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454 SECTION 5  •  Virology

BOX 44.4  Clinical Summary

Molluscum contagiosum: A 5-year-old girl has a group of wart-
like growths on her arm that exude white material on squeez-
ing.

Fig. 44.5  Orf lesion on the finger of a taxidermist. (Courtesy Joe Mey- A
ers, MD, Akron, Ohio.)
B
than cases of smallpox. Several of these complications were
severe and even fatal. Therefore routine smallpox vaccina- Fig. 44.6  Molluscum contagiosum. (A) Skin lesions (arrows). (B) Micro-
tion began to be discontinued in the 1970s and was totally scopic view; epidermis is filled with molluscum bodies (magnification
discontinued after 1980, but it has been reintroduced for 100×).
military personnel and first responders in case of biowarfare.
molluscum contagiosum differ significantly from other pox
Complications from vaccination included encephalitis lesions because they are nodular to wartlike (Fig. 44.6A).
and progressive infection (vaccinia necrosum), the latter They begin as papules and then become pearl-like umbili-
occurring occasionally in immunocompromised patients cated nodules that are 2 to 10 mm in diameter and have
who were inadvertently vaccinated. Recent cases of vac- a central caseous plug that can be squeezed out. They
cine-related disease have been noted in family members are most common on the trunk, genitalia, and proximal
and contacts of immunized military personnel (see Clinical extremities and usually occur in a cluster of 5 to 20 nod-
Case 44.1). The virus was transmitted to these individuals ules. The incubation period for molluscum contagiosum is
by contact with vesicular fluid. They can be treated with 2 to 8 weeks. The disease is more common in children than
vaccinia immune globulin and antiviral drugs.  adults, but its incidence is increasing in sexually active and
immunocompromised individuals.
ORF, COWPOX, AND MONKEYPOX
Human infection with the orf (poxvirus of sheep and goat) or The diagnosis of molluscum contagiosum is confirmed
cowpox (vaccinia) virus is usually an occupational hazard histologically by the finding of characteristic large, eosin-
resulting from direct contact with lesions on the animal. A sin- ophilic, cytoplasmic inclusions (molluscum bodies) in
gle nodular lesion usually forms on the point of contact, such
as the fingers, hand, or forearm, and is hemorrhagic (cowpox)
or granulomatous (orf or pseudocowpox) (Fig. 44.5). Vesicu-
lar lesions frequently develop and then regress in 25 to 35
days, generally without scar formation. The lesions may be
mistaken for anthrax. The virus can be grown in culture or
seen directly with electron microscopy, but it is usually diag-
nosed from the symptoms and patient history.

The more than 100 cases of illnesses resembling smallpox
have been attributed to the monkeypox virus. Except for the
outbreak in Illinois, Indiana, and Wisconsin in 2003, they
all have occurred in western and central Africa, especially
in Zaire. Monkeypox causes a milder version of smallpox
disease, including the pocklike rash. 

MOLLUSCUM CONTAGIOSUM
Molluscum contagiosum is a common disease affecting
3% to 20% of the population (Box 44.4). The lesions of

44  •  Poxviruses 455

Recombinant plasmid HYBRID POXVIRUSES FOR GENE DELIVERY AND
cloning vector VACCINES
Plasmid The vaccinia and canarypox viruses are used as expression
DNA vectors to produce live recombinant/hybrid vaccines for
Foreign more virulent infectious agents (Fig. 44.7). Immunization
gene with the recombinant poxvirus results from expression of the
Vaccinia foreign gene and its presentation to the immune response,
DNA almost as if by infection with the other agent. A vaccinia
hybrid virus containing the G-protein of rabies virus soaked
Introduced by transfection onto a bait food and dropped into forests has been used suc-
cessfully to immunize raccoons, foxes, and other mammals.
Nucleus Experimental vaccines for human immunodeficiency virus
(HIV), hepatitis B, influenza, and other viruses have also been
Gene from Recombination prepared using these techniques. The potential for producing
vector of vaccinia other vaccines in this manner is unlimited.
Gene from sequences
rescuing virus Hybrid vaccinia viruses are also being used for oncolytic
Replication of recombinant agents to selectively kill tumors and for gene replacement
vaccinia DNA with foreign gene therapy.

Infection of cell Maturation Foreign   For questions see StudentConsult.com.
Infectious Release of gene
vaccinia virus: recombinant Bibliography
“rescuing virus” vaccinia virus
containing Breman, J.G., Henderson, D.A., 2002. Diagnosis and management of
foreign gene smallpox. N. Engl. J. Med. 346, 1300–1308.

Vaccination with Burrell, C., Howard, C., Murphy, F., 2016. Fenner and White’s Medical
live virus capable of Virology, fifth ed. Academic, New York.
producing foreign
immunizing antigen Cohen, J., Powderly, W.G., 2004. Infectious Diseases, second ed. Mosby,
Fig. 44.7  Vaccinia virus as an expression vector for the production of St Louis.
live recombinant vaccines. (Modified from Piccini, A., Paoletti, E., 1988.
Vaccinia: virus, vector, vaccine. Adv. Virus Res. 34, 43–64.) Fenner, F., 1982. A successful eradication campaign: Global eradication of
smallpox. Rev. Infect. Dis. 4, 916–930.
epithelial cells (see Fig. 44.6B). These bodies can be seen
in biopsy specimens or in the expressed caseous core of a Flint, S.J., Racaniello, V.R., et al., 2015. Principles of Virology, fourth ed.
nodule. MCV cannot be grown in tissue culture or animal American Society for Microbiology Press, Washington, DC.
models.
Knipe, D.M., Howley, P.M., 2013. Fields Virology, sixth ed. Lippincott Wil-
Lesions of molluscum contagiosum usually disappear liams & Wilkins, Philadelphia.
within 2 to 12 months, presumably as a result of immune
responses. The nodules can be removed by curettage Mandell, G.L., Bennet, J.E., Dolin, R., 2015. Principles and Practice of
(scraping) or by the application of liquid nitrogen or iodine Infectious Diseases, eighth ed. Saunders, Philadelphia.
solutions. 
Patel, N.A., Diven, D., 2018. Vaccinia. http://emedicine.medscape.com/ar
ticle/231773-overview. Accessed July 28, 2018.

Randall, C.M.H., Shisler, J.L., 2013. Molluscum contagiosum virus. Future
Virol. 8, 561–573. Website: www.medscape.com/viewarticle/805709
_print. Accessed July 28, 2018.

Richman, D.D., Whitley, R.J., Hayden, F.G., 2017. Clinical Virology,
fourth ed. American Society for Microbiology Press, Washington, DC.

Strauss, J.M., Strauss, E.G., 2002. Viruses and Human Disease. Academic,
San Diego.

Poxvirus vectors RSS Joost H.C.M. Kreijtz, Sarah C. Gilbert and Gerd Sut-
ter Vaccine, 2013-09-06, Volume 31, Issue 39, Pages 4217-4219,
https://www.clinicalkey.com/#!/content/journal/1-s2.0-S026441
0X13008839.

Questions

1. The structure of poxviruses is more complex than that of 4 . What characteristics of smallpox facilitated its elimina-
most other viruses. What problems does this complexity tion?
create for viral replication?
5 . Vaccinia virus is being used as a vector for the devel-
2. Poxviruses replicate in the cytoplasm. What problems opment of hybrid vaccines. Why is vaccinia virus well
does this feature create for viral replication? suited to this task? Which infectious agents would be
appropriate for a vaccinia hybrid vaccine, and why?
3 . How does the immune response to smallpox infection
in an immunologically naive person differ from that in 6. How does molluscum contagiosum infection resemble
a vaccinated person? When is antibody present in each that of human papillomavirus?
case? What stage or stages of viral dissemination are
blocked in each case? (see https://www.clinicalkey.com/#!/content/journal/
1-s2.0-S0264410X13008839).

455.e1

45 Parvoviruses

A 6-year-old girl had a viral respiratory infection and 3. What disease signs occur after infection of an adult? Of a
then became very pale, weak, tired, and severely ane- fetus?
mic because of a transient aplastic crisis.
1. What predisposing condition exacerbated the relatively   Answers to these questions are available on Student
Consult.com.
benign disease in this child?
2. What cell type is the host for this virus, and what deter-

mines this tropism?

Summaries Clinically Significant Organisms ᑏᑏ Children: erythema infectiosum (fifth Diagnosis
disease); high fever during viremia
PARVOVIRUSES followed later by rash ᑏᑏ Symptomatology, confirmation by
polymerase chain reaction genome
Trigger Words ᑏᑏ Individuals with chronic anemia: analysis of blood
B19, fifth disease, slapped cheeks, aplastic crisis
Treatment, Prevention, and Control
aplastic crisis, sickle crisis, spontane- ᑏᑏ Adults: arthralgia and arthritis
ous abortions ᑏᑏ Fetus: anemia-related disease and ᑏᑏ No modes of control or treatment

Biology, Virulence, and Disease death (hydrops fetalis)
ᑏᑏ Small, icosahedral capsid, single-strand
Epidemiology
DNA genome
ᑏᑏ Must replicate in growing cell: ery- ᑏᑏ Transmitted by aerosols, direct contact

throid precursor cells

The Parvoviridae are the smallest of the deoxyribonucleic Structure and Replication
acid (DNA) viruses. Their small size and limited genetic rep-
ertoire make them more dependent than any other DNA The parvoviruses are extremely small (18 to 26 nm in
virus on the host cell, or they require the presence of a diameter) and have a nonenveloped icosahedral capsid
helper virus to replicate. B19 and bocavirus cause human (Fig. 45.1 and Box 45.1). The B19 virus genome contains
disease, and adeno-associated viruses (AAVs) are used for one linear, single-stranded DNA molecule with a molecular
gene replacement therapy. mass of 1.5 to 1.8 × 106 Da (5500 bases in length) (Box
45.2). Plus or minus DNA strands are packaged separately
B19 normally causes erythema infectiosum, or fifth into virions. The genome encodes three structural and two
disease, which is a mild febrile exanthematous disease that major nonstructural proteins. Unlike larger DNA viruses,
occurs in children. It goes by the latter name because it was the parvoviruses must infect mitotically active cells because
counted as one of five classic childhood exanthems (the first they do not encode the means to stimulate cell growth or
four being varicella, rubella, roseola, and measles). B19 is also a polymerase. Only one serotype of B19 is known to exist.
responsible for episodes of aplastic crisis in patients with
chronic hemolytic anemia and is associated with acute B19 virus replicates in mitotically active cells and prefers
polyarthritis in adults. Infection of the fetus during preg- cells of the erythroid lineage, such as fresh human bone
nancy can result in hydrops fetalis and abortion. Bocavirus marrow cells, erythroid cells from fetal liver, and erythroid
is a recently discovered virus that can cause acute respiratory leukemia cells (Fig. 45.2). After binding to the erythrocyte
disease, which may become severe in young children. blood group P antigen (globoside) and its internalization, the
virion is uncoated, and the single-stranded DNA genome is
Other parvoviruses, such as RA-1 (isolated from a person delivered to the nucleus. Factors available only during the S
with rheumatoid arthritis), fecal parvoviruses, and PARV4 phase of the cell’s growth cycle and cellular DNA polymer-
may cause nonspecific viral symptoms and will not be ­discussed ases are required to generate a complementary DNA strand.
further. Feline and canine parvoviruses do not cause human
disease and are preventable with vaccination of the pet. The single-stranded DNA virion genome is converted to
a double-stranded DNA version, which is required for tran-
AAVs are members of the genus Dependovirus. They com- scription and replication. Inverted repeat sequences of DNA
monly infect humans but replicate only in association with at both ends of the genome fold back and hybridize with the
a second “helper” virus, which is usually an adenovirus. genome to create a primer for the cell’s DNA polymerase.
Dependoviruses neither cause illness nor modify infection This creates the complementary strand and replicates the
by their helper viruses. These properties and the propensity genome. The two major nonstructural proteins and the VP1
of AAVs to integrate into the host chromosome have made and VP2 structural capsid proteins are synthesized in the
genetically modified AAVs excellent candidates for use in
gene-replacement therapy.
456

45  •  Parvoviruses 457

Lysis by nuclear
and cytoplasmic
membrane
degeneration

Assembly

؉ DNA Structural and
؊ DNA nonstructural
؉ DNA proteins

؎ DNA mRNA
Transcription

؉ DNA

Fig. 45.1  Electron micrograph of parvovirus. Parvoviruses are small Nucleus Uncoating
(18 to 26 nm), nonenveloped viruses with single-stranded DNA. (Cour-
tesy Centers for Disease Control and Prevention, Atlanta, Georgia.) Internalized through
coated pits
BOX 45.1  Unique Properties of
Parvoviruses Infects mitotically
active erythroid
Smallest DNA virus precursor cells
Naked icosahedral capsid
Single-stranded (+ or − sense) DNA genome
Requirement of growing cells (B19) or helper virus (dependovirus)

for replication

BOX 45.2  Parvovirus Genome Fig. 45.2  Postulated replication of parvovirus (B19) based on infor-
mation from related viruses (minute virus of mice). The internalized
Single-stranded linear DNA genome. parvovirus delivers its genome to the nucleus, in which the single-
Approximately 5.5 kilobases in length. stranded (plus or minus) DNA is converted to double-stranded DNA
Plus and minus strands packaged into separate B19 virions. by host factors, and DNA polymerases present only in growing cells.
Ends of the genome have inverted repeats that hybridize to form Transcription, replication, and assembly occur in the nucleus. Virus is
released by cell lysis.
hairpin loops and a primer for DNA synthesis.
Separate coding regions for nonstructural and structural proteins. BOX 45.3  Disease Mechanisms of B19
Parvovirus
cytoplasm, and the structural proteins go to the nucleus, in
which the virion is assembled. The VP2 protein is cleaved Spreads by respiratory and oral secretions.
later to produce VP3. The nuclear and cytoplasmic mem- Infects mitotically active erythroid precursor cells in bone
brane degenerates, and the virus is released on cell lysis. 
marrow and establishes lytic infection.
Pathogenesis and Immunity Establishes large viremia and can cross the placenta.
Antibody is important for resolution and prophylaxis.
B19 targets and is cytolytic for erythroid precursor cells Causes biphasic disease.
(Box 45.3). B19 disease is determined by the direct killing
of these cells and the subsequent immune response to the Initial phase is related to viremia:
infection (rash and arthralgia). The immunopathogenesis Flulike symptoms and viral shedding
for B19 and rubella are similar; both are caused by immune
complexes with virions, hence both cause rash and arthral- Later phase is related to immune response:
gia in adults. Circulating immune complexes of antibody and virions that
do not fix complement
Studies performed in volunteers suggest that B19 virus Erythematous maculopapular rash, arthralgia, and arthritis
first replicates in the nasopharynx or upper respiratory
tract and then spreads by viremia to the bone marrow and Depletion of erythroid precursor cells and destabilization of eryth-
elsewhere, where it replicates and kills erythroid precur- rocytes initiate aplastic crisis in persons with chronic anemia
sor cells (Fig. 45.3). Bocavirus also initiates infection in the and cause hydrops fetalis in a fetus.
respiratory tract, replicates in the respiratory epithelium,
and causes disease. B19 viral disease has a biphasic course. The initial febrile
stage is the infectious stage. During this time, erythrocyte
production is stopped for approximately 1 week because of
the viral killing of erythroid precursor cells. A large viremia
occurs within 8 days of infection and is accompanied by
nonspecific flulike symptoms. Large numbers of viruses are

458 SECTION 5  •  Virology

Viral replication in BOX 45.4  Epidemiology of B19 Parvovirus
upper respiratory Infection
tract
Disease/Viral Factors
Virus in Local Viremia Rash and
upper replication arthralgia Capsid virus resistant to inactivation
respiratory (Erythema infectiosum Contagious period precedes symptoms
tract or fifth disease) Virus crosses placenta and infects fetus 

Viral replication in Normal host Transmission
erythroid precursor (Slight drop in
cells in bone marrow hemoglobin level) Transmitted via respiratory droplets 

Host with chronic Who Is at Risk?
hemolytic anemia
(Life-threatening aplastic crisis) Children, especially those in elementary school: erythema infec-
tiosum (fifth disease)
Fig. 45.3  Mechanism of spread of parvovirus within the body.
Parents of children with B19 infection
also released into oral and respiratory secretions. Antibody Pregnant women: fetal infection and disease
stops the viremia and is important for resolution of the dis- Persons with chronic anemia: aplastic crisis 
ease but contributes to the symptoms.
Geography/Season
The second, symptomatic, stage is immune mediated. The rash
and arthralgia seen in this stage coincide with the appear- Virus found worldwide
ance of virus-specific antibody, the disappearance of detect- Fifth disease more common in late winter and spring 
able B19 virus, and the formation of immune complexes.
Modes of Control
Hosts with chronic hemolytic anemia (e.g., sickle cell
anemia) who are infected with B19 are at risk for a life- No modes of control
threatening reticulocytopenia, which is referred to as
aplastic crisis. The reticulocytopenia results from the BOX 45.5  Clinical Consequences of
combination of B19 depletion of red blood cell precursors Parvovirus (B19) Infection
and the shortened life span of erythrocytes caused by the
underlying anemia.  Mild flulike illness (fever, headache, chills, myalgia, malaise)
Erythema infectiosum (fifth disease)
Epidemiology Aplastic crisis in persons with chronic anemia
Arthropathy (polyarthritis: symptoms in many joints)
Approximately 65% of the adult population has been Risk of fetal loss (hydrops fetalis) as a result of B19 virus crossing
infected with B19 by age 40 (Box 45.4). Erythema infec-
tiosum is most common in children and adolescents aged 4 the placenta, causing anemia-related disease but not congeni-
to 15 years, who are a source of contagion. Arthralgia and tal anomalies
arthritis are likely to occur in adults.
Lytic infection phase Noninfectious
Respiratory droplets and oral secretions transmit the virus Decreased reticulocyte immunologic phase
before the onset of the rash. Disease usually occurs in late and hemoglobin levels
winter and spring. Parenteral transmission of the virus by Virus-specific
a blood clotting–factor concentrate has also been described. Virus in throat IgG antibody
present
Bocavirus is found worldwide and causes disease in Viremia
children younger than 2 years. The virus is transmitted in
respiratory secretions but also can be isolated from stool.  Nonspecific flulike Rash/arthralgia
symptoms
Clinical Syndromes
Incubation Fever, headache, (Erythema
B19 virus, as stated earlier, is the cause of erythema infectio- chills, myalgia infectiosum)
sum (fifth disease) (Box 45.5). Infection starts with an unre-
markable prodromal period of 7 to 10 days during which 07 14 21 28
the person is contagious. Infection of a normal host may Inoculation of Days Virus very difficult to
cause either no noticeable symptoms or fever and nonspe- upper respiratory
cific symptoms (e.g., fever, runny nose, sore throat, chills, tract isolate from any site
malaise, myalgia, headache), as well as a slight decrease in after this time
hemoglobin levels (Fig. 45.4). This period is followed by a
Fig. 45.4  Time course of parvovirus (B19) infection. B19 causes bipha-
sic disease: first, an initial lytic infection phase characterized by febrile
flulike symptoms, and then a noninfectious immunologic phase char-
acterized by a rash and arthralgia. IgG, Immunoglobulin G.

45  •  Parvoviruses 459

BOX 45.6  Clinical Summary

A 10-year-old patient has a 5-day history of a flulike illness
(headache, fever, muscle pain, feels tired) and then a week later
develops an intensely red rash over the cheeks and a fainter “lacy”
rash over the trunk and extremities.

Fig. 45.5  A “slapped-cheek” appearance is typical of the rash for ery- these people causes a transient reduction in erythropoiesis
thema infectiosum. (From Hart, C.A., Broadhead, R.L., 1992. A Color Atlas in the bone marrow. The reduction results in a transient
of Pediatric Infectious Diseases. Wolfe, London, UK.) reticulocytopenia that lasts 7 to 10 days and a decrease in
hemoglobin level. An aplastic crisis is accompanied by fever
Clinical Case 45.1  B19 Infection of a and nonspecific symptoms such as malaise, myalgia, chills,
Transplant Recipient and itching. A maculopapular rash with arthralgia and
some joint swelling may also be present.
Persistent, rather than transient, anemia occurs on human
parvovirus B19 infection of immunosuppressed individu- B19 infection of a seronegative mother increases the
als. One such case was reported by Pamidi and associates risk for fetal death. The virus can infect the fetus and kill
(Transplantation 69:2666–2669, 2000). After 1 year of erythrocyte precursors, causing anemia, edema, hypoxia,
immunosuppressive therapy (mycophenolate mofetil, and congestive heart failure (hydrops fetalis). Infection of
prednisone, and tacrolimus) after a kidney transplant, a seropositive pregnant women often has no adverse effect on
46-year-old man complained of dyspnea, lightheaded- the fetus. There is no evidence that B19 causes congenital
ness, and fatigue on exercise. Laboratory tests confirmed abnormalities (Box 45.6; see Box 45.5).
a diagnosis of anemia. Bone marrow analysis indicated
erythroid hyperplasia with a predominance of immature Bocavirus may cause mild or severe acute respiratory dis-
erythroblasts. Proerythroblasts could be found, with deep ease. The more severe disease occurs in children younger
basophilic cytoplasm and intranuclear inclusions that than age 2, who may have bronchiolitis with wheezing and
immunohistologically stained for B19 antigen. The patient a viremia that extends long beyond the disease. A fatal case
received 16 units of packed red blood cells over 6 weeks, of bocavirus bronchiolitis has been reported. 
with continued anemia. Serology indicated the presence
of IgM (1:10) but insignificant IgG anti-B19 antibody. Laboratory Diagnosis
Treatment with intravenous IgG for 5 days resulted in
a dramatic improvement. Immunosuppressive therapy The diagnosis of erythema infectiosum is usually based on
of this patient prevented class switch to an IgG antibody the clinical presentation. For B19 disease to be definitively
response and expansion because of the lack of helper T diagnosed; however, specific immunoglobulin (Ig)M or
cells. Resolution of the encapsidated parvovirus is depend- viral DNA must be detected (i.e., to distinguish the rash of
ent on a robust antibody response, and in its absence, the B19 from that of rubella in a pregnant woman). Enzyme-
normal transient anemia resulting from virus replication linked immunosorbent assays for B19 IgM and IgG are
in erythroid precursors cannot be resolved. available. The polymerase chain reaction test is a very sen-
sitive method for detecting the B19 and bocavirus genomes
distinctive rash on the cheeks, which appear to have in clinical samples. Virus isolation is not performed. 
been slapped. The rash then usually spreads, especially to
exposed skin such as the arms and legs (Fig. 45.5), and then Treatment, Prevention, and
subsides over 1 to 2 weeks (Clinical Case 45.1). Control

B19 infection in adults causes polyarthritis (with or No specific antiviral treatment or means of control are avail-
without a rash) that can last for weeks, months, or longer. able. Vaccines are available for dog and cat parvoviruses.
Arthritis of the hands, wrists, knees, and ankles predomi-   For questions see StudentConsult.com.
nates. The rash may precede the arthritis but often does not
occur. B19 infection of immunocompromised people may Bibliography
result in chronic disease.
Allander, T., 2008. Human bocavirus. J. Clin. Virol. 41, 29–33.
The most serious complication of parvovirus infection Berns, K.I., 1990. Parvovirus replication. Microbiol. Rev. 54, 316–329.
is the aplastic crisis that occurs in patients with chronic Brown, K.E., 2010. The expanding range of parvoviruses which infect
hemolytic anemia (e.g., sickle cell anemia). Infection in
humans. Rev. Med. Virol. 20, 231–244.
CDC Parvoviruses B19. https://www.cdc.gov/parvovirusb19/fifth-

disease.html. Accessed July 28, 2018.
Cennimo D.J., Dieudonne, A. Parvovirus B19 Infection. http://emedicine.

medscape.com/article/961063-overview. Accessed November 4, 2014.
Chorba, T., Coccia, P., Holman, R.C., et al., 1986. The role of parvovirus

B19 in aplastic crisis and erythema infectiosum (fifth disease). J. Infect.
Dis. 154, 383–393.
Cohen, J., Powderly, W.G., 2004. Infectious Diseases, second ed. Mosby,
St Louis.

460 SECTION 5  •  Virology

Flint, S.J., Racaniello, V.R., et al., 2015. Principles of Virology, fourth ed. 10 (5), e1004036. https://doi.org/10.1371/journal.ppat.1004036.
American Society for Microbiology Press, Washington, DC. Accessed 28 July 2018.
Naides, S.J., Scharosch, L.L., Foto, F., et al., 1990. Rheumatologic manifes-
Flower, B., MacMahon, E, Erythrovirus B19 infection, Medicine 45:12, tations of human parvovirus B19 infection in adults. Arthritis Rheum.
772–776. 33, 1297–1309.
Richman, D.D., Whitley, R.J., Hayden, F.G., 2017. Clinical Virology,
Knipe, D.M., Howley, P.M., 2013. Fields Virology, sixth ed. Lippincott fourth ed. American Society for Microbiology Press, Washington, DC.
­Williams & Wilkins, Philadelphia. Ursic, T., et al., 2011. Human bocavirus as the cause of a life-threatening
infection. J. Clin. Microbiol. 49, 1179–1181.
Mandell, G.L., Bennet, J.E., Dolin, R., 2015. Principles and Practice of Young, N.S., Brown, K.E., 2004. Parvovirus B19. N. Engl. J. Med. 350,
Infectious Diseases, eighth ed. Saunders, Philadelphia. 586–597.

Matthews, P.C., Malik, A., Simmons, R., Sharp, C., Simmonds, P., Klener-
man, P., 2014. PARV4: An emerging tetraparvovirus. PLoS Pathog.

Case Study and Questions 3 . What caused the symptoms?
4 . Were the symptoms of the mother and daughter related?
Mrs. Doe brought her daughter to the pediatrician with the 5. What underlying condition would put the daughter at
complaint of a rash. The daughter’s face appeared as if it had
been slapped, but she had no fever or other notable symp- increased risk for serious disease after B19 infection?
toms. On questioning, Mrs. Doe reported that her daughter The mother?
had had a mild cold within the previous 2 weeks and that 6 . Why is quarantine a poor means of limiting the spread of
she herself was currently having more joint pain than usual B19 parvovirus?
and felt very tired.
1 . What features of this history indicate a parvovirus B19

etiology?
2. Was the child infectious at presentation? If not, when

was she contagious?

460.e1

46 Picornaviruses

A 9-day-old infant with a fever and who appeared an enterovirus that was subsequently identified as
to be septic progressed to multisystem organ dys- echovirus 11. Several days earlier, the mother had
function syndrome with a combination of hepa- had a slight fever and a cold.
titis, meningoencephalitis, myocarditis, and 1. How did the baby become infected?
pneumonia. The cerebrospinal fluid (CSF) had nor- 2 . How does the viral structure facilitate virus spread in the
mal glucose levels and lacked neutrophil infiltrate.
The infant was started on acyclovir therapy for a body and transmission to others?
suspected congenital herpes simplex virus (HSV) 3 . What type of immunity is protective for this virus, and
infection. Genome analysis (polymerase chain
reaction [PCR] and reverse transcriptase [RT]- why was the baby not protected?
PCR) of the CSF did not detect HSV but did detect
  Answers to these questions are available on Student
Consult.com.

Summaries Clinically Significant Organisms

PICORNAVIRUSES ᑏᑏ Capsid virus resistant to inactivation RHINOVIRUSES
ᑏᑏ Initial replication may be in the respira-
Trigger Words ᑏᑏ Acid labile and cannot replicate at body
tory tract, oropharynx, or gastrointestinal temperature
Polio: flaccid paralysis, major and minor tract but does not cause enteric disease.
disease, fecal-oral ᑏᑏ Polio: cytolytic infection of motor ᑏᑏ Restricted to upper respiratory tract
neurons of anterior horn and brainstem, ᑏᑏ Common cold
Coxsackievirus A: vesicular diseases, paralysis Epidemiology
meningitis; coxsackievirus B (body): ᑏᑏ Coxsackievirus A: herpangina, hand-
pleurodynia, myocarditis foot-and-mouth disease, common cold, ᑏᑏ Enteroviruses transmitted by fecal-oral
meningitis route and aerosols
Other echovirus and enteroviruses: like ᑏᑏ Coxsackievirus B: pleurodynia, neonatal
coxsackievirus and hepatitis A virus myocarditis, type 1 diabetes ᑏᑏ Rhinoviruses transmitted by aerosols
ᑏᑏ Echoviruses: like coxsackievirus and contact
Rhinoviruses: common cold, acid labile, ᑏᑏ Parechoviruses: like coxsackie and
does not replicate above 33° C major cause of neonatal viral sepsis and Diagnosis
meningitis
Biology, Virulence, and Disease ᑏᑏ Immune assays (ELISA) or RT-PCR
HEPATOVIRUS: Hepatitis A virusa genome analysis of blood, CSF, or other
ᑏᑏ Small size, icosahedral capsid, positive relevant sample
RNA genome with terminal protein ᑏᑏ Properties like enterovirus
ᑏᑏ Human virus Treatment, Prevention, and Control
ᑏᑏ Genome is sufficient for infection ᑏᑏ Liver disease caused by immune
ᑏᑏ Encodes RNA-dependent RNA poly- ᑏᑏ OPV and IPV polio vaccines
response
merase, replicates in cytoplasm

ENTEROVIRUSES

ᑏᑏ Disease caused by lytic infection of impor-
tant target tissue

aHepatitis A virus is discussed in Chapter 55.
CSF, Cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; IPV, inactivated polio vaccine; OPV, oral polio vaccine; RT-PCR, reverse transcriptase poly-

merase chain reaction.

Picornaviridae is one of the largest families of viruses and enterovirus. Likewise, several different serotypes may cause the
includes some of the most important human and animal same disease, depending on the target tissue affected.
viruses (Box 46.1). As the name indicates, these viruses
are small (pico) ribonucleic acid (RNA) viruses that have The capsids of enteroviruses are very resistant to harsh
a naked capsid structure. The family has more than 230 environmental conditions (sewage systems) and the condi-
members divided into nine genera, including Enterovi- tions in the gastrointestinal tract, which facilitates their
rus, Rhinovirus, Hepatovirus (hepatitis A virus; discussed in transmission by the fecal-oral route. Although they may ini-
­Chapter 55), Cardiovirus, and Aphthovirus. The enterovi- tiate infection in the gastrointestinal tract, the enteroviruses
ruses are distinguished from the rhinoviruses by the stability rarely cause enteric disease. In fact, most infections are usu-
of the capsid at pH 3, the optimum temperature for growth, ally asymptomatic. The best-known and most-studied picor-
the mode of transmission, and their diseases (Box 46.2). navirus is poliovirus, of which there are three serotypes.

At least 90 serotypes of human enteroviruses exist and are Coxsackieviruses are named after the town of Cox-
classified as polioviruses, coxsackieviruses A and B, echoviruses, sackie, New York, in which they were first isolated. They
parechoviruses or for the more recently discovered viruses, as are divided into two groups, A and B, on the basis of certain
numbered enteroviruses (e.g., enterovirus D68). Several differ- biological and antigenic differences and are further subdi-
ent disease syndromes may be caused by a specific serotype of vided into numeric serotypes on the basis of additional anti-
genic differences.

461

462 SECTION 5  •  Virology

BOX 46.1 Picornaviridae Fig. 46.1  Electron micrograph of poliovirus. (Courtesy Centers for Dis-
ease Control and Prevention, Atlanta, Georgia.)
Enterovirus
Poliovirus types 1, 2, and 3 plus-sense RNA of approximately 7200 to 8450 bases. The
Coxsackievirus A 24 types genome has a polyA (polyadenosine) sequence at the 3′
Coxsackievirus B 6 types end and a small protein, VPg (viral protein genome-linked;
Echovirusa 34 types 22 to 24 amino acids), attached to the 5′ end. The polyA
Parechovirus 16 types sequence enhances the infectivity of the RNA, and the VPg
Enterovirus 4 is important in packaging the genome into the capsid and
initiating viral RNA synthesis. The naked picornavirus genome
Hepatovirus is sufficient for infection if microinjected into a cell. 
Hepatitis A virus
Replication
Rhinovirus: >100 types+
Cardiovirus The specificity of the picornavirus interaction for cellular
Aphthovirus receptors is the major determinant of the target tissue tro-
pism and disease (see Fig. 36.12). The VP1 proteins at the
aEnteric, cytopathic, human, orphan + virus. vertices of the virion contain a canyon structure to which
the receptor binds. Pleconaril and related antiviral com-
BOX 46.2  Unique Properties of Human pounds contain a 3-methylisoxazole group that binds to the
Picornaviruses floor of this canyon and alters its conformation to prevent
the uncoating of the virus.
Virion is a naked, small (25 to 30 nm), icosahedral capsid enclos-
ing a single-stranded positive RNA genome. The picornaviruses can be categorized according to their
cell-surface receptor specificity. The receptors for poliovi-
Enteroviruses are resistant to pH 3 to pH 9, detergents, mild sew- ruses, some coxsackieviruses, and rhinoviruses are mem-
age treatment, and heat. bers of the immunoglobulin superfamily of proteins. At
least 80% of the rhinoviruses and several serotypes of cox-
Rhinoviruses are labile at acidic pH; optimum growth temperature sackievirus bind to the intercellular adhesion molecule-1
is 33° C. (ICAM-1) expressed on epithelial cells, fibroblasts, and
endothelial cells. Several coxsackieviruses, echoviruses,
Genome is an mRNA. and other enteroviruses bind to decay accelerating factor
Naked genome is sufficient for infection. (CD55), and coxsackievirus B shares a receptor with adeno-
Virus replicates in cytoplasm. virus. Poliovirus binds to a different molecule (PVR/CD155)
Viral RNA is translated into polyprotein, which is then cleaved that is similar to the receptor for HSV. The poliovirus recep-
tor is present on many different human cells, but not all of
into enzymatic and structural proteins. these cells will replicate the virus.
Most viruses are cytolytic.
On binding to the receptor, the VP4 is released and the
mRNA, Messenger ribonucleic acid. capsid is weakened. The genome is then injected directly
across the membrane through a channel created by the
The name echovirus is derived from enteric cytopathic VP1 protein at one of the vertices of the virion. The genome
human orphan because the disease associated with these binds directly to ribosomes, despite the lack of a 5′-cap struc-
agents was not initially known. Parechoviruses were ture. The ribosomes recognize a unique internal RNA loop
thought to be echoviruses. Since 1967, newly isolated (internal ribosome entry site [IRES]) in the genome that is
enteroviruses have been distinguished numerically. also present in some cellular mRNAs. A polyprotein con-
taining all the viral protein sequences is synthesized within
The human rhinoviruses consist of at least 100 sero- 10 to 15 minutes of infection. This polyprotein is cleaved
types and are the major cause of the common cold. They by viral proteases encoded in it. Viral proteins tether the
are sensitive to acidic pH and replicate poorly at temperatures
above 33° C. These properties usually limit rhinoviruses to
causing upper respiratory tract infections.

Structure

The plus-strand RNA of the picornaviruses is surrounded by
an icosahedral capsid that is approximately 30 nm in diam-
eter. The icosahedral capsid has 12 pentameric vertices, each
of which is composed of five protomeric units of proteins. The
protomers are made of four virion polypeptides (VP1 to VP4).
VP2 and VP4 are generated by the cleavage of a precursor,
VP0. VP4 in the virion solidifies the structure, but it is not gen-
erated until the genome is incorporated into the capsid. This
protein is released on binding of the virus to the cellular recep-
tor. The capsids are stable in the presence of heat, acid, and
detergent, with the exception of the rhinoviruses, which are
labile to acid. The capsid structure is so regular that paracrys-
tals of virions often form in infected cells (Figs. 46.1 and 46.2).

The genome of the picornaviruses resembles a mes-
senger RNA (mRNA) (Fig. 46.3). It is a single strand of

46  •  Picornaviruses 463

A VP1 B
Canyon
Pentamer COOH

VP2

VP4 VP3
Protomer
RNA core

ICAM-1

VPg NH2

CD

Fig. 46.2  (A) Cryoelectron microscopy computer-generated reconstruction of human rhinovirus 16. (B) Cryoelectron microscopy reconstruction of
the interaction of a soluble form of intercellular adhesion molecule-1 (ICAM-1) with human rhinovirus 16. Note: There is one ICAM-1 per capsomere. (C)
Structure of the human rhinovirus. (D) Binding of the ICAM-1 molecule within the canyon of the virion triggers the opening of the capsid for release of
the genome into the cell. RNA, Ribonucleic acid; VP1, 2, 3, 4, viral protein 1, 2, 3, 4; VPg, viral protein genome-linked. (A and B, Courtesy Tim Baker, Purdue
University, West Lafayette, Indiana.)

Structural Nonstructural

IRES

VP4 VP2 VP3 VP1 2A 2B 2C 3A 3B p3rCo RdRp

5′ VPg 3′

Fig. 46.3  Structure of the picornavirus genome. The genome (7200 to 8400 bases) is translated as a polyprotein that is cleaved by viral-encoded
proteases into individual proteins. Viral genes: VP1, 2, 3, 4, capsid proteins 1, 2, 3, 4; 2A cleaves eIF4g to inhibit host protein synthesis; 2B, 2C, 3A, 3B
generate membrane-binding, vesicle-forming proteins that facilitate replication; 3B also encodes VPg genome-binding protein; 3Cpro, protease; RdRp,
RNA-dependent RNA polymerase. (Redrawn from Whitton, J.L., Cornell, C.T., Feuer, R., 2005. Host and virus determinants of picornavirus pathogenesis and
tropism. Nat. Rev. Microbiol. 3, 765–776.)

genome to endoplasmic reticulum membranes, and the cap-binding protein (eIF4-G) of the ribosome by a poliovirus
machinery for replication of the genome is collected into a protease prevents most cellular mRNA from binding to the
vesicle. The viral RNA-dependent RNA polymerase gener- ribosome. Inhibition of transcription factors decreases cel-
ates a negative-strand RNA template from which the new lular mRNA synthesis, and permeability changes induced
mRNA/genome can be synthesized. The amount of viral by picornaviruses reduce the ability of cellular mRNA to
mRNA increases rapidly in the cell, with the number of viral bind to the ribosome. In addition, viral mRNA can out-
RNA molecules reaching as many as 400,000 per cell. compete cellular mRNA for the factors required in protein
synthesis. These activities contribute to the cytopathologic
The genome encodes a polyprotein that is proteolytically effect of the virus on the target cell.
cleaved by viral-encoded proteases to produce the enzy-
matic and structural proteins of the virus (see Fig. 46.3). In As the viral genome is being replicated and translated,
addition to the capsid proteins and VPg, the picornaviruses the structural proteins VP0, VP1, and VP3 are cleaved from
encode at least two proteases and an RNA-dependent RNA the polyprotein by viral-encoded proteases and assembled
polymerase. into subunits. Five subunits associate into pentamers,
and 12 pentamers associate to form the procapsid. After
Most picornaviruses inhibit cellular RNA and protein syn- insertion of the genome, VP0 is cleaved into VP2 and VP4
thesis during infection. For example, cleavage of the cell’s

464 SECTION 5  •  Virology

to complete the capsid. As many as 100,000 virions per of neurons to polio and to old age may result in paralysis
cell may be produced and released on cell lysis. The entire later in life; this is termed postpolio syndrome.
replication cycle may be as short as 3 to 4 hours. 
Viral shedding from the oropharynx blood or the cere-
Enteroviruses bral spinal fluid can be detected for a short time before and
during symptoms, whereas viral production and shedding
PATHOGENESIS AND IMMUNITY from the intestine may last for 30 days or longer, even in the
Contrary to their name, enteroviruses do not usually cause presence of a humoral immune response.
enteric disease, but they do replicate within and are trans-
mitted by the fecal-oral route. The diseases produced by the Antibody is the major protective immune response to the enterovi-
enteroviruses are determined mainly by differences in tissue ruses. Secretory antibody can prevent the initial establishment
tropism and the cytolytic capacity of the virus (Fig. 46.4; of infection in the oropharynx and gastrointestinal tract, and
Box 46.3). The virions are impervious to stomach acid, serum antibody prevents viremic spread to the target tissue
proteases, and bile. Enteroviruses are acquired through and therefore prevents disease. The time course for antibody
the upper respiratory tract and mouth. Viral replication development after infection with a live vaccine is presented in
is initiated in the mucosa and lymphoid tissue of the ton- Fig. 46.10. Cell-mediated immunity is not usually involved in
sils and pharynx, and the virus later infects M cells and protection but may play a role in resolution and pathogenesis. 
lymphocytes of the Peyer patches and enterocytes in the
intestinal mucosa. Primary viremia spreads the virus to EPIDEMIOLOGY
receptor-bearing target tissues, including the reticuloendo-
thelial cells of the lymph nodes, spleen, and liver, to initiate The enteroviruses are exclusively human pathogens (Box
a second phase of viral replication, resulting in a secondary 46.4). As the name implies, these viruses primarily spread via
viremia and symptoms. the fecal-oral route. Asymptomatic shedding can occur
for up to a month, putting virus into the environment. Poor
Most enteroviruses are cytolytic, replicating rapidly and sanitation and crowded living conditions foster transmission
causing direct damage to the target cell. of the viruses (Fig. 46.5). Sewage contamination of water
supplies can result in enterovirus epidemics. Outbreaks of
In the case of poliovirus, the virus gains access to the brain enterovirus disease are seen in schools and day-care settings,
by infecting skeletal muscle and traveling up the inner- and summer is the major season for such disease. The cox-
vating nerves to the brain, similar to the rabies virus (see sackieviruses and echoviruses may also be spread in aerosol
Chapter 50). The virus is cytolytic for the motor neurons droplets and cause respiratory tract infections.
of the anterior horn and brainstem. The location and num-
ber of nerve cells destroyed by the virus govern the extent of With the success of the polio vaccines, the wild-type
paralysis and whether and when other neurons can rein- poliovirus has been eliminated from the Western Hemi-
nervate the muscle and restore activity. The combined loss sphere (Fig. 46.6) and most, but not all, of the world. Para-
lytic polio was never eliminated from Nigeria, Afghanistan,
Antibody Enterovirus, and Pakistan, and the viruses have spread from these coun-
blockage echo, tries to others. A small but significant number of vaccine-
coxsackie, related cases of polio result from mutation in the VP1 gene
polio of one of the three strains that reestablishes neurovirulence
HAV (circulating vaccine-derived poliovirus [cVDPV] 2) in the
live vaccine virus. Infectious poliovirus is feared to remain
Replication in sewage for very long periods because of the hardy nature
in oropharynx
BOX 46.3  Disease Mechanisms of
Primary Picornaviruses
viremia:
blood- Enteroviruses enter via the oropharynx, intestinal mucosa, or up-
stream per respiratory tract and infect the underlying lymphatic tissue;
rhinoviruses are restricted to the upper respiratory tract.
Secondary Target tissue
viremia In the absence of serum antibody, enterovirus spreads by viremia
to cells of a receptor-bearing target tissue.
Echo, Skin Muscle Brain Meninges Liver
Different picornaviruses bind to different receptors, many of
coxsackie A which are members of the immunoglobulin superfamily (i.e.,
intercellular adhesion molecule-1).
Hand-foot-and- Echo, Polio, HAV
The infected target tissue determines the subsequent disease.
mouth disease coxsackie coxsackie Virus shed Viral, rather than immune, pathologic effects are usually responsi-
in stool
A, B Echo, polio, ble for causing disease.
The secretory antibody response is transitory but can prevent the
coxsackie
initiation of infection.
Rash, Heart Thorax Hepatitis Serum antibody blocks viremic spread to target tissue, preventing

herpangina Meningitis disease.
Enterovirus is shed in feces for long periods.
Myocarditis, Encephalitis Infection is often asymptomatic or causes mild, flulike, or upper
pericarditis Paralytic disease
respiratory tract disease.
Pleurodynia

Fig. 46.4  Pathogenesis of enterovirus infection. The target tissue
infected by the enterovirus determines the predominant disease
caused by the virus. Coxsackie, Coxsackievirus; echo, echovirus; HAV,
hepatitis A virus; polio, poliovirus.

46  •  Picornaviruses 465

of the virions, extending the risk of contact and the need for Similar to poliovirus infection, coxsackievirus A disease is
vaccination programs. generally more severe in adults than in children. Coxsackie­
virus B and some of the echoviruses (especially echovirus
Polioviruses are spread most often during the summer 11) can be particularly harmful to infants. Specific entero-
and autumn. Paralytic polio was once considered a middle viruses are attributed to causing an increased incidence of
class disease because good hygiene would delay exposure acute flaccid myelitis, resembling polio disease, in 2018. 
of a person to the virus until late childhood, the adolescent
years, or adulthood, when infection would produce the CLINICAL SYNDROMES
most severe symptoms. Infection during early childhood is The clinical syndromes produced by the enteroviruses are
more likely to be asymptomatic or cause very mild disease. determined by several factors including (1) viral serotype;
(2) infecting dose; (3) tissue tropism; (4) portal of entry;
BOX 46.4  Epidemiology of Enterovirus (5) patient’s age, gender, and state of health; and (6) preg-
Infections nancy (Table 46.1). The incubation period for enterovirus
disease varies from 1 to 35 days, depending on the virus,
Disease/Viral Factors the target tissue, and the person’s age. Viruses that affect
oral and respiratory sites have the shortest incubation
Nature of disease correlates with specific enterovirus periods.
Severity of disease correlates with age of person Poliovirus Infections
Infection often asymptomatic, with viral shedding There are three poliovirus types, with 85% of the cases of
Virion resistant to environmental conditions (detergents, acid, paralytic polio caused by type 1. Reversion of the attenu-
ated vaccine virus type 2 to virulence can cause vaccine-
drying, mild sewage treatment, and heat)  associated disease. Wild-type polio infections are rare
because of the success of polio vaccines (see Fig. 46.6). As
Transmission noted earlier, however, vaccine-associated cases of polio do
occur, and some populations remain unvaccinated, putting
Fecal-oral route: poor hygiene, dirty diapers (especially in day-care them at risk for infection. Poliovirus may cause one of the
settings) following four outcomes in unvaccinated people, depending
on the progression of the infection (Fig. 46.7):
Ingestion via contaminated food and water 1 . Asymptomatic illness results if the viral infection is
Contact with infected hands and fomites
Inhalation of infectious aerosols  limited to the oropharynx and the gut. At least 90% of
poliovirus infections are asymptomatic.
Who Is at Risk? 2. Abortive poliomyelitis, the minor illness, is a non-
specific febrile illness occurring in approximately 5% of
Young children: at risk for polio (asymptomatic or mild disease) infected people. Fever, headache, malaise, sore throat,
Older children and adults: at risk for polio (asymptomatic to and vomiting occur in such persons within 3 to 4 days
of exposure.
paralytic disease) 3 . Nonparalytic poliomyelitis or aseptic meningitis
Newborns and neonates: at highest risk for serious coxsackievirus, occurs in 1% to 2% of patients with poliovirus infections.
In this disease, the virus progresses into the central ner-
echovirus, and enterovirus disease 

Geography/Season

Viruses have worldwide distribution; wild-type polio virtually
eradicated in most countries because of vaccination programs

Disease more common in summer 

Modes of Control

For polio, live oral polio vaccine (trivalent OPV) or inactivated
trivalent polio vaccine (IPV) is administered

For other enteroviruses, no vaccine; good hygiene limits spread

Cases per 100,000 population

Human 40
fecal matter
Paralytic/nonparalytic
Sewage Solid waste
Hand landfills Estimated Paralytic only
30 cases Killed
Water supply poliovirus
Shellfish 20 vaccine (IPV)
introduced

Live oral
poliovirus
10 vaccine (OPV)
introduced

1941 45 50 55 60 65 70 92
Year

Fig. 46.5  Transmission of enteroviruses. The capsid structure is resis- Fig. 46.6  Incidence of polio in the United States. Killed (inactivated)
tant to mild sewage treatment, salt water, detergents, and temperature polio vaccine (IPV) was introduced in 1955, and live oral polio vaccine
changes, allowing these viruses to be transmitted by fecal-oral routes, (OPV) was introduced in 1961 and 1962. Wild-type polio has been erad-
by fomites, and on hands. icated in the United States. (Courtesy Centers for Disease Control and
Prevention, 1973. Against Disease: 1972. U.S. Government Printing Office,
Washington, DC.)

466 SECTION 5  •  Virology

TABLE 46.1  Summary of Clinical Syndromes Associated with Major Enterovirus Groupsa

Syndrome Occurrence Polioviruses Coxsackievirus A Coxsackievirus B Echo-/Enterovirusesb
Asymptomatic Frequent + + + +
Paralytic disease Sporadic + + + + (enteroD68)
Encephalitis, meningitis Outbreaks + + + +
Carditis Sporadic — + + +
Neonatal disease Outbreaks — — + +
Pleurodynia Outbreaks — — + —
Herpangina Common — + — —
Hand-foot-and-mouth disease Common — + — —
Rash disease Common — + + +
Acute hemorrhagic conjunctivitis Epidemics — + + (entero70)
Respiratory tract infections Common + + + +
Undifferentiated fever Common + + + +
Diarrhea, gastrointestinal disease Uncommon — — — +
Diabetes, pancreatitis Uncommon — — + —
Orchitis Uncommon — — + —

aA member(s) of this family cause(s) this disease.
bEnteroviruses 68 to 71+.

Antibody to the anterior horn cells of the spinal cord and to the
motor cortex of the brain. The severity of paralysis is
Paralysis determined by the extent of the neuronal infection and
by which neurons are affected. Paralytic poliomyeli-
Major illness tis is characterized by an asymmetric flaccid paralysis
(meningitis) with no sensory loss. The degree of paralysis varies in
that it may involve only a few muscle groups (e.g., one
Minor Meningeal irritation leg) or there may be complete flaccid paralysis of all
illness Stiffness of neck or back four extremities. The paralysis may then progress over
the first few days and may result in complete recov-
Prodrome Fever CNS invasion ery, residual paralysis, or death. Most recoveries occur
malaise within 6 months, but as long as 2 years may be required
for complete remission.
headache Bulbar poliomyelitis can be more severe, may
involve the muscles of the pharynx, vocal cords, and
nausea Virus in stool respiration, and may result in death in 75% of patients.
Iron lungs, chambers that provided external respiratory
Virus in Viremia compression, were used during the 1950s to assist the
breathing of patients with such polio disease. Before vac-
oropharynx cination programs, iron lungs filled the wards of chil-
dren’s hospitals.
0 3 56 10 12 35 Postpolio syndrome is a sequela of poliomyelitis that
may occur much later in life (30 to 40 years later) in 29% of
Fig. 46.7  Progression of poliovirus infection. Infection may be asymp- the original victims. Affected persons suffer a deterioration
tomatic or may progress to minor or major disease. CNS, Central ner- of the originally affected muscles. Poliovirus is not present,
vous system. but the syndrome is believed to result from a loss of neurons
in the initially affected nerves. 
vous system and the meninges, causing back pain and Coxsackievirus and Echovirus Infections
muscle spasms in addition to the symptoms of the minor Several clinical syndromes may be caused by either a cox-
illness. sackievirus or an echovirus (e.g., aseptic meningitis), but
4. Paralytic polio, the major illness, occurs in 0.1% certain illnesses are specifically associated with coxsacki-
to 2.0% of persons with poliovirus infections and is the eviruses. Coxsackievirus A is associated with diseases
most severe outcome. It appears 3 to 4 days after the involving vesicular lesions (e.g., herpangina), whereas
minor illness has subsided, producing a biphasic ill- coxsackievirus B (B for body) is most frequently associ-
ness. In this disease, the virus spreads from the blood ated with myocarditis and pleurodynia. Coxsackieviruses,

46  •  Picornaviruses 467

Clinical Case 46.1  Polio-like Disease Fig. 46.9  Hand-foot-and-mouth disease caused by coxsackie A virus
Caused by Coxsackievirus A (A) Lesions initially appear in the oral cavity and then develop within 1
day on the palms and, as seen here, the soles. (From Habif, T.P., Clinical
In a case reported by Yoshimura and Kurashige (Brain Dermatology: A Color Guide to Diagnosis and Therapy, third ed. Mosby,
Dev 20:540–542, 1998), a 4-year-old child’s onset of St. Louis, MO.)
abdominal pain, distended abdomen, inability to urinate,
and inability to walk prompted admission to the hospital. The virus can be recovered from the lesions or from feces.
All abdominal reflexes were gone, accompanied by bladder The disease is self-limited and requires only symptomatic
and rectal dysfunction. Pain and temperature sense was management.
normal. CSF showed an increase in cell count, with 393
cells/mm3 and with 95% neutrophils and 5% lympho- Hand-foot-and-mouth disease is a vesicular exan-
cytes. CSF protein and glucose were within normal values. them usually caused by coxsackievirus A16. The name
Serologic analysis was negative for poliovirus, echovirus, is descriptive because the main features of this infection
and coxsackievirus types A4, A7, A9, B1, and B5, viruses consist of vesicular lesions on the hands, feet, mouth, and
reported to cause polio-like paralytic disease. Antibody for tongue (Fig. 46.9). The patient is mildly febrile, and the ill-
coxsackievirus A10 was detected during the acute phase ness subsides in a few days.
(titer = 32) and after 4 weeks (titer = 128). Three weeks
after admission, the child was able to walk again, but mild Pleurodynia (Bornholm disease), also known as the
dysfunction of the bladder and rectum remained, even 3 devil’s grip, is an acute illness in which patients have a
months after admission. Although routine immunization sudden onset of fever and unilateral low thoracic, pleuritic
has eliminated polio-induced paralysis in most parts of the chest pain that may be excruciating. Abdominal pain and
world, polio-like disease can still be caused by other picor- even vomiting may also occur, and muscles on the involved
naviruses and revertants of the vaccine-related strains of side may be extremely tender. Pleurodynia lasts an aver-
polio. age of 4 days but may relapse after the condition has been
CSF, Cerebrospinal fluid. asymptomatic for several days. Coxsackievirus B is the
causative agent.
Fig. 46.8  Herpangina. Characteristic discrete vesicles are seen on the
anterior tonsillar pillars. (Courtesy Dr. GDW McKendrick; from Lambert, Myocardial and pericardial infections caused by
H.P., et al., 1982. Infectious Diseases Illustrated: An integrated text and coxsackievirus B occur sporadically in older children and
color atlas. Gower, London.) adults but are most threatening in newborns. Neonates
with these infections have febrile illnesses and sudden and
enterovirus D68, and other picornaviruses can also cause unexplained onset of heart failure. Cyanosis, tachycardia,
a polio-like flacid paralytic disease (Clinical Case 46.1). The cardiomegaly, and hepatomegaly occur. The mortality
most common result of infection is lack of symptoms or a associated with the infection is high, and autopsy typically
mild upper respiratory tract or flulike disease. reveals involvement of other organ systems, including
the brain, liver, and pancreas. Acute benign pericarditis
Herpangina is caused by several types of coxsackievi- affects young adults but may be seen in older persons. The
rus A and is not related to a herpesvirus infection. Fever, symptoms resemble those of myocardial infarction with
sore throat, pain on swallowing, anorexia, and vomiting fever.
accompany this disease. The classic finding is vesicular
ulcerated lesions around the soft palate and uvula (Fig. Viral (aseptic) meningitis is an acute febrile illness
46.8). Less typically, the lesions affect the hard palate. accompanied by headache and signs of meningeal irritation,
including nuchal rigidity. Petechiae or a rash may occur in
patients with enteroviral meningitis. Recovery is usually
uneventful unless the illness is associated with encepha-
litis (meningoencephalitis) or occurs in children younger
than 1 year. Outbreaks of picornavirus meningitis (echo-
virus 11) occur each year during the summer and autumn.

468 SECTION 5  •  Virology

Fever, rash, and common coldlike symptoms may occur in Serology can be used to confirm an enterovirus infection
patients infected with echoviruses or coxsackieviruses. The through detection of specific IgM or the finding of a four-
rash is usually maculopapular but may occasionally be pete- fold increase in the antibody titer between the time of the
chial or even vesicular. The petechial type of eruption can be acute illness and the period of convalescence. Because of
confused with the rash of meningococcemia, which is life- their many serotypes, this approach may not be practical
threatening and must be treated. Enteroviral disease is usually for detection of echovirus and coxsackievirus unless a spe-
less intense for the child than meningococcemia. Coxsacki- cific virus is suspected. 
eviruses A21 and A24 and echoviruses 11 and 20 can cause
rhinovirus-like symptoms resembling the common cold.  TREATMENT, PREVENTION, AND CONTROL
Other Enterovirus Diseases Prevention of paralytic poliomyelitis is one of the triumphs
Enterovirus 70 and a variant of coxsackievirus A24 have of modern medicine. By 1979, infections with the wild-type
been associated with an extremely contagious ocular dis- poliovirus disappeared from the United States, with the
ease, acute hemorrhagic conjunctivitis. The infection number of cases of polio decreasing from 21,000 per year in
causes subconjunctival hemorrhages and conjunctivitis. the prevaccine era to 18 in unvaccinated patients in 1977.
The disease has a 24-hour incubation period and resolves Similar to smallpox, polio has been targeted for elimination.
within 1 or 2 weeks. Parechoviruses (including HPeV1 Health care delivery to underdeveloped countries is more
and HPeV2, previously named echovirus 22 and 23) are a difficult, and for this reason, wild-type viral disease still
major cause of viral sepsis-like illness, meningitis, and sud- exists in Africa, the Middle East, and Asia. Misinformation,
den death in neonates and infants. Coxsackievirus A16, misunderstanding, and political unrest in Africa and other
enterovirus-A71, and D68 have been isolated from spinal parts of the world have also limited acceptance of polio vac-
fluid of children with acute flaccid paralysis. Some strains of cination. New worldwide vaccination programs have been
coxsackievirus B, echovirus, and parechovirus can be trans- developed to reach the goal.
mitted transplacentally to the fetus. Infection of the fetus or
an infant by this or another route may produce severe dis- The two types of poliovirus vaccine are (1) inactivated
seminated disease. Coxsackievirus B infections of the beta polio vaccine (IPV), developed by Jonas Salk, and (2)
cells of the pancreas are a major cause of type 1 insulin- live attenuated oral polio vaccine (OPV), developed by
dependent diabetes as a result of immune destruction of Albert Sabin. Both vaccines incorporate the three strains
the islets of Langerhans.  of polio, are stable, are relatively inexpensive, and induce
a protective antibody response (Fig. 46.10). The IPV was
LABORATORY DIAGNOSIS proven effective in 1955, but the oral vaccine took its place
Clinical Chemistry because it is less expensive, easy to administer, limits pro-
CSF from enterovirus aseptic meningitis can be distin- duction of virus and virus transmission, and elicits life-
guished from bacterial meningitis. The CSF lacks neutro- long and mucosal immunity (Table 46.2). The IPV is now
phils, and the glucose level is usually normal or slightly low. favored based on its safety profile.
The CSF protein level is normal to slightly elevated. The CSF
is rarely positive for the virus.  The OPV was attenuated (i.e., rendered less virulent)
Culture by passage in human or monkey cell cultures. Attenuation
Polioviruses may be isolated from the patient’s pharynx yielded a virus that can replicate in the oropharynx and
during the first few days of illness, from the feces for as long intestinal tract but cannot infect neuronal cells. The vac-
as 30 days, but only rarely from CSF. The virus grows well cine elicits IgA and IgG that can stop virus spread in and
in monkey kidney tissue culture. Coxsackieviruses and from the gut as well as spread within the body. A mixed
echoviruses can usually be isolated from the throat and blessing of the live vaccine strain is that it is shed in feces for
stool during infection and often from CSF in patients with weeks and may be spread to close contacts. The spread will
meningitis. Virus is rarely isolated in patients with myocar- immunize or reimmunize close contacts, promoting mass
ditis because the symptoms occur several weeks after the immunization. The major drawbacks of the live vaccine are
initial infection. Coxsackievirus B can be grown on primary that (1) the vaccine virus may infect an immunologically
monkey or human embryo kidney cells. Many strains of compromised person, and (2) there is a remote potential for
coxsackievirus A do not grow in tissue culture but can be the virus to revert to its virulent form and cause paralytic
grown in suckling mice.  disease (less than 1 per 4 million doses administered versus
Genome and Serology Studies 1 in 100 persons infected with the wild-type poliovirus).
The exact type of enterovirus can be determined through
the use of specific antibody and antigen assays (e.g., In the absence of wild-type poliovirus, IPV has less poten-
neutralization, immunofluorescence, enzyme-linked tial for vaccine-related disease and is the vaccine of choice
immunosorbent assay) or RT-PCR detection of viral for routine vaccination. Children should receive the IPV
RNA. RT-PCR of clinical samples has become a rapid and at 2 months, 4 months, and 15 months and then at 4 to 6
routine method to detect the presence of an enterovirus years of age. In addition, with the elimination of wild-type
or distinguish a specific enterovirus, depending on the polio, the next step is to stop the use of the oral vaccine to
primers used. eliminate all polio from the world.

There are no vaccines for other enteroviruses. Transmis-
sion of these viruses can presumably be reduced by improve-
ments in hygiene and living conditions. Enteroviruses are
impervious to most common disinfectants and detergents
but can be inactivated by formaldehyde, hypochlorite, and
chlorine. 

46  •  Picornaviruses 469

Inactivated polio vaccine TABLE 46.2  Advantages and Disadvantages of Polio
512 Vaccines

Serum IgG Vaccine Advantages Disadvantages
128
Poliovirus antibody titer OPV Effective Risk of vaccine-associated polio-

Lifelong immunity myelitis in vaccine recipients or

32 Induction of secretory contacts; spread of vaccine to
Serum IgA
antibody response contacts without their consent
8
similar to that of

natural infection

Prevents spread of virus Not safe for administration to

2 Nasal and Serum IgM in feces immunodeficient patients
duodenal IgA
1 Spread of attenuated
Vaccination 16 32 48 64 80 96
Days virus to contacts

promotes indirect

immunization

Inexpensive and easy to

administer

Live polio vaccine No need for repeated
512
booster vaccine
Serum IgG
Herd immunity

Poliovirus antibody titer IPV Effective Lack of induction of secretory

128 Good stability during antibody

transport and in Booster vaccine needed for lifelong

32 Nasal IgA storage immunity

Safe administration in Requires sterile syringes and

immunodeficient needles

8 Serum IgA patients Injection more painful than oral
Duodenal
2 IgA No risk of vaccine- administration

1 Serum IgM related disease Higher community immunization
Vaccination 16
32 48 64 80 96 levels needed than with live
Days
vaccine

Does not prevent replication and

spread of virus from gastrointes-

tinal tract

Fig. 46.10  Serum and secretory antibody response to intramuscular IPV, Inactive polio vaccine; OPV, live oral polio vaccine.
inoculation of inactivated polio vaccine (IPV) and to oral live attenuated
polio vaccine (OPV). Note the presence of secretory IgA induced by the replication occurs in the nose, and the onset and severity of
OPV. Ig, Immunoglobulin. (Modified from Ogra, P., Fishaut, M., Gallagher, the symptoms correlate with the time of viral shedding and
M.R., 1980. Viral vaccination via the mucosal routes. Reviews of Infectious quantity (titer) of virus shed. Infected cells release bradyki-
Diseases 2:352–369. Copyright 1980, University of Chicago Press.) nin and histamine, which cause a “runny nose.”

Rhinoviruses Interferon, which is generated in response to the infec-
tion, may limit progression of the infection and contribute
Rhinoviruses are the most important cause of the common to the symptoms. Immunity to rhinoviruses is transient and
cold and upper respiratory tract infections. Such infections unlikely to prevent subsequent infection (because of the
are self-limited, however, and do not cause serious disease. numerous serotypes of the virus). Both nasal secretory IgA
More than 100 serotypes of rhinovirus have been identified. and serum IgG serotype specific antibody are induced by a
At least 80% of the rhinoviruses have a common receptor primary rhinovirus infection and can be detected within
that is also used by some of the coxsackieviruses. This recep- a week of infection. The protective secretory IgA response
tor has been identified as ICAM-1, which is a member of the dissipates quickly, and immunity begins to wane approxi-
immunoglobulin superfamily and is expressed on epithelial, mately 18 months after infection. Cell-mediated immunity
fibroblast, and B-lymphoblastoid cells. is not likely to play an important role in controlling rhino-
virus infections. 
PATHOGENESIS AND IMMUNITY
Unlike the enteroviruses, rhinoviruses are unable to rep- EPIDEMIOLOGY
licate in the gastrointestinal tract. The rhinoviruses Rhinoviruses cause at least half of all upper respiratory
are labile to acidic pH. Also, they grow best at 33° C, tract infections (Box 46.5). Other agents likely to cause the
a feature that contributes to their preference for the cooler symptoms of the common cold are enteroviruses, corona-
environment of the nasal mucosa. Infection can be initiated viruses, adenoviruses, and parainfluenza viruses. Rhinovi-
by as little as one infectious viral particle. During the peak ruses can be transmitted by two mechanisms: as aerosols
of illness, nasal secretions contain concentrations of 500 and on fomites (e.g., by hands or on contaminated inani-
to 1000 infectious virions per milliliter. The virus enters mate objects). Hands appear to be the major vector, and
through the nose, mouth, or eyes and initiates infection of direct person-to-person contact is the predominant mode
the upper respiratory tract, including the throat. Most viral of spread. These nonenveloped viruses are extremely stable
and can survive on such objects for many hours.

470 SECTION 5  •  Virology

BOX 46.5  Epidemiology of Rhinovirus BOX 46.6  Clinical Summaries
Infections
Poliovirus
Disease/Viral Factors Polio: A 12-year-old girl from Nigeria has headache, fever, nausea,
Virion is resistant to drying and detergents
Multiple serotypes preclude prior immunity and stiff neck. Symptoms improve and then recur several days
Replication occurs at optimum temperature of 33° C and cooler later, with weakness and paralysis of her legs. She has no his-
tory of polio immunization. 
temperatures  Coxsackievirus A
Transmission Herpangina: Vesicular lesions on the tongue and roof of the
Direct contact via infected hands and fomites mouth of a 7-year-old patient accompany fever, sore throat,
Inhalation of infectious droplets  and pain on swallowing. 
Who Is at Risk? Coxsackievirus B (B for body)
Persons of all ages  Pleurodynia: A 13-year-old boy has fever and severe chest pain
Geography/Season with headache, fatigue, and aching muscles lasting for 4 days. 
Virus found worldwide Coxsackievirus or Echovirus
Disease more common in early autumn and late spring  Aseptic meningitis: A 7-month-old infant with fever and rash
Modes of Control appears listless, with a stiff neck. A sample of his cerebrospinal
Washing hands and disinfecting contaminated objects help fluid contains lymphocytes but has normal glucose and no
bacteria. Full recovery occurs within 1 week. 
prevent spread Rhinovirus
Common cold: A 25-year-old office worker develops a runny
Rhinoviruses produce clinical illness in only half of the nose, mild cough, and malaise with a low-grade fever. A cow-
persons infected. Asymptomatic persons are also capable of orker has had similar symptoms for the past few days.
spreading the virus, even though they may produce less of it.
and the demonstration of acid lability. Serotyping is rarely
Rhinovirus “colds” occur most often in early autumn and necessary but can be performed with the use of pools of spe-
late spring in persons living in temperate climates. This may cific neutralizing sera. Identification can also be made by
reflect social patterns (e.g., return to school and day care) genome analysis by RT-PCR. The performance of serologic
rather than any change in the virus itself. testing to document rhinovirus infection is not practical. 

Rates of infection are highest in infants and children. TREATMENT, PREVENTION, AND CONTROL
Children younger than 2 years “share” their colds with There are many over-the-counter remedies for the common
their families. Secondary infections occur in approximately cold. Nasal vasoconstrictors may provide relief, but their
50% of family members, especially other children. use may be followed by rebound congestion and a worsen-
ing of symptoms. Inhaling hot, humidified air, and even the
Many different rhinovirus serotypes may be found in a steam from hot chicken soup, may actually help by increas-
given community during a specific cold season, but the pre- ing nasal drainage.
dominant strains are usually the newly categorized serotypes.
This pattern indicates the existence of a gradual antigenic No antiviral drugs are available for picornavirus disease.
drift (mutation) similar to that seen for the influenza virus.  Pleconaril and similar experimental antiviral drugs (e.g.,
arildone, rhodanine, disoxaril) contain a 3-methylisoxazole
CLINICAL SYNDROMES group that inserts into the base of the receptor-binding can-
Common cold symptoms caused by rhinoviruses cannot yon and blocks uncoating of the virus. Enviroxime inhibits
readily be distinguished from those caused by other viral the viral RNA-dependent RNA polymerase. Rhinovirus is
respiratory pathogens (e.g., enteroviruses, paramyxovi- not a good candidate for a vaccine program. The multiple
ruses, coronaviruses) (Box 46.6). An upper respiratory serotypes and other causes of the common cold, the appar-
tract infection usually begins with sneezing, which is soon ent antigenic drift in rhinoviral antigens, the requirement
followed by rhinorrhea (runny nose). The rhinorrhea for secretory IgA production, and the transience of the
increases and is then accompanied by symptoms of nasal antibody response pose major problems for vaccine devel-
obstruction. Mild sore throat also occurs, along with head- opment. In addition, the benefit-to-risk ratio would be very
ache and malaise but usually without fever. The illness low because rhinoviruses do not cause significant disease.
peaks in 3 to 4 days, but the cough and nasal symptoms
may persist for 7 to 10 days or longer.  Handwashing and disinfection of contaminated objects
are the best means of preventing viral spread. Virucidal
LABORATORY DIAGNOSIS facial tissues impregnated with citric acid may also limit
The clinical syndrome of the common cold is usually so rhinovirus spread.
characteristic that laboratory diagnosis is unnecessary.
Virus can be obtained from nasal washings. Rhinoviruses   For a case study and questions see StudentConsult.com.
are grown in human diploid fibroblast cells (e.g., WI-38) at
33° C. Virus is identified by the typical cytopathologic effect

46  •  Picornaviruses 471

Bibliography Websites
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776.

Case Study and Questions 1. What were the key signs and symptoms in this case?
2 . What was the differential diagnosis?
A 6-year-old girl was brought to the doctor’s office at 4:30 3 . What signs and symptoms suggested an enterovirus
p.m. because she had a sore throat, had been unusually tired,
and was napping excessively. Her temperature was 39° C. infection?
She had a sore throat, enlarged tonsils, and a faint rash on 4 . How would the diagnosis be confirmed?
her back. At 10:30 p.m., the patient’s mother reported that 5. What were the most likely sources and means of infec-
the child had vomited three times, continued to nap exces-
sively, and complained of a headache when awake. The tion?
doctor examined the child at 11:30 p.m. and noted that she 6. What were the target tissue and mechanism of patho-
was lethargic and aroused only when her head was turned,
complaining that her back hurt. Her CSF contained no red genesis?
blood cells, but there were 28 white blood cells/mm3, half
polymorphonuclear neutrophils and half lymphocytes. The
glucose and protein levels in the CSF were normal, and Gram
stain of a specimen of CSF showed no bacteria.

471.e1

47 Coronaviruses and

Noroviruses

A 17-year-old student complains that he has a cold. 4 . What are the likely causes of the gastroenteritis? How
1 . What are the possible causes? does the 24-hour incubation period help narrow down
2 . What properties of the virus restrict the infection to the the diagnosis?

upper respiratory tract? 5. How does this agent cause diarrhea?
3. How is it transmitted and acquired? 6. What is the best means of detecting the agent?

A day after eating burritos at a fast food restaurant,  Answers to these questions are available on Student
several medical students complained of serious diar- Consult.com.
rhea, nausea, vomiting, and a mild fever for 2 days.
Other patrons also had gastroenteritis.

Summaries  Clinically Significant Organisms

CORONAVIRUSES Epidemiology Biology, Virulence, and Disease
ᑏᑏ Transmitted by aerosols, direct contact,
Trigger Words ᑏᑏ Small size, capsid, (+) RNA genome
fecal oral, contaminated swimming ᑏᑏ Very resistant to environment, including
Common cold, SARS, MERS pools
detergents and other disinfectants
Biology, Virulence, and Disease Diagnosis ᑏᑏ Encodes RNA-dependent RNA poly-
ᑏᑏ Symptomatology, RT-PCR genome
ᑏᑏ Medium size, enveloped, (+) RNA genome merase, replicates in cytoplasm
ᑏᑏ Detergent resistant because of glyco- analysis, or respiratory secretions ᑏᑏ Damages intestinal brush border
ᑏᑏ Diarrhea with nausea and vomiting
protein corona (exception to the rule for Treatment, Prevention, and Control
enveloped viruses) ᑏᑏ Quarantine for SARS, MERS Epidemiology
ᑏᑏ Encodes RNA-dependent RNA poly-
merase, replicates in cytoplasm NOROVIRUSES (CALICIVIRIDAE) ᑏᑏ Transmitted by fecal-oral route, in
ᑏᑏ Most coronaviruses cannot replicate at Trigger Words contaminated foods and water; very
body temperature, restricted to upper Outbreaks of diarrhea, cruise ships, watery resistant to inactivation
respiratory tract
ᑏᑏ Most coronaviruses cause the common diarrhea, vomiting Diagnosis
cold
ᑏᑏ MERS and SARS can replicate at 37°  C ᑏᑏ Symptomatology, RT-PCR genome analysis
and cause severe pneumonias
Treatment, Prevention, and Control

ᑏᑏ Supportive care

MERS, Middle East respiratory syndrome; RT-PCR, reverse transcriptase-polymerase chain reaction; SARS, severe acute respiratory syndrome.

Coronaviruses glycoproteins on the surface of the envelope appear as club-
shaped projections that appear as a halo (corona) around
Coronaviruses are named for the solar corona–like appear- the virus. Unlike most enveloped viruses, the “corona”
ance (the surface projections) of their virions when viewed formed by the glycoproteins allows the virus to endure the
with an electron microscope (Fig. 47.1). Coronaviruses conditions in the gastrointestinal tract and be spread by the
are the second most prevalent cause of the common cold fecal-oral route.
(rhinoviruses are the first). Coronaviruses have caused out-
breaks of severe acute respiratory syndrome coronavi- The large plus-stranded RNA genome (27,000 to 30,000
rus (SARS-CoV) in China and the Middle East (Middle East bases) associates with the N protein to form a helical nucleo-
respiratory syndrome coronavirus [MERS-CoV]). Electron capsid. Protein synthesis occurs in two phases, similar to
microscopic findings have also linked coronaviruses to gas- that of the togaviruses. On infection, the genome is trans-
troenteritis in children and adults. lated to produce a polyprotein that is cleaved to produce
an RNA-dependent RNA polymerase (L [225,000 Da]) and
STRUCTURE AND REPLICATION other proteins. Transcription and replication of the genome
Coronaviruses are enveloped virions with the longest occurs within membrane vesicles created by viral proteins.
positive (+) ribonucleic acid (RNA) genome. Viri- The L protein produces and then uses a negative-sense
ons measure 80 to 160 nm in diameter (Box 47.1). The template RNA to replicate new genomes and produce five
to seven individual messenger RNAs (mRNAs) for the
472 individual viral proteins.

47  •  Coronaviruses and Noroviruses 473

A Transmembrane
glycoprotein E
Spike
glycoprotein (S) Lipid
bilayer

Matrix (M)
protein

Nucleoprotein N
RNA

B

Fig. 47.1  (A) Electron micrograph of the human respiratory coronavirus (magnification 90,000×). (B) Model of a coronavirus. The viral nucleocapsid
is a long, flexible helix composed of the positive-strand genomic RNA and many molecules of the phosphorylated nucleocapsid protein N. The viral
envelope consists of a lipid bilayer derived from the intracellular membranes of the host cell, two or three viral glycoproteins (Spike [S], E, possibly
hemagglutinin-esterase [HE]), and a matrix protein. (A, Courtesy Centers for Disease Control and Prevention, Atlanta, Georgia. B, Modified from Fields, B.F.,
Knipe, D.M., 1985. Virology. Raven, New York, NY.)

Virions contain the glycoproteins E1 (20,000 to 30,000 coronaviruses, including SARS-CoV and MERS-CoV, can
Da) and E2 (160,000 to 200,000 Da) and a core nucleo- replicate at 37° C and cause systemic disease in humans.
protein (N [47,000 to 55,000 Da]); some strains also Coronaviruses cause cytolytic infections and when inocu-
contain a hemagglutinin neuraminidase (E3 [120,000 to lated into the respiratory tracts of human volunteers, they
140,000 Da]) (Table 47.1). The E2 glycoprotein is respon- infect and disrupt the function of ciliated epithelial cells
sible for mediating viral attachment and membrane fusion (Box 47.2).
and is the target of neutralizing antibodies. The E1 glyco-
protein is a transmembrane matrix protein. The replica- The virus is most likely spread by aerosols. Most human
tion scheme for coronaviruses is shown in Fig. 47.2.  coronaviruses cause an upper respiratory tract infection,
accounting for approximately 10% to 15% of upper respi-
PATHOGENESIS AND CLINICAL SYNDROMES ratory tract infections in humans. The disease is similar to
Most human coronaviruses have an optimum tempera- the common cold caused by rhinoviruses but with a lon-
ture for viral growth of 33° C to 35°  C; therefore infection ger incubation period (average, 3 days). The infection may
remains localized to the upper respiratory tract. Animal exacerbate a preexisting chronic pulmonary disease, such
as asthma or bronchitis, and on rare occasions may cause
pneumonia.

474 SECTION 5  •  Virology

BOX 47.1  Unique Features of Table 47.1  Major Human Coronavirus Proteins
Coronaviruses
Molecular
Virus has medium-sized virions with a solar corona–like appear-
ance. Weight

Single-stranded, positive-sense RNA genome is enclosed in an Proteins (kDa) Location Functions
envelope containing the E2 viral attachment protein, E1 matrix
protein, and N nucleocapsid protein. E2 (peplomeric 160-200 Envelope Binding to host
glycoprotein) spikes cells; fusion
Translation of genome occurs in two phases: (1) the early phase (peplomer) activity
produces an RNA polymerase (L), and (2) the late phase, from a H1 (hemagglutinin 60-66
negative-sense RNA template, yields structural and nonstruc- protein) Peplomer Hemagglutination
tural proteins.
N (nucleoprotein) 47-55 Core Ribonucleoprotein
Virus assembles at the rough endoplasmic reticulum.
Virus is difficult to isolate and grow in routine cell culture. E1 (matrix 20-30 Envelope Transmembrane
glycoprotein) protein
Infections occur mainly in infants and children. Coro-
navirus disease appears either sporadically or in outbreaks L (polymerase) 225 Infected cell Polymerase activity
in the winter and spring. Usually, one strain predominates
in an outbreak. Antibodies to coronaviruses are uniformly Modified from Balows, A., Hausler, W.J., Lennette, E.H., et al., 1998. Laboratory
present by adulthood, but reinfections are common, despite Diagnosis of Infectious Diseases: Principles and Practice. Springer-Verlag,
the preexisting serum antibodies. New York, NY.

Coronavirus-like particles have also been seen in electron LABORATORY DIAGNOSIS
micrographs of stool specimens obtained from adults and Laboratory tests are not routinely performed to diagnose
children with diarrhea and gastroenteritis and in infants coronavirus infections other than for SARS and MERS. RT-
with neonatal necrotizing enterocolitis. PCR is the method of choice for detection of the viral RNA
genome in respiratory and stool samples. Virus isolation of
SARS-CoV and MERS-CoV are zoonoses. The outbreaks the coronaviruses is difficult and for SARS-CoV and MERS-
of these viral diseases have occurred when the animal CoV requires stringent biosafety level 3 (BSL-3) conditions. 
reservoir has come in contact with man. SARS-CoV and
MERS-CoV are cytolytic viruses that can replicate at body TREATMENT, PREVENTION, AND CONTROL
temperatures in epithelial cells, lymphocytes, and leuko- Control of respiratory transmission of the common cold
cytes. A combination of viral pathogenesis and immuno- form of coronavirus would be difficult and is probably
pathogenesis causes significant lung, kidney, liver, and unnecessary because of the mildness of the infection.
gastrointestinal tissue damage and depletion of immune Strict quarantine of infected individuals and screen-
cells. ing for fever in travelers from a region with an out-
break of SARS-CoV and MERS-CoV limit the spread of
SARS is a form of atypical pneumonia characterized these viruses. No vaccine or specific antiviral therapy is
by high fever (>38° C), chills, rigors, headache, dizziness, available. 
malaise, myalgia, cough, or breathing difficulty, leading to
acute respiratory distress syndrome. Up to 20% of patients Noroviruses
will also develop diarrhea. Persons with SARS were exposed
within the previous 10 days. Mortality is at least 10% of Norovirus is the most common cause of foodborne disease
symptomatic people. Although SARS-CoV is most likely outbreaks in the United States. The noroviruses are mem-
transmitted in respiratory droplets, it is also present in bers of the Caliciviridae family, which like astroviruses, are
sweat, urine, and feces. small, round gastroenteritis viruses. Norwalk virus, the
prototypical norovirus, was discovered during an epidemic
The outbreak of SARS started in November 2002 in of acute gastroenteritis in Norwalk, Ohio, in 1968 on elec-
South China’s Guangdong Province, was brought to Hong tron microscopic examination of stool samples from adults.
Kong by a physician working within the original outbreak, Many of the other viruses in this family also bear the names
and then was brought to Vietnam, Toronto, and other of the geographic locations in which they were identified
places by travelers. The virus was shown to be a corona- (Box 47.3).
virus by its electron microscopic morphology and by RT-
PCR. The virus apparently jumped to man from animals STRUCTURE AND REPLICATION
(masked-palm civets, raccoon dogs, and Chinese ferret bad- Noroviruses resemble and are approximately the same size
gers) raised for food. A World Health Organization (WHO) as the picornaviruses. Their positive-sense RNA genome
global alert prompted containment measures to control the (≈7500 bases) has a VPg protein (viral protein genome-
spread of the virus and limited the outbreak to 8000 known linked) and a 3′ terminal polyadenylate sequence similar
diseased individuals, but there were at least 784 deaths. to picornaviruses. The genome is contained in a 27-nm
Travel restrictions and public concern resulted in a loss of naked capsid consisting of 60,000-Da capsid proteins.
hundreds of millions of dollars in travel and other business. Norwalk virion capsid is icosahedral with a ragged outline.

MERS-CoV also causes acute respiratory distress syn-
drome, with a 50% mortality of those identified as infected
with MERS. Most of the cases of MERS have occurred in the
Arabian Peninsula. Bats and camels are the natural reser-
voirs of MERS-CoV. 

47  •  Coronaviruses and Noroviruses 475

Viral attachment/adsorption Exocytosis

+ Genomic 5′ 3′
RNA 5′ RNA proteins
+ Genomic
RNA 3′ “L” protein Smooth-walled
polymerase vesicles

– Negative 3′ Template 5′

strand 5′ 3′ L

NS2

(HE)

mRNA S Golgi
NS4 Bud into lumen of
rough endoplasmic
E reticulum for
assembly
M

5′ +Genomic RNA 3′ N

+ Genomic
RNA

Nucleus

Nucleocapsid

Fig. 47.2  Replication of human coronaviruses. The E2 glycoprotein interacts with receptors on epithelial cells, the virus fuses or is endocytosed into
the cell, and the genome is released into the cytoplasm. Protein synthesis is divided into early and late phases, similar to that in the togaviruses. The
genome binds to ribosomes, and an RNA-dependent RNA polymerase is translated. This enzyme generates a full-length, negative-sense RNA template
for the production of new virion genomes and six individual mRNAs for the other coronavirus proteins. The genome associates with rough endoplasmic
reticulum membranes modified by virion proteins and buds into the lumen of the rough endoplasmic reticulum. Vesicles that contain the virus migrate
to the cell membrane, and the virus is released by exocytosis. (Modified from Balows, A., Hausler, W.J., Lennette, E.H., et al., 1988. Laboratory Diagnosis of
Infectious Diseases: Principles and Practice. Springer-Verlag, New York, NY.)

BOX 47.2  Disease Mechanisms of Human BOX 47.3  Characteristics of Noroviruses
Coronaviruses
Viruses are small capsid viruses distinguishable by capsid mor-
Human coronavirus infects and kills epithelial cells of the upper phology.
respiratory tract.
Viruses are resistant to environmental pressure, such as deter-
Virus replicates best at 33° C to 35° C; therefore it prefers the up- gents, drying, and acid.
per respiratory tract.
Viruses are transmitted by fecal-oral route in contaminated water,
Reinfection occurs in the presence of serum antibodies. food, vomitus.
The glycoprotein “corona” helps this enveloped virus survive the
Viruses cause outbreaks of gastroenteritis.
gastrointestinal tract. Disease resolves after 48 hours, without serious consequences.
SARS-CoV and MERS-CoV replicate at 37° C, kill cells and initiate
viruses in tissue culture cells produces Norwalk virus–like
inflammatory responses in the lung. particles. These particles were used to show that Norwalk
viruses bind to the carbohydrate of either the A, B, or O
MERS-CoV, Middle East respiratory syndrome coronavirus; SARS-CoV, blood group antigen on the cell surface. The noroviruses
severe acute respiratory syndrome coronavirus. enter and exit cells similar to the picornaviruses but tran-
scribe an early and late mRNA similar to the togaviruses
The capsomeres of noroviruses, other caliciviruses, and and coronaviruses. The early mRNA encodes a polyprotein
astroviruses differ in conformation. Antibodies from sero- containing the RNA polymerase and other enzymes. The
positive people can also be used to distinguish these viruses. late mRNA encodes the capsid proteins. 

Most caliciviruses and astroviruses can be grown in rou-
tine cell culture, but the Norwalk viruses cannot. Expres-
sion of the structural protein genes of different Norwalk

476 SECTION 5  •  Virology

PATHOGENESIS Clinical Case 47.1  Norwalk Virus
The norovirus strains that infect humans can only infect Outbreak
humans. As few as 10 virions will initiate disease in humans.
The virus infects and damages the small intestine, prevent- Brummer-Korvenkontio and associates (Epidemiol Infect
ing proper absorption of water and nutrients and causing a 129:335–360, 2002) described an outbreak of gastroen-
watery diarrhea. Gastric emptying may be delayed, causing teritis in children who had attended a concert; infection
vomiting. Shedding of the virus may continue for 2 weeks was traced back to contamination of a specific seating area,
after symptoms have ceased. Immunity is generally short- bathrooms, and other areas visited by one individual. A
lived at best and may not be protective. The large number of male concert attendee was ill before attending a concert
strains and high rate of mutation allow reinfection despite and then vomited four times in the concert hall: in a waste
antibodies from a previous exposure.  bin in the corridor, into the toilets, onto the floor of the fire
escape, and on a carpeted area in the walkway. His family
EPIDEMIOLOGY members showed symptoms within 24 hours. A children’s
Norwalk and related viruses typically cause outbreaks of concert for several schools was held the next day. Children
gastroenteritis from a common source of contamination sitting in the same section as the incident case and those
(e.g., water, shellfish, salad, raspberries, food service). who traversed the contaminated carpet had the highest
These viruses are transmitted mainly by the fecal-oral incidence of disease, characterized by watery diarrhea and
route in stool and vomitus. The virus is resistant to dry- vomiting for approximately 2 days. RT-PCR analysis of
ing and heat and can remain on surfaces for long periods. fecal samples from two ill children detected Norwalk virus
Infected individuals shed the largest amounts of the virus genomic RNA. Infected vomit may have up to a million
when sick and for 3 days after recovery but continue to viruses per milliliter, and only 10 to 100 viruses are re-
shed the virus for up to 4 weeks. During peak shedding, quired to transmit the disease. Contact with contaminated
100 billion virions are released per gram of feces. Up to shoes, hands, clothing, or aerosols may have infected the
30% of infected individuals are asymptomatic but can children. The encapsidated nature of the Norwalk virus
spread the infection. makes it resistant to routine cleansers; disinfection usually
requires freshly prepared hypochlorite bleach–containing
Outbreaks in developed countries may occur year-round solutions or steam cleaning.
and have been described in schools, resorts, hospitals, nurs-
ing homes, restaurants, and cruise ships. Common-source RT-PCR, Reverse transcriptase-polymerase chain reaction.
outbreaks can often be traced to a careless, infected food
handler. The Centers for Disease Control and Prevention BOX 47.4  Clinical Summaries
estimates that nearly 50% (23 million U.S. cases per year) of
all foodborne outbreaks of gastroenteritis can be attributed Coronaviruses
to noroviruses, which is a tribute to the importance of this Common cold: A 25-year-old office worker develops a runny
virus. As many as 70% of children in the United States have
antibodies to noroviruses by the age of 7 years.  nose, mild cough, malaise, and a low-grade fever. A coworker
has had similar symptoms for the past few days.
CLINICAL SYNDROMES SARS: A 45-year-old businessman returned from a 2-week trip
Norwalk and related viruses cause symptoms similar to to China. Five days after returning home to the United States,
those caused by the rotaviruses but in adults and children he developed a fever of 101.5° F (38.6° C) and cough. Now he
(Clinical Case 47.1; Box 47.4). Infection causes an acute observes that it is harder to catch his breath. 
onset of diarrhea, nausea, vomiting, and abdominal Norovirus
cramps, especially in children (Fig. 47.3). Bloody stools do Norwalk virus: On the third day of a cruise (incubation period
not occur. Fever may occur in as many as a third of patients. of 24 to 60 hours), a group of 45 passengers on a cruise ship
The incubation period is usually 12 to 48 hours, and the ill- experienced watery diarrhea, nausea, and vomiting for 12 to 60
ness usually resolves within 1 to 3 days without problems hours, depending on the individual.
but can last up to 6 days. 
SARS, Severe acute respiratory syndrome.
LABORATORY DIAGNOSIS
The use of RT-PCR for detection of the norovirus genome in TREATMENT, PREVENTION, AND CONTROL
stool or emesis samples has enhanced the speed and detec- There is no specific treatment for the diarrhea caused by
tion of the virus during outbreaks. Immunoelectron micros- caliciviruses or other small, round gastroenteritis viruses
copy can be used to concentrate and identify the virus other than oral rehydration therapy. Outbreaks may be
from stool. Addition of an antibody directed against the minimized by handling food carefully and by maintaining
suspected agent causes the virus to aggregate, facilitating the purity of the water supply. Careful hand washing is also
recognition. Enzyme-linked immunosorbent assay (ELISA) important. More resistant to environmental pressures than
tests have been developed to detect the virus, viral antigen, polioviruses or rotaviruses, the Norwalk virus is resistant to
and antibody to the virus. The other calicivirus-like agents heat (60° C), pH 3, detergent, and even the chlorine levels of
are more difficult to detect.  drinking water. Contaminated surfaces can be cleaned with
a 1:50 to 1:10 dilution of household bleach.

47  •  Coronaviruses and Noroviruses 477

Diarrhea Hall, A.J., Eisenbart, V.G., Etingüe, A., Gould, L., Lopman, B.A., Parashar,
Vomiting U.D., 2012. Epidemiology of Foodborne Norovirus Outbreaks, United
Abdominal cramps States, 2001–2008. Emerg. Infect. Dis. 18 (10), 1566–1573. https://dx.
doi.org/10.3201/eid1810.120833.
Nausea
Headache Patel, M.M., Hall, A.J., Vinje, J., et al., 2009. Noroviruses: a comprehensive
review. J. Clin. Virol. 44, 1–8.
Anorexia and malaise
Fever Tan, M., Huang, P., Meller, J., et  al., 2003. Mutations within the P2
012345 domain of norovirus capsid affect binding to human histo-blood group
antigens: evidence for a binding pocket. J. Virol. 77, 12562–12571.
Days after challenge
Fig. 47.3  Response to ingestion of Norwalk virus. Symptoms vary in Coronaviruses
severity. Graham, R.L., Donaldson, E.F., Baric, R.S., 2013. A decade after SARS:

  For a case study and questions see StudentConsult.com strategies for controlling emerging coronaviruses. Nat. Rev. Microbiol.
11, 836–848.
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Accessed January 2, 2019.

Case Study and Questions 2 . What was the most likely means of viral transmission?
3 . What physical characteristics of the virus allowed it to
Several adults complained of serious diarrhea, nausea, vom-
iting, and a mild fever 2 days after visiting Le Café Grease. be transmitted by these means?
The symptoms were too severe to result from food poisoning 4 . What public health measures could be followed to pre-
or a routine gastroenteritis but lasted only 24 hours.
1. What characteristics distinguished this disease from a vent such outbreaks?

rotavirus infection?

477.e1

48 Paramyxoviruses

A 10-year-old boy presented with cough, conjunc- 1 . How does measles replicate?
tivitis, and coryza plus fever and lymphadenopathy, 2 . What are the characteristic signs of measles?
which progressed to a rash that spread from the hair- 3. How is it transmitted?
line down his face and then his body. Within 10 days, 4. Why was the boy susceptible to measles?
the disease appeared to run its course, but a week 5 . What other complications are associated with measles?
after the start of the rash, an abrupt onset of head-
ache, vomiting, and confusion progressed to coma,  Answers to these questions are available on Student
which is consistent with encephalitis. Consult.com.

Summaries  Clinically Significant Organisms

PARAMYXOVIRUSES ᑏᑏ Fusion protein promotes entry and Epidemiology
c­ ell-cell fusion (syncytia)
Trigger Words ᑏᑏ Transmitted by aerosols
ᑏᑏ Cell-mediated immune response Diagnosis
ᑏᑏ Fusion, syncytia, aerosols, envelope e­ ssential for control but causes
ᑏᑏ Measles: cough, conjunctivitis, coryza, pho- p­ athogenesis ᑏᑏ Symptomatology, RT-PCR genome
analysis of respiratory secretions
tophobia, Koplik spots, rash, fever, SSPE, ᑏᑏ Measles: maculopapular rash, high fever
postmeasles encephalitis with cough, conjunctivitis, coryza, Koplik Treatment, Prevention, and Control
ᑏᑏ Mumps: parotitis, orchitis, aseptic meningitis spots (small gray lesions in mouth); more
ᑏᑏ Parainfluenza: croup, barking seal, severe if vitamin A deficient, giant cell ᑏᑏ Live attenuated vaccine for measles and
p­ neumonia pneumonia if T-cell deficient, postmea- mumps; RSV: passive immunization for
ᑏᑏ RSV: infant, pneumonia sles encephalitis, SSPE 5–7 years later premature infants at high risk; aerosol-
caused by measles variant ized ribavirin
Biology, Virulence, and Disease
ᑏᑏ Mumps: parotitis, orchitis, aseptic
ᑏᑏ Large size, enveloped, (−) RNA genome, meningitis
fusion protein
ᑏᑏ Parainfluenza: common cold, croup,
ᑏᑏ Encodes RNA-dependent RNA poly- bronchitis
merase, replicates in cytoplasm
ᑏᑏ RSV: common cold, pneumonia, bron-
ᑏᑏ Parainfluenza and mumps bind to sialic chiolitis, life-threatening for premature
acid and encode neuraminidase activity infants
(HN glycoprotein); measles and RSV
glycoprotein bind to proteins

RSV, Respiratory syncytial virus; RT-PCR, reverse transcriptase-polymerase chain reaction; SSPE, subacute sclerosing panencephalitis.

The Paramyxoviridae include the genera Morbillivirus, and lower respiratory tract infections, primarily in children,
Paramyxovirus, and Pneumovirus (Table 48.1; Box 48.1). including the common cold, pharyngitis, croup, bronchitis,
Human pathogens within the morbilliviruses include the bronchiolitis, and pneumonia. The mumps virus causes a
measles virus; within the paramyxoviruses, the para- systemic infection whose most prominent clinical manifes-
influenza and mumps viruses; and within the pneu- tation is parotitis. RSV causes mild upper respiratory tract
moviruses, the respiratory syncytial virus (RSV) and infections in children and adults but can cause life-threat-
metapneumovirus. A new group of highly pathogenic ening pneumonia in infants.
paramyxoviruses, including two zoonosis-causing viruses,
Nipah virus and Hendra virus, was identified in 1998 after Measles and mumps viruses have only one serotype,
an outbreak of severe encephalitis in Malaysia and Singa- and protection is provided by effective live vaccines. In
pore. Their virions have similar morphologies and protein the United States and other developed countries, success-
components. Importantly, paramyxoviruses induce cell- ful vaccination programs using the live attenuated measles
to-cell fusion (syncytia formation and multinucle- and mumps vaccines have made measles and mumps rare.
ated giant cells). The reduction in measles has led to the virtual elimina-
tion of the serious sequelae of measles in these countries.
These agents cause some well-known major diseases. Unfortunately, large and serious outbreaks of measles and
The measles virus causes a potentially serious generalized mumps are now occurring in the United States and Europe
infection characterized by a maculopapular rash (rube- because of increased noncompliance with the vaccine
ola). Parainfluenza and metapneumoviruses cause upper programs.
478

48  •  Paramyxoviruses 479

TABLE 48.1 Paramyxoviridae F1 and F2 glycopeptides held together by a disulfide bond.
Additional proteins (V and C) result from alternative tran-
Genus Human Pathogen scripts of the P gene and facilitate escape from innate host
protections.
Morbillivirus Measles virus
Paramyxovirus Parainfluenza viruses 1-4 Replication of the paramyxoviruses is initiated by the
Mumps virus binding of the HN, H, or G glycoprotein on the virion enve-
lope to their receptors. The HN of parainfluenza viruses
Pneumovirus Respiratory syncytial virus bind to sialic acid on cell-surface glycolipids and glycopro-
Metapneumovirus teins. Like influenza, they use the neuraminidase activity
to cleave sialic acid on viral and cellular glycoproteins to
BOX 48.1  Unique Features of the prevent binding to itself and the infected cell proteins to
Paramyxoviridae facilitate exit from the cell. The other paramyxoviruses
bind to protein receptors and do not need neuraminidase
Large virion consists of a negative-sense RNA genome in a helical activity. The F protein promotes fusion of the envelope with
nucleocapsid surrounded by an envelope. the plasma membrane. Paramyxoviruses are also able to
induce cell-to-cell fusion, creating multinucleated giant
The three genera can be distinguished by the activities of the viral cells (syncytia).
attachment protein: HN of parainfluenza virus and mumps virus
binds to sialic acid and red blood cells (hemagglutinin and neu- Replication of the genome occurs in a manner similar to
raminidase activity), neuraminidase facilitates release from cell; that of other negative-strand RNA viruses (i.e., rhabdovi-
H of measles virus binds protein receptors and is also a hemag- ruses). The RNA polymerase is carried into the cell as part of
glutinin; G of RSV binds to cells but is not a hemagglutinin. the nucleocapsid. Transcription, protein synthesis, and rep-
lication of the genome all occur in the host cell’s cytoplasm.
Virus replicates in the cytoplasm. The genome is transcribed into individual messenger RNAs
Virions penetrate the cell by fusion with the plasma membrane (mRNAs) and a full-length positive-sense RNA template.
New genomes associate with the L, N, and P proteins to form
and exit by budding from the plasma membrane without killing helical nucleocapsids that associate with the M proteins on
the cell. viral glycoprotein-modified plasma membranes. The glyco-
Viruses induce cell-to-cell fusion, causing multinucleated giant proteins are synthesized and processed like cellular glyco-
cells (syncytia). proteins. Mature virions then bud from the host cell plasma
Cell-mediated immunity causes many of the symptoms but is membrane and exit without killing the cell. Replication of
essential for control of the infection. the paramyxoviruses is represented by the RSV infectious
Paramyxoviridae are transmitted in respiratory droplets and cycle shown in Fig. 48.2. 
initiate infection in the respiratory tract.
Measles and mumps establish viremia and spread to other body Measles Virus
sites.
Measles, also known as rubeola, is one of the five classic
Structure and Replication childhood exanthems, along with rubella, roseola, fifth dis-
ease, and chickenpox. Historically, measles was one of the
Paramyxoviruses are relatively large viruses with a nega- most common and unpleasant viral infections, with serious
tive-sense, single-stranded ribonucleic acid (RNA) (5 potential sequelae. Before 1960, more than 90% of the pop-
to 8 × 106 Da) genome in a helical nucleocapsid surrounded ulation younger than 20 years had experienced the rash,
by a pleomorphic envelope of approximately 156 to 300 high fever, cough, conjunctivitis, and coryza of measles.
nm (Fig. 48.1). They are similar in many respects to ortho- Measles is still one of the most prominent causes of disease
myxoviruses but are larger and do not have the segmented (>10 million cases per year) and death (120,000 deaths in
genome of the influenza viruses. Although there are simi- 2012) worldwide in unvaccinated populations. The devel-
larities in paramyxovirus genomes, the order of the protein- opment of effective vaccine programs has made measles a
coding regions differs for each genus. The paramyxovirus rare disease in developed countries, but children remain
proteins are listed in Table 48.2. unvaccinated or do not receive their boosters and outbreaks
of measles occur.
The nucleocapsid consists of the negative-sense, single-
stranded RNA associated with the nucleoprotein (N), poly- PATHOGENESIS AND IMMUNITY
merase phosphoprotein (P), and large (L) protein. The Measles virus can infect many cell types because of the pres-
L protein is the RNA polymerase, the P protein facilitates ence of its receptors, CD46 (complement regulatory protein)
RNA synthesis, and the N protein helps maintain genomic and nectin 4 poliovirus receptor-like 4 (PVRL4) on epithelial
structure. The nucleocapsid associates with the matrix (M) and other cells and CD150 (signaling lymphocyte-activa-
protein lining the inside of the virion envelope. The envelope tion molecule [SLAM]) on dendritic cells and lymphocytes.
contains two glycoproteins, a fusion (F) protein, and a viral Binding to CD150 promotes the viremic spread in dendritic
attachment protein (hemagglutinin-neuraminidase [HN], cells, and B and T lymphocytes throughout the body. Mea-
hemagglutinin [H], or glycoprotein [G] protein) (see Box sles is known for its propensity to cause cell fusion, leading
48.1). To express membrane-fusing activity, the F protein to the formation of giant cells (Box 48.2) and the ability to
must be activated by proteolytic cleavage, which produces

480 SECTION 5  •  Virology

Larger glycoprotein (HN, H, G)
(viral attachment protein)
Smaller glycoprotein
(fusion [F])

Lipid bilayer

Nucleocapsid

Matrix (M)
protein

AB

Fig. 48.1  (A) Model of paramyxovirus. The helical nucleocapsid—consisting of negative-sense, single-stranded RNA and the polymerase (P), nucleo-
protein (N), and large protein (L)—associates with the matrix (M) protein at the envelope membrane surface. The nucleocapsid contains RNA tran-
scriptase activity. The envelope contains the viral attachment glycoprotein (hemagglutinin-neuraminidase [HN], hemagglutinin [H], or G-protein [G],
depending on the virus) and the fusion (F) protein. (B) Electron micrograph of a disrupted paramyxovirus, showing the helical nucleocapsid. (A, Modified
from Jawetz, E., Melnick, J.L., Adelberg, E.A., 1987. Review of Medical Microbiology, 17th ed. Appleton & Lange, Norwalk, CT. B, Courtesy Centers for Disease
Control and Prevention, Atlanta, GA.)

TABLE 48.2  Major Viral-Encoded Proteins of Paramyxoviruses

Gene and Proteinsa,b Virion Location Protein Function

N: nucleoprotein Major internal protein Protection of viral RNA
P: phosphoprotein and C and V proteins Association with nucleoprotein Part of transcription complex; C and V are antagonists

M: matrix Inside virion envelope of innate responses
F: fusion protein Transmembranous envelope glycoprotein
Assembly of virions
G: glycoprotein (HN, H, G)c Transmembranous envelope glycoprotein
L: polymerase (large) Association with nucleoprotein Protein promotes fusion of cells, hemolysis, and viral
entry

Viral attachment protein

Polymerase

aIn order on the genome.
bPneumoviruses also encode an SH and M2 protein.
cGlycoproteins differ for the different paramyxoviruses: HN, hemagglutinin-neuraminidase; H, hemagglutinin; G, glycoprotein.

pass directly from cell to cell to escape antibody control. lifelong immunity to the virus. Death caused by pneumo-
Virus production occurs with eventual cell lysis. Persistent nia, diarrhea, or encephalitis can occur. The time course of
infections without lysis can occur in certain cell types (e.g., measles infection is shown in Fig. 48.4.
human brain cells).
Measles can cause encephalitis in three ways: (1) direct
Measles is highly contagious and is transmitted from infection of neurons, (2) a postinfectious encephalitis that is
person to person by respiratory droplets (Fig. 48.3). After believed to be immune mediated, and (3) subacute scleros-
local replication of virus in epithelial cells of the respiratory ing panencephalitis (SSPE) caused by a defective variant of
tract, the virus infects monocytes and lymphocytes, and measles generated during the acute disease. The SSPE virus
the virus is spread through the lymphatic system and by a replicates poorly, stays cell associated, and causes symp-
cell-associated viremia. The wide dissemination of the virus toms and cytopathologic effect in neurons many years after
causes infection of the conjunctiva, respiratory tract, uri- acute disease.
nary tract, small blood vessels, lymphatic system, and cen-
tral nervous system. The characteristic maculopapular Measles and other paramyxoviruses are excellent induc-
measles rash is caused by the inflammation resulting from ers of interferon (IFN)-α and IFN-β but also have mecha-
immune T cells targeted to measles-infected epithelial cells. nisms to antagonize their action. Cell-mediated immunity
Recovery follows the rash in most patients, who then have is essential for control of the measles infection because a
great deal of virus production proceeds before cell death and

48  •  Paramyxoviruses 481

RSV Absorption/fusion Glyco- Inoculation Local replication Lymphatic Viremia
proteins of respiratory in respiratory spread
tract tract

Viral ER Nucleus Rash Virus-infected Conjunctivae Wide
(Ϫ) RNA 5' Golgi endothelial Respiratory tract dissemination
cells plus Urinary tract
3' Matrix protein immune Small blood vessels
T cells Lymphatic system
CNS

Transcription

Template mRNAs Recovery Postinfectious Subacute No resolution of
(ϩ) RNA Translation (lifelong encephalitis sclerosing acute infection
immunity) (immunopathologic: panencephalitis caused by
etiology) (defective defective CMI
Assembly of RNA and protein measles virus (frequently fatal
Viral infection of CNS) outcome)
(Ϫ) RNA
genome

Rare Outcomes

Fig. 48.3  Mechanisms of spread of the measles virus within the body
and the pathogenesis of measles. CMI, Cell-mediated immunity; CNS,
central nervous system.

Postinfectious SSPE
encephalitis (rare) (rare)

Rash

Fig. 48.2  Replication of paramyxoviruses. The virus binds to glyco- CCC Koplik
lipids or proteins and fuses with the cell surface. Individual messenger and P spots
RNAs (mRNAs) for each protein and a full-length template are tran-
scribed from the genome. Replication occurs in the cytoplasm. Pro- Respiratory tract
teins associate with the new genome, and the nucleocapsid associates symptoms
with matrix and glycoprotein-modified plasma membranes. The virus
leaves the cell by budding. (−), Negative sense; (+), positive sense; ER, Virus in respiratory
endoplasmic reticulum; RSV, respiratory syncytial virus. (Modified from tract and urine
Balows, A. et al., 1988. Laboratory Diagnosis of Infectious Diseases: Prin-
ciples and Practice. Springer-Verlag, New York, NY.) Viremia

BOX 48.2  Disease Mechanisms of Measles Virus-specific
Virus antibody present

Virus infects epithelial cells of respiratory tract. Incubation period
Virus spreads systemically in lymphocytes by viremia.
Virus replicates in cells of conjunctivae, respiratory tract, urinary 07 14 Many
Days years
tract, lymphatic system, blood vessels, and CNS. Inoculation of
Rash is caused by T-cell response to virus-infected epithelial cells. respiratory tract
Virus causes immunosuppression.
Cell-mediated immunity is essential to control infection. Fig. 48.4  Time course of measles virus infection. Characteristic pro-
Sequelae in the CNS may result from immunopathogenesis drome symptoms are cough, conjunctivitis, coryza, and photophobia
(CCC and P), followed by the appearance of Koplik spots and rash. SSPE,
(postinfectious measles encephalitis) or development of defec- Subacute sclerosing panencephalitis.
tive mutants (subacute sclerosing panencephalitis).
more severe for people deficient in vitamin A. Vitamin A is
CNS, Central nervous system. important for optimal effector T-cell function and resolution
of measles infection. Antibody, including maternal anti-
cell–cell transmission by fusion promotes escape from anti- body and passive immunization, can block the viremic but
body. T-cell–deficient children who are infected with mea- not cell-cell spread of the virus to prevent or lessen disease.
sles have an atypical presentation consisting of giant cell There is only one serotype of measles, and immune protec-
pneumonia without a rash. The immune response is also tion from future disease is lifelong.
responsible for most of the symptoms of measles. Measles is

482 SECTION 5  •  Virology

BOX 48.3  Epidemiology of Measles TABLE 48.3  Clinical Consequences of Measles Virus
Infection
Disease/Viral Factors
Disorder Symptoms
Virus has large enveloped virion that is easily inactivated by dry-
ness and acid. Measles Characteristic maculopapular rash, cough, con-
Atypical measles junctivitis, coryza, photophobia, Koplik spots
Contagion period precedes symptoms.
Very contagious with 95% infectivity rate. Complications: otitis media, croup, pneumonia,
Host range is limited to humans. blindness, encephalitis
Only one serotype exists.
Immunity is lifelong.  More intense rash (most prominent in distal
Transmission areas); possible vesicles, petechiae, purpura,
or urticaria
Inhalation of large-droplet aerosols. 
Who Is at Risk? Postmeasles Acute onset of headache, confusion, vomiting,
encephalitis possible coma after rash dissipates
Unvaccinated people, especially infants <1 year old.
Malnourished people, especially vitamin A deficient, who have Subacute sclerosing Central nervous system manifestations (e.g.,
panencephalitis personality, behavior, and memory changes;
more serious outcomes. myoclonic jerks; spasticity; blindness)
Immunocompromised people, who have more serious outcomes. 
Geography/Season in the winter and spring. Measles is still common in people
living in developing countries, especially in individuals who
Virus found worldwide. refuse immunization or who have not received a booster in
Virus endemic from autumn to spring, possibly because of crowd- their teenage years. Despite the effectiveness of vaccination
programs, poor compliance and the prevaccinated popu-
ing indoors.  lation (children <2 years) continue to provide susceptible
Modes of Control individuals. The virus may surface from within the com-
munity or can be imported by immigration from areas of
Live attenuated vaccine (Schwartz or Moraten variants of Edmon- the world lacking an effective vaccine program. Once again,
ston B strain) can be administered. outbreaks of measles are occurring more often in the United
States, France, and England. In the United States, outbreaks
Immune serum globulin can be administered after exposure. are often initiated by cases imported from other countries
and then spread to unvaccinated or unboosted individuals,
Measles infection is immunosuppressive. The virus including infants. An outbreak of measles in a day-care cen-
depresses the immune response by (1) directly infecting ter (10 infants too young to have been vaccinated and two
and killing monocytes and T and B cells and (2) depress- adults) was traced to an infant from the Philippines.
ing interleukin (IL)-12 production and TH1-type T-cell
helper responses. Depression of cell-mediated immune and Immunocompromised, malnourished, and vitamin A–
delayed-type hypersensitivity (DTH) responses increases deficient people with measles may not be able to resolve the
risk to concurrent opportunistic and other infections. This infection, resulting in death. Measles is the most significant
immunosuppression lasts for weeks or months after the cause of death in children age 1 to 5 years in several coun-
disease.  tries that do not have effective vaccination programs. 

EPIDEMIOLOGY CLINICAL SYNDROMES
Measles is a serious febrile illness (Table 48.3). The incu-
Measles is one of the most contagious infections known bation period lasts 7 to 13 days, and the prodrome starts
(Box 48.3). The virus is efficiently spread in respiratory with 2 to 4 days of high fever and “CCC and P” (cough,
secretions before and after the onset of characteristic symp- coryza, conjunctivitis, and photophobia). The disease is
toms. In a household, approximately 90% of exposed sus- most infectious during this time.
ceptible people become infected, and 95% of these people
develop clinical disease. After 2 days of prodromal illness, the typical mucous
membrane lesions known as Koplik spots (Fig. 48.5)
The measles virus has only one serotype and infects only appear. They are seen most commonly on the buccal
humans, and infection usually manifests with symptoms. mucosa across from the molars, but they may appear on
These properties facilitated the development of an effective other mucous membranes as well, including the conjunc-
vaccine program. Once vaccination was introduced, the tivae and the vagina. The vesicular lesions, which last 24
yearly incidence of measles dropped dramatically in the to 48 hours, are usually small (1 to 2 mm) and are best
United States, from 300 to 1.3 per 100,000 (U.S. statis- described as grains of salt surrounded by a red halo. Their
tics for 1981 to 1988). This change represented a 99.5% appearance with the other disease signs establishes with
reduction in the incidence of infection from the prevaccina- certainty the diagnosis of measles.
tion years of 1955 to 1962. Incidences of measles must be
reported to state and federal health departments. In areas Within 12 to 24 hours of the appearance of Koplik spots,
without a vaccine program, epidemics tend to occur in 1- the exanthem of measles starts below the ears and spreads
to 3-year cycles, when a sufficient number of susceptible over the body. The rash is maculopapular and is usually
people have accumulated. Many of these cases occur in very extensive, and often the lesions become confluent. The
preschool-age children who have not been vaccinated and rash, which takes 1 or 2 days to cover the body, fades in the
live in large urban areas. The incidence of infection peaks

48  •  Paramyxoviruses 483

Fig. 48.5  Koplik spots in the mouth and exanthem. Koplik spots usu- in the malnourished and for the extremes of age. Bacterial
ally precede the measles rash and may be seen for the first day or two superinfection is common in patients with pneumonia
after the rash appears. (Courtesy Dr. J.I. Pugh, St Albans City Hospital, caused by the measles virus.
West Hertfordshire, England. From Emond, R.T.D., Rowland, H.A.K., 1995. A
Color Atlas of Infectious Diseases, third ed. Mosby, London, UK.) One of the most feared complications of measles is
encephalitis, which occurs in as few as 0.5% of those
Fig. 48.6  Measles rash. (A) A maculopapular rash appears on the face infected but carries a fatality rate of 15%. Encephalitis
and becomes confluent. (B) The rash then appears on the trunk. (From may rarely occur during acute disease but usually begins
Habif, T.P., 2015. Clinical Dermatology: Color Guide to Diagnosis and Ther- 7 to 10 days after the onset of illness. This postinfectious
apy, sixth ed. ©2015, Elsevier.) encephalitis is caused by immunopathologic reactions, is
associated with demyelination of neurons, and occurs more
same order in which it appeared. The fever is highest and often in older children and adults.
the patient is sickest on the day the rash appears (Fig. 48.6).
Atypical measles occurred in people who received
Pneumonia, which can also be a serious complication, the older inactivated measles vaccine and were subse-
accounts for 60% of the deaths caused by measles. Similar quently exposed to the wild-type measles virus. It may
to the incidence of the other complications associated with also rarely occur in those vaccinated with the attenu-
measles, the mortality associated with pneumonia is higher ated virus vaccine. Prior sensitization with insufficient
protection can enhance the immunopathologic response
to the challenge by the wild-type measles virus. The ill-
ness begins abruptly and is a more intense presentation
of measles.

Infections of the immunocompromised and mal-
nourished, especially vitamin A–deficient, child cause
the most severe measles disease (Clinical Case 48.1). Giant
cell pneumonia without rash occurs in children lacking
T-cell immunity. Whereas the death rate of measles in the
United States is only 0.1%, complications, severe bacterial
superinfection, and pneumonia in malnourished children
result in up to 60% mortality.

SSPE is an extremely serious, very late neurologic
sequela of measles that afflicts approximately 7 of every 1
million patients. The incidence of SSPE has decreased mark-
edly because of measles vaccination programs.

This disease occurs when a defective measles virus per-
sists in the brain, affects multiple loci in the brain (pan-
encephalitis), and acts as a slow virus. The virus can
replicate and spread directly from cell to cell but is not
released. SSPE is most prevalent in children who were
initially infected when younger than 2 years and occurs
approximately 7 years after clinical measles. The patient
demonstrates changes in personality, behavior, cognition,
and memory, followed by myoclonic jerks, blindness, and
spasticity, and progresses to coma and death. Unusually
high levels of measles antibodies are found in the blood
and cerebrospinal fluid of patients with SSPE. Measles
antigen and genome can be detected in neurons, as well
as Cowdry type A inclusion bodies (these inclusion bodies
are usually a marker for herpes simplex virus but also are
seen in SSPE). 

LABORATORY DIAGNOSIS
The clinical manifestations of measles are usually so char-
acteristic that it is rarely necessary to perform laboratory
tests to establish the diagnosis. The measles virus should
not be isolated. Respiratory tract secretions, urine, blood,
and brain tissue are the recommended specimens. It is best
to collect respiratory and blood specimens during the pro-
dromal stage and until 1 to 2 days after the appearance of
the rash. Measles antigen can be detected with immuno-
fluorescence in pharyngeal cells or urinary sediment, or the
measles genome can be identified by reverse transcriptase-
polymerase chain reaction (RT-PCR) in respiratory tract

484 SECTION 5  •  Virology

Clinical Case 48.1  Measles in the BOX 48.4  Measles-Mumps-Rubella Vaccine
Immunocompromised Child
Composition: live attenuated viruses
The lack of cell-mediated immune responses allows Measles: Schwartz or Moraten substrains of Edmonston B strain
measles infection of immunocompromised individuals to Mumps: Jeryl Lynn strain
progress to serious outcomes. In a case reported by Pullan Rubella: RA/27-3 strain
and associates (Br Med J 1:1562–1565, 1976), within 3 Vaccination schedule: after 12 months of age and at age 4 to 6
days of exposure to measles, a child on chemotherapy for
ALL received pooled immunoglobulin. Despite the IgG ther- years or before junior high school (12 years of age)
apy, 23 days after exposure, she developed an extensive Efficiency: 95% lifelong immunization with a single dose
measles rash that became hemorrhagic. She had a fever of
39.5° C and bronchopneumonia. Measles was grown from Data from https://www.vaccines.gov/diseases/.
nasopharyngeal secretions, and immunohistochemistry
identified giant cells (syncytia) containing measles antigen mature and antibodies from the mother have been cleared.
within the secretions. Her chemotherapy was stopped, and The vaccine is given in combination with mumps and
she received several massive doses of immunoglobulin. She rubella (measles-mumps-rubella [MMR] vaccine) and
started to improve 1 month after the onset of the rash. the varicella vaccines (Box 48.4). Although early child-
hood immunization is successful in more than 95% of vac-
In another case, during the 2.5 years that a boy was cinees, revaccination before grade school or junior high
under treatment for ALL, he suffered severe herpes simplex school is required in many states. Because of the very con-
virus infections around the mouth and herpes zoster on his tagious nature of measles, vaccine-induced herd immu-
trunk. During the third year on therapy, he was exposed nity is very important to prevent spread of the virus in the
to measles from his sister and received pooled IgG. After 19 population. A decrease to 93% immunized within the pop-
days, he developed mild respiratory symptoms but no rash. ulation creates a risk of a measles outbreak. Complacency
After 29 days, he refused to go to school and misbehaved; or misinformation regarding immunization risks causes
behavioral changes progressed. After 9 weeks, he devel- many parents to refrain from vaccinating their children,
oped focal motor seizures, increased drowsiness, slurring putting them at risk of infection, disease, and becoming
of speech, and confusion, which progressed to coma and sources of contagion to others.
death within 8 days of the onset of seizures. Serology
indicated a lack of measles antibody. Autopsy indicated the Because measles is strictly a human virus with only one
presence of cytomegalovirus but not measles in the lungs. serotype, it is a good candidate for eradication, but this
The brain showed extensive degeneration, but no virus is prevented by difficulties in distributing the vaccine to
was isolated from the samples. Brain sections indicated regions that lack proper refrigeration facilities (e.g., Africa)
large intranuclear and cytoplasmic inclusion bodies with and distribution networks.
tubular structures that resembled measles nucleocapsids
in the cytoplasm. Immunofluorescence with antibody from Hospitals in areas experiencing endemic measles may
individuals with SSPE or antimeasles antibody indicated wish to vaccinate or check the immune status of their
the presence of measles antigen. These cases illustrate the employees to decrease the risk of nosocomial transmis-
excessive pathology measles can cause in the absence of sion. Pregnant women, immunocompromised individu-
a competent T-cell response. The lack of immune control als, and people with allergies to gelatin or neomycin
allowed progression of the virus to the brain, in which it or (components of the vaccine) should not receive the MMR
a variant (SSPE) caused pathology leading to encephalitis. vaccine. Exposed susceptible people who are immuno-
ALL, Acute lymphoblastic leukemia; SSPE, subacute scleros- compromised should be given immunoglobulin to lessen
the risk and severity of clinical illness. This product is
ing panencephalitis. most effective if given within 6 days of exposure. High-
dose vitamin A treatment reduces the risk of measles
secretions, urine, blood, and brain tissue. Characteristic mortality and is recommended by the World Health
cytopathologic effects, including multinucleated giant cells Organization. No specific antiviral treatment is available
with cytoplasmic inclusion bodies, can be seen in Giemsa- for measles. 
stained cells taken from the upper respiratory tract and uri-
nary sediment. Parainfluenza Viruses

Antibody, especially immunoglobulin (Ig)M, can be Parainfluenza viruses, which were discovered in the late
detected when the rash is present.  1950s, are respiratory viruses that usually cause mild
TREATMENT, PREVENTION, AND CONTROL coldlike symptoms but can also cause serious respi-
As stated previously, a live attenuated measles vaccine, ratory tract disease. Four serologic types within the
in use in the United States since 1963, has been respon- parainfluenza genus are human pathogens. Types 1,
sible for significant reduction in the incidence of measles. 2, and 3 are second only to RSV as important causes of
The Schwartz or Moraten attenuated strains of the origi- severe lower respiratory tract infection in infants and
nal Edmonston B vaccine are currently being used. Live young children. They are especially associated with
attenuated vaccine is given to all children after 12 months laryngotracheobronchitis (croup). Type 4 causes
of age when the T-cell immune responses are sufficiently only mild upper respiratory tract infection in children
and adults.

48  •  Paramyxoviruses 485

BOX 48.5  Disease Mechanisms of BOX 48.6  Epidemiology of Parainfluenza
Parainfluenza Viruses Virus Infections

There are four serotypes of parainfluenza viruses. Disease/Viral Factors
Infection is limited to the respiratory tract; upper respiratory Virus has a large enveloped virion that is easily inactivated by

tract disease is most common, but significant disease can occur dryness and acid.
with lower respiratory tract infection. Contagion period precedes symptoms and may occur in absence
Parainfluenza viruses do not cause viremia or become systemic.
Diseases include coldlike symptoms, bronchitis (inflammation of of symptoms.
bronchial tubes), and croup (laryngotracheobronchitis). Host range is limited to humans.
Infection induces protective immunity of short duration. Reinfection can occur later in life. 
Transmission
PATHOGENESIS AND IMMUNITY Inhalation of large-droplet aerosols. 
Parainfluenza viruses infect epithelial cells of the upper Who Is at Risk?
respiratory tract (Box 48.5). The virus replicates more rap- Children: at risk for mild disease or croup.
idly than measles and mumps viruses and can cause giant Adults: at risk for reinfection with milder symptoms. 
cell formation and cell lysis. Unlike measles and mumps Geography/Season
viruses, the parainfluenza viruses rarely cause viremia. Virus is ubiquitous and worldwide.
The viruses generally stay in the upper respiratory tract, Incidence is seasonal. 
causing only coldlike symptoms. In approximately 25% Modes of Control
of cases, the virus spreads to the lower respiratory tract, There are no modes of control.
and in 2% to 3%, disease may take the severe form of
laryngotracheobronchitis. children recover within 48 hours. The principal differential
diagnosis is epiglottitis caused by Haemophilus influenzae. 
The cell-mediated immune response both causes cell
damage and confers protection. IgA responses are protec- LABORATORY DIAGNOSIS
tive but short-lived. Parainfluenza viruses manipulate Rapid RT-PCR techniques are the method of choice to detect
cell-mediated immunity to limit development of memory. and identify parainfluenza viruses from respiratory secre-
Multiple serotypes and the short duration of immunity after tions. Parainfluenza virus is isolated from nasal washings
natural infection make reinfection common, but the reinfec- and respiratory secretions and grows well in primary mon-
tion disease is milder, suggesting at least partial immunity.  key kidney cells. Similar to other paramyxoviruses, the viri-
ons are labile during transit to the laboratory and cannot
EPIDEMIOLOGY be frozen at −20° C. The presence of virus-infected cells in
Parainfluenza viruses are ubiquitous, and infection is aspirates or in cell culture is indicated by the finding of syn-
common (Box 48.6). The virus is transmitted by person- cytia and is identified with immunofluorescence. Similar
to-person contact and respiratory droplets. Primary to the hemagglutinin of the influenza viruses, the hemag-
infections usually occur in infants and children younger glutinin of the parainfluenza viruses promotes hemadsorp-
than 5 years. Reinfections occur throughout life, indicat- tion and hemagglutination. The serotype of the virus can
ing short-lived immunity. Infections with parainfluenza be determined through the use of specific antibody to block
viruses 1 and 2, the major causes of croup, tend to occur infection (neutralization) and hemadsorption or hemagglu-
in the autumn, whereas parainfluenza virus 3 infections tination (hemagglutination inhibition). 
occur throughout the year. All these viruses spread read-
ily within hospitals and can cause outbreaks in nurseries TREATMENT, PREVENTION, AND CONTROL
and pediatric wards.  Treatment of croup consists of the administration of nebu-
lized cold or hot steam and careful monitoring of the upper
CLINICAL SYNDROMES airway. On rare occasions, intubation may become neces-
Parainfluenza viruses 1, 2, and 3 may cause respiratory sary. No specific antiviral agents are available.
tract syndromes ranging from a mild coldlike upper
respiratory tract infection (coryza, pharyngitis, mild Vaccination with killed vaccines is ineffective, possibly
bronchitis, wheezing, and fever) to bronchiolitis and because they fail to induce local secretory antibody and
pneumonia. Older children and adults generally experi- appropriate cellular immunity. No live attenuated vaccine
ence milder infections than those seen in young children, is available. 
although pneumonia may occur in the elderly.
Mumps Virus
A parainfluenza virus infection in infants may be more
severe than infections in adults, causing bronchiolitis, Mumps virus is the cause of acute, benign viral parotitis
pneumonia, and most notably croup (laryngotracheo- (painful swelling of the salivary glands). Mumps is rarely
bronchitis). Croup results in subglottal swelling that may
close the airway. Hoarseness, a “seal bark” cough, tachy-
pnea, tachycardia, and suprasternal retraction develop in
infected patients after a 2- to 6-day incubation period. Most

486 SECTION 5  •  Virology

BOX 48.7  Disease Mechanisms of Mumps Meningoencephalitis
Virus
Orchitis
Virus infects epithelial cells of respiratory tract.
Virus spreads systemically by viremia. Parotitis
Infection of parotid gland, testes, and central nervous system.
Principal symptom is swelling of parotid and other glands caused Virus-specific
antibody present
by inflammation.
Cell-mediated immunity is essential for control of infection and Recovery of
virus from CSF
responsible for causing some of the symptoms. Recovery of virus
Antibody is not sufficient because of the virus’ ability to spread from mouth or urine

cell to cell.

Inoculation Local Viremia Systemic Incubation
of respiratory replication infection
tract

Pancreas Testes Parotid gland 0 7 14 21 28 35 42
May be associated Ovaries Virus multiplies in Days
with onset of Peripheral nerves ductal epithelial cells;
juvenile diabetes Eye Local inflammation Inoculation of
Inner ear causes marked respiratory tract
Central nervous swelling
Fig. 48.8  Time course of mumps virus infection. CSF, Cerebrospinal
system fluid.

Fig. 48.7  Mechanism of spread of mumps virus within the body. BOX 48.8  Epidemiology of Mumps Virus

seen in countries that promote the use of the live vaccine, Disease/Viral Factors
which is administered with the measles and rubella live
vaccines, but outbreaks have occurred recently. Virus has large enveloped virion that is easily inactivated by dry-
ness and acid.
Mumps virus was isolated in embryonated eggs in 1945
and in cell culture in 1955. The virus is most closely related Contagion period precedes symptoms.
to parainfluenza virus 2, but there is no cross-immunity Virus may cause asymptomatic shedding.
with the parainfluenza viruses. Host range is limited to humans.
Only one serotype exists.
PATHOGENESIS AND IMMUNITY Immunity is lifelong. 
The HN glycoprotein of mumps virus binds to sialic acid and
initiates infection of the epithelial cells of the upper respira- Transmission
tory tract. The virus progresses to the parotid gland, either by
way of the Stensen duct or by means of a viremia (Box 48.7). Inhalation of large-droplet aerosols. 
Like other paramyxoviruses, mumps causes syncytia forma-
tion. The virus is spread by viremia throughout the body to Who Is at Risk?
the testes, ovary, pancreas, thyroid, and other organs. Infec-
tion of the central nervous system, especially the meninges, Unvaccinated people, especially infants <1 year old.
occurs in as many as 50% of those infected (Fig. 48.7). T cells Immunocompromised people, who have more serious outcomes. 
are important for resolution but also cause immunopatho-
genesis. Inflammatory responses cause swelling of glands Geography/Season
and are mainly responsible for the symptoms. The time
course of human infection is shown in Fig. 48.8. There is Virus is found worldwide.
only one serotype of mumps, and immunity is lifelong.  Virus is endemic in late winter and early spring. 

EPIDEMIOLOGY Modes of Control
Mumps, like measles, is a very communicable disease with
only one serotype, and it infects only humans (Box 48.8). Live attenuated vaccine (Jeryl Lynn strain) is part of measles-
In the absence of vaccination programs, infection occurs in mumps-rubella vaccine.
90% of people by the age of 15 years. The virus spreads by
direct person-to-person contact and respiratory droplets. The virus is released in respiratory secretions from patients
who are asymptomatic and during the 7-day period before
clinical illness, so it is virtually impossible to control the
spread of the virus. Living or working in close quarters pro-
motes the spread of the virus, and the incidence of the infec-
tion is greatest in the winter and spring. 

CLINICAL SYNDROMES
Mumps infections are often asymptomatic. Clinical ill-
ness usually manifests as a parotitis that is almost always
bilateral and accompanied by fever. Onset is sudden. Oral

48  •  Paramyxoviruses 487

examination reveals redness and swelling of the ostium of BOX 48.9  Disease Mechanisms of
the Stensen (parotid) duct. The swelling of other glands Respiratory Syncytial Virus
(epididymoorchitis, oophoritis, mastitis, pancreatitis, and
thyroiditis) and meningoencephalitis may occur a few days Virus causes localized infection of respiratory tract.
after the onset of the viral infection but can occur in the Virus does not cause viremia or systemic spread.
absence of parotitis. The swelling that results from mumps Pneumonia results from cytopathologic spread of virus (including
orchitis may cause sterility. Mumps virus involves the cen-
tral nervous system in approximately 50% of patients; 10% syncytia).
of those affected may exhibit mild meningitis, with 5 per Bronchiolitis is most likely mediated by the host’s immune
1000 cases of encephalitis. 
response.
LABORATORY DIAGNOSIS Narrow airways of young infants are readily obstructed by virus-
The clinical diagnosis of mumps can be confirmed by RT-
PCR detection of viral genomes or assay of IgM or antigen induced pathologic effects.
by enzyme-linked immunosorbent assay (ELISA). Virus can Maternal antibody is insufficient to protect infant from infection.
be recovered from saliva, urine, the pharynx, secretions Natural infection does not prevent reinfection.
from the Stensen duct, and cerebrospinal fluid. Virus is
present in saliva for approximately 5 days after the onset of BOX 48.10  Epidemiology of Respiratory
symptoms and in urine for as long as 2 weeks. Mumps virus Syncytial Virus
grows well in monkey kidney cells, causing the formation
of multinucleated giant cells. Hemadsorption of guinea pig Disease/Viral Factors
erythrocytes also occurs on virus-infected cells because of Virus has a large enveloped virion that is easily inactivated by
the viral hemagglutinin. 
dryness and acid.
TREATMENT, PREVENTION, AND CONTROL Contagion period precedes symptoms and may occur in the
Vaccines provide the only effective means for preventing
the spread of mumps infection. Since the introduction of the absence of symptoms.
live attenuated vaccine (Jeryl Lynn vaccine) in the United Host range is limited to humans. 
States in 1967 and its administration as part of the MMR Transmission
vaccine at 1 year of age, the yearly incidence of the infec- Inhalation of large-droplet aerosols. 
tion has declined from 76 to less than 1 per 100,000, until Who Is at Risk?
recently. As with measles, outbreaks caused by increas- Infants: lower respiratory tract infection (bronchiolitis and pneu-
ing numbers of individuals who are unvaccinated or who
did not receive a booster immunization have occurred. In monia).
2014, there was an outbreak in Columbus, Ohio, in schools Premature neonates: serious disease.
and universities, with more than 230 reported cases. Anti- Children: spectrum of disease from mild to pneumonia.
viral agents are not available.  Adults: reinfection with milder symptoms.
Immunocompromised, chronic heart and lung problems: serious
Respiratory Syncytial Virus
disease. 
RSV, first isolated from a chimpanzee in 1956, is a member Geography/Season
of the Pneumovirus genus. There are two types and many Virus is ubiquitous and found worldwide.
different strains of RSV causing the same diseases. The gly- Incidence is seasonal. 
coprotein of RSV does not bind to sialic acid or red blood Modes of Control
cells; therefore the virus does not need or have a neuramin- Immunoglobulin is available for infants at high risk.
idase. It is the most common cause of fatal acute respi- Aerosol ribavirin is available for infants with serious disease.
ratory tract infection in infants and young children. It
infects virtually everyone by 2 years of age, and reinfections of “plugs” of mucus, fibrin, and necrotic material within
occur throughout life, even among elderly persons. smaller airways. The narrow airways of young infants
are readily obstructed by such plugs. RSV can exacerbate
PATHOGENESIS AND IMMUNITY previous lung disease and asthma. Natural immunity does
RSV produces an infection that is localized to the respiratory not prevent reinfection, and vaccination with killed vac-
tract (Box 48.9). It binds to many different cell-surface pro- cine was ineffective or enhanced the severity of subsequent
teins and heparan sulfate proteoglycans. As the name sug- disease. 
gests, RSV induces syncytia. The pathologic effect of RSV
is mainly caused by immunologically mediated cell injury. EPIDEMIOLOGY
Neutrophils play a large role in the inflammation. Necro-
sis of the bronchi and bronchioles leads to the formation RSV is very prevalent in young children; almost all chil-
dren have been infected by 2 years of age (Box 48.10), with
global annual infection rates of 64 million and mortality of
160,000. As many as 25% to 40% of these cases involve
the lower respiratory tract, and 1% are severe enough to
necessitate hospitalization (occurring in as many as 95,000
children in the United States each year).

488 SECTION 5  •  Virology

TABLE 48.4  Clinical Consequences of Respiratory BOX 48.11  Clinical Summaries
Syncytial Virus Infection
Measles: An 18-year-old woman had been home for 10 days
Disorder Age Group Affected after a trip to Haiti when she developed a fever, cough, runny
nose, and mild redness of her eyes. She now has a red, slightly
Bronchiolitis, pneumonia, or Fever, cough, dyspnea, and raised rash over her face, trunk, and extremities. There are
both cyanosis in children <1 year several 1-mm white lesions inside her mouth. She was never
immunized for measles because of misinformation that an “egg
Febrile rhinitis and pharyngitis Pneumonia in elderly, or those allergy” would be a problem. The vaccine is not produced in
with chronic heart disease, eggs.
chronic lung disease, or those
who are immunocompromised Mumps: A 30-year-old man returning from a trip to Russia experi-
enced a 1- to 2-day period of headache and decreased appetite,
Children followed by swelling over both sides of his jaw. The swelling
extended from the bottom of the jaw to in front of the ear. Five
Common cold Older children and adults days after the jaw swelling appeared, the patient began com-
plaining of nausea and lower abdominal and testicular pain. He
RSV infections almost always occur in the winter. Unlike never received a booster immunization with the MMR vaccine.
influenza, which may occasionally skip a year, RSV epidem-
ics occur every year. Croup: An irritable 2-year-old toddler with little appetite has a
sore throat, fever, and hoarse voice and coughs with the sound
The virus is very contagious, with an incubation period of a barking seal. A high-pitched noise (stridor) is heard on inha-
of 4 to 5 days. Virus is shed in respiratory secretions for lation. Flaring of the nostrils indicates difficulty breathing.
many days after infection, especially by infants. The virus
is transmitted in aerosols but also on hands and by fomites. nebulized cold steam. Aerosolized ribavirin, a guanosine
analog, is approved for treatment of infants with severe
Introduction of the virus into a nursery, especially into disease, but its use is infrequent. Prophylactic and thera-
an intensive care nursery, can be devastating. Virtually peutic passive immunization with anti-RSV immuno-
every infant becomes infected, and the infection is associ- globulin or monoclonal antibody (palivizumab) is available
ated with considerable morbidity and occasionally death. for young children at high risk to serious disease.
Infants born prematurely and children younger than 2
years with complicated congenital heart disease or chronic Infected children must be isolated. Infection-control mea-
lung disease are at high risk to serious RSV disease. Out- sures are required for hospital staff caring for infected chil-
breaks of serious disease also may occur among the elderly dren to avoid transmitting the virus to uninfected patients.
population (e.g., in nursing homes).  These measures include handwashing and wearing gowns,
goggles, and masks.
CLINICAL SYNDROMES
RSV can cause any respiratory tract illness, from a com- No vaccine is currently available for RSV prophylaxis. A
mon cold to pneumonia (Table 48.4; Box 48.11). Upper previously available vaccine containing inactivated RSV
respiratory tract infection with prominent rhinorrhea caused recipients to have more severe RSV disease when
(runny nose) is most common in older children and adults. subsequently exposed to the live virus. This development
A more severe lower respiratory tract illness, bronchiol- is thought to be the result of a heightened immunologic
itis, may occur in infants. Because of inflammation at the response at the time of exposure to the wild virus. 
level of the bronchiole, there is air trapping and decreased
ventilation. Clinically, the patient usually has low-grade Human Metapneumovirus
fever, tachypnea, tachycardia, and expiratory wheezes
over the lungs. Bronchiolitis is usually self-limited, but it Human metapneumovirus is a recently recognized member
can be a frightening disease to observe in an infant. Rein- of the Pneumovirinae subfamily. Use of RT-PCR methods
fection may present as a common cold or exacerbation of was and remains the means of detecting the pneumoviruses
asthma. RSV may be fatal in premature infants, persons and distinguishing them from other respiratory disease
with underlying lung disease, and immunocompromised viruses. Its identity was unknown until recently because it
people.  is difficult to grow in cell culture. The virus is ubiquitous,
and almost all 5-year-old children have experienced a virus
LABORATORY DIAGNOSIS infection and are seropositive.
RSV is difficult to isolate in cell culture. Presence of the
viral genome in infected cells and nasal washings can be As with its close cousin RSV, infections by human meta-
detected by RT-PCR techniques. Enzyme immunoassay can pneumovirus may be asymptomatic, cause common cold–
detect viral antigen in washings and immunofluorescence type disease, or cause serious bronchiolitis and pneumonia.
on exfoliated cells.  Seronegative children, the elderly, and immunocompro-
mised people are at risk for disease. Human metapneumo-
TREATMENT, PREVENTION, AND CONTROL virus probably causes 15% of common colds in children,
In otherwise healthy infants, treatment is supportive, con- especially those complicated by otitis media. Signs of disease
sisting of administration of oxygen, intravenous fluids, and usually include cough, sore throat, runny nose, and high
fever. Approximately 10% of patients with metapneumovi-
rus will experience wheezing, dyspnea, pneumonia, bron-
chitis, or bronchiolitis. As with other common cold agents,

48  •  Paramyxoviruses 489

laboratory identification of the virus is not performed rou- Gershon, A., Hotez, P., Katz, S., 2004. Krugman’s Infectious Diseases of
tinely but can be performed by RT-PCR. Supportive care is Children, eleventh ed. Mosby, St Louis.
the only therapy available for these infections. 
Griffin, D.E., Oldstone, M.M., 2009. Measles: pathogenesis and control.
Nipah and Hendra Viruses Curr Top Microbiol Immunol 330 (1).

A new paramyxovirus, Nipah virus, was isolated from Griffiths, C., Drews, S.J., Marchanta, D.J., 2017. Respiratory syncytial
patients after an outbreak of severe encephalitis in Malay- virus: infection, detection, and new options for prevention and treat-
sia and Singapore in 1998. Nipah virus is more closely ment. Clin. Micro. Rev. 30, 277–319.
related to the Hendra virus, which was discovered in 1994
in Australia, than to other paramyxoviruses. Both viruses Hart, C.A., Broadhead, R.L., 1992. Color atlas of Pediatric Infectious Dis-
have broad host ranges, including pigs, humans, dogs, eases. Mosby, St Louis.
horses, cats, and other mammals. For Nipah virus, the res-
ervoir is a fruit bat (flying fox). The virus can be obtained Hinman, A.R., 1982. Potential candidates for eradication. Rev. Infect. Dis.
from fruit contaminated by infected bats or amplified in 4, 933–939.
pigs and then spread to humans. The human is an acci-
dental host for these viruses, but the outcome of human Knipe, D.M., Howley, P.M., 2013. Fields Virology, sixth ed. Lippincott Wil-
infection is severe. Disease signs for Nipah virus include liams & Wilkins, New York.
flulike symptoms, seizures, and coma. Of the 269 cases
occurring in 1999, 108 were fatal. Another epidemic in Ludlow, M., McQuaid, S., Milner, D., de Swart, R.L., Duprex, W.P., 2015.
Bangladesh in 2004 had a higher mortality rate. More Pathological consequences of systemic measles virus infection. J. Pathol.
recent outbreaks have occurred in India and neighboring 235, 253–265. https://doi.org/10.1002/path.4457. (wileyonlinelibra
countries. ry.com).

  For case studies and questions see Student­Consult.com Mandell, G.L., Bennet, J.E., Dolin, R., 2015. Principles and Practice of
Infectious Diseases, eighth ed. Saunders, Philadelphia.
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Meulen, V., Billeter, M.A., 1995. Measles virus. Curr. Top. Microbiol.
Allen, I.V., McQuaid, S., Penalva, R., Ludlow, M., Duprex, W.P., Rima, Immunol. 191, 1–196.
B.K., 2018. Macrophages and dendritic cells are the predominant cells
infected in measles in humans. mSphere 3. e00570-17. https://doi.org/ Moss, W.J., Griffen, D.E., 2012. Measles. Lancet 379, 153–164.
10.1128/mSphere.00570-17. Phadke, V.K., Bednarczyk, R.A., Salmon, D.A., et  al., 2016. Association

Anderson LJ, Graham BS. Challenges and Opportunities for Respiratory between vaccine refusal and vaccine-preventable diseases in the United
Syncytial Virus Vaccines. Current Topics in Microbiology and Immu- States. A review of measles and pertussis. JAMA 315 (11), 1149–1158.
nology 372, 2013. Strauss, J.M., Strauss, E.G., 2007. Viruses and Human Disease, second ed.
Academic, San Diego.
Editors (view affiliations)
Cohen, J., Powderly, W.G., 2004. Infectious Diseases, second ed. Mosby, Websites
Centers for Disease Control and Prevention, Human parainfluenza viruses
St Louis.
Collier, L., Oxford, J., 2011. Human Virology, fourth ed. Oxford University (HPIVs). www.cdc.gov/parainfluenza/index.html. Accessed August 5,
2018.
Press, Oxford. Centers for Disease Control and Prevention, Measles (rubeola).
de Swart, R.L., Ludlow, M., de Witte, L., Yanagi, Y., van Amerongen, G., www.cdc.gov/measles/index.html. Accessed August 5, 2018.
Centers for Disease Control and Prevention, Mumps.
et  al., 2007. Predominant infection of CD150 lymphocytes and den- www.cdc.gov/mumps/index.html. Accessed August 5, 2018.
dritic cells during measles virus infection of macaques. PLoS Pathog. 3 Centers for Disease Control and Prevention, Respiratory syncytial virus
(11), e178. https://doi.org/10.1371/journal.ppat.0030178. infection (RSV). www.cdc.gov/rsv/. Accessed August 5, 2018.
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Measles, mumps, Rubella Vaccines. https://www.vaccines.gov/diseases/.
Accessed August 5, 2018.

Case Studies and Questions A 13-month-old child had a runny nose, mild cough, and
low-grade fever for several days. The cough got worse and
An 18-year-old college freshman complained of a cough, sounded like “barking.” The child made a wheezing sound
runny nose, and conjunctivitis. The physician in the cam- when agitated. The child appeared well except for the
pus health center noticed small white lesions inside the cough. A lateral radiograph of the neck showed a subglottic
patient’s mouth. The next day, a confluent red rash covered narrowing.
his face and neck. 7. W hat are the specific and common names for these
1 . What clinical characteristics of this case were diagnostic
symptoms?
for measles? 8. What other agents would cause a similar clinical pre-
2. Are any laboratory tests readily available to confirm the
sentation (differential diagnosis)?
diagnosis? If so, what are they? 9. Are there readily available laboratory tests to confirm
3 . Is there a possible treatment for this patient?
4 . When was this patient contagious? this diagnosis? If so, what are they?
5. Why is this disease not common in the United States? 10. Was there a possible treatment for this child?
6. Provide several possible reasons for this person’s suscep- 11. W hen was this child contagious, and how was the

tibility to measles at 18 years of age. virus transmitted?

489.e1

49 Orthomyxoviruses

On April 15, 2009, a 33-year-old woman from Cali- April 21, the patient developed acute respiratory dis-
fornia at 35 weeks’ gestation had a 1-day history tress syndrome (ARDS). The patient began receiving
of myalgias, dry cough, and low-grade fever when oseltamivir on April 28 and broad-spectrum antibi-
examined by her obstetrician-gynecologist. The otics but died on May 4.1
patient had not recently traveled to Mexico. Rapid 1 . How did the woman acquire the infection?
influenza diagnostic testing performed in the phy- 2 . What is the normal presentation, and what is abnormal
sician’s office was positive. On April 19, she was
examined in a local emergency department, with about this presentation of influenza?
worsening shortness of breath, fever, and produc- 3. What put the woman at higher risk and why?
tive cough. She experienced severe respiratory dis- 4 . How did this strain of influenza evolve?
tress and was intubated and placed on mechanical
ventilation. An emergency cesarean delivery was  Answers to these questions are available on Student
performed, resulting in a healthy female infant. On Consult.com.

Summaries Clinically Significant Organisms

ORTHOMYXOVIRUSES ᑏᑏ Binds to sialic acid (HA glycoprotein) Diagnosis
and encodes neuraminidase activity (NA
Trigger Words glycoprotein) ᑏᑏ Symptomatology, RT-PCR genome
analysis of respiratory secretions, immu-
Aerosols, envelope, segmented genome/ ᑏᑏ Preexisting antibody can block disease nology tests (ELISA), hemagglutination
reassortment, hemagglutinin, neur- ᑏᑏ Cell-mediated immune response impor- and hemagglutination inhibition
aminidase, antigenic drift (outbreaks),
antigenic shift (pandemics), zoonosis tant for control but causes pathogenesis Treatment, Prevention, and Control
ᑏᑏ Influenza A, not influenza B, is a zoonosis
Biology, Virulence, and Disease ᑏᑏ Acute flulike symptoms caused by large ᑏᑏ Annual vaccine contains two influenza
A and one or two influenza B strains:
ᑏᑏ Large size, enveloped, (−) segmented cytokine release inactivated vaccines contain HA and NA,
RNA genome ᑏᑏ Extensive destruction of ciliated epithelium live attenuated nasal vaccine (for 2 to 49
ᑏᑏ Pneumonia by influenza or secondary year olds)
ᑏᑏ Encodes RNA-dependent RNA poly-
merase, replicates in nucleus (exception bacterial infection ᑏᑏ Neuraminidase, the M2 channel and
to the rule) the cap-dependent endonuclease are
Epidemiology targets for antiviral drugs
ᑏᑏ Each segment encodes one or two
proteins ᑏᑏ Transmitted by aerosols
ᑏᑏ Annual epidemics caused by mutations,
ᑏᑏ Mixed infection results in genetic mixing
of segments: reassortment pandemics caused by reassortment of
genome segments between human and
animal viruses

ELISA, Enzyme-linked immunosorbent assay; RT-PCR, reverse transcriptase-polymerase chain reaction.

Influenza A and B viruses are the most important members segments among different human and animal (influenza A)
of the Orthomyxoviridae family. Influenza A is a zoono- strains of virus. This genetic instability is responsible for the
sis and can be found in many different animals, including annual epidemics (mutation: drift) and, for influenza A,
birds, pigs, horses, bats, seals, and whales. Influenza C periodic pandemics (reassortment: shift) of influenza
causes only mild respiratory illness, and influenza D infects infection worldwide.
cattle but is not known to cause human disease. Thogoto-
viruses are arboviruses, including the tick-borne Bourbon Influenza is one of the most prevalent and significant viral
virus. This virus is so named because it caused a lethal infections. Probably the most famous influenza pandemic
infection in Bourbon, Kansas, in 2014. The orthomyxovi- (worldwide) is the Spanish influenza that swept the world
ruses are enveloped and have a segmented negative- from 1918 to 1919, killing 20 to 40 million people. In fact,
sense ribonucleic acid (RNA) genome. The segmented more people died of influenza during that time than in the
genome of these viruses facilitates the development of new battles of World War I. Pandemics caused by novel influ-
strains through mutation and reassortment of the gene enza viruses occurred in 1918, 1947, 1957, 1968, 1977,
and 2009. According to the Centers for Disease Control and
1Adapted from Centers for Disease Control and Prevention (CDC): Novel Prevention (CDC), more than 80,000 deaths from 2017 to
influenza A (H1N1) virus infections in three pregnant women—United 2018 could be attributed to influenza in the United States.
States, April–May 2009, MMWR Morb Mortal Wkly Rep 58:497–500. Fortunately, prophylaxis with vaccines and antiviral drugs
www.cdc.gov/mmwr/preview/mmwrhtml/mm58d0512a1.htm. is available.

490 Influenza viruses cause respiratory symptoms and the
classic flulike symptoms of fever, malaise, headache, and

49  •  Orthomyxoviruses 491

Envelope Hemagglutinin

Matrix protein Neuraminidase
underlying the
M2 ion channel
envelope
RNP: RNA, B
A Polymerase, and NP

RNP

C

Fig. 49.1  (A) Model of influenza A virus. (B and C) Electron micrographs of influenza A virus. NP, Nucleoprotein; RNA, ribonucleic acid; RNP, ribonucleo-
protein complex. (Courtesy Centers for Disease Control and Prevention, Atlanta, GA.)

myalgias (body aches). The term flu, however, has been BOX 49.1  Unique Features of the Influenza
mistakenly used to refer to many other respiratory and viral A and B Viruses
infections (e.g., “intestinal flu”).
The enveloped virion has a genome of eight unique negative-
Structure and Replication sense RNA nucleocapsid segments.

Influenza virions are pleomorphic, appearing spherical Hemagglutinin glycoprotein is the viral attachment protein
or tubular (Fig. 49.1; Box 49.1) and ranging in diameter and fusion protein; it elicits neutralizing, protective antibody
from 80 to 120 nm. The genome of the influenza A and B responses.
viruses consists of eight different helical nucleocapsid
segments, each of which contains a negative-sense RNA Influenza transcribes and replicates its genome in the target cell
associated with the nucleoprotein (NP) and the tran- nucleus but assembles and buds from the plasma membrane.
scriptase (RNA polymerase components: PB1, PB2,
PA) (Table 49.1). Influenza C has only seven genomic The polymerase uses capped cellular mRNA as primers for mRNA
segments. synthesis, and this is a target for baloxavir marboxil.

The genomic segments in the influenza A virus range The antiviral drugs amantadine and rimantadine target the M2
from 890 to 2340 bases. The proteins are encoded on sepa- (membrane) protein for influenza A only to inhibit the uncoating
rate segments except for the nonstructural proteins (NS1 step.
and NS2) and the M1 and M2 proteins, each of which are
transcribed from one segment. The antiviral drugs zanamivir, oseltamivir, and peramivir inhibit
the neuraminidase protein of influenza A and B.

The segmented genome promotes genetic diversity caused by
mutation and reassortment of segments on infection with two
different strains.

Influenza A infects humans, other mammals, and birds (zoonosis).

492 SECTION 5  •  Virology

TABLE 49.1  Products of Influenza Gene Segments 1 (−)RNA 3
Binding Transcription
Segmenta Protein Function 2 Uncoating 8 ((+) RNA)8
Cap-mRNA-polyA
1 PB2 Polymerase component 5 Replication
2 PB1 Polymerase component 4 Protein Nucleus
synthesis
3 PA Polymerase component M M M M 6 Assembly
NS1
4 HA Hemagglutinin, viral attachment protein, NS2
fusion protein, target of neutralizing PB1 ER
antibody PB2 4
PA
5 NP Nucleocapsid protein NP HA Golgi
M1 NA
6 NA Neuraminidase (cleaves sialic acid and M2
promotes virus release)
HA NA
7b M1 Matrix protein: viral structural protein
(interacts with nucleocapsid and enve- 7 Budding
lope, promotes assembly) exit

M2 Membrane protein (forms membrane Fig. 49.2  Replication of influenza A virus. After binding (1) to sialic
channel and target for amantadine, acid–containing receptors, influenza is endocytosed and fuses (2) with
facilitates uncoating and HA p­ roduction) the vesicle membrane. Unlike for most other ribonucleic acid (RNA)
viruses, transcription (3) and replication (5) of the genome occur in
8b NS1 Nonstructural protein (inhibits cellular the nucleus. Viral proteins are synthesized (4), helical ribonucleopro-
messenger RNA translation) tein complex nucleocapsid segments form and associate (6) with the
M1 protein–lined membranes containing M2 and the hemagglutinin
NS2 Nonstructural protein (promotes export of (HA) and neuraminidase (NA) glycoproteins. The virus buds (7) from the
nucleocapsid from nucleus) plasma membrane and eventually kills the cell. (−), Negative sense; (+),
positive sense; ER, endoplasmic reticulum; NP, nucleocapsid protein;
aListed in decreasing order of size. NS1, NS2, nonstructural proteins 1 and 2; PA, PB1, PB2, polymerase com-
bEncodes two messenger RNAs. ponents; polyA, polyadenylate.

The envelope contains two glycoproteins, hemaggluti- HAs bind to different sialic acid structures and, for influenza
nin (HA) and neuraminidase (NA), and the membrane A (HA1 to H16), this determines the host, human and ani-
(M2) protein and is internally lined by the matrix (M1) mal, and site in the lung that can be infected. The virus is
protein. The HA forms a spike-shaped trimer; each unit then internalized into a coated vesicle and transferred to
is activated by a protease and is cleaved into two subunits an endosome. Acidification of the endosome causes the HA
held together by a disulfide bond (see Fig. 36.7). The HA has to bend over and expose hydrophobic fusion-promoting
several functions: it is the viral attachment protein, binding regions of the protein. The viral envelope then fuses with
to sialic acid on epithelial cell-surface receptors; it promotes the endosome membrane. The proton channel formed by
fusion of the envelope to the cell membrane at acidic pH; it the M2 protein promotes acidification of the envelope con-
hemagglutinates (binds and aggregates) human, chicken, tents to break the interaction between the M1 protein and
and guinea pig red blood cells; and it elicits the protective the NP, allowing uncoating and delivery of the nucleocap-
neutralizing antibody response. There are 18 different sub- sid into the cytoplasm.
types of HA designated H1, H2, …, H18. The HA undergoes
minor (“drift”) and major (“shift”) changes in receptor spec- Unlike most RNA viruses, the influenza nucleocapsid
ificity and antigenicity. Shifts occur only with influenza travels to the nucleus, where it is transcribed into messen-
A virus. ger RNA (mRNA). The transcriptase (PA, PB1, and PB2)
uses host cell mRNA as a primer for viral mRNA synthe-
The NA glycoprotein forms a tetramer and has enzyme sis. In so doing, it steals the methylated cap region of the
activity. The NA cleaves the sialic acid on glycolipids and RNA, which is the sequence required for efficient binding
glycoproteins, including the cell receptor. Cleavage of the to ribosomes. This activity of PB2 is a target for baloxavir
sialic acid on newly synthesized HA and cellular glycopro- marboxil. All the genomic segments are transcribed into
teins limits binding and prevents clumping of the HA and 5′-capped, 3′-polyadenylated (polyA) mRNA for individual
virions and facilitates the release of virus from infected cells, proteins except the segments for the M1, M2, and NS1, NS2
making NA a target for antiviral drugs, including zana- proteins, which are each differentially spliced (using cellu-
mivir (Relenza) and oseltamivir (Tamiflu). The NA of lar enzymes) to produce two different mRNAs. The mRNAs
influenza A virus also undergoes antigenic shift, and the different are translated into protein in the cytoplasm. The HA and
NAs are designated N1, N2, …, N11. NA glycoproteins are processed by the endoplasmic reticu-
lum and the Golgi apparatus. The M2 protein inserts into
The M1, M2, and NP proteins are type specific; therefore cellular membranes. Its proton channel prevents acidifica-
they are used to differentiate influenza A from B or C viruses. tion of Golgi and other vesicles, preventing acid-induced
The M1 proteins line the inside of the virion and promote folding and inactivation of the HA within the cell. The HA
assembly. The M2 protein forms a proton channel in and NA are then transported to the cell surface, in which
membranes and promotes uncoating and viral release. The the HA protein is activated by cleavage by host proteases.
M2 of influenza A is a target for the antiviral drugs aman-
tadine and rimantadine.

Viral replication begins with the binding of HA to sialic
acid on cell-surface glycoproteins (Fig. 49.2). The different

49  •  Orthomyxoviruses 493

Positive-sense RNA templates for each segment are pro- Key: Antibody Future protection
duced, and the negative-sense RNA genome is replicated
in the nucleus. The genomic segments associate with poly- Major contributors to T-cell
merase and NP proteins to form nucleocapsids, and the NS2 pathogenesis of responses
protein facilitates the transport of ribonucleocapsids into influenza syndrome
the cytoplasm, where they interact with the M1 protein–
lined plasma membrane sections containing M2, HA, and Immune response
NA. The virus buds selectively from the apical (airway) sur-
face of the cell as a result of the preferential insertion of the Less frequent outcomes
HA in this membrane. The virus is released approximately
8 hours after infection.  Interferon
induction
Pathogenesis and Immunity
Aerosol Replication Desquamation of Influenza
Influenza initially establishes a local upper respiratory tract inoculation in respiratory mucus-secreting syndrome
infection (Fig. 49.3; Box 49.2). To do so, the virus first tar- of virus tract and ciliated cells
gets and kills mucus-secreting, ciliated, and other epithelial
cells, causing the loss of this primary defense system. With a Pneumonia Secondary bacterial infection
lack of ciliated epithelium, swallowed oral and nasal bacte-
ria (e.g., Staphylococcus aureus) cannot be expelled and may Primary viral pneumonia
cause pneumonia. NA facilitates the development of the
infection by cleaving sialic acid (neuraminic acid) residues CNS, muscle
of the mucus, providing access to tissue. Preferential release involvement
of the virus at the apical surface of epithelial cells and into
the lung promotes cell-to-cell spread and transmission to Fig. 49.3  Pathogenesis of influenza A virus. The symptoms of influ-
other hosts. In the lower respiratory tract, the infection can enza are caused by viral pathologic and immunopathologic effects, but
cause severe desquamation (shedding) of bronchial or alve- the infection may promote secondary bacterial infection. CNS, Central
olar epithelium down to a single-cell basal layer or to the nervous system.
basement membrane.
BOX 49.2  Disease Mechanisms of Influenza
In addition to compromising the mucociliary defenses of A and B Viruses
the respiratory tract, influenza infection promotes bacterial
adhesion to the epithelial cells. Pneumonia may result from Virus infects the upper and lower respiratory tract.
a viral pathogenesis or from a secondary bacterial infection. Systemic symptoms are caused by the interferon and cytokine
Influenza may also cause a transient or low-level viremia
but rarely involves tissues other than the lung. response to the virus. Local symptoms result from epithelial cell
damage, including ciliated and mucus-secreting cells.
Influenza infection is an excellent inducer of interferon Interferon and cell-mediated immune responses (natural killer
which is protective. Interferon α and λ promote antiviral and T cells) are important for immune resolution and immu-
activity. The NS1 protein can counteract some of its action. nopathogenesis.
Systemic interferon and cytokine responses peak at 3 to 4 Infected people are predisposed to bacterial superinfection
days postinfection. Type I interferon is responsible for the sys- because of the loss of natural barriers and exposure of binding
temic flulike symptoms. This is almost the same time when sites on epithelial cells.
virus is present in nasal washes. Recovery caused by innate Antibody is important for future protection against infection and
protections often precedes detection of antibody in serum or is specific for defined epitopes on HA and NA proteins.
secretions. T-cell responses are important for effecting recov- The HA and NA of influenza A virus can undergo major (reassort-
ery and immunopathogenesis, but preexisting antibody, ment: shift) and minor (mutation: drift) antigenic changes
including vaccine-induced antibody, can prevent disease. As to ensure the presence of immunologically naive susceptible
for measles, influenza infection depresses macrophage and people.
T-cell function, hindering immune resolution. Influenza B virus undergoes only minor antigenic changes.

Protection against reinfection is primarily associated HA, Hemagglutinin; NA, neuraminidase.
with the development of neutralizing antibodies to HA, but
antibodies to NA are also protective. The antibody response The symptoms and time course of the disease are deter-
is specific for each strain of influenza, whereas the cell- mined by the extent of viral and immune killing of epi-
mediated immune response is more general and is capable thelial tissue and cytokine action. Influenza is normally a
of reacting to influenza strains of the same type (influenza self-limited disease that rarely involves organs other than
A or B virus). Antigenic targets for T-cell responses include the lung. The acute onset of many of the classic flu symp-
peptides from HA and from the nucleocapsid proteins (NP, toms (e.g., fever, malaise, headache, and myalgia) is associ-
PB2) and M1 protein. The NP, PB2, and M1 proteins differ ated with interferon and cytokine induction. Virus production
considerably for influenza A and B but minimally between may be controlled within 4 to 6 days postinfection, but tis-
strains of these viruses; hence T-cell memory may provide sue damage caused by innate and immune inflammatory
future protection against infection by a strain different from responses continues. Repair of the compromised tissue is
the immunizing strain. initiated within 3 to 5 days of the start of symptoms but
may take as long as a month or more, especially for elderly
people. The time course of influenza virus infection is illus-
trated in Fig. 49.4. 

494 SECTION 5  •  Virology

Pathologic changes evident TABLE 49.2  Influenza Pandemics Resulting from
in respiratory tract Antigenic Shift

Interferon Pathogenesis Year of Pandemic Influenza A Subtype
induction
Laboratory 1918 H1N1
Cell-mediated immune detection 1947 H1N1
response above baseline
1957 H2N2; Asian flu strain
Virus in respiratory
secretions 1968 H3N2; Hong Kong flu strain

Rise in virus-specific 1977 H1N1; Russian
antibody
1997, 2003 H5N1: China, avian

2009 H1N1, swine flu

Symptomatic Convalescence Antigenic shifts occur infrequently, but the pandemics
influenza-like disease they cause can be devastating (Table 49.2). For example,
Clinical the prevalent influenza A virus in 1947 was the H1N1 sub-
Secondary bacterial disease type. In 1957, there was a shift in both antigens, resulting
infection in an H2N2 subtype. H3N2 appeared in 1968, and H1N1
reappeared in 1977. The reappearance of H1N1 put the
Incubation population younger than age 30 years at risk of disease.
Prior exposure and an anamnestic antibody response pro-
0 2 4 6 8 10 12 14 28 tected members of the population older than 30 years.
Days
The genetic diversity of influenza A is fostered by its seg-
Inoculation of mented genomic structure and ability to infect and replicate
respiratory tract in humans and many animal species (zoonosis), including
birds and pigs. Hybrid viruses are created by coinfection of
Fig. 49.4  Time course of influenza A virus infection. The classic “flu a cell with different strains of influenza A virus, allowing
syndrome” occurs early. Later, pneumonia may result from bacterial the genomic segments to randomly associate into new viri-
pathogenesis, viral pathogenesis, or immunopathogenesis. ons. An exchange of the HA glycoproteins may generate a
new virus that can infect an immunologically naive human
Epidemiology population. Fig. 49.5 depicts the origins of the pandemic A/
California/04/2009/H1N1 virus through multiple reas-
Strains of influenza A virus are classified by the following sortments of human, avian, and pig influenza viruses,
characteristics: resulting in a virus that was able to infect humans (Clinical
1. Type (A) Case 49.1).
2 . Host of origin (chicken, swine, equine), if not human
3 . Place of original isolation Influenza infection is spread readily via small airborne
4 . Strain number droplets expelled during talking, breathing, and coughing.
5. Year of original isolation People are most contagious in the first 3 to 4 days of illness,
6. HA and NA type but the period may extend to a week after becoming sick.
Low humidity and cool temperatures stabilize the virus,
For example, a current strain of influenza virus might and close proximity during the winter months promotes
be designated A/duck/Alberta/35/76 (H1N1), meaning its spread. The virus can also survive on countertops for as
that it is an influenza A virus that was first isolated from long as a day.
a duck in Alberta in 1976 and contains HA (H1) and NA
(N1) antigens. The most susceptible population is children, and
school-aged children are most likely to spread the infec-
Strains of influenza B are designated by (1) type, (2) geog- tion. Contagion precedes symptoms and lasts for a long
raphy, (3) strain number, and (4) year of isolation (e.g., B/ time, especially in children. Children, immunosup-
Singapore/3/64) but without specific mention of HA or NA pressed people (including pregnant women), the elderly,
antigens because influenza B does not undergo antigenic and people with heart and lung ailments (including
shift or pandemics as does influenza A. smokers) are at highest risk for more serious disease,
pneumonia, or other complications of infection. More
Minor antigenic changes resulting from mutation than 90% of mortalities occur in patients who are older
of the HA and NA genes are called antigenic drift. This than 65 years, but rapidly progressing lethal bacterial
process occurs every 2 to 3 years, causing local outbreaks pneumonias secondary to influenza can occur in young
of influenza A and B infection. Major antigenic changes healthy individuals.
(antigenic shift) result from reassortment of genomes
among different strains, including animal strains. This pro- Influenza A viruses are also spread to humans by aero-
cess occurs only with the influenza A virus. Such changes are sols from animals and in the feces of domestic and wild
often associated with the occurrence of pandemics. In con- water fowl. Because of its high population density and close
trast to influenza A, influenza B is predominantly a human virus proximity of humans, pigs, chickens, and ducks, China
and does not undergo antigenic shift. is often the breeding ground for new reassortant viruses

49  •  Orthomyxoviruses 495

North American S1 S4 S7
Avian S2 S5 S8
A1 A5 S3 S6
A2 A6
A3 A7 Human H3N2 Swine
A4 A8 H1 H5
H2 H6 Previous Previous
H3 H7 reassortants reassortants
H4 H8

A1 H4 S7 A1 S4 S7 ES1 ES4 ES7
H2 S5 S8 H2 S5 S8 ES2 ES5 ES8
A3 H6 A3 H6 ES3 ES6
Triple reassortment Swine H1N2
Eurasian swine
H1N1/H3N2

A1 S4 ES7
H2 S5 S8
A3 ES6

A1: PB2
H2: PB1
A3: PA
S4: H1
S5: NP
ES6: N1
ES7: M
S8: NS
Human virus
A/California 04/2009

Fig. 49.5  Generation of A/California/04/2009 (H1N1) pandemic swine flu by multiple reassortments of genomic segments of influenza A virus. The
pandemic H1N1 virus arose from the mixing of a triple reassortment of avian, human, and swine viruses with two other swine viruses, each of which
was also generated by reassortment between swine, human, and other influenza viruses. This new virus emerged in the spring of 2009 (out of season)
in Mexico but was first identified in California.

Clinical Case 49.1  Pandemic Influenza A/California/04/2009 (H1N1)

In the spring of 2009, a new amantadine- and rimantadine- other outbreaks, this virus had a tendency to affect younger
resistant reassortant H1N1 virus was detected in a 10-year-old and healthier individuals. Of interest, many people older than
patient in California and proceeded to cause a pandemic. As 60 years had cross-reactive antibody resulting from prior ex-
indicated in Fig. 49.5, the virus is a triple-triple reassortant posure to an H1N1 influenza virus. Neuraminidase inhibitors
of multiple swine, avian, and human influenza viruses. The were made available for prophylaxis, but detection of resistant
virus originated in Mexico and rapidly spread as many cases strains became a concern. By September, a vaccine had been
went unrecognized because of the unseasonal nature of the developed, approved, and manufactured and was available for
outbreak. Up to 25,000 deaths occurred worldwide, primar- distribution on a prioritized basis, and then it was administered
ily in people between the ages of 22 months and 57 years. with the seasonal influenza vaccine. The pandemic was de-
People with chronic medical conditions, especially pregnant clared over by August 2010, and the H1N1 virus joined H3N2
women, were at greatest risk to complications, but unlike and influenza B as a seasonal virus.

and the source of many of the pandemic strains of influ- was isolated from at least 18 humans and caused six deaths
enza. Inhalation of large amounts of virus (shared living in Hong Kong (Clinical Case 49.2). Although primarily a
environments) can lead to infection, killing of cells of the virus of poultry, close contact has caused human infection
lower human lung, and serious disease. In 1997, a highly with H7N9. Outbreaks in 2013 and 2014 of lethal H7N9
pathogenic avian influenza virus (HPAIV) (H5N1) strain disease in China have been traced to chicken-to-human

496 SECTION 5  •  Virology BOX 49.3  Epidemiology of Influenza A and
B Viruses
Clinical Case 49.2  H5N1 Avian
Influenza Disease/Viral Factors

The first case of H5N1 avian influenza in a human Virus has a large, enveloped virion that is easily inactivated by dry-
was described by Ku and Chan (J Paediatr Child Health ness, acid, and detergents.
35:207–208, 1999). After a 3-year-old boy from China
developed a fever of 40° C and abdominal pain, he was Segmented genome facilitates major genetic changes, especially
given antibiotics and aspirin. On the third day, he was on hemagglutinin and neuraminidase proteins.
hospitalized with a sore throat, and his chest radiograph
demonstrated bronchial inflammation. Blood studies Influenza A infects many vertebrate species, including other mam-
showed a left shift with 9% band forms. On the sixth day, mals and birds.
the boy was still febrile and fully conscious, but on the
seventh day, his fever increased, he was hyperventilating, Coinfection with animal and human strains of influenza A can
and his blood oxygen levels decreased. A chest radiograph generate very different virus strains by genetic reassortment.
indicated severe pneumonia. The patient was intubated.
On the eighth day, the boy was diagnosed with fulminant Transmission of virus often precedes symptoms. 
sepsis and ARDS. Therapy for ARDS and other attempts
to improve oxygen uptake were unsuccessful. He was Transmission
treated empirically for sepsis, herpes simplex virus infec-
tion (acyclovir), methicillin-resistant Staphylococcus au- Virus is spread by inhalation of small aerosol droplets expelled
reus (vancomycin), and fungal infection (amphotericin B), during talking, breathing, and coughing.
but his condition deteriorated further, with disseminated
intravascular coagulation and liver and renal failure. Virus likes a cool, less humid atmosphere (e.g., winter heating
He died on the 11th day. Laboratory results indicated season).
elevated influenza A antibody on the eighth day, and
influenza A was isolated from a tracheal isolate taken Virus is extensively spread by schoolchildren. 
on the ninth day. The isolate was sent to the Centers for
Disease Control and Prevention and elsewhere, in which Who Is at Risk?
it was typed as H5N1 avian influenza and named A/Hong
Kong/156/97 (H5N1). The child may have contracted Seronegative people
the virus while playing with pet ducklings and chickens Adults: classic flu syndrome.
at his kindergarten. Although the H5N1 virus still has Children: asymptomatic to severe respiratory tract infections.
difficulty infecting humans, this case demonstrates the High-risk groups: elderly and immunocompromised people, peo-
speed and severity of the respiratory and systemic mani-
festations of avian influenza H5N1 disease. ple in nursing homes or with underlying cardiac or respiratory
ARDS, Acute respiratory distress syndrome problems (including asthma sufferers and smokers). 

Geography/Season

Worldwide occurrence. Epidemics are local; pandemics are world-
wide.

Disease is more common in winter. 

Modes of Control

Antiviral drugs have been approved for prophylaxis or early treat-
ment.

Killed and live vaccines contain predicted yearly strains of influ-
enza A and B viruses.

transmission in live poultry markets. Outbreaks of avian Clinical Syndromes
influenza require destruction of all potentially infected
birds, such as the 1.6 million chickens in Hong Kong, to Depending on the degree of immunity to the infecting strain
destroy the potential source of the virus. of virus and other factors, disease may range from asymp-
tomatic to severe (Box 49.4). Patients with underlying
The changing antigenic nature of influenza ensures a cardiorespiratory disease, people with immune deficiency
large proportion of immunologically naive susceptible people (even that associated with pregnancy), the elderly, and
(especially children) in the population each year (Box 49.3). smokers are more prone to have a severe case.
An influenza outbreak can be readily detected from increased
absenteeism in schools and at work and the number of emer- After an incubation period of 1 to 4 days, the “flu syn-
gency department visits. The influenza season for the North- drome” begins with a brief prodrome of malaise and head-
ern Hemisphere is usually from late fall to early spring. ache lasting a few hours. The prodrome is followed by the
abrupt and intense onset of a high fever, chills, severe
Extensive surveillance of influenza A and B outbreaks myalgias, loss of appetite, weakness and fatigue, sore throat,
is conducted to identify new strains that should be incor- runny or stuffy nose, and usually a nonproductive cough.
porated into new vaccines. The prevalence of a particu- The fever persists for 3 to 8 days, and unless a complication
lar strain of influenza A or B virus changes each year and occurs, recovery is complete within 7 to 10 days. Influenza
reflects the particular immunologic naïveté of the popula- in young children (<3 years) resembles other severe respi-
tion at that time. In 2018, influenza A (H3N2) was the pre- ratory tract infections, potentially causing bronchiolitis,
dominant strain and caused severe illness, particularly in croup, otitis media, vomiting, and abdominal pain, accom-
children and elderly individuals (≥65 years). Surveillance panied rarely by febrile convulsions (Table 49.3). Influenza
also extends into the animal populations because of the pos- B disease is similar to influenza A disease.
sible presence of recombinant animal influenza A strains
that can cause human pandemics. 

49  •  Orthomyxoviruses 497

Influenza may directly cause pneumonia, but it more multiorgan failure, and Reye syndrome. The inflamma-
commonly promotes a secondary bacterial superinfec- tory response can trigger sepsis and exacerbate asthma and
tion that leads to bronchitis or a rapidly progressing and chronic heart disease. Reye syndrome is an acute encepha-
potentially lethal pneumonia. The tissue damage caused litis that affects children and occurs after a variety of acute
by progressive influenza virus infection of alveoli can be febrile viral infections, including varicella and influenza B
extensive, leading to hypoxia and bilateral pneumonia. and A diseases. Children given salicylates (aspirin) are at
Secondary bacterial infection usually involves Streptococ- increased risk for this syndrome. In addition to encepha-
cus pneumoniae, Haemophilus influenzae, or S. aureus. In lopathy, hepatic dysfunction is present. The mortality rate
these infections, sputum usually is produced and becomes may be as high as 40%. 
purulent.
Laboratory Diagnosis
The inflammatory responses initiated by influenza dis-
ease may cause myocarditis, myositis (inflammation of The diagnosis of influenza is usually based on the character-
muscle), encephalopathy, postinfluenza encephalitis, istic symptoms, the season, and the presence of the virus in
the community. Influenza viruses are obtained from respi-
BOX 49.4  Clinical Summary ratory secretions taken early in the illness. Rapid techniques
detect and identify the influenza genome or antigens of the
Influenza A: A 70-year-old woman has rapid onset of fever with virus (Table 49.4). Rapid antigen assays (<30 minutes) can
headache, myalgia, sore throat, and nonproductive cough. The detect and distinguish influenza A and B. Reverse transcrip-
disease progresses to pneumonia with bacterial involvement. tase-polymerase chain reaction (RT-PCR) and multiplex
There is no history of recent immunization with influenza A RT-PCR assays can detect and distinguish influenza A and
vaccine. Her husband is treated with amantadine or a neurami- B, different strains (e.g., H5N1), other respiratory viruses,
nidase inhibitor. and bacteria. Enzyme immunoassay or immunofluores-
cence can be used to detect viral antigen in exfoliated cells,
TABLE 49.3  Diseases Associated With Influenza Virus respiratory secretions, or cell culture. Immunofluorescence
Infection or inhibition of hemadsorption or hemagglutination (hem-
agglutination inhibition) with specific antibody (see Fig.
Disorder Symptoms 39.6) can also detect and distinguish different influenza
strains.
Acute influenza infection in Rapid onset of fever, malaise, myalgia,
adults sore throat, and nonproductive The virus can be isolated in primary monkey kidney
cough cell cultures or the Madin-Darby canine kidney cell line.
Acute influenza infection in Although cytolytic, the cytopathologic effects of the
children Acute disease similar to that in adults virus are often difficult to distinguish but may be noted
but with higher fever, gastrointes- within as few as 2 days (average, 4 days). Before the
Complications of influenza tinal tract symptoms (abdominal cytopathologic effects develop, the addition of guinea pig
virus infection pain, vomiting), otitis media, myosi- erythrocytes may reveal hemadsorption (adherence of
tis, and more frequent croup these erythrocytes to HA-expressing infected cells) (see
Fig. 39.5). Addition of influenza virus–containing fluids
Primary viral pneumonia to erythrocytes promotes formation of a gel-like aggre-
Secondary bacterial pneumonia gate resulting from hemagglutination. Hemaggluti-
Myositis and cardiac involvement nation and hemadsorption are not specific to influenza
Neurologic syndromes: viruses; parainfluenza and other viruses also exhibit
Guillain-Barré syndrome these properties. 
Encephalopathy
Encephalitis
Reye syndrome

TABLE 49.4  Laboratory Diagnosis of Influenza Virus Infection

Test Detects
Presence of virus; limited cytopathologic effects
Cell culture in primary monkey kidney or Madin-Darby canine kidney cells Presence of hemagglutinin protein on cell surface
Hemadsorption to infected cells Presence of virus in secretions
Type and strain of influenza virus or specificity of antibody
Hemagglutination Identification of influenza type and strain
Influenza virus and antigens in respiratory secretions or tissue culture
Hemagglutination inhibition Seroepidemiology

Antibody inhibition of hemadsorption Detection and identification of influenza type and strain

Immunofluorescence, ELISA

Serology: hemagglutination inhibition, hemadsorption inhibition, ELISA,
immunofluorescence, complement fixation

Genomics: rapid viral RNA detection assays, RT-PCR, multiplex RT-PCR,
sequence analysis

ELISA, Enzyme-linked immunosorbent assay; RT-PCR, reverse transcriptase-polymerase chain reaction.

498 SECTION 5  •  Virology

Treatment, Prevention, and Vaccination is routinely recommended for all individu-
Control als and especially persons older than 50 years, health care
workers, pregnant women who will be in their second or
Hundreds of millions of dollars are spent on acetaminophen, third trimester during flu season, people living in a nurs-
antihistamines, and similar drugs to relieve the symptoms ing home, people with chronic pulmonary heart disease,
of influenza. The antiviral drug amantadine and its analog and others at high risk. Pain at the injection site may result
rimantadine target the M2 protein and inhibit an uncoat- from an Arthus reaction to an annual immunization. Many
ing step of the influenza A virus but do not affect the influenza health care facilities require their personnel to be vacci-
B and C viruses. These drugs are no longer recommended in nated. Persons with serious allergies to eggs can get the
the United States due to extensive resistance. Zanamivir, recombinant or tissue culture–generated vaccines or the
oseltamivir, and peramivir inhibit both influenza A and live vaccine.
B as enzyme inhibitors of NA. Without NA, the HA of the
virus binds to sialic acid on other glycoproteins and viral Although the efficacy of the influenza vaccines may not
particles to form clumps or stick to the cell surface, prevent- be 100% for all the viruses, they still reduce the incidence
ing virus release. Zanamivir is inhaled, whereas oseltamivir and risk for severe disease. According to the CDC, more
is taken orally as a pill. These drugs are effective for prophy- than 5 million flu illnesses and 85,000 hospitalizations
laxis and for treatment during the first 24 to 48 hours after were prevented in the United States in the 2016–2017 sea-
the onset of influenza illness. Treatment cannot prevent son because of vaccination.
the later host-induced immunopathogenic stages of the
disease. Naturally resistant or mutant strains are selected Newer approaches to influenza vaccines include RNA
when antiviral prophylaxis is used and are becoming more and DNA vaccines and universal influenza A vaccines.
prevalent. Stockpiles of oseltamivir have been developed in RNA and DNA vaccines can be generated from genome
many countries as a rapid response to an outbreak and an sequences within weeks of an outbreak and from smaller
alternative to vaccines. Baloxavir marboxil is a new Food and possibly mobile facilities. Molecular regions of the HA
and Drug Administration (FDA) approved antiinfluenza protein involved in fusion are being investigated for univer-
drug that targets the activity of the viral polymerase (PB2) sal influenza A vaccines.
that snatches the 5′ cap of cellular mRNAs and uses it as a
primer for transcription of viral mRNAs. THOGOTOVIRUSES
Thogotoviruses have six or seven genomic segments and
The airborne spread of influenza is almost impossible to are arboviruses capable of infecting humans and other ver-
limit. However, the best way to control the virus is through tebrates. They are spread primarily by ticks but also possibly
immunization. Natural immunization, which results from by mosquitoes. In 2014, a previously healthy man died of a
prior exposure, is protective for long periods. Vaccines rep- tick-borne disease that resembled Rocky Mountain spotted
resenting the “strains of the year” and antiviral drug pro- fever. It is named the Bourbon virus after Bourbon, Kansas,
phylaxis can also prevent infection. in which it was isolated.

The inactivated subunit influenza vaccines are a mix-   For a case study and questions see StudentC­ onsult.com
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