TORCH Infections

Krishna Dummula, MD

Case of Interest
Baby girl E. - 24 wk GA 25 yr old G3 P0020 mother Mother presented in PTL - Born via SVD APGAR scores21,65 and 710; BW-584 gm, microcephaly Prenatal labs none abnormal Hospital course notable for
Respiratory distress syndrome Clinical Sepsis PDA, s/p ligation Anemia and persistent thrombocytopenia NEC (DOL # 45), s/p ileostomy (DOL # 58) Hyperbilirubinemia due to cholestasis Germinal matrix hemorrhage

Died at 64 days of life

Clinical cause of death was sepsis

Autopsy consent was obtained ascertain cause of death

Autopsy Findings
Gross findings
NEC with segmental involvement of jejunum Extensive peritoneal fibrous adhesions Hepatic necrosis

Microscopic findings
Intranuclear and intracytoplasmic viral inclusions characteristic of CMV
In kidneys, lungs, anterior pituitary gland and thyroid

Placental pathology
Neither villitis nor inclusions were seen on H&E Immunohistochemical stain for CMV negative

Source of CMV infection unclear

Congenital or postnatal Breast feeding / transfusion

TORCH The Name Game

Fuerst HT. Flame or Bird. Pediatrics 1975;56;107

Estimated Incidence of Perinatal TORCH 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

Index of Suspicion
When do you think of TORCH infections?
IUGR infants Hepato-splenomegaly Thrombocytopenia Unusual rash Concerning maternal history Classic findings of any specific infection

Distinctive Features

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)

Screening for TORCH Infections

TORCH titers not helpful
Tests both IgG and IgM IgM can be present for prolonged periods (3 months to more than an year in toxo 1)

Pattern of TORCH test use has a poor diagnostic return 2

Follow-up titers infrequently done

1. 2.

Boyer KM et al., Toxoplasmosis. In: Textbook of Pediatric Infectious Diseases 5th ed, Saunders, Phil. 2004. p. 2755 Leland D et al., The use of TORCH titers. PEDIATRICS 1983; 72 (1): 41-43

Cost Effectiveness of Screening Questioned

Khan et al., 2000:
Examined cost and number of diagnoses of TORCH infections in 75 infants with IUGR Screened with TORCH titers, urine cx., HUS 3 infants had a probable infection
One infant by + CMV Cx. Two infants by HUS None had a + IgM for TORCH

Combined cost of evaluation = $51,715 Concluded work up for TORCH infections in IUGR was not cost effective
Khan, NA, Kazzi, SN. Yield and costs of screening growth-retarded infants for torch infections. Am J Perinatol 2000; 17:131.

Diagnosing TORCH Infection

Do not use TORCH titers Good maternal/prenatal history
most infections - are mild illnesses often unrecognized

Thorough exam of infant Directed labs/studies based on most likely diagnosis

Diagnosis of TORCH Infections

Serology CMV HSV Toxo R ubella Syphilis ++++ +/+++ C ulture ++++ ++++ + +++ + Histopath + +++ PC R + +++ + + +

Cytomegalovirus

Epidemiology of Congenital CMV

Overall birth prevalence of congenital CMV was 0.64% 1
10,000 to 80,000 infants born /year with congenital CMV infection Estimated annual societal cost approaches $2 billion (1991) 2

About 11% of live-born infants - symptomatic

Mortality rate 30% Severe neurologic morbidity 80%

Transmission Rates:
Primary infection in mother 32% Recurrent infection during pregnancy - 1.4%

Risk factors for congenital CMV infection

non-white race low socioeconomic status premature birth NICU admittance
1. 2. Kenneson A and Cannon MJ. National Center on Birth Defects and Developmental Disabilities - Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007;17(4):253-76 Yow MD, Demmler GJ. Congenital cytomegalovirus disease-20 years is long enough. N Engl J Med 1992;326:702-3 in Prober C. Congenital cytomegalovirus (CMV) infections: Hats off to ALABAMA . The Journal of Pediatrics , Volume 143 , Issue 1 , Pages 4 - 6

Natal and Postnatal Infection

Intrapartum From Cervical and Vaginal Secretions
2% to 28% of seropositive pregnant women shed CMV Approximately 50% of exposed infants become infected Develop clinical signs of CMV disease at about 4 to 6 weeks of age.

Postpartum period Breast Feeding

9% to 88% of seropositive women shed CMV into their milk. 50% to 60% of infants become infected. Show no significant clinical signs (re-activation disease)

Blood Transfusions
2 -20% from unscreened or unfiltered blood

Stehel EK and Sanchez PJ. Cytomegalovirus Infection in the Fetus and Neonate. NeoReviews 2005;6;e38-e45

The Asymptomatic Congenital CMV

90% of congenital CMV asymptomatic at birth 0.5 15% of these are at risk for psychomotor, hearing, neurologic, ocular, or dental abnormalities within first few years of life 5-10% of cases may have sensorineural hearing loss

Clinical findings - Congenital CMV

Diagnosing Congenital CMV

Should be diagnosed within the first 3 weeks after birth 1 > 3 weeks: cannot exclude the possibility of postnatal infection due to exposure to CMV in the maternal cervical-vaginal tract Distinction is important - because prenatal infection has been associated with long-term sequelae such as hearing impairment. Gold standard
Detection of the virus in the urine (or saliva) by cytopathic effect in tissue culture Takes up to 3 weeks for results

The shell-vial method

which detects early antigen production after viral infection of fibroblasts can yield results in 24 hours highly sensitive and specific

1.

Demmler GJ. Infectious Diseases Society of America and Centers for Disease Control. Summary of a workshop on surveillance for congenital cytomegalovirus disease. Rev Infect Dis 1991; 13:315

PCR in the diagnosis of CMV

Preferred method for detection in CSF and amniotic fluid (+) CSF CMV-PCR - associated with a more severe neurologic outcome. (+) blood CMV-PCR - associated with development of hearing loss in infants who have congenital CMV infection. CMV PCR also has been performed on dried blood spot samples obtained by heel stick from newborns.
may offer an opportunity for screening all newborns for congenital CMV infection 2
1. 2. Stehel EK and Sanchez PJ. Cytomegalovirus Infection in the Fetus and Neonate. NeoReviews 2005;6;e38-e45 Vauloup-Fellous C et al., Evaluation of Cytomegalovirus (CMV) DNA Quantification in Dried Blood Spots: Retrospective Study of CMV Congenital Infection. Journal of Clinical Microbiology, November 2007; 45 (11): 3804-3806

Majority of infectious chorionic villitis is due to CMV

Characteristic placental pathology
Lymphoplasmacytic Stromal hemosiderin deposition Sclerosis and dystrophic mineralizations ("tombstones" of infected cells and villous damage) Intranuclear or cytoplasmic trophoblastic epithelial inclusions

Faye-Petersen, O. M. et al. Demystifying the Pathologic Diagnoses of Villitis and Fetal Thrombotic Vasculopathy. Neoreviews 2008;9:e399-e410

Congenital CMV Leading cause of non-genetic sensorineural hearing loss

23% of all prelingual hearing deficits Most children manifest within the first 2 postnatal years The hearing loss may be fluctuating and progressive
Hence, a complete audiologic examination should be performed as soon as possible after the diagnosis of CMV infection Followed by periodic hearing evaluations for the first few postnatal years.

Preferred hearing tests for monitoring of evolving hearing loss:

Audio evoked potential testing Brainstem evoked potential testing

Adler SP and Marshall B. Cytomegalovirus Infections. Pediatr Rev. 2007 Mar;28(3):92-100

Predictors of Hearing Loss in Children with Congenital CMV

Rivera, L. B. et al. Predictors of Hearing Loss in Children With Symptomatic Congenital Cytomegalovirus Infection. Pediatrics 2002;110:762-767

Relationship between Urine CMV titres and hearing loss

Rivera, L. B. et al. Predictors of Hearing Loss in Children With Symptomatic Congenital Cytomegalovirus Infection. Pediatrics 2002;110:762-767

Prevention and Screening

Mainstay of prevention
avoidance of exposure standard precautions hand hygiene Greater risk to the pregnant health care worker asymptomatic infant unidentified

Routine serologic screening Pregnant Women

Not recommended - no prophylactic or therapeutic interventions are available Ubiquitous nature of CMV - not excluded from caring for infants who are infected with CMV

Infant
Routine screening of all newborns for CMV is not recommended Newborns who do not pass their hearing screen may be screened for CMV

Treatment of Congenital CMV

Primarily - supportive care Ganciclovir
Inhibits viral DNA polymerase, thereby acting as a chain terminator during elongation of newly synthesized viral DNA The most common adverse effect in neonates is neutropenia, which occurs in as many as 60% of recipients

Kimberlin D. Effect of Ganciclovir Therapy on Hearing in Symptomatic Congenital Cytomegalovirus Disease Involving the Central Nervous System: A Randomized, Controlled Trial . The Journal of Pediatrics, 2003; 143 (1): 16 - 25

Ganciclovir therapy for infants who had congenital CMV infection involving the central nervous system - I

Kimberlin, 2003: multicenter, randomized

evaluated safety and efficacy of IV ganciclovir for 6 weeks versus no therapy 100 CMV-infected neonates ( 32 weeks of gestation, birth weight of 1,200 g) 47 evaluable infants 25 ganciclovir recipients primary end point was improved brainstemevoked response (BSER) between baseline and 6-month follow-up
Kimberlin D. Effect of Ganciclovir Therapy on Hearing in Symptomatic Congenital Cytomegalovirus Disease Involving the Central Nervous System: A Randomized, Controlled Trial. The Journal of Pediatrics, 2003; 143 (1): 16 - 25

Ganciclovir therapy for infants who had congenital CMV infection involving the central nervous system - II
Infants from treatment group (84%) were significantly more likely to have either improved or normal hearing at 6 months than untreated infants (59%) At 1 or more years of age, those who received ganciclovir (0%) were significantly less likely to have worse hearing than the untreated group (41%) Other beneficial effects
significant decrease in median time to normalization of the alanine aminotransferase concentration improved weight gain and head circumference after 6 weeks of therapy no change in mortality

Neurodevelopmental assessments were not performed, and it is not known if ganciclovir therapy affects the long-term prognosis in these infants
Kimberlin D. Effect of Ganciclovir Therapy on Hearing in Symptomatic Congenital Cytomegalovirus Disease Involving the Central Nervous System: A Randomized, Controlled Trial. The Journal of Pediatrics, 2003; 143 (1): 16 - 25

CMV Breast Feeding

Freezing of expressed human milk
20C for 3 to 7 days significantly diminishes CMV titers but does not eliminate infectivity completely

Pasteurization (62.5C) required for complete neutralization

this is not routinely done or available

In Preterm infants
potential benefits far outweigh the potential risk of symptomatic CMV
Stehel EK and Sanchez PJ. Cytomegalovirus Infection in the Fetus and Neonate. NeoReviews 2005;6;e38-e45 Pickering KL. The Red Book, 2006. American Academy of Pediatrics 27th Ed.

The kinetics of CMV DNA copy numbers in breast milk

Yasuda, A. et al. Evaluation of Cytomegalovirus Infections transmitted via Breast Milk in Preterm Infants With a Real-Time Polymerase Chain Reaction Assay. Pediatrics 2003;111:1333-1336

Blood Transfusions
An important iatrogenic source Incidence of infection with untreated transfusates is about 15% Usually occurs in infants who weigh less than 1,300 g The risk of infection is related to:
volume of transfused blood number of donors elevated CFT titers to CMV in donor blood

Diagnosis and Screening Algorithm for CMV infection in pregnant women

Munro SC et al., Diagnosis of and Screening for CMV infection in Pregnant Women. J. Clin Micro 2005; 43 (9); 4713-4718

Toxoplasmosis

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

Congenital Toxoplasmosis in the United States 1 in 1000 to 1 in 10000 Primary maternal infection in pregnancy 1 in 3 risk of fetal infection
Infection rate higher with infection in 3rd trimester Fetal death higher with infection in 1st trimester
American Academy of Pediatrics. Toxoplasma gondii Infections. In: The Red Book 2006, 27th Ed. p.666

Clinical Manifestations
Asymptomatic at birth in 70% - 90% Symptoms become apparent later in life Classic Triad
Chorioretinitis * Hydrocephalus Intracranial calcifications

Consequences of intrauterine meningo-encephalitis Initially asymptomatic infants are still at high risk of developing abnormalities, especially chorioretinitis

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
serology with IgM / IgA (IFA, ELISA, ISAGA) IgA more sensitive than IgM
Boyer KM. Diagnostic testing for congenital toxoplasmosis. Pediatric Infect Dis J 2001; 20:59

Toxoplasma Screening
Prenatal testing with varied sensitivity not useful for screening Routine neonatal screening with IgM testing implemented in some areas 1
Identifies infected asymptomatic infants who may benefit from therapy

1.

Guerina NG et al., Neonatal screening and early treatment for congenital Toxoplasma gondii infection. The New England Regional Toxoplasma Working Group. NEJM 1994; 330:1858

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)
American Academy of Pediatrics. Toxoplasma gondii Infections. In: The Red Book 2006, 27th Ed. p.666-668

Thank You