Download Treatment of Neonates Exposed to and Infected with HSV

Treatment of Neonates Exposed to and
Infected with HSV
Michael T. Brady, MD
Pediatric Professor
The Ohio State University
Associate Medical Director
Nationwide Children’s Hostile
Faculty Disclosure
Michael T. Brady, M.D.
In the past 12 months, I have not had a
significant financial interest or other
relationship with the manufacturer(s) of the
product(s) or provider(s) of the service(s) that
will be discussed in this presentation.
Epidemiology of Neonatal HSV
• Perinatal infections are primarily horizontal (motherto-infant)
• HSV-2 – 75%; HSV-1 - 25% (HSV-1 is increasing)
• Only  30% of women who give birth to an infant
with HSV have a history of current or prior HSV
genital infections.
• Risk of transmission to newborn from mother with
active HSV at the time of delivery:
 First episode/primary genital infection-60%
 First episode/non-primary infection-25%
 Recurrent genital infection-1-3%
HSV in Pregnancy
• Approximately 1% of women are HSV culturepositive at term (recurrent >> primary); most
are without symptoms or lesions
• 90% of pregnant women with genital HSV do not
know they are infected
• 67% of mothers with HSV-infected neonates deny
ever having any symptoms of genital herpes
prior to delivery
HSV During Pregnancy
• Symptomatic Genital Infection
– Can be either a primary, non-primary first
episode (prior non-genital HSV) or a recurrent
infection
– Symptoms include:
• Painful tender vesicles; dysuria
• Fever, headache, lymphadenopathy (not noted with
recurrent infection)
• Primary disease involves vulva, vagina, cervix and
urethra
• Recurrent disease typically involves only the vulva
• In most cases, infection is asymptomatic or mild
and infection is not recognized as HSV
Primary Genital Herpes Simplex
Infection During Pregnancy
• HSV-2 - -75%
HSV-1 - - 25 (proportion is increasing)
• Disseminated infection (viremia) including HSV
meningitis (benign) occurs but is rare
• Infections before 20 weeks gestation are
associated with increased risk of
spontaneous abortion
Perinatal Herpes Simplex
Transmission
• Intrauterine (rare: 5%)
– Transplacental (viremia; primary infection)
– Ascending ( ROM)
• Intrapartum/Natal (most common – 85%)
• Post-natal (horizontal) (10%)
– Family members/friends
– Nosocomial
Perinatal Herpes Simplex
Source of HSV
Source
Maternal genital tract
(HSV-1 – 25%; HSV-2 – 75%)
Percent
80-85
Maternal non-genital (HSV-1)
5
Non-Maternal (HSV-1)
(other family/nosocomial, etc.)
5-15
Pathogenesis of Neonatal HSV
Infection
Maternal Genital Herpes Simplex Virus Infection
Intrauterine Infection (5%)
(transplacental or ascending)
Intrapartum transmission (85%)
Postnatal (horizontal)
Infection (10%)
Viremia =
Disseminated Disease
25%
Localized
(Skin, Eye, and/or Mouth)
45%
Hutto C, et al. J Pediatr. 1987:110:97-101.
Neuronal Spread =
Localized Encephalitis
30%
Perinatal Herpes Simplex
Risk for Transmission
Characteristic
Risk
Maternal infection
Primary (60%)>>Recurrent (2%)
Maternal genital lesions
Symptomatic >Asymptomatic
Gestational age
Premature>Full-term
Method of delivery
Vaginal >C-section
Duration of ROM
>6 hours>> <4 hours
Instrumentation
Scalp elelectrode/instrument
delivery >> none
HSV Shedding at Delivery
Maternal Infection
Primary
Secondary
Vital titer
(viral particles)
>106/0.2 mL
102-103/0.2 mL
Duration of shedding
14-21 days
2-5 days
Cervical involvement
Common
Rare
Absent
Variable
HSV Antibody
Neonatal Herpes Simplex
Clinical Manifestations
• Local (skin, eye and/or mouth = SEM) (45%)
• Central nervous system (30%)
• Disseminated (25%)
Neonatal Herpes Simplex
• Mean onset of symptoms:
– SEM – mean -11 days postpartum ( range: 3-20 days)
– Disseminated: mean – 11 days postpartum (range:
3-20 days)
– CNS: mean – 17 days postpartum (range: 7-35 days)
• 70% of untreated SEM  CNS/disseminated
• Recurrences after treatment are not uncommon: skin
recurrences >>>CNS recurrences
Presentation of SEM Disease
• Vesicles are seen in 83%
• Presents around 3-20 days of life
• Lesions may appear anywhere including oropharyngeal lesions
– Often on the scalp, particularly those born vaginally
– Thorough examination of the entire body is essential
• Localized SEM, but at risk of progression to serious disease
• Conjunctivitis in 25%
• Fever in 17%
Neonatal Herpes Simplex Skin Lesions
• May be single or multiple
• Present as crops or clusters of vesicles with
surrounding erythema
• Vesicles are small (1-6 mm) and do not break
easily (bullous impetigo lesions are friable)
• Frequently at site of presentation or trauma
(e.g. scalp electrode, forceps, etc.)
Lesion at site of scalp monitor treated
with Neosporin for 3d
17 day old; lesion present since day 6 of life
Lesion on lip & tongue after sucking on HSV infected breast
Presentation of CNS Disease
• Presents around 7-35 days (mean 17 days) of life
• Associated with lethargy, seizures, temperature
instability, poor feeding, irritability, tremors,
bulging fontanelle
• 60-70% have vesicles at one point in course;
frequently absent at first symptoms
• Can involve multiple parts of brain
– In contrast to temporal lobe predilection in herpes
encephalitis in older children and adults
Neonatal Herpes Simplex Encephalitis
• CSF pleocytosis – common but not
universal; usually mononuclear cells
• CSF protein – usually elevated
• CSF detection of HSV
– Viral culture (5% positive)
– HSV DNA detection by PCR (>90%); occasionally
first LP will be negative while PCR on repeat
will become positive
39d old infant who presented to OSH at 29d of life with fever and
irritability; CSF 57,250 RBC, 75 WBC, 84% M/L. Treated with
ampicillin/cefotaxime. Transferred to CH on 33d of life. CSF 350 RBC,
130 WBC, 98% M/L, protein 685; HSV PCR (+)
Presentation of Disseminated HSV
•
•
•
•
•
Presents at 3-20 days of life (mean 11 days)
80% develop skin lesions; some later in course
20% may never develop any vesicles
CNS affected in 60-75%
Symptoms suggestive of severe bacterial
sepsis with respiratory symptoms, liver
failure, DIC and shock
– Hepatomegaly and jaundice
– Pneumonia with progressive respiratory
Neonatal Herpes Simplex
Disseminated: Clinical Presentations
• Vesicular lesions on skin at
Presentation (58%)
• Conjunctivitis (17%)
• Lethargy (47%)
• Fever (56%)
• Seizures (22%)
• DIC (34%)
• Pneumonia (47%)
Diagnosis of Neonatal HSV
• Surface cultures (even in absence of lesions)
– Swabs of mouth, nasopharynx, conjunctivae, rectum
• Swab of lesions-PCR and/or viral culture
• CSF for PCR (± culture)
• Whole blood for PCR (in addition to standard work-up,
above)*
– No data exist to support use of serial blood PCR assay to
monitor response to therapy
• Blood for alanine aminotransferase (ALT)*
• DFA staining of vesicle scrapings (optional)
* New in 2012 Red Book (Report of the Committee on Infectious Diseases)
Neonatal Herpes Simplex - Diagnosis
• Rapid – fluorescent antibody
• skin vesicles - >80% sensitivity, other sites (NP,
conjunctiva much lower)
• Viral culture (sensitivity based on duration of lesion)
• Aspirate fluid from vesicles or scrap base of lesion –
cotton swab; not Calcium alginate
• Viral transport media: ice or -70o
• Growth 1-7 days
• PCR
• CSF - ~98% sensitive overall, initial result occasionally
false-negative
• Lesions, buffy coat, blood, urine-more sensitive than
culture, especially older lesions; usually much more rapid
results.
Management of Neonates Perinatally
Exposed to HSV
Classification of
Maternal HSV Genital Infection
Documented First Episode Primary
Infection
Documented First Episode NonPrimary Infection
PCR/Culture from Genital
Lesion
Maternal HSV-1 and HSV-2
IgG Ab Status
Positive, either virus
Both negative
Positive for HSV-1
Positive for HSV-2 AND
negative for HSV-1
Positive for HSV-2
Positive for HSV-1 AND
negative for HSV-2
Positive for HSV-1 OR HSV-2
Not available
Assume First Episode (Primary or NonPrimary) Infection
Negative OR not available†
Recurrent Infection
Negative for HSV-1 and/or
HSV-2, OR not available
Positive for HSV-1
Positive for HSV-1
Positive for HSV-2
Positive for HSV-2
† When genital lesion is strongly suspicious for HSV, clinical judgment should supersede the virologic test results. If in retrospect the
genital lesion was not likely to be caused by HSV and the PCR/culture is negative, departure from the algorithm may be warranted.
Risk of Transmission
Type of Maternal Infection
Women delivered (n=58,288)
Adapted from:
JAMA 2003;289:203-209
Cultured within 48 hrs (n=39,949) (69%)
Subclinical shedding (n=128) (0.3%)
Serologies available (n=121) (95%)
First episode genital HSV (n=23) (19%)
Recurrent genital HSV (n=98) (81%)
1º HSV-1
(n=3) (13%)
1º HSV-2
(n=4) (17%)
Non-1º HSV-1
(n=1) (4%)
Non-1º HSV-2
(n=15) (65%)
HSV-1 (n=8)
(8%)
HSV-2 (n=90)
(92%)
Infant with
HSV (n=3)
Infant with
HSV (n=1)
Infant with
HSV (n=0)
Infant with
HSV (n=4)
Infant with
HSV (n=2)
Infant with
HSV (n=0)
57%
25%
2%
Neonates Delivered to Women
with History of Genital Herpes but no active
lesions
• Observe for signs of infection (e.g., vesicular lesions of
the skin, respiratory distress, seizures, or signs of
sepsis)
• Should not obtain surface cultures for HSV at 12-24
hours of life
• Should not receive empiric parenteral acyclovir
• Educate parents about the signs and symptoms of
neonatal HSV infection during the first 6 weeks of life
Red Book: 2012 Report of the Committee on Infectious Diseases
Management of asymptomatic neonates born to women with active genital herpes lesions
Asymptomatic neonate following vaginal or cesarean delivery to mother with
visible genital lesions that are characteristic of HSV
AAP COID/COFN
Pediatrics
2013;131(2):e635-e646
Obstetric provider obtains swab of lesion for HSV PCR and culture
Type all positives
Maternal history of genital HSV preceding pregnancy?
no
yes
Send maternal type specific serology, if test assays are available at the delivery hospital
At ~24 hours of age* obtain from the neonate:
• HSV surface cultures (and PCRs if desired)
• HSV blood PCR
• CSF cell count, chemistries, and HSV PCR
• Serum ALT
Start IV acyclovir at 60mg/kg/day in three divided doses
Determine Maternal HSV Infection Classification
First Episode Primary or
First Episode Non-Primary
Go to Treatment Algorithm
* Immediate evaluation and
treatment may be considered if:
• prolonged rupture of membranes
(> 4-6 hours)
• prematurity (≤ 37 weeks gestation)
At ~ 24 hours of age* obtain from the neonate:
• HSV surface cultures (and PCRs if desired)
• HSV blood PCR
If infant remains asymptomatic, do not start acyclovir
Neonatal surface
cultures negative, AND
blood and surface PCRs
negative
Neonatal surface
cultures positive, OR
blood or surface PCRs
positive
Educate family on signs
and symptoms of
neonatal HSV disease
and follow closely
Obtain CSF cell
count, chemistries
and HSV PCR.
Send serum ALT.
Start IV acyclovir
at 60mg/kg/day in
three divided
doses
Recurrent Infection
Neonatal virology
studies negative
(PCRs negative; viral
cultures negative at
48-72 hours
Neonatal PCRs or
viral cultures positive
Stop acyclovir.
Educate family for
signs and symptoms
of neonatal HSV
disease and follow
closely
Go to Treatment
Algorithm
Go to Treatment
Algorithm
Neonates Delivered to Women
with Active Genital HSV Lesions
• Obtain HSV cultures at 12-24 hours of life
• If mother has first-episode genital infection, some experts
recommend empiric parenteral acyclovir treatment
– Can begin after HSV cultures are obtained at 12-24 hours of life
– Can begin at birth (still obtain HSV cultures prior to starting antiviral
therapy)
• Most experts would not empirically treat neonates born to
women with active recurrent genital HSV lesions with
acyclovir
• First-episode clinical infections are not always primary
infections
Red Book: 2012 Report of the Committee on Infectious Diseases, pp. 398-408
HSV Culture Follow-up
• If the neonate’s HSV cultures obtained at 12- 24
hours of life subsequently grow, HSV
infection is confirmed and the baby should
then be evaluated for HSV disease
(including LP, ALT)
– No evidence of HSV disease: empiric treatment x 10d
– Evidence of HSV disease: treatment x 14-21 days
Red Book: 2012 Report of the Committee on Infectious Diseases, pp. 398-408
Treatment Algorithm
AAP COID/COFN
Pediatrics
2013;131(2):e635-e646
Patient remains asymptomatic, CSF indices not indicative of
infection, CSF and blood PCR negative, and normal serum
ALT*
No
Yes
Treatment of Infection and Proven
Disease
Treat with intravenous acyclovir
at 60 mg/kg/DAY in three divided
daily doses for 14 days (SEM) or
21 days (CNS or disseminated)
Additional evaluation may be
indicated
Preemptive Therapy of Infection
but No Proven Disease
Treat with intravenous acyclovir
at 60 mg/kg/DAY in three divided
daily doses for 10 days
Repeat CSF HSV PCR near end of
21 day course of treatment†
Positive
Negative
Continue
intravenous
acyclovir for
7 days more
D/C
intravenous
acyclovir
after 21 day
treatment
course
• For this algorithm, ALT values more
than two-times the upper limit of
normal may be considered suggestive
of neonatal disseminated HSV disease
for HSV-exposed neonates
† If evidence of CNS disease at
beginning of therapy
Neonatal Herpes Simplex
Treatment
• Intravenous acyclovir is therapy of choice
• Acyclovir dose of 60 mg/kg/day is more
effective than 30 mg/kg/day
– 14 days for SEM disease
– 21 days for CNS/disseminated disease
• For conjunctivitis – topical 1% trifluridine
– 1 gtt affected eye q 2 hrs
– Follow with ophthalmology
Neonatal Herpes Simplex
Prognosis with Treatment (Acyclovir)
Survival
Normal
Local SEM
100%
100%
CNS
84%
32%
Disseminated
71%
82%
Percentage
Neonatal Morbidity Among Survivors With
Known Outcomes After 12 Months
100
90
80
70
60
50
40
30
20
10
0
n=46
n=2
n=28
n=13
n=5
n=18
Severe
Moderate
Mild
Normal
30
mg/kg/d
60
mg/kg/d
SEM Disease
30
mg/kg/d
60
mg/kg/d
CNS Disease
Kimberlin D. Sem Pediatr Infect Dis 2005;16:271
30
mg/kg/d
60
mg/kg/d
Disseminated
Disease
Study of 74 infants (45 CNS, 29 SEM) between 8/97 and 4/08
randomized to receive PO acyclovir vs placebo for 6 months
after completion of IV acyclovir therapy
Kimberlin D et al. New England Journal of Medicine 2011;365:1284-92
Percentage
Neonatal Morbidity Among Survivors: With
and Without Past-Therapy Suppression
100
90
80
70
60
50
40
30
20
10
0
n=28
n=13
n=11
n=13
Severe
Moderate
Mild
Normal
30
mg/kg/d
60
mg/kg/d
CNS Disease
CASG 101
N Engl J Med 2011;365:1284-92
60
mg/kg/d +
placebo
60
mg/kg/d +
suppression
CNS Disease
CASG 103
N Engl J Med 2011;365(14):1284-92
Percentage
Bayley Mental Score at 12 Months
100
90
80
70
60
50
40
30
20
10
0
n=28
n=13
n=11
n=13
Severe
Moderate
Mild
Normal
30
60
mg/kg/d mg/kg/d
CNS Disease
CASG 101
P>0.13
60
60
mg/kg/d + mg/kg/d +
placebo suppression
CNS Disease
CASG 103
P=0.40
Bayley Mental Score at 12 Months
CASG 103
(CNS Involvement Study)
CASG 104
(SEM Study)
Acyclovir
N=16
Placebo
N=12
Acyclovir
N=8
Placebo
N=7
Median
90.5
66.5
95
84
Adjusted
Mean
88.24†
68.12†
91.82‡
84.92‡
P-value by
ANCOVA*
0.046
0.263
*Adjusted for covariates at baseline which were unbalanced between treatment groups: †Head
‡Enrollment weight
circumference at birth, birth weight, enrollment weight
N Engl J Med 2011;365:1284-92
Redbook 2012 comment:
“Use of oral acyclovir suppressive therapy for the six months
following treatment of acute neonatal HSV disease recently has
been shown to improve neurodevelopmental outcomes in infants
with HSV CNS disease, and to prevent skin recurrences in infants
with any disease classification of neonatal HSV. The dose that
should be used is 300 mg/m2/dose administered three times daily
for six months; absolute neutrophil counts should be assessed
at 2 and 4 weeks after initiating suppressive therapy, and then
monthly during the treatment period.”
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