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39
C H A P T E R
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RNA Enveloped Viruses
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CHAPTER CONTENTS

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ORTHOMYXOVIRUSES Other Togaviruses
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Influenza Viruses RHABDOVIRUSES

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PARAMYXOVIRUSES Rabies Virus

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Measles Virus RETROVIRUSES
Mumps Virus Human T-Cell Lymphotropic Virus
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Respiratory Syncytial Virus FILOVIRUSES
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Parainfluenza Viruses Ebola Virus
CORONAVIRUSES Marburg Virus
Coronavirus Self-Assessment Questions
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TOGAVIRUSES Summaries of Organisms
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Rubella Virus Practice Questions: USMLE & Course Examinations
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ORTHOMYXOVIRUSES  
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INFLUENZA VIRUSES features of influenza virus and compares them with the
clinical features of the other medically important viruses in
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Influenza viruses are important human pathogens because this chapter.
they cause both outbreaks of influenza that sicken and kill In 1997, an outbreak of human influenza (avian influ-
thousands of people each year as well as infrequent but enza, bird flu) caused by an H5N1 strain of influenza A
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devastating worldwide epidemics (pandemics). virus began. This outbreak and subsequent outbreaks are
Influenza viruses are the only members of the ortho-
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described on page 317. In 2009, there was an outbreak of
myxovirus family. The orthomyxoviruses differ from the human influenza caused by H1N1 influenza A virus of
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paramyxoviruses primarily in that the former have a swine origin (swine-origin influenza virus, S-OIV). This
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segmented RNA genome (usually eight pieces), whereas outbreak and the subsequent pandemic are described on
the RNA genome of the latter consists of a single piece.1
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page 317. In 2013, an outbreak of influenza caused by an

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The term myxo refers to the observation that these
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H7N9 strain of influenza virus occurred.

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viruses interact with mucins (glycoproteins on the sur-

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face of cells).
1. Human Influenza Virus
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In addition, the orthomyxoviruses are smaller (110 nm

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in diameter) than the paramyxoviruses (150 nm in diame- Disease

ter). See Table 39–1 for additional differences. Influenza A virus causes worldwide epidemics (pandemics)
Table 39–2 shows a comparison of influenza A virus of influenza, influenza B virus causes major outbreaks of
with several other viruses that infect the respiratory tract.
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influenza, and influenza C virus causes mild respiratory

Table 39–3 describes some of the important clinical tract infections but does not cause outbreaks of influenza.
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Pandemics occur when a variant of influenza A virus that

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1
contains a new hemagglutinin against which people do not
The total molecular weight of influenza virus RNA is approximately
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(2–4) × 106, whereas the molecular weight of paramyxovirus RNA is have preexisting antibodies is introduced into the human
population.
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higher, approximately (5–8) × 106.

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311
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312 PART IV  Clinical Virology
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TABLE 39–1  Properties of Orthomyxoviruses and Paramyxoviruses
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Property Orthomyxoviruses Paramyxoviruses

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Viruses Influenza A, B, and C viruses Measles, mumps, respiratory syncytial, and parainfluenza
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viruses
Genome Segmented (eight pieces) single-stranded RNA of Nonsegmented single-stranded RNA of negative polarity
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negative polarity
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Virion RNA polymerase Yes Yes
Capsid Helical Helical
Envelope Yes Yes
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Size Smaller (110 nm) Larger (150 nm)
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Hemagglutinin and neuraminidase on the same spike1

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Surface spikes Hemagglutinin and neuraminidase on different
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spikes
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Giant cell formation No Yes

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Individual viruses differ in detail. See Table 39–4.
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TABLE 39–2  Features of Viruses That Infect the Respiratory Tract1
Lifelong
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Number of Immunity to Vaccine Viral
Virus Disease Serotypes Disease Available Latency Treatment
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RNA viruses            
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Influenza virus Influenza Many No + – Amantadine rimantadine,
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oseltamivir, zanamivir
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Parainfluenza virus Croup Many No – – None
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Respiratory syncytial virus Bronchiolitis Two Incomplete – – Ribavirin

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Rubella virus Rubella One Yes + – None

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Measles virus Measles One Yes + – None
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Mumps virus Parotitis, meningitis One Yes + – None
Rhinovirus Common cold Many No – – None
2
Coronavirus Common cold, SARS Three No – – None
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Coxsackie virus Herpangina, pleuro- Many No – – None
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dynia, myocarditis
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DNA viruses            
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3
Herpes simplex virus type 1 Gingivostomatitis One No – + Acyclovir in immunodefi-
cient patients
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Varicella-zoster virus Chickenpox, shingles One Yes for varicella; – + Acyclovir in immunodefi-
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no for zoster cient patients

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Cytomegalovirus Pneumonia in One No3 – + Ganciclovir

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immunocompro-
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Epstein–Barr virus Infectious One Yes – + None

mononucleosis
Adenovirus Pharyngitis, Many No +4 + None
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pneumonia
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1
Influenza virus, parainfluenza virus, respiratory syncytial virus, rubella virus, measles virus, mumps virus, and coronavirus are enveloped RNA viruses and are described in this
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chapter.
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2
SARS is severe acute respiratory syndrome.
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No because reactivation of latent virus can cause disease.
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For military recruits only.
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CHAPTER 39  RNA Enveloped Viruses 313
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TABLE 39–3  Clinical Features of Certain RNA Enveloped Viruses
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Immune Globulins

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Virus Rash Occurs Giant Cells Formed Type of Vaccine Commonly Used
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Influenza No No Killed No
Respiratory syncytial No Yes None No
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Measles Yes Yes Live No
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Rubella Yes No Live No
Rabies No No Killed Yes
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The pandemics caused by influenza A virus occur infre- tains an RNA-dependent RNA polymerase, which tran-

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quently (the last one was in 1968), but major outbreaks scribes the negative-polarity genome into mRNA.
caused by this virus occur virtually every year in many The envelope is covered with two different types of
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countries. Each year, influenza is the most common cause spikes, a hemagglutinin and a neuraminidase.2 Influenza

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of respiratory tract infections that result in physician visits A virus has 16 antigenically distinct types of hemagglutinin

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and hospitalizations in the United States. and 9 antigenically distinct types of neuraminidase. As
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In the 1918 influenza pandemic, more Americans died discussed later, some of these types cause disease in
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than in World War I, World War II, the Korean War, and humans, but most of the types typically cause disease in
the Vietnam War combined. Influenza B virus does not other animal species such as birds, horses, and pigs.
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cause pandemics, and the major outbreaks caused by this The function of the hemagglutinin is to bind to the cell
virus do not occur as often as those caused by influenza A surface receptor (neuraminic acid, sialic acid) to initiate
virus. It is estimated that approximately 36,000 people die infection of the cell. In the clinical laboratory, the hemag-
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of influenza each year in the United States. glutinin agglutinates red blood cells, which is the basis of a
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diagnostic test called the hemagglutination inhibition test.
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Important Properties The hemagglutinin is also the target of neutralizing anti-

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Influenza virus is composed of a segmented single- body (i.e., antibody against the hemagglutinin inhibits
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stranded RNA genome, a helical nucleocapsid, and an infection of the cell).
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outer lipoprotein envelope (Figure 39–1). The virion con- The neuraminidase cleaves neuraminic acid (sialic acid)
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to release progeny virus from the infected cell. The hemag-

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glutinin functions at the beginning of infection, whereas
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the neuraminidase functions at the end. Neuraminidase
also degrades the protective layer of mucus in the respira-
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tory tract. This enhances the ability of the virus to gain
access to the respiratory epithelial cells.
Influenza viruses, especially influenza A virus, show
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changes in the antigenicity of their hemagglutinin and
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neuraminidase proteins; this property contributes to their
capacity to cause devastating worldwide epidemics (pan-
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demics). There are two types of antigenic changes: (1)
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antigenic shift, which is a major change based on the reas-
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sortment of segments of the genome RNA; and (2) anti- f

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genic drift, which is a minor change based on mutations in

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the genome RNA. Note that in reassortment, entire seg-

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ments of RNA are exchanged, each one of which codes for

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a single protein (e.g., the hemagglutinin) (Figure 39–2).

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Influenza A virus has two matrix proteins: The M1

matrix protein is located between the internal nucleopro-
tein and the envelope and provides structural integrity. The
FIGURE 39–1  Influenza virus—electron micrograph. Long M2 matrix protein forms an ion channel between the
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arrow points to the helical nucleocapsid of influenza virus. The

interior of the virus and the external milieu. This ion
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nucleocapsid contains the segmented, negative-polarity genome

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RNA. Short arrow points to the spikes on the virion envelope. The channel plays an essential role in the uncoating of the
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spikes are the hemagglutinin and neuraminidase proteins. (Source:

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Dr. Erskine Palmer and Dr. M. Martin, Public Health Image Library, Centers for 2
Paramyxoviruses also have a hemagglutinin and a neuraminidase, but
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Disease Control and Prevention.) the two proteins are located on the same spike.
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314 PART IV  Clinical Virology
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Human Chicken functions, but the one pertinent to virulence is its ability to
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influenza influenza
virus virus inhibit the production of interferon mRNA. As a result,

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innate defenses are reduced and viral virulence is corre-
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spondingly enhanced.
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Many species of animals (e.g., aquatic birds, chickens,
swine, and horses) have their own influenza A viruses.
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These animal viruses are the source of the RNA segments
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that encode the antigenic shift variants that cause epidem-
ics among humans. For example, if an avian and a human
influenza A virus infect the same cell (e.g., in a farmer’s
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respiratory tract), reassortment could occur and a new
Lung cell
variant of the human A virus, bearing the avian virus hem-
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agglutinin, may appear (see Figure 39–1).
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Reassortment of There is evidence that aquatic birds (waterfowl) are a
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RNA genome segments
common source of these new genes and that the reassort-
ment event leading to new human strains occurs in pigs. In

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other words, pigs may serve as the “mixing bowl” within

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which the human, avian, and swine viruses reassort. There
are 16 types of hemagglutinin (H1 to H16) and 9 types of
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neuraminidase (N1 to N9) found in waterfowl. In humans,
three types of hemagglutinin (H1, H2, and H3) and two
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types of neuraminidase (N1 and N2) predominate.
New strain Because influenza B virus is only a human virus, there is
of influenza
no animal source of new RNA segments. Influenza B virus
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virus
therefore does not undergo antigenic shifts. It does, how-
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FIGURE 39–2  Antigenic shift in influenza virus. A human ever, undergo enough antigenic drift that the current strain
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strain of influenza virus containing the gene encoding one antigenic

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must be included in the new version of the influenza vac-
type of hemagglutinin (colored orange) infects the same lung cell as
cine produced each year. Influenza B virus has no antigens
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a chicken strain of influenza virus containing the gene encoding a
in common with influenza A virus.
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different antigenic type of hemagglutinin (colored black). Reassort-

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ment of the genome RNA segments that encode the hemagglutinin A/Philippines/82 (H3N2) illustrates the nomenclature
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of influenza viruses. “A” refers to the group antigen. Next

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occurs, and a new strain of influenza virus is produced containing the
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chicken type of hemagglutinin (colored black). are the location and year the virus was isolated. H3N2 is the
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designation of the hemagglutinin (H) and neuraminidase
(N) types. The H1N1 and H3N2 strains of influenza A
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virion after it enters the cell. It transports protons into the virus are the most common at this time and are the strains
virion causing the disruption of the envelope, which frees included in the current vaccine. The H2N2 strain caused a
the nucleocapsid containing the genome RNA, allowing it pandemic in 1957.
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to migrate to the nucleus.
Summary of Replicative Cycle
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Influenza viruses have both group-specific and type-
specific antigens. The virus adsorbs to the cell when the viral hemagglutinin
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interacts with sialic acid receptors on the cell surface. (The
(1) The internal ribonucleoprotein in the nucleocapsid
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hemagglutinin on the virion surface is cleaved by extracel-
is the group-specific antigen that distinguishes influenza A,
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lular proteases to generate a modified hemagglutinin that f

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B, and C viruses.
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actually mediates attachment to the cell surface.) The virus

(2) The hemagglutinin and the neuraminidase are the
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then enters the cell in vesicles and uncoats within an endo-

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type-specific antigens located on the surface. Antibody

some. Uncoating is facilitated by the low pH within the
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against the hemagglutinin neutralizes the infectivity of the

endosome. Protons pass through the ion channel formed
virus (and prevents disease), whereas antibody against the
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by the M2 protein into the interior of the virion. This dis-

group-specific antigen (which is located internally) does
rupts the virion envelope and frees the nucleocapsid to
not. Antibody against the neuraminidase does not neutral-
enter the cytoplasm and then migrate to the nucleus where
ize infectivity but does reduce disease by decreasing the
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the genome RNA is transcribed.

amount of virus released from the infected cell and thus
The virion RNA polymerase transcribes the eight
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reducing spread of the virus to adjacent cells.

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genome segments into eight mRNAs in the nucleus. Syn-

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An important determinant of the virulence of this virus thesis of the eight mRNAs occurs in the nucleus because a
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is a nonstructural protein called NS-1 encoded by the methylated guanosine “cap” is required. The cap is obtained
genome RNA of influenza virus. NS-1 has several from cellular nuclear RNAs in a process called “cap
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CHAPTER 39  RNA Enveloped Viruses 315
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snatching.” Most of the mRNAs move to the cytoplasm, pharynx, and lower respiratory tract sites such as the lar-
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where they are translated into viral proteins. Some of the ynx, trachea, and bronchi. Pneumonia, which involves the

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viral mRNAs remain in the nucleus, where they serve as the alveoli may also occur.
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template for the synthesis of the negative-strand RNA After the virus has been inhaled, the neuraminidase
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genomes for the progeny virions. Replication of the prog- degrades the protective mucus layer, allowing the virus to
eny genomes is performed by a different subunit of the viral gain access to the cells of the upper and lower respiratory
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RNA polymerase (acting as a replicase) from the subunit tract. The infection is limited primarily to this area because
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that functioned earlier as a transcriptase that synthesized the proteases that cleave the hemagglutinin are located in
the mRNAs. Two newly synthesized proteins, NP protein the respiratory tract.
and matrix protein, bind to the progeny RNA genome in Despite systemic symptoms, viremia rarely occurs. The
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the nucleus, and that complex is transported to the systemic symptoms, such as severe myalgias, are due to
cytoplasm. cytokines circulating in the blood. There is necrosis of the
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The helical ribonucleoprotein assembles in the cyto- superficial layers of the respiratory epithelium. Influenza
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plasm, matrix protein mediates the interaction of the virus pneumonia, which can complicate influenza, is inter-
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nucleocapsid with the envelope, and the virion is released stitial in location.
from the cell by budding from the outer cell membrane at Immunity depends mainly on secretory IgA in the respi-

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the site where the hemagglutinin and neuraminidase are ratory tract. IgG is also produced but is less protective.

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located. The neuraminidase releases the virus by cleaving Cytotoxic T cells also play a protective role.
neuraminic acid on the cell surface at the site of the bud-
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ding progeny virions. Influenza virus, hepatitis delta virus, Clinical Findings
and retroviruses are the only RNA viruses that have an
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After an incubation period of 24 to 48 hours, fever, myal-
important stage of their replication take place in the gias, headache, sore throat, and cough develop suddenly.
nucleus. Severe myalgias (muscle pains) coupled with respiratory
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tract symptoms are typical of influenza. Vomiting and diar-
Transmission & Epidemiology rhea are rare. The symptoms usually resolve spontaneously
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The virus is transmitted by airborne respiratory droplets. in 4 to 7 days, but influenzal or bacterial pneumonia may
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The ability of influenza A virus to cause epidemics is complicate the course. One of the well-known complications
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dependent on antigenic changes in the hemagglutinin and of influenza is pneumonia caused by either Staphylococcus
neuraminidase. As mentioned previously, influenza A virus aureus or Streptococcus pneumoniae.
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undergoes both major antigenic shifts as well as minor Reye’s syndrome, characterized by encephalopathy and
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antigenic drifts. Antigenic shift variants appear infre- liver degeneration, is a rare, life-threatening complication
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quently, whereas drift variants appear virtually every year. in children following some viral infections, particularly
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The last major antigenic shift that caused a pandemic in influenza B and chickenpox. Aspirin given to reduce fever
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humans was in 1968 when H3N2 emerged. Epidemics and in viral infections has been implicated in the pathogenesis
pandemics (worldwide epidemics) occur when the antige- of Reye’s syndrome.
nicity of the virus has changed sufficiently that the preexist-
ing immunity of many people is no longer effective. The
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Laboratory Diagnosis
antigenicity of influenza B virus undergoes antigenic drift
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Although most diagnoses of influenza are made on clinical
but not antigenic shift. The antigenic changes exhibited by grounds, laboratory tests are available. The test most com-
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influenza B virus are less dramatic and less frequent than monly used is an enzyme-linked immunosorbent assay
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those of influenza A virus. (ELISA) for viral antigen in respiratory secretions such as
Influenza occurs primarily in the winter months of
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nasal or throat washings, nasal or throat swabs, or sputum.f

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December to February in the northern hemisphere, when
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Several rapid ELISA tests suitable for a physician’s office

influenza and bacterial pneumonia secondary to influenza
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laboratory are available. Two tests (FLU OIA and QuickVue

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cause a significant number of deaths, especially in older Influenza Test) are based on detection of viral antigen using
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people. The morbidity of influenza in children younger monoclonal antibodies, and a third test (ZSTATFLU) is
than 2 years is also very high, second only to the morbidity
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based on detection of viral neuraminidase using a substrate

in the elderly. In the southern hemisphere (e.g., in Australia of the enzyme that changes color when cleaved by neur-
and New Zealand), influenza occurs primarily in the winter aminidase. The rationale for using the rapid tests is that
months of June through August. In the tropics, influenza
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treatment with the neuraminidase inhibitors should be

occurs year round with little seasonal variation. instituted within 48 hours of the onset of symptoms. Other
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tests such as direct fluorescent antibody and polymerase

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Pathogenesis & Immunity chain reaction (PCR) are also used.

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Influenza virus infection causes inflammation of the Influenza can also be diagnosed by the detection of anti-
mucosa of upper respiratory tract sites such as the nose and bodies in the patient’s serum. A rise in antibody titer of at
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316 PART IV  Clinical Virology
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least fourfold in paired serum samples taken early in the strains (H1N1 and H3N2) and one B strain. In 2013, quad-
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illness and 10 days later is sufficient for diagnosis. Either rivalent vaccines containing two A strains and two B strains

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the hemagglutination inhibition or complement fixation became available. The vaccine is usually reformulated each
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(CF) test can be used to assay the antibody titer. Because year to contain the current antigenic strains.
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the second sample is taken 10 days later, this approach is There are two main types of influenza vaccines available
used to make a retrospective diagnosis, often for epidemio- in the United States, a killed vaccine and a live, attenuated
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logic purposes. vaccine. The vaccine that has been used for many years is a
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killed vaccine containing purified protein subunits of the
Treatment virus (hemagglutinin and neuraminidase). The virus is
inactivated with formaldehyde and then treated with a lipid
Oseltamivir (Tamiflu) taken orally and zanamivir (Relenza)
solvent that disaggregates the virions. Note that the hemag-
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inhaled into the nose are the two most commonly used
glutinin is the most important antigen because it elicits
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drugs for the treatment of influenza. A third drug, perami-

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neutralizing antibody. This vaccine is typically adminis-
vir (Rapivab) is administered intravenously and became
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tered intramuscularly. A high-dose killed vaccine that
available in 2015. They are members of a class of drugs
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contains four times as much hemagglutinin as the standard
called neuraminidase inhibitors, which act by inhibiting
vaccine is recommended for those over 65 years of age. In

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the release of virus from infected cells. This limits the
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2011, a killed influenza vaccine that can be administered

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extent of the infection by reducing the spread of virus from
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intradermally became available.
one cell to another. These drugs are effective against both
The other vaccine is a live, attenuated vaccine contain-
influenza A and B viruses.
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ing temperature-sensitive mutants of influenza A and B
Resistance to Tamiflu occurs but currently is not clini-
viruses. These temperature-sensitive mutants can repli-
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cally significant. Some isolates of H1N1 influenza virus are
cate in the cooler (33°C) nasal mucosa where they induce
resistant to Tamiflu. However, H3N2 strains are still sus-
IgA, but not in the warmer (37°C) lower respiratory tract.
ceptible to Tamiflu. Both H1N1 and H3N2 strains remained
The live virus in the vaccine therefore immunizes but
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om

m
susceptible to Relenza. All influenza B strains are suscepti-
does not cause disease. This vaccine is administered by
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co
ble to Tamiflu and Relenza.
spraying into the nose (“nasal mist”). This vaccine is rec-
c

Tamiflu pills are administered orally, whereas Relenza

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e.

e.
ommended for children whereas the inactivated vaccine is
is delivered by inhaling the powder directly into the respi-
recommended for adults. The live vaccine should not be
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ratory tract. Clinical studies showed they reduce the dura-
given to pregnant women or to immunocompromised
sf

tion of symptoms by 1 to 2 days. They also reduce the

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individuals.
amount of virus produced and therefore reduce the chance
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Most of the vaccines described above are made in

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of spread to others. These drugs are most effective when
chicken eggs, and anyone who has a significant allergy to
o

taken within 48 hours of the onset of symptoms. In 2015,

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eb
egg proteins (e.g., anaphylaxis) should not receive these
some concern regarding the efficacy of Tamiflu and
vaccines. However, in 2012, the U.S. Food and Drug
m

m
Relenza arose. Additional studies are needed to resolve
Administration (FDA) approved a killed influenza vaccine
this issue.
(Flucelvax) made in calf kidney cell culture. This vaccine
Amantadine (Symmetrel) is approved for both the
has two advantages: It can be given to those with egg
treatment and prevention of influenza A. However, 90% of
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allergy, and it has a short turnaround time, so the latest
the H3N2 strains in the United States are resistant to
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drift mutant can be used.
amantadine (and rimantadine, see later), and so these
Also in 2012, the FDA approved a recombinant vaccine
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drugs are no longer recommended. These drugs block the
(Flublok) made by inserting the gene encoding the viral
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re
M2 ion channel, thereby inhibiting uncoating. Resistance
hemagglutinin into an insect virus (baculovirus) that is
is caused primarily by mutations in the gene for the M2
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propagated in insect cell culture. This vaccine contains

f
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protein.
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purified hemagglutinin as the immunogen. This vaccine

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Note that amantadine is effective only against influenza can also be given to those with egg allergy.
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A, not against influenza B. Rimantadine (Flumadine), a Note that the killed vaccine is not a good immunogen,
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derivative of amantadine, can also be used for treatment because little IgA is made and the titer of IgG is relatively
and prevention of influenza A and has fewer side effects
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low. Protection lasts only 6 months. Yearly boosters are

than amantadine. It should be emphasized that the vaccine recommended and should be given shortly before the flu
is preferred over these drugs in the prevention of season (e.g., in October). These boosters also provide an
influenza.
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opportunity to immunize against the latest antigenic

changes. The vaccine should be given to all persons 6
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Prevention
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months and older who do not have a contraindication to

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e.

The main mode of prevention is the vaccine, which con- receive the vaccine. It is especially important that people
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tains both influenza A and B viruses. Prior to 2013, the with chronic diseases, particularly respiratory and cardio-
vaccine was trivalent and contained recent isolates of two A vascular conditions, receive the vaccine. It should also be
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 e

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CHAPTER 39  RNA Enveloped Viruses 317
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e.

e.

e.

e.
given to health care personnel who are likely to transmit disease in humans for many years. This is attributed to two
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the virus to those at high risk. features of the H5N1 strain, namely, relative resistance to

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One side effect of the influenza vaccine used in the interferon and increased induction of cytokines, especially
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1970s containing the swine influenza strain that caused tumor necrosis factor. The increase in cytokines is thought
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influenza in humans was an increased risk of Guillain- to mediate the pathogenesis of the pneumonia and acute
Barré syndrome, which is characterized by an ascending respiratory distress syndrome (ARDS) seen in H5N1
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paralysis. Analysis of the side effects of the influenza vac- infection.
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cines in use during the last 10 years has shown no increased The H5N1 strain is sensitive to the neuraminidase
risk of Guillain-Barré syndrome. inhibitors, oseltamivir (Tamiflu) and zanamivir (Relenza),
In addition to the vaccine, influenza can be prevented by but not to amantadine and rimantadine. Tamiflu is the
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m
using oseltamivir (Tamiflu), which is described in the treat- drug of choice for both treatment and prevention. There is
ment section earlier. Oseltamivir is particularly useful in no human vaccine available against the H5N1 strain, but
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elderly people who have not been immunized and who may there is one available for use in avian species. In 2008, the
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have been exposed. Note that this drug should not be FDA approved an inactivated vaccine against H5N1 influ-
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thought of as a substitute for the vaccine. Immunization is enza virus, but as of this writing, it is not available to the
the most reliable mode of prevention. public. The vaccine is being stockpiled in the National

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Emergency Reserve.

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2. Avian Influenza Virus
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Infection in Humans H7N9 Influenza Virus
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In 2013, an outbreak of influenza caused by an H7N9
H5N1 Influenza Virus
strain of influenza virus occurred. Prior to this time, the
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In 1997, the H5N1 strain of influenza A virus that causes H7N9 strain affected only birds, especially chickens. As
avian influenza, primarily in chickens, caused an aggres- of July 2013, 133 people have been diagnosed with influ-
sive form of human influenza with high mortality in Hong enza caused by this virus, 43 of whom have died (32%
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m
Kong. In the winter of 2003–2004, an outbreak of avian mortality rate). Cases have been limited to China and
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influenza caused by H5N1 strain killed thousands of Taiwan. There has been no sustained person-to-person
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chickens in several Asian countries. Millions of chickens

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spread.
were killed in an effort to stop the spread of the disease. All of the genes of this virus are of avian origin. It
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Four hundred eight human cases of H5N1 influenza acquired its H7 gene from ducks and its N9 gene from wild
sf

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occurred between 2003 and February 2009, resulting in birds, and all the other genes are from an influenza strain
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254 deaths (a mortality rate of 62%). Note that these 408 that infects bramblings, a bird common in Asia and
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people were infected directly from chickens. Both the
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Europe. This H7N9 strain is susceptible to the neuramini-

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respiratory secretions and the chicken guano contain dase inhibitors, oseltamivir and zanamivir. There is no
infectious virus. vaccine.
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The spread of the H5N1 strain from person to person
occurs rarely but remains a major concern because it could 3. Swine Influenza Virus
increase dramatically if reassortment with the human-
Infection in Humans
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adapted strains occurs. In 2005, the H5N1 virus spread
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from Asia to Siberia and into eastern Europe, where it In April 2009, a novel swine origin strain of influenza A
killed thousands of birds but has not caused human dis- (H1N1) virus (swine-origin influenza virus, S-OIV) caused
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ease. As of this writing (February 2016), there have been no an outbreak of human influenza, which appeared first in
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cases of human influenza caused by an H5N1 virus in the Mexico, then in the United States, followed by spread to
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United States. However, there have been two cases of 208 countries by December 2009. The Centers for Disease f
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human influenza caused by an H7N2 strain of avian influ- Control and Prevention (CDC) uses the name “novel influ-
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enza virus. enza A (H1N1)” for this virus.

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The ability of the H5N1 strain to infect chickens (and As of December 2009, millions of cases have occurred
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other birds) more effectively than humans is due to the worldwide. There have been so many cases that most coun-
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presence of a certain type of viral receptor throughout the tries have stopped documenting the number of cases.
mucosa of the chicken respiratory tract. In contrast, Worldwide there have been 9596 deaths, of which 1445
humans have this type of receptor only in the alveoli, not in have occurred in the United States. On June 11, 2009, the
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the upper respiratory tract. This explains why humans are World Health Organization (WHO) declared a level 6 pan-
rarely infected with the H5N1 strain. However, when the demic (the highest level alert). By August 2010, the number
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exposure is intense, the virus is able to reach the alveoli and of cases had declined significantly and the pandemic warn-
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causes severe pneumonia. ing was rescinded. As of this writing in February 2016, the
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The virulence of the H5N1 strain is significantly greater number of cases in the United States and worldwide have
than the H1N1 and H3N2 strains that have been causing significantly declined.
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 e

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318 PART IV  Clinical Virology
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The disease affected primarily young people (60% of of the genes that are not polymerase genes are of North
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cases were 18 years old or younger). Symptoms were in American swine origin and the polymerase genes have the

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general mild, with the few fatalities occurring in medically same origin as the quadruple reassortant. This strain does
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compromised patients. There was no outbreak of swine not have genes of Eurasian swine origin.
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influenza in pigs prior to this human outbreak. Eating pork The key point is that most people worldwide do not
does not transmit the virus. have protective antibodies against the swine hemagglutinin
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S-OIV is a quadruple reassortant: The hemagglutinin, of S-OIV even though they may have antibodies against the
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nucleoprotein, and nonstructural protein genes are of seasonal strain of H1N1 virus acquired either by immuni-
North American swine origin, the neuraminidase and zation or by exposure to the virus itself. Note also that
matrix protein genes are of Eurasian swine origin, the genes S-OIV spreads readily from human to human in contrast to
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that encode two subunits of the polymerase are of North the avian H5N1 strain that does not.
American avian origin, and the gene that encodes the third A PCR test for the diagnosis of S-OIV infection is avail-
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subunit of the polymerase is of human H3N2 origin. able. S-OIV is sensitive to oseltamivir and zanamivir but
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A triple reassortant strain circulated in North American resistant to amantadine and rimantadine. Both an inacti-
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swine for several years prior to 2009 but caused human vated and a live, attenuated vaccine against S-OIV became
influenza only rarely. In the triple reassortant strain, all five widely available in November 2009.

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PARAMYXOVIRUSES  
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The paramyxovirus family contains four important human Important Properties
pathogens: measles virus, mumps virus, respiratory syncy-
The genome RNA and nucleocapsid of measles virus are
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tial virus, and parainfluenza viruses. They differ from
those of a typical paramyxovirus (see earlier). The virion
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orthomyxoviruses in that their genomes are not seg-
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has two types of envelope spikes, one with hemagglutinat-

mented, they have a larger diameter, and their surface
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ing activity and the other with cell-fusing and hemolytic
spikes are different (see Table 39–1).
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activities (see Table 39–4). It has a single serotype, and the
Paramyxoviruses are composed of one piece of single-
hemagglutinin is the antigen against which neutralizing
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stranded RNA, a helical nucleocapsid, and an outer lipopro-

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antibody is directed. Humans are the natural host.
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tein envelope. The virion contains an RNA-dependent RNA

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polymerase, which transcribes the negative-polarity
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genome into mRNA. The genome is therefore not infectious.

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The envelope is covered with spikes, which contain hemag-
Summary of Replicative Cycle
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m
glutinin, neuraminidase, or a fusion protein that causes cell After adsorption to the cell surface via its hemaggluti-
fusion and, in some cases, hemolysis (Table 39–4). nin, the virus penetrates and uncoats and the virion
RNA polymerase transcribes the negative-strand genome
into mRNA. Multiple mRNAs are synthesized, each of
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MEASLES VIRUS which is translated into the specific viral proteins; no
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polyprotein analogous to that synthesized by poliovirus
Disease
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is made. The helical nucleocapsid is assembled, the
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This virus causes measles, a disease characterized by a matrix protein mediates the interaction with the enve-
maculopapular rash. It occurs primarily in childhood. (See lope, and the virus is released by budding from the cell
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“Clinical Findings” section for additional information.) membrane.
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TABLE 39–4  Envelope Spikes of Paramyxoviruses

m

Virus Hemagglutinin Neuraminidase Fusion Protein1

Measles virus + – +
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Mumps virus2 + + +
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Respiratory syncytial virus – – +

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2
Parainfluenza virus + + +
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1
The measles and mumps fusion proteins are hemolysins also.
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2
In mumps and parainfluenza viruses, the hemagglutinin and neuraminidase are on the same spike, and the fusion protein is on a different spike.
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CHAPTER 39  RNA Enveloped Viruses 319
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e.
Transmission & Epidemiology the surface of human macrophages, the production of
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interleukin-12 (IL-12), which is necessary for cell-mediated
Measles virus is transmitted via respiratory droplets pro-

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immunity to occur, is suppressed.
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duced by coughing and sneezing both during the prodro-
mal period and for a few days after the rash appears.
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Measles occurs worldwide, usually in outbreaks every 2 to Clinical Findings
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3 years, when the number of susceptible children reaches a After an incubation period of 10 to 14 days, a prodromal
high level. The WHO estimates there are 30 million cases phase characterized by fever, conjunctivitis (causing photo-
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m
of measles each year worldwide. phobia), running nose, and coughing occurs. Koplik’s
In the year 2000, CDC declared measles eliminated spots are bright red lesions with a white, central dot that are
from the United States. Elimination meant that sustained located on the buccal mucosa and are virtually diagnostic.
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transmission within the United States no longer occurred. A few days later, a maculopapular rash appears on the face
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However, cases acquired abroad (imported cases) followed and proceeds gradually down the body to the lower

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by small outbreaks continue to occur. extremities, including the palms and soles (Figure 39–3).
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The attack rate is one of the highest of viral diseases; The rash develops a brownish hue several days later.
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most children contract the clinical disease on exposure. The complications of measles can be quite severe.

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When this virus is introduced into a population that has Encephalitis occurs at a rate of 1 per 1000 cases of measles.
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not experienced measles, such as the inhabitants of the The mortality rate of encephalitis is 10%, and there are
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Hawaiian Islands in the 1800s, devastating epidemics permanent sequelae, such as deafness and mental retarda-
occur. In malnourished children, especially those in devel- tion, in 40% of cases. In addition, both primary measles
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oping countries, measles is a much more serious disease (giant cell) pneumonia and secondary bacterial pneumonia
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m
than in well-nourished children. Vitamin A deficiency is occur. Bacterial otitis media is quite common. Subacute
especially important in this regard, and supplementation of sclerosing panencephalitis (SSPE) is a rare, fatal disease of
this vitamin greatly reduces the severity of measles. Patients the central nervous system that occurs several years after
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with deficient cell-mediated immunity (e.g., AIDS patients) measles (see Chapter 44).
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have a severe, life-threatening disease when they contract
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measles.
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Pathogenesis & Immunity
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After infecting the cells lining the upper respiratory tract,
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the virus enters the blood and infects reticuloendothelial

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cells, where it replicates again. It then spreads via the blood
o
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to the skin. The rash is caused primarily by cytotoxic T
cells attacking the measles virus–infected vascular endo-
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m
thelial cells in the skin. Antibody-mediated vasculitis may
also play a role. Shortly after the rash appears, the virus can
no longer be recovered and the patient can no longer
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spread the virus to others. Multinucleated giant cells,
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which form as a result of the fusion protein in the spikes,
are characteristic of the lesions.
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e.
Lifelong immunity occurs in individuals who have had
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the disease. Although IgG antibody may play a role in neu-

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tralizing the virus during the viremic stage, cell-mediated f

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immunity is more important. The importance of cell-

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mediated immunity is illustrated by the fact that agamma-

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globulinemic children have a normal course of disease, are

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subsequently immune, and are protected by immunization.

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Maternal antibody passes the placenta, and infants are pro-

tected during the first 6 months of life.
Infection with measles virus can transiently depress
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cell-mediated immunity against other intracellular micro-

organisms, such as Mycobacterium tuberculosis, leading to a
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loss of purified protein derivative (PPD) skin test reactivity,

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reactivation of dormant organisms, and clinical disease. FIGURE 39–3  Measles—note splotchy “morbilliform” macular-
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The proposed mechanism for this unusual finding is that papular rash. (Source: Public Health Image Library, Centers for Disease Control
when measles virus binds to its receptor (called CD46) on
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and Prevention.)
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320 PART IV  Clinical Virology
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Measles in a pregnant woman leads to an increased risk spikes: one with both hemagglutinin and neuraminidase
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of stillbirth rather than congenital abnormalities. Measles activities and the other with cell-fusing and hemolytic

f
virus infection of the fetus is more severe than rubella virus activities (see Table 39–4).
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infection, so the former typically causes fetal death, whereas The virus has a single serotype. Neutralizing antibody is
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the latter causes congenital abnormalities. directed against the hemagglutinin. The internal nucleo-
Atypical measles occurs in some people who were given capsid protein is the S (soluble) antigen detected in the CF
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the killed vaccine and were subsequently infected with test used for diagnosis. Humans are the natural host.
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measles virus. It is characterized by an atypical rash without
Koplik’s spots. Because the killed vaccine has not been used Summary of Replicative Cycle
for many years, atypical measles occurs only in adults and Replication is similar to that of measles virus (see page 318).
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is infrequent.
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Transmission & Epidemiology

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Laboratory Diagnosis
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Mumps virus is transmitted via respiratory droplets.
Most diagnoses are made on clinical grounds, but the virus Mumps occurs worldwide, with a peak incidence in the
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can be isolated in cell culture. A greater than fourfold rise winter. About 30% of children have a subclinical (inappar-

sf
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in antibody titer can be used to diagnose difficult cases. ent) infection, which confers immunity. There were only

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PCR assay is also used. 683 reported cases of mumps in the United States in
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1997—a finding attributed to the widespread use of the
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Treatment vaccine. However, in 2006, a resurgence of mumps
There is no antiviral therapy available. occurred, with 6584 cases being recorded despite a high
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(87%) coverage rate for the vaccine.
Prevention
Pathogenesis & Immunity
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Prevention rests on immunization with the live, attenuated
The virus infects the upper respiratory tract and then
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vaccine. The vaccine is effective and causes few side effects.
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It is given subcutaneously to children at 15 months of age, spreads through the blood to infect the salivary glands,
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usually in combination with rubella and mumps vaccines. especially the parotid gland, testes, ovaries, pancreas, and,
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The vaccine should not be given to children prior to 15 in some cases, meninges. Alternatively, the virus may
ascend from the buccal mucosa up Stensen’s duct to the
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months of age, because maternal antibody in the child

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parotid gland.
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can neutralize the virus and reduce the immune response.

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Because immunity can wane, a booster dose is recom- Lifelong immunity occurs in persons who have had the
o

mended. The vaccine contains live virus, so it should not be disease. There is a popular misconception that unilateral
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given to immunocompromised persons or pregnant mumps can be followed by mumps on the other side.
Mumps occurs only once; subsequent cases of parotitis can
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m
women. The vaccine has decreased the number of cases of
measles greatly in the United States; there were only 138 be caused by other viruses such as parainfluenza viruses, by
reported cases of measles in 1997. However, outbreaks still bacteria, and by duct stones. Maternal antibody passes the
placenta and provides protection during the first 6 months
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occur among unimmunized individuals (e.g., children in
inner cities and in developing countries). of life.
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The killed vaccine should not be used. Immune globu-
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e.
lin can be used to modify the disease if given to unimmu- Clinical Findings
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re
nized individuals early in the incubation period. This is After an incubation period of 18 to 21 days, a prodromal
especially necessary if the unimmunized individuals are
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stage of fever, malaise, and anorexia is followed by tender f

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immunocompromised.
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swelling of the salivary glands, either unilateral or bilateral

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(Figure 39–4). There is a characteristic increase in parotid

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gland pain when drinking citrus juices. The disease is typi-

MUMPS VIRUS
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cally benign and resolves spontaneously within 1 week.

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Disease Two complications are of significance. One is orchitis in

postpubertal males, which, if bilateral, can result in sterility.
This virus causes mumps, a disease characterized by salivary
Postpubertal males have a fibrous tunica albuginea, which
gland swelling. It occurs primarily in childhood. (See “Clini-
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resists expansion, thereby causing pressure necrosis of the

cal Findings” section for a more complete description.)
spermatocytes. Unilateral orchitis, although quite painful,
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does not lead to sterility. The other complication is menin-

Important Properties
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e.

gitis, which is usually benign, self-limited, and without

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The genome RNA and nucleocapsid are those of a typical sequelae. Mumps virus, Coxsackie virus, and echovirus are
paramyxovirus. The virion has two types of envelope the three most frequent causes of viral (aseptic) meningitis.
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CHAPTER 39  RNA Enveloped Viruses 321
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Prevention
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Prevention consists of immunization with the live, attenu-

f
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ated vaccine. The vaccine is effective and long-lasting (at
least 10 years) and causes few side effects. Two immuniza-
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tions are recommended, one at 15 months and a booster
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dose at 4 to 6 years, usually in combination with measles
and rubella vaccines. Because it is a live vaccine, it should
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not be given to immunocompromised persons or pregnant
women. Immune globulin is not useful for preventing or
mitigating mumps orchitis.
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In the late 1980s, outbreaks of mumps occurred in
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both immunized and unimmunized people. This led to

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the recommendation in 1989 that a second course of the
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MMR (measles, mumps, rubella) vaccine be adminis-
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tered. The incidence of mumps fell, and outbreaks did not

sf
occur until 2006, when 6584 cases occurred, primarily in
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college-age individuals who, surprisingly, had received
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two doses of the vaccine. Waning immunity after the sec-
ond dose and immunization with a different genotype
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eb

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from the genotype that caused the outbreak are suggested
m

m
explanations.
In 2009 and again in 2014, outbreaks of mumps occurred
in young adults including those who had received two
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om

m
doses of vaccine. In many individuals, more than 10 years
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had elapsed since their last MMR immunization, indicating
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FIGURE 39–4  Mumps—note bilateral swelling of neck due to that waning immunity may play a role.
e.

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e.

e.
inflammation of salivary glands. Note also absence of a rash as
re

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mumps is not a rash disease, unlike measles and rubella. (Source:
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Dr. Patricia Smith and Dr. Barbara Rice, Public Health Image Library, Centers for
RESPIRATORY SYNCYTIAL VIRUS
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Disease Control and Prevention.)

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o

Diseases
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The widespread use of the vaccine in the United States has
led to a marked decrease in the incidence of mumps Respiratory syncytial virus (RSV) is the most important
m

m
meningitis. cause of pneumonia and bronchiolitis in infants. It is also
an important cause of otitis media in children and of pneu-
monia in the elderly and in patients with chronic cardio-
Laboratory Diagnosis pulmonary diseases.
m

m
The diagnosis of mumps is usually made clinically, but
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laboratory tests are available for confirmation. The virus
Important Properties
e.

e.

e.

e.
can be isolated in cell culture from saliva, spinal fluid, or
urine. PCR assay can also be used. In addition, a fourfold
re

fre

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re
The genome RNA and nucleocapsid are those of a typical
rise in antibody titer in either the hemagglutination inhibi-
sf

paramyxovirus (see Table 39–1). Its surface spikes are f

ks

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tion or the CF test is diagnostic. A single CF test that assays fusion proteins, not hemagglutinins or neuraminidases
ok

both the S and the V (viral) antigens can also be used.

oo

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(see Table 39–4). The fusion protein causes cells to fuse,

o

Because antibody to S antigen appears early and is short- forming multinucleated giant cells (syncytia), which give
eb

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lived, it indicates current infection. If only V antibody is rise to the name of the virus.
found, the patient has had mumps in the past.
m

Humans are the natural hosts of RSV. For many years,

A mumps skin test based on delayed hypersensitivity RSV was thought to have one serotype; however, two sero-
can be used to detect previous infection, but serologic types, designated subgroup A and subgroup B, have been
tests are preferred. The mumps skin test is widely used to detected by monoclonal antibody tests. Antibody against
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determine whether a patient’s cell-mediated immunity is the fusion protein neutralizes infectivity.
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competent.
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Treatment Summary of Replicative Cycle

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There is no antiviral therapy for mumps. Replication is similar to that of measles virus (see page 318).
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322 PART IV  Clinical Virology
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e.

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Transmission & Epidemiology regarding its effectiveness. A combination of ribavirin and
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hyperimmune globulins against RSV may be more
Transmission occurs via respiratory droplets and by direct

f
effective.
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contact of contaminated hands with the nose or mouth.
RSV causes outbreaks of respiratory infections every win-
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ter, in contrast to many other “cold” viruses, which reenter Prevention
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the community every few years. It occurs worldwide, and There is no vaccine. Previous attempts to protect with a
virtually everyone has been infected by the age of 3 years. killed vaccine resulted in an increase in severity of symp-
m

m
RSV also causes outbreaks of respiratory infections in hos- toms. Passive immunization with a monoclonal antibody
pitalized infants; these outbreaks can be controlled by directed against the fusion protein of RSV (palivizumab,
handwashing and use of gloves, which interrupt transmis- Synagis) can be used for prophylaxis in premature or
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om

m
sion by hospital personnel. immunocompromised infants. Hyperimmune globulins
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(RespiGam) are also available for prophylaxis in these

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Pathogenesis & Immunity infants and in children with chronic lung disease. Noso-
e.

e.

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e.
RSV infection in infants is more severe and more often comial outbreaks can be limited by handwashing and use
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involves the lower respiratory tract than in older children of gloves.

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and adults. The infection is localized to the respiratory

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tract; viremia does not occur.
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The severe disease in infants may have an immuno- PARAINFLUENZA VIRUSES
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pathogenic mechanism. Maternal antibody passed to the
infant may react with the virus, form immune complexes,
Diseases
m

m
and damage the respiratory tract cells. Trials with a killed These viruses cause croup (acute laryngotracheobronchitis),
vaccine resulted in more severe disease, an unexpected laryngitis, bronchiolitis, and pneumonia in children and a
finding that supports such a mechanism. disease resembling the common cold in adults.
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Most individuals have multiple infections caused by
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RSV, indicating that immunity is incomplete. The reason Important Properties
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for this is unknown, but it is not due to antigenic variation

e.

e.

e.

e.
The genome RNA and nucleocapsid are those of a typical
of the virus. IgA respiratory antibody reduces the fre-
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fre

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paramyxovirus (see Table 39–1). The surface spikes con-
quency of RSV infection as a person ages.
sist of hemagglutinin (H), neuraminidase (N), and fusion
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(F) proteins (see Table 39–4). The fusion protein mediates
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Clinical Findings
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the formation of multinucleated giant cells. The H and N
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In infants, RSV is an important cause of lower respiratory proteins are on the same spike; the F protein is on a sepa-
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tract diseases such as bronchiolitis and pneumonia. RSV is rate spike. Both humans and animals are infected by para-
also an important cause of otitis media in young children. influenza viruses, but the animal strains do not infect
m

m
In older children and young, healthy adults, RSV causes humans. There are four types, which are distinguished by
respiratory tract infections such as the common cold and antigenicity, cytopathic effect, and pathogenicity (see
bronchitis. However, in the elderly (people older than 65 later). Antibody to either the H or the F protein neutral-
m

m
years of age) and in adults with chronic cardiopulmonary izes infectivity.
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diseases, RSV causes severe lower respiratory tract disease,
including pneumonia.
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e.
Summary of Replicative Cycle
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Replication is similar to that of measles virus (see page 318).
Laboratory Diagnosis
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An enzyme immunoassay (“rapid antigen test”) that detects
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Transmission & Epidemiology

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the presence of RSV antigens in respiratory secretions is

o

commonly used. The presence of the virus can be detected These viruses are transmitted via respiratory droplets.
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by immunofluorescence on smears of respiratory epithe- They cause disease worldwide, primarily in the winter
lium or by isolation in cell culture. The cytopathic effect in months.
m

cell culture is characterized by the formation of multinucle-

ated giant cells. A fourfold or greater rise in antibody titer Pathogenesis & Immunity
is also diagnostic. A reverse transcriptase polymerase chain
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These viruses cause upper and lower respiratory tract

reaction (RT-PCR) test is also available. disease without viremia. A large proportion of infections
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are subclinical. Parainfluenza viruses 1 and 2 are major

Treatment
e.

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causes of croup. Parainfluenza virus 3 is the most com-

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Aerosolized ribavirin (Virazole) is recommended for mon parainfluenza virus isolated from children with
severely ill hospitalized infants, but there is uncertainty lower respiratory tract infection in the United States.
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CHAPTER 39  RNA Enveloped Viruses 323
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Parainfluenza virus 4 rarely causes disease, except for the Laboratory Diagnosis
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common cold.
Most infections are diagnosed clinically. The diagnosis can

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be made in the laboratory either by isolating the virus in
Clinical Findings cell culture or by observing a fourfold or greater rise in
oo

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Parainfluenza viruses are best known as the main cause of antibody titer. PCR assay can also be used.
croup in children younger than 5 years of age. Croup is
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characterized by a harsh cough and hoarseness. In addition
m

m
to croup, these viruses cause a variety of respiratory dis-
eases such as the common cold, pharyngitis, laryngitis, Treatment & Prevention
otitis media, bronchitis, and pneumonia. There is neither antiviral therapy nor a vaccine available.
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e.

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CORONAVIRUSES  

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CORONAVIRUS Transmission & Epidemiology
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Coronaviruses are transmitted by the respiratory aero-
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Diseases sol. Infection occurs worldwide and occurs early in life,
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m
Coronaviruses are an important cause of the common cold, as evidenced by finding antibody in more than half of
probably second only to rhinoviruses in frequency. In 2002, children. Outbreaks occur primarily in the winter on a
a new disease, an atypical pneumonia called severe acute 2- to 3-year cycle.
respiratory syndrome (SARS), emerged. In 2012, another
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SARS originated in China in November 2002 and spread
severe pneumonia called Middle East respiratory syndrome rapidly to other countries. As of this writing, there have
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emerged.
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been 8300 cases and 785 deaths—a fatality rate of approxi-

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mately 9%. Human-to-human transmission occurs, and
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some patients with SARS are thought to be “super-spread-
Important Properties ers.” Early in the outbreak, many hospital personnel were
sf

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Coronaviruses have a nonsegmented, single-stranded, affected, but respiratory infection control procedures have
ok

positive-polarity RNA genome. They are enveloped

oo

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greatly reduced the spread within hospitals. There are
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viruses with a helical nucleocapsid. There is no virion many animal coronaviruses, and they are suspected of
eb

eb

eb

eb
polymerase. In the electron microscope, prominent club- being the source of CoV-SARS. The horseshoe bat appears
shaped spikes in the form of a corona (halo) can be seen.
m

m
to be the natural reservoir for CoV-SARS, with the civet cat
There are two serotypes called 229E and OC43. The serving as an intermediate host.
genome sequence of the coronavirus that caused the SARS In 2012–2013, a new human coronavirus caused an out-
(CoV-SARS) outbreak is different from that of the exist- break of serious, often fatal pneumonia in Saudi Arabia and
m

m
ing human strains. The genome sequence of different other countries in the region. The disease is called Middle
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isolates of CoV-SARS is very similar, so the antigenicity of East respiratory syndrome (MERS), and the virus is called
the virus is likely to be quite stable. The receptor for the
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e.
MERS coronavirus (MERS-CoV). Its closest relative is a bat
SARS coronavirus on the surface of cells is angiotensin- coronavirus, and bats are thought to be a reservoir. Close
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converting enzyme-2. contact with camels appears to be the mode of transmission

re
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to humans. The risk of person-to-person transmission is
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Summary of Replicative Cycle low but has occurred in hospitals with inadequate infection
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o

control. Another name for the virus is human coronavirus-

The virus adsorbs to cells via its surface spikes (hemag-
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EMC (HCoV-EMC).
glutinin), after which it enters the cytoplasm, where it is
m

uncoated. The positive-strand genome is translated into

two large polypeptides, which are self-cleaved by the Pathogenesis & Immunity
virus-encoded protease. Two of these peptides aggregate Coronavirus infection is typically limited to the mucosal
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to form the RNA polymerase that replicates the genome. cells of the respiratory tract. Approximately 50% of infec-
In addition, mRNAs are synthesized and then translated tions are asymptomatic, and it is unclear what role they
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into the structural proteins. The virus is assembled and play in the spread of infection. Immunity following infec-
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e.

e.

e.

obtains its envelope from the endoplasmic reticulum, tion appears to be brief, and reinfection can occur.
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not from the plasma membrane. Replication occurs in Pneumonia caused by SARS coronavirus is character-
ized by diffuse edema resulting in hypoxia. The binding of
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the cytoplasm.
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324 PART IV  Clinical Virology
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e.

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the virus to angiotensin-converting enzyme-2 (ACE-2) on Chest X-ray reveals interstitial “ground-glass” infiltrates
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the surface of respiratory tract epithelium may contribute that do not cavitate. Leukopenia and thrombocytopenia are

f
to the dysregulation of fluid balance that causes the edema seen. The incubation period for SARS ranges from 2 to 10
ks

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in the alveolar space. MERS-CoV binds to CD-26 on the days, with a mean of 5 days. The clinical findings of MERS
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respiratory mucosa, not to ACE-2. are similar to those of SARS.
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Clinical Findings Laboratory Diagnosis
m

m
The common cold caused by coronavirus is characterized The diagnosis of the “common cold” is primarily a clinical
by coryza (rhinorrhea, runny nose), scratchy sore throat, one. If SARS or MERS is suspected, antibody-based and
and low-grade fever. This illness typically lasts several days PCR-based tests can be used.
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and has no long-term sequelae. Coronaviruses also cause
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bronchitis. Treatment & Prevention

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SARS is a severe atypical pneumonia characterized by a
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e.

e.

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There is no antiviral therapy or vaccine available. A combi-
fever of at least 38°C, nonproductive cough, dyspnea, and
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re
nation of ribavirin and steroids has been tried in the treat-
hypoxia. Chills, rigors, malaise, and headache commonly ment of life-threatening cases of SARS, but their efficacy is

sf
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occur, but sore throat and rhinorrhea are uncommon. uncertain.

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TOGAVIRUSES  
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RUBELLA VIRUS Transmission & Epidemiology
The virus is transmitted via respiratory droplets and from
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Diseases mother to fetus transplacentally. The disease occurs
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This virus causes rubella and congenital rubella syndrome. worldwide. In areas where the vaccine is not used, epidem-
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Congenital rubella syndrome is characterized by congeni-

e.

e.

e.

e.
ics occur every 6 to 9 years.
tal malformations. In 2005, the CDC declared rubella eliminated from the
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United States and in 2015 rubella was declared eliminated
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Important Properties from the Western hemisphere. The few cases that occur in
ok

the United States are acquired outside and imported into

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Rubella virus is a member of the togavirus family. It is
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composed of one piece of single-stranded RNA, an icosa- this country. Elimination was made possible by the wide-
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hedral nucleocapsid, and a lipoprotein envelope. How- spread use of the vaccine. As a result, cytomegalovirus is a
much more common cause of congenital malformations in
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m
ever, unlike the paramyxoviruses, such as measles and
mumps viruses, it has a positive-strand RNA and there- the United States than is rubella virus.
fore has no virion polymerase. Its surface spikes contain
hemagglutinin. The virus has a single antigenic type. Anti- Pathogenesis & Immunity
m

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body against hemagglutinin neutralizes infectivity.
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Initial replication of the virus occurs in the nasopharynx and
Humans are the natural host.
local lymph nodes. From there it spreads via the blood to the
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e.

e.

e.
internal organs and skin. The origin of the rash is unclear; it
Summary of Replicative Cycle
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may be due to antigen/antibody–mediated vasculitis.

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Because knowledge of rubella virus replication is incom- Natural infection leads to lifelong immunity. Second f
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ok

plete, the following cycle is based on the replication of cases of rubella do not occur; similar rashes are caused by
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other togaviruses. After penetration of the cell and uncoat- other viruses, such as Coxsackie viruses and echoviruses.
o

ing, the plus-strand RNA genome is translated into several Antibody crosses the placenta and protects the newborn.
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nonstructural and structural proteins. Note the difference

m

between togaviruses and poliovirus, which also has a plus-

strand RNA genome but translates its RNA into a single Clinical Findings
large polyprotein, which is subsequently cleaved. One of Rubella
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the nonstructural rubella proteins is an RNA-dependent Rubella is a milder, shorter disease than measles. After an
RNA polymerase, which replicates the genome first by incubation period of 14 to 21 days, a brief prodromal
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making a minus-strand template and then, from that, plus- period with fever and malaise is followed by a maculopapu-
e.

e.

e.

e.

strand progeny. Both replication and assembly occur in the lar rash, which starts on the face and progresses downward
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cytoplasm, and the envelope is acquired from the outer to involve the extremities (Figure 39–5). Posterior auricular
membrane as the virion exits the cell. lymphadenopathy is characteristic. The rash typically lasts
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CHAPTER 39  RNA Enveloped Viruses 325
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e.

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identified by its ability to interfere with echovirus CPE. If
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rubella virus is present in the patient’s specimen and has

f
grown in the cell culture, no CPE will appear when the
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culture is superinfected with an echovirus. The diagnosis
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can also be made by observing a fourfold or greater rise in
antibody titer between acute-phase and convalescent-phase
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eb

eb

eb
sera in the hemagglutination inhibition test or ELISA or by
m

m
observing the presence of IgM antibody in a single acute-
phase serum sample. PCR assay can also be used.
In a pregnant woman exposed to rubella virus, the pres-
ence of IgM antibody indicates recent infection, whereas
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a 1:8 or greater titer of IgG antibody indicates immunity
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and consequent protection of the fetus. If recent infection
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e.

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has occurred, an amniocentesis can reveal whether there is
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rubella virus in the amniotic fluid, which indicates definite
fetal infection.

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oo

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Treatment
There is no antiviral therapy.
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m

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Prevention
Prevention involves immunization with the live, attenu-
ated vaccine. The vaccine is effective and long-lasting (at
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FIGURE 39–5  Rubella—note fine, almost confluent macular- least 10 years) and causes few side effects, except for tran-
papular rash. (Used with permission from Stephen E. Gellis, MD.)
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co
sient arthralgias in some women. It is given subcutaneously
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to children at 15 months of age (usually in combination

e.

e.

e.

e.
3 days. When rubella occurs in adults, especially women, with measles and mumps vaccine) and to unimmunized
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polyarthritis caused by immune complexes often occurs. young adult women if they are not pregnant and will use
sf

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contraception for the next 3 months. There is no evidence
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Congenital Rubella Syndrome that the vaccine virus causes malformations. Because it is a
oo

oo

oo
live vaccine, it should not be given to immunocompro-
o

The significance of rubella virus is not as a cause of mild

eb

eb

eb

eb
childhood disease but as a teratogen. When a nonimmune mised patients or to pregnant women.
pregnant woman is infected during the first trimester, The vaccine has caused a significant reduction in the
m

m
especially the first month, significant congenital malforma- incidence of both rubella and congenital rubella syndrome.
tions can occur as a result of maternal viremia and fetal It induces some respiratory IgA, thereby interrupting the
infection. The increased rate of abnormalities during the spread of virulent virus by nasal carriage.
m

m
early weeks of pregnancy is attributed to the very sensitive Immune serum globulins (IG) can be given to pregnant
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organ development that occurs at that time. The malforma- women in the first trimester who have been exposed to a
tions are widespread and involve primarily the heart (e.g., known case of rubella and for whom termination of the
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e.

e.

e.
patent ductus arteriosus), the eyes (e.g., cataracts), and the pregnancy is not an option. The main problems with giving
re

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re
brain (e.g., deafness and mental retardation). IG are that there are instances in which it fails to prevent
sf

In addition, some children infected in utero can con-

f
fetal infection and that it may confuse the interpretation of
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ok

tinue to excrete rubella virus for months after birth, which serologic tests. If termination of the pregnancy is an option,
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is a significant public health hazard because the virus can it is recommended to attempt to determine whether the
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mother and fetus have been infected as described in the

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be transmitted to pregnant women. Some congenital shed-

ders are asymptomatic and without malformations and preceding “Laboratory Diagnosis” section.
m

hence can be diagnosed only if the virus is isolated. Con- To protect pregnant women from exposure to rubella
genitally infected infants also have significant IgM titers virus, many hospitals require their personnel to demon-
and persistent IgG titers long after maternal antibody has strate immunity, either by serologic testing or by proof of
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disappeared. immunization.
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Laboratory Diagnosis OTHER TOGAVIRUSES

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Rubella virus can be grown in cell culture, but it produces Several other medically important togaviruses are described
little cytopathic effect (CPE). It is therefore usually in the chapter on arboviruses (see Chapter 42).
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326 PART IV  Clinical Virology
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RHABDOVIRUSES  
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RABIES VIRUS sequence of the genome RNA. For example, a person devel-
oped clinical rabies in the United States, but sequencing of
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Disease the genome RNA revealed that the virus was the Mexican
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This virus causes rabies, an encephalitis. strain. It was later discovered that the man had been bitten
by a dog while in Mexico several months earlier.
m

m
Important Properties
Rabies virus is the only medically important member of the
Pathogenesis & Immunity
The virus multiplies locally at the bite site, infects the sen-
m

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m
rhabdovirus family. It has a single-stranded RNA enclosed
within a bullet-shaped capsid surrounded by a lipoprotein sory neurons, and moves by axonal transport to the cen-
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co
tral nervous system. During its transport within the nerve,

c
envelope. Because the genome RNA has negative polarity,
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the virion contains an RNA-dependent RNA polymerase. the virus is sheltered from the immune system and little, if
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Rabies virus has a single antigenic type. The antigenicity any, immune response occurs. The virus multiplies in the
central nervous system and then travels down the periph-

sf
resides in the envelope glycoprotein spikes.
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Rabies virus has a broad host range: It can infect all eral nerves to the salivary glands and other organs. From

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the salivary glands, it enters the saliva to be transmitted by
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mammals, but only certain mammals are important sources
of infection for humans (see later). the bite. There is no viremic stage.
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Within the central nervous system, encephalitis devel-
Summary of Replicative Cycle ops, with the death of neurons and demyelination. Infected
m

m
neurons contain an eosinophilic cytoplasmic inclusion
Rabies virus attaches to the acetylcholine receptor on the called a Negri body, which is important in laboratory diag-
cell surface. After entry into the cell, the virion RNA poly- nosis of rabies (Figure 39–6). Because so few individuals
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merase synthesizes five mRNAs that code for viral proteins. have survived rabies, there is no information regarding
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After replication of the genome viral RNA by a virus- immunity to disease upon being bitten again.
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encoded RNA polymerase, progeny RNA is assembled with

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virion proteins to form the nucleocapsid, and the envelope
Clinical Findings
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is acquired as the virion buds through the cell membrane.
sf

The incubation period varies, according to the location of

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Transmission & Epidemiology the bite, from as short as 2 weeks to 16 weeks or longer. It
ok

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is shorter when bites are sustained on the head rather than
The virus is transmitted by the bite of a rabid animal that
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on the leg, because the virus has a shorter distance to travel

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manifests aggressive, biting behavior induced by the viral
to reach the central nervous system.
encephalitis. The virus is in the saliva of the rabid animal.
m

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Clinically, the patient exhibits a prodrome of nonspe-
In the United States, transmission is usually from the bite of
cific symptoms such as fever, anorexia, and changes in
wild animals such as skunks, raccoons, and bats; dogs and
cats are frequently immunized and therefore are rarely
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sources of human infection. In recent years, bats have been
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the source of most cases of human rabies in the United
States. Rodents and rabbits do not transmit rabies.
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Human rabies has also occurred in the United States in
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people who have not been bitten, so-called “nonbite” expo-

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sures. The most important example of this type of trans-

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mission is exposure to aerosols of bat secretions containing

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rabies virus. Another rare example is transmission in trans-

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plants of corneas taken from patients who died of undiag-

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nosed rabies.
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In the United States, fewer than 10 cases of rabies

occur each year (mostly imported), whereas in developing
countries there are hundreds of cases, mostly due to rabid
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dogs. In 2007, the United States was declared “canine-

rabies free”—the result of the widespread immunization
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of dogs. Worldwide, approximately 50,000 people die of FIGURE 39–6  Rabies virus—Negri body. Arrow points to a
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rabies each year. “Negri body,” an inclusion body in the cytoplasm of an infected
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The country of origin and the reservoir host of a strain of neuron. (Source: Public Health Image Library, Centers for Disease Control and
rabies virus can often be identified by determining the base
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Prevention.)
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CHAPTER 39  RNA Enveloped Viruses 327
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sensation at the bite site called paresthesias. After the pro- There are two approaches to prevention of rabies in
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drome, rabies manifests as either of two forms: “furious” humans: preexposure and postexposure immunization.

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(encephalitic) or “dumb” (paralytic). The furious form Preexposure immunization with rabies vaccine should be
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occurs in about 80% of cases. In the furious form, agitation, given to individuals in high-risk groups, such as veterinarians,
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delirium, seizures, and hydrophobia occur. Hydrophobia is zookeepers, and travelers to areas of hyperendemic infection
an aversion to swallowing water because of painful spasm (e.g., Peace Corps members). Preexposure immunization con-
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of the pharyngeal muscles. In contrast, in the dumb form, sists of three doses given on days 0, 7, and 21 or 28. Booster
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these symptoms do not occur. Rather, the spinal cord is doses are given as needed to maintain an antibody titer of 1:5.
primarily involved, and an ascending paralysis occurs. The rabies vaccine is also used routinely postexposure
Death almost invariably occurs following both forms, but (i.e., after the person has been exposed to the virus via ani-
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m
with the advent of life support systems, a few individuals mal bite). The long incubation period of the disease allows
have survived. the virus in the vaccine sufficient time to induce protective
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immunity.
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Laboratory Diagnosis Postexposure immunization involves the use of both the
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Rapid diagnosis of rabies infection in the animal is usually vaccine and human rabies immune globulin (RIG, obtained
from hyperimmunized persons) plus immediate cleaning of

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made by examination of brain tissue by using either PCR
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the wound. This is an example of passive–active immuniza-

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assay, fluorescent antibody to rabies virus, or histologic
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staining of Negri bodies in the cytoplasm of hippocampal tion. Tetanus immunization should also be considered.
neurons (see Figure 39–6). The virus can be isolated from The decision to give postexposure immunization depends
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the animal brain by growth in cell culture, but this takes too on a variety of factors, such as (1) the type of animal (all wild
animal attacks demand immunization); (2) whether an attack
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long to be useful in the decision of whether to give the
vaccine. by a domestic animal was provoked, whether the animal was
Rabies in humans can be diagnosed by PCR assay; by immunized adequately, and whether the animal is available to
be observed; and (3) whether rabies is endemic in the area.
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fluorescent antibody staining of a biopsy specimen, usually
taken from the skin of the neck at the hairline; by isolation The advice of local public health officials should be sought.
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Hospital personnel exposed to a patient with rabies need not
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of the virus from sources such as saliva, spinal fluid, and

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brain tissue; or by a rise in titer of antibody to the virus. be immunized unless a significant exposure has occurred
(e.g., a traumatic wound to the health care worker).
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Negri bodies can be demonstrated in corneal scrapings and
in autopsy specimens of the brain. If the decision is to immunize, both HDCV and RIG are
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recommended. Five doses of HDCV are given (on days 0, 3, 7,
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14, and 28), but RIG is given only once with the first dose of
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Treatment
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HDCV (at a different site). HDCV and RIG are given at differ-
There is no antiviral therapy for a patient with rabies. Only
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ent sites to prevent neutralization of the virus in the vaccine by
supportive treatment is available. the antibody in the RIG. As much as possible of the RIG is
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given into the bite site, and the remainder is given intramus-
Prevention cularly. If the animal has been captured, it should be observed
In the United States, the rabies vaccine contains inactivated for 10 days and euthanized if symptoms develop. The brain of
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virus grown in human diploid cells. (Vaccine grown in the animal should be examined by immunofluorescence.
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monkey lung cells or chick embryo cells is also available.) In The vaccine for immunization of dogs and cats consists
other countries, the duck embryo vaccine or various nerve of inactivated rabies virus. The first immunization is usu-
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tissue vaccines are available as well. Duck embryo vaccine ally given at 3 months of age, with booster doses given
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has low immunogenicity, and the nerve tissue vaccines can either annually or at 3-year intervals. In the United States,
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cause an allergic encephalomyelitis as a result of a cross- an alternative vaccine used in dogs and cats contains live
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reaction with human myelin. For these reasons, the human canarypox virus genetically engineered to contain the gene
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diploid cell vaccine (HDCV) is preferred. for the envelope protein of rabies virus.
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RETROVIRUSES  
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HUMAN T-CELL LYMPHOTROPIC Disease

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VIRUS Human T-cell lymphotropic virus-1 (HTLV-1) causes two

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distinctly different diseases: a cancer called adult T-cell

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There are two important human retroviruses: human T-cell

leukemia/lymphoma and a neurologic disease called
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lymphotropic virus, which is described here, and human

HTLV-associated myelopathy (also known as tropical spas-
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immunodeficiency virus (HIV), which is described in

tic paraparesis or chronic progressive myelopathy). HTLV-2
Chapter 45.
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328 PART IV  Clinical Virology
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also appears to cause these diseases, but the association is which migrates to the nucleus and integrates into cell DNA.
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less clearly documented. (All information in this section Viral mRNA is made by host cell RNA polymerase, and

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refers to HTLV-1 unless otherwise stated.) transcription is upregulated by Tax protein, as mentioned
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earlier. The Rex protein controls the synthesis of the gag/pol
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Important Properties mRNA, the env mRNA, and their subsequent transport to
the cytoplasm, where they are translated into structural viral
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HTLV and HIV are the two medically important members
proteins. Full-length RNA destined to become progeny
of the retrovirus family. Both are enveloped viruses with
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genome RNA is also synthesized and transported to the
reverse transcriptase in the virion and two copies of a sin-
cytoplasm. The virion nucleocapsid is assembled in the
gle-stranded, positive-polarity RNA genome. However,
cytoplasm, and budding occurs at the outer cell membrane.
HTLV does not kill T cells, whereas HIV does. In fact,
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Cleavage of precursor polypeptides into functional struc-
HTLV does just the opposite; it causes malignant transfor-
tural proteins is mediated by the virus-encoded protease.
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mation that “immortalizes” the infected T cells and allows

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them to proliferate in an uncontrolled manner.
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The genes in the HTLV genome whose functions have Transmission & Epidemiology
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been clearly identified are the three structural genes com- HTLV is transmitted primarily by intravenous drug use,

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sexual contact, or breast feeding. Transplacental trans-
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mon to all retroviruses, namely, gag, pol, and env, plus two

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regulatory genes, tax and rex. In general, HTLV genes and mission has been rarely documented. Transmission by
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proteins are similar to those of HIV in size and function, blood transfusion has greatly decreased in the United
States with the advent of screening donated blood for
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but the genes differ in base sequence, and therefore the
proteins differ in amino acid sequence (and antigenicity). antibodies to HTLV and discarding those that are posi-
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For example, p24 is the major nucleocapsid protein in both tive. Transmission by processed blood products, such as
HTLV and HIV, but they differ antigenically. The virions of immune serum globulins, has not occurred. Transmis-
both HTLV and HIV contain a reverse transcriptase, inte- sion is thought to occur primarily by the transfer of
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grase, and protease. The envelope proteins of HTLV are infected cells rather than free, extracellular virus. For
example, whole blood, but not plasma, is a major source,
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gp46 and gp21, whereas those of HIV are gp120 and gp41.
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The proteins encoded by the tax and rex genes play the and infected lymphocytes in semen are the main source
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same functional roles as those encoded by the HIV regula- of sexually transmitted virus.
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tory genes, tat and rev. The Tax protein is a transcriptional HTLV infection is endemic in certain geographic areas,
namely, the Caribbean region including southern Florida,
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activator, and the Rex protein governs the processing of

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eastern South America, western Africa, and southern
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viral mRNA and its export from the nucleus to the cyto-
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plasm. Tax protein is required for malignant transforma- Japan. The rate of seropositive adults is as high as 20% in
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tion of T cells. some of these areas, but infection can occur anywhere
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In contrast to other oncogenic retroviruses, such as because infected individuals migrate from these areas of
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Rous sarcoma virus in chickens (see page 363), HTLV does endemic infection. At least half the people in the United
not possess an oncogene in its genome and does not inte- States who are infected with HTLV are infected with
grate its proviral DNA at a specific site near a cellular onco- HTLV-2, usually acquired via intravenous drug use.
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gene in the T-cell DNA (i.e., it does not cause insertional
mutagenesis). Rather, it is the activation of transcription of Pathogenesis & Immunity
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both cellular and viral mRNA synthesis by the Tax protein HTLV causes two distinct diseases, each with a different
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that initiates oncogenesis. The Tax protein activates the type of pathogenesis. One disease is adult T-cell leuke-
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synthesis of IL-2 (which is T-cell growth factor) and of the mia/lymphoma (ATL) in which HTLV infection of CD4-
IL-2 receptor. IL-2 promotes rapid T-cell growth and even-
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positive T lymphocytes induces malignant transformation.

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tually malignant transformation of the T cell.
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As described earlier, HTLV-encoded Tax protein

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The stability of the genes of HTLV is much greater than enhances synthesis of IL-2 (T-cell growth factor) and
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that of HIV. As a consequence, HTLV does not show the IL-2 receptor, which initiates the uncontrolled growth
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high degree of variability of the antigenicity of the envelope characteristic of a cancer cell. All the malignant T cells
proteins that occurs in HIV.
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contain the same integrated proviral DNA, indicating

that the malignancy is monoclonal (i.e., it arose from a
Summary of Replicative Cycle single HTLV-infected cell). HTLV remains latent within
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The replication of HTLV is thought to follow a typical retro- the malignant T cells (i.e., HTLV is typically not pro-
viral cycle, but specific information has been difficult to duced by the malignant cells).
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obtain because the virus grows poorly in cell culture. HTLV The other disease is HTLV-associated myelopathy
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primarily infects CD4-positive T lymphocytes. The cellular (HAM), also known as tropical spastic paraparesis or
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receptor for the virus is unknown. Within the cytoplasm, chronic progressive myelopathy. HAM is a demyelinating
reverse transcriptase synthesizes a DNA copy of the genome, disease of the brain and spinal cord, especially of the motor
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CHAPTER 39  RNA Enveloped Viruses 329
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neurons in the spinal cord. HAM is caused either by an Laboratory Diagnosis
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autoimmune cross-reaction in which the immune response
Infection with HTLV is determined by detecting antibodies

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against HTLV damages the neurons or by cytotoxic T cells
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against the virus in the patient’s serum using the ELISA test.
that kill HTLV-infected neurons.
The Western blot assay is used to confirm a positive ELISA
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result. PCR assay can detect the presence of HTLV RNA or
Clinical Findings
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DNA within infected cells. The laboratory tests used to
ATL is characterized by lymphadenopathy, hepatospleno- screen donated blood contain only HTLV-1 antigens, but
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megaly, lytic bone lesions, and skin lesions. These features because there is cross-reactivity between HTLV-1 and
are caused by proliferating T cells infiltrating these organs. HTLV-2, the presence of antibodies against both viruses is
In the blood, the malignant T cells have a distinct “flower- usually detected. However, some HTLV-2 antibodies are
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shaped” nucleus. Hypercalcemia due to increased osteoclast missed in these routine screening tests. Isolation of HTLV in
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activity within the bone lesions is seen. Patients with ATL cell culture from the patient’s specimens is not done.

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often have reduced cell-mediated immunity, and opportu- ATL is diagnosed by finding malignant T cells in the
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nistic infections with fungi and viruses are common. lesions. The diagnosis of HAM is supported by the pres-
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The clinical features of HAM include gait disturbance, ence of HTLV antibody in the spinal fluid or finding HTLV

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nucleic acids in cells in the spinal fluid.
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weakness of the lower limbs, and low back pain. Loss of

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bowel and bladder control may occur. Loss of motor func-
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tion is much greater than sensory loss. T cells with a
Treatment & Prevention
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“flower-shaped” nucleus can be found in the spinal fluid.
Magnetic resonance imaging of the brain shows nonspe- There is no specific antiviral treatment for HTLV infection,
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cific findings. Progression of symptoms occurs slowly over and no antiviral drug will cure latent infections by HTLV.
a period of years. HAM occurs primarily in women of ATL is treated with anticancer chemotherapy regimens.
middle age. The disease resembles multiple sclerosis except Antiviral drugs have not been effective in the treatment of
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that HAM does not exhibit the remissions characteristic of HAM. Corticosteroids and danazol have produced
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multiple sclerosis. improvement in some patients.
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Both ATL and HAM are relatively rare diseases. The vast There is no vaccine against HTLV. Preventive measures
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majority of people infected with HTLV develop asymptom- include screening donated blood for the presence of anti-
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atic infections, usually detected by the presence of anti- bodies, using condoms to prevent sexual transmission, and
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body. Only a small subset of those infected develop either encouraging women with HTLV antibodies to refrain from
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ATL or HAM. breast feeding.

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FILOVIRUSES  
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There are two important filoviruses that cause human m

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disease: Ebola virus and Marburg virus. Filoviruses are
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long filamentous (filo = thread) viruses. They are the lon-
gest viruses, often measuring thousands of nanometers
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(Figure 39–7).
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EBOLA VIRUS
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Disease
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Ebola virus causes Ebola hemorrhagic fever (EHF). The

virus is named for the river in Zaire that was the site of
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the first known outbreak of EHF in 1976. A devastating

epidemic of EHF occurred in several West African coun-
tries, especially Liberia, Sierra Leone, and Guinea in
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2014–2015.
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FIGURE 39–7  Ebola virus—electron micrograph. Long arrow

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points to a typical virion of Ebola virus. Short arrow points to the

Important Properties
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“shepherd’s crook” appearance of some Ebola virions. (Source: Dr. Erskine

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Ebola virus has a single-stranded, nonsegmented, negative Palmer and Dr. Russell Regnery, Public Health Image Library, Centers for Disease
polarity RNA genome. There is an RNA-dependent RNA
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Control and Prevention.)

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330 PART IV  Clinical Virology
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polymerase in the virion. The nucleocapsid has helical and 2000s. Then in 2014–2015, the largest epidemic
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symmetry. The surface proteins of Ebola virus are antigeni- occurred in Liberia, Sierra Leone, and Guinea in which

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cally distinct from those of Marburg virus. more than 10,000 people died. The fatality rate is 60% in
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Ebola virus is one of the most virulent human viruses this epidemic. This epidemic included cases in both rural
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and is cultured only under the highest biosafety contain- and highly populated areas.
ment (BSL-4). It can be inactivated by lipid solvents and
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bleach (hypochlorite). Pathogenesis & Immunity
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There are five types: Ebola-Zaire is the most pathogenic
The high mortality rate of Ebola virus is attributed to sev-
for humans and Ebola-Reston is pathogenic for monkeys
eral viral virulence factors: Its glycoprotein kills endothelial
but not for humans. Ebola-Sudan is also highly pathogenic.
cells, resulting in hemorrhage, and two other proteins
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The degree of pathogenicity of Ebola-Ivory Coast (Tai For-
inhibit the induction and action of interferon. Lympho-
est) and Ebola-Bundibugyo for humans is uncertain
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cytes, macrophages, and dendritic cells are killed. As a

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because the number of cases is relatively small. The Zaire,
result, the antibody response is often ineffective in prevent-
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Sudan, Ivory Coast, and Bundibugyo types are found in
ing disease. Hepatocytes are also killed leading to liver
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Africa whereas the Reston type originated in the
failure.
Philippines.

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Clinical Findings
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Summary of Replicative Cycle The incubation period is typically 5 to 7 days but may be up
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The general outline of its replication is similar to that of to 21 days. EHF begins with a constellation of symptoms
other negative-stranded RNA enveloped viruses. After the some of which are fever, headache, sore throat, myalgia,
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virion envelope glycoproteins bind to the surface of the arthralgia, epigastric pain, vomiting, and diarrhea. Later,
human cell, the nucleocapsid enters the cytoplasm where bleeding into the skin and gastrointestinal tract occurs, fol-
the virion RNA polymerase transcribes the seven genes lowed by shock and disseminated intravascular coagulation
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into individual messenger RNAs. The m-RNAs are trans- leading to multiorgan failure. The hemorrhages are the
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lated into structural and nonstructural proteins. The result of both severe thrombocytopenia and death of endo-
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negative-strand progeny genome is synthesized by the thelial cells. Marked lymphopenia occurs. The mortality
virus-encoded RNA polymerase using a plus-strand tem- rate associated with this virus can be up to 90%.
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plate. The newly synthesized nucleocapsid proteins sur- In some patients who recover from EHF, a post-Ebola
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round both the progeny genome and the virion RNA syndrome (PES) occurs. The findings in PES include eye
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polymerase. The matrix protein then mediates the inter- pain, blurred vision, hearing loss, headache, joint pain,
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action of the nucleocapsid protein with the outer cell
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fatigue, and insomnia. In one patient with uveitis, infec-

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membrane at the site of the progeny envelope proteins. tious Ebola virus was recovered from fluid aspirated from
The progeny virus then buds from the surface of the the interior of his eye several months after recovery.
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infected cell.
Laboratory Diagnosis
Transmission & Epidemiology
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Diagnosis is most often made by detecting viral antigens in
serum using an ELISA assay, by detecting viral RNA using
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The natural reservoir of Ebola virus is unknown. Fruit bats
or rodents are suspected of being the reservoir. Monkeys a PCR assay, or by detecting IgM antibody in the serum.
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can be infected but, because they become sick and die, are (Extreme care must be taken when handling specimens in
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unlikely to be the natural reservoir. The mode of transmis- the laboratory.) The virus can be cultured in monkey cells
in BSL-4 containment facility. Electron microscopy may
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sion from the reservoir host to humans is unknown.

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reveal the long rod-shape of a filovirus, implicating either
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Transmission from human to human occurs via blood

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and body fluids. Hospital personnel without adequate pro- Ebola virus or Marburg virus.
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tection are especially at risk. Many cases arise by secondary

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transmission from contact with the patient’s blood or secre- Treatment & Prevention
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tions (e.g., in hospital staff). Reuse of needles and syringes No antiviral therapy is available. Supportive therapy includ-
has been implicated in the spread in some hospitals in ing intravenous fluids and electrolytes is useful. Treatment
resource-poor countries. There is no evidence for human with immune serum globulins containing antibody to
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disease occurring via airborne transmission or by casual Ebola virus has had variable results. An experimental
personal contact. There is evidence of Ebola virus persist- monoclonal antibody (ZMapp) was used in the 2014 epi-
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ing in the semen of survivors of the disease. demic but its effectiveness is uncertain.
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Subsequent to the first recorded outbreak of EHF in Prevention centers on limiting secondary spread by
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1976, there have been sporadic outbreaks in rural areas in proper handling of patient’s secretions and blood and by
various sub-Saharan African countries, mostly in the 1990s the wearing of personal protective equipment (PPE).
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CHAPTER 39  RNA Enveloped Viruses 331
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Quarantine of individuals thought to be exposed for 21 days 3. Regarding measles virus and the disease measles, which one of

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is also important. There is no vaccine. Several candidate the following statements is most accurate?

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vaccines are being tested as of this writing. (A) The measles vaccine contains killed virus as the immunogen.
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(B) One of the main sequelae of measles is autoimmune glomeru-
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lonephritis and kidney failure.
MARBURG VIRUS (C) Measles is unlikely to be eradicated because there is a signifi-
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cant animal reservoir for this virus.
Marburg virus and Ebola virus are similar in that they both (D) Fecal–oral transmission during the diaper stage is the main
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cause hemorrhagic fever and are members of the filovirus mode of acquisition of measles virus.
family; however, they are antigenically distinct. Marburg (E) This virus has only one antigenic type, and lifelong immunity
virus was first recognized as a cause of human disease in occurs in patients who have had measles.
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1967 in Marburg, Germany. The common feature of the 4. Regarding respiratory syncytial virus (RSV), which one of the
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infected individuals was their exposure to African green following statements is most accurate?

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monkeys that had recently arrived from Uganda. As with (A) RSV is an important cause of bronchiolitis in infants.
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Ebola virus, the natural reservoir of Marburg virus is (B) RSV causes tumors in newborn animals but not in
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unknown, although bats are suspected. humans.
(C) The RSV vaccine is recommended for all children prior to

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The clinical picture of this hemorrhagic fever is as
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entering school.

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described for Ebola virus (see earlier). In 2005, an outbreak
(D) Amantadine should be given to elderly nursing home resi-
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of hemorrhagic fever caused by Marburg virus killed hun-
dents to prevent outbreaks of disease caused by RSV.
dreds of people in Angola. No cases of disease caused by
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(E) RSV forms intranuclear inclusion bodies within neutrophils
Marburg virus occurred in the United States prior to 2008. that are important in diagnosis by the clinical laboratory.
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However, in that year, a U.S. traveler became ill after visit- 5. Regarding rubella virus, which one of the following statements is
ing a cave in Uganda inhabited by fruit bats. He returned to most accurate?
the United States, where he was diagnosed with Marburg (A) Systemic infection with rubella virus often causes severe liver
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hemorrhagic fever. He recovered without sequelae. damage resulting in cirrhosis.
The diagnosis is made by PCR assay or detecting a rise in (B) If a pregnant woman is infected during the first trimester,
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IgM antibody titer. No antiviral therapy or vaccine is available. significant fetal abnormalities typically result.
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As with Ebola virus, secondary cases among medical per- (C) The main source of virus is adults who have recovered from
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sonnel have occurred; therefore, stringent infection control the disease but are chronic carriers of the virus.
practices must be instituted to prevent nosocomial spread. (D) Immunization of both male and female health care workers
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with the formalin-inactivated vaccine is recommended.
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(E) The significant changes in the antigenicity of this virus are

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SELF-ASSESSMENT QUESTIONS attributed to reassortment of the segments of its genome.
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6. Regarding rabies virus and the disease rabies, which one of the
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1. Regarding influenza virus, which one of the following statements following statements is most accurate?
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is most accurate? (A) Finding intranuclear inclusion bodies within macrophages is
(A) The virion contains an RNA-dependent DNA polymerase. presumptive evidence of rabies virus infection.
(B) Its surface proteins, hemagglutinin and neuraminidase, have (B) Lamivudine is used to treat rabies because it inhibits the
multiple serologic types. RNA-dependent DNA polymerase in the virion.
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(C) The protein that undergoes antigenic variation most often is (C) In the United States, skunks and bats are more likely to trans-
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the internal ribonucleoprotein. mit rabies virus to people than are dogs and cats.
(D) Antigenic drift involves major changes in antigenicity that
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(D) The incubation period of the disease is usually 2 to 4 days,
result from reassortment of the segments of its RNA genome. leading to the rapid progression of the encephalitis and
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(E) The neuraminidase on the virion surface mediates the inter- death.
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action of the virus with the receptors on the respiratory tract

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(E) After the animal bite, rabies virus enters the bloodstream,
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epithelium. replicates in internal organs such as the liver, and then

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2. Regarding influenza virus and the disease influenza, which one reaches the central nervous system during the secondary
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of the following statements is most accurate? viremia.

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(A) Both the killed and the live, attenuated vaccines induce life- 7. A woman was hiking in an isolated area when a skunk appeared
and bit her on the leg. She now presents to your emergency room
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long immunity.
(B) Influenza A virus causes more severe disease and more wide- about an hour after the bite. Which one of the following is the
spread epidemics than does influenza B virus. most appropriate thing to do?
(C) The genome of influenza A virus has eight segments, but the (A) Give rabies vaccine and hyperimmune globulin immediately.
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genome of influenza B virus is in one piece. (B) Reassure her that rabies is not a problem because skunks do
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(D) The classification of influenza viruses into A, B, and C viruses not carry rabies.
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is based on antigenic differences in their hemagglutinin. (C) Quarantine the animal for 10 days and only treat her if signs
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(E) Chronic carriers (i.e., patients from whom influenza virus is of rabies appear in the animal.
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isolated at least 6 months after the acute disease) are an (D) Test the patient’s serum for antibodies now and in 10 days to
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important source of human infection. see if there is a rise in antibody titer before treating her.
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332 PART IV  Clinical Virology
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8. Human T-cell lymphotropic virus (HTLV) causes T-cell leuke- ANSWERS
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mia in adults. Regarding this virus, which one of the following
1. (B)

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statements is most accurate?
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(A) HTLV is transmitted primarily by the fecal–oral route. 2. (B)
3. (E)
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(B) Oseltamivir cures the latent state established by HTLV within
T cells. 4. (A)
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(C) The genome of HTLV consists of double-stranded RNA; 5. (B)
therefore, there is no polymerase in the virion. 6. (C)
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(D) HTLV is associated with leukemia in Japan, but the virus has 7. (A)
not appeared in the United States at the present time. 8. (E)
(E) Oncogenesis by HTLV is related to a viral transcription factor 9. (D)
(E)
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that activates the production of interleukin-2 and its 10.
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receptor.

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9. Your patient is a 75-year-old woman with fever, chills, and myal-
SUMMARIES OF ORGANISMS
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gias that began yesterday. It is January and an outbreak of influ-
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enza is occurring in the retirement community in which she Brief summaries of the organisms described in this chapter
lives. A rapid test for influenza antigen is positive. Which one of

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begin on page 671. Please consult these summaries for a rapid
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the following is the best choice of drug to treat the infection?
review of the essential material.

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(A) Acyclovir
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(B) Amantadine
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(C) Interferon
(D) Oseltamivir PRACTICE QUESTIONS: USMLE &
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(E) Ribavirin COURSE EXAMINATIONS
10. Regarding Ebola virus, which one of the following is most
accurate? Questions on the topics discussed in this chapter can be found
in the Clinical Virology section of Part XIII: USMLE (National
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(A) Skunks and raccoons are the main natural reservoirs for
Ebola virus. Board) Practice Questions starting on page 723. Also see Part
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XIV: USMLE (National Board) Practice Examination starting
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(B) In endemic areas, most people are latently infected with Ebola
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virus. on page 751.
(C) People known to be exposed to Ebola virus should be given
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ganciclovir to prevent disease.
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(D) Ebola hemorrhagic fever occurs primarily in people with
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deficient cell-mediated immunity.

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(E) The appearance of Ebola virus in the electron microscope is
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that of a long thread, which often has a curved end.

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42
C H A P T E R
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Arboviruses
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CHAPTER CONTENTS
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Introduction Colorado Tick Fever Virus

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Important Properties West Nile Virus
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Transmission Important Arboviruses that Primarily Cause Disease
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Clinical Findings & Epidemiology Outside the United States
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Important Arboviruses That Cause Disease in the Yellow Fever Virus
United States Dengue Virus
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Eastern Equine Encephalitis Virus Chikungunya Virus
Western Equine Encephalitis Virus Self-Assessment Questions
St. Louis Encephalitis Virus Summaries of Organisms
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California Encephalitis Virus Practice Questions: USMLE & Course Examinations
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INTRODUCTION (1) Togaviruses2 are characterized by an icosahedral

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nucleocapsid surrounded by an envelope and a single-

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Arbovirus is an acronym for arthropod-borne virus and stranded, positive-polarity RNA genome. They are 70 nm
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highlights the fact that these viruses are transmitted by in diameter, in contrast to the flaviviruses, which are 40 to
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arthropods, primarily mosquitoes and ticks. It is a collective 50 nm in diameter (see later). Togaviruses are divided into
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name for a large group of diverse viruses, more than 600 at two families, alphaviruses and rubiviruses. Only alphavi-
last count. In general, they are named either for the diseases ruses are considered here. The only rubivirus is rubella
they cause (e.g., yellow fever virus) or for the place where virus, which is discussed in Chapter 39.
they were first isolated (e.g., St. Louis encephalitis virus). (2) Flaviviruses3 are similar to togaviruses in that they
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A new group of viruses called roboviruses has recently also have an icosahedral nucleocapsid surrounded by an
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emerged. The term robo refers to the fact that these viruses envelope and a single-stranded, positive-polarity RNA
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are rodent-borne (i.e., they are transmitted directly from genome, but the flaviviruses are only 40 to 50 nm in diam-
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rodents to humans without an arthropod vector). Trans- eter, whereas the togaviruses have a diameter of 70 nm.
mission occurs when dried rodent excrement is inhaled (3) Bunyaviruses4 have a helical nucleocapsid sur-
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into the human lung, as when sweeping the floor of a cabin. rounded by an envelope and a genome consisting of three
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Two roboviruses cause a respiratory distress syndrome that

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segments of negative-polarity RNA that are hydrogen-

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is often fatal: Sin Nombre virus (a hantavirus) and White- bonded together.
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water Arroyo virus (an arenavirus). These viruses are

described in Chapter 46.
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Transmission
The life cycle of the arboviruses is based on the ability of
Important Properties these viruses to multiply in both the vertebrate host and
Most arboviruses are classified in three families,1 namely,
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togaviruses, flaviviruses, and bunyaviruses (Table 42–1).

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2
Toga means cloak.
1 3
A few arboviruses belong to two other families. For example, Colorado Flavi means yellow, as in yellow fever.
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4
tick virus is a reovirus; Kern Canyon virus and vesicular stomatitis virus “Bunya” is short for Bunyamwera—the town in Africa where the proto-
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are rhabdoviruses. type virus was located.

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354
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CHAPTER 42  Arboviruses 355
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TABLE 42–1  Classification of Major Arboviruses blood ingested during an insect bite. After ingestion, the
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virus replicates in the gut of the arthropod and then
Viruses of Medical Interest

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spreads to other organs, including the salivary glands.
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Family Genus in the Americas
Only the female of the species serves as the vector of the
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Togavirus Alphavirus1 Eastern equine encephalitis virus, virus, because only she requires a blood meal in order for
western equine encephalitis
progeny to be produced. An obligatory length of time,
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virus, chikungunya virus
called the extrinsic incubation period,5 must pass before
Flavivirus Flavivirus2 St. Louis encephalitis virus, yellow
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fever virus, dengue virus, West the virus has replicated sufficiently for the saliva of the
Nile virus vector to contain enough virus to transmit an infectious
Bunyavirus Bunyavirus3 California encephalitis virus dose. For most viruses, the extrinsic incubation period
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ranges from 7 to 14 days.
Reovirus Orbivirus Colorado tick fever virus
In addition to transmission through vertebrates, some
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Alphaviruses of other regions include Chikungunya, Mayaro, O’Nyong-Nyong, Ross arboviruses are transmitted by vertical “transovarian” pas-
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River, and Semliki Forest viruses.
2 sage from the mother tick to her offspring. Vertical trans-
Flaviviruses of other regions include Japanese encephalitis, Kyasanur Forest, Murray
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Valley encephalitis, Omsk hemorrhagic fever, Powassan encephalitis viruses, and mission has important survival value for the virus if a
vertebrate host is unavailable.

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West Nile viruses.
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Humans are involved in the transmission cycle of arbo-
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Bunyaviruses of other regions include the Bunyamwera complex of viruses and

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Oropouche virus.
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viruses in two different ways. Usually, humans are dead-
end hosts, because the concentration of virus in human
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the bloodsucking vector (Figure 42–1). For effective blood is too low and the duration of viremia is too brief for
transmission to occur, the virus must be present in the the next bite to transmit the virus. However, in some dis-
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bloodstream of the vertebrate host (viremia) in suffi- eases (e.g., yellow fever and dengue), humans have a high-
ciently high titer to be taken up in the small volume of level viremia and act as reservoirs of the virus.
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Incidental hosts
(humans and horses)
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FIGURE 42–1  Arbovirus transmission cycle. Arboviruses typically cycle between the vertebrate reservoir host, often a bird, and the
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vector, often a mosquito. The infected vector can also bite other hosts, such as humans and horses, which are “dead-end” hosts because their
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viremia is too low to provide the vector with an infectious dose. (Source: Centers for Disease Control and Prevention.)
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5
The intrinsic incubation period is the interval between the time of the bite and the appearance of symptoms in the human host.
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356 PART IV  Clinical Virology
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Infection by arboviruses usually does not result in dis- severe disease and is associated with the highest fatality
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ease either in the arthropod vector or in the vertebrate rate (approximately 50%). In its natural habitat, the virus

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animal that serves as the natural host. Disease occurs pri- is transmitted primarily by the swamp mosquito, Culi-
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marily when the virus infects dead-end hosts. For example, seta, among the small wild birds of the Atlantic and Gulf
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yellow fever virus cycles harmlessly among the jungle mon- Coast states. Species of Aedes mosquitoes are suspected of
keys in South America, but when the virus infects a human, carrying the virus from its wild bird reservoir to the
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yellow fever can occur. principal dead-end hosts, horses, and humans. The
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number of cases of human encephalitis caused by EEE
Clinical Findings & Epidemiology virus in the United States usually ranges from zero to four
per year, but outbreaks involving hundreds of cases also
Most human arboviral infections are asymptomatic. Of
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occur. Subclinical infections greatly exceed the number of
those infections that are symptomatic, most are acute
overt cases.
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febrile illnesses. A minority of infections cause neuroinva-

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The encephalitis is characterized by the sudden onset of
sive disease, such as encephalitis and meningitis. The dis-
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severe headache, nausea, vomiting, and fever. Changes in
eases caused by arboviruses range in severity from mild to
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mental status, such as confusion and stupor, ensue. A rap-
rapidly fatal.
idly progressive downhill course with nuchal rigidity, sei-

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The clinical picture usually fits one of three categories:
zures, and coma occurs. If the patient survives, the central

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(1) encephalitis; (2) hemorrhagic fever; or (3) fever with
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nervous system sequelae are usually severe. Immunity fol-
myalgias, arthralgias, and nonhemorrhagic rash. The
lowing the infection is lifelong.
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pathogenesis of these diseases involves not only the cytoci-
The diagnosis is made by either isolating the virus or
dal effect of the virus, but also, in some, a prominent
demonstrating a rise in antibody titer. Clinicians should
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immunopathologic component. After recovery from the
have a high index of suspicion in the summer months in
disease, immunity is usually lifelong.
the appropriate geographic areas. The disease does not
The arboviral diseases occur primarily in the tropics but
occur in the winter because mosquitoes are not active. It is
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are also found in temperate zones such as the United States
not known how the virus survives the winter—in birds,
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and as far north as Alaska and Siberia. They have a tendency
mosquitoes, or perhaps some other animal.
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to cause sudden outbreaks of disease, generally at the inter-

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No antiviral therapy is available. A killed vaccine is
face between human communities and jungle or forest areas.
available to protect horses but not humans. The disease is
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too rare for production of a human vaccine to be economi-
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IMPORTANT ARBOVIRUSES cally feasible.
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THAT CAUSE DISEASE IN THE
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UNITED STATES Western Equine Encephalitis Virus

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Western equine encephalitis (WEE) virus causes disease
Eastern Equine Encephalitis Virus
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more frequently than does EEE virus, but the illness is less
Of the four encephalitis viruses listed in Table 42–2, east- severe. Inapparent infections outnumber the apparent by at
ern equine encephalitis (EEE) virus causes the most least 100:1. The number of cases in the United States
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TABLE 42–2  Epidemiology of Important Arbovirus Diseases in the United States
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Approximate
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Disease1 Vector Animal Reservoir Geographic Distribution Incidence Per Year2
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EEE Mosquito Wild birds3 Atlantic and Gulf states   0–4
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  5–204
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WEE Mosquito Wild birds West of Mississippi

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SLE Mosquito Wild birds Widespread in southern, central,  10–304

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and western states

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CE Mosquito Small mammals North-central states  40–80

CTF Tick Small mammals Rocky Mountains 100–300
West Nile Mosquito Wild birds Endemic in Africa; Widespread in 700–1000
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encephalitis United States
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CE = California encephalitis; CTF = Colorado tick fever; EEE = eastern equine encephalitis virus; SLE = St. Louis encephalitis; WEE = western equine encephalitis virus.
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1
Venezuelan equine encephalitis virus causes disease in the United States too rarely to be included.
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2
Human cases.
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Horses are dead-end hosts, not reservoirs.
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Hundreds of cases during an outbreak.
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CHAPTER 42  Arboviruses 357
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usually ranges between 5 and 20 per year, and the fatality the Rocky Mountains. There are approximately 100 to 300
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rate is roughly 2%. cases per year in the United States.

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The virus is transmitted primarily by Culex mosquitoes The disease occurs primarily in people hiking or camp-
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among the wild bird population of the western states, espe- ing in the Rocky Mountains and is characterized by fever,
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cially in areas with irrigated farmland. headache, retro-orbital pain, and severe myalgia. The diag-
The clinical picture of WEE virus infection is similar but nosis is made either by isolating the virus from the blood or
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less severe than that caused by EEE virus. Sequelae are less by detecting a rise in antibody titer. No antiviral therapy or
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common. The diagnosis is made by isolating the virus or vaccine is available. Prevention involves wearing protective
observing a rise in antibody titer. There is no antiviral ther- clothing and inspecting the skin for ticks.
apy. There is a killed vaccine for horses but not for humans.
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West Nile Virus
St. Louis Encephalitis Virus
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West Nile virus (WNV) is the most common cause of

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St. Louis encephalitis (SLE) virus causes disease over a wider
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neuroinvasive (encephalitis, meningitis) arboviral dis-
geographic area than do EEE and WEE viruses. It is found in ease in the United States. WNV caused an outbreak of
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the southern, central, and western states and causes 10 to encephalitis in New York City and environs in July, August,

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30 cases of encephalitis per year in the United States. and September 1999. This is the first time WNV caused

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The virus is transmitted by several species of Culex disease in the United States. In this outbreak, there were 27
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mosquitoes that vary depending on location. Again, small confirmed cases and 23 probable cases, including 5 deaths.
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wild birds, especially English sparrows, are the reservoir, Many birds, especially crows, died as well. No human cases
and humans are dead-end hosts. Although EEE and WEE occurred after area-wide spraying of mosquito-control
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viruses are predominantly rural, SLE virus occurs in urban compounds and the onset of cooler weather.
areas because these mosquitoes prefer to breed in stagnant In the summer of the year 2000, there were 18 cases and
wastewater. 1 death, and by July 2001, the virus had spread to many
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SLE virus causes moderately severe encephalitis with a states along the East Coast (from New Hampshire to
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fatality rate that approaches 10%. Most infections are inap- Florida) and as far west as Louisiana. In 2002, there was a
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parent. Sequelae are uncommon. marked increase in the number of cases. There were more
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The diagnosis is usually made serologically, because the than 4000 cases, 274 people died, and the virus had spread
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virus is difficult to isolate. No antiviral therapy or vaccine as far west as Colorado. In 2003, there were 7700 cases, of
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is available.
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whom 166 died, and the virus had spread to California. In
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2012, there were 3142 reported cases and 134 deaths. Each
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California Encephalitis Virus year, WNV causes the highest number of deaths due to a
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California encephalitis (CE) virus was first isolated from mosquito-borne encephalitis in the United States. It is not
mosquitoes in California in 1952, but its name is something known how WNV entered the United States, but either an
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of a misnomer because most human disease occurs in the infected traveler or an infected mosquito brought by an
north-central states. The strain of CE virus that causes airplane seems likely to be involved.
encephalitis most frequently is called La Crosse for the city WNV is a flavivirus that is classified in the same anti-
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in Wisconsin where it was isolated. CE virus is the only one genic group as SLE virus. It is endemic in Africa but has
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of the four major encephalitis viruses in the United States caused encephalitis in areas of Europe and Asia as well.
that is a member of the bunyavirus family. Wild birds are the main reservoir of this virus, which is
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La Crosse virus is transmitted by the mosquito Aedes transmitted by mosquitoes, especially Culex species.
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triseriatus among forest rodents. The virus is passed trans- Humans are dead-end hosts. Transmission of the virus via
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solid organ transplants has also occurred. f

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ovarially in mosquitoes and thus survives the winter when
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mosquitoes are not active. The clinical picture can be mild, The most important clinical picture is encephalitis with
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resembling enteroviral meningitis, or severe, resembling or without signs of meningitis, typically in a person over
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60 years of age. Encephalitis occurs in about 1% of infections,

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herpes encephalitis. Death rarely occurs. Diagnosis is usu-

ally made serologically rather than by isolation of the virus. fever and headache without encephalitis occur in about 20%,
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No antiviral therapy or vaccine is available. and roughly 80% of infections are asymptomatic.
The laboratory diagnosis can be made by either isola-
tion of the virus from brain tissue, blood, or spinal fluid or
Colorado Tick Fever Virus
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by detection of antibodies in spinal fluid or blood. Poly-

Of the five diseases described in Table 42–2, Colorado tick merase chain reaction (PCR)–based assays are also avail-
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fever (CTF) is the most easily distinguished from the oth- able. No antiviral therapy or vaccine is available. In an
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ers, both biologically and clinically. CTF virus is a reovirus attempt to prevent blood-borne transmission, blood banks
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transmitted by the wood tick Dermacentor andersoni screen donated blood for the presence of WNV using
among the small rodents (e.g., chipmunks and squirrels) of nucleic acid probes specific for the virus.
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358 PART IV  Clinical Virology
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IMPORTANT ARBOVIRUSES THAT infected mosquito bites the person, the intrinsic incuba-
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tion period is 3 to 6 days.
PRIMARILY CAUSE DISEASE

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OUTSIDE THE UNITED STATES Diagnosis in the laboratory can be made either by isolat-
ing the virus or by detecting a rise in antibody titer. No
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Although yellow fever and dengue are not endemic in the antiviral therapy is available, and the mortality rate is high.
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United States, extensive travel by Americans to tropical If the patient recovers, no chronic infection ensues and
areas means that imported cases occur. It is reasonable, lifelong immunity is conferred.
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therefore, that physicians in the United States be Prevention of yellow fever involves mosquito control
acquainted with these two diseases. Both yellow fever and immunization with the vaccine containing live, attenu-
virus and dengue virus are classified as flaviviruses. ated yellow fever virus. Travelers to and residents of
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Table 42–3 describes the epidemiology of the important endemic areas should be immunized. Protection lasts up to
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arboviral diseases that occur primarily outside the United 10 years, and boosters are required every 10 years for trav-

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States. Japanese encephalitis virus, also a flavivirus and an elers entering certain countries. Epidemics still occur in
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important cause of epidemic encephalitis in Asia, is parts of tropical Africa and South America. Because it is a
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described in Chapter 46. live vaccine, it should not be given to immunocompro-

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mised people or to pregnant women.

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Yellow Fever Virus
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As the name implies, yellow fever is characterized by jaun- Dengue Virus
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dice and fever. It is a severe, life-threatening disease that
Although dengue fever is not endemic in the United States,
begins with the sudden onset of fever, headache, myalgias,
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some tourists to the Caribbean and other tropical areas
and photophobia. After this prodrome, the symptoms
return with this disease. In recent years, there were 100 to
progress to involve the liver, kidneys, and heart. Prostration
200 cases per year in the United States, mostly in the south-
and shock occur, accompanied by upper gastrointestinal
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ern and eastern states. No indigenous transmission
tract hemorrhage with hematemesis (“black vomit”).
occurred within the United States. It is estimated that about
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Yellow fever occurs primarily in the tropical areas of
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20 million people are infected with dengue virus each year

Africa and South America. In the epidemiology of yellow
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worldwide. Dengue is the most common insect-borne viral
fever, two distinct cycles exist in nature, with different
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disease in the world.
reservoirs and vectors.
Classic dengue fever (breakbone fever) begins sud-
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(1) Jungle yellow fever is a disease of monkeys in tropi- denly with an influenzalike syndrome consisting of fever,
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cal Africa and South America; it is transmitted primarily by malaise, retro-orbital pain, and headache. Severe pains in
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the treetop mosquitoes of the Haemagogus species. Mon- muscles (myalgia) and joints (arthralgia, breakbone) occur.
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keys are the permanent reservoir, whereas humans are Enlarged lymph nodes, facial flushing, a maculopapular
accidental hosts. Humans (e.g., tree cutters) are infected rash, and leukopenia are common. After a week or so, the
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when they enter the jungle occupationally. symptoms regress but weakness may persist. Although
(2) In contrast, urban yellow fever is a disease of unpleasant, this typical form of dengue is rarely fatal and
humans that is transmitted by the mosquito Aedes aegypti, has few sequelae.
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which breeds in stagnant water. In the urban form of the In contrast, dengue hemorrhagic fever is a much more
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disease, humans are the reservoir. For effective transmis- severe disease, with a fatality rate that approaches 10%. The
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sion to occur, the virus must replicate in the mosquito dur- initial picture is the same as classic dengue, but then shock
ing the 12- to 14-day extrinsic incubation period. After the and hemorrhage, especially into the gastrointestinal tract
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TABLE 42–3  Epidemiology of Important Arboviral Diseases Outside the United States
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Disease Vector Animal Reservoir Geographic Distribution Vaccine Available

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Yellow fever       Yes

1. Urban Aedes mosquito Humans Tropical Africa and South America  
2. Jungle Haemagogus mosquito Monkeys Tropical Africa and South America  
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Dengue Aedes mosquito Humans; probably Tropical areas, especially Caribbean No

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-monkeys also
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Chikungunya virus Aedes mosquito Humans Tropical areas, especially Caribbean No

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CHAPTER 42  Arboviruses 359
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and skin, develop. Dengue hemorrhagic fever occurs par- single-stranded, positive-polarity RNA genome. It is
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ticularly in southern Asia, whereas the classic form is found transmitted by species of Aedes mosquitoes, both A.

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in tropical areas worldwide. aegypti and Aedes albopictus. The latter mosquito is
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Hemorrhagic shock syndrome is due to the produc- found in the United States, so the potential for outbreaks
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tion of large amounts of cross-reacting antibody at the exists. Humans are the most important reservoir but
time of a second dengue infection. The pathogenesis is as infection of nonhuman primates is thought to sustain the
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follows: The patient recovers from classic dengue caused virus in nonpopulated areas.
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by one of the four serotypes, and antibody against that Individuals returning to the United States from areas
serotype is produced. When the patient is infected with where outbreaks have occurred have been diagnosed with
another serotype of dengue virus, an anamnestic, hetero- chikungunya fever. Laboratory diagnosis involves detecting
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typic response occurs, and large amounts of cross-reacting the virus in blood either by PCR assay for viral RNA or by
antibody to the first serotype are produced. There are two enzyme-linked immunosorbent assay (ELISA) for IgM anti-
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hypotheses about what happens next. One is that immune body. There is no antiviral therapy and no vaccine is available.
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complexes composed of virus and antibody are formed
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that activate complement, causing increased vascular
permeability and thrombocytopenia. The other is that SELF-ASSESSMENT QUESTIONS

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the antibodies increase the entry of virus into monocytes

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1. An outbreak of dengue hemorrhagic fever (DHF) recently
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and macrophages, with the consequent liberation of a occurred in two Central American countries. Regarding dengue
large amount of cytokines. In either scenario, shock and and DHF, which one of the following is the most accurate?
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hemorrhage result. (A) Humans are dead-end hosts for dengue virus.
Dengue virus is transmitted by the Aedes aegypti mos-
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(B) DHF occurs primarily in individuals who are deficient in the
quito, which is also the vector of yellow fever virus. late-acting complement components.
Humans are the reservoir for dengue virus, but a jungle (C) Dengue virus is transmitted by Aedes mosquitoes, and mon-
cycle involving monkeys as the reservoir and other Aedes keys are an important natural reservoir.
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species as vectors is suspected. (D) The vaccine containing live, attenuated dengue virus is recom-
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mended for those living or traveling in endemic areas.
The diagnosis can be made in the laboratory either by
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(E) DHF occurs more often in people infected for the first time
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isolation of the virus in cell culture or by serologic tests that than when they are reinfected because antibody protects
demonstrate the presence IgM antibody or a fourfold or
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against reinfection.
greater rise in antibody titer in acute and convalescent sera. 2. Yellow fever still exists in many tropical areas of the globe. Which
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A PCR assay that detects virus in the blood is also available. one of the following is the best reason yellow fever still exists?
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No antiviral therapy or vaccine for dengue is available. (A) Sewage disposal is inadequate in many areas.
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Outbreaks are controlled by using insecticides and draining (B) Both humans and monkeys are reservoirs for yellow fever virus.
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stagnant water that serves as the breeding place for the (C) The virus has mutated, so the existing vaccine is no longer
mosquitoes. Personal protection includes using mosquito effective.
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repellent and wearing clothing that covers the entire body (D) The vaccine has been withdrawn because it was found to have
(Note that a dengue vaccine composed of live attenuated unacceptable side effects.
(E) The people in developing countries cannot afford to take
yellow fever vaccine virus genetically engineered to pro-
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amantadine when they enter endemic areas.
duce proteins from dengue virus that serve as the immuno- 3. Regarding West Nile virus (WNV), which one of the following is
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gen was approved by Mexico in 2015 but is not available in the most accurate?
the United States.)
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(A) Rodents are the main reservoir for WNV.
(B) WNV does not cause disease in the United States.
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Chikungunya Virus (C) WNV is transmitted primarily by Ixodes ticks.

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(D) Most infections are asymptomatic, but the elderly are at risk for
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This virus causes chikungunya fever characterized by the encephalitis.

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sudden onset of high fever and joint pains, especially of the (E) The live, attenuated vaccine should be administered to elderly
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wrists and ankles. Joint involvement is bilateral and sym- adults in endemic areas.
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metric. A macular or maculopapular rash over much of the 4. An outbreak of febrile disease involving severe joint pain and an
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body is common. Encephalitis may occur. Outbreaks erythematous macular rash has occurred on several Caribbean
involving millions of people in India, Africa, and the islands. Infection with chikungunya virus is suspected. Which one
islands in the Indian Ocean have occurred in the years of the following is correct regarding this virus?
(A) Its genome is composed of double-stranded DNA.
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from 2004 to 2006. In 2013 to 2014, this virus moved to the

(B) It is transmitted by Aedes mosquitoes.
western hemisphere causing outbreaks involving thou-
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(C) Wild birds are the most important reservoir.

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sands of people on many Caribbean islands and in the state (D) Laboratory diagnosis involves electron microscopy to observe
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of Florida. the very long filamentous shape of the virus.

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Chikungunya virus is an RNA enveloped virus and is (E) The killed vaccine should be administered to travelers to
a member of the Togavirus family. It has a
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endemic regions.
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360 PART IV  Clinical Virology
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ANSWERS PRACTICE QUESTIONS: USMLE &
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1. (C) COURSE EXAMINATIONS

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2. (B)
Questions on the topics discussed in this chapter can be found
3. (D)
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in the Clinical Virology section of Part XIII: USMLE (National
4. (B)
Board) Practice Questions starting on page 723. Also see Part
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XIV: USMLE (National Board) Practice Examination starting
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SUMMARIES OF ORGANISMS on page 751.

Brief summaries of the organisms described in this chapter

begin on page 676. Please consult these summaries for a rapid
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review of the essential material.
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