Neonatal infections
Pathogenesis and EpidemiologyInfections are a frequent and important cause of neonatal and infant morbidity and mortality. As many as 2% of fetuses are infected in utero, and up to 10% of infants have infections in the 1st mo of life.
Why infection in neonate is different?
1.Different mode of transmission.
2.Immunological defieciency
3.Coexisting condition often complicate the diagnosis of neon. Infection
4.The clinical manifestations of newborn infections vary include subclinical infection, mild to severe manifestations of focal or systemic infection,rarely, congenital syndromes.
5. Maternal infection that is the source for transplacental inf. Often undiagnosed. because the mother was either asymptomatic or had nonspecific signs and symptoms at the time of acute infection.
6. A wide variety of etiologic agents including bacteria, viruses, fungi, protozoa, and mycoplasmas
7.Immature, very low birthweight (VLBW) newborns have improved survival but remain in the hospital for a long time in an environment that puts them at continuous risk for acquired infections.
Etiology of Fetal and Neonatal Infection
A number of agents may infect newborns in utero, intrapartum, or postpartum .
1.Intrauterine transplacental infections of significance to the fetus and/or newborn include syphilis, rubella, CMV, toxoplasmosis, parvovirus B19, and varicella. Although HSV, HIV, HBV, HCV, and (TB) can each result in transplacental infection, the most common mode of transmission for these agents is intrapartum
2. during labor and delivery with passage through an infected birth canal (HIV, HSV, HBV),
3. postpartum, from contact with an infected mother or caretaker (TB) or with infected breast milk (HIV).
Sepsis and Meningitis
The incidence of sepsis is approximately 1:1500 in full-term infants and 1:250 in preterm infants. The sixfold-higher rate of sepsis among preterm infants compared with term infants relates to the more immature immunologic systems of preterm infants and to their prolonged periods of hospitalization, which increase risk of nosocomially acquired infectious diseases,Bacterial sepsis and meningitis often are linked closely in neonates. The incidence of meningitis is approximately 1 in 20 cases of sepsis.The causative organisms isolated most frequently are the same as for neonatal sepsis: group B streptococci, E. coli, and L. monocytogenes. Gram-negative organisms, such as Klebsiella and Serratia marcescens, are more common in less developed countries and coagulase-negative staphylococci need to be considered in VLBW infants.
Male infants seem to be more susceptible to neonatal infection than female infants. Severely premature infants are at even greater risk secondary to less effective defense mechanisms and deficient transfer of antibodies from the mother to the fetus(which occurs mostly after 32 weeks).
Neonates in the neonatal ICU live in a hostile environment, with exposure to endotracheal tubes, central arterial and venous catheters, and blood draws all predisposing to bacteremia and meningitis. Genetic factors have been implicated in the ability of bacteria to cross the blood-brain barrier. This penetration has been noted for group B streptococci, E. coli, Listeria, Citrobacter, and Streptococcus pneumoniae.
Neonatal sepsis presents during three periods. Early-onset sepsis (birth to 7 days) often begins in utero and usually is a result of infection caused by the bacteria in the mother's genitourinary tract (vertical mother-to-child transmission) so acquired before or during delivery.
Organisms related to this sepsis include group B streptococci, E. coli, Klebsiella, L. monocytogenes, and nontypable H. influenzae
Risk factors for early-onset sepsis include
1.vaginal colonization with group B streptococci,
2.prolonged rupture of the membranes (>18 hours).
3. amnionitis.
4.maternal fever or leukocytosis.
5. fetal tachycardia.
6. preterm birth.
7. male sex is unexplained additional risk factors for neonatal sepsis.
Clinical manifestations of sepsis as poor feeding, pallor, apnea, lethargy, hypothermia, or an abnormal cry-may be nonspecific. Profound neutropenia, hypoxia, and hypotension may be refractory to treatment with broad-spectrum antibiotics ,mechanical ventilation, and vasopressors such as dopamine and dobutamine. In the initial stages of early-onset septicemia in a preterm infant, it is often difficult to differentiate sepsis from RDS. Because of this difficulty, premature infants with RDS receive broad-spectrum antibiotics.
The clinical manifestations of sepsis are difficult to separate from the manifestations of meningitis in the neonate.
Infants with early-onset sepsis should be evaluated by blood and CSF cultures, CSF Gram stain, cell count, and protein and glucose levels. Normal newborns generally have an elevated CSF protein content (100 to 150 mg/dL) and may have 25 to 30/mm3 white blood cells (mean 9/mm3), which are 75% lymphocytes in the absence of infection. Some infants with neonatal meningitis caused by group B streptococci do not have an elevated CSF leukocyte count but are seen to have microorganisms in the CSF on Gram stain.
In addition to culture, other methods of identifying the pathogenic bacteria are the determination of bacterial antigen in samples of blood, urine, or CSF. In cases of neonatal meningitis, the ratio of CSF glucose to blood glucose usually is less than 50%.
The PCR test primarily is used to identify viral infections. Serial complete blood counts should be performed to identify neutropenia, an increased number of immature neutrophils (bands), and thrombocytopenia.
C-reactive protein levels are often elevated in neonatal patients with bacterial sepsis.
A chest radiograph also should be obtained to determine the presence of pneumonia. In addition to the traditional neonatal pathogens, pneumonia in VLBW infants may be the result of acquisition of maternal genital mycoplasmal agent (e.g., U. urealyticum or M. hominis).
Arterial blood gases should be monitored to detect hypoxemia and metabolic acidosis (caused by hypoxia , shock or both).
Blood pressure, urine output, and peripheral perfusion should be monitored to determine the need to treat septic shock with fluids and vasopressor agents.
The mainstay of treatment for sepsis and meningitis is antibiotic therapy. Antibiotics are used to suppress bacterial growth, allowing the infant's defense mechanisms time to respond. In addition, support measures, such as assisted ventilation and cardiovascular support, are equally important to the management of the infant.
A combination of ampicillin and an aminoglycoside (usually gentamicin) for 10 to 14 days is effective treatment against most organisms responsible for early-onset sepsis. The combination of ampicillin and cefotaxime also is proposed as an alternative method of treatment. If meningitis is present, the treatment should be extended to 21 days or 14 days after a negative result from a CSF culture. Persistently positive results from CSF cultures are common with neonatal meningitis caused by gram-negative m.o even with appropriate antibiotic treatment, and may be present for 2 to 3 days after antibiotic. High-dose penicillin (250,000 to 450,000 U/kg/24 hr) is appropriate for group B streptococcal meningitis. Inhaled nitric oxide, ECMO (in term infants), or both may improve the outcome of sepsis-related pulmonary HT.
Intrapartum antibiotics are used to reduce vertical transmission of GBS as well as to lessen neonatal morbidity after preterm rupture of membranes. Intrapartum chemoprophylaxis does not reduce the rates of late-onset GBS disease and has no effect on the rates of infection with non-GBS pathogens.prophylaxis include ampicilin 2g once then 1g every 6hr for at least 48hr is adequate for GBS disease. Of concern is a possible increase in gram-negative infections (especially E. coli) in VLBW and possibly term infants in spite of a reduction in early GBS sepsis by intrapartum antibiotics.
Late-onset sepsis (8 to 28 days) usually occurs in a healthy full-term infant who was discharged in good health from the normal newborn nursery.
Clinical manifestations may include lethargy, poor feeding, hypotonia, apathy, seizures, bulging fontanel, fever, and direct-reacting hyperbilirubinemia. In addition to bacteremia, hematogenous seeding may result in focal infections, such as meningitis (in 75% of cases), osteomyelitis (group B streptococci.,S. aureus), arthritis (gonococcus, S. aureus, Candida albicans, gram-negative bacteria), and urinary tract infection (gram-negative bacteria).
The evaluation of infants with late-onset sepsis is similar to that for infants with early-onset sepsis, with special attention given to a careful physical examination of the bones (infants with osteomyelitis may exhibit pseudoparalysis) and to the laboratory examination and culture of urine obtained by sterile supra-pubic aspiration or urethral catheterization .
Late-onset sepsis may be caused by the same pathogens as early-onset sepsis, but infants exhibiting sepsis late in the neonatal period also may have infections caused by the pathogens usually found in older infants (H. influenzae, S. pneumoniae, and Neisseria meningitidis). In addition, viral agents (HSV, CMV, or enteroviruses) may manifest with a late-onset, sepsis-like picture.
Because of the increased rate of resistance of H. influenzae and pneumococcus to ampicillin, some centers begin treatment with ampicillin and a third-generation cephalosporin (and vancomycin if meningitis is present) when sepsis occurs in the last week of the first month of life. The treatment of late-onset neonatal sepsis and meningitis is the same as that for early-onset sepsis .
Nosocomial Infections:
Nosocomial (hospital-acquired) infections are defined as infections occurring after 3 days of life that are not directly acquired from the mother's genital tract. For the purposes of surveillance health care–associated infections in newborns as those that result from passage through the birth canal as well as infections that occur from exogenous sources such as health care personnel, visitors, and equipment in the health care environment.
The majority of nosocomial infections occur in preterm or term infants who require intensive care(<1% in healthy term infant).
Risk factors for nosocomial infection
1. prematurity, LBW.
2. invasive procedures, indwelling vascular catheters, parenteral
nutrition with lipid emulsions, endotracheal tubes, ventricular shunts.
3.alterations in the skin and/or mucous membrane barriers
4. frequent use of broad-spectrum antibiotics
5.prolonged hospital stay.
Almost one quarter of VLBW infants (<1,500 g BW) experience nosocomial infections. Rates of infections increase with decreasing gestational age and birthweight.
Various bacterial and fungal agents colonize hospitalized infants, health care workers, and visitors. Pathogenic agents can be transmitted by direct contact or indirectly via contaminated equipment, intravenous fluids, medications, blood products, or enteral feedings.
Coagulase-negative staphylococci are the most frequent neonatal nosocomial pathogens.other gram postive (staph.aureus, enterococci),gram negative(E.coli,klebsiella,),fungi(candida).Viral organisms may also cause nosocomial infection in the NICU; they include RSV, varicella, influenza, rotavirus, and enteroviruses.
The mean age at onset of the 1st episode of late-onset nosocomial sepsis is 2-3 wk.
The initial clinical manifestations of nosocomial infection in a premature infant may be subtle and include apnea and bradycardia, temperature instability, abdominal distention, and poor feeding. In the later stages, signs of infection are shock, DIC, worsening respiratory status, and local reactions, such as omphalitis, eye discharge, diarrhea, and bullous impetigo.
The treatment of nosocomially acquired sepsis depends on the indigenous microbiologic flora of the particular hospital and the antibiotic sensitivities. Because S. aureus (occasionally methicillin-resistant), Staphylococcus epidermidis (methicillin-resistant), and gram-negative pathogens are common nosocomial bacterial agents in many nurseries, a combination of vancomycin or oxacillin/nafcillin (some use ampicillin) with an aminoglycoside (gentamicin or tobramycin) is appropriate. For Pseudomonas infection, initial therapy should consist of antipseudomonal agent, such as piperacillin, ticarcillin,meropenem, or ceftazidime, and an aminoglycoside.
Persistent signs of infection despite antibacterial treatment suggest candidal or viral sepsis.
Complications and Prognosis
Complications of bacterial or fungal infections may be divided into those related to the acute inflammatory process and those that underlie neonatal problems such as respiratory distress and fluid and electrolyte abnormalities.
Complications of bacteremic infections include endocarditis, septic emboli, abscess formation, septic joints with residual disability, and osteomyelitis and bone destruction. Recurrent bacteremia is rare (<5% of patients). Candidemia may lead to vasculitis, endocarditis, and endophthalmitis as well as abscesses in the kidneys, liver, lungs, and brain. Sequelae of sepsis may result from septic shock, DIC, or organ failure.
Reported mortality rates in neonatal sepsis are as low as 10% because all bacteremic infections are included in the definition
The case fatality rate for neonatal bacterial meningitis is between 20% and 25%. Many of these patients have associated sepsis. Risk factors for death or for moderate or severe disability include seizure duration >72 hr, coma, need for inotropic agents, and leukopenia.
Ophthalmia Neonatorum
This form of conjunctivitis, occurring in infants younger than 4 wk of age, is the most common eye disease of newborns.
Silver nitrate instillation may result in a mild self-limited chemical conjunctivitis, whereas Neisseria gonorrhoeae and Pseudomonas are capable of causing corneal perforation, blindness, and death.
Epidemiology
Conjunctivitis during the neonatal period is usually acquired during vaginal delivery and reflects the sexually transmitted infections prevalent in the community.
the incidence of gonococcal ophthalmia neonatorum decreased in industrialized countries secondary to widespread use of silver nitrate prophylaxis and prenatal screening and treatment of maternal gonorrhea.(from10% to 0.3%).
Clinical Manifestations
The clinical manifestations of the various forms of ophthalmia neonatorum are not specific enough to allow an accurate diagnosis .Regardless of its cause, ophthalmia neonatorum is characterized by redness and chemosis (swelling) of the conjunctiva, edema of the eyelids, and discharge, which may be purulent.
Neonatal conjunctivitis is a potentially blinding condition. The infection may also have associated systemic manifestations that require treatment. Therefore, any newborn infant who develops signs of conjunctivitis needs a prompt and comprehensive systemic and ocular evaluation to determine the agent causing the infection and the appropriate treatment.
The onset of inflammation caused by silver nitrate drops usually occurs within 6-12 hr after birth, with clearing by 24-48 hr. The usual incubation period for conjunctivitis due to N. gonorrhoeae is 2-5 days, and for that due to C. trachomatis, it is 5-14 days.
Gonococcal infection may be present at birth or be delayed beyond 5 days of life owing to partial suppression by ocular prophylaxis. The time of onset of disease with other bacteria is highly variable.
Gonococcal conjunctivitis begins with mild inflammation and a serosanguineous discharge. Within 24 hr, the discharge becomes thick and purulent, and tense edema of the eyelids with marked chemosis occurs.
If proper treatment is delayed, the infection may spread to involve the deeper layers of the conjunctivae and the cornea. Complications include corneal ulceration and perforation, iridocyclitis, anterior synechiae, and rarely panophthalmitis.
Conjunctivitis caused by C. trachomatis (inclusion blennorrhea) may vary from mild inflammation to severe swelling of the eyelids with copious purulent discharge.
Conjunctivitis due to Staphylococcus aureus or other organisms is similar to that produced by C. trachomatis. Conjunctivitis due to Pseudomonas aeruginosa is uncommon, acquired in the nursery, and a potentially serious process. It is characterized by the appearance on days 5-18 of edema, erythema of the lids ,purulent discharge, pannus formation, endophthalmitis, sepsis, shock, and death.
Diagnosis
Conjunctivitis appearing after 48 hr should be evaluated for a possibly infectious cause.
Gram stain of the purulent discharge should be performed and the material cultured.
If a viral cause is suspected, a swab should be submitted in tissue culture media for virus isolation.
In chlamydial conjunctivitis, the diagnosis is made by examining Giemsa-stained epithelial cells scraped from the tarsal conjunctivae for the characteristic intracytoplasmic inclusions, by isolating the organisms from a conjunctival swab using special tissue culture techniques, by immunofluorescent staining of conjunctival scrapings for chlamydial inclusions, or by tests for chlamydial antigen or DNA..
The differential diagnosis of ophthalmia neonatorum includes dacryocystitis caused by congenital nasolacrimal duct obstruction with lacrimal sac distention (dacryocystocele).
Treatment
Treatment of infants in whom gonococcal ophthalmia is suspected and the Gram stain shows the characteristic intracellular gram-negative diplococci should be initiated immediately with ceftriaxone, 50 mg/kg/24 hr for 1 dose, not to exceed 125 mg.The eye should also be irrigated initially with saline every 10-30 min, gradually increasing to 2-hr intervals until the purulent discharge has cleared. An alternative regimen includes cefotaxime (100 mg/kg/24 hr given IV or IM every 12 hr for 7 days or 100 mg/kg as a single dose).
Neonatal conjunctivitis secondary to Chlamydia is treated with oral erythromycin (50 mg/kg/24 hr in 4 divided doses) for 2 wk. This cures conjunctivitis and may prevent subsequent chlamydial pneumonia.
Pseudomonas neonatal conjunctivitis is treated with systemic antibiotics, including an aminoglycoside, plus local saline irrigation and gentamicin ophthalmic ointment.
Staphylococcal conjunctivitis is treated with parenteral methicillin and local saline irrigation.
Prognosis and Prevention
Drops of 0.5% erythromycin or 1% silver nitrate are instilled directly into the open eyes at birth using wax or plastic single-dose containers. Saline irrigation after silver nitrate application is unnecessary. Silver nitrate is ineffective against active infection and may have limited use against Chlamydia. Povidone-iodine (2% solution) may also be an effective prophylactic agent.
An infant born to a woman who has untreated gonococcal infection should receive a single dose of ceftriaxone, 50 mg/kg (maximum 125 mg) IV or IM, in addition to topical prophylaxis.
Neither topical prophylaxis nor topical treatment prevents the afebrile pneumonia that occurs in 10-20% of infants exposed to C.trachomatis. It is important that infants with chlamydial disease receive systemic treatment.
Neonatal Tetanus (Clostridium tetani)
EtiologyTetanus is an acute, spastic paralytic illness historically called lockjaw that is caused by the neurotoxin produced by Clostridium tetani, a motile, gram-positive, spore-forming obligate anaerobe whose natural habitat worldwide is soil, dust, and the alimentary tracts of various animals. C. tetani forms spores terminally, producing a drumstick or tennis racket appearance microscopically.
Epidemiology
Is The most common form, neonatal (or umbilical) tetanus, kills approximately 500,000 infants each year, with about 80% of deaths in just 12 tropical Asian and African countries
It occurs in infants whose mothers are not immunized. In addition, an estimated 15,000-30,000 unimmunized women worldwide die each year of maternal tetanus, which results from postpartum, postabortal, or postsurgical wound infection with C. tetani.
Pathogenesis
Tetanus occurs after introduced spores germinate, multiply, and produce tetanus toxin in the low oxidation-reduction potential (Eh) of an infected injury site.Tetanus toxin binds at the neuromuscular junction and enters the motor nerve by endocytosis, after which it undergoes retrograde axonal transport to the cytoplasm of the α-motoneuron.The toxin exits the motoneuron in the spinal cord and next enters adjacent spinal inhibitory interneurons, where it prevents release of the neurotransmitters glycine and γ-aminobutyric acid (GABA).The autonomic nervous system is also rendered unstable in tetanus.
Because C. tetani is not an invasive organism, its toxin-producing vegetative cells remain where introduced into the wound, which may display local inflammatory changes and a mixed bact.flora.
Clinical Manifestations
Tetanus is most often generalized but may also be localized. The incubation period typically is 2-14 days but may be as long as months after the injury.
Neonatal tetanus, the infantile form of generalized tetanus, typically manifests within 3-12 days of birth as progressive difficulty in feeding (sucking and swallowing), after being able to suck at birth, associated hunger, and crying. Paralysis or diminished movement, stiffness and rigidity to the touch, and spasms, with or without opisthotonos, are characteristic. The umbilical stump may hold remnants of dirt, dung, clotted blood, or serum, or it may appear relatively benign. Bronchopneumonia, presumably resulting from aspiration,is a common complication and cause of death.
Diagnosis
The picture of tetanus is one of the most dramatic in medicine, and the diagnosis may be established clinically. The typical setting is an unimmunized patient (and/or mother) who was injured or born within the preceding 2 wk, who presents with trismus, other rigid muscles, and a clear sensorium.
A peripheral leukocytosis may result from a secondary bacterial infection of the wound or may be stress induced from the sustained tetanic spasms. The CSF fluid is normal, although the intense muscle contractions may raise intracranial pressure. Neither the EEG nor the EMG shows a characteristic pattern. C. tetani is not always visible on Gram stain of wound material and is isolated in only about 30% of cases .
Treatment
Management of tetanus requires eradication of C. tetani and the wound environment conducive to its anaerobic multiplication, neutralization of all accessible tetanus toxin, control of seizures and respiration, palliation, provision of meticulous supportive care, and, finally, prevention of recurrences.Excision of the umbilical stump in the neonate with tetanus is no longer recommended
Tetanus toxin cannot be neutralized by TIG after it has begun its axonal ascent to the spinal cord. TIG should be given as soon as possible in order to neutralize toxin that diffuses from the wound into the circulation before the toxin can bind at distant muscle groups.
A single intramuscular injection of 500 U of TIG is sufficient to neutralize systemic tetanus toxin, but total doses as high as 3,000-6,000 U are also recommended If TIG is unavailable, use of human intravenous immunoglobulin (IVIG) may be necessary.
Another alternative is equine- or bovine-derived tetanus antitoxin (TAT). The usual dose of TAT is 50,000-100,000 U, with half given intramuscularly and half intravenously, but as little as 10,000 U may be sufficient.
The human-derived immunoglobulins are much preferred because of their longer half-lives (30 days) and the virtual absence of allergic and serum sickness adverse effects.
Penicillin G (100,000 U/kg/day divided every 4-6 hr IV for 10-14 days) remains the antibiotic of choice because of its effective clostridiocidal action and its diffusibility, Metronidazole (500 mg every 8hr IV for adults) appears to be equally effective. Erythromycin and tetracycline (for persons >8 yr of age) are alternatives for penicillin-allergic patients.
All patients with generalized tetanus need muscle relaxants. Diazepam provides both relaxation and seizure control. The initial dose of 0.1-0.2 mg/kg every 3-6 hr given intravenously is subsequently titrated to control the tetanic spasms, after which the effective dose is sustained for 2-6 wk before a tapered withdrawal.
Magnesium sulfate, other benzodiazepines (midazolam), chlorpromazine, dantrolene, and baclofen are also used.
The highest survival rates in generalized tetanus are achieved with neuromuscular blocking agents such as vecuronium and pancuronium.
Autonomic instability is regulated with standard α- or β- (or both) blocking agents; morphine has also proved useful.
Prognosis
Recovery in tetanus occurs through regeneration of synapses within the spinal cord and thereby the restoration of muscle relaxation. However, because an episode of tetanus does not result in the production of toxin-neutralizing antibodies, active immunization with tetanus toxoid at discharge with provision for completion of the primary series is mandatory.
The most important factor that influences outcome is the quality of supportive care.
An unfavorable prognosis is associated with onset of trismus <7 days after injury and with onset of generalized tetanic spasms <3 days after onset of trismus. Sequelae of hypoxic brain injury, especially in infants, include cerebral palsy, diminished mental abilities, and behavioral difficulties. Most fatalities occur within the 1st wk of illness.
Prevention
Active immunization should begin in early infancy with combined diphtheria toxoid–tetanus toxoid–acellular pertussis (DTaP) vaccine at 2, 4, and 6 mo of age, with a booster at 4-6 yr of age and at 10-yr intervals thereafter throughout adult life (tetanus and reduced diphtheria toxoid Td] or tetanus, and reduced diphtheria and pertussis toxoids [Tdap].
Immunization of women with tetanus toxoid prevents neonatal tetanus, and the World Health Organization is currently engaged in a global campaign for elimination of neonatal tetanus through maternal immunization with at least 2 doses of tetanus toxoid..
Congenital infections
Congenital Infections an infection acquired transplacentally during gestation is a congenital infection. Numerous pathogens that produce mild or subclinical disease in older infants and children can cause severe disease in neonates who acquire such infections prenatally or perinatally. Sepsis, meningitis, pneumonia, and other infections caused by numerous perinatally acquired pathogens are the cause of significant neonatal morbidity and mortality.
Congenital infections include a well-known group of fungal, bacterial, and viral pathogens: toxoplasmosis, rubella, CMV, HSV, varicella-zoster virus, congenital syphilis, parvovirus, HIV, hepatitis B, Neisseria gonorrhoeae, Chlamydia, and Mycobacterium tuberculosis.
Many of the clinical manifestations of congenital infections are similar, including IUGR, nonimmune hydrops, anemia, thrombocytopenia, jaundice, hepatosplenomegaly, chorioretinitis, and congenital malformations
Evaluation of patients thought to have a congenital infection should include attempts to isolate the organism by culture (for rubella, CMV, HSV, gonorrhea, and M. tuberculosis), to identify the antigen of the pathogen (for hepatitis B and C. trachomatis), to identify the pathogen's genome with PCR, and to identify specific fetal production of antibodies (IgM or increasing titer of IgG for Toxoplasma, syphilis, parvovirus, HIV, or Borrelia).
Treatment is not always available, specific, or effective. Nonetheless, some encouraging results have been reported for preventing the disease and for specifically treating the infant when the correct diagnosis is made .
TOXOPLASMOSIS….
Vertical transmission of Toxoplasma gondii occurs by transplacental transfer of the organism from the mother to the fetus after an acute maternal infection.
Fetal infection rarely can occur after reactivation of disease in an immunocompromised pregnant mother. Transmission from an acutely infected mother to her fetus occurs in about 30% to 40% of cases, but the rate varies directly with gestational age. Transmission rates and the timing of fetal infection correlate directly with placental blood flow; the risk of infection increases throughout gestation to 90% or greater near term.
The severity of fetal disease varies inversely with the gestational age at which maternal infection occurs. Most infants have subclinical infection with no overt disease at birth; however, specific ophthalmologic and CNS evaluations may reveal abnormalities.
The classic findings of hydrocephalus, chorioretinitis, and intra-cerebral calcifications suggest the diagnosis of congenital toxoplasmosis.
Affected infants tend to be SGA, develop early-onset jaundice, have hepatosplenomegaly, and present with a generalized maculopapular rash. Seizures are common, and skull films may reveal diffuse cortical calcifications in contrast to the peri-ventricular pattern observed with CMV. These infants are at increased risk for long-term neurologic and neurodevelopmental complications. Serologic tests are the primary means of diagnosis.
IgG-specific antibodies achieve a peak concentration 1 to 2 months after infection and remain positive indefinitely. For infants with seroconversion or a fourfold increase in IgG titers, specific IgM antibody determinations should be performed in patients to confirm disease. Especially for congenital infections, measurement of IgA and IgE antibodies can be useful to confirm the disease. Thorough ophthalmologic, auditory, and neurologic evaluations (head CT and CSF) indicated
For symptomatic and asymptomatic congenital infection, initial therapy should include pyrimethamine (supplemented with folic acid) combined with sulfadiazine. Duration of therapy is often prolonged even up to 1 year.
RUBELLA.
With the widespread use of vaccination, congenital rubella is rare. Acquired in utero during early gestation, rubella can cause severe neonatal consequences.
The occurrence of congenital defects approaches 85% if infection is acquired during the first 4 weeks of gestation; close to 40% spontaneously abort or are stillborn. If infection occurs during weeks 13 to 16, 35% of infants can have abnormalities. Infection after 4 months' gestation does not seem to cause disease.
The most common characteristic abnormalities associated with congenital rubella include ophthalmologic (cataracts, retinopathy, and glaucoma) Retinal findings described as salt-and-pepper retinopathy are the most common ocular abnormality but have little early effect on vision. Unilateral or bilateral cataracts are the most serious eye finding, occurring in about a third of infants, cardiac (PDA and peripheral pulmonary artery stenosis), Cardiac abnormalities occur in half of the children infected during the 1st 8 wk of gestation. Patent ductus arteriosus is the most frequently reported cardiac defect, followed by lesions of the pulmonary arteries and valvular disease, auditory (sensorineural hearing loss) Nerve deafness is the single most common finding among infants with CRS, and neurologic (behavioral disorders, meningoencephalitis, and mental retardation) Neurologic abnormalities are common and may progress following birth. Meningoencephalitis is present in 10-20% of infants with CRS and may persist for up to 12 mo. Additionally, infants can present with growth retardation, hepatosplenomegaly, early-onset jaundice, thrombocytopenia, radiolucent bone disease, and purpuric skin lesions ("blueberry muffin" appearance from dermal erythropoiesis).other Causes of blueberry rash include other congenital viral infections(CMV and parvovirus), congenital neoplastic disease,and Rh hemolytic disease. A variety of late-onset manifestations of CRS have been recognized. In addition to PRP(post rubella panencephalitis), they include diabetes mellitus (20%), thyroid dysfunction (5%), and glaucoma and visual abnormalities associated with the retinopathy, which had previously been considered benign,also hearing loss and autism.
Treatment
There is no specific treatment available for either acquired rubella or CRS. Management of children with CRS requires pediatric, cardiac, audiologic, ophthalmologic, and neurologic evaluation and follow-up because many manifestations may not be readily apparent initially or may worsen with time. Hearing screening is of special importance, because early intervention may improve outcomes in children with hearing problems due to CRS.
Prevention:
Children with CRS may excrete the virus in respiratory secretions up to 1 yr of age, so contact precautions should be maintained for them until then, unless repeated cultures of urine and pharyngeal secretions have negative results. Similar precautions apply to patients with CRS with regard to attendance in school and out-of-home child care. Exposure of susceptible pregnant women poses a potential risk to the fetus. For pregnant women exposed to rubella, a blood specimen should be obtained as soon as possible for rubella IgG–specific antibody testing and feozen sample should be saved, If the rubella antibody test result is positive, the mother is likely immune. If the rubella antibody test is negative, a 2nd specimen should be obtained 2-3 wk later and tested concurrently with the saved specimen. If both of these test negative, a 3rd specimen should be obtained 6 wk after exposure and tested concurrently with the saved specimen. If both the 2nd and 3rd specimens test negative, infection has not occurred. A negative 1st specimen and a positive test result in either the 2nd or 3rd specimen indicate that seroconversion has occurred in the mother, , suggesting recent infection. Counseling should be provided about the risks and benefits of termination of pregnancy. The use of immune globulin for susceptible pregnant women exposed to rubella is considered only if termination of pregnancy is not an option because of maternal preferences. In such circumstances, immune globulin 0.55 mL/kg IM may be given with the understanding that prophylaxis may reduce the risk for clinically apparent infection but does not guarantee prevention of fetal infection.
Vaccination
Rubella vaccine administered in combination with measles and mumps (MMR) or also with varicella (MMRV) in a 2-dose regimen at 12-15 mo and 4-6 yr of age. Vaccine should not be administered to severely immunocompromised patients (e.g., transplant recipients). Patients with HIV infection who are not severely immunocompromised may benefit from vaccination. Fever is not a contraindication, but if a more serious illness is suspected, immunization should be delayed. Vaccine should not be administered during pregnancy.
*****Reinfection with wild virus occurs postnatally in both individualswho were previously infected with wild-virus rubella and in vaccinated individuals.
CYTOMEGALOVIRUS
CMV is the most common congenital infection and the leading cause of sensorineural hearing loss, mental retardation, retinal disease, and cerebral palsy. Congenital CMV occurs in about 0.5% to 1.5% of births. When primary infection occurs in mothers during a pregnancy, the virus is transmitted to the fetus in approximately 35% of cases. Rates of CMV infection are three to seven times greater among infants born to adolescent mothers.
The risk for transmission of CMV to the fetus is independent of gestational age at the time of maternal infection
The earlier in gestation that the primary maternal infection occurs, the more symptomatic the infant will be at birth. The most common sources of CMV for primary infections occurring in mothers during pregnancy are sexual contacts and contact with young children. It is well known that CMV can be transmitted to the fetus even when maternal infection occurred long before conception. This transmission can occur as the result of virus reactivation, chronic infection, or reinfection with a new strain.
More than 90% of infants who have congenital CMV infection exhibit no clinical evidence of disease at birth. Approximately 10% of infected infants have symptoms at birth. Findings include SGA, microcephaly, thrombocytopenia, hepatosplenomegaly, hepatitis, intracranial calcifications, chorioretinitis, and hearing abnormalities
Some infants can present with a blueberry muffin appearance as the result of dermal erythropoiesis. Skull films may reveal periventricular calcifications. An additional 10% of infected infants may not present until later in infancy or early childhood, when they are found to have sensorineural hearing loss and developmental delays. Mortality is 10% to 15% among symptomatic newborns. Perinatal CMV infection acquired during birth or from mother's milk is not associated with newborn illness or CNS sequelae
CMV is diagnosed by detection of virus in the urine or saliva. Detection is often accomplished by traditional virus culture methods, but can take several weeks to obtain a result. Rapid culture methods using centrifugation to enhance infectivity and monoclonal antibody to detect early antigens in infected tissue culture can give results in 24 hours.
PCR also can be used to detect small amounts of CMV DNA in the urine. Detection of CMV within the first 3 weeks after birth is considered proof of congenital CMV infection.
Treatment
Studies on the use of ganciclovir (6 mg/kg/dose every 12 hr IV for the 1st 6 wk of life) concluded that treatment both prevents hearing deterioration and improves or maintains normal hearing function at 6 mo of age, and may prevent hearing deterioration that occurs after 1 yr of age. In addition, infants with severe perinatal CMV infection following breast milk ingestion have been successfully treated with ganciclovir. Preliminary evidence suggests that 6 mo of oral valganciclovir may be more effective and less toxic than intravenous ganciclovir in infants with symptomatic CMV infection.Prevention
Pregnant women who are CMV seropositive are at low risk of delivering a symptomatic newborn. If possible, pregnant women should undergo CMV serologic testing, especially if they provide care for young children who are potential CMV excreters. Pregnant women who are CMV seronegative should be counseled regarding good handwashing and other hygienic measures and avoidance of contact with oral secretions of others.. An uncontrolled trial has shown that the use of CMV hyperimmune globulin in pregnant women with primary CMV can lessen the risk of transmission to the unborn baby and can even reduce the risk of disease in the infected fetus.
****Regarding active immunization An adjuvant recombinant glycoproteinB, a major protein component of the envelope and target of neutralizing antibodies, has been shown to induce virus-neutralizingantibodies and CD4+ T-lymphocyte proliferative responses. Moreover,this vaccine reduced virus acquisition by approximately 50% in a small trial carried out in young women. However, closer examination of this vaccine trial revealed that protection was very short-lived and that the effectiveness of the vaccine, although statistically significant, was not convincingly demonstrated because of the small numbers of subjectsin the trial.
HIV …..
ETIOLOGYThe cause of AIDS is HIV, a single-stranded RNA virus of the retrovirus family that produces a reverse transcriptase enabling the viral RNA to act as a template for DNA transcription and integration into the host genome. HIV-1 causes 99% of all human cases. HIV-2, which is less virulent, causes 1% to 9% of cases.
HIV infects human helper T cells (CD4 cells) and cells of monocyte-macrophage lineage via interaction of viral protein gp120 with the CD4 molecule and chemokines that serve as coreceptors, permitting membrane fusion and cell entry. Other cells bearing CD4, such as microglia, astrocytes, oligodendroglia, and placental tissues, also may be infected with HIV.
Horizontal transmission of HIV is by unprotected heterosexual or homosexual contact and IV drug use. Transmission by contaminated blood and blood products has been eliminated in developed countries, but still occurs in developing countries. Vertical transmission of HIV from mother to infant may occur transplacentally in utero, during birth, or by breast-feeding.
Risk factors for perinatal transmission
prematurity, rupture of membranes more than 4 hours, and high maternal circulating levels of HIV at delivery.
Perinatal transmission can be decreased from approximately 25% to less than 8%with antiretroviral treatment of the mother before and during delivery and postnatal treatment of the infant.
In untreated infants, the mean incubation interval for development of an AIDS-defining condition after vertical transmission is 5 months (range 1 to 24 months) compared with an incubation period after horizontal transmission of generally 7 to 10 years.
CLINICAL MANIFESTATIONS
Initial symptoms with vertical transmission vary and may include failure to thrive, neurodevelopmental delay, lymphadenopathy, hepatosplenomegaly, chronic or recurrent diarrhea, interstitial pneumonia, or oral thrush. These findings may be subtle and remarkable only by their persistence. Manifestations that are more common in children than adults with HIV infection include recurrent bacterial infections, lymphoid hyperplasia, chronic parotid swelling, lymphocytic interstitial pneumonitis, and earlier onset of progressive neurologic deterioration.
Pulmonary manifestations of HIV infection are common and include P. jirovecii (carinii) pneumonia, which can present early in infancy as a primary pneumonia characterized by hypoxia, tachypnea, retractions, elevated serum lactate dehydrogenase, and fever. Infants born to HIV-infected mothers receive prophylaxis and are prospectively tested for infection.
LABORATORY AND IMAGING STUDIES….
HIV infection can be diagnosed definitively by 1 month of age and in virtually all infected infants by 6 months of age using viral diagnostic assays (RNA PCR, DNA PCR, or virus culture). Maternal antibodies may be detectable until 12 to 15 months of age, and a positive serologic test is not considered diagnostic until 18 months of age.
Diagnostic viral testing should be performed by 48 hours of age, at 1 to 2 months of age, and at 3 to 6 months of age. An additional test at 14 days of age is often performed because the diagnostic sensitivity increases rapidly by 2 weeks of age.
HIV DNA PCR is the preferred virologic method for diagnosing HIV infection during infancy and identifies 38% of infected infants at 48 hours and 96% at 28 days. HIV RNA PCR has 25% to 40% sensitivity during the first weeks of life, increasing to 90% to 100% by 2 to 3 months of age. HIV culture is complicated and not routinely performed.
HIV infection of an exposed infant is confirmed if virologic tests are positive on two separate occasions.
HIV infection can be reasonably excluded in nonbreastfed infants with at least two virologic tests performed at older than 1 month of age, with one test being performed at older than 4 months of age, or at least two negative antibody tests performed at older than 6 months of age, with an interval of at least 1 month between the tests. Loss of HIV antibody combined with negative HIV DNA PCR confirms the absence of HIV infection. Persistence of a positive HIV antibody test at older than 18 months of age indicates HIV infection.
DIFFERENTIAL DIAGNOSIS The differential diagnosis of AIDS in infants includes primary immunodeficiency syndromes and intrauterine infection. Prominence of individual symptoms, such as diarrhea, may suggest other etiologies.
TREATMENT
Because the risk of HIV progression is fourfold to sixfold greater in infants and very young children, treatment recommendations for children are more aggressive than for adults. All age groups show rapid increases in risk as CD4 cell percentage declines to less than 15%.
Initiation of therapy is recommended for infants less than 12 months of age regardless of symptoms of HIV disease or HIV RNA level. Initiation of therapy is recommended for all children 1 to 5 years of age with AIDS or significant HIV-related symptoms or CD4 below 25% regardless of symptoms or HIV RNA level. For children older than 5 years with AIDS or significant HIV-related symptoms, CD4 count below 350/mm3 should be treated. Indications for treatment of adolescents and adults include CD4 cell count less than 200 to 350/mm3 or plasma HIV RNA levels above 55,000 copies/mL.
Combination therapy with highly active antiretroviral therapy (HAART) is recommended Antiretroviral drugs include nucleoside analogue or nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors(ritonavir, nelfinavir, fosamprenavir, tipranavir, and lopinavir), and fusion inhibitors(enfuvirtide). Combination therapy with dual nucleoside reverse transcriptase inhibitor combinations (zidovudine-lamivudine, zidovudine-didanosine, or stavudine-lamivudine) and a protease inhibitor is a common initial regimen for all children with HIV. The goal of therapy is to reduce the plasma HIV RNA to below the level of detection and normalize or preserve the patient’s immune status.
All HIV-exposed and infected children should receive standard pediatric immunizations. In general, live oral polio vaccine should not be given .The risk and benefits of rotavirus vaccination should be considered in infants born to HIV-infected mothers. Because <1% of these infants in developed countries will develop HIV infection, the vaccine should be given. In other situations, the considerable attenuation of the vaccine's strains should be taken into account and unless the infant has clinical symptoms of AIDS or CD4 <15%, vaccination seems to be appropriate. Other live bacterial vaccines (e.g., bacillus Calmette-Guarin [BCG]) should be avoided due to the high incidence of BCG-related disease in HIV-infected infants. Varicella and measles-mumps-rubella (MMR) vaccines are recommended for children who are not severely immunosuppressed (i.e., CD4 cell percentage ≥15%), but neither varicella nor MMR vaccines should be given to severely immunocompromised children (i.e., CD4 cell <15%). Of note, prior immunizations do not always provide protection, as evidenced by outbreaks of measles and pertussis in immunized HIV-infected children. Durability of vaccine-induced titers is often short, especially if vaccines are administered when the child's CD4 cell is <15%, and re-immunization when the CD4 count has increased (i.e., >15%) may be indicated.
In addition to heptavalent pneumococcal conjugate vaccine, 23-valent pneumococcal polysaccharide vaccine is recommended for HIV-infected children at 2 years of age and adolescents.
VZV vaccine should be given only to asymptomatic, nonimmunosuppressed children beginning at 12 months of age as two doses of vaccine at least 3 months apart. Inactivated split influenza virus vaccine should be administered annually to all HIV-infected children 6 months old or older. HIV-infected children exposed to varicella or measles should receive VZIG or immunoglobulin prophylaxis.
complications
*Prophylactic regimens are integral for the care of HIV-infected children. All infants between 4-6 wk and 1 yr of age who are proven to be HIV-infected should receive prophylaxis to prevent Pneumocystis jiroveci infection regardless of the CD4 count or percentage. The best prophylactic regimen is 150 mg/m2/day of trimethoprim component of TMP/SMZ given as 1-2 daily doses 3 days per wk.
*Clarithromycin prophylaxis for Mycobacterium avium-complex infection is provided if CD4 cell counts are below 50/mm3.
**P. jiroveci pneumonia is treated with high-dose TMP-SMZ and corticosteroids. Oral and gastrointestinal candidiasis is common in children and usually responds to imidazole therapy.
*VZV infection may be severe and should be treated with acyclovir or other antivirals. Recurrent herpes simplex virus(HSV) infections also may require long-term antiviral prophylaxis.
**Children and adults with HIV are prone to malignancies,especially non-Hodgkin lymphomas, with the gastrointestinal tract being the most common site. Leiomyosarcomas are the second most common tumors among HIV-infected children.Kaposi sarcoma, caused by HHV-8, is distinctly rare in childrenwith HIV.
PROGNOSIS
The availability of HAART has improved the prognosis for HIV and AIDS dramatically. Risk of death is directly related to the degree of immunosuppression, viral load, and young age. Children less than 1 year of age with very low CD4 percentiles and high viral loads have the poorest prognosis.
PREVENTION
The rate of vertical transmission is reduced to less than 8% by chemoprophylaxis with a regimen of zidovudine to the mother (100 mg five times/24 hr orally) started by 4 weeks' gestation and continued during delivery (2 mg/kg loading dose intravenously followed by 1 mg/kg/hr intravenously) and to the newborn for the first 6 weeks of life (2 mg/kg every 6 hours orally). Other regimens incorporating single-dose nevirapine for infants have been shown to be similarly effective and are used in developing countries.. Scheduled cesarean section at 38 weeks to prevent vertical transmission is recommended for women with HIV RNAlevels greater than 1000 copies/mL, but it is unclear whether cesarean section is beneficial when viral load is less than 1000copies/mL or when membranes have already ruptured.
Preventing HIV infection in adults decreases the incidence of infection in children. Prevention of pediatric AIDS includes avoidance of pregnancy and breast-feeding (in developed countries) in high-risk women. Screening of blood donors has reduced markedly the risk of HIV transmission from blood products. HIV infection almost never is transmitted in a casual or nonsexual household setting.
the WHO recommends that in low-resource countries where other diseases (diarrhea, pneumonia, malnutrition) substantially contributeto a high infant mortality rate, the benefit of breastfeeding outweighs the risk for HIV transmission, and HIV-infected women in developing countries should breastfeed their infants for at least the 1st 6 mo of life. But Where replacement feeding is readily available and safe, it seems reasonable for women to substitute infant formula for breast milk if they are known to be HIV infected or are at risk for ongoing sexual or parenteral exposure to HIV.