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Congenital CMV Infection ~ 1% of US Newborns – Mononucleosis Syndrome ~ 10% Healthy Children & Adults

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Congenital CMV Infection ~ 1% of US Newborns – Mononucleosis Syndrome ~ 10% Healthy Children & Adults Pediatric Infections in Iowa A potpourri of midwestern pathogens Amaran Moodley MD Pediatric Infectious Diseases Blank Childrens Hospital Objectives • Discuss the epidemiology, presentation and management of pediatric infections that are not well recognized but known to occur in Iowa. This will include tick-borne, mosquito-borne and travel related infections Case #1 23 month old boy presents with fever and limp HPI: • Fever 3 weeks ago for 3-4 days followed by limp and refusal to straighten left leg or bear weight • Seen on multiple occasions by PCP and diagnosed with viral illness and "muscle sprain“ • No trauma to left leg, no penetrating injury • No antibiotics received 1 Case #1 PMH: • No previous hospitalizations • No history of severe, invasive infections like meningitis, pneumonia or musculoskeletal infections • No previous surgeries except for ear tubes in December 2016 Immunizations: UTD Exposures: no previous MRSA infections Case #1 Exam: • General: awake, sitting up in bed, no distress, no pallor, non toxic • HEENT: conjunctiva normal, normal oropharynx • Chest: no respiratory distress • CVS: normal rate and rythym, no murmur • Abdomen: soft, non tender, no organomegaly • CNS: grossly non-focal exam • Skin: no rashes • Msk: left thigh and calf non tender. Left knee with swelling and decreased ROM. No other joint or extremity swelling or redness • Lymph: no significant cervical, axillary or inguinal nodes Case #1 Labs: CRP: 1.2 -> 2.3 ESR: 23 WBC: 16, 000 hgb: 12.0 plts: 354,000 (N:60, L: 26, M13) Blood culture: no growth Imaging: contrast MRI 2 Case #1 - Contrast MRI of left extremity Case #1 Joint fluid: • WBC: 23,000 (N:75%) • Culture negative (aerobic, anaerobic, fungal, AFB) • PCR sent to Arkansas Children’s Hospital POSITIVE FOR Kingella kingae Course: • Treated with IV Cefazolin for 2 weeks then switched to oral Cephalexin for 4 weeks with complete recovery Case #1 – Kingella kingae Pathogens causing acute bacterial osteomyelitis and septic arthritis in children • Staph Aureus (MSSA and MRSA) • Streptococcus pyogenes (GAS) • Streptococcus pneumoniae • Kingella kingae • Gram negatives like Salmonella species 3 Case #1 – Kingella kingae Kingella kingae • Colonizes posterior pharynx of children • Invasive infection may follow URI or stomatitis • Children between 6-48 months of age affected • Joints: knee, hip, ankle. Bones: femur, tibia • Subacute presentation more common • Does not readily grow in culture, molecular studies helpful • Susceptible to most beta lactam antibiotics Case #2 A female infant is born at 32 weeks gestation and is noticed to be small for age Birth and maternal history • Born by C-section to a 21 year old woman • IUGR diagnosed prenatally by serial US • 1st trimester screens negative (HIV, Hep B, syphilis) • Mother had URI ~8 weeks prior to delivery, otherwise healthy • No travel history during pregnancy Case #2 Physical exam findings: • Microcephaly (<1%) • Hepatosplenomegaly with mild jaundice • No petechial rash, hypotonia, cataract or heart murmur Labs • WBC: 14,000 Hgb: 14.0 Plts: 67,000 • AST: 330 U/L ALT: 290 U/L Bilirubin: 5.7 m/dL • Urine PCR: CMV positive 4 Cytomegalovirus • Beta Herpes Virus that establishes latency • Asymptomatic shedding of virus in saliva, urine, genital secretions, breast milk, blood • Three clinical syndromes: – Immune compromised hosts (multi-organ) – Congenital CMV infection ~ 1% of US newborns – Mononucleosis syndrome ~ 10% healthy children & adults Epidemiology of CMV infection • Common infection – 50.4% of 6-49y infected* – 56% females – 45% males – 6-11 yrs (37.5%) – 12-19 yrs (42.7%) – 20-29 yrs (49.5%) – 30-39 yrs (56.7%) – 40-49 yrs (58%) – > 80 yrs (90%) Fig. CMV seroprevalence among US women of reproductive age Bate et al. 2010 CID Congenital CMV infection • Most frequent congenital infection (~0.7%) • Trans-placental transmission of CMV from mother to fetus • Distinct from intrapartum or postnatal infection acquired through infected cervical secretions or breast milk • Leading cause of non-genetic sensorineural hearing loss 5 Congenital CMV infection • ~60% of women of reproductive age are seropositive • 1% transmission risk with maternal non-primary CMV • ~40% of women of reproductive age are seronegative • 1-4% of seronegative women acquire CMV during pregnancy • 30-40% transmission risk with maternal primary CMV • Risk of symptomatic disease and sequelae highest in 1st trimester infections Epidemiology of congenital CMV infection Live born infants CMV seronegative Live born infants Live Live births with congenital women with with congenital Race births per among CMV from primary infection CMV from mothers year CMV + mothers with non- during pregnancy with primary (1988- women primary infection (1-2% risk) infection 1994) (1.4%) (30-40% risk) 1,108,775 White 2,409,000 15523 16150 5218 (46%) 452,360 Black 582,000 6333 6652 2149 (78%) 575,923 Mexican 701,000 8062 4184 1355 (82%) Total 3,692,000 29,918 (77%) 8,722 (23%) Wang et al. 2011 CID Congenital CMV infection • 30,000-40,000 infants born each year in the US with congenital CMV infection • 10-15% of CMV infected newborns are symptomatic 50-60% develop sequelae • 85-90% of CMV infected newborns have subclinical or asymptomatic infection 10-15% develop sequelae 6 Public health impact of congenital CMV in Iowa USA (2014) Iowa (2015) Number of live births 3,988,076 39,375 Rate of congenital CMV 7/1000 Rate of Down syndrome 1.4/1000 Number of infected infants 27,916 275 Symptomatic at birth (10%) 2,792 27 Fatal disease (5%) 139 1 Permanent sequelae (60%) 1,675 16 Asymptomatic at birth (90%) 25,124 247 Permanent sequelae (10-15%) 2,512-3,769 25-37 Total number with sequelae 4,187-5,444 41-53 Source: IDPH and CDC Sequelae of congenital CMV infection • Sensorineural hearing loss 15% • Bilateral Hearing loss 9% • IQ < 70 10% • Retinitis 6% • Cerebral palsy 5% • Seizures 5% Fig. Estimated annual number of US children with long term sequelae caused by various diseases Canon M.J. 2009 J Clin Virol Symptomatic congenital infection • Small for gestational age 50% • Hepatosplenomegaly 60% • Petechial or purpuric rash 76% • Neurologic: 68% – Hypotonia 27% – Poor suck 19% – Seizures 7% – Microcephaly 53% • Jaundice 67% • Hepatitis (ALT >80 units/L) 83% • Thrombocytopenia – <100 x 103 77% – <50 x 103 53% Boppana et al. 1992 PIDJ 7 Congenital CMV infection Fig. CMV infected infant with hepatosplenomegaly and petechial rash. Source: AAP Congenital CMV: CNS disease Figures: Periventricular calcifications in infants with early, late 2nd trimester and late perinatal CMV infection Fink et al. 2010 Radiographics Hearing Sequelae of Congenital CMV infection • Leading cause of non-genetic hearing loss in childhood • CMV-related sensorineural hearing loss (SNHL) may be present at birth but is frequently delayed in onset • Severity of hearing loss is variable – Unilateral high frequency loss to profound bilateral loss • Progression and fluctuation of hearing loss may occur in children with CMV-related SNHL 8 Diagnosis of congenital CMV infection • Prenatal diagnosis: + maternal serology and amniocentesis • Urine CMV shell vial culture or PCR (gold standard) • Saliva CMV PCR: sensitivity (97-100%), specificity (100%)* • Dried blood spot: sensitivity (95-100%), specificity (98-99%)** • Serology not recommended: CMV IgM and IgG • Other evaluations: – LFTs, bilirubin, CBCd, serum creatinine – Neuroimaging (US or MRI) – Hearing assessment (BAER/ABR) – Eye exam *Leruez-Ville et al. 2011 CID ** Boppana et al. 2011 NEJM Treatment of Congenital CMV: CASG 112 Randomized Placebo Controlled Blinded Investigation of 6 weeks versus 6 months of Oral Valganciclovir in Infants with Symptomatic Congenital CMV 6 weeks Valganciclovir 6 months treatment Worse or remained 27% 43% abnormal 57% Improved or remained 73% normal Figs. Change in hearing between birth and 12 months Treatment of Congenital CMV: CASG 112 6 weeks versus 6 months of Oral Valganciclovir in Symptomatic Congenital CMV Toxicity: • No significant difference in degree of neutropenia between 2 treatment groups • Less neutropenia with Valganciclovir than Ganciclovir • Blood CMV viral load did not correlate with outcomes 9 Treatment of Congenital CMV: CASG 112 Conclusions • Antiviral therapy in neonates with symptomatic congenital CMV disease modestly improves audiologic and developmental outcomes • Duration of treatment is 6 months • No controlled data exist to support treatment of babies with asymptomatic congenital CMV Follow up of Congenital CMV after NICU discharge • Monthly ID clinic follow up • Monthly CBCd, CMP • Periodic Hearing and developmental assessments • Ophthalmology follow up • Congenital CMV family support groups Iowa Congenital CMV Bill 10 Prevention of congenital CMV infection Case #3 PC: 15 year old boy with fever for 8 days HPC: Illness began with fever, vomiting, nausea and mild cough. Then developed central abdominal pain Fever for 3-4 days, followed by no fever for 2 days, then fever again for 3 days. Well in between fever episodes No headache, red eyes, rhinorrhea, rash, joint pain or swelling Case #3 PMH: Healthy, no previous hospitalizations, fully immunized Meds: Used to take Minocycline for acne for 1 year but stopped 1 month ago Exposure history: No sick contacts at home or school No travel outside USA or mid-western US No unpasteurized dairy ingestion No TB contacts Positive for recent mosquito bites. No known tick bites No farm animal exposure, no ingestion of well water 11 Case #3 Rocky Mountain National Park Case #3 Case #3 Physical
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