Neonatology. Lesson 4. Topics:

TORCH-infections in children.

1.     Embryo- and fetopathies.

2.     Intrauterine infections (TORCH-syndrome).

3.      Intrauterine growth retardation.

Embryo- and fetopathies. Intrauterine growth retardation.

Etiology: surround, factors, and maternal factors; medical, and obstetric complications of pregnancy. Pathogenesis: the main pathogenetical factor is fetoplacental insufficiency with uteroplacental blood circulation problems as a background. Then developed chronic fetal hypoxia and metabolism changes.

Classification:

Etiological: maternal, placental, fetal, combined factors.

Clinical types: a) hypotrophic (antenatal hypotrophy): after delivery body weight deficit is seen with normal length and head circumference (pathologic factors influenced during 3 trimester of pregnancy).

b) hypoplastic – after delivery body weight, length, head circumference are less theormal (pathologic factors influenced during II and III trimester of pregnancy).

c) dysplastic – retardation of weight, growth, head circumference are accompanied by dysembriogenesis.

By severity: I (mild), II (moderate), III (severe) (Tabl. 1)

By duration: without complications, with complications and accompanied pathology.

Diagnostic features of the intrauterine growth retardation

1.     Anamnesis: pathologic ethyological factors;

2.     Weight – length coefficient (in mature newborns), trophic index, percentage of the weight deficiency (in premature newborns).

3.     Clinical features: wrinkled and dry skin, desquamation or epidermis, soft tissues pressure is decreased, leak of subcutaneous fat.

 

 

Table 1. Grades of the intrauterine growth and development retardation.

Peculiarities of adaptation: Adaptation is long and changed; large percentage and long duration of prime weight loss; long umbilical wound epithelization; decreased neonatal reflexes; low resistance to the illnesses; continued jaundice.

     Principles of treatment:

1.     Peculiarities of feeding.

2.     Medicine which includes: ferments of the gastro-intestinal tract, adaptogens, immune modulators; parenteral feeding, plasma.

3.     Vitamins.

4.       Antioxidants and anabolics (cartritin, tocopherol).

Ambulatory care and prevention

1.     After body weight has beeormalized – observation of pediatrician once a month during one year; neurologist, orthopedist ophthalmologist – once during one year.

2.     Rehabilitation therapy: two courses 2-3 weeks duration

a)     simulative drugs (apical, pentoxyl, metyluracyl, natrii nucleinatis), antioxidants;

b)    vitamins;

c)     aromatic bathes, massage, gymnastics.

3.     Antenatal diagnosis of the intrauterine grows retardation;

4.     Treatment of the pregnant women, pregnancy complications preventions.

 

 

 

Intrauterine infections (TORCH-syndrome).

– Toxoplasmosis

– Other (Chlamydial infections, congenital syphilis, lysteria infection)

– Rubella

– Cytomegaloviral (CMV) infection

– Herpes simplex viral (HSV) infection

Congenital Infections so-called TORCH infections (toxoplasmosis, other, rubella, Cytomegalovirus infection, and herpes simplex infection). The newborn infant is more vulnerable than the older child to certain infections.  The preterm baby is even less able to withstand infection and more liable to suffer serious complications. Infection of the fetus can result in embryonic death, stillbirth, prematurity, intrauterine growth retardation, developmental abnormalities or congenital disease.

	Tabl. 2. Effect of Infection on the Fetus and Newborn Infant
Organism or disease	Prematurity	In utero Growth Retardation and Low Birth Weight	Developmental Anomalies	Congenital Disease	Persistant Postnatal Infection
Viruses
Rubella	–	+	+	+	+
CMV	+	+	+	+	+
HSV	+	–	–	+	+
VZV	–	(+)	+	+	+
Enteroviruses	–	–	(+)	+	–
Hepatitis B	+	–	–	+	+
HIV	(+)	(+)	(+)	+	+
Erythrovirus B19 (Parvovirus B19)	–	–	–	+	–
Bacteria
Treponema pallidum	+	–	–	+	+
Mycobacterium tuberculosis	+	–	–	+	+
Listeria monocytogenes	+	–	–	+	–
Campylobacter fetus	+	–	–	+	–
Salmonella typhosa	+	–	–	+	–
B. burgdorferi	–	–	–	+	–
Parasites
Toxoplasma gondii	+	+	–	+	+
Plasmodium spp.	(+)	+	–	+	+
Trypanosoma cruzi	+	+	–	+	–

+ = evidence for effect; – = no evidence for effect; (+) = association of effect with infection has been suggested and is under consideration.

Clinical findings are rarely disease specific but include (Tabl. 3):

·                   Low birthweight for gestational age.

·                   Prematurity.

·                   Seizures

·                   Chorio-retinitis

·                   Purpura

·                   Chronic rash

·                   Cerebral calcification

·                   Micro-ophthalmia

·                   Jaundice

·                   Anaemia

·                   Hepatosplenomegaly

·                   Pneumonitis

Tabl 3. Clinical features of congenital infections.

 

Cytomegalovirus (CMV) infection Of all the human herpesviruses described to date, infection with cytomegalovirus (CMV) arguably is the most important cause of morbidity and mortality. Although primary infection with this agent generally is asymptomatic in healthy adults, CMV has emerged in recent years as the most important cause of congenital infection in the developed world, commonly leading to mental retardation and developmental disability.

Causes CMV is a member of the family of 8 human herpesviruses, designated as human herpesvirus 5 (HHV-5). Transmission of CMV infection may occur throughout life, chiefly via contact with infected secretions (saliva, urine, and fomites). Acquisition of CMV in the newborn period is common. Approximately 1% (range 0.5-2.5%) of all newborns are infected congenitally with CMV. Most of these infections occur in infants born to mothers with preexisting immunity and are clinically silent at birth.

The route of congenital infection is presumed to be transplacental. CMV also may be transmitted perinatally, both by aspiration of cervicovaginal secretions in the birth canal and by breastfeeding. More than 50% of infants fed with breast milk that contains infectious virus become infected with CMV.

CLINICAL Congenital CMV infection may be present as Cytomegalic inclusion disease:

·                   Approximately 10% of congenitally infected infants have clinical evidence of disease at birth. The most severe form of congenital CMV infection is referred to as cytomegalic inclusion disease (CID).

·                   CID almost always occurs in women who have primary CMV infection during pregnancy, although rare cases are described in women with preexisting immunity who presumably have reactivation of infection during pregnancy.

·                   CID is characterized by intrauterine growth retardation, hepatosplenomegaly, hematological abnormalities (particularly thrombocytopenia), and a variety of cutaneous manifestations, including petechiae and purpura (ie, blueberry muffin baby). However, the most significant manifestations of CID are those involving the central nervous system. Microcephaly, ventriculomegaly, cerebral atrophy, chorioretinitis, and sensorineural hearing loss are the most commoeurological consequences of CID.

·                   Intracerebral calcifications typically demonstrate a periventricular distribution and commonly are encountered by CT scan. The finding of intracranial calcifications is predictive of cognitive and audiologic deficits in later life and predicts a poor neurodevelopmental prognosis.

·                   Overall, 90% of infants who survive symptomatic CID have significant long-term neurological and neurodevelopmental sequelae. Indeed, it has been estimated that congenital CMV may be second only to Down syndrome as an identifiable cause of mental retardation in children.

Asymptomatic congenital CMV

·                     Most infants with congenital CMV infection are born to women who have preexisting immunity to CMV. These infants appear clinically normal at birth; however, even though infants with congenital CMV infection appear well, they may have subtle growth retardation compared to uninfected infants. Although asymptomatic at birth, these infants, nevertheless, are at risk for neurodevelopmental sequelae.

·                     The major consequence of inapparent congenital CMV infection is sensorineural hearing loss. Approximately 15-20% of these infants will have unilateral or bilateral deafness. Routine newborn audiologic screening may not detect cases of CMV-associated hearing loss because this deficit may develop months or even years after delivery.

Acquired CMV infection:

·                     Perinatal acquisition of CMV usually occurs secondary to exposure to infected secretions in the birth canal or via breastfeeding. Most infections are asymptomatic. Indeed, in some reviews, CMV acquired through breast milk has been referred to as a form of natural immunization.

·                     Some infants who acquire CMV infection perinatally may have signs and symptoms of disease, including lymphadenopathy, hepatitis, and pneumonitis, which may be severe on occasion. Interestingly, these infections do not appear to carry any risk of neurological or neurodevelopmental sequelae.

Investigations

·                   Urine culture for CMV (must be in first two weeks of life to confirm congenital infection). Urine must be chilled and transported immediately to the lab on melting ice.

·                   Cord or infant blood for CMV PCR .

·                   Head ultrasound.

·                   Long term: serial audiology and developmental assessment, head circumference, ophthalmology.

TREATMENT  Medical care consists of good nutritional support, vigorous supportive care for end-organ syndromes (particularly pneumonia in immunocompromised patients), and specific antiviral therapy.

Currently, 3 antiviral therapies are approved for prophylaxis and/or therapy of CMV infection. Experience with these agents is limited in children.

Ganciclovir (Cytovene) Pediatric Dose <3 months: Not established; >3 months: Administer as in adults. Adult Dos:

·                   Induction: 5 mg/kg IV bid for 2-3 wk, followed by maintenance dose;

·                   IV maintenance: 5 mg/kg IV qd for the duration of therapy; 2.5 mg/kg/dose IV q8h has been used in some patients with CMV pneumonitis

·                   PO maintenance: 1 g PO q8h limited to HIV-positive individuals ieed of long-term anti-CMV therapy for CMV retinitis

Relatively little information exists concerning the use of GCV in the setting of congenital CMV infection. Because some of the neurological sequelae of congenital CMV, particularly sensorineural hearing loss, progress postnatally, the presentation of results from a recently terminated nationwide collaborative trial are of interest. Intravenous GCV led to improvement or stabilization of hearing in a significant number of 6-month-old infants. Case reports have suggested the efficacy of GCV for acutely ill neonates with life-threatening CMV disease (eg, pneumonia).

Cidofovir (Vistide) — Nucleotide analog that selectively inhibits viral DNA production in CMV and other herpes viruses. Pediatric Dose not established.

Foscarnet (Foscavir) — Organic analog of inorganic pyrophosphate that inhibits replication of known herpesviruses, including CMV, HSV-1, and HSV-2. Pediatric Dose <12 years: Not established; >12 years: Administer as in adults. Adult Dose 90 mg/kg IV q12h infused over a minimum of 1 h for 14-21 d.

 Immunoglobulins — Used as passive immunization for the prevention of symptomatic CMV disease. Have been useful in the control of CMV disease.

Immune globulin intravenous (Gamimune, Gammagard, Sandoglobulin, Gammar-P) Adult Dose 500 mg/kg IV qod for 10 doses in combination with GCV, followed by 500 mg/kg IV 2 times per wk for 8 additional doses. Pediatric Dose Not established.

CMV-Ig (CytoGam) — A CMV hyperimmunoglobulin has been shown to decrease incidence of CMV disease when administered posttransplant to high-risk transplant recipients.

Prevention:Until the goal of a CMV vaccine is realized, educating women of childbearing age about the risks of CMV and about how to avoid disease transmission are the only control strategies available.

 

 

Tabl 4. Differential diagnosis of different  congenital infections.

Clinical Sign	Rubella virus	CMV	HSV	Toxoplasma gondii	Treponema pallidum	Streptococcus agalactiae (Grp B) or E. coli
Hepatosplenomegaly	+	+	+	+	+	+
Jaundice	+	+	+	+	+	+
Adenopathy	+	–	–	+	+	–
Pneumonitis	+	+	+	+	+	+
Skin Lesions Petechiae/purpura	+	+	+	+	+	+
Vesicles	–	+	++	–	+	–
Maculopapular exanthems	–	–	+	+	++	–
CNS Lesions Meningoencephalitis	+	+	+	+	+	+
Microcephaly	–	++	+	+	–	–
Hydrocephalus	+	+	+	++	–	–
Intracranial calcifications	–	++	–	++	–	–
Paralysis	–	–	–	–	–	–
Hearing deficits	+	+	–	–	+	–
Heart lesions Myocarditis	+	–	+	+	–	–
Congenital defects	++	–	–	–	–	–
Bone lesions	++	–	–	+	++	–
Eye Lesions Glaucoma	++	–	–	–	+	–
Chorioretinitis or retinopathy	++	+	+	++	+	–
Cataracts	++	–	+	+	–	–
Optic atrophy	–	+	–	+	–	–
Microphtalmia	+	–	–	+	–	–
Uveitis	–	_	–	+	+	–
Conjunctivitis or keratoconjunctivitis	_	_	++	–	–	–

 

 

Rubella Rubella and congenital rubella syndrome are caused by rubella virus. The major complication of rubella is its teratogenic effects when pregnant women contract the disease, especially in the early weeks of gestation. The virus can be transmitted to the fetus through the placenta and is capable of causing serious congenital defects, abortions, and stillbirths. Congenital rubella occurs in about 90% of women with confirmed rubella infection during the first 20 weeks of pregnancy. 

Pathophysiology: Congenital rubella syndrome Fetal infection occurs transplacentally during the maternal viremic phase, but the mechanisms by which rubella virus causes fetal damage are poorly understood. The fetal defects observed in congenital rubella syndrome are likely secondary to vasculitis resulting in tissue necrosis without inflammation. Another possible mechanism is direct viral damage of infected cells. Studies have demonstrated that cells infected with rubella in the early fetal period have reduced mitotic activity. This may be the result of chromosomal breakage or due to production of a protein that inhibits mitosis. Regardless of the mechanism, any injury affecting the fetus in the first trimester (during the phase of organogenesis) results in congenital organ defects.

CLINICAL Congenital rubella history focuses on the following:

·                   The number of weeks of pregnancy when maternal exposure to rubella occurred (The risk of congenital rubella syndrome is higher if maternal exposure occurs during the first trimester.)

·                   Maternal history of immunization or medical history of rubella

·                   Evidence of intrauterine growth retardation during pregnancy

·                   Manifestations suggestive of congenital rubella syndrome in a child

Physical: The classic triad presentation of congenital rubella syndrome consists of the following:

·                     Sensorineural hearing loss is the most common manifestation of congenital rubella syndrome. It occurs in approximately 58% of patients. Studies have demonstrated that approximately 40% of patients with congenital rubella syndrome may present with deafness as the only abnormality without other manifestations. Hearing impairment may be bilateral or unilateral and may not be apparent until the second year of life.

·                     Ocular abnormalities including cataract, infantile glaucoma, and pigmentary retinopathy occur in approximately 43% of children with congenital rubella syndrome. Both eyes are affected in 80% of patients, and the most frequent findings are cataract and rubella retinopathy. Rubella retinopathy consists of a salt-and-pepper pigmentary change or a mottled, blotchy, irregular pigmentation, usually with the greatest density in the macula. The retinopathy is benign and nonprogressive and does not interfere with vision (in contrast to the cataracts) unless choroid neovascularization develops in the macula.

·                     Congenital heart disease including patent ductus arteriosus (PDA) and pulmonary artery stenosis is present in 50% of infants infected in the first 2 months of gestation. Cardiac defects and deafness occur in all infants infected during the first 10 weeks of pregnancy and deafness alone is noted in one third of those infected at 13-16 weeks of gestation.

Other findings in congenital rubella syndrome include the following:

·                     Intrauterine growth retardation, prematurity, stillbirth, and abortion

·                     Central nervous system abnormalities, including mental retardation, behavioral disorders, encephalographic abnormalities, hypotonia, meningoencephalitis, and microcephaly

·                     Hepatosplenomegaly

·                     Jaundice

·                     Hepatitis

·                     Skin manifestations, including blueberry muffin spots that represent dermal erythropoiesis and dermatoglyphic abnormalities

·                     Bone lesions, such as radiographic lucencies

·                     Endocrine disorders, including late manifestations in congenital rubella syndrome usually occurring in the second or third decade of life (eg, thyroid abnormalities, diabetes mellitus)

·                     Hematologic disorders, such as anemia and thrombocytopenic purpura

Investigations  Mother: Check antenatal serology and perform if result not available (mother may have IgG from infection very early in pregnancy, so documented seropositivity from a previous pregnancy is more reliable). Baby:  Infection of the fetus is CHRONIC, so congenitally infected infants will shed virus at high titre for many months.

·                   Urine and CSF for rubella virus PCR.

·                   White blood cells (cord blood or infant blood) for rubella PCR.

·                   Serum (cord or infant blood) for rubella IgM.

TREATMENT Medical Care: Treatment is supportive. Provide vision screening and hearing screening for asymptomatic newborns.

Treatment of symptomatic newborns is as follows:

·                   Provide careful evaluation of the eyes and ophthalmology referral for babies with corneal clouding, cataract, and retinopathy. Corneal clouding may indicate infantile glaucoma.

·                   Babies with congenital rubella syndrome who develop respiratory distress may require supportive treatment in the intensive care unit.

·                   Hepatosplenomegaly is monitored clinically. No intervention is required.

·                   Patients with hyperbilirubinemia may require phototherapy or exchange transfusions if jaundice is severe to prevent kernicterus.

·                   True hemorrhagic difficulties have not been a major problem; however, IVIG may be considered in infants who develop severe thrombocytopenia. Corticosteroids are not indicated.

·                   Infants who have a rubella-related heart abnormality should be carefully observed for signs of congestive heart failure. Echocardiography may be essential for diagnosis of heart defects.

Contact isolation is required for patients with congenital rubella during hospitalizations because babies are infected at birth and usually are contagious until older than 1 year unless viral cultures have produced negative results.

Drug therapy is currently not a component of the standard of care for rubella.

Further Outpatient Care: Careful follow-up care after discharge from the hospital for patients with congenital rubella syndrome is composed of the following:

·                   Hearing evaluation

·                   Vision screening

·                   Developmental screening

·                   Monitor blood sugar levels and perform thyroid function tests when clinically indicated.

·                   Education and rehabilitation follow-up care are important for children with congenital rubella.

Prophylaxis Care of women who are pregnant and exposed to rubella virus

·                     If a pregnant woman is exposed to rubella virus in the first trimester of gestation, serologic investigation should be performed promptly.

·                     A blood sample should be obtained as soon as possible and tested for rubella antibody. An aliquot of frozen serum should be stored for possible repeated testing later to determine any rise in titers. If the woman has rubella-specific IgG antibody in a properly performed test at the time of exposure, she is immune. It is highly unlikely that her pregnancy will be complicated with congenital rubella syndrome. However, some authorities would retest her in 2-3 weeks because maternal reinfection complicated with congenital rubella syndrome has been very rarely reported in the literature.

·                     If antibody is not detectable in the initial sample, a second serum specimen should be collected 2-3 weeks later and tested concurrently with the first serum sample in the same laboratory. If the second test result is agaiegative, another serology is warranted 6 weeks after exposure and is tested concurrently with the first specimen. A negative test result in both specimens indicates that infection has not occurred. A positive test result in the second and not the first (seroconversion) indicates recent infection.

·                     The options for a woman exposed to rubella in early pregnancy include pregnancy termination for confirmed infection or administration of IG if termination is not acceptable under any circumstances.

Postexposure prophylaxis during pregnancy

·                   IG administered to a pregnant woman following exposure to rubella is controversial and may not prevent infection of the fetus. The IG may modify the clinical manifestations in the mother without diminishing the viral replication and, therefore, leave the fetus unprotected.

·                   Because infants with congenital rubella syndrome have been born to women who received passive immunoprophylaxis shortly after exposure, rubella IG postexposure prophylaxis in pregnancy is not recommended.

·                   The CDC recommends that IG be used only if a susceptible pregnant woman who has been exposed to rubella will not consider pregnancy termination under any circumstances.

·                   Whether a higher dose of IG given intravenously is useful to prevent congenital rubella syndrome is unknown.

Toxoplasmosis Toxoplasma gondii is a widely distributed protozoan that usually causes an asymptomatic infection in the healthy host. In Fig. 1 and Fig. 2 is shown simplified life-cycle of Toxoplasma gondii. Toxoplasmosis refers to a symptomatic infection by T gondii and can be acute or chronic. Apart from disease in immunocompromised individuals, congenital toxoplasmosis is the most serious manifestation of infection, resulting from vertical transmission of T gondii from a parasitemic mother to her offspring. The severity of disease depends on the gestational age at transmission. Ophthalmologic and neurologic disabilities are the most important consequences of infection and can be present even when the congenital infection is asymptomatic. Congenital toxoplasmosis is a preventable disease. Prepregnancy screening accompanied by serial titers and appropriate counseling in women with initial negative titers would minimize cases.

Fig. 1. Toxoplasma life-cycle.

 

Fig. 2. Toxoplasma life-cycle.

Pathophysiology: T gondii is an obligate intracellular protozoan. It has an intestinal and an extraintestinal cycle in cats but only an extraintestinal cycle in other hosts, including herbivores, omnivores, and carnivores.

Vertical transmission is the cause of congenital toxoplasmosis. The infection can occur in utero or during a vaginal delivery. Transmission by breastfeeding has not been demonstrated. In general, only primary infection during pregnancy results in congenital toxoplasmosis. Infections that occur before but within 6 months of conception may result in transplacental transmission. Intrauterine exposure can result in an uninfected infant or infection that ranges from being asymptomatic to causing stillbirth. Approximately 30% of exposed fetuses acquire the infection, but most of the infants are asymptomatic. The severity of infection in the fetus depends on the gestational age at the time of transmission.

In general, earlier infection is more severe but less frequent. As a consequence, 85% of live infants with congenital infection appear normal at birth. Very early infections (ie, occurring in the first trimester) may result in fetal death in utero or in a newborn with severe central nervous system (CNS) involvement, such as cerebral calcifications and hydrocephalus.

Mortality/Morbidity: Fetuses and immunocompromised individuals are at particularly high risk for severe sequelae and even death. Infection acquired postnatally is usually much less severe.

·                   Newborns with acute congenital toxoplasmosis often die in the first month of life.

·                   Subacute congenital disease may not be observed until some time after birth, when symptoms start to appear.

CLINICAL History: Pediatric toxoplasmosis can be acute or chronic, asymptomatic or symptomatic, and congenital or postnatally acquired.

Congenital toxoplasmosis is the consequence of transplacental hematogenous fetal infection by T gondii during primary infection in pregnant women. Primary infection in an otherwise healthy pregnant woman is asymptomatic in 60% of cases. Symptoms during pregnancy are frequently mild. The most common manifestations are fatigue, malaise, a low-grade fever, lymphadenopathy, and myalgias. Latent Toxoplasma infection with reactivation during pregnancy may lead to congenital infection only in immunocompromised women (most commonly, those with AIDS).

The classic triad of chorioretinitis, hydrocephalus, and intracranial calcifications cannot be used as a strict diagnostic criterion for congenital toxoplasmosis because a large number of cases would be missed. Congenital toxoplasmosis may occur in the following forms:

·                   Neonatal disease

·                   Disease occurring in the first months of life

·                   Sequelae or relapse of previously undiagnosed infection

·                   Subclinical infection

When clinically recognized in the neonate, congenital toxoplasmosis is very severe. Signs of generalized infection are usually present, such as intrauterine growth retardation, jaundice, hepatomegaly, splenomegaly, lymphadenopathy, and a rash. Neurologic signs are severe and always present. They include microcephaly or macrocephaly, bulging fontanelle, nystagmus, abnormal muscle tone, seizures, and delay of developmental milestone acquisition.

·                   Most cases of chorioretinitis result from congenital infection, although patients are often asymptomatic until later in life. Symptoms include blurred vision, scotoma, pain, photophobia, and epiphora. Impairment of central vision occurs when the macula is involved, but vision may improve as inflammation resolves. Relapses of chorioretinitis are frequent but rarely accompanied by systemic signs or symptoms.

·                   Latent toxoplasmosis may reactivate in women with human immunodeficiency virus (HIV) and result in congenital transmission. Congenital toxoplasmosis in the infant with HIV appears to run a more rapid course than in infants without HIV.

Physical:

·                   Lymphadenopathy is the most common form of symptomatic acute toxoplasmosis in immunocompetent individuals.

·                   Patients typically present with painless firm lymphadenopathy that is confined to one chain of nodes, which are most commonly cervical. The suboccipital, supraclavicular, axillary, and inguinal groups may also be involved.

·                   Other physical manifestations include a low-grade fever, occasional hepatosplenomegaly (Fig. 3), and a rash.

·                   Ophthalmologic examination reveals multiple yellow-white cottonlike patches with indistinct margins located in small clusters in the posterior pole.

·                   Characteristically, a focal necrotizing retinitis develops that may atrophy and generate black pigment, or it may be associated with panuveitis. Papillitis is usually indicative of CNS disease. Flare-up of congenitally acquired chorioretinitis is often associated with scarred lesions in proximity to the fresh lesions.

·                   Because of multifocal involvement of the CNS, clinical findings vary widely. They include alterations in mental status, seizures, motor weakness, cranial nerve disorders, sensory abnormalities, cerebellar signs, meningismus, movement disorders, and neuropsychiatric manifestations in patients with immunocompromise.

Fig. 3. Toxoplasma gondii Infections (Toxoplasmosis). Infant girl with congenital toxoplasmosis with hepatosplenomegaly.

 

Investigation of babies born to toxoplasma IgM positive mothers

The following samples will enable search for toxoplasma DNA (by PCR) in baby’s blood, placenta and amniotic fluid.

If suspected after delivery:

·                   Maternal serum for toxoplasma IgG and IgM

·                   Infant serum (red top) for toxoplasma IgG, IgM and infant blood (CPD or EDTA tube) for PCR

·                   Head ultrasound, CT-scan (Fig.4)

·                   CSF for M, C and S, protein, glucose and toxoplasma PCR

·                   Tissue culture (Fig. 5)

Fig. 4.

Cranial CT

scan of infant born with symptomatic congenital cytomegalovirus infection. Neurological involvement is evident, manifest as ventriculomegaly and periventricular calcifications.

Fig. 5. Toxoplasmosis. Toxoplasma gondii trophozoites in tissue culture.

Treatment

·                   prenatal treatment of the mother in preventing adverse fetal outcomes with spiramycin. If documented fetal infection is noted in the prenatal period (via amniotic PCR), consider treatment with pyrimethamine and sulfadiazine.

·                   Treat infant for clinically, serologically, or maternally apparent disease with pyrimethamine and sulfadiazine for 1 year. Folinic acid should be given to prevent bone marrow suppression. A year of treatment allows the infant to become immunocompetent and will reduce neurologic sequelae compared to a shorter course of treatment. A pediatric infectious disease (ID) consultation should be obtained.

·                   Corticosteroid for ocular disease and CNS infection (high level of CSF protein), add prednisone 1mg/kg/d divided q 12 hours until CSF protein is normal and/or ocular inflammation resolves.

MEDICATION

·                   Sulfadiazine (Microsulfon) Pediatric Dose: Acquired toxoplasmosis: >1 year: 75 mg/kg/d PO once, followed by 50 mg/kg/d for 2-4 wk; Congenital toxoplasmosis: 100 mg/kg/d PO once, followed by 100 mg/kg/d divided q12h for 2-6 mo.

·                   Dapsone (Avlosulfon) Pediatric Dose: >1 month: 1 mg/kg/d PO; not to exceed 25 mg/d.

·                   Clindamycin (Cleocin) Pediatric Dose: 8-20 mg/kg/d PO as hydrochloride (cap) or 8-25 mg/kg/d PO as palmitate (susp) divided tid/qid; not to exceed 1.8 g/d. 20-40 mg/kg/d IV/IM divided tid/qid; not to exceed 4.8 g/d/

·                   Pyrimethamine (Daraprim) Pediatric Dose: 2 mg/kg/d PO divided q12h for 2-4 d initially, then 1 mg/kg/d PO qd or divided q12h for 1 mo; not to exceed 25 mg/d.

·                   Azithromycin (Zithromax) Pediatric Dose: 10 mg/kg as single dose on day 1, not to exceed 500 mg/d; followed by 5 mg/kg on days 2-5, not to exceed 250 mg/d.

·                   Spiramycin (Rovamycine) Pediatric Dose: 50-100 mg/kg/d PO divided bid/qid for 3-4 wk.

·                   Leucovorin (Wellcovorin) — Also called folinic acid. Derivative of folic acid used with folic acid antagonists, such as sulfonamides and pyrimethamine. Pediatric Dose: 5-10 mg PO 3 times/wk

 

 

Prevention:

Preventing the infection is particularly important for women who are pregnant and for patients who are seronegative and immunocompromised.

·                   Avoid consuming raw or undercooked meat, unpasteurized milk, and uncooked eggs.

·                   Wash hands after touching raw meat and after gardening or having other contact with soil.

·                   Wash fruits and vegetables.

·                   Avoid contact with cat feces.

·                   To attempt to prevent congenital toxoplasmosis, routine serologic screening of pregnant women has been performed in order to identify fetuses at risk of becoming infected.

Table 3. Prophylaxis to Prevent First Episode and Recurrence of Toxoplasmosis in Children

Prevention of Indication First Choice Alternatives First episode of toxoplasmosis1 Severe immunosuppression and presence of IgG antibody to Toxoplasma TMP-SMX, 150–750 mg/m2 per day in 2 divided doses, orally, every day Dapsone (children 1 mo of age), 2 mg/kg or 15 mg/m2 (max 25 mg), orally, every day, PLUS pyrimethamine, 1 mg/kg, orally, every day, PLUS leucovorin, 5 mg, orally, every 3 days Atovaquone, children 1–3 mo and >24 mo of age: 30 mg/kg, orally, every day; children 14–24 mo of age: 45 mg/kg, orally, every day Recurrence of toxoplasmosis2 Prior toxoplasmic encephalitis Sulfadiazine, 85–120 mg/kg per day in 2–4 divided doses, orally, every day, PLUS pyrimethamine, 1 mg/kg or 15 mg/m2 (max 25 mg), orally, every day, PLUS leucovorin, 5 mg, orally, every 3 days Clindamycin, 20–30 mg/kg per day in 3 divided doses, orally, every day, PLUS pyrimethamine, 1 mg/kg, orally, every day, PLUS leucovorin, 5 mg, orally, every 3 days Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-exposed and infected children. MMWR Recomm Rep. 2004;53(RR–14):1–63 1 Protection against toxoplasmosis is provided by the preferred antipneumocystis regimens and possibly by atovaquone. Atovaquone may be used with or without pyrimethamine. Pyrimethamine alone probably provides little, if any, protection (for information about severe immunosuppression, see Table 3.50, p 540). 2 Only pyrimethamine plus sulfadiazine confers protection against Pneumocystis jiroveci pneumonia as well as toxoplasmosis. Although the clindamycin plus pyrimethamine regimen is recommended in adults, this regimen has not been tested in children. However, these drugs are safe and are used for other infections.

 

Herpes Simplex infection Approximately 1500-2000 new cases of neonatal HSV infection are diagnosed each year. Neonatal HSV infection often leads to long-term neurologic impairment and eveeonatal death.

Despite strategies designed to prevent perinatal transmission, the number of cases of neonatal HSV infection continues to rise, mirroring the rising prevalence of genital herpes infection in women of childbearing age.

Etiology HSV is a DNA virus. HSV has 2 subtypes: herpes simplex virus 1 (HSV-1) and HSV-2. Although each is a distinct virus, they share some antigenic components (eg, antibodies that react to one type may “neutralize” the other).

HSV-1 infections were traditionally associated with the oral area (fever blisters), whereas HSV-2 infections occurred in the genital region.

PERINATAL TRANSMISSION OF HSV HSV can be vertically transmitted to the infant during the antenatal, intranatal, or postnatal periods.

Antenatal Five percent of all cases of neonatal HSV infection result from in utero transmission. With primary infection, transient viremia occurs. HSV has a potential risk for hematogenous spread to the placenta and to the fetus. Hematogenous spread can produce a spectrum of findings similar to other TORCH  infections, eg, microcephaly, microphthalmia, intracranial calcifications, and chorioretinitis.

Intranatal Intranatal infection accounts for the majority of infected infants and occurs from passage of the infant through an infected birth canal. Seventy-five to 90% of infants with neonatal HSV are born to asymptomatic mothers who have no history of HSV infection.

Postnatal Postnatal transmission of HSV can occur through contact with infected parents or health care workers.

Clinical findings

·                   Average incubation 6 days; can be up to 20.

·                   Disseminated disease may mimic fulminate sepsis with seizures, jaundice, hepatitis, encephalitis, DIC, or pneumonia. If untreated, up to 90% mortality.

·                   Local mucocutaneous disease may be mild. Conjunctivitis, keratitis, or chorioretinitis can result in vision loss and blindness.

Investigations

·                   Skin vesicles: swab for viral culture and HSV PCR

·                   Swabs from eyes, mouth/nasopharynx for HSV culture.

·                   WBCs (CPD or EDTA tube) for HSV PCR

·                   CSF – cells, protein, glucose, culture, viral culture and HSV PCR.

·                   Head CT/EEG may localise disease but not essential.

·                   Subtype specific (HSV1 and 2) serology may be useful on mother and baby.

·                   Ophthalmic consultation.

Prevention and treatment.

·                   Any active lesions during pregnancy should be cultured to confirm disease. Active disease at delivery mandates C-section. Routine use of PCR to identify asymptomatic shedders is not yet standard of care.

·                   If vaginal delivery occurs over active lesions or >4 hours, begin acyclovir 30 mg/kg/d IV Q8h for 14-21 days. doses as high as 45-60 mg/kg/d divided q8h have been used in full-term infants. Premature infants: 20 mg/kg/d PO/IV divided q12h for 14-21 d.

·                   Infected mother and infant should be kept in contact isolation.

Chlamydial Infections Chlamydia can cause diseases of many systems. The most frequent disease, caused by Chlamydia trachomatis, is a sexually transmitted.

Pathophysiology: C trachomatis is an obligate intracellular bacterium that infects the urethra and cervix. The bacterium usually is spread through sexual activity and can be spread vertically, causing conjunctivitis and pneumonia in newborns. The transmission rate from infected mother to newborn is 50%, causing conjunctivitis (most cases) or pneumonia (10-20%). The incubation period is 1-5 weeks.

CLINICAL History:

·                   Symptoms for pneumonia begin in children aged 1-3 months and for conjunctivitis in children aged 1-2 weeks.

·                   Cough, fever in pneumonia (classic description is afebrile)

·                   Eye discharge, swelling in conjunctivitis

·                   Mother with diagnosed or suspected chlamydial infection during pregnancy

Physical:

·                   Fever, cough, wheezing, and pulmonary crackles in pneumonia

·                   Conjunctival erythema, mucoid discharge, and/or periorbital swelling in conjunctivitis

Lab Studies:

Nonculture tests that detect antigens or deoxyribonucleic acid (DNA) of chlamydia using molecular techniques

·                   Direct immunofluorescent antibody (DFA, MicroTrak), enzyme immunoassay (EIA, Chlamydiazyme), and DNA probes (PACE Gen-Probe) all are approximately 80% sensitive and 95% specific.

·                   Polymerase chain reaction (PCR) and ligase chain reaction (LCR) have sensitivity and specificity approaching 100% but still are very expensive to perform on a routine basis.

Infants with suspected pneumonitis

·                   Perform a nasopharyngeal (NP) swab for chlamydia culture. Currently available rapid tests are not approved for use on NP-derived specimens.

·                   In severe or complicated cases, bronchoalveolar lavage fluid can be sent for chlamydia culture as well. A CBC that demonstrates peripheral eosinophilia in the right clinical situation offers additional supportive evidence for C trachomatous pneumonia.

Infants with suspected chlamydia conjunctivitis

·                   Perform an antigen/DNA detection test and/or chlamydia culture by scraping of palpebral conjunctiva.

·                   If the mother has had documented chlamydial infection during pregnancy that went untreated, treat the infant presumptively, even without confirmation of infection.

TREATMENT

·                   Erythromycin (E.E.S., Eryc, E-Mycin) – Newborns with chlamydia conjunctivitis or pneumonia: Erythromycin (base) 50 mg/kg/d PO divided qid for 14 d.

·                   Amoxicillin (Trimox, Amoxil) – 30-40 mg/kg/d PO divided tid for 7-10 d.

·                   Sulfisoxazole — Less effective than most other regimens. Pediatric Dose: 120-150 mg/kg/d PO divided qid.

 

Syphilis Syphilis is a communicable disease caused by Treponema pallidum, which belongs to the Spirochaetaceae family.

Pathophysiology: Congenital syphilis is caused by transplacental transmission of spirochetes; the transmission rate approaches 100%. Perinatal death may result from congenital infection in more than 40% of affected, untreated pregnancies. Among survivors, manifestations traditionally have been divided into early and late stages. Manifestations are defined as early if they appear in the first 2 years of life and late if they develop after age 2 years.

Because inflammatory changes do not occur in the fetus until after the first trimester of pregnancy, organogenesis is unaffected. Nevertheless, all organ systems may be involved. With early-onset disease, manifestations result from transplacental spirochetemia and are analogous to the secondary stage of acquired syphilis. Congenital syphilis does not have a primary stage. Late-onset disease is seen in patients older than 2 years and is not considered contagious.

CLINICAL History: Most recognized syphilitic disease in children is congenital. A pregnant woman with syphilis who has not received therapy or who has received inadequate therapy may transmit the infection to the fetus at any clinical stage of the disease.

Early-onset congenital syphilis

·                   Most affected infants are asymptomatic at birth and are identified only by routine prenatal screening. If untreated, symptoms develop within weeks or months. The typical stillborn or highly symptomatic newborn is born prematurely with an enlarged liver and spleen, skeletal involvement, and often pneumonia and bullous skin lesions.

·                   The earliest signs of congenital syphilis may be poor feeding and snuffles (ie, syphilitic rhinitis).

Physical: Early-onset congenital syphilis

·                   Early manifestations of congenital infection are varied and involve multiple organ systems. The most striking lesions affect the mucocutaneous tissues and bones. Mucous patches, rhinitis, and condylomatous lesions are highly characteristic features of mucous membrane involvement in congenital syphilis.

·                   Nasal fluid is highly infectious. Snuffles are followed quickly by a diffuse maculopapular desquamative rash that involves extensive sloughing of the epithelium, particularly on the palms and soles and about the mouth and anus. In contrast to acquired syphilis, a vesicular rash and bullae may develop. These lesions are highly infectious.

·                   Hepatomegaly is reported in almost 100% of cases, and biochemical evidence of liver dysfunction usually is observed.

Late-onset congenital syphilis

·                   Scarring from the early systemic disease causes late manifestations of congenital syphilis.

·                   Manifestations include neurosyphilis and involvement of the teeth, bones, eyes, and the eighth cranial nerve.

Investigations

·                   Peripheral blood counting, liver function tests and syphilis serology on infant blood

·                   Maternal syphilis serology.

·                   CSF for VDRL, cells protein and glucose.

·                   Long bone xrays.

·                   Darkfield microscopy of skin lesions, nasal discharge, placental tissue or amniotic fluid may show spirochaetes (but majority of cases have none of these).

TREATMENT  

·                   Congenital syphilis iewborns: Aqueous crystalline penicillin G is recommended if congenital syphilis is proved or highly suspected. The recommended dosage is 100,000-150,000 U/kg/d IV q8-12h to complete a 10- to 14-day course.

·                   Congenital syphilis in older infants and children: Treat diagnosed infants older than 4 weeks with aqueous crystalline penicillin (200,000-300,000 U/kg/d IV q6h for 10-14 d).

·                   Neurosyphilis: The recommended treatment is aqueous crystalline penicillin G, 200,000-300,000 U/kg/d IM (50,000 U/kg q4-6h) for 10-14 days, followed by a single dose of benzathine penicillin 50,000 U/kg/dose in 3 weekly doses.

Further Outpatient Care:

·                     Follow up congenital syphilis with evaluation at ages 1, 2, 4, 6, and 12 months. Obtain nontreponemal titers at ages 3, 6, and 12 months after conclusion of treatment. Nontreponemal antibody titers should decline by age 3 months and should be nonreactive by age 6 months. Consider retreatment for patients with persistently stable titers, including low titers.

·                     Infants who are treated for congenital neurosyphilis should undergo repeat clinical evaluation and CSF examination at 6-month intervals until their CSF examination result is normal. A positive CSF VDRL result at age 6 months is an indication for retreatment.

Prevention: Indications for syphilis screening include the following:

·                     All women at first prenatal visit and high-risk women again at 28 weeks’ gestation

·                     All women delivering a stillborn infant

·                     All newborns older than 22 weeks’ gestation whose mothers were not screened

Listeria Infection Listeriosis is an infection caused by a gram-positive motile bacterium, Listeria monocytogenes. Listeriosis is relatively rare and occurs primarily iewborn infants, elderly patients, and patients who are immunocompromised.

Pathophysiology: Ingestion of Listeria by pregnant women can result in a flulike illness. Many pregnant women can carry Listeria asymptomatically in their GI tract or vagina. Maternal infection with Listeria can result in chorioamnionitis, premature labor, spontaneous abortion, or stillbirth. Fetal infection can occur via transplacental transmission. Vertical transmission also can occur from mother to infant via passage through an infected birth canal or ascending infection through ruptured amniotic membranes.

Two clinical presentations of neonatal infections occur, early onset (<5 d) and late onset (>5 d). Early-onset neonatal listeriosis usually is associated with sepsis or meningitis. Late-onset neonatal listeriosis frequently presents with purulent meningitis. Listeriosis often involves many organs with microabscesses or granulomas.

Mortality/Morbidity: Early-onset neonatal listeriosis has a 20-30% mortality rate. Late-onset neonatal listeriosis has a 0-20% mortality rate. Hydrocephalus, mental retardation, and other CNS sequelae have been reported in survivors of Listeria meningitis.

CLINICAL

·                   Early-onset neonatal infections (<5 d) begin at the mean age of 1.5 days.

·                   Late-onset neonatal infections (>5 d) begin at the mean age of 14 days.

Physical: Listeriosis presents in the same manner as other more commoeonatal pathogens, such as group B streptococci and Escherichia coli.

·                   Respiratory distress – Tachypnea, grunting, apnea, and retractions

·                   Temperature instability

·                   Poor feeding

·                   Lethargy/irritability

·                   Seizures

·                   Granulomatous rash – Disseminated small pale nodules

Lab Studies:

1.                   Blood culture

2.                   Cerebrospinal fluid culture

3.                   Respiratory tract culture

4.                   Histopathology and culture of rush

5.                   Culture of other infected tissues: (Joint, Pericardial fluid, Pleural fluid, Amniotic fluid, Placenta, Gastric aspirate).

Imaging Studies: CT scan or MRI may be useful to detect abscesses in brain or liver.

TREATMENT Medical Care: Care of a newborn includes antibiotics as well as careful monitoring of the patients temperature, respiratory system, fluid and electrolyte balance, nutrition, and cardiovascular support.

Ampicillin alone or in combination with an aminoglycoside is the therapy of choice. Listeria is not susceptible to cephalosporins of any generation.

Drug Name	Ampicillin (Marcillin, Omnipen, Polycillin, Principen)
Pediatric Dose	Ampicillin dosing based on 25-100 mg/kg/dose slow IV push (higher doses typically used for meningitis) Gestational age <29 weeks Postnatal age of 0-28 days: Interval 12 h Postnatal age of >28 days: Interval 8 h Gestational age 30-36 weeks Postnatal age of 0-14 days: Interval 12 h Postnatal age of >14 days: Interval 8 h Gestational age 37-44 weeks Postnatal age of 0-7 days: Interval 12 h Postnatal age of >7 days: Interval 8 h Gestational age >44 weeks All postnatal ages: 6 h
Drug Name	Gentamicin (Garamycin, Gentacidin) — Useful in combination with ampicillin against listeria.
Pediatric Dose	Usual neonatal maintenance dosage for treatment of septicemia or meningitis depends upon gestational and postnatal age Gentamicieonatal dosing scheme: Loading dose of 4 mg/kg can be given Maintenance dose: 2.5-3 mg/kg/dose IV over 30 min (consider using 3 mg/kg/dose) Gestational age <29 weeks Postnatal age of 0-28 days: Interval 24 h Postnatal age of >28 days: Interval 24 h (consider using 3 mg/kg/dose) Gestational age 30-36 weeks Postnatal age of 0-14 days: Interval 24 h (consider using 3 mg/kg/dose) Postnatal age of >14 days: Interval 24 h Gestational age >37 weeks Postnatal age of 0-7 days: Interval 12 h Postnatal age of >7 days: Interval 8 h

 

 

Drug Name	Penicillin G (Pfizerpen) — Can be used as an alternative to ampicillin.
Pediatric Dose	250,000-400,000 U/kg/d IV divided q4-6h

Tratment of TORCH-infection you can find although here.

 

Prevention: Advice for all persons:

·                   Wash hands, knives, and cutting boards after handling uncooked food.

·                   Cook all meat thoroughly.

·                   Wash all vegetables thoroughly.

·                   Keep raw meats separate from other foods during preparation to avoid cross-contamination.

Advice for pregnant patients or patients with immunocompromised:

·                   Avoid soft cheeses such as feta, Brie, blue cheese, Mexican-style cheese, and Camembert.

·                   Thoroughly reheat leftovers.

·                   Avoid deli foods unless thoroughly heated.

Prognosis: Prognosis is guarded depending on whether meningitis or shock is present. Hydrocephalus, mental retardation, and other CNS sequelae have been reported following meningitis.