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VIROLOGY CASE-BASED SMALL GROUP DISCUSSION
SESSION 29
EXANTHEMS
THURSDAY, APRIL 19, 2001
10:30AM – 12:30PM
Reading Assignment:
Sherris Medical Microbiology, Chapters 33, 37, 42
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CASE HISTORY 1
The patient was an 8 year-old female who presented to her pediatrician with fever and a diffuse rash (onset
3 days ago). On examination she was irritable but alert. She had fever for the first two days of the rash
but since then has not had fever. She had diffuse vesiculopustular lesions over her entire body, with some
areas showing older, crusted lesions. The liver and spleen were not enlarged. Her pediatrician examined
her and confirmed a diagnosis of chickenpox. The patient's mother expressed concern about her other
child, a 3 year old boy currently undergoing chemotherapy.
BACKGROUND
The finding of generalized vesicular, pustular, and crusted skin lesions at various stages of evolution
is characteristic of varicella. This illness is due to primary infection with varicella-zoster virus
(VZV), which is a member of the herpesvirus group. These are enveloped, double-stranded DNA
viruses.
STUDY QUESTIONS
1.
If the patient developed a complication requiring hospital admission, what type of isolation would
be required?
Patients with VZV infection, especially chickenpox, are very contagious. Persons without a
history of chickenpox are susceptible. Chickenpox in adults can be more severe, with an
increased incidence of complications. Hospitalized patients with chickenpox must be in
negative airflow respiratory isolation, and strict infection control measures regarding skin
contact (hand-washing, use of gloves and gowns, etc.) must be implemented.
Hospital workers without a history of chickenpox or those already known to be seronegative
for VZV should not come into contact with these patients.
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2.
What is known about the pathogenesis of the infection?
3.
The pediatrician made a clinical diagnosis. Should laboratory tests be run to confirm the
diagnosis?
No. The diagnosis of chickenpox is often made on the basis of clinical findings alone. For
laboratory confirmation, the virus can be isolated but this is rarely requested because the
virus grows slowly in tissue culture, often requiring 2 to 3 weeks for isolation. Rapid and
sensitive immunofluorescence assays are available and can be performed on scrapings taken
from vesicular lesions. A Tzanck test can be performed, but is insensitive. The Tzanck test
detects multinuclear giant cells, a cell type characteristically seen with VZV and HSV
infections.
4.
Are there any effective anti-viral agents that act against this virus?
Acyclovir is beneficial in treating varicella in immunocompromised children with varicella,
and may be useful in adults and selected immunocompetent children with varicella.
Acyclovir (ACV) is a nucleoside analogue of guanosine. ACV has selective action against
those herpesviruses that encode a Thymidine Kinase (TK). The viral Thymidine Kinase
activates the drug by phosphorylation, and host cell enzymes complete the process to the
triphosphate form. No initial phosphorylation occurs in uninfected cells, and thus there is
no active drug to inhibit cellular DNA synthesis or to cause toxicity.
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Activation of acyclovir (acycloguanosine) in herpes simplex viral infected cells.
Acyclovir is converted to acycloguanosine monophosphate (acyclovir GMP) by the
herpes-specific viral thymidine kinase and then to acyclovir GTP by cellular
kinases.
In herpesvirus infected cells, ACV triphosphate competes with guanosine triphosphate and causes
termination of the growing viral DNA chain because there is no 3'-hydroxyl group on the ACV
molecule to allow chain elongation. The selectivity and minimal toxicity of ACV is also due to its
100-fold greater utilization by the viral DNA polymerase than by cellular DNA polymerase.
Mutations in either the herpesvirus TK or polymerase can generate ACV resistant strains. These
resistant strains are less virulent but can still cause disease in immunocompromised patients.
Activity of ACV against herpesviruses directly correlates with the capacity of the virus to produce
TK. The order of TK induction and ACV sensitivity is:
HSV-1 and HSV-2 > VZV>>EBV>>>CMV
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5.
Are there any long term consequences associated with this viral infection? What bacterial
superinfections may occur with varicella? What are other complications of varicella?
Zoster (shingles) can occur later in life as a result of reactivation of VZV from latent
infection in ganglia. Typically, skin lesions appear in a dermatomal distribution innervated
by the specific dorsal root or extramedullary cranial ganglia where VZV had been latent.
Pain often occurs with the rash and can persist even after the skin lesions heal. This
complication is more common in elderly patients. Rarely, skin lesions disseminate beyond
the primary dermatome involved. In immunosuppressed patients, however, complicating
viremia can occur with dissemination to extradermatomal skin sites, lungs, liver, and
central nervous system. This latter condition is called disseminated zoster. Group A
streptococcus and staphylococcus aureus may cause superinfections following varicella,
including osteomyelitis, myositis, bacteremias, pneumonia and toxic shock syndrome.
6.
A new vaccine against VZV is available. Describe it. Should the 3 year-old boy receive the
vaccine or any other therapy? What are the current recommendations for the use of the vaccine?
The VZV vaccine was licenced in March, 1995. If the boy was not vaccinated prior to his
chemotherapy and has not previously had varicella, he should receive VZIG (varicella
immune globulin) to help neutralize the virus infection.
Vaccine is generally not given to immunosuppressed patients; however, it may be available
through a research protocol to children with ALL who have been in remission for 1 year.
7.
Two weeks later, the patients mother who did not have a history of chickenpox and is 39 weeks
pregnant, develops varicella. She develops respiratory distress and is admitted. The next day she
delivers the infant. What should be done for the baby and mother?
The mother should receive acyclovir. The baby should receive VZIG (varicella immune
globulin) to try to neutralize the viral infection. If the treatment is successful, the baby may
be susceptible to VZV in later life. VZIG is recommended to infants whose mothers have
onset of chickenpox 5 days before and 2 days after delivery (baby will have been viremic
without adequate time for mother to give baby VZV antibody).If the infant develops
varicella despite VZIG, acyclovir should be used to treat the baby because of the high
morbidity and mortality of these infections.
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8.
Two weeks after that, a nurse who cared for the mother develops chickenpox. She thought that
she had the illness, but questioned her mother who reported that she had not. The nurse had been
at work for the past 2 days and had been on the Pediatric ward, caring for children with
hematologic malignancies. What action should be taken? What could have been done to prevent
this problem?
All exposed susceptible immunocompromised children should receive VZIG. This problem
could have been prevented if a history of prior varicella were taken on all employees and a
VZV IgG titer performed on those without a history of varicella to check for immunity. All
non-immune personnel should be vaccinated with the live-attenuated vaccine.
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CASE HISTORY 2
The patient is a 3 year-old female who has had a temperature of 101.5o F for two days. On the second day
of fever, she developed a lace-like rash on the arms and trunk, and her cheeks became intensely red, with a
"slapped cheek" appearance characteristic of infection with Parvovirus B19. The fever resolved on the
third day, and the rash faded over the next week. She has continued to be playful during the illness and is
drinking liquids well.
BACKGROUND
The "slapped cheek" appearance is typical of parvovirus B19 infection. Parvovirus B19 is a single
stranded DNA virus with no envelope.
In addition to asymptomatic infection, parvovirus B19 can cause erythema infectiosum. Erythema
infectiosum (fifth disease) is a benign rash of childhood. Infected persons develop fever and facial
erythema described as a "slapped cheek" appearance. A lacy reticular rash may occur on the trunk
and extremities. Other clinical syndromes caused by parvovirus B19 are an acute symmetrical
peripheral arthritis in adults, TAC (transient aplastic crises) in patients with hemoglobinopathies
(e.g., sickle cell disease), chronic anemia in immunodeficient patients, and intrauterine infection and
fetal death.
STUDY QUESTIONS
1.
How is the virus transmitted? Is the child contagious?
Parvovirus B19 can be transmitted by the respiratory route and by transfusions. (By early
adulthood, 30 to 60% of the population have acquired parvovirus B19 infection). This child
is no longer infectious, but likely exposed all household contacts prior to the development of
the rash.
2.
What is known about the pathogenesis of the infection?
Parvovirus B19 infects and lyses erythroid precursor cells. This can lead to transient
aplastic crises (TAC) in patients with hemolytic states. Bone marrow examinations in these
patients characteristically show erythroid hypoplasia. The duration of TAC is usually 7 to
10 days. Fetal death appears to be caused by severe anemia. Fetal infections may not
always be fatal. There is no association of parvovirus B19 with congenital anomalies.
Patients with TAC have a high virus load and are very contagious. Patients with Fifth
disease are experiencing an immune-mediated reaction to the virus following viremia, and
are not contagious at the time of the rash.
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3.
This patient didnt even go to the doctor. What other parvovirus B-19 infected patients are more
likely to be seen in the clinic or hospital? Are these patients contagious?
Patients are generally contagious at the initial (prodrome) phase of the illness, not when the
rash is present. The clinical consequences of this effect are generally trivial, unless the
patient is already compromised by a chronic hemolytic process, such as sickle cell disease or
thalassemia, in which maximal erythropoiesis is continually needed to counterbalance
increased destruction of circulating erythrocytes. Primary infection by parvovirus B19 in
such patients often produces an acute, severe, sometimes fatal anemia manifested as a rapid
fall in red blood cell counts and hemoglobin. This may present initially with no clinical
symptoms other than fever, and is commonly referred to as transient aplastic crisis. These
patients are highly contagious and should be placed in respiratory isolation.
Immunocompromised patients, such as individuals with AIDS, sometimes have difficulty
clearing the virus and develop persistent anemia with reticulocytopenia. Parvovirus B19
has also been occasionally implicated as a cause of persistent bone marrow failure and an
acute hemophagocytic syndrome.
Serious complications are extremely rare; however active transplacental transmission of
parvovirus B19 can occur during primary infections in pregnancy, sometimes resulting in
stillbirth of fetuses that are profoundly anemic. The progress can be so severe that hypoxic
damage to the heart, liver, and other tissues leads to extensive edema (hydrops fetalis). The
frequency of such adverse outcomes is as yet undetermined.
4.
If you had to confirm the diagnosis, how could you do it?
The diagnosis can be made by demonstrating parvovirus B19 IgM serum antibodies in the
patient with Fifth disease or by the presence of parvovirus B19 DNA or antigen in the
serum in the patient with aplastic crisis. Histopathologically, eosinophilic intranuclear
inclusions in infected tissues or virus particles seen by electron microscopy can lead to the
diagnosis. Although parvovirus B19 can replicate in bone marrow explant cultures, no
routine virus isolation methods are currently available for diagnostic purposes.
5.
The patients mother is pregnant and expresses concern about her unborn child. What do you tell
her?
She should be informed that parvovirus B19 is a common illness which she likely had as a
child. However, if she does experience a primary infection, her unborn child should be
monitored (by ultrasound) for possible hydrops.
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CASE HISTORY 3
The patient is a 12 month old white female with fever to 104o F daily for 4 days. She has been examined
twice during this time by her pediatrician, who found no abnormalities on physical exam. A blood culture
obtained on the second day of fever was negative for bacterial growth after 2 days. The following morning
the fever abruptly resolved. That evening over a few hours time, the child developed an erythematous
maculopapular rash over the entire body characteristic of infection with HHV-6. She was alert, playful
and taking fluids orally well. The rash faded over the next 2-3 days.
BACKGROUND
Human Herpesvirus Type 6 (Enveloped, double stranded DNA virus).
STUDY QUESTIONS
1.
How is the virus transmitted?
Most likely, it is spread by close personal contact or by the respiratory route.
2.
What is known about the pathogenesis of the infection? Why is this illness often a cause of
emergency room visits?
HHV-6 infection is ubiquitous in young children and results in an appreciable burden on
our health care resources. It accounted for 10% of visits to the emergency department for
acute febrile illness among children in the first 2 years of life, and for 20% of such visits
among those 6 to 12 months old. Its protean manifestations and the lack of means of
diagnosis often resulted in lengthy and costly evaluations and hospitalizations. The actual
human and financial costs, however, cannot be estimated without a better understanding of
the spectrum and consequences of HHV-6 infection.
Most initial HHV-6 infections in normal children are benign, although there are case
reports of occasional complications, including thrombocytopenia, granulocytopenia,
hepatitis, and disseminated infection. The most common complications are central nervous
system manifestations, as has been long suggested by reports associating roseola with
seizures, bulging of the anterior fontanelle, meningoencephalitis, and encephalopathy.
HHV-6 accounted for one third of the febrile seizures evaluated in children two years of age
or less in one emergency department. Seizures occurred in 19.4 % of those 6 months or
older and in 36% of those 12 to 15 months of age -- significantly more often than in agematched children with febrile illnesses not due to HHV-6. The mechanism by which HHV-6
cause central nervous system manifestations remains unclear, but it may involve more than
the high fevers. In several recent Japanese
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reports HHV-6 DNA was detected in the cerebrospinal fluid of infants with roseola
complicated by neurologic symptoms and in eight patients with recurrent febrile
convulsions. These finding raise the possibility of direct invasion of the central nervous
system during the viremic phase of the initial illness, with possible subsequent latency.
3.
Both case studies 2 and 3 are generally diagnosed clinically. List the distinguishing features of
these two infections?
HHV-6 generally presents with higher fever (104o versus 101-102oF) and fever persists for a
longer time (4 days versus 2 days). The rash starts when the fever resolves. The rashes are
distinct, parvo = slapped cheek and lace-like rash on arms and trunk which is present at
the time of the fever. HHV-6 = erythematous rash over the entire body.
4.
Are there any vaccines available to prevent this disease?
No.
5.
Are there any effective anti-viral agents that act against this virus?
No.
6.
Are there any long term consequences associated with this viral infection?
There is latent infection of T cells. HHV-6 appears to be capable of reactivation in
immunosuppressed patients, but the clinical significance of reactivation is unknown.
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CASE HISTORY 4
A 13 month old Hispanic male was brought to the emergency room by his mother for fever and cough.
The family had arrived in Chicago 1 week ago from Mexico where they had previously resided. The child
had fever to 39o C for two days, persistent cough, rhinorrhea and conjunctivitis. Today the mother had
noted a red rash on the neck and behind the ears. There was no rash on the rest of the body. The child had
received immunizations at 2, 4 and 6 months of age but none since then. The physician noted that the
mouth was very red with white spots near the molars the size of coarse salt and made a diagnosis of
measles. Over the next 1-2 days, the rash spread to involve the entire body and then all symptoms resolved
over the next few days. A 4 month old cousin resided with the family.
BACKGROUND
Measles virus in an enveloped single-stranded RNA virus with hemagglutinating and fusion
glycoproteins.
STUDY QUESTIONS
1.
If the patient needed to be admitted, what isolation would be appropriate?
Negative-airflow respiratory isolation. The virus is transmitted by inhalation via large
droplet aerosols or by airborne spread. The highest attack rates have been in childhood,
usually sparing infants less than 6 months of age because of passively acquired antibody;
however, a shift in age-specific attack rates to greater involvement of adolescents and young
adults was observed in the United States in the 1980s. This shift is believed to be
attributable to the influence of immunization: younger children may be better immunized
to limit spread of the virus, whereas older age groups may have missed effective
immunization or earlier infection by the wild virus. A marked decline in measles in the
early 1990s may reflect decreased transmission as increased immunization coverage takes
effect. In the first half of 1993 only 167 cases were reported by US health departments
compared to 13,787 during the same months of 1900, a 99% decrease.
Epidemics tend to occur during the winter and spring in 1- to 3-year cycles and increasingly
are limited to one dose vaccine failures or groups who do not accept immunizations. The
infection rate among exposed susceptible subjects in a classroom or household setting is
estimated at 85%, and more than 95% of those infected become ill. The period of
communicability is estimated to be 3 to 5 days before appearance of the rash to 4 days
afterward.
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2.
What is known about the pathogenesis of the infection?
After implantation in the upper respiratory tract, viral replication proceeds in the
respiratory mucosal epithelium. The effect within individual respiratory cells is profound.
Even though measles does not directly restrict host cell metabolism, susceptible cells are
damaged or destroyed by virtue of the intense viral replicative activity and the promotion of
cell fusion with formation of syncytia. This results in disruption of the cellular cytoskeleton,
chromosomal disorganization, and the appearance of inclusion bodies within the nucleus
and cytoplasm. Replication is followed by viremic and lymphatic dissemination throughout
the host to distant sites, including lymphoid tissues, bone marrow, abdominal viscera, and
skin. Virus can be demonstrated in the blood during the first week after illness onset, and
viruria persists for up to 4 days after the appearance of rash. During the viremic phase,
measles virus infects T and B lymphocytes, circulating monocytes and polymorphonuclear
leukocytes without producing cytolysis. The effect of B lymphocytes has been shown to
suppress immunoglobulin synthesis; in addition, generation of natural killer cell activity
appears to be impaired. There is also evidence that the capability of polymorphonuclear
leukocytes to generate oxygen radicals is diminished, perhaps directly by the virus or by
activated suppressor T cells. This may further explain the enhanced susceptibility to
bacterial superinfections. In addition, virion components can be detected in biopsy
specimens of Koplik's spots and vascular endothelial cells in the areas of skin rash.
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3.
List the clinical signs that the physician focused on to make an accurate clinical diagnosis of
measles. What test could be done to confirm the diagnosis?





Cough
Coryza
Conjunctivitis
Rash
Koplik spots
Clinically, measles is usually so characteristic that it is rarely necessary to perform
laboratory tests to make a diagnosis. Measles virus is difficult to isolate and grow. The
virus can be grown in primary human or monkey cell cultures. Respiratory tract
secretions, urine, blood, and brain tissue are recommended specimens. Respiratory and
blood specimens are best collected during the prodromal stage up to 1 to 2 days after the
appearance of the rash.
Antibody, especially IgM, can be detected when the rash is present and is the best means to
confirm the diagnosis.
4.
Describe the vaccine that is available to prevent this infection. Why wasnt this child vaccinated?
Vaccine coverage in many developing countries (such as Mexico) is poor, and the child is at
about the usual age for vaccine.
A live attenuated measles vaccine in use since 1963 has significantly reduced the incidence
of measles in the United States. The current Schwartz or Moraten attenuated strains of the
original Edmonston B vaccine are currently being used in the United States. Live
attenuated vaccine is given to all children after 12 months of age, in combination with
mumps and rubella vaccine (MMR vaccine). Although successful results are greater than
95%, revaccination is being suggested for children before grade school or junior high
school. (A killed measles vaccine, introduced in 1963 and subsequently discontinued,
provided only short-term immune protection. Recipients of killed vaccine were at risk for
the more serious atypical measles presentation upon infection).
Hospitals in areas experiencing endemic measles may wish to vaccinate or check the
immune status of their employees to decrease the risk of nosocomial transmission.
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5.
Are there any effective anti-viral agents that act against this virus? What is the appropriate
treatment? Should any therapy be prescribed for the 4 month old cousin?
Exposed susceptible individuals who are immunocompromised and <2 year old infants
should be given immune serum globulin to modify their measles infection. This product is
most effective if given within 6 days of exposure. [Babies <2 year old are at a higher risk
for development of SSPE (subacute sclerosing panencephalitis)] There are no effective antiviral agents. Treatment is supportive only.
6.
Are there any long term consequences associated with this viral infection?
Subacute sclerosing panencephalitis (SSPE) is an extremely serious, very late neurological
sequelae of measles that occurs in about 7 in 1,000,000 patients. In SSPE a defective
measles virus persists in the brain and acts as a slow virus. The virus can replicate and
spread directly from cell to cell but is not released. Many months or years after clinical
measles the patient develops changes in personality, behavior, and memory. Myoclonic
jerks, blindness and spasticity follow. Unusually high levels of measles antibodies are found
in the blood and spinal fluid. Eosinophilic inclusion bodies composed of paramyxoviruslike nucleocapsids are present in the brains of patients with SSPE. The incidence of SSPE
has decreased markedly with the success of measles vaccination.
SSPE does not occur with immunization.
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Case 1:
(Chickenpox)
 Slide 1: Rash, low power
 Slide 2: Rash, high power
Case 2:
(Erythema infectiosum)

Slide 3: Rash, slapped-cheeks syndrome
Case 3:
(Roseola)
 Slide 4: Rash involving ear
 Slide 5: Rash on patient’s back
Case 4
(Measles)
 Slide 6:
 Slide 7:
 Slide 8:
 Slide 9:
Erythematous maculopapular rash
Koplik spots on buccal mucosa
Rash on trunk and upper extremities
Rash beginning to clear after about 5 days
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OPTIONAL ARTICTLES FOR CASE STUDIES
1. Recommendations for the use of live attenuated varicella vaccine. (1995),
Committee on Infectious Diseases, PEDIATRICS, Vol 95, No 5:791-796.
2. Varicella – Related Deaths Among Children – United States, 1997. (1998)
3. Human Parvovirus B19: Historical and clinical review. (1987), Joseph Thurn,
Reviews of Infectious Diseases, Vol 10 No 5:1005-1011.
4. Human herpesvirus-6 Infection in children. (1994), Caroline Breese Hall, M.D.,
Christine E. Long, M.P.H., Kenneth C. Schnabel, M.B.A., Mary T. Caserta, M.D.,
Kim M. McIntyre, B.S., Maria A. Constanzo, B.A., Anne Knott, B.A., Stephen
Dewhurst, Ph.D., Richard A. Insel, M.D., and Leon G. Epstein, M.D., The New
England Journal of Medicine, Vol 331, No 7, 432-438.
5. Epidemiologic Notes and Reports, Update: Measles Outbreak – Chicago, 1989.
(1990), Morbidity and Mortality Weekly Report, Vol 39 No 19:317-19, 32526.
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