TORCH InfectionsTORCH InfectionsKrishna Dummula, MDKrishna Dummula, MD

Case of InterestCase of Interest Baby girl E. Baby girl E. -- 24 wk GA24 wk GA 25 yr old G3 P0020 mother25 yr old G3 P0020 mother Mother presented in PTL Mother presented in PTL -- Born via SVDBorn via SVD APGAR scoresAPGAR scores2211,6,655 and 7and 71010; BW; BW--584 gm, 584 gm, microcephalymicrocephaly Prenatal labs Prenatal labs none abnormalnone abnormal Hospital course notable forHospital course notable for

zz Respiratory distress syndromeRespiratory distress syndromezz Clinical Sepsis Clinical Sepsis zz PDA, PDA, s/ps/p ligationligationzz Anemia and persistent thrombocytopeniaAnemia and persistent thrombocytopeniazz NEC (DOL # 45), NEC (DOL # 45), s/ps/p ileostomy (DOL # 58)ileostomy (DOL # 58)zz Hyperbilirubinemia due to cholestasisHyperbilirubinemia due to cholestasiszz Germinal matrix hemorrhageGerminal matrix hemorrhage

Died at 64 days of lifeDied at 64 days of lifezz Clinical cause of death was sepsisClinical cause of death was sepsis

Autopsy consent was obtained Autopsy consent was obtained ascertain cause of deathascertain cause of death

Autopsy FindingsAutopsy Findings Gross findingsGross findings

zz NEC with segmental involvement of jejunumNEC with segmental involvement of jejunumzz Extensive peritoneal fibrous adhesionsExtensive peritoneal fibrous adhesionszz Hepatic necrosisHepatic necrosis

Microscopic findingsMicroscopic findingszz IntranuclearIntranuclear and and intracytoplasmicintracytoplasmic viral inclusions characteristic of viral inclusions characteristic of

CMVCMV In kidneys, lungs, anterior pituitary gland and thyroidIn kidneys, lungs, anterior pituitary gland and thyroid

Placental pathologyPlacental pathologyzz Neither Neither villitisvillitis nor inclusions were seen on H&Enor inclusions were seen on H&Ezz ImmunohistochemicalImmunohistochemical stain for CMV stain for CMV negativenegative

Source of CMV infection Source of CMV infection unclearunclearzz Congenital or postnatalCongenital or postnatalzz Breast feeding / transfusionBreast feeding / transfusion

TORCH TORCH The Name GameThe Name Game

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

Estimated Incidence of Perinatal Estimated Incidence of Perinatal TORCH Infections in U.S.TORCH Infections in U.S.

CMV CMV 1% live births (51% live births (5--20% of 20% of infants by 1infants by 1--2 mo age)2 mo age)

HSVHSV 0.1 0.1 -- 0.5 per 1000 births0.5 per 1000 births Syphilis Syphilis 0.1 0.1 -- 0.5 per 10000.5 per 1000 ToxoplasmaToxoplasma 0.1 0.1 -- 0.2 per 10000.2 per 1000 RubellaRubella Approaching ZeroApproaching Zero

Index of SuspicionIndex of Suspicion

When do you think of TORCH infections?When do you think of TORCH infections?zz IUGR infantsIUGR infantszz HepatoHepato--splenomegalysplenomegalyzz ThrombocytopeniaThrombocytopeniazz Unusual rashUnusual rashzz Concerning maternal historyConcerning maternal historyzz ClassicClassic findings of any specific infectionfindings of any specific infection

Distinctive FeaturesDistinctive Features

Intracranial calcifications (Intracranial calcifications (ToxoToxo, CMV), CMV) Cataracts (Rubella, HSV)Cataracts (Rubella, HSV) ChorioretinitisChorioretinitis ((ToxoToxo, CMV), CMV) Bone lesions (Syphilis, Rubella)Bone lesions (Syphilis, Rubella) Congenital heart disease (Rubella)Congenital heart disease (Rubella) MicrocephalyMicrocephaly (CMV) (CMV) Hydrocephalus Hydrocephalus

((ToxoToxo)) Vesicles (HSV, VZV, Syphilis)Vesicles (HSV, VZV, Syphilis)

Screening for TORCH InfectionsScreening for TORCH Infections

TORCH titers TORCH titers not helpfulnot helpfulzz Tests both Tests both IgGIgG and and IgMIgMzz IgMIgM can be present for prolonged periodscan be present for prolonged periods

(3 months to more than an year in (3 months to more than an year in toxotoxo 11)) Pattern of TORCH test use has a poor Pattern of TORCH test use has a poor

diagnostic return diagnostic return 22zz FollowFollow--up titers infrequently doneup titers infrequently done

1. Boyer KM et al., Toxoplasmosis. In: Textbook of Pediatric Infectious Diseases 5th ed, Saunders, Phil. 2004. p. 2755

2. Leland D et al., The use of TORCH titers. PEDIATRICS 1983; 72 (1): 41-43

Cost Effectiveness of Screening Cost Effectiveness of Screening --QuestionedQuestioned

Khan et al., 2000:Khan et al., 2000:zz Examined cost and number of diagnoses of TORCH Examined cost and number of diagnoses of TORCH

infections in 75 infants with IUGRinfections in 75 infants with IUGRzz Screened with TORCH titers, urine Screened with TORCH titers, urine cxcx., HUS., HUSzz 3 infants had a probable infection3 infants had a probable infection

One infant by + CMV One infant by + CMV CxCx.. Two infants by HUSTwo infants by HUS None had a + None had a + IgMIgM for TORCHfor TORCH

zz Combined cost of evaluation = $51,715Combined cost of evaluation = $51,715zz Concluded Concluded work up for TORCH infections in IUGR work up for TORCH infections in IUGR

was not cost effectivewas 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 InfectionDiagnosing TORCH Infection

Do not use TORCH titers Do not use TORCH titers Good maternal/prenatal historyGood maternal/prenatal history

zz most infections most infections -- are mild illnesses often are mild illnesses often unrecognizedunrecognized

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

diagnosisdiagnosis

Diagnosis of TORCH InfectionsDiagnosis of TORCH Infections

Serology Culture Histopath PCR

CM V - ++++ + +

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

Toxo ++++ + - +

Rubella +/- +++ - +

Syphilis +++ + - +

CytomegalovirusCytomegalovirus

Epidemiology of Congenital CMVEpidemiology of Congenital CMV Overall birth prevalence of congenital CMV was 0.64% 1

z 10,000 to 80,000 infants born /year with congenital CMV infectionz Estimated annual societal cost approaches $2 billion (1991) 2

About 11% of live-born infants - symptomaticz Mortality rate 30%z Severe neurologic morbidity 80%

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

Risk factors for congenital CMV infectionz non-white racez low socioeconomic statusz premature birth

z NICU admittance1. 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

2. 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 InfectionNatal and Postnatal InfectionIntrapartum From Cervical and Vaginal Secretions

z 2% to 28% of seropositive pregnant women shed CMV z Approximately 50% of exposed infants become infectedz Develop clinical signs of CMV disease at about 4 to 6 weeks of

age.Postpartum period Breast Feeding

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

Blood Transfusionsz 2 -20% from unscreened or unfiltered blood

Stehel EK and Sanchez PJ. Cytomegalovirus Infection in the Fetus and Neonate. NeoReviews2005;6;e38-e45

The Asymptomatic Congenital The Asymptomatic Congenital CMVCMV

90% of congenital CMV 90% of congenital CMV asymptomatic at birthasymptomatic at birth 0.5 0.5 15% of these are at risk for psychomotor, 15% of these are at risk for psychomotor,

hearing, neurologic, ocular, or dental hearing, neurologic, ocular, or dental abnormalities within first few years of lifeabnormalities within first few years of life

55--10% of cases may have 10% of cases may have sensorineuralsensorineural hearing hearing lossloss

Clinical findings Clinical findings -- Congenital CMVCongenital 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

z Detection of the virus in the urine (or saliva) by cytopathic effect in tissue culture

z Takes up to 3 weeks for results The shell-vial method

z which detects early antigen production after viral infection of fibroblastsz can yield results in 24 hoursz 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 CMVPCR 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. z may offer an opportunity for screening all newborns for

congenital CMV infection 2

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

2. 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

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

Majority of infectious chorionic Majority of infectious chorionic villitisvillitis is due to CMVis due to CMV

Characteristic placental Characteristic placental pathologypathology

LymphoplasmacyticLymphoplasmacytic StromalStromal hemosiderinhemosiderin depositiondeposition Sclerosis and dystrophic Sclerosis and dystrophic

mineralizationsmineralizations ("tombstones" of ("tombstones" of infected cells and villous damage) infected cells and villous damage)

IntranuclearIntranuclear or or cytoplasmiccytoplasmictrophoblastictrophoblastic epithelial inclusions epithelial inclusions

Congenital CMV Congenital CMV Leading cause of Leading cause of nonnon--genetic genetic sensorineuralsensorineural hearing losshearing loss 23% of all prelingual hearing deficits Most children manifest within the first 2 postnatal years The hearing loss may be fluctuating and progressive

z Hence, a complete audiologic examination should be performed as soon as possible after the diagnosis of CMV infection

z Followed by periodic hearing evaluations for the first few postnatal years.

Preferred hearing tests for monitoring of evolving hearing loss:z Audio evoked potential testingz Brainstem evoked potential testing

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

Predictors of Hearing Loss in Predictors of Hearing Loss in Children with Congenital CMVChildren with Congenital CMV

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

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

Prevention and ScreeningPrevention and Screening Mainstay of prevention

z avoidance of exposure z standard precautions hand hygienez Greater risk to the pregnant health care worker unidentified

asymptomatic infantRoutine serologic screening Pregnant Women

z Not recommended - no prophylactic or therapeutic interventions are available

z Ubiquitous nature of CMV - not excluded from caring for infants who are infected with CMV

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

CMV

Treatment of Congenital CMVTreatment of Congenital CMVPrimarily - supportive careGanciclovir

z Inhibits viral DNA polymerase, thereby acting as a chain terminator during elongation of newly synthesized viral DNA

z 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 z evaluated safety and efficacy of IV ganciclovir

for 6 weeks versus no therapyz 100 CMV-infected neonates ( 32 weeks of

gestation, birth weight of 1,200 g) z 47 evaluable infants 25 ganciclovir

recipientsz primary end point was improved brainstem-

evoked 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

z Infants from treatment group (84%) were significantly more likely to have either improved or normal hearing at 6 months than untreated infants (59%)

z 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%)

z 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

z 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 CMV Breast FeedingBreast Feeding Freezing of expressed human milk

z 20C for 3 to 7 days z significantly diminishes CMV titersz but does not eliminate infectivity completely

Pasteurization (62.5C) required for complete neutralizationz this is not routinely done or available

In Preterm infants z potential benefits far outweigh the potential

risk of symptomatic CMVStehel EK and Sanchez PJ. Cytomegalovirus Infection in the Fetus and Neonate. NeoReviews 2005;6;e38-e45Pickering KL. The Red Book, 2006. American Academy of Pediatrics 27th Ed.

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

The kinetics of CMV DNA copy numbers in breast milk

Blood TransfusionsBlood 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:

z volume of transfused bloodz number of donorsz elevated CFT titers to CMV in donor blood

Diagnosis and Screening Algorithm for CMV Diagnosis and Screening Algorithm for CMV infection in pregnant womeninfection 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

ToxoplasmosisToxoplasmosis

ToxoplasmosisToxoplasmosis Caused by protozoan Caused by protozoan Toxoplasma gondiiToxoplasma gondii Domestic cat is the definitive host with infections Domestic cat is the definitive host with infections

via:via:zz Ingestion of cysts (meats, garden products)Ingestion of cysts (meats, garden products)zz Contact with oocysts in fecesContact with oocysts in feces

Congenital Toxoplasmosis in the United States Congenital Toxoplasmosis in the United States 1 in 1000 to 1 in 100001 in 1000 to 1 in 10000

Primary maternal infection in pregnancy Primary maternal infection in pregnancy 1 in 3 1 in 3 risk of fetal infectionrisk of fetal infectionzz Infection rate higher with infection in 3Infection rate higher with infection in 3rdrd trimestertrimesterzz Fetal death higher with infection in 1Fetal death higher with infection in 1stst trimestertrimester

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

Clinical ManifestationsClinical Manifestations Asymptomatic at birth in 70% Asymptomatic at birth in 70% -- 90%90% Symptoms become apparent later in Symptoms become apparent later in

lifelife Classic TriadClassic Triad

zz ChorioretinitisChorioretinitis **zz HydrocephalusHydrocephaluszz Intracranial calcificationsIntracranial calcifications

Consequences of intrauterine Consequences of intrauterine meningomeningo--encephalitisencephalitis

Initially asymptomatic infants are still Initially asymptomatic infants are still at high risk of developing at high risk of developing abnormalities, especially abnormalities, especially chorioretinitischorioretinitis

DiagnosisDiagnosis

Maternal Maternal IgGIgG testing indicates past testing indicates past infection (but wheninfection (but when?)?)

Can be isolated in culture from placenta, Can be isolated in culture from placenta, umbilical cord, infant serumumbilical cord, infant serum

PCR testing on WBC, CSF, placentaPCR testing on WBC, CSF, placentazz Not standardizedNot standardized

NewbornNewbornzz serology with serology with IgMIgM / / IgAIgA (IFA, ELISA, ISAGA)(IFA, ELISA, ISAGA)zz IgAIgA more sensitive than more sensitive than IgMIgM

Boyer KM. Diagnostic testing for congenital toxoplasmosis. Pediatric Infect Dis J 2001; 20:59

Toxoplasma ScreeningToxoplasma Screening

Prenatal testing with varied sensitivity not Prenatal testing with varied sensitivity not useful for screeninguseful for screening

Routine neonatal screening with Routine neonatal screening with IgMIgMtesting implemented in some areas testing implemented in some areas 11zz Identifies infected asymptomatic infants who Identifies infected asymptomatic infants who

may benefit from therapymay 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 TreatmentPrevention and Treatment Treatment for pregnant mothers diagnosed with acute Treatment for pregnant mothers diagnosed with acute toxotoxo

zz SpiramycinSpiramycin dailydaily MacrolideMacrolide antibioticantibiotic

zz Small studies have shown this reduces likelihood of congenital Small studies have shown this reduces likelihood of congenital transmission (up to 50%)transmission (up to 50%)

If infant diagnosed prenatally, treat momIf infant diagnosed prenatally, treat momzz SpiramycinSpiramycin, , pyrimethaminepyrimethamine (anti(anti--malarial, malarial, dihydrofolatedihydrofolate reductasereductase

inhibinhib), and sulfadiazine (sulfa antibiotic)), and sulfadiazine (sulfa antibiotic)zz LeucovorinLeucovorin rescue with rescue with pyrimethaminepyrimethamine

Symptomatic infantsSymptomatic infantszz PyrimethaminePyrimethamine (with (with leucovorinleucovorin rescue) and sulfadiazinerescue) and sulfadiazinezz Treatment for 12 months totalTreatment for 12 months total

Asymptomatic infantsAsymptomatic infantszz Course of same medicationsCourse of same medicationszz Improved neurologic and developmental outcomes demonstrated Improved neurologic and developmental outcomes demonstrated

(compared to untreated pts or those treated for only one month)(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

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