torch infections
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TORCH InfectionsTORCH InfectionsKrishna Dummula, MDKrishna Dummula, MD
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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
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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
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TORCH TORCH The Name GameThe Name Game
Fuerst HT. Flame or Bird. Pediatrics 1975;56;107
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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
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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
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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)
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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
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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.
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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
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Diagnosis of TORCH InfectionsDiagnosis of TORCH Infections
Serology Culture Histopath PCR
CM V - ++++ + +
HSV - ++++ +++ +++
Toxo ++++ + - +
Rubella +/- +++ - +
Syphilis +++ + - +
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CytomegalovirusCytomegalovirus
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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
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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
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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
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Clinical findings Clinical findings -- Congenital CMVCongenital CMV
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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ToxoplasmosisToxoplasmosis
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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
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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
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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
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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
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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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