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TOXOPLASMOSIS

TOXOPLASMOSIS. Primary maternal infection: 1 in 900 births (90% mothers are asymptomatic) Re-activation with immuno-suppression Cong Toxo in US – 1:1000 – 1:10,000 Transmission: 40% 1 st , 2 nd trimester: 17%, 25% 3 rd trimester: 65% Severity greater earlier in pregnancy;

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TOXOPLASMOSIS

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  1. TOXOPLASMOSIS • Primary maternal infection: 1 in 900 births (90% mothers are asymptomatic) • Re-activation with immuno-suppression • Cong Toxo in US – 1:1000 – 1:10,000 • Transmission: 40% • 1st, 2nd trimester: 17%, 25% • 3rd trimester: 65% • Severity greater earlier in pregnancy; severe congenital infection rare > 20 weeks

  2. PRENATAL SCREENING& Rx • Most neonates with cong toxo are asymptomaticat birth; if untreated, most develop severeeye/ neurologic disease by adolescence. • Most mothers asymptomatic; risk factors present in <50%; only 8% screened in pregnancy • Important - Rx is available for fetus/ infant • Treatment of fetus/infant substantially reduces disease progression Boyer et al and the Toxoplasma Study Group; AJOG 192, 2005

  3. NEONATAL SCREENING& MANAGEMENT(Massachusetts 1986, New Hampshire 1988-92) • Screening filter paper_ IgM capture immunoassay100 of 635,000 infants positive Confirmedin 52 - specific IgG, IgM (1:10,000) • 50 of 52 were identified only byscreening All were treated; only 1 of 46 developed a neurologic deficitonly 1 had serious eye lesion – a macular scar • Screening identifiessubclinicalinfections, & early Rx reduces severe sequelae. Guerina et a l NEJM 330:1858-6, 943

  4. NEONATAL SCREENING PROGRAM • Screening program for Toxo is feasible as systems in place for specimens • Costs: screening and follow up ~100,000 infants = $220,000/yr,< $30,000/ infant identified. • Cost-benefit ratio is favorable. • Follow-up indicatesthat there has been little progression of disease in infantstreated from birth.

  5. TOXO – PRENATAL DIAGNOSIS • Amniotic Fluid - PCR parasite particles • AF and fetal blood – specific IgM, IgA, IgG • Blood / placental tissue inoculation into mice • Fetal HUS - calcifications / hydrocephalus • Isolation of parasite placenta, amniotic fluid, fetal blood

  6. TOXO - ANTEPARTUM THERAPYConsult ID. • Documented maternal infection: Unlike CMV, antepartum Rx with Spiramycin is indicated - even if AF studies are negative. • Documented fetal infection > 17 wks gest: pyrimethamine & sulfadiazine • Severe cong disease (25%): termination?? • HIV pos pts: evaluate and treat carefully

  7. VARICELLA Chickenpox in pregnancy rare = 5 in 10,000 • Maternal Inf: < 20 weeks gest: Varicella embryopathy in 2% infants • Maternal Inf: > 20 weeks gest Inapparent varicella, Zoster in early childhood  • Maternal Inf: 5d before to 2d after delivery Neonatal VZV inf/ pneumonia (can be fatal)

  8. VARICELLA IN PREGNANCY

  9. VARICELLA IN PREGNANCY

  10. FETAL VARICELLA SYNDROME - FVS • Low birth weight • Skin: Cicatrical lesions in dermatomal distribution • Bone: Limb hypoplasia equinovarus, calcaneovalgus; hypoplasia mandible, clavicle, scapula, digits. • CNS: MR, seizures, cortical atrophy • Eye: chorioretinitis, nystagmus, microphthalmia, cataract, corneal opacities, optic atrophy,

  11. NEAR-TERM MATERNAL VARICELLA Within 5 d before to 2 d after deliveryNeonatal attack rate 25% - 50% Neonatal disease severe as mat antibody develops only > 5th day of mom’s rashIncubation - 9 to 15 days Severe varicella pneumonia. Disseminated cutaneous & visceral lesionsMortality > 30%, if untreated.

  12. HORIZONTAL TRANSMISSION-VARICELLA • Unusual • Most neonates: protected by mat. antibody • 30 wk, < 1 kg. neonates: could be susceptible - VZIG • Screen rapidly for VZV antibodyVZIG to susceptible neonates • VZIG to all neonates following exposure ?

  13. B19 INFECTION IN PREGNANCY • Fetal inf - 30% to 50%. • Most fetal infectionsare self-limited • Fetal loss: 15% <20 wks vs. 2% >20 wks • Parvo virus binds to an antigen ofthe P-system blood group – P antigen • Viral infection offetal erythrocyte precursors causes destruction & arrestof RBC production. • Fetus can develop anemia, myocarditis, CHF and nonimmune hydrops

  14. PARVO VIRUS INFECTION • 50% pregnant women immune. • Infection in pregnancy = 2- 3% • If a pregnant woman is exposed IgG and IgM should be determined ASAP • IgG antibody shortlyafter exposure indicates preexisting immunity • If susceptible, repeat serologies 4 wks. • B19-specific IgM antibody indicates recent infection. • Monitor for possible fetal involvement.

  15. Monitoring in Pregnancy • MSAFP ? • Wkly US • Developmentof hydrops 2 to 17 wks • Doppler - middle cerebralpeak systolic velocity is a sensitive indicator of fetal anemia and may precedethe development of hydrops. (sensitivity =94%, specificity=93%) • Increased blood velocity in anemicfetuses probably reflects the increased CO thatoccurs with the decline in blood viscosity.

  16. HYDROPS - PARVOVIRUS • Spontaneous resolution of anemia and hydropsoften occurs if > 20wks • Fetus can rapidly deteriorate and should be monitored • If fetal anemia or hydrops persists determine fetal hemoglobin level. • If fetal Hgb is <5 g/dL consider intrauterine blood transfusion

  17. CONGENITAL CMV INFECTION • Most common congenital infection 1% newborns infected 40,000 /yr in US • Leading infectious cause of: Mental Retardation, Cerebral Palsy, or, most commonly, hearing impairment involving > 8,000 infants/ yr in the US

  18. CONGENITAL CMVINFECTION • Live births/yr - US 4,000,000 • Congenital infection 1% 40,000 Symptomatic 10% 4,000 Fatal 10% Sequelae 90% Asymptomatic 90% 36,000 Sequelae 15% • Total sequelae/death 8150

  19. EPIDEMIOLOGY • 40-60% mid/upper SE vs. 80% low SE infected • US: 40-85% adults seropositive In developing countries, almost 100%. • After an active replication stage, CMV enters a latent stage in leukocytes and other tissues. Like other herpes viruses, CMV reactivates during relative immuno-compromise, such as pregnancy

  20. TRANSPLACENTALTRANSMISSION • PRIMARY MATERNAL INFECTION: 2-6% mothers/yr seroconvert in pregnancy Transmission 40 – 50 % Earlier mat. inf. = more severe the fetal inf. • RECURRENT MATERNAL INFECTION:Transmission 0.5-1.5%most infants asymptomatic • REINFECTION – new CMV strain

  21. RECURRENT MATERNAL INFECTION • Preconceptional immunity offers only partial protection • Of 46 mothers with preexisting immunity,16 infants had symptomatic inf. 11 of 16 mothers - new epitopes of the virus • Co-infection with HIV is a risk factor

  22. TRANSMISSION • Natal: 2%-28% of seropositive women shed CMV during delivery. ~ 50% of their infants develop CMV at 4-6 wks • Postnatal: human milk or saliva blood transfusions

  23. NATAL INFECTION • Incubation: 4 to 12 wks • Term infants: afebrile pneumonia-50% of exposed infants. rarely, hepatitis or encephalitis. mild – maternal CMV IgG antibodies, no sequelae or SNHL • Preterm infants <1,500 g: more severe pneumonitis exacerbation of BPD postnatal steroids -progression of CMV inf

  24. BREAST MILK TRANSMISSION • Seropositive mothers: shed virus 20% – 70% of the time in BM • 60% term infants fed virus positive breast milk develop inf but it is benign due to mat(Ig)G. • 15%-25% preterm infants (no mat IgG) develop symptoms: As & Bs, hepatosplenomegaly, pallor, neutropenia, thrombocytopenia, elevated LFT. Neurologic sequelae ?? • Co-infection with HIV - risk fctor

  25. TRANSFUSION-ACQUIREDCMV • Infection in LBW infants may be severe • Characterized by a gray ashen pallor, respiratory distress, pneumonia, hepatosplenomegaly, hepatitis, atypical lymphocytosis, thrombocytopenia, and hemolytic anemia • 10% mortality.

  26. Nonimmune hydrops Prematurity, IUGR Jaundice Hepatosplenomegaly Petechiae, Purpura Blueberry muffin spots Chorioretinitis Microcephaly Lethargy Poor feeding Hypotonia Seizures Inguinal hernia Defective enamelizationof deciduous teeth:40% symp newborns5% asymptomatic CLINICAL SIGNS

  27. Pneumonia Calcifications(periventricular, thalamic, cortical) Ventriculomegaly - Cortical dysplasia Anemia Thrombocytopenia Elev. liver enzymes Hyperbili (direct and indirect) Elevated CSF protein CLINICAL SIGNS

  28. SENSORINEURAL HEARING LOSS Most common birth defect in the US All etiologies 4000/yr Sympt. CMV 300- 500/yr(30%-65% SNHL) Asympt. CMV 1500- 2000/yr(8%-15% SNHL)

  29. SENSORINEURAL HEARING LOSS • UN Hearing Screen can miss CMV - SNHL. SNHL can develop after newborn period. • SNHL is progressive ~ hearing deterioration throughout childhood and into adolescence. • Cochlear implantation - as early as 1 year of age if bilateral profound hearing loss

  30. DAIGNOSIS - CMV CULTURE • Virus must be isolated in urine /saliva <3 wks of age to prove congenital infection • If >3 wks of age, cannot differentiate congenital, natal, or postnatal infection unless the infant previously has had a negative culture. This distinction is important because congenital infection is associated with hearing impairment. • Shell-vial culture-helps rapid identification.

  31. CMV DNA PCR & CMV-IgM CMV DNA PCR • CSF: preferred test positive result = poor neurologic outcome. • Blood; positive = active infection associated with hearing loss • Newborn heel stick dried blood spots: opportunity for universal screening? CMV IgM not recommended for neonates False-positives and false-negatives occur

  32. Rx - GANCYCLOVIR • RCT – 6mg/kg q12; IV x 6 wk, central line • 1991-99, 100 infants enrolled • <1month of age, > 32wk gest. BW >1200g • With CNS involvement: • microcephaly, abnormal CT scan or HUS,abnormal CSF, chorioretinitis, hearing loss <1month of age, > 32 wk gest, BW<1200g Kimberlin, Lin, Sanchez et al ACOG abstract 2000

  33. Rx GANCYCLOVIR • RCT – 100 infants, 6mg/kg q12; IV x 6 wkassociation between GCV Rx and lack of progression of SNHL (up to 2 yrs) • Produces significant neutropenia (63% in Rx group vs 20% placebo) • Oral val-ganciclovir trial ongoing.

  34. MATERNAL DIAGNOSISIs it primary infection? • IgG seroconversion – ELISA • New CMV specific IgM – immunoblot • IgG avidity index: Anti CMV IgG has low avidity for first 14 wks after conversion • IgG avidity index & IgM–immunoblot combination may help identify primary inf.Guerra et al: AM. J Ob Gyn 2000

  35. CMV - PRENATAL US • Oligohydramnios • Polyhydramnios • IUGR • Fetal ascites, hyper-echogenic bowel • Microcephaly, ventriculomegaly • Intracranial calcifications • Hepatosplenomegaly

  36. CMV - PRENATAL DIAGNOSISFetus infected? Symptomatic? • Viral culture amniotic Fluid • Viral culture fetal blood • DNA-PCR & quantitative PCR • CMV-IgM in cordocentesis – not v. sensitive • Ultrasound • Hematologic tests Guerra et al: AM. J Ob Gyn 2000

  37. CHILD CARE CENTERS • Plastic surfaces and toys harbor CMV for hours • Viruria: ~ 70% infected >18 mth old children. • 30% seroconversion among mothers whose children shed CMV vs 0% if children don’t shed • Child to mother transmission confirmed. • Young children in child care centers are important source of primary CMV infection for pregnant women.

  38. PREVENTION • Meticulous hand hygiene after exposure to urine or saliva from infants and toddlers and immunocompromised patients • Standard precautions only. • Pregnant women are not excluded from caring for infants who are infected with CMV. • Routine screening is not recommended for women of childbearing age as no interventions are available.

  39. Transfusion-acquired infection:CMV antibody-negative blood products, leukofiltration of blood to remove WBC,frozen deglycerolized RBCs as they lack viable leukocytes. Breast Milk acquired CMV:Freezing human milk –20°C for 3-7d. Pasteurization (62.5°C) not routinely available. CMV vaccine - investigational. PREVENTION

  40. GENITAL HSV– ALARMING PREVALENCE • 30% women of childbearing age have antibodies to HSV-2 • Seroconversion during pregnancy: 2% - 3% • Genital HSV-1 infections increasing !! • Overall, 500,000 new cases/ yr. added to the pool of > 45 million cases in the US.*

  41. NEONATAL HSV INFECTIONTragedy for the neonate/family • 1:3200 LB = 1,500 cases/yr in the US • Intrapartum transmission > 90% • HSV-2 = 75%; HSV-1 = 25% cases • The severity of neonatal HSV disease, has increased over the past 5 years

  42. HSV –INTRAPARTUM TRANSMISSION • If vaginal delivery and 1st episode primary g-HSV 57% 1st episode non-primary g-HSV 25% reactivated g-HSV at delivery: 2 % • Most mothers - no history or symptoms Brown ZA, JAMA 2003;289:203–209.

  43. IMPORTANCE OF MATERNAL IMMUNITY • HSV inf occurred in 4 of 9 infants born to women who acquired genital HSV near the onset of labor, 5 had lesions at the time of labor, none had antibodies to HSV type • HSV inf occurred in 0 of 94 infants born to women who acquired genital HSV earlier during pregnancy, all had seroconverted before the onset of labor • (4 of 9) vs. (0 of 94) P<0.001 NEJM, 97

  44. RISK FACTORS-NEONATAL INFECTION 40,000 cultured in labor – 202 positive (0.5%)neonatal infection = 10/202 = 5% Odds Ratio • Culture positive 346 • CS (1% vs 8%) 0.14 • First episode infection 33 • Fetal monitoring 7 • HSV-1 vs HSV-2 17 Brown et al (2003 - JAMA)

  45. Neonatal HSV -Incidence & Outcomehi-dose acyclovir

  46. HSV- EARLY DETECTION/ RX • Time from onset to Rx = 6 days has not changed in 20 years; because, >75% mothers are asymptomatic; > 50% infants have no skin lesions • Need high index of suspicion • Vesicular skin lesions: begin Rx (pending Cx) • Check liver transaminases in sick infants  in disseminated HSV

  47. HSV-CULTURES • Culture at 24 - 48 hrs – results in 2-7dskin, conjunctiva, mouth/nasopharynx, rectal, urine, blood, CSF • Hi-risk /symptomatic: Rx pending cultures • Positive cultures from any site obtained > 48hrs = viral replication rather than colonization • CSF cultures usually negative in encephalitis PCR DNA-CSF test of choice test before & after RX

  48. HSV: DIAGNOSTIC TESTS • Tzanck prep – low sensitivity, not recommended as diagnostic test • DFA stain scrapings– same day, sensitive • ELISA – detection of HSV in skin lesions • Eye consult • EEG, MRI (temporal lobe involved) • Histopathology

  49. HSV:TREATMENT • IV acyclovir: 60 mg/kg/d IV– in 3 divided doses “Hi dose” – has greatly improved survival & morbidity • 21d for CNS &/or disseminated; 14 d for SEM • Ocular disease – topical Rx in addition to IV Rx(trifluridine or iododeoxyuridine or vidarabine)

  50. ORAL ACYCLOVIR SUPPRESSIVE RX • Acyclovir 300mg/m2 /dose PO TID • 16 Infants with confirmed HSV-2 SEM • Rx initiated < 1 month; Rx for 6 months • 13/16 (80%) had no recurrences • Historical controls – 54% no recurrences • SE-neutropenia; resistant HSV mutant Kimberlin et al-CASG-J Ped Inf Dis 1996

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