What are the causes, prevention, diagnosis, and treatment of TORCH (Toxoplasmosis, Rubella, Cytomegalovirus, Herpes simplex virus) infections in a child with suspected developmental delays due to congenital infections?

TORCH Infections: Causes, Prevention, Diagnosis, and Treatment

Causes and Pathogens

TORCH infections are congenital infections caused by specific pathogens that cross the placenta and infect the fetus, with the acronym representing Toxoplasmosis, Other infections (primarily syphilis), Rubella, Cytomegalovirus (CMV), and Herpes simplex virus (HSV). 1, 2

The primary causative organisms include:

• Toxoplasma gondii: Transmitted through undercooked meat or cat feces exposure, with transmission risk increasing from 2-6% in first trimester to 81% in late pregnancy 3
• Cytomegalovirus (CMV): The most commonly observed congenital infection, accounting for 2-10% of cases with echogenic bowel on ultrasound 3
• Rubella virus: Now eliminated in the Americas through immunization 2
• Herpes simplex virus (HSV): Types 1 and 2, with 80% of symptomatic infants showing cutaneous vesicles, oral ulcers, or conjunctivitis 4
• Other pathogens: Including varicella zoster virus, parvovirus B19, enteroviruses, and Zika virus 3, 1

Clinical Presentations and Developmental Impact

70-90% of infants with congenital TORCH infections are asymptomatic at birth, but the majority will develop late sequelae with onset ranging from several months to years after birth, making ongoing surveillance critical even in apparently healthy infants. 3, 5

Toxoplasmosis Manifestations

• Chorioretinitis: The predominant late manifestation, appearing as white retinal lesions with minimal hemorrhage and potentially causing visual loss 5
• Neurologic sequelae: Including microcephaly, intracerebral calcification, hydrocephalus, seizures (may develop de novo between 3-5 years of age), and intellectual impairment 3, 5
• Recurrent eye lesions: Approximately 36% recurrence rate in severely affected children and 9% in those with mild disease at birth 5
• Progressive deterioration: Can occur if untreated, including development of microcephaly, intellectual impairment, and motor deficits 5

CMV Manifestations

• At birth: Maculopapular rash, hepatosplenomegaly, jaundice, thrombocytopenia, paraventricular calcification, and intrauterine growth retardation 3, 4
• Late sequelae: Hearing loss, visual impairment, neurologic deficits, and developmental delays 5

HSV Manifestations

• Acute presentation: Cutaneous vesicles (80% of symptomatic cases), oral ulcers, conjunctivitis, with potential for disseminated disease involving CNS and eyes 4
• HSV encephalitis: Can present at any age with fever, altered consciousness, seizures, and focal neurologic deficits 5

Rubella Manifestations

• Classic triad: Deafness, congenital heart disease, and retinopathy 4
• Additional findings: Brain calcification and intrauterine growth retardation 4

Diagnostic Approach

Initial Evaluation for Suspected Congenital Infection

Congenital infections should be suspected in newborns with hydrops fetalis, microcephaly, seizures, cataract, hearing loss, congenital heart disease, hepatosplenomegaly, jaundice, or rash. 1

Toxoplasmosis Diagnosis

All HIV-infected pregnant women should undergo serologic testing for Toxoplasma, and all infants whose mothers are both HIV-infected and seropositive for Toxoplasma should be evaluated for congenital toxoplasmosis. 3

Diagnostic workup includes:

• Serologic testing: Toxoplasma-specific IgG, IgM ISAGA, and IgA ELISA at birth 3
• Confirmatory testing: All positive IgM results from commercial laboratories must be confirmed at a toxoplasmosis reference laboratory, as approximately 60% represent false-positives or chronic infections 6
• PCR testing: Peripheral blood, urine, and CSF Toxoplasma PCR should be performed when there is strong suspicion of congenital toxoplasmosis 3
• Imaging: Head ultrasonography or brain MRI (more sensitive than CT) to detect hydrocephalus, calcifications, or other CNS lesions 3, 5
• Ophthalmologic examination: Essential at birth and repeated regularly, as isolated ocular toxoplasmosis usually occurs with CNS involvement 3, 5

CSF Toxoplasma PCR should be performed in infants with positive Toxoplasma IgM ISAGA and/or IgA ELISA, those born to mothers with confirmed acute T. gondii infection during pregnancy with positive amniotic fluid PCR or abnormal fetal ultrasound, and those whose mothers had recently acquired infection in second or third trimester without antepartum treatment. 3

CMV Diagnosis

CMV IgG and IgM titers should be drawn regardless of maternal symptoms, with IgG avidity testing as applicable. 3

• Confirmatory testing: If results suggest primary CMV infection (IgM positive and IgG positive with low avidity or IgG seroconversion), amniocentesis should be considered 3
• Optimal timing: Amniocentesis with PCR for CMV DNA is most sensitive when performed after 21 weeks of gestation and >6 weeks from maternal infection 3

Follow-up Monitoring Schedule

For confirmed congenital toxoplasmosis, detailed physical examination should be performed at birth and every 2-3 months during the first year of life, then every 4-6 months thereafter. 3, 6

• Neurologic evaluation: Same schedule as physical examination 3, 6
• Serologic follow-up: Monitor IgG titers every 4-6 weeks for appropriate decrease (IgG half-life is 30 days) until complete disappearance 3, 6
• Ophthalmologic surveillance: Critical for detecting new or recurrent chorioretinal lesions that can develop years after birth 5

Treatment

Toxoplasmosis Treatment in Pregnancy

Pregnant women with suspected or confirmed toxoplasmosis before 18 weeks gestation should receive spiramycin 1g (or 3 million IU) orally three times daily, switching to combination therapy with pyrimethamine plus sulfadiazine plus folinic acid at or after 18 weeks gestation or if fetal infection is confirmed. 7

Congenital Toxoplasmosis Treatment in Infants

The preferred treatment for congenital toxoplasmosis is pyrimethamine (loading dose of 2 mg/kg/day for 2 days, then 1 mg/kg/day for 2-6 months, followed by 1 mg/kg three times weekly) combined with sulfadiazine (50 mg/kg/dose twice daily), with supplementary leucovorin (folinic acid) to minimize pyrimethamine-associated hematologic toxicity. 3

• Duration: The recommended duration of treatment is 12 months for infants without HIV infection 3
• Monitoring: Complete blood count should be performed at least weekly while on daily pyrimethamine and at least monthly while on less than daily dosing 3
• Leucovorin requirement: Must always be administered with pyrimethamine to prevent bone marrow suppression 3, 5

Toxoplasmic Encephalitis Treatment

For HIV-infected children with acquired CNS, ocular, or systemic toxoplasmosis, treatment consists of pyrimethamine (2 mg/kg/day for 3 days, followed by 1 mg/kg/day) and leucovorin (10-25 mg/day) plus sulfadiazine (25-50 mg/kg/dose four times daily), with acute therapy continued for 6 weeks assuming clinical and radiological improvement. 3, 5

HSV Treatment

Acyclovir should be initiated immediately upon suspicion of HSV encephalitis, even with atypical presentations. 5

• Pregnancy management: Acyclovir for primary HSV infection or severe disease during pregnancy has no increased risk for major birth defects based on decades of safety data 7
• Prophylaxis: Antiviral prophylaxis in the third trimester should be offered to women with a history of genital herpes to reduce recurrence risk at delivery 7

CMV Treatment Considerations

Valganciclovir is indicated for prevention of CMV disease in pediatric heart transplant patients 4 months to 16 years of age, but efficacy and safety have not been established for treatment of congenital CMV infection in infants. 8

Prevention Strategies

Primary prevention of maternal infections during pregnancy is the cornerstone of prevention of congenital infection. 1

Toxoplasmosis Prevention

• Dietary precautions: Avoid undercooked meat and unwashed fruits/vegetables 3
• Cat exposure: Avoid handling cat litter or wear gloves when necessary 3
• Screening: Monthly serologic screening during pregnancy in high-prevalence regions 3

CMV Prevention

For fetuses with isolated echogenic bowel, evaluation for cystic fibrosis and fetal CMV infection is recommended. 3

• Third-trimester ultrasound: Recommended for reassessment and evaluation of fetal growth for all fetuses with isolated echogenic bowel due to association with fetal growth restriction 3

General Prevention

• Immunization: Rubella vaccination before pregnancy (eliminated in Americas) 2
• Hepatitis B management: Tenofovir disoproxil fumarate at 24-28 weeks gestation for pregnant women with HBV DNA >200,000 IU/ml 7

Critical Pitfalls to Avoid

Do not assume a normal newborn screen excludes TORCH infection—most affected infants are asymptomatic at birth and develop problems later. 5

• Do not rely on maternal history alone: Many infected mothers are asymptomatic during pregnancy, with only 48% of mothers of infants with congenital toxoplasmosis having clinical symptoms or reported risk factors 3
• Do not rely on commercial laboratory IgM results alone: False positives are frequent and lead to unnecessary interventions; confirmation at reference laboratories is mandatory 7, 6
• Do not dismiss mild symptoms: Single seizure, transient ataxia, or headache may represent milder forms of encephalitis requiring treatment 5
• Do not exclude toxoplasmic encephalitis based on negative serology alone: In HIV-infected children, cases have been reported without detectable IgG antibodies 5
• Do not delay spiramycin initiation: If acute toxoplasmosis is clinically suspected, start treatment while awaiting confirmatory testing, as early treatment reduces transmission risk 7
• Do not treat immunocompetent non-pregnant adults with chronic toxoplasmosis: Treatment is not indicated for chronic infection (>3 months before) in immunocompetent individuals 6

Timing-Critical Interventions

Delay of more than 8 weeks from maternal seroconversion to initiation of maternal treatment is associated with increased risk of chorioretinitis in the first 2 years of life (HR: 2.54; 95% CI: 1.14-5.65). 3

Treatment benefit is lost when antepartum treatment is initiated more than 4 weeks after seroconversion, with 72% lower odds of intracranial lesions when treatment begins within 4 weeks (OR: 0.28; 95% CI: 0.08-0.75). 3