with numerous infections and noninfectious inflammatory pulmonary insults. D, Axial chest CT shows right lower lobe superior segmental
dense consolidation (double arrowheads), suggestive of a lobar pneumonia pattern. (Courtesy Michael Gotway, MD.)
eFigure 32-11 Seasonal influenza A infection complicated by bacterial

pneumonia. Frontal chest radiograph in a pediatric patient shows multifo-
cal bilateral consolidation. The patient had been diagnosed with seasonal
influenza A infection 2 weeks earlier and was recovering but then developed
a high fever and new productive cough. (Courtesy Michael Gotway, MD.)
A B
eFigure 32-12 Respiratory syncytial virus (RSV) bronchiolitis and pneumonia: chest radiographic findings. A, Frontal chest radiograph in a young
child with RSV bronchiolitis shows bilateral basal streaky opacities associated with significant diaphragmatic flattening bilaterally, consistent with “air
trapping” due to small airway inflammation and obstruction. B, Frontal chest radiograph in an infant with RSV pneumonia shows patchy, somewhat
perihilar-predominant bronchovascular thickening. The right diaphragm is somewhat flattened, suggesting basal air trapping. (Courtesy Michael Gotway, MD.)
A C
B D
eFigure 32-13 Respiratory syncytial virus pneumonia: chest CT findings. A–D, Axial chest CT displayed in lung windows shows multifocal, bilateral
patchy areas of ground-glass opacity associated with more focal right upper lobe posterior segmental consolidation (arrows). In some areas the ground-
glass opacity is associated with intralobular interstitial thickening and interlobular septal thickening (arrowheads). Small solid nodules (C, double arrow-
heads) are also present. (Courtesy Michael Gotway, MD.)
A B
eFigure 32-14 Varicella-zoster virus (VZV) pneumonia: chest radiographic findings of acute infection. A, Frontal chest radiograph in a young patient
with VZV pneumonia shows bilateral poorly defined nodular opacities, ultimately nonspecific but typical of VZV pulmonary infection. B, Frontal chest
radiograph in a heart transplant patient with acute VZV infection shows multifocal, bilateral, poorly defined nodules without pleural effusion. (Courtesy
Michael Gotway, MD.)
eFigure 32-15 Varicella-zoster virus pneumonia: chest radiographic

findings of remote infection. Frontal chest radiograph shows numerous,
small, circumscribed bilateral calcified nodules. (Courtesy Michael Gotway,
MD.)
A D
B E
C F
eFigure 32-16 Varicella-zoster virus pneumonia: chest CT findings of acute infection. A–F, Axial chest CT displayed in lung windows shows multiple,
bilateral small nodules, most of which are poorly defined. A faint ground-glass opacity halo is present around one of the nodules (arrow). The imaging
findings are consistent with pulmonary infection but nonspecific as regards the etiologic agent. (Courtesy Michael Gotway, MD.)
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Infectious Diseases of The Lungs: Viral Infections

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Infectious Diseases of The Lungs: Viral Infections

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SECTION H

INFECTIOUS DISEASES OF THE LUNGS

INTRODUCTION Croup Influenza Virus

INTRODUCTION the replication of which is generally restricted to the

Table 32-1 Viral Infections of the Respiratory Tract

Virus Percentage of Cases*

*Estimated percentage of colds annually.

eustachian tube dysfunction. Colds are associated with

many patients with acute viral infections. Also, because

populations, both can be seen as sporadic cases. In young

Adenovirus Pneumonia. Adenovirus was first recog-

eTable 32-1 Adenoviruses Associated with Respiratory Tract

*Adapted from Hierholzer JC: Adenoviruses in the immunocompromised

Table 32-4 Target Groups for Influenza Immunization*

■ All persons aged ≥50 years

■ Adults and children who have chronic pulmonary (including

asthma) or cardiovascular (except isolated hypertension), renal,

immunosuppression caused by medications or by HIV infection)

■ Children and adolescents (aged 6 months to 18 years) who are

receiving long-term aspirin therapy and who might be at risk for

■ American Indians/Alaska Natives

■ Persons who are morbidly obese (BMI ≥40)

PERSONS WHO CAN TRANSMIT INFLUENZA TO THOSE

Although vaccine virus can be recovered from vacci-

In contrast to the earlier vaccine experience, passive

introduce it into their homes, infecting other family

affected. Mortality depends on the degree of immunosup-

Burton DR, Poignard P, Stanfield RL, et al: Broadly neutralizing antibodies

eFIGURE IMAGE GALLERY

eFigure 32-3 Chest CT: infectious bronchiolitis. Axial chest CT displayed

eFigure 32-4 Chest radiography: measles pneumonia. Frontal chest

eFigure 32-7 Seasonal influenza A infection: variable chest radio-

eFigure 32-11 Seasonal influenza A infection complicated by bacterial

eFigure 32-15 Varicella-zoster virus pneumonia: chest radiographic

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Burton DR, Poignard P, Stanfield RL, et al: Broadly neutralizing antibodies