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TORCH Infections
Krishna Dummula, MD
Case of Interest
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Baby girl E. - 24 wk GA
25 yr old G3 P0020 mother
Mother presented in PTL - Born via SVD
APGAR scores–21,65 and 710; BW-584 gm, microcephaly
Prenatal labs – none abnormal
Hospital course notable for
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Died at 64 days of life
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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
Clinical cause of death was sepsis
Autopsy consent was obtained – ascertain cause of death
Autopsy Findings
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Gross findings
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NEC with segmental involvement of jejunum
Extensive peritoneal fibrous adhesions
Hepatic necrosis
Microscopic findings
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Intranuclear and intracytoplasmic viral inclusions characteristic of
CMV
• In kidneys, lungs, anterior pituitary gland and thyroid
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Placental pathology
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Neither villitis nor inclusions were seen on H&E
Immunohistochemical stain for CMV – negative
Source of CMV infection – unclear
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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.
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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
¾ When do you think of TORCH infections?
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IUGR infants
Hepato-splenomegaly
Thrombocytopenia
Unusual rash
Concerning maternal history
“Classic” findings of any specific infection
Distinctive Features
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Intracranial calcifications (Toxo, CMV)
Cataracts (Rubella, HSV)
Chorioretinitis (Toxo, CMV)
Bone lesions (Syphilis, Rubella)
Congenital heart disease (Rubella)
Microcephaly (CMV) ÅÆ Hydrocephalus
(Toxo)
Vesicles (HSV, VZV, Syphilis)
Screening for TORCH Infections
¾ TORCH titers – not helpful
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Tests both IgG and IgM
IgM can be present for prolonged periods
(3 months to more than an year in toxo 1)
¾ Pattern of TORCH test use has a poor
diagnostic return 2
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Follow-up 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 Questioned
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Khan et al., 2000:
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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
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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
¾ Do not use TORCH titers
¾ Good maternal/prenatal history
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most infections - are mild illnesses often
unrecognized
¾ Thorough exam of infant
¾ Directed labs/studies based on most likely
diagnosis
Diagnosis of TORCH Infections
Serology
C ulture
Histopath
PC R
CMV
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HSV
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Toxo
++++
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R ubella
+/-
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+
Syphilis
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Cytomegalovirus
Epidemiology of Congenital CMV
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Overall birth prevalence of congenital CMV was 0.64% 1
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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
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Mortality rate – 30%
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Severe neurologic morbidity – 80%
Transmission Rates:
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Primary infection in mother – 32%
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Recurrent infection during pregnancy - 1.4%
Risk factors for congenital CMV infection
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non-white race
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low socioeconomic status
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premature birth
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NICU admittance
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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 Infection
Intrapartum – From Cervical and Vaginal Secretions
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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
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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
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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
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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
¾ Distinction is important - because prenatal infection has been
associated with long-term sequelae such as hearing impairment.
¾ Gold standard
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The shell-vial method
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Detection of the virus in the urine (or saliva) by cytopathic effect in
tissue culture
Takes up to 3 weeks for results
which detects early antigen production after viral infection of fibroblasts
can yield results in 24 hours
highly sensitive and specific
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
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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.
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may offer an opportunity for screening all newborns for
congenital CMV infection 2
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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
Majority of infectious chorionic
villitis is due to CMV
Characteristic placental
pathology
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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
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23% of all prelingual hearing deficits
Most children manifest within the first 2 postnatal years
The hearing loss may be fluctuating and progressive
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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:
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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
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Mainstay of prevention
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avoidance of exposure
standard precautions – hand hygiene
Greater risk to the pregnant health care worker Æ unidentified
asymptomatic infant
Routine serologic screening
¾ Pregnant Women
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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
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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
¾ Primarily
- supportive care
¾ Ganciclovir
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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
¾ Kimberlin,
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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
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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
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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
¾ Freezing
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of expressed human milk
20°C for 3 to 7 days
significantly diminishes CMV titers
but does not eliminate infectivity completely
¾ Pasteurization
(62.5°C) required for
complete neutralization
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¾ In
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this is not routinely done or available
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
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important iatrogenic source
¾ Incidence of infection with untreated
transfusates is about 15%
¾ Usually occurs in infants who weigh less
than 1,300 g
¾ The risk of infection is related to:
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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
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Caused by protozoan – Toxoplasma gondii
Domestic cat is the definitive host with infections
via:
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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 Æ 1 in 3
risk of fetal infection
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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%
¾ Symptoms become apparent later in
life
¾ Classic Triad
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Chorioretinitis *
Hydrocephalus
Intracranial calcifications
Consequences of intrauterine
meningo-encephalitis
¾ Initially asymptomatic infants are still
at high risk of developing
abnormalities, especially chorioretinitis
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Diagnosis
¾ Maternal IgG testing indicates past
infection (but when…?)
¾ Can be isolated in culture from placenta,
umbilical cord, infant serum
¾ PCR testing on WBC, CSF, placenta
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Not standardized
¾ Newborn
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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
¾ Prenatal testing with varied sensitivity not
useful for screening
¾ Routine neonatal screening with IgM
testing implemented in some areas 1
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Identifies infected asymptomatic infants who
may benefit from therapy
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
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Treatment for pregnant mothers diagnosed with acute toxo
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Spiramycin daily
• Macrolide antibiotic
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If infant diagnosed prenatally, treat mom
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Spiramycin, pyrimethamine (anti-malarial, dihydrofolate reductase
inhib), and sulfadiazine (sulfa antibiotic)
Leucovorin rescue with pyrimethamine
Symptomatic infants
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Small studies have shown this reduces likelihood of congenital
transmission (up to 50%)
Pyrimethamine (with leucovorin rescue) and sulfadiazine
Treatment for 12 months total
Asymptomatic infants
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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
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