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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
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
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 patients 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 didnt 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 patients 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.
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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 age-matched 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