Congenital Infections

Question 1

Congenital Infections

Definitions

Answer 1

• Congenital = born with it
• Prenatal = before birth
• Perinatal = around the time of birth (24-48 hrs before and after)
• Postnatal = after birth
• Neonatal = during the first 28 days of life
  
  • Most at risk time of life for spontaneous acquisition and invasion of microorganisms
    
    • Immune system immature
    • Unable to localize infection ⇒ dissemination more common (ex. HSV)
• Intrauterine = while in the womb
  
  • Most common route of transmission

Question 2

Congenital Infections

Routes of Transmission

Answer 2

• Transplacental: bacteremia, viremia, parasitemia
  
  • Most common
• Ascending from cervix: esp. after rupture membranes, amnionitis
• During delivery: cervical secretions, blood
• Postnatal: contact, airborne, fecal-oral, breastmilk

Question 3

Congenital Infection

Vulnerability

Answer 3

• Maternal exposure: pregnant women frequently live w/ children
• Maternal immune suppression: pregnancy itself
  
  • ↓ Maternal response to fetal Ag
• Maternal primary infection: highest risk for fetus
  
  • No maternal adaptive immune defense
• Immunologic immaturity: fetus > neonate > 1 mo. Old
  
  • IgM used to dx congenital infections
• Gestational age at congenital infection: early ⇒ worst
• Age at postnatal infection: < 2 wks ⇒ worst

Question 4

Congenital Infection

Clinical Manifestations

Answer 4

• Most congenital infections are asymptomatic/inapparent at birth
• Possible signs of congenital infection include:
  
  • Fetal death/premature birth
  • Intrauterine growth retardation: small for gestational age
  • Abnormal brain growth: microcephaly, hydrocephalus, intracranial calcifications
  • Ocular abnormalities: chorioretinitis, cataracts, microphthalmia
  • Hepatosplenomegaly
  • Bone abnormalities: lytic lesions, celery stalking
  • Hematologic abnormalities: anemia, thrombocytopenia
  • Skin lesions: petechiae, extramedullary hematopoiesis

Question 5

Major Congenital Infections

Answer 5

1. Toxoplasma
2. Cytomegalovirus
3. Rubella
4. Treponema pallidum
5. Zika virus

Question 6

Major Perinatal Infections

Answer 6

Question 7

Toxoplasma Gondii

Lifecycle

Answer 7

Question 8

Toxoplasma Gondii

Congenital Disease

Answer 8

• Pregnant woman acquires 1° infection w/ T. gondii
  
  • Cats are the definitive hosts
  • Humans become infected via ingestion of oocysts from cat feces or contaminated animal meat
• If during 1^st trimester ⇒ usu. spontaneous abortion or stillbirth
• > 70% of congenitally acquired toxoplasmosis is unapparent at birth, but will manifest months to yrs later
• Clinical manifestations include:
  
  • Intellectual disability / Learning disabilities
  • Intracranial calcifications and hydrocephalus
  • Visual impairment & chorioretinitis
  • Hearing loss
  • Hepatosplenomegaly
  • Thrombocytopenia

Question 9

Chorioretinitis

Appearance

Answer 9

Question 10

Toxoplasma Gondii

Diagnosis

Answer 10

Congenital Infection or Symptomatic Primary Infection

• Acute active infection dx by serology
  
  • High seropositivity in general pop. (20–50% in US)
  • Pay attention to ↑ IgG titers (4-fold) and presence of specific IgM

Question 11

Rubella

General Characteristics

Answer 11

• Rubella virus
  
  • Togavirus
    
    • Same characteristics as Arboviruses except is not transmitted by arthropod vector
  • ⊕-sense ssRNA
  • Replicates in the cytoplasm & buds off cytoplasmic membrane
• Rubella (“little red” or German measles, or 3-day measles)
  
  • 1 of the 5 childhood exanthems (also measles, rubeola, fifth disease and chickenpox)
• Only one serotype of virus

Question 12

Rubella

Transmission and Epidemiology

Answer 12

• Occurs via respiratory route, or transmitted vertically during first 20 wks of pregnancy from nonimmune mother → fetus
• Humans are the only host for the virus
• Peak incidence: late winter and early spring
• Epidemics occur every 6-9 yrs

Question 13

Rubella

Pathogenesis and Clinical Disease

Answer 13

1° infection w/ postnatal rubella virus

• Starts in the upper respiratory tract
• Virus replicates in lymphoid tissue
• Ass. w/ the prodromal phase (1-2 wks) ⇒ lymphadenopathy and flu-like symptoms
• Viremia → dissemination
• Ab vs virus appears → onset of mild erythematous maculopapular rash and arthralgias (adolescents and adults)
  
  • Probably immune complex mediated
  • Rash lasts ~ 3 days
• Virus shed for ~ 1 wk after onset of rash and from 7-14 days prior to the rash
• 25-50% of infections are asymptomatic

Question 14

Rubella

Congenital Infection

Answer 14

• Vertical transmission during first 20 wks of pregnancy from nonimmune mother → fetus
• Virus replicates in the placenta and travels via blood in the fetus
• Occurrence of congenital defects
  
  • > 50% if infection occurs in 1^st month of gestation
  • 20-30% in the 2^nd month
  • 5% in the 3^rd or 4^th month
• Most common anomalies are ophthalmologic, cardiac, auditory and neurologic
  
  • Triad is deafness, PDA and cataracts
  • Almost all will have intellectual disability and chorioretinitis
  • Frequently growth retarded
• Small # of infants may shed virus from nasopharynx or urine for ≤ 1 year

Question 15

Rubella

Diagnosis

Answer 15

• In congenitally infected infants, virus can be isolated from nasal specimens, blood, urine and CSF (PCR)
• Rubella specific IgM usu. indicates congenital infection
• 4-fold increase of rubella specific IgG in serum over several months can also confirm dx
• Many states have implemented prenatal screening of pregnant women for anti-rubella titers to determine at risk women

Question 16

Rubella

Prevention

Answer 16

• Live attenuated Rubella virus is administered along w/ the measles and mumps vaccines (MMR)
  
  • Part of the mandatory childhood immunization program
  • 2 immunizations
• Vaccine is contraindicated for non-immune pregnant women, but is administered during the immediate post-partum period
• Primary purpose of vaccination is to prevent congenital rubella

Question 17

Cytomegalovirus

Adult Infection

Answer 17

Question 18

Cytomegalovirus

Congenital or Perinatal Infection

Answer 18

• ~1% of live births are infected in utero
  
  • Usu. d/t 1° infection of the mother during pregnancy
• Transmission can also result from passage through the birth canal and postnatally by ingesting virus containing breast milk
• Most full-term infants who acquire infection during or after birth have asymptomatic infections
• Preterm infants at higher risk for interstitial pneumonia or hepatitis
• Clinical manifestations:
  
  • 10-20% dx w/ intellectual disability or deafness
  • Microcephaly, chorioretinitis, hepatosplenomegaly, jaundice
  • CMV likes to be periventricular in the brain ⇒ microcephaly, periventricular calcifications and hydrocephalus ex vacuo
  • Extramedullary hematopoiesis ⇒ hepatosplenomegaly & Blueberry muffin lesions (palpable purpura)

Question 19

Congenital or Perinatal CMV

Manifestations

Answer 19

Question 20

Congenital Cytomegalovirus

Diagnosis

Answer 20

Isolation of virus (by PCR) from urine

Serology – IgM at birth, rising IgG titers

Question 21

Treponema pallidum

Congenital Infection

Answer 21

• 100% of pregnant mothers susceptible to new Syphilis infection
  
  • No protection from prior infections
• Unique clinical manifestations:
  
  • Celery stalk osteomyelitis
  • Dental and long bone deformities
  • Keratitis ⇒ blindness

Question 22

Congenital Syphilis

Manifestations

Answer 22

Celery stalk osteomyelitis

Dental and long bone deformities

Keratitis ⇒ blindness

Question 23

Zika Virus

Answer 23

• Maternal infection during pregnancy:
  
  • 1^st trimester (@ 7-13 wks, up to 18 wks gestation) ⇒ anomalies noted
  • Risk of microcephaly is 1-13%
• Zika causes ↑ apoptosis in the fetal brain
• Between 6-32 wks gestation ⇒ fetal loss reported
• Avoid travel to or having sex w/ traveler from endemic area during/just before pregnancy

Question 24

Listeria monocytogenes

Morphology and General Characteristics

Answer 24

• Listeria are fairly widespread and cause a spectrum of disease in animals and humans
• Listeria monocytogenes ⇒ human disease
• Normal bowel flora
  
  • Also common among fowl and cattle
• Short, gram-⊕, non-spore forming rods
  
  • May resemble diphtheroids
• Aerobe
• Grow at temperatures as low as 4°C

Question 25

Listeria monocytogenes Transmission and Epidemiology

Answer 25

* Ubiquitous, found in **soil, water, vegetation and a variety of animals** * **Asymptomatic intestinal carriage** in 2-12% of humans * _Transmission:_ * 1° by **ingestion of contaminated food** * **Dairy products**, particularly unpasteurized milk, soft cheeses * **Prepared meats**, such as hot dogs and cold cuts * L. monocytogenes able to _grow at 4__°__C_ ⇒ **pathogenic inoculum sizes can be reached _during refrigeration_** * Elderly, pregnant women, immunocompromised ⇒ ↑ risk * Incidence of listeriosis in AIDS pts significantly increasing * _If acquired by a pregnant woman_, can be **transferred across the placenta to the developing fetus** * Frequently results in **miscarriage, stillbirth or severely ill newborn**

Question 26

Listeria monocytogenes Pathogenesis

Answer 26

* L. monocytogenes is a **facultative intracellular pathogen** * Can replicate both _within and outside of cells_ * Invades cells of the GI tract: **undifferentiated epithelial cells, M cells, intestinal crypt cells, and MΦ** * Invasion mediated by **internalin** * _Once inside the cell_, L. monocytogenes produces a _pore-forming cytolysin_, **listeriolysin O (LLO)** * Aids escape from vacuole → host cytoplasm ⇒ avoids killing * Resistance mediated by **activated MΦ** via **inactivation of listeriolysin O** by oxidative metabolites * MΦ activation dependent on recruitment of **inflammatory T cells (T_H1)** ⇒ secrete cytokines like **IFN-****γ**

Question 27

Listeria monocytogenes Clinical Syndromes

Answer 27

* **Early-onset disease in the neonate** * 1° infection of pregnant mother * Asymptomatic vs flu-like sx or UTI * _In utero fetal infection_ ⇒ **granulomatosis infantiseptica** * Serious disease characterized by **disseminated abscesses and granulomas** in multiple organs * **Late-onset disease in the neonate** * _Perinatal infection_ from Listeria colonizing the vagina * Disease is **much less severe** than early-onset disease & occurs less frequently * Appears _2-3 wks after birth_ as **meningitis and septicemia** * **Meningitis** * Occurs in **neonates** and **immunosuppressed adults** * Meningitis is the _most common infection caused by Listeria in adults_ * Most often occurs in pts w/ depressed CMI * **Bacteremia and endocarditis** * Occur in pts w/ depressed CMI

Question 28

Listeria monocytogenes Diagnosis

Answer 28

* **Culture** L. monocytogenes from **blood, CSF or focal lesions** * Grow on _blood agar_ ⇒ **small zone of beta hemolysis** around colonies * **Catalase** **⊕** * **CAMP ⊖** * Characteristic **tumbling end-over-end motility** at 25°C * **Serologic tests** available

Question 29

Listeria monocytogenes Treatment and Control

Answer 29

* Several abx including **penicillin G, ampicillin, erythromycin and chloramphenicol** * Immunity ass. w/ **CMI**, esp. **activation of MΦ by INF-****γ** * _High risk individuals:_ * **Avoid eating raw, unpasteurized cheeses, processed meats** (hotdogs, cold cuts) unless steaming hot * **Thoroughly wash raw vegetables**