Diagnosis and Therapy of Perinatal Infections 2006 (Beyond “TORCH” Titers)

B. Keith English, M.D.

Professor of PediatricsUniversity of Tennessee Health

Science Center, Memphis

Perinatal Infections

• Perinatal infections are those acquired before, during, or shortly after birth

• Perinatal infections thus include in utero infections, natal infections (those acquired during the birth process), and early postnatal infections--the time before and after birth is arbitrary

Diagnosis of Perinatal Infections• “TORCH” was a useful acronym but led

to the use of a poor test..the “TORCH TITER”

• Serology IS the way to diagnose certain congenital or perinatal infections (e.g., syphilis, toxoplasmosis) but has NO ROLE in diagnosing others (e.g., HSV, CMV)

Spectrum of Perinatal Infections• Pyogenic bacterial infections (group B

streptococcus, E. coli, etc.)• Congenital and perinatal viral infections

(e.g., CMV, HSV, parvovirus, HIV)• Congenital syphilis• Congenital infections due to protozoan

parasites (e.g., toxoplasmosis)

Diagnosis of Perinatal Non-Pyogenic Infections: 2006

Serology Culture Histopath PCR

CMV - ++++ + +

HSV - ++++ +++ +++

Toxo ++++ + (R)* - + (R)

Rubella +/- +++ - + (R)

Syphilis +++ + (R)* - + (R)

* animal inoculation

Estimated Incidence of Perinatal Non-Pyogenic Infections in U.S.

• CMV 1% live births (5-20% of infants by 1-2 mo age)

• HSV 0.1 - 0.5 per 1000 births• Syphilis 0.1 - 0.5 per 1000• Toxoplasma 0.1 - 0.2 per 1000• Rubella Approaching Zero

Frequency of Congenital Infections which are Not Apparent

• CMV (> 90%)• Rubella (60-70%)• Toxoplasmosis (75%)• Syphilis (50%)• HSV (rare; less than 5%)

Common Findings:Congenital Non-Pyogenic Infections

• Hepatosplenomegaly• Jaundice• Pneumonia• Adenopathy• Petechiae• Meningoencephalitis

Distinctive Features:Congenital Non-Pyogenic Infections

• Intracranial calcifications (Toxo, CMV)• Cataracts (rubella, HSV)• Chorioretinitis (Toxo, CMV)• Bone lesions (syphilis, rubella)• Congenital heart disease (rubella)• Microcephaly (CMV); Hydrocephalus

(Toxo)• Vesicles (HSV, VZV, syphilis)

Congenital HIV Infection

• Congenital HIV infection is a preventable disease--maternal screening is the key

• Diagnosis in neonates and infants depends upon viral culture and PCR

• Serology of little value

Congenital syphilis

• Mother’s serology and treatment history are very important; serology still the mainstay of diagnosis

• PCR and IgM immunoblots are promising research tools but not yet easily available

• Penicillin remains the gold standard for therapy: 10-14 day treatment courses

Congenital rubella syndrome

• Uncommon today in the U.S. (MMR)• Severe cases with mental retardation,

microcephaly, cataracts, deafness, intradermal erythropoiesis (“blueberry muffin” appearance)

• Mother’s serology is the key• Diagnosis by viral culture and, soon,

PCR

Congenital Toxoplasmosis I

• Under-recognized in U.S.--especially milder cases (which are the majority)

• Transmission more common late in pregnancy, but more severe disease associated with 1st trimester transmission

• Severe cases often with hydrocephalus, chorioretinitis, jaundice, splenomegaly, intracranial calcifications (diffuse)

Congenital Toxoplasmosis

Congenital Toxoplasmosis II

• Congenital toxoplasmosis is a treatable disease, but early diagnosis is essential

• Up to 80-90% of congenitally infected neonates develop ophthalmological and/or other neurological sequelae

• Treatment is complicated and prolonged, requiring up to a year of pyrimethamine and sulfadiazine

Congenital Toxoplasmosis III

• Serology is currently the best way to make the diagnosis, BUT commercially available assays not reliable

• Negative serology in mom and/or baby essentially excludes the Dx

• Positive titers require confirmation by reference lab (Palo Alto, CA)

Congenital Toxoplasmosis IV

• Obstetricians must have a high index of suspicion for primary toxoplasmosis during pregnancy

• Screening programs may be justified to detect asymptomatic cases

• Prevention is the key-- avoid cat litter exposure, undercooked beef

Perinatal Infections due to Cytomegalovirus • CMV infections are highly prevalent in neonates, and

are probably more common than all other perinatal infections combined

• CMV infections can be acquired in utero, natally, or postnatally--and frequently are:

• congenital: 0.6-2.4% live births• natal: 2-6% neonates• postnatal: up to 14-21% of neonates!!

Congenital CMV Infections

• Most (>90%) asymptomatic• Primary maternal infection leads to fetal

infection in 30-50% of cases--10-15% of these have overt clinical disease

• Secondary maternal infection less likely to lead to fetal infection (1-2% ) but can do so and may lead to severe disease (Boppana et al, NEJM 2001, 344: 1366)

Symptomatic Congenital CMV Infection• Jaundice (62%)• Petechiae (58%)• Hepatosplenomegaly (50%)• IUGR (33%); Preterm (25%)• Microcephaly (21%)• Chorioretinitis (12%)• Fatal outcome (4%)

Sequelae of Congenital CMV Infections I• Neurological sequelae are the most common,

and most severe: • >90% of newborns with symptomatic congenital

CMV infection have visual, audiologic and/or other neurological sequelae

• - 5-17% of newborns with asymptomatic congenital CMV infection develop neurological sequelae (esp. hearing loss)

Congenital CMV

Congenital CMV

Sequelae of Congenital CMV Infections II• Cranial CT is a good predictor of sequelae in

neonates with congenital CMV infection• Most common abnormality is intracerebral

calcification (typically periventricular)• Boppana et al (Pediatrics 99:409, 1997)

reported that 90% of neonates with abnormal CT scan developed at least 1 sequelae, c/w 29% of babies with normal scans

• Only 1/17 neonates with nl CT had IQ < 70 (c/w 59% of those with abnl scan)

Diagnosis of Congenital CMV Infections• Isolation of CMV from urine or other

body fluid (CSF, blood, saliva) in the first 21 days of life is considered proof of congenital infection

• Serologic tests are unreliable; IgM tests currently available have both false positive and false negative results

• PCR may be useful in selected cases

Antiviral Therapy for Congenital CMV Infection?

• Ganciclovir has been shown to be effective therapy for certain CMV infections in immunocompromised hosts (e.g., retinitis or enterocolitis in HIV-infected patients)

• Neonatal experience with ganciclovir is limited, the toxicity of the drug is considerable (e.g., platelets, neutrophils), and oral bioavailability unreliable

Phase III Trial of Ganciclovir for Congenital CMV Disease I

• Phase III randomized trial of ganciclovir for symptomatic congenital CMV infections involving the CNS (Kimberlin et al, J. Pediatrics, 143:17,2003)

• One Hundred Neonates enrolled by NIAID CASG (9 centers)—however, only 42 were fully evaluable….

Phase III Trial of Ganciclovir for Congenital CMV Disease II

• Neonates randomized to receive 6 weeks of IV ganciclovir (6 mg/kg/dose q 12 hours) through a central venous catheter or no therapy

• Primary endpoint of study was hearing test: BSER performed at baseline and at 6 mos

Phase III Trial of Ganciclovir for Congenital CMV Disease III

• No significant difference in mortality (6% GCV, 12% untreated)

• Median head circumference (HC) growth at 6 weeks was greater in the GCV group vs. the untreated group (3.5 vs 2.65 cm) p = 0.022

Phase III Trial of Ganciclovir for Congenital CMV Disease IV

• HEARING LOSS/IMPROVEMENT• Hearing Improvement was more likely

in the GCV treated group at 6 and 12 mos (OR 4.31, 4.03), while Hearing Deterioration was less likely in the GCV group at 6 & 12 mos (OR 0.029/0.073)

• 84% GCV recipients (21/25) had stable or improved hearing at 6 mos c/w 59% of control pts (10/17)(p=0.06)

Phase III Trial of Ganciclovir for Congenital CMV Disease V

TOXICITY

• 29/46 (63%) GCV recipients

experienced Grade 3 or Grade 4 neutropenia, compared with 9/43 (21%) untreated control patients

Ganciclovir for Congenital CMV: Pittsburgh Experience I

Michaels et al (PIDJ, 22: 504, 1993) reported their experience with the treatment of 9 children with congenital CMV infection with sequential IV (median duration 1 year) followed by oral (median duration 0.83 yr) GCV

0/9 pts had progressive hearing loss (2/5 with hearing loss had improvement)

Ganciclovir for Congenital CMV: Pittsburgh Experience II

7/9 children had at least 1 significant complication of GCV therapy: 6 CVL infections3 CVL malfunctions1 Neutropenia

Ganciclovir Therapy for Congenital CMV? 2006• A six week course of IV ganciclovir may reduce the

rate of long-term hearing loss in neonates with symptomatic CMV infection

• However, this regimen is associated with significant toxicity, long-term followup data are lacking, and the optimal duration of therapy (if any) is unknown

• Potential benefits of antiviral therapy for asymptomatically infected neonates may be greater

Antiviral Therapy for Congenital CMV? 2006• Current role for IV ganciclovir uncertain: therapy

“may be considered for patients with symptomatic congenital CMV disease involving the CNS” (Kimberlin et al, 2003)

• 2006 Red Book says that it “is not recommended routinely because of insufficient efficacy data”

• ?? Treatment of neonates with worsening retinitis or hepatitis, severe pneumonia, or persistent severe thrombocytopenia ?? Duration of therapy ??

Antiviral Therapy for Congenital CMV? 2006

• More effective, less toxic, oral agent needed for future studies---prolonged Rx may be required: CASG study of oral valganciclovir (approved for therapy of CMV retinitis in AIDS patients) is underway (enrollment completed, followup in progress)

Prevention of CMV Infections?

A vaccine to prevent CMV infections is desperately needed

Trials of candidate vaccines are underway

CMV Vaccine development a “Level One” priority of the IOM

Perinatal Infections due to Herpes Simplex Virus• Timing and character of infection quite

different from CMV or rubella or toxoplasmosis or syphilis

• Rarely causes fetal infection; most infections are natal or postnatal

• Serology generally useless in the diagnosis of neonatal HSV infections

Herpetic Skin Lesions

More HSV skin lesions

Epidemiology of Genital Herpes• Predominately HSV-2, but up to 30% of

cases due to HSV-1 in some studies• HSV-2 seroprevalence 10-20% upper

SES, 40-60% lower SES• Point prevalence of genital HSV in

pregnant women 1%• HSV shedding at delivery 0.35%

(1/300)

Genital HSV-Primary vs. Recurrent• Primary disease more often

symptomatic and associated with greater (>10(6) viral particles) and more prolonged (>3 wks) viral shedding

• Recurrent episodes associated with 1000 - 10,000 fold less viral shedding (e.g., 10(2) to 10 (3) viral particles) for shorter durations (e.g., 2-5 days)

Timing of Perinatal HSV Infections

• INTRAPARTUM > 85%• POSTPARTUM 10%• INTRAUTERINE < 5%

Perinatal HSV Infections

• 65% HSV-2• 35% HSV-1• HSV-1 infections more likely to

disseminate and result in fatal outcome; paradoxically, encephalitis due to HSV-2 more severe than that due to HSV-1

Perinatal HSV Infections:Maternal/Obstetric History

• Maternal History often unreliable or misleading; <40% of mothers of neonates with proven HSV infection have Hx of herpetic lesions

• History of recurrent lesions (vs. primary) reduces likelihood of neonatal infection

• Trauma, including scalp electrode placement, may increase the likelihood of neonatal infection

Perinatal HSV Infections- Relationto Timing of Maternal Infection

• Neonates born to women with primary genital HSV infection at very high risk (at least 30-50%) of perinatal HSV infection

• Neonates born to women with recurrent genital HSV infection are at MUCH lower risk (less than 3%) of infection

• These differences likely reflect both viral titer and role of maternal antibody

Perinatal HSV Infection(Clinical Features)

• Skin-Eye-Mouth (SEM) disease; most present at 6-10 days of age

• Disseminated disease (with or without CNS involvement); most present at 5-7 days of age, but occasionally earlier

• Encephalitis alone; presents later, mean age of Dx 16-17 days (? Sx 3-5 d earlier)

Perinatal HSV infections:Prognosis and Sequelae

• Disease initially limited to SEM will disseminate to viscera and/or brain in > 70% of cases without therapy (even with therapy, 25% have some long-term CNS sequelae)

• Disseminated disease has > 80% mortality if untreated; rare survivors usually severely impaired

• Greatest impact of therapy has been to prevent dissemination in neonates with SEM disease

Diagnosis of Perinatal HSV Infections I.• Cutaneous disease usually easy to Dx;

characteristic clusters of vesicles on an erythematous base

• Disseminated HSV infection may be fulminant or insidious --overlap with bacterial sepsis• -- Only 40-50% have skin lesions• -- Must consider the diagnosis in “septic” neonate,

esp. in first 10 days of life...

Diagnosis of Perinatal HSV Infections II. • Neonates who present at 2-3 weeks of age

with encephalitis usually do NOT have visceral dissemination; <50% ever have skin lesions

• Must consider Dx in any neonate with meningitis or evidence of encephalitis

• CSF studies usually reveal lymphocytic pleocytosis (early), elevated protein (later), and occasionally hemorrhage and/or low Glu (later)

Diagnosis of Perinatal HSV Infection III.• “TORCH TITERS” are of NO value in

diagnosing perinatal HSV infections, and should not be ordered

• Older serologic tests could not reliably differentiate HSV-1 from HSV-2

• IgM-based tests are unreliable• SeroNEGATIVE mothers may have

primary disease (greatest risk to baby)

Diagnosis of Perinatal HSV Infections IV.• Rapid Dx available by DFA testing of

specimen from skin lesions• Culture (of lesions and/or mucosal sites) is

the gold standard for Dx but is insensitive in detection of CNS involvement

• PCR detection of HSV nucleic acid now the method of choice to Dx CNS disease and may provide prognostic information -- PCR of blood may also be useful

Treatment of Perinatal HSV Infections: 2006• Acyclovir is the drug of choice; use 60

mg/kg/day (20 mg/kg/dose, q 8h)• Duration of therapy at least 14 days for

SEM; at least 21 days for neonates with CNS involvement

• Consider CSF PCR at end of therapy for neonates with CNS involvement

High-Dose Acyclovir:Toxicity• Case reports of renal failure, but only

2/72 pts (3%) had Cr >2 mg/d in large NIAID study

• Neutropenia: ANC < 1000 in 19%(compared with 13% in patients receiving 45 mg/kg/d & 3% in historical controls receiving 30 mg/kg/d)

Care of Neonates Whose Mothers Have Active Genital Lesions I

Risk of disease in newborn is LOW (less than 3%) if mother has RECURRENT disease

Risk of disease in newborn is HIGH (perhaps 50% or more) if mother has primary genital HSV infection

Care of Neonates Whose Mothers Have Active Genital Lesions II

In low risk setting (recurrent HSV in mother), most experts do NOT recommend empiric acyclovir, but would obtain mucosal cultures at 24-48h and educate family about “signs and symptoms of neonatal HSV infection”

Care of Neonates Whose Mothers Have Active Genital Lesions III In high risk setting (primary HSV in mother),

most experts would obtain mucosal cultures at birth or at 24 hrs of age and either (A) initiate therapy if Cx positive, or (B) begin empiric acyclovir and then D/C if Cx negative

Some experts advocate longer course of therapy in this setting (when mom documented to have primary infection) even if neonate’s cultures are negative

Care of Neonates Whose Mothers Have Active Genital Lesions IV

Problem is distinguishing between primary and recurrent disease: new serologic methods that can distinguish HSV-1 and HSV-2 antibodies make this easier… but will obstetricians perform them?

Prevention of Neonatal Herpes The Future

New serologic tests make it possible to identify women who are at risk for acquisition of HSV-1 or HSV-2 during pregnancy (e.g., seronegative woman, seropositive spouse) Gardella, et al, Am J Obstet Gynecol 2006, 193:1891.

Vaccine to prevent primary and/or recurrent HSV infection is needed