Congenital Infections microbiology..pptx

Congenital Infections

1. Congenital Infections COMPETENCY COVERED 1.1,8.15

2. LEARNING OBJECTIVES 2 At the end of the session, the students will be able to understand: Congenital Toxoplasmosis Congenital Rubella Syndrome (CRS) Congenital Cytomegalovirus Infection Neonatal Herpes Other Teratogenic Agents

3. INTRODUCTION 3 Vertical transmission refers to the spread of infections from mother-to-baby, which may occur either by transplacental route (congenital infection), during delivery or after delivery.

4. Congenital Infections 4 Congenital infections refers to infections that cross the placenta to infect the fetus and results in developmental defects in the fetus (congenital malformation). Agents of congenital infections are abbreviated by an acronym ‘ TORCH’ Infections.

5. TORCH Infections 5 T oxoplasmosis O ther infections: Congenital syphilis: Treponema pallidum , Varicella-zoster virus infection , Human parvovirus infection, Zika virus disease, Congenital trypanosomiasis: Trypanosoma cruzi , Malaria: Plasmodium falciparum R ubella C ytomegalovirus (CMV) H erpes simplex virus

6. Perinatal Infections (During Delivery) 6 Perinatal infections occur while the baby passes through an infected birth canal. These infections are caused by the agents of sexually transmitted infections. Also include the infections transmitted through contamination with fecal matter during the delivery.

7. Perinatal Infections (During Delivery) 7 Agents causing perinatal infections include: Bacteria : Group B streptococci, E. coli, Listeria monocytogenes, Neisseria gonorrhoeae, Chlamydia trachomatis Viruses: Herpes simplex virus, Cytomegalovirus , Enteroviruses , Hepatitis B virus, HIV.

8. Postnatal Infections (After Delivery) 8 These infections spread from mother to baby following delivery, usually during breastfeeding. All the organisms listed under perinatal infection can also cause postnatal infection. In addition, various organisms from the nursery environment - multidrug resistant gram-negative bacilli can also cause postnatal infections.

9. CONGENITAL TOXOPLASMOSIS 9

10. CONGENITAL TOXOPLASMOSIS 10 Toxoplasma - most common parasite to be teratogenic . The incidence of congenital toxoplasmosis is approximately 1 per1000 live births. Also causes encephalitis in HIV-infected individuals

11. Transmission 11 Transplacental transmission of T. gondii from mother-to-fetus - occur at any time during the pregnancy. Tachyzoites are the infective forms. Gestational age: Main factor that influences the fetal outcome. As the gestation proceeds, the chance of transmission of infection increases but the severity of the infection declines.

12. If the mother becomes infected during the first trimester, the incidence of transplacental infection is lowest (15%), but the disease in the neonate is most severe. If maternal infection occurs during the third trimester, the incidence of transplacental infection is maximum (65%), but the infant is usually asymptomatic at birth If the mother is infected before pregnancy, then the fetus is mostly uninfected, except when the mother is immunocompromised. 12 Transmission

13. Clinical Manifestations 13 Initially asymptomatic ,but the persistence of infection in the newborn can result in severe disease. Classical triad comprises of: chorioretinitis , hydrocephalus, and intracranial calcifications Other manifestations - stillbirth, psychomotor disturbance and microcephaly.

14. Clinical Manifestations 14 Ocular involvement: E yes are involved later in life when the cyst ruptures. Most frequently, it causes bilateral chorioretinitis leading to profound visual impairment . Other ocular manifestations include blurred vision, scotoma, photophobia, strabismus and glaucoma. If ocular involvement occurs without history of congenital infection, it is mostly unilateral.

15. Clinical Manifestations 15 Congenital toxoplasmosis is an important cause of repeated abortion and infertility. Hence , routine antenatal screening for Toxoplasma antibodies is advised in many developed countries.

16. Laboratory Diagnosis - Antenatal Diagnosis 16 If acute infection is documented in a pregnant women, the following algorithm: Ultrasonography of fetus - done at 20–24 weeks of gestation and repeated every 2–4 weeks for detecting the lesions of congenital infection PCR and/or isolation: Amniotic fluid sample is collected, centrifuged and the pellet is subjected to PCR and/or isolation in mouse or tissue culture. If either or both found positive, then the antenatal diagnosis is confirmed.

17. Laboratory Diagnosis - Postnatal Diagnosis 17 Isolation of the parasite at delivery from amniotic fluid, placenta and cord leukocyte IgM and IgG: Newborn and maternal sera are subjected to detection of IgG or IgM by IFA or ELISA IgG titer ≥1,000 in neonate indicates possible diagnosis, t o be confirmed by IgM testing. IgM titer of neonate ≥1:4 after 2 weeks of age indicates probable diagnosis and guides the clinicians to initiate treatment to the neonate.

18. Laboratory Diagnosis - Postnatal Diagnosis 18 IgA detection (neonatal and maternal blood): IgA appears to be more sensitive than IgM for the diagnosis of congenital toxoplasmosis. IgA antibodies - disappear within 10 days of birth hence persistence of IgA beyond 10 days confirms the postnatal infection

19. Laboratory Diagnosis - Postnatal Diagnosis 19 IgE detection (neonatal and maternal blood) PCR in neonatal and maternal blood detecting specific genes of T. gondii Fundus examination – to rule out chorioretinitis .

20. Treatment of Congenital toxoplasmosis 20 Neonates with congenital toxoplasmosis - daily oral pyrimethamine (1 mg/kg) and sulfadiazine (100 mg/kg) with folinic acid for 1 year.

21. CONGENITAL RUBELLA SYNDROME (CRS) 21

22. CONGENITAL RUBELLA SYNDROME (CRS) 22 Rubella is a highly teratogenic virus Transmission - Both the risk of transmission to fetus and severity of congenital infection - maximum if the mother acquires the infection during first trimester of pregnancy. Risk after 5th month of pregnancy is almost negligible (90% risk at 11 weeks vs 20% risk at 20 weeks of gestation).

23. Clinical Manifestation 23 Clinical manifestation of CRS can be grouped into: Permanent congenital d efects Transient reversible congenital c hanges

24. Permanent Congenital Defects 24 Classical triad consists of: Ear defect : Sensory neural deafness (most common defect of congenital rubella syndrome) Ocular defects: Salt-and-pepper retinopathy is the most common ocular defect followed by cataract Cardiac defect: Patent ductus arteriosus (PDA) followed by pulmonary artery stenosis and ventricular septal defect. CNS defects - microcephaly, mental retardation, motor delay and autism.

25. Transient Congenital Changes 25 Hepatosplenomegaly, bone lesions and intrauterine growth retardation (IUGR) may be seen. Occasionally, thrombocytopenia with petechiae ( Blueberry muffin syndrome ) may also be seen.

26. Laboratory Diagnosis 26 IgM antibodies do not cross placenta; their presence in a neonate is diagnostic of congenital rubella infection IgG antibodies: IgG antibodies persisting in baby’s serum beyond the expected time of disappearance of maternal IgG (9 months of age) -criterion to diagnose congenital rubella infection

27. Laboratory Diagnosis 27 Isolation of virus - throat swab, to lesser extent from urine (excreted up to 1 year) and CSF. More likely to be positive in the first six months after the birth Reverse transcriptase PCR - detect the viral RNA.

28. Epidemiology Congenital rubella remains an important public health problem globally. WHO Southeast Asia Region has implemented a program for elimination of rubella/congenital rubella syndrome (CRS) along with measles by introducing a ‘Strategic Plan for achieving and maintaining Measles and Rubella/CRS elimination in 2020–2024’. 28

29. Prevention 29 Universal immunization of all woman of reproductive age (first priority group) and all children of 1–14 years age with rubella vaccine. Live-attenuated vaccine (RA 27/3). Airborne precautions should be taken to prevent transmission from rubella patients to pregnant mothers.

30. CYTOMEGALOVIRUS INFECTIONS 30

31. CYTOMEGALOVIRUS INFECTIONS 31 CMV is the largest virus causing massive enlargement of infected host cell. Properties of CMV are similar to any other herpesvirus , with some minor differences. CMV belongs to β-subfamily dsDNA is the largest among herpesviruses. Host specificity : Cytomegaloviruses are strictly species-specific.

32. CYTOMEGALOVIRUS INFECTIONS 32 Cell type specificity - In vivo, CMV infects kidney and salivary glands; where it undergoes latency. Cell-to-cell spread – CMV is closely associated with the cells and spread primarily cell to cell.

33. Clinical Manifestations 33 CMV causes an array of clinical syndromes: Congenital Perinatal infections CMV mononucleosis Severe infection in immunocompromised & transplant recipients

34. Congenital CMV Infection 34 Most common intrauterine infection associated with congenital defects. Cytomegalic inclusion disease develops in about 5% of the infected fetus . The remaining are although asymptomatic at birth, 5–20% of them may develop significant psychomotor, hearing, ocular, or dental defects over the next few years.

35. Congenital CMV Infection 35 Congenital defects include - Most common defects - petechiae , hepatosplenomegaly, and jaundice (60–80% of cases). Less common defects - microcephaly, cerebral calcifications, intrauterine growth retardation, and prematurity (30–50% of cases). Sensorineural hearing loss may occur in up to 10–15% of asymptomatic infants Occasional defects are inguinal hernias and chorioretinitis

36. Congenital CMV Infection 36 Risk is maximum if the infection occurs in early pregnancy and if the mother is primarily infected during pregnancy (one third of the primarily infected mothers transmit the virus to fetus in contrast to 1% of reactivated mothers) Mortality rate is very high (20%).

37. Perinatal CMV Infection 37 Transmission to the new-born occurs either during Delivery-through infected birth canal or Post natal- through infected breast milk / secretions from mother . Mostly asymptomatic, but shed virus in urine from 8-12 weeks of age, up to several years. Few infants, especially premature babies develop interstitial pneumonitis.

38. Immunocompetent Adults 38 In healthy adults, CMV produces an infection following blood transfusion called mononucleosis like syndrome, characterized by the presence of atypical lymphocytes .

39. Immunocompromised Host 39 In AIDS patients (CD4 count <50/µL) - CMV may cause chorioretinitis , gastroenteritis, dementia and other disseminated CMV infection.

40. Immunocompromised Host 40 Organ transplant recipients - Most common viral infection (1 to 4 months post transplantation) Bilateral interstitial pneumonia Febrile leukopenia - solid organ transplants recipients Obliterative bronchiolitis in lung transplants Graft atherosclerosis in heart transplants Rejection of renal allografts

41. Epidemiology 41 Transmission- Oral and respiratory spread Transplacental route (mother to fetus ) Blood transfusion Organ transplantation Sexual contact ( in young adults)

42. Epidemiology 42 Reservoir - Humans are the only known host for CMV. Source - Virus may be shed in urine, saliva, semen, breast milk, and cervical secretions, and is carried in circulating white blood cells Endemic :CMV is endemic worldwide, present throughout the year without any seasonal variation Risk factors such as low socioeconomic status and poor personal hygiene facilitate the infection Prevalence is high in underdeveloped nations .

43. Laboratory diagnosis of Cytomegalovirus infections 43 Cytopathology — In urine CMV produces characteristic inclusions in addition to the usual intranuclear inclusions seen in other herpesviruses (owl’s eye appearance).

44. Laboratory diagnosis of Cytomegalovirus infections 44 Virus isolation: Human fibroblasts cell line culture—detects CPE after 2–3 weeks Shell vial culture—detects viral antigens in infected cell lines by IF (1–2 days).

45. Laboratory diagnosis of Cytomegalovirus infections 45 Antibody detection —by ELISA using pp150, pp65, pp52, glycoprotein antigens. CMV IgM antibodies appear in 1-2 weeks after infection and indicates recent on going infection. It drops to below detectable levels within several months after infection. CMV IgG antibodies are produced few days after IgM and persist lifelong. Its presence indicates either a recent or past infections, which can be differenciated by performing IgG avidity test.

46. Laboratory diagnosis of Cytomegalovirus infections 46 Antigen detection such as pp65 antigen Molecular methods —PCR and real-time PCR is highly sensitive and specific, have replaced gold standard culture technique in most laboratories. It can quantitate the viral DNA load, hence it is the method of choice to monitor the treatment response.

47. Treatment of Cytomegalovirus infections 47 CMV does not respond to acyclovir. The following drugs are used for treatment of CMV infections. Ganciclovir Valganciclovir Foscarnet Cidofovir CMV immunoglobulin

48. Prophylaxis 48 Both ganciclovir and valganciclovir have been used successfully fo r prophylaxis and pre-emptive therapy in transplant recipients CMV immunoglobulin has shown to be effective in preventing congenital infection, when given to mother during pregnancy .

49. NEONATAL HERPES 49

50. NEONATAL HERPES 50 Neonatal herpes (caused by herpes simplex virus) is rare, occurring in an estimated 10 out of every 100,000 births globally. serious condition - lead to neurologic disability or death

51. NEONATAL HERPES 51 Transmission - During birth from the maternal genital tract Risk of developing neonatal herpes is maximum (10 times more)if the mother recently acquires the virus (primary infection) than those who are presented with recurrent infection. HSV-2 is more common to cause neonatal herpes (50 to 70% of total cases) than HSV-1. I t presents as two forms: neonatal herpes or congenital herpes.

52. NEONATAL HERPES 52 Neonatal Herpes: Babies are almost always symptomatic and present in one of the three forms: Local lesions involving skin, eye and mouth are the most frequent manifestations typically presents at 9-11 days of life. Disseminated disease presents with septic appreance , with deranged liver function tests, presents in 9-11 days of life. CNS infections among HSV infected people neonates are at higher risks of CNS infections.

53. NEONATAL HERPES 53 Congenital herpes: I n utero infection presents with v esicles or scarring, eye disease microcephaly or hydrocephalus Mortality: Neonatal herpes is associated with high mortality (65% without treatment) Diagnosis: PCR of vesicle lesions, blood or CSF. For asymptomatic infants born to women with active herpes - swabs from conjunctiva, nasopharynx, mouth or anus.

54. NEONATAL HERPES 54 Treatment: Neonates with presumed herpes infection should be treated with antiviral drug such as acyclovir for 6–12 months Prevention: Treatment of genital herpes in mother before delivery and prevention of acquiring a new genital herpes infection in late pregnancy are the key measures to prevent neonatal herpes.

55. OTHER TERATOGENIC AGENTS 55

56. Varicella-zoster Virus (VZV) Infection 56 Chickenpox in pregnancy can affect both mother and the fetus. Mothers are at high-risk of developing varicella pneumonia Fetus can develop two types of infection; depending upon the gestational period at which it acquires infection.

57. Fetal or Congenital Varicella Syndrome (Infection in Early Pregnancy ) 57 Transmission: Varicella-zoster virus (VZV) is highly teratogenic. Risk of transmission is maximum when mother: Acquires primary infection during pregnancy Acquires infection at early pregnancy ( risk of transmission in 25% whereas risk of developing into disease in 0.4% in <12 weeks and 2% in 13-20 weeks of gestation.

58. Fetal or Congenital Varicella Syndrome (Infection in Early Pregnancy ) 58 Characterized by: Cicatricial skin lesions and limb hypoplasia (most characteristic anomaly) CNS defects: microcephaly, mental retardation and seizures Ocular defects- chorioretinitis , microphthalmia , and cataracts Renal system- hydroureter and hydronephrosis Autonomic system- neurogenic bladder Low birthweight

59. Neonatal Varicella (Infection Near Delivery) 59 If mother develops chickenpox more than 5 days before delivery - baby is mostly asymptomatic - protective maternal antibody which prevents the transmission of the virus during delivery. If mother develops chickenpox 5 days before to 2 days after the delivery - maternal antibodies - not produced in such a short time - dissemination of virus occurs in the baby to cause neonatal varicella; a severe form of chickenpox with mortality rate exceeding 30%.

60. Parvovirus Infection 60 Parvovirus can cause non-immune hydrops fetalis in fetus - results in fatal anemia and fetal death. Transplacental transmission occurs in 30% of cases Maximum risk - second trimester. In children - causes exanthematous lesions (called fifth disease)

61. Zika Virus Disease 61 Zika virus (ZIKV) has recently gained attention due to recent large outbreaks that occurred in 2015–16 worldwide. Arbovirus ; ssRNA virus, belongs to family Flaviviridae . Named after its place of discovery, Zika forest in Uganda Monkeys are the reservoirs.

62. Transmission 62 Primary transmitted by Aedes aegypti mosquito. Other modes include—mother-to-child transmission (common in first trimester) and rarely through sexual contact, blood transfusion and organ transplantation.

63. Epidemiology 63 Till date, a total of 87 countries have had evidence of ZIKV infection. Outbreaks have been recorded in Africa, the Americas, Asia and the Pacific; the largest outbreak occurred in 2015–16 in Brazil.

64. Clinical Manifestations 64 Incubation period - few days to 1 week. Zika Fever: Fever with rash and conjunctivitis Congenital Zika syndrome (CZS): characterized by maicrocephaly and other neurological manifestations Neurological complications: Guillain-Barré syndrome, neuropathy and myelitis.

65. Laboratory Diagnosis 65 Nucleic acid testing (NAT): RT-PCR - investigation of choice. It can detect ZIKV RNA in blood and urine up to 7 days of onset of symptoms IgM antibody detection: Appears in blood after 1 week of symptoms and remains positive up to several months. Cross reacts with dengue antibodies.

66. Treatment of Zika virus disease 66 No effective treatment and vaccine is available so far. Only symptomatic treatment - fluid replacement and analgesic such as acetaminophen

67. General Preventive Measures 67 Mosquito control measures Infected patients should prevent mosquito bites for the first week of illness Sex restriction: CDC recommends - condom use or abstinence - 3 months for males and 2 months for females after travel to area with Zika outbreak Pregnant women should NOT travel to areas with Zika virus outbreaks.

68. Congenital Syphilis ( Treponema pallidum ) 68 Though transmission of T. pallidum across the placenta may occur at any stage of pregnancy, fetal damage occurs only after fourth month of gestation. Untreated cases of early maternal syphilis - higher risk. Antenatal screening and treatment of positive cases during pregnancy - prevent congenital syphilis.

69. Manifestations 69 Earliest manifestations occur within 2 years of age. Affected children are infectious and they suffer from rhinitis (or snuffles), mucocutaneous lesions, bone changes, hepatosplenomegaly and lymphadenopathy.

70. Manifestations 70 Late congenital syphilis occurs after 2 years and is non-infectious. Characterized by interstitial keratitis, eighth-nerve deafness, bilateral knee effusions ( Clutton’s joints). Residual stigmata may remain for long time such as: Hutchinson’s teeth (notched central incisors) Mulberry molars (molars with poorly developed cusps) Saddle nose, and saber shins.

71. Diagnosis of Congenital Syphilis 71 Definitive Diagnosis: Demonstration of T. pallidum by dark ground microscopy (DGM) of umbilical cord, placenta, nasal discharge, or skin lesion material

72. Diagnosis of Congenital Syphilis 72 Presumptive Diagnosis: Reactive treponemal test in infant plus One of the following additional criteria in infant: Clinical signs/symptoms of congenital syphilis Abnormal CSF findings without other cause Reactive VDRL-CSF test Reactive IgM antibody test specific for syphilis (IgM FTA ABS or IgM ELISA).

73. Congenital Trypanosomiasis 73 Rarely, T. cruzi can be transmitted transplacentally both in acute and chronic stages of the disease. Manifests as low birth weight, stillbirth, rarely myocarditis and neurological alterations

74. Congenital Trypanosomiasis (Cont..) 74 Diagnosis is made by the following methods. Antibody detection: Detection of IgM and IgA Antigen detection: T. cruzi specific antigens from serum and urine of the infected patients - detected by ELISA Molecular methods: PCR - detects T. cruzi specific kinetoplast or nuclear DNA in blood of the neonate

75. Malaria in Pregnancy 75 Plasmodium falciparum - transmitted by transplacental route Merozoites (or trophozoites ) - infective form. Malaria during pregnancy increases the risk of fetal distress - result in premature labor, low birth weight and still birth. In areas with high malaria transmission, pregnant women are particularly vulnerable to severe anemia, hypoglycemia and acute pulmonary edema.

76. Malaria in Pregnancy 76 HRP2 antigen - reliable marker to diagnose malaria in pregnancy In pregnant women, cord blood and placental impression smears - used to make thin and thick smears.

77. Questions: 77 Q1. Classical triad of congenital rubella syndrome consists of all except: Ear defect Ocular defect Cardiac defect Kidney defect

78. Questions: 78 Q2. The risk of congenital infection by cytomegalovirus is maximum, if mother acquires the infection in: a. First trimester b. Second trimester c. Third trimester d. During delivery