this presentation is the intellectual property of the...

Forty-Eighth Annual Teaching Conference Pediatrics for the Practitioner -UT Health Science Center

San Antonio School of Medicine –June 10-12, 2011

This presentation is the intellectual property of the author/presenter. Contact them for permission to

reprint and/or distribute.

Deena E. Sutter, MD, FAAP

LtCol, USAF

Pediatric Infectious Disease Service

Brooke Army Medical Center

Deena E. Sutter, MD, FAAP has no

relevant financial relationships with

commercial interests to disclose.

Why Prenatal Screening for an

Infectious Disease?

Effective intervention for prevention

Effective intervention (pre- or post-natal) for treatment

If the incidence of disease is common enough that it is cost-effective

If transmission is common enough to warrant screening If significant sequelae are rare, though, it’s a problem

If there is high risk of severe effects if transmitted Preparing the parent

Elective termination

Ensure vaccination of mother post-partum





Who makes the guidelines?

ACOG

ACIP/CDC

IDSA

USPSTF

USPHS

DoD/VA

AAP

AAFP

Surprise, surprise, they often have

different recommendations!

How about TORCH titers?

Cytomegalovirus Ab, IgM

Herpes simplex Ab, IgM

Rubella Ab, IgM

Toxoplasma Ab, IgM

False-positive rate for titers obtained

without specific clinical indication is high

Accurate diagnoses are rare with these

– JUST DON’T ORDER THEM!

Congenital/Perinatal Infections

Routine Testing Directed Testing

HIV*

Syphilis*

Hepatitis B*

Group B Strep

UA/Urine culture

CMV

Toxoplasma

Herpes Simplex

Parvovirus B19

Hepatitis C

HTLV

T cruzi (Chagas)

M tuberculosis

Test immediately and again in 3rd trimester if high-risk

High risk /non-immune

(variable)

•GC/Chlamydia*

•VZV

•Rubella







HIV*

Syphilis*

Hepatitis B*

Group B Strep

UA/Urine culture

CMV

Toxoplasma

Herpes Simplex

Parvovirus B19

Hepatitis C

HTLV

T cruzi (Chagas)

M tuberculosis



(variable)

•GC/Chlamydia*

•VZV

•Rubella

Serologic Assays

Antibody response as simple measure of immunity Not always best measure

○ Windows of IgG vs IgM presence highly variable

○ IgM may be cross-reactive (nonspecific)

LOTS of different types of serologic tests!

○ Sensitivity and specificity vary based on test

○ PPV and NPV related to overall prevalence of infection

Nonspecific screening assays may need specific/sensitive assays to follow (HIV, syphilis)

Some extremely complicated (toxoplasma)

Tests for Pathogens or Antigens

Viral or bacterial cultures – only a few of

the pathogens (GBS, HSV, CMV)

Nucleic acid testing (PCR, other) –

amniotic fluid, placenta, or fetal body

fluids/tissue

Occasionally ID from maternal or infant

blood

Antigen tests – HBSAg (blood), HSV or

VZV DFA (vesicles)






Vaccine-Preventable


HIV*

Syphilis*

Hepatitis B*

Group B Strep

UA/Urine culture

CMV

Toxoplasma

Herpes Simplex

Parvovirus B19

Hepatitis C

HTLV

T cruzi (Chagas)

M tuberculosis



(variable)

•GC/Chlamydia*

•VZV

•Rubella

Rubella “screening only”

No intervention

Rubella IgG – is mom immune?

>90% seroresponse to vaccine

○ Live-virus vaccine contraindicated in pregnancy

○ Goal to immunize women of childbearing age who

are not pregnant

Documentation of 1 or more doses is sufficient

evidence of immunity in pregnancy (CDC)

DoD guidelines recommend universal serology

○ Recommendation to avoid exposure (limited

evidence)

○ Immunization of susceptible women post-partum

Congenital Rubella Syndrome

99% decline after implementation of

vaccine in 1969

Few cases per year, essentially all

imported

Wkly Epidemiol Rec. 2010 Oct 15;85(42):413-8.

Controlling rubella and preventing congenital rubella

syndrome – global progress, 2009.





Cohen & Powderly: Infectious Diseases, 3rd ed.

Congenital Varicella

Rare development of congenital varicella

even when pregnant women infected

Rates of natural disease decreased with

vaccine (90-95% response) – congenital

infection even more rare

Of more concern – severe varicella in infants

exposed perinatally or preterm infants

without maternal immunity

VZV – screening, with potential

intervention in case of exposure Obtain test if proof of immunity does not exist IgG negative - vaccinate after delivery

Birth before 1980 NOT an accepted proof of immunity

Most women of childbearing age - screening if immunization records not available

Varizig – (IND hyperimmune globulin) If suspected infection = immunoglobulin for mom

For neonates with maternal symptoms 5 days prior to or 2 days post-delivery

Neonates with presumed lack of maternal antibody and post-natal exposure





Hepatitis B Immunization of high-risk groups 1980’s-1990’s

1999 - Universal immunization of all infants

recommended

Hepatitis B

Rates of congenital infection have fallen dramatically since vaccination (first high-risk, then universal) was implemented

From 1990 to 2004, reported incidence of hepatitis B in children declined 96% (from 3.0/100,000 to 0.16/100,000)

All women are screened with Hepatitis B surface antigen (HBSAg) Not surface antibody – this is an indicator of

prior immunization, or recovery from natural infection

Hepatitis B serologies

Interpretation HBSAb HBSAg Anti-HBc HBeAg

Susceptible –

unimmunized

or

nonresponder

- - - -

Immunized,

Immune+ - - -

Prior infection,

Immune, not

infectious

+ - + -

Chronic carrier,

infectious- + + -

Chronic carrier,

highly

infectious

- + + +





CDC, 2006

Hepatitis B

If HBSAg is positive

Additional serologic evaluation, liver function

tests, DNA PCR

○ Determination whether she is a chronic carrier

(low viral load, HBSAg+/HBcAb+) or at

highest risk for transmission (high viral load

with HBeAg)

Infants born to HBSAg mothers should all

receive HB vaccine AND HBIG within 12

hours of birth

Hepatitis B

90% of perinatal infections

can be prevented with

appropriate screening and

prophylaxis

Up to 90% of infants

born to HBSAg and

HBeAg+ mothers will

be infected

90% of infants

infected

congenitally will

be chronically

infected

Acute infection will

resolve in 90% of

adults who are

infected





(Often confusing test results)



HIV*

Syphilis*

Hepatitis B*

Group B Strep

UA/Urine culture

CMV

Toxoplasma

Herpes Simplex

Parvovirus B19

Hepatitis C

HTLV

T cruzi (Chagas)

M tuberculosis



(variable)

•GC/Chlamydia*

•VZV

•Rubella

Congenital CMV BY FAR the most common congenital

infection in the US

Estimated 40,000 cases per year (out of approximately 4 million births per year = 1% of all live births)○ Primary infection in non-immune women

○ Young women with toddlers, daycare workers

90-95% asymptomatic○ Development of SN hearing loss

possible in asymptomatic

○ Routine screening NOT indicated Efficacy of gancyclovir in asymptomatic or

mildly symptomatic still unclear

Toxicity – neutropenia, central line placement





Congenital CMV – Labs

Prenatal

Mom with febrile illness +/- rash

And/or infant with abnormalities on

ultrasound

○ Maternal CMV IgM

○ High-avidity IgG assays

○ Amniotic fluid culture (60% sensitive) or PCR

(near 100%)

○ Fetal blood (cordocentesis) – less sensitive


Postnatal

Viral culture – gold standard

○ Urine, saliva, tissue

○ May take 2 or more weeks, but high sensitivity (90%+)

○ Modifications such as shell vial or microtiter plate with IF Abs for quicker results

PCR

○ Highly sensitive Blood, urine, CSF, saliva, tissue

Quantitative PCR from blood

- Varying data on prognostic value of viral load


Serologic assays for newborn

IgM – relatively insensitive (60-80%)

IgG - persistence past 3-4 months may be

helpful in late dx

After 2 weeks of life, any positive test

(PCR, culture, IgM) could be post-natal

infection

Viral shedding for months is common





Congenital Toxoplasmosis

Toxoplasma

gondii

Parasite –

protozoan

Zoonosis – cats

(oocysts),

undercooked meat

(tissue cysts)

Incidence of 1-

10/10,000 in US

Kliegman: Nelson Textbook of Pediatrics, 18th ed.

Classic triad:

-Hydrocephalus

-Intracranial calcifications

-Chorioretinitis

Like CMV, many asymptomatic 80% of women infected in

last few weeks of pregnancy transmit

○ Almost all subclinical

○ Risk for late ophtho findings

Diagnostic Methods

Traditionally, based on clinical suspicion and suggesting laboratory findings

Elevated CSF protein, mononuclear pleocytosis

Histologic evidence (often from autopsy or placenta)

Culture methods – mouse innoculation or tissue culture

PCR assays

Have replaced most culture diagnostics

○ Highly sensitive

CSF, placenta, amniotic fluid, other tissues

Neonatal parasitemia varies (15-75%) depending on disease presentation





Serologic assays

Primary method of diagnosis

Numerous methods employed

Sabin-Feldman dye test, Complement fixation,

IHA, Agglutination, IFA, various ELISA assays

Most labs employ conventional ELISA

○ SHOULD NOT BE USED TO DIAGNOSE

MATERNAL OR FETAL INFECTION - High rates

of false-positive IgM

IgM double sandwich ELISA

Immunosorbent Agglutination Assay

(ISAGA)

IgM, IgA, IgE

Testing in the United States

Palo Alto –

Toxoplasma serology laboratory

www.pamf.org

HIV

1994 - PACTG-076

Transmission reduced from 25.5% to 8.3%

with ZDV-only regimen in mother and infant

Since then - dramatic progress in ART –

most women already on 3-drug HAART

Undetectable viral load and no other risk

factors – risk likely 1-2% or less

Today – estimated 100-300 infants

infected annually





Diagnostic Testing

First prenatal visit

HIV ELISA followed by confirmatory WB

Opt-in vs opt-out testing

○ CDC recommends “opt-out” meaning no separate consent

If negative, repeat in 3rd trimester (<36 weeks)

○ CDC says to “consider” and “recommended” in high-risk areas or high risk behavior

○ Rapid testing at time of delivery False positives in patient with low risk can be a problem

EXAMPLE – prevalence of 0.1% HIV positive

- Test with 99.1 specificity

- PPV is only 10%

Results need to be communicated quickly

- Infant-only regimens less effective

HIV+ mom….Testing the infant

Prior to 2009 DNA-PCR was the only recommended test Test in first 48 hours of life recommended

○ Only 25-40% positive

○ Suggests in-utero transmission

2009 Red Book - changes Viral load (RNA-PCR) is acceptable option

○ High sensitivity

48 hour test no longer recommended Consider when high-maternal viral load or no maternal

treatment

○ Recommended @14 days, 1-2 months, 4-6 months





HIV-1 Exclusion in Infants

Presumptive exclusion*

2 negative virologic tests

(2+ weeks and 4+

weeks)

1 negative virologic test

after 4 weeks

HIV Ab after 6 months

Definitive exclusion

2 negative tests (1+

months and 4+ months)

2 negative HIV Ab tests

after 6 months

No clinical or other lab

evidence of

immunodeficiency or HIV

*If presumptive exclusion, PCP prophylaxis no

longer indicated at 4-6 weeks

Infant with Unknown Maternal

Status

Foreign adoptees

Infants of mothers without documented

prenatal testing, or possible seroconversion

after testing in 1st trimester

HIV-1 Ab with reflex Western Blot – if > 6m

Positive WB after 18 months diagnostic

Syphilis

“We’re calling from Ft Hood. We have a

mom and a baby with positive RPRs,

and we don’t know what workup to do.”





Congenital Syphilis Rates from 1-100/100,000 live births

Dramatic decrease since late 1980’s

;

www.marchofdimes.com

Congenital Syphilis

Culture (rabbit infectivity test), darkfield

microscopy, PCR not widely available

Nearly all diagnostic labs are serological

Combination of non-treponemal (screening)

and treponemal testing

Comparison of maternal and infant titers





Remember

RPR/VDRL are non-treponemal antibodies

Antibodies to cardiolipin

Titers reflective of disease activity

○ False positives with connective tissue disease,

other infections

○ + RPR in mom with + treponemal Ab = syphilis

Treponemal tests

FTA-ABS, TP-PA, Syphilis IgG (ELISA)

Usually positive for life

Adequate Maternal Therapy Penicillin G (IM Benzathine, 2.4m U x 1 or x 3)

>30 days prior to delivery

4-fold decrease in RPR titer

Must be documented!

If above are not met, full workup of infant (CSF studies, CBC, long bone films) required If workup negative – 50K U/kg Benzathine PenG IM x 1

If infant has with RPR 4x > maternal RPR and/or clinical signs of syphilis Evaluate with LP, CBC, other tests “as indicated”

Treat – PenG 100-150K U/kg/day x 10 days or procaine 50K U/kg/day x 10days

If infant RPR less than 4x maternal, treatment adequate 50K U/kg Benzathine PCN x 1

May defer therapy if able to follow infant closely with RPRs

Follow the Flowchart!

Red Book®: 2009 Report

of the Committee on

Infectious Diseases - 28th

Ed.

Long: Principles

and Practice of

Pediatric Infectious

Diseases, 3rd ed.;





Perinatal HSV

1/3,000 to 1/20,000 live births

Not usually “congenital” – disease

occurs around time of delivery

Ascending infection or during vaginal

delivery

Approximately 30-50% of women with

primary transmission vs 1-2% of women

with recurrence (seropositive)

75% of perinatal HSV – no maternal history

Perinatal HSV

Routine screening NOT indicated

60% of women of childbearing age have HSV-1 and 23% have HSV-2 antibodies

Serology rarely helpful unless indicates acute maternal infection at time of delivery

○ Need clinical suspicion (genital lesions, febrile illness, new sexual partner)

○ Most seroconversions are asymptomatic

Viral shedding in patients even when symptomatic – PCR/culture not indicated but may be useful if genital lesions present





Workup of Infant with HSV+ Mother

Surface cultures (12-24 hours of life) Skin (lesions), conjunctivae, rectum, urine,

oropharynx

HSV culture – gold standard○ Cell culture - 48-72h, stained with fluorescent Abs

PCR of CSF or blood (do not send surface swabs for PCR)○ CSF 75-90% sensitive, may need to repeat if

negative but evidence of CNS disease

○ Serum PCR – 40-70% sensitive – more likely in disseminated HSV

Serologies usually not helpful

Vesicles – DFA less sensitive than culture○ Tzank smear – insensitive

In utero (3%)

Disseminated infection

20-30%

Delivery 1 week

CNS disease

30%

2 weeks

SEM disease

30-40%

4 weeks3 weeks

Timeline of Perinatal HSV Infection

Manifestations

•Most patients will have workup days to weeks post-delivery

•Surface cultures not indicated, CSF studies ALWAYS

indicated, plus virologic/antigen testing of lesions, LFTs, CBC

Summary

Testing for perinatal or congenital

infections can be tricky

Need to know the incidence of disease

The epidemiology of transmission

Which labs are indicated, and which are not

If labs results are available which were not

indicated – know the significance!

AAP Red Book is always a good starting

place

this presentation is the intellectual property of the...

Documents