Download - Intrauterine Infection
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Intrauterine Infection
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Intrauterine infection
• Abortion /stillbirth• Congenital Malformation• IUGR• Prematurity• Acute neonatal disease/delayed neonatal
disease• Asymptomatic• Persistent infection with late sequelae
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• Timing (which trimester)
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Signs & symptoms of IU infections• IUGR• Microcephalus/hydrocephalus• Intracranial calcifications• Chorioretinitis• Cataracts• Myocarditis• Pneumonia• HSM• Direct hyperbilirubinemia• Anemia/thrombocytopenia• Seizures/SNHL/blindness• Skin
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Blueberry Muffin
• Dermal erythropoiesis• CMV• Rubella• Parvo• Congenital Leukemia• Rh hemolytic disease
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Pregnant Women Screening (CDC)
• HIV• Syphilis• HBsAg• C trachomatis• N gonorrhhoeae if at risk• GBS (35-37 w)
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Toxoplasmosis
Toxoplasma gondii human infection:• Undercooked meat (oocysts)• Contact with contaminated materials
(sandbox) (oocysts)• Organ/BM transplantation (tachyzoite/cyst)• IU (maternal infection during pregnancy)
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Primary Acquired Toxoplasmosis
• Mononucleosis like (fever, myalgia, rash, lymphadenopathy, hepatitis, meningitis, encephalitis, pericarditis, unilateral chorioretinitis, myo/pericarditis)
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Ocular Toxoplasmosis
Congenital or acquired30-40% of chorioretinitis in USA and western Europe
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Toxoplasmosis in immunocompromised
• AIDS, malignancy, cytotoxic therapy, organ transplants, stem cell transplant (Tox+→Tox-)
• CNS 50%, also heart, lung, GI• Toxoplasmic encephalitis 25 to 50% untreated
HIV
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Congenital Toxoplasmosis
• 1st trimester 17% severe infection• 3rd trimester 65% mild infection • Susceptibility (HLA DQ3 etc)• Wide range of presentation• 50% of infected are asymptomatic at birth almost all of them
will develop ocular involvement• 10% severe CNS & systemic• Untreated that presents later in the first 1yr 80% IQ<70• IUGR, lymphadenopathy, HSM, pneumonitis, nephrotis
syndrome, metaphyseal lucency• SIADH, hypothyroidism, hypopit
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Congenital Toxoplasmosis
• Hydrocephalus• Seizures• Microcephalus, developmental delay• CSF abnormal in 30% (sometimes protein
>1gr)• Calcifications more in caudate nucleus and
basal ganglia• SNHL static or progressive?
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Diagnosis of Toxoplasmosis
• Cultures (mice peritoneal fluid or tissue cultures 6-10 days for tachyzoites, if mouse survives and seroconverts at 6 weeks brain cysts)
• Serology:Sabin-Feldman dye testSpecific, sensitive, difficult
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Serology cont.• IgG indirect fluorescent antibody 1-2wk after infection, peaks at 6-8 wk, persist fo life at
low titers, not standardised• IgM IFA for older children, only 25% of congenital• IGM ELISA more sensitive and specific (50-75%)• ISAGA (immunosorbent agglutination assay) combines
IGA, IGE and IGA, no FP is the best fot congenital infection
• Differential agglutination (HS/AC) (useful for pregnant women)
“recent antigen” “late antigen”
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Diagnosis cont.
• Avidity (12 vs 16 wk)• Body fluid coefficient• Enzyme-linked immunofiltration assay ELIFA
85% sensitivity for congenital Toxo• PCR in amniotic fluid 17-21 gest week 95%
sensitive, PCR from WBC of neonate• Ocular = characteristic lesion with positive
serology
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Newborn suspected of toxo?
• General, ophtalmologic, neurologic ex• Head CT• Toxo PCR from peripheral blood buffy coat• Toxo specific and total IGG, IGM, IGE, IGA• CSF for Toxo PCR (+general CSF )• Mice inoculation
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Treatment
• Pyrimethamine & Sulfadiazine
• Folinic acid (leukovorin) !!!• During pregnancy Spiramycin
Contraindicated in first trimesterDHFR inhibitor, bone marrow↓
Rash, hematuria, crystalluriaHypersensitivity, especially with HIV
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Duration of treatment
• Acquired (if at all…) 4-6 wk• Ocular untill sharp borders usually 2-4 wks +
steroids• AIDS for life or until CD4>200 for more than 6
mts and no lesions• Congenital for 1 year
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Pregnant woman
• If infection during the 6 mo prior to conception treat as described for the pregnant
• Spiramycin for prevention if motherdevelops acute toxo until 24 w
• If fetus is infected P&S&FA after 1st trimester• Acute toxo after 24 w = P&S&A• Amniotic fluid PCR 17-21 wk• Prevention!!!
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HSV
Specific antiviral therapyNonspecific antiviral therapyPassive immunizationActive immunization
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HSV
• Primary• Non-primary first infection• Recurrent symptomatic and asymptomatic
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• Only in humans• Direct mucocutaneous contact• Any anatomic site• Predisposition
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Incidence of Neonatal HSV Infection and Other Congenital Infections in North America.
Corey L, Wald A. N Engl J Med 2009;361:1376-1385.
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Clinical Presentation
• Herpes Gingivostomatitis• Herpes Labialis• Herpes gladiatorum/scrumpox• Whitlow• Eczema Herpeticum• Genital Herpes (15% aseptic meningitis)• Ocular Herpes
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HSV Clinical Manifestations cont.
• CNS infection: HSV1 encephalitis, Mollaret meningitis (HSV2)• Immunocompromised: mucositis, esophagitis,
tracheobronchitis, pneumonitis, sepsis-like
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Pathogenesis of Neonatal Herpes Simplex Virus (HSV) Infection.
Corey L, Wald A. N Engl J Med 2009;361:1376-1385.
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Perinatal inf
• Fewer than 30% of mothers have history of herpes
• Primary (>30% risk) vs recurrent (<2%)• Scalp electrodes• Intrauterine: skin vesicles, microcephaly,
keratononjuctivitis• During delivery: SEM, encephalitis,
disseminated
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SEM
• 5-11 days few small vesicles• If untreated may progress
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Encephalitis
• 8-17 days irritability, lethargy, poor feeding, poor tone, seizures
• Usually no fever• Vesicles 60%• If untreated 50% will die
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Disseminated
• 5-11 days• Sepsis• Vesicles 75%• If untreated 90% will die
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Dx
• DNA PCR• HSV IGM unreliable• HSV IGG only for retrospect• Cultures
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Tx
• Acyclovir• Valacyclovir• Famciclovir (prodrug of penciclovir)• Foscarnet, cidofovir• Perinatal infection – high dose (60mg/kg/day)
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Common Misperceptions about Neonatal Herpes.
Corey L, Wald A. N Engl J Med 2009;361:1376-1385.
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Outcome of Neonatal Herpes.
Corey L, Wald A. N Engl J Med 2009;361:1376-1385.
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Cytomegalovirus
• The most common cause of congenital infection
• Important opportunistic pathogen• β-herpes group• Large (200-300nm)
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Pathogenesis
• Attachment gB, gH proteins (interact with cell surface heparan sulfate)
• Cytoplasmic inclusion typical (accumulation of nucleocapsids and tegument in the Golgi ap.)
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Pathogenesis
• Mucosal (UR or genital)• Viremia• Leukocytes and endothelial cells infection• CMV-encoded cell traffic machinery• Different tissues tropism (PM healthy people
CMV was found in salivary, lung, kidney, liver, pancreas, gut, etc)
• Viral shedding 4-6 weeks after acquisition (saliva, urine, genital)
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Pathogenesis cont
• Interfere with immune response• Maintenance of viral genome in CD34+ cells,
also kidney and salivary• Severity of disease parallels the immunity
impairment• Antibodies modify cannot prevent infection• Critical role of T-cell mediated (most severe
infection after BMT recipients, AIDS (<100cd4) and solid organ after ATG treatment)
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Pathogenesis
• Majority of congenital infections are benign• Congenital symptomatic at birth CMV=Microcephaly, IC calcifications, CSF protein↑↑,
seizures, cochlear, vestibular defects (Mondini dysplasia), retinitis, hepatitis
• 40% of maternal primary are transmittes• First trimester = 26% symptomatic (32%),
third=6%(15%)
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Epidemiology
• At areas with high seropositivity >50% positive at 1 yr, >90% of first time mothers
• US overall prevalence is 59%• Child care centers• Second peak adolescents (sexual transmission)• Vertical (10% of seropositive mothers shed
CMV at genital tract, 50% of neonates will be infected)
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Epidemiology
• Congenital CMV 0.2-2.2% live births• Nosocomial: breast milk, blood products
(leukocytes!), organ T, BMT, BW<1250g• Child care workers at risk, medical workers are
considered not at risk
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Clinical
• Heterophil-negative mononucleosis (mean duration of fever 14 days)
• Peak ALT usually <300 IU/L• The expected course is recovery without
sequellae in healthy host
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Clinical – unusual complications
• DVT, uveitis, persistant trmbocytopenia, hemolytic anemia, myocarditis, GI ulcerations, transverse myelitis, Guillain-Barre, encephalitis
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Clinical manifestations – congenital CMV
• >90% appear healthy at birth• 7-10% petechiae, microcephaly,
thrombocytopenia, conjugated hyperbilirubinemia, optic atrophy, seizures, poor sucking reflex etc etc
• 5% of asymptomatic at birth will have CNS seq• 7-10% will have progressive SNHL
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CMV in premature
• 20y ago transfusion related syndrome in VLBW• Rare today because of leukocytes filtration• 59% of premature <1500 gr newborns of CMV
positive mothers who were fed mother’s milk were infected, half of them symptomatic (?)
• Compared with term less maternal IGG• Symptoms = sepsis like• No consensus, controversial studies
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Transplant patients
• Solid organ: Most common RN DP (majority will develop disease w/o
treatment)Can occur at RP also if profound immunosuppressed (5-25%)4-12 weeks after transplantationFever, malaise arthralgia, hepatitis, pancytopemia,
deterioration of graft functionPneumonitis is more common in lung or heart lung
transplantsAntithmocyte globulin or anti Tlymph ab at risk
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Hematopoietic Stem Cell Transplantation
• Similar as SOT• Pneumonia and GI disease!!!• Prior to routine antiviral therapy 40% interstitial
pneumonia (half of them CMV with 50% mortality)
• At risk DP RN, GVH, lymphopenia• Due to ativiral therapy only 5% HSCT will
develop CMV during first 120 d but late onset disease has become a problem
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CMV in AIDS
• Extremely low CD4 (<50)• Usually retinitis, esophagitis or colitis• Controversial in neurological AIDS syndromes• Adults>children
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Lab
• In the healthy IGG, IGM (unreliable during pregnancy), IGG avidity
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Lab - congenital
• Detection of CMV in body fluids within first 3 weeks
• Culture, shell vial, PCR• Quantification in blood – to assess risk of
sequella
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Lab Dx Immunocompromised
• Quantification of CMV DNA in blood (different techniques: whole blood, leukocytes, plasma)
• pp65 antigenemia (immunofluorescence staining)
• Lack of standartization
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Rx
• Acquired healthy – not indicated• Congenital symptomatic ganciclovir 12
mg/kg/day in two doses daily for 6 weeks “deserve consideration”
• Congenital asymptomatic “no evidence to support” but…
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