Ashley M. Maranich, MD CPT/USA/MC Pediatric Infectious Disease Fellow TORCH Infections Ashley M. Maranich, MD CPT/USA/MC Pediatric Infectious Disease Fellow

TORCH Infections T=toxoplasmosis O=other (syphilis) R=rubella C=cytomegalovirus (CMV) H=herpes simplex (HSV)

You are taking care of a term newborn male with birth weight/length <10th %ile. Physical exam is normal except for a slightly enlarged liver span. A CBC is significant for low platelets. What, if anything, do you worry about? How do you proceed with a work-up?

Index of Suspicion When do you think of TORCH infections? IUGR infants HSM Thrombocytopenia Unusual rash Concerning maternal history “Classic” findings of any specific infection

Diagnosing TORCH Infection !!!!!!DO NOT USE TORCH TITERS!!!!!!

Diagnosing TORCH Infection Good maternal/prenatal history Remember most infections of concern are mild illnesses often unrecognized Thorough exam of infant Directed labs/studies based on most likely diagnosis… Again, DO NOT USE TORCH TITERS!

Screening TORCH Infections Retrospective study of 75/182 infants with IUGR who were screened for TORCH infections 1/75 with clinical findings, 11/75 with abnl lab findings All patients screened: TORCH titers, urine CMV culture, head US Only 3 diagnosed with infection NONE by TORCH titer!! Overall cost of all tests = $51,715 “Shotgun” screening approach NOT cost effective nor particularly useful Diagnostic work-up should be logical and directed by history/exam findings Khan, NA, Kazzi, SN. Yield and costs of screening growth-retarded infants for torch infections. Am J Perinatol 2000; 17:131.

Toxoplasmosis Caused by protozoan – Toxoplasma gondii Domestic cat is the definitive host with infections via: Ingestion of cysts (meats, garden products) Contact with oocysts in feces Much higher prevalence of infection in European countries (ie France, Greece) Acute infection usually asymptomatic 1/3 risk of fetal infection with primary maternal infection in pregnancy Infection rate higher with infxn in 3rd trimester Fetal death higher with infxn in 1st trimester

Clinical Manifestations Most (70-90%) are asymptomatic at birth Classic triad of symptoms: Chorioretinitis Hydrocephalus Intracranial calcifications Other symptoms include fever, rash, HSM, microcephaly, seizures, jaundice, thrombocytopenia, lymphadenopathy Initially asymptomatic infants are still at high risk of developing abnormalities, especially chorioretinitis

Chorioretinitis of congenital toxo

Diagnosis Maternal IgG testing indicates past infection (but when…?) Can be isolated in culture from placenta, umbilical cord, infant serum PCR testing on WBC, CSF, placenta Not standardized Newborn serologies with IgM/IgA

Toxo Screening Prenatal testing with varied sensitivity not useful for screening Neonatal screening with IgM testing implemented in some areas Identifies infected asymptomatic infants who may benefit from therapy

Prevention and Treatment Treatment for pregnant mothers diagnosed with acute toxo Spiramycin daily Macrolide antibiotic Small studies have shown this reduces likelihood of congenital transmission (up to 50%) If infant diagnosed prenatally, treat mom Spiramycin, pyrimethamine (anti-malarial, dihydrofolate reductase inhib), and sulfadiazine (sulfa antibiotic) Leucovorin rescue with pyrimethamine Symptomatic infants Pyrimethamine (with leucovorin rescue) and sulfadiazine Treatment for 12 months total Asymptomatic infants Course of same medications Improved neurologic and developmental outcomes demonstrated (compared to untreated pts or those treated for only one month)

Syphilis Treponema pallidum (spirochete) Transmitted via sexual contact Placental transmission as early as 6wks gestation Typically occurs during second half Mom with primary or secondary syphilis more likely to transmit than latent disease Large decrease in congenital syphilis since late 1990s In 2002, only 11.2 cases/100,000 live births reported

From MMWR – Aug 2004

From MMWR – Aug 2004

Congenital Syphilis 2/3 of affected live-born infants are asymptomatic at birth Clinical symptoms split into early or late (2 years is cutoff) 3 major classifications: Fetal effects Early effects Late effects

Clinical Manifestations Fetal: Stillbirth Neonatal death Hydrops fetalis Intrauterine death in 25% Perinatal mortality in 25-30% if untreated

Clinical Manifestations Early congenital (typically 1st 5 weeks): Cutaneous lesions (palms/soles) HSM Jaundice Anemia Snuffles Periostitis and metaphysial dystrophy Funisitis (umbilical cord vasculitis)

Periostitis of long bones seen in neonatal syphilis

Clinical Manifestations Late congenital: Frontal bossing Short maxilla High palatal arch Hutchinson teeth 8th nerve deafness Saddle nose Perioral fissures Can be prevented with appropriate treatment

Hutchinson teeth – late result of congenital syphilis

Diagnosing Syphilis (Not in Newborns) Available serologic testing RPR/VDRL: nontreponemal test Sensitive but NOT specific Quantitative, so can follow to determine disease activity and treatment response MHA-TP/FTA-ABS: specific treponemal test Used for confirmatory testing Qualitative, once positive always positive RPR/VDRL screen in ALL pregnant women early in pregnancy and at time of birth This is easily treated!!

CDC Definition of Congenital Syphilis Confirmed if T. pallidum identified in skin lesions, placenta, umbilical cord, or at autopsy Presumptive diagnosis if any of: Physical exam findings CSF findings (positive VDRL) Osteitis on long bone x-rays Funisitis (“barber shop pole” umbilical cord) RPR/VDRL >4 times maternal test Positive IgM antibody

Diagnosing Congenital Syphilis IgG can represent maternal antibody, not infant infection This is VERY intricate and often confusing Consult your RedBook (or peds ID folks) when faced with this situation

Treatment Penicillin G is THE drug of choice for ALL syphilis infections Maternal treatment during pregnancy very effective (overall 98% success) Treat newborn if: They meet CDC diagnostic criteria Mom was treated <4wks before delivery Mom treated with non-PCN med Maternal titers do not show adequate response (less than 4-fold decline)

Rubella Single-stranded RNA virus Vaccine-preventable disease No longer considered endemic in the U.S. Mild, self-limiting illness Infection earlier in pregnancy has a higher probability of affected infant

Reported rubella and CRS: United States, 1966-2004 Meissner, H. C. et al. Pediatrics 2006;117:933-935 Copyright ©2006 American Academy of Pediatrics

Clinical Manifestations Sensorineural hearing loss (50-75%) Cataracts and glaucoma (20-50%) Cardiac malformations (20-50%) Neurologic (10-20%) Others to include growth retardation, bone disease, HSM, thrombocytopenia, “blueberry muffin” lesions

“Blueberry muffin” spots representing extramedullary hematopoesis

Diagnosis Maternal IgG may represent immunization or past infection - Useless! Can isolate virus from nasal secretions Less frequently from throat, blood, urine, CSF Serologic testing IgM = recent postnatal or congenital infection Rising monthly IgG titers suggest congenital infection Diagnosis after 1 year of age difficult to establish

Treatment Prevention…immunize, immunize, immunize! Supportive care only with parent education

Cytomegalovirus (CMV) Most common congenital viral infection ~40,000 infants per year in the U.S. Mild, self limiting illness Transmission can occur with primary infection or reactivation of virus 40% risk of transmission in primary infxn Studies suggest increased risk of transmission later in pregnancy However, more severe sequalae associated with earlier acquisition

Clinical Manifestations 90% are asymptomatic at birth! Up to 15% develop symptoms later, notably sensorineural hearing loss Symptomatic infection SGA, HSM, petechiae, jaundice, chorioretinitis, periventricular calcifications, neurological deficits >80% develop long term complications Hearing loss, vision impairment, developmental delay

Ventriculomegaly and calcifications of congenital CMV

Diagnosis Maternal IgG shows only past infection Infection common – this is useless Viral isolation from urine or saliva in 1st 3weeks of life Afterwards may represent post-natal infection Viral load and DNA copies can be assessed by PCR Less useful for diagnosis, but helps in following viral activity in patient Serologies not helpful given high antibody in population

Treatment Ganciclovir x6wks in symptomatic infants Studies show improvement or no progression of hearing loss at 6mos No other outcomes evaluated (development, etc.) Neutropenia often leads to cessation of therapy Treatment currently not recommended in asymptomatic infants due to side effects Area of active research to include use of valgancyclovir, treating asx patients, etc.

Herpes Simplex (HSV) HSV1 or HSV2 Primarily transmitted through infected maternal genital tract Rationale for C-section delivery prior to membrane rupture Primary infection with greater transmission risk than reactivation

Clinical Manifestations Most are asymptomatic at birth 3 patterns of ~ equal frequency with symptoms between birth and 4wks: Skin, eyes, mouth (SEM) CNS disease Disseminated disease (present earliest) Initial manifestations very nonspecific with skin lesions NOT necessarily present

Presentations of congenital HSV

Diagnosis Culture of maternal lesions if present at delivery Cultures in infant: Skin lesions, oro/nasopharynx, eyes, urine, blood, rectum/stool, CSF CSF PCR Serologies again not helpful given high prevalence of HSV antibodies in population

Treatment High dose acyclovir 60mg/kg/day divided q8hrs X21days for disseminated, CNS disease X14days for SEM Ocular involvement requires topical therapy as well

Which TORCH Infection Presents With… Snuffles? syphilis Chorioretinitis, hydrocephalus, and intracranial calcifications? toxo Blueberry muffin lesions? rubella Periventricular calcifications? CMV No symptoms? All of them

Which TORCH Infections Can Absolutely Be Prevented? Rubella Syphilis

When Are TORCH Titers Helpful in Diagnosing Congenital Infection? NEVER!

Questions?