Infectious Diseases

Infectious Diseases Immunizations, Pathogens, Organ Systems HHV- 6/7, HSV, PARVOVIRUS B19, HEPATITIS C, ENTEROVIRUSES, RSV

David Turner, M.D.

1

HHV-6, HHV-7, HHV-8 HHV-6 and HHV-7 actually causes infection at a little older age and



more towards the second year of life rather than the first year of life

HHV-6, HHV-7 • •



as we see with HHV-6.

Associated with exanthem subitum and CNS disease

HHV-8 doesn't affect many children. In the past couple of years it has

HHV-7 specific for acute hemiplegia of childhood

been described and identified. It is nearly universally present in all

HHV-8 (Kaposi’s sarcoma herpes virus, KSHV)

cases of Kaposi's sarcoma tissues. It is also found in AIDS related B-

•

cell lymphomas that are based in body cavities, and many of those

Cause of Kaposi's sarcoma

had coinfection with Epstein-Barr virus. It is thought that it may actually be necessary to have the HHV-8 for transformation of a precursor cell that proliferates monoclonally and causes these tumors.

2

HHV-6: Epidemiology and Transmission

Focusing on HHV-6, a little about the epidemiology and transmission. Roseola was first described in 1913. In 1950, transmissibility

 

Year-round, world wide distribution Antibody is present in 85% pregnant women, with active transport across placenta



Newborn antibody levels decline in first 5 months of life (6%). The highest seroprevalence (86%) occurs at 1 year

  

Lower mean titers are present after 40 years (60%) Increased prevalence IgM 6 months to 1 year of age Route of transmission: saliva most likely; no congenital or perinatal syndrome; not transmitted in breast milk

was actually demonstrated although it wasn't until 1986 that the particular virus was identified. We know that we see these infections year-round and there is worldwide distribution. There is antibody present in 85% of pregnant women with active transport across the placenta. Hence, in the very early weeks, the infants are protected. The antibody declines in the first five months of life to a low of 6%, then increases to its highest seroprevalence of 86% at one year. So, by one year of age, most infants have an HHV-6 infection. Titers fall after 40 years of age and there is increased prevalence of IgM six months to one year of age. Saliva is the most likely route of transmission. There is no congenital/perinatal symptom that has been described, and this virus has not been found in breast milk.

3

HHV-6: Clinical Manifestations The most commonly seen clinical manifestations, or most well

•

Roseola (exanthem subitum, sixth disease)

described, are roseola or the exanthem subitum (sixth disease).

•

CNS: Febrile seizures, meningoencephalitis

Central nervous system manifestations include febrile seizures and

•

Nonspecific febrile illness

meningoencephalitis. In fact, it has been shown that as many as one-

•

Lymphadenopathy

third of the first febrile seizures may be actually associated with

•

Hepatitis

HHV-6 infection, and febrile seizures may actually occur as a result

•

Intussusception

of reactivation of the virus.

•

Transplant

patients:

Pneumonitis,

fever,

mononucleosis-like syndrome

4

HHV-6: Association with CNS Disease

Nonspecific febrile illness. In a large study in Rochester, it was demonstrated that of those infants who presented with fever for



Exanthem subitum (ES) may be complicated by febrile seizures

(0.6-50%),

bulging

anterior

fontanel,

meningoencephalitis, hemiplegia, permanent paresis, mental retardation.

 

Local production of antibody in CNS documented. HHV-6 gene sequence detected in brain tissue of child with ES and fatal fulminant hepatitis.



Mechanism of association with febrile seizure: Reactivation of CNS HHV-6 by fever in patients with history of neurologic symptoms at time of acute ES.



Possible etiologic role in multiple sclerosis HHV-6 virion proteins expressed in nuclei of oligodendrocytes in MS patients in association with MS plaques

evaluation to the emergency room, 21% actually had infection with HHV-6. The only thing that distinguished those children was that those who had HHV-6 isolated were not more likely to have rash, but the only clinical feature that was different and seen at an increased rate was otitis media. Lymphadenopathy, and in young adults a specific syndrome of lymphadenitis, associated with fever and fatigue, and very large nodes may occur. Hepatitis, especially neonatal hepatitis, has been associated. There is some information about patients with intussusception that it may be actually caused by a lymph node enlargement that may be related to this virus. In transplant patients, pneumonitis, fever and a mono-like syndrome has been described, and this may be particularly important because for these more serious types of infections. HHV-6 is susceptible to the activity of ganciclovir. Kawasaki disease, chronic fatigue syndrome, AIDS, autoimmune diseases and SIDS have no association with HHV-6.

The association with central nervous system disease. There are several reports that substantiate this and this is also true for the HHV7, and specifically there have been reports for HHV-7 being associated with acute hemiplegia of childhood. Exanthem subitum may be complicated by febrile seizures, 0.6 to as many as 50%. A bulging anterior fontanelle, meningoencephalitis, hemiplegia, permanent paresis and mental retardation occur in very rare cases. It has been shown that there is local production of the antibody to HHV-6 in the CNS, and the HHV-6 gene sequence has been detected in brain tissue of a child with exanthem subitum and fatal fulminant hepatitis. The mechanism of association with recurrent febrile seizures is thought to be a reactivation of CNS HHV-6 by fever in patients who have a history of neurologic signs and symptoms at the time of acute infection. Although this has been debated, it does look like it may have a possible etiologic role in multiple sclerosis, in that the HHV-6 virion proteins are expressed in the nuclei of oligodendrocytes in MS patients in association with the MS plaques.

I think that we've learned a lot about the epidemiology of this virus and that we will continue to learn a lot about the possible clinical manifestations. For most of our immunocompetent patients, there is really no role or indication for treatment at this time.

5

HSV: Risk of Transmission to the Neonate

Herpes simplex infection. Perinatal herpes simplex. Know that women who have HSV infections may have asymptomatic lesions as

• First episode lesion:

50%

• First episode asymptomatic:

33%

• Recurrent lesion:

4%

dependent on several factors. If it is a first episode lesion, and there is actually a lesion present and a primary infection, and that infant is delivered vaginally, there is a 50% risk of transmission to the

• Known past infection, no visible lesions/prodrome

often as 1% of the time. But the risk of transmission to the neonate is

0.04%

neonate. If the first episode is actually asymptomatic there is a 33% risk. If there is a recurrent lesion there is a 4% risk. If there is a known past infection, but no visible lesions or prodrome, the risk goes down dramatically to 0.04%.

6

Other Risk Factors For Development of Neonatal Herpes

The premature infant is at greater risk for neonatal herpes and this is probably related to factors of antibody deficiency and antiviral killing

   

Prematurity Prolonged rupture of membranes Vaginal delivery

activity. Prolonged rupture of the membranes, vaginal delivery, and the scalp electrode as well as other maneuvers that can potentially break the skin, such as the use of forceps.

Scalp electrode

7

Prevention of Neonatal HSV: Minimal Obstetrical Role

The role of the obstetrician to prevent neonatal herpes is really quite minimal. There is very little that he or she can do. Cultures during

 

Vaccine not yet available Cultures during pregnancy •

Prenatal cultures are not predictive if neonatal infection

•

Cultures are done at delivery in women with past history of herpes to facilitate early diagnosis of neonatal infection



Recognition of active lesions during labor is usually followed by C-section delivery



Antenatal acyclovir suppression is effective

pregnancy are not predictive. Those women who are culture positive at times at the end of pregnancy may not be culture positive and may not have virus present at the time of delivery and vice versa. However, women who have a past history of herpes may benefit from having cultures done at the time of delivery, merely to help facilitate our early diagnosis of neonatal infection. The important role of the obstetrician is, of course, recognition of active lesions during labor and performance of a c-section delivery if those lesions are visible. The lesions that are present in the sacral area and the thigh area and buttocks. Can be covered and protected, a vaginal delivery can still be done. There are some studies in small numbers of patients who have recurrent herpes lesions, and using acyclovir suppression at the end of pregnancy does seem to decrease the exposure of the infant.

8

Indications for Maternal Acyclovir    

Although acyclovir is not recommended routinely, there are some

Maternal varicella

situations where acyclovir may be used in the pregnant woman. One

Severe first episode HSV

is the presence of maternal varicella. A very severe primary episode

Maternal immunosuppression associated with HSV

of HSV. If there is some maternal immunosuppression associated

recurrence

with a recurrence. Treatment or suppression of new herpes lesion

Treatment or suppression of new herpes lesion formation

formation in the preterm premature rupture of membranes.

in preterm premature ROM The skin, eye or mucosal lesions alone account for 40% of the cases, and those cases have the best prognosis. 25% have disseminated disease and 35% are central nervous system infection.

If the infant is delivered to a mother and the infant is exposed and has delivered vaginally, there is no recommendation to use prophylactic acyclovir at that time. Surface culturing is recommended at 36 hours of age, and the newborn is observed with a very low threshold for starting acyclovir.

9

Prevention of Neonatal HSV: Pediatric Role - Diagnosis and Therapy 

Skin lesions (40%) •

DFA of scraping of base: Sensitivity >80%, few false positives

•



Viral, bacterial cultures

Disseminated (25%) •

Maternal genital cultures

•

Cultures of multiple infant sites: conjunctiva, nose, mouth, rectum, skin, CSF, buffy coat



CNS (35%) -

CSF culture, PCR, cell count, protein

-

EEG: diffusely abnormal

-

CT/MRI

10

Treatment of Perinatal HSV Infections 

The DFA (direct fluorescent antibody) test of the scraping of the base

Acyclovir IV

of the lesion, if a lesion is present, is a more reliable, more sensitive

Dose: 30 - 45 - 60 mg/kg/day Duration:

and specific than the culture. And it is currently the test that is

10 days; 21 days if CNS

involvement Suppression:

recommended. The DFA is usually done by a microbiology lab 24 hours a day. The classic skin lesion has a red base with vesicles with

Oral

acyclovir

months sk in

for

6

clear fluid and sometimes we've seen lesions that looked more

recurrent

pustular and do not look like typical herpetic lesions. So we have to

lesions

x

(300

have a very high index of suspicion.

mg/m2/dose tid)

 

Vidarabine

If we are considering disseminated disease, and this is a particularly

New antivirals

important consideration in what looks like overwhelming bacterial sepsis, especially if DIC and shock and liver abnormalities are present, and bacterial cultures are negative, then we need to consider herpes as the cause of this presentation. It is important to culture the baby from multiple sites. Surface cultures may be helpful. Conjunctiva, nose, mouth, rectum, skin and then of course, CSF and buffy coat. Sometimes the buffy coat will be the main place that we would recover the virus. The herpes virus will generally be recovered in 2448 hours after cultures are set up. Maternal genital cultures may possibly be helpful, again, when we have a suspicion that this may well be the cause of this infant's disseminated disease. But in such a situation, with presumed disseminated disease, initiation of therapy should be done. In addition, as you all know, the negative history is certainly not helpful. It does not rule out infection.

And finally, for central nervous system infection, the diagnosis is really dependent on three things. That is the analysis of the CSF, the EEG and the CT or MRI. In the neonate, the MRI is actually more helpful and more likely to show abnormalities prior to the CT scan. For the CSF, we send for viral culture, but the ability to isolate herpes virus from CSF is very low. The PCR has improved our diagnostic ability tremendously and is very sensitive and specific. The cell count and protein can be highly variable and can actually look very benign. The presence or absence of red cells, I think, is not a specific indicator of a herpes connection. We certainly see infants that we may suspect of having herpes infection and the initial MRI may be normal, then if we repeat that in a few days we may actually see abnormalities. On the EEG, we see defuse abnormalities, not just a localized findings, as we see in older children. The neonatal herpes encephalitis tends to be more diffuse.

11

Once we have a reasonable degree of suspicion, we embark on treatment and the mainstay of treatment is acyclovir IV. I've listed the dose here. When we are dealing with central nervous system infection, I think we have tended to increase our dosage over the years. We initially started with 30 mg/kg/day and increased to 45, and when we have well-established central nervous system infection, the dose of 60 mg/kg/day is preferred in the neonate. There are studies that show that this is safe and perhaps a bit more effective. We have certainly seen a number of babies who, at the end of ten days, still have signs of ongoing disease and if we truly have central nervous system involvement we should treat for 21 days and this should help to prevent recurrences.

Another problematic area of neonatal herpes has been the recurrence of skin lesions. There are data that indicate those infants who just have localized skin lesions and no evidence of any other area being involved are likely to have recurrences in the first six months. In fact, those who have more than three recurrences in the first six months of life have a higher incidence of having neurologic abnormalities at two years of age. It has been demonstrated that in some of those infants with recurrences of skin lesions without other signs or central nervous system involvement and with a normal CSF, HSV DNA has been demonstrated during recurrence. So, there is concern that when those skin lesions recur, there may also be a reactivation in the central nervous system. Therefore, it has been suggested, and this is currently being studied, so this is not a routine recommendation, that there may be a role for p.o. acyclovir for suppression for six months. At least in preliminary studies, there is information that demonstrates that this dose of three times a day will inhibit or prevent the recurrence for the time the infants are on it. But we really need larger information to make this a routine recommendation, but I certainly would consider it. Vidarabine is an alternative drug, although we do not use that. We prefer acyclovir. There is probably equivalent efficacy but vidarabine is more difficult to administer. There are new antiviral agents available that have been used in adults. But I am not aware of any experience with them yet in neonates, so acyclovir is still our mainstay of therapy.

I would like to turn now to the human parvovirus B19. This agent causes the "slapped-cheek" appearance of fifth disease. The mode of transmission of this virus is primarily in respiratory secretions and in those with chronic anemia, it may also be in the blood as well. We see secondary infections in up to 50% of household contacts who are

12

Human Parvovirus B19

susceptible. It is lower for adults in schools and daycare centers. The associated diseases that have been described for parvovirus B19 is

  

fifth disease, the erythema infectiosum. Arthralgias, arthritis, Aplastic

Mode of transmission: Respiratory secretions; possibly

crisis in chronic hemolytic anemias, and this is certainly true in those

blood.

patients with sickle cell disease. Chronic anemia in the

Secondary infections occur in less than 50% in house-

immunocompromised patients, especially HIV patients. When

holds, lower for adults in schools, day care centers.

infection can be documented in pregnancy, the risk of fetal hydrops

Associated diseases:

and death has been estimated to be from less than 1% to a maximum

•

of 9%, but probably less than 1% is a more accurate estimate.

"Fifth disease"/"Erythema infectiosum" Arthralgia, arthritis





•

Aplastic crisis in chronic hemolytic anemias

The pathogenesis of the infection and the effect on the chronic

•

Chronic anemia in immunocompromised

anemia and the hydrops in infants is the tropism for dividing

•

Fetal hydrops, death (<1-9% risk)

erythrocyte precursors. Diagnostically, we are able to make this

Diagnosis

diagnosis now using serology, an IgM and an IgG test. PCR also can

•

Serology: IgM, IgG

be very useful, especially in the immunocompromised patients.

•

PCR, especially immunocompromised

Treatment consists of IVIG for chronic anemia.

Treatment •

IVIG for chronic anemia

I would like to say a few words about parvovirus B19 in pregnancy because this becomes a major concern in pregnant women at the times when there are outbreaks in the community. I think we can best summarize the information and counsel the women using these estimates. The estimated risks of adverse effects. Roughly about 50% of pregnant women are susceptible. So, if there is an outbreak in the community and you have a pregnant woman who is concerned, it may well be that she is already protected and has antibodies. And if she has pre-existing antibodies, then she and her fetus are protected. There is overall 6% risk of infection during a community outbreak and then there is a 10% risk of fetal death if exposed in the second trimester. There is a 1% overall risk of fetal death. It is also important to stress that even when infection has been documented during pregnancy and the fetus has been shown to be affected, that spontaneous resolution has been documented by ultrasound.

13

Parvovirus B19 in Pregnancy 



Management of the exposure of a pregnant woman. We should first

Estimated risks of adverse effects

establish the serologic status with IgG and IgM. Perform serial

•

50% pregnant women susceptible

sonograms and even measure alpha fetal protein to determine the

•

6% risk of infection during community outbreak

well-being of the fetus, and in the most severe cases, there are reports

•

10% risk of fetal death if exposed 2nd trimester

of using intrauterine transfusions and using digitalis if the infant

•

1% overall risk fetal death

shows sign of heart failure. But clearly there is not an indication for

Management of exposure

an automatic interruption of pregnancy and the prognosis can be quite

•

Establish serologic status IgG, IgM

good. There has been no fetal syndrome that has been identified. It

•

Serial Sonograms, alpha fetal protein

has just been the hydrops and in some cases, death.

•

Intrauterine transfusion, digitalization

•

Spontaneous resolution documented

14

Isolation of Patients Infected with Parvovirus B19

Those patients who have fifths disease, once we know they have fifths disease and you have the rash, they are no longer infectious. If



Fifth disease: Droplet isolate in early stages; none after appearance of rash



Viremic (aplastic crisis): Droplet isolation for duration of illness; no roommate with chronic hemolytic anemia, pregnancy, immunocompromise



Household contact of viremic patients: Droplet isolation from day 7-18 after exposure



Pregnant women: Avoid above patients, household contacts

we could identify them in the early stages, we would put them in droplet precautions. But once we know that is what they have, they are not infectious. Those who have aplastic crisis and are viremic should be in droplet precautions for the duration of illness and their blood should be handled very carefully. Pregnant women are advised to minimize their contact with them. It has been shown that looking at the occupations and looking at the risk of women acquiring infection, the greatest risk is women who have exposure to children in the home and after that is women in schools or in daycare centers. In fact, in one series where medical personnel were looked at, there were no acquisitions of infection. In several clusters of parvovirus infection in the hospital, the health care workers who had been exposed to patients with parvovirus B19, some have shown that there has been nosocomial spread but others have shown there has actually been no spread. So, I think that observing the standard precautions is protecting and helping the workers to not increase risk.

15

Hepatitis C Virus: Clinical Features Hepatitis C virus. The incubation period can be 2 to 26 weeks. Five

Incubation period:

   

2-26 weeks

to 12 weeks for most. If it is actually infused, 4-7 days among

5-12 weeks for most; 4-7

recipients of pooled coagulation factors. In fact, with perinatal

days among recipients of

transmission when it does occur, by PCR, the virus can actually be

pooled coagulation fac-

demonstrated as early as one week after delivery. In general, hepatitis

tors

C virus is associated with mild acute disease and only a modest

Mild acute disease

increase in the ALT from 60 to 600. 25% of the patients will be

Modest increase in ALT (60-600)

icteric. The extrahepatic manifestations associated with acute

25% of patients are icteric

hepatitis may include a serum sickness-like syndrome, blood

Extrahepatic manifestations associated with acute hepatitis:

Serum

sickness-like

syndrome

dyscrasias, arthritis, and membranoproliferative glomerulonephritis.

blood

dyscrasias (granulocytosis, aplastic anemia) arthritis membranoproliferative glomerulonephritis



Chronic hepatitis (elevated enzymes > 6 months ) 5075% overall



Long-term outcome chronic hepatitis

10 years

cirrhosis

20 years

hepatocellular carcinoma

30 years

16

Hepatitis C: Perinatal Transmission   

The problem with hepatitis C virus is the very high incidence of

Rate of perinatal transmission: 4-50%

chronic disease. Overall, probably 50 to 75% have chronic disease

Source. Blood, breast milk

and they can have different patterns. They may just have a

Risk factors

monophasic pattern. They may fluctuate. Their liver enzymes may go

•

Titer of HCV RNA

up and down and you will see them at certain times when you think

•

Specific genotype: subtypes 1 b, 3a most com-

they are completely normal, but they actually still have the virus on

mon

board and have chronic disease, or they may plateau. The long term

•

Mode of delivery

outcome in chronic hepatitis is 10 years, and that will lead to cirrhosis

•

HIV coinfection

by 20 years, and by 30 years hepatocellular carcinoma.

One of the reasons for the chronic infection of this particular virus is there is an extremely high rate of mutation of the RNA genome. Although antibodies actually form to the particular virus, the virus as it replicates is mutating and so the viruses that are present are not the same viruses to which the antibody was formed and the antibody is not a neutralizing antibody. That is just kind of an interesting explanation.

But really the rate of transmission is dependent upon the test that is being used. When using the HCV RNA, actually measuring the viral particles, we have come up with higher rates of transmission. The sources are blood and there is at least one report of breast milk being a source of transmission of hepatitis C.

Risk factors that predict which infants will acquire an infection include the titer of the HCV RNA. Those women who have antibodies to hepatitis C, but have cleared the HCV RNA and are not positive, are at very low risk of transmission to the infants. Those who have high titer are much more likely to transmit. Vaginal delivery is associated with a higher rate of perinatal transmission.

17

Hepatitis C: Diagnosis with Antibody Assays

If we look at antibody assays, these can be difficult in diagnosing early infection because they can take many weeks to months before



ELISA -

Second generation U.S., third generation abroad

-

Addition of segment from viral core that is more specific marker

-

False negatives due to delay in production of antibody

antibody is actually formed. The ELISA is what is done most commonly and there are 1st, 2nd and 3rd generation ELISAs. The generations vary by just the addition of different segments of the viral core that make it a more specific test. The 1st generation test is much too nonspecific and has too many false positives in the low risk population and I would not recommend doing 1st generation tests at all. Second generation tests on the other hand are actually fairly accurate and give much less in the way of false positives. The RIBA test, which is the recombinant amino blot assay, is used as a confirmatory test. The problem with the RIBA is that it is very expensive and therefore should not be used routinely. It can be used as a supplemental test when a first generation ELISA is borderline. The second generation ELISA is generally accurate enough that we would not need to go to the RIBA. There is a strong correlation with the second generation RIBA and the HCV RNA. But if one had the choice I would rather measure the viral particles directly.

18

Hepatitis C: Diagnosis with Antigen Assays

Antigen Assays include the PCR and the branch DNA that actually measure the quantity of virus and are the best predictor of the risk of



PCR • •

transmission and are the best way to follow response to therapy.

Measures replicating viral RNA particles. More sensitive for detecting very low levels of virus, especially in early stages before antibody production and in immunocompromised patients who do not produce antibody.

•



Best predictor of risk of transmission.

bDNA •

Branched DNA signal amplification assay

•

Measures amounts of HCV RNA by augmenting viral signal

•

Relatively insensitive

•

Most useful to monitor treatment

19

Treatment Hepatitis C Virus  

Treatment. Interferon alpha has not been met with the success that

Agents. Interferon alpha ± ribavirin

was hoped for. There is about a 50% response rate and of those who

Predictors of response

respond, 50% will relapse. However, there is some new information

•

HCV RNA level~ pretreatment

that by combining interferon alpha with ribavirin we may get a better,

•

HCV genotype

more long lasting response. What can predict response? With the

-

Type 1 (70-80% of cases) has a <10% re-

HCV RNA level pretreatment, the higher levels are less likely to

sponse rate

respond. And then specific genotypes. The type 1 that has less than

Type 2 or 3 has a >40 % response rate

a 10% response rate and of course that accounts for most of the U.S.

Liver transplant: infection transmitted but milder

cases. But other types will have greater than 40% response rate.

disease

Hepatitis C actually accounts for 40% of the liver transplant recipi-

-



ents in this country, and it is an indication for liver transplant. It is certainly not a contraindication. Although hepatitis C infection will be transmitted to the transplanted organ, the disease is much milder.

20

Enteroviruses: Coxsackie A/B, Echovirus, Numbered 68-71

Enteroviruses. These are a group of viruses, the Coxsackie, the echo, and the numbered 68-71. There are many nonspecific, non-CNS



manifestations. What we see mostly is a nonspecific febrile illness,

Non CNS clinical manifestations •

Nonspecific febrile illness ± rash

•

Myocarditis (coxsackie B)

•

Hemorrhagic

conjunctivitis

associated with Coxsackie B can be especially problematic. Hemor-

(coxsackie

enterovirus 70)



but we never really know this is an enterovirus. Myocarditis is

•

Herpangina

•

Hand-foot-mouth syndrome

•

Bornholm disease (pleurodynia)

•

Overwhelming neonatal sepsis

•

Diarrhea and vomiting (uncommon)

A24,

rhagic conjunctivitis and then a variety of other manifestations. The overwhelming neonatal sepsis that can be seen can look exactly like disseminated herpes or herpes simplex central nervous system infection, so culture or PCR are necessary to really identify the Agent. the Coxsackie viruses may be a trigger for juvenile diabetes mellitus.

Trigger for juvenile diabetes mellitus

21

Enteroviruses: CNS Manifestations -- Aseptic Meningitis

If we look at the clinical manifestations in the central nervous system, what we see most commonly is aseptic meningitis. We can actually

         



identify specific viral pathogens in 50-70% of the cases. The non-

Specific viral pathogen 55-70%

polio enteroviruses account for 80-92% of cases. Typically, we see a

Non-polio enterovirus 80-92%

biphasic fever pattern, headache, photophobia, but really very

75,000 cases per year in U.S.

nonspecific symptoms. It is a fairly short-lived illness. The CSF

Biphasic fever pattern

shows a mild pleocytosis with minimal elevation of protein. And

Headache

glucose may be depressed or may not be. It is generally a fairly mild,

Photophobia

self-limited disease.

Nonspecific Duration <1 week

We can also see a more pure encephalitis, which may be focal or

Long term sequelae minimal if any

generalized, and this has been associated with a more devastating

Encephalitis •

Focal, generalized

•

More devastating acute disease

•

Long term sequelae

acute disease and long term sequelae. Possible associations that are not as clear include paralytic myelitis, cerebellar ataxia, GuillainBarré syndrome and transverse myelitis.

Possible (?) •

And finally the chronic meningoencephalitis in patients who have

Paralytic myelitis, cerebellar ataxia, GBS, transverse myelitis



agammaglobulinemic or hypogammaglobulinemic patients are

Chronic meningoencephalitis in patients with altered immunity •

Affects

susceptible because, unlike many other viruses that depend on cell media in the immunity for clearance of the virus, the enteroviruses

Cleared from host by antibody-mediated mechanisms

•

altered immunity, specifically, altered humoral immunity. The

actually depend on antibody mediated mechanisms. The duration of illness can be many years and the effective therapy for keeping this

agammaglobulinemia

or

hypogammaglobulinemia •

Duration of illness many years

•

Effective treatment: IVIG, intraventricular IG, but

illness under control is IVIG and intraventricular administration of immunoglobulin. But we can still demonstrate virus to be present even when the immunoglobulin is being given.

pos. PCR may persist

22

Enteroviruses  

Enteroviral PCR is commercially available that is very sensitive and

Diagnosis. Viral culture, PCR, serology

specific. It has been able to allow us to identify these patients with

Treatment

enteroviral aseptic meningitis in completing our workup. Culture

•

IVIG for chronic CNS infection, myocarditis, ?neo-

results can be helpful but can take much longer, whereas the PCR

natal

would be available more readily. Then, of course, we can do

Antivirals, immunomodulating agents investigational

serology. For treatment there are really no antiviral agents available

e.g. 1' interferon

at this time. There is some investigation of immunomodulating

•



Isolation: contact

agents, gamma interferon. IVIG has been used for the chronic central nervous system infection as well as myocarditis. There is some suggestion that in neonates it may be helpful, but the neonatal disease is a very overwhelming, highly fatal myocarditis and hepatitis associated with the echoviruses.

23

Clinical Uses of Ribavirin in RSV Infections

RSV. The bottom line with ribavirin is that there just does not seem to be a lot of support for its efficacy. As you know, these are the



Underlying conditions that place infant at high risk for severe or complicated RSV: •

Congestive heart disease (especially with pulmonary hypertension), bronchopulmonary dysplasia, other chronic lung conditions, cystic fibrosis, immunodeficiency syndromes (especially severe combined immunodeficiency syndrome, HIV), recent transplant recipients, chemotherapy for malignancy.



Hospitalized patients with progression of severe lower tract disease.



Possible candidates with other chronic disorders: Multiple congenital anomalies, neurologic, metabolic, GI diseases.

recommendations to consider ribavirin when there are underlying conditions that place infants at particularly great risk. Of interest is a more recent study published indicating that in the congenital heart disease baby, with the better recognition and better support, the mortality is much lower than had been reported in some of the earlier studies. So, this may be one reason why we don't see a benefit from ribavirin. There was a meta analysis published. That assessed the efficacy of ribavirin and the bottom line statement was that there was no significant reduction rate or respiratory deterioration, but strong trends were demonstrated. No decrease in the length of hospitalization. The effect on the number of days of mechanical ventilation was conflicting results with trends in the direction of benefit. The studies of non-ventilated patients were dependent on very subjective scoring systems.

Should you be in a situation that you are using ribavirin and there is concern about exposure to personnel, especially pregnant women, basically I think there is very little risk to the pregnant woman who is exposed to ribavirin in the hospital.

24

Ribavirin Therapy for RSV Infections: A Metananalysis

Our emphasis now is on prevention. There have been two major studies in the use of the RSV-IGIV prophylaxis. These data are from



No significant reduction rate or respiratory deterioration, but strong trends demonstrated

 

No decrease in length of hospitalization Effect on number of days of mechanical ventilation: Conflicting results with trends in direction of benefit



Studies of non-ventilated patients: Results are dependent on subjective scoring system

the first study that was published in 1993 that identified the high-risk individuals, those with BPD or those receiving oxygen therapy, and treated them prophylactically once a month with an infusion of RSV high titer IGIV. Dosage that had the effect-- was 750 mg/kg. The different reductions that were demonstrated. Lower tract illness, any lower tract illness and moderate or severe and respiratory disease score, hospitalization, total hospital days/100, ICU admission, total ICU days/100. These all show from 30-80% reduction in those who received the prophylaxis. In addition, there was a significant reduction in acute otitis media and this was probably related to those cases caused solely by RSV as well as RSV working as a cofactor with bacterial otitis.

The American Academy published recommendations are to consider the use of RSV-IGIV. The highest risk group is, of course, those infants who were two years old or less during an RSV season, who have a history of BPD and received oxygen treatment within six months prior to the RSV season. You should consider prophylaxis for at least one RSV season, and, for the most severely affected, perhaps two RSV seasons. Another group to consider are those who are 32 weeks of gestation or less but have no history of BPD. The most premature infants, 28 weeks or less, should be considered for up to 12 months of age and those 29-32 weeks gestation, for up to six months of age. It is not approved for infants with congenital heart disease, because of the observations in the early study of some adverse reactions which were probably not related to the IGIV. We may, however, consider its use in an asymptomatic, stable, acyanotic child with heart disease. There are no specific recommendations for immunocompromised patients, but it may be that those who are immunocompromised, who are receiving IVIG for other reasons during the RSV season, we may want to consider using the RSVIGIV at that time.

Monthly administrations during the RSV season is recommended. The RSV season can be different times in different communities in different parts of the country. So, it is particularly important to be in communication with your health department to determine what the anticipated RSV season is in your area and also to be aware of what your RSV identification is in your microbiology lab in your commu-

25

Ribavirin: Precautions for Health

nity when you are starting to see cases. The dose is 750 mg/kg IV. One must remember that if you are giving a high titer immunoglobu-

Care Workers and Visitors

lin like this, there is likely to be antibody to other viruses as well. So, immunization with the MMR and the varicella should be deferred for



Administer in well-ventilated rooms: 6 air changes per hour; negative ventilation hood, tent, mask; single patient per room



Consider methods to lower air contamination when patient is not on ventilator: •

High dose, intermittent regimen

•

Stop aerosol administration temporarily when hood

nine months until the last dose of RSV-IGIV. There is no need for supplemental doses of other vaccines. They should respond just as well. There really has been no efficacy demonstrated for the use of RSV-IGIV in an outbreak in a closed unit such as a BICU or a special care nursery. Really, the emphasis must be, in the setting in the hospital, on strict infection control techniques for prevention in group settings.

or tent is open



Advise pregnant women, especially first trimester, to avoid direct care during ribavirin administration

  

Use 3M respirator mask for additional protection Goggles for contact lens wearers Gloves for all personnel who handle and prepare ribavirin and who clean the associated equipment; goggles for cleaning



Reassurance when exposure occurs prior to knowledge of pregnancy

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Effect of RSV-IGIV Prophylaxis in High-risk Infants

Measurement

% Reduction

Lower tract illness Any

59 69

Moderate/severe

Respiratory disease score

30

Hospitalization

65

Total hospital days/100

63

ICU admission

86

Total ICU days/100

97

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RSV-IGIV Recommendations 

2 years old, bronchopulmonary dysplasia, oxygen therapy within 6 months of RSV season: Consider prophylaxis for 2 RSV seasons in the most severely effected



32 weeks gestation, no bronchopulmonary dysplasia 28 weeks gestation: up to 12 months of age 29-32 wks. gestation: up to 6 mos. of age



Not approved for infants with congestive heart disease. May consider if asymptomatic, acyanotic



Immunocompromised patients: No recommendations. Consider substitution of monthly IVIG with RSV-IGIV during RSV season



Interval of administration •

Monthly during RSV season, usually November to March

•

Consult local health deptartment for regional differences

 

Dose: 750 mg/kg Immunization with MMR, varicella deferred for 9 mos. after last dose RSV-IGIV

 

No need for supplemental doses of other vaccines No efficacy demonstrated for RSV-IGIV in an RSV outbreak in a high risk unit



Emphasize strict infection control techniques for prevention in group settings

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Hall CB, Long CE, Schnabel KC, et al. Human

herpesvirus-6 infection in Children: A prospective study of complications and reactivation. N Engl J Med 1994;331:4328. 2.

Lyall E.G., Hons BSC, Hons MB. Human herpesvirus 6:

primary infection and the central nervous system. Pediatr Infect Dis J 1996; 15:693-6. 3.

Asano Y, Suga S, Yoshikawa T, et al. Clinical features

and viral excretion in an infant with primary human herpesvirus 7 infection. Pediatrics 1995;95:187-90. 4.

Torigoe S., Koide, W., Yamada M, et al. Human herpes

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Scott, LL., Perinatal herpes: current status and obstetric

management strategies. Pediatr Infect Dis j 1995; 14: 82732. 6.

Whitley RJ and Lakeman F. Herpes Simplex Virus

infections of the central nervous system: therapeutic and diagnostic considerations. Clinical Infectious Diseases 1995; 20:414-20. 7.

Kohl S. The neonatal human's immune response to

herpes simplex virus infection: a critical review. Pediatr Infect Dis 1989; 8:67-74. 8.

Kohl S, Loo L-S, Rench MA, et al. Effect of intrave-

nously administered immune globulin on functional antibody to herpes simplex virus in low birth weight neonates. J Pediatr 1989; 115:135-39. 9.

Whitley R, Arvin A, Prober C, et al. A controlled trial

comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. N Engl J Med 1991; 324:444. 10. Kimberlin D, Powell D, Gruber W, et al. Administration

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of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and mouth: results of a phase 1/11 trial. Pediatr Infect Dis J 1996;15:247-54.

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