Congenital Infections
Congenital Infections: Excerpt from Pediatric Infectious Disease
Basic Considerations
The diagnosis of congenital and perinatal infections is complicated by several
issues:
1. Infected babies may be asymptomatic or minimally symptomatic when born, only
to develop symptoms and disabilities in the following weeks, months, or even
years.
2. Babies born symptomatic may have findings such as anemia, thrombocytopenia,
jaundice, and microcephaly, which can be the result of infections with several
different pathogens (e.g., cytomegalovirus [CMV], syphilis, rubella).
3. Laboratory evaluation for congenital and some perinatal infections has often
included the use of TORCH titers (i.e., toxoplasmosis, rubella, CMV, and
herpes). TORCH titers are immunoglobulin G (IgG) antibodies that readily cross
the placenta and may persist for months in the neonatal circulation. As 50% of
adults have serologic evidence of previous infection with CMV, herpes simplex
virus, or toxoplasmosis, up to 50% of newborns tested will have positive TORCH
titers for these organisms. TORCH titers are of no value in the diagnosis of
congenital and perinatal infections. Rather, a disease-specific approach using
precise clinical and laboratory methods is required.
Cytomegalovirus
Epidemiology
CMV is the most common congenital infection, affecting 1% to 2% of all newborns.
The rate of infection in a fetus of a mother with primary infection is between
40% and 50%; the rate of infection is less than 1% if the mother has
reactivated infection. Most infected infants (90%) are asymptomatic at birth;
only 10% of these children have long-term sequelae. The most common sequela is
asymptomatic congenital CMV infection sensorineural hearing loss. This hearing
loss can be progressive and may be unilateral or bilateral.
Presentation
Ten percent of infants with congenital CMV infection are symptomatic at birth.
These patients often present with multiple organ system involvement, including
intrauterine growth retardation, petechiae, anemia, leukopenia, and
thrombocytopenia. A classic finding on computed tomography of the head in
congenital CMV is periventricular calcification (Fig. 3.1). The predilection
for the calcification in this area is believed to be related to the tendency of
CMV to infect the rapidly dividing germinal matrix cells. Magnetic resonance
imaging of neonates with congenital CMV infection may also reveal irregular
areas in the junction of the gray and white matter, accompanied by the presence
of ventricular pseudocysts. Patients with congenital CMV may have continual
neurologic damage even after birth, which is thought to be secondary to
persistent viral replication.
Diagnosis
The gold standard of diagnosis is isolation of the virus, usually from the
urine. Urine viral cultures are often positive within days because the kidney
is a principal site of viral replication. Proof of congenital infection is
based on obtaining appropriate specimens within 3 weeks of birth. After this
time, distinguishing between intrauterine infection and perinatal infection may
be difficult.
Management
Patients with congenital CMV infection are at risk for a variety of
disabilities, including developmental delay and hearing loss. Symptomatic
children are considered to have the highest risk for long-term abnormalities,
although recent longitudinal studies have found predicting disability
difficult. It is known that the major disability in asymptomatic congenital CMV
infection is sensorineural hearing loss. This hearing loss may be progressive
in affected infants. After a diagnosis of congenital CMV is made, routine
assessments should be instituted. It has been recommended that a careful
ophthalmology exam be performed at 12 months, 3 years, and at entrance to
preschool. Audiology examinations should be done every 3 months until 3 years
of age and then annually.
No definitive protocols exist for the treatment of congenital CMV infection.
Clinical trials are in progress; a recent randomized clinical trial comparing
outcomes in symptomatic infants given the antiviral agent ganciclovir with
those in patients receiving no treatment suggested that there may be a benefit
from treatment, the greatest benefit in treated children being a reduction in
hearing loss. In early protocols of treatment of CMV, symptomatic infants were
administered intravenous ganciclovir for 6 weeks; later studies extended
treatment of affected infants with intravenous and then oral ganciclovir for up
to 1 year. Currently, it is not recommended that asymptomatic infants found to
be congenitally infected receive ganciclovir. These children should be followed
carefully for the development of sensorineural hearing loss. Neonates with
life-threatening symptomatic disease, including intractable thrombocytopenia,
pneumonia, or hepatic failure, are candidates for antiviral therapy. It is my
experience and the experience of investigators nationally that therapy can be
very beneficial in these cases.
Complications of ganciclovir include difficulties in maintaining intravenous
access and neutropenia. There will likely be continued efforts to identify
precisely and treat those infants likely to have long-term sequelae from
congenital CMV infection and those most likely to benefit from therapy.
Herpes Simplex Virus
Epidemiology
Depending on the population surveyed, as many as 10% to 15% of women report a
history of genital herpes. This number may actually be higher because many
infected women do not have a history of visible genital lesions. Previously,
pregnant women who reported a history of genital herpes had weekly viral
cultures obtained as they approached delivery. However, when results of the
viral cultures become available, typically in 7 days, they were of little
value. This practice of weekly viral cultures has been replaced by a more basic
approach; women who do not have active lesions at the time of delivery are
often allowed to deliver vaginally.
The current practice is such that exposure to herpesvirus can never be avoided,
and pediatricians must be vigilant to the various manifestations of neonatal
herpes. The manifestations of neonatal herpes usually present in the first
month of life.
Presentation
Mucocutaneous Disease
Herpetic vesicles can appear on the scalp, mouth, eyes, and skin. Although
children with mucocutaneous disease may initially be well appearing, 75%
progress to disseminated disease (Fig. 3.2).
Encephalitis
Encephalitis may present with lethargy, seizures, and a cerebrospinal
pleocytosis that shows a lymphocytic predominance. In infants with meningitis
or encephalitis, positive temporal lobe spikes on electroencephalogram (EEG)
are found in 80% of cases and represent a noninvasive means of diagnosis. This
is often misdiagnosed as aseptic meningitis or as the more common enteroviral
meningitis. Aseptic meningitis in the first month of life should be considered
herpes until proved otherwise.
Pneumonia
Rarely, herpes can present with progressive pneumonia in the neonatal period.
This is usually not associated with skin vesicles but can be associated with
dissemination, with increased liver function tests, coagulopathy, and organ
failure.
Disseminated Disease
Disseminated disease is often associated with fever, coagulopathy, and
abnormalities of liver function tests. Vesicles are usually not present
initially. Disseminated disease has a very high mortality rate, even when
treated appropriately. A persistently febrile neonate, particularly if blood
cultures remain negative and liver enzymes are elevated, should raise strong
suspicion of herpes (Table 3.1).
Diagnosis
The first issue in diagnosis is a clinical suspicion of herpes simplex disease.
Herpetic vesicles in the neonatal period are an emergency. If there is any
suspicion regarding whether a skin lesion is a vesicle, empiric acyclovir
should be started while appropriate studies are obtained. This is very similar
to the management of the febrile neonate, in whom empiric antibiotics are
started until blood cultures are final. Aseptic meningitis in the neonate
should also be considered herpes until proved otherwise.
There are several ways of making the diagnosis of neonatal herpes. Vesicles can
be scraped to obtain viral culture and tested for direct fluorescent
antibodies; these have relatively high yield. Polymerase chain reaction (PCR)
of the serum and spinal fluid is now considered the gold standard for
diagnosis. Even in neonates with only mucocutaneous disease, the rate of a
positive serum PCR can be greater than 50%. There are increasing reports of
reduced sensitivity of cerebrospinal fluid (CSF) PCR in diagnosing pediatric
herpes simplex encephalitis, particularly if CSF has been obtained on the first
day of illness. In patients with a compatible clinical picture of herpes
simplex encephalitis, particularly if an alternative diagnosis such as
enterovirus has not been confirmed, it may be prudent to continue treatment
until a second sample of CSF has been obtained and tested.
Management
Treatment of neonatal herpes is intravenous acyclovir. Herpes simplex disease in
the neonate is never treated either empirically or definitively with topical or
oral acyclovir. The dose is 60 mg/kg per day in three divided doses. The
treatment duration is 14 days for mucocutaneous disease and 21 days for
disseminated disease or in neonates in whom central nervous system (CNS)
involvement is suspected. Supportive care in terms of controlling seizures and
coagulopathy is also critical in the management of these patients.
Herpes simplex virus is a latent virus, and it is assumed that most neonates
with infection will develop latent infection. There is ongoing concern that
reactivation of latent virus in infants with a history of neonatal infection
may be associated with continued morbidity. Children with a history of
mucocutaneous disease often have recurrences of their vesicles; the effect of
this on long-term development is uncertain. Studies conducted at the National
Institute of Allergy and Infectious Disease have found that infants with more
than three recurrences of mucocutaneous vesicles have a higher incidence of
neurologic sequelae. It is postulated that cutaneous reactivation may be
associated with subclinical reactivation in the CNS.
There have been initial clinical trials to enroll children with recurrent
cutaneous herpes on long-term oral acyclovir therapy given at 300 mg/m
2 per dose two or three times daily for 6 months. Although this does seem to
prevent herpes recurrences, nearly half of the children develop neutropenia,
defined as white blood cell counts of less than 1,000/m
3. Currently, there is no consensus regarding preventative therapy; this should
be answered in the future by prospective clinical trials.
Congenital Syphilis
Epidemiology
Congenital syphilis results from inadequate or late treatment of syphilis in a
pregnant woman. Infection passed to the newborn can result in stillbirth,
symptomatic neonatal disease, or infection that does not manifest until later
in childhood.
Presentation
Infected infants may appear normal at birth, only to manifest symptoms in the
first year of life. These infants may present with mucocutaneous lesions,
anemia, and organomegaly. Congenital syphilis nephrotic syndrome or an
osteochondritis that causes decreased movement of the affected extremity
(pseudoparalysis of Parrot) may be seen. Late manifestations of congential
syphilis include interstitial keratitis and notching of the central incisors
(Hutchinson
’s teeth).
Evaluation
There are two types of serologic tests used for the diagnosis of syphilis in
adults. The nontreponemal tests include the VDRL and RPR. These can be
quantitated by titers and, after successful therapy, usually become
nonreactive. The treponemal tests, which include MHA-TP and FTA-ABS, are not
quantitative and are thought to remain positive for life. All syphilis serology
crosses the placenta and, like other TORCH titers, cannot be used for diagnosis
in neonates. Because an infected infant may be asymptomatic at birth (only to
develop the disease in later life), we therefore have an unusual situation in
which both laboratory tests and physical examination are not helpful in the
diagnosis of congenital syphilis.
In the early 1990s, new criteria were established for the presumptive diagnosis
of congenital syphilis. An infant born to a mother considered untreated or
inadequately treated receives the presumptive diagnosis of congenital syphilis.
The definition of inadequate maternal treatment includes the following:
• Syphilis during pregnancy treated with a nonpenicillin regimen, such as
erythromycin
• Syphilis during pregnancy treated with an appropriate penicillin regimen
without the expected posttherapy decrease in nontreponemal titers
• Syphilis treated less than 1 month before delivery
• Syphilis treated before pregnancy but with insufficient serologic follow-up to
assess the response to treatment
Some investigators believe that the rate of fetal infection from a mother with
secondary syphilis in pregnancy is so high that treatment should also be
considered for all those infants as well.
Children with a presumptive diagnosis of congenital syphilis should have the
following evaluation:
• Physical exam, although it should be stressed that infected infants appear be
normal at birth
• Nontreponemal and treponemal tests done from infant blood rather than cord
blood
• CSF for cells, protein, and VDRL
• Complete blood count and platelet count
• Long-bone radiographs looking for osteolytic lesions
A major part of the evaluation for congenital syphilis in the infant includes
the evaluation for congenital neurosyphilis. The diagnosis of congenital
neurosyphilis is important because several forms of penicillin, including
penicillin G benzathine, do not reach treponicidal concentrations in the CSF.
The gold standard for CNS disease is the rabbit infectivity test. This test
involves the inoculation of clinical specimens into rabbits and is sensitive
enough to detect as few as 10 organisms. Unfortunately, this test is not
routinely available outside research laboratories.
Controversy continues about the best diagnostic approach to document CNS
involvement in congenital syphilis. Recently, PCR of blood and CSF, in addition
to IgM immunoblotting, has been developed. Compared with the rabbit infectivity
test, these studies were found to identify 94% and 100% of infants with CNS
disease, respectively. It is hoped that these tests will become widely
available in the future. In infants with otherwise normal clinical, laboratory,
and radiographic studies, CNS involvement is unusual.
Management
Asymptomatic infants who have normal CSF results, complete blood counts, and
radiographic examination (and therefore low likelihood of CNS involvement) may
be treated with a single dose of intramuscular benzathine penicillin at a dose
of 50,000 units/kg. Neonates who have abnormalities on physical exam or
laboratory evaluation should be treated with aqueous penicillin G, 100,000 to
150,000 units/kg per day administered at 50,000 units/kg per dose intravenously
every 12 hours for the first 7 days of life and every 8 hours thereafter for a
total of 10 days. An additional option for these patients with proven or highly
probable disease includes procaine penicillin, 50,000 units/kg per dose given
intramuscularly once a day for 10 days.
Follow-up is critical in infants treated for congenital syphilis. Serologic
nontreponemal tests should be performed 3, 6, and 12 months after conclusion of
treatment. Nontreponemal titers should be nonreactive by 6 months of age if
treatment was adequate. Children with increasing titers or persistent stable
titers should be considered for repeat treatment.
Congenital Rubella
Epidemiology
Congenital rubella infection is unusual because the readily available vaccine
prevents infection in mothers of childbearing age. However, cases still occur
in populations that are not optimally vaccinated. Most cases of congenital
rubella are the result of primary maternal disease during pregnancy. The risk
for fetal infection is highest during early gestation, although the most severe
manifestations occur when infection is in the last trimester.
Presentation
Patients born with congenital rubella usually suffer from severe intrauterine
growth retardation as well as a variety of cardiac, ophthalmologic, and
neurologic defects. The most common congenital heart defects include patent
ductus arteriosis and pulmonary artery stenosis. Cataracts occur in more than
30% of cases. Severe cases often have
“celery stalk” appearance of long bones visible on plain radiographs. Organomegaly,
thrombocytopenia, and purpuric skin lesions may also be seen. There is
considerable clinical overlap in patients with congenital CMV. As with many
congenital infections, many children may be asymptomatic at birth but develop
manifestations later in life.
Diagnosis
Diagnosis is made by detection of rubella-specific serum IgM antibodies.
Congenital infection can also be diagnosed by documenting increasing serum
concentrations of infant rubella IgG over several months. Virus is readily
excreted from throat, urine, and CSF, but viral isolation of rubella is
difficult and usually not achieved.
Management
At the present time, there is no treatment for infants with congenital rubella.
Defects of the eyes are managed as needed. Contact isolation is recommended for
children with proven or presumed congenital rubella during the first year of
life.
Congenital Toxoplasmosis
Epidemiology
Congenital toxoplasmosis occurs when a woman acquires primary infection during
pregnancy. Overall transmission rate is between 20% and 30%. The rate of
transmission is low when women are infected in the first trimester, but when
infection occurs during this time, infants are more severely affected.
Conversely, if infections occur later in pregnancy, the risk for transmission
is high, but infected infants are less likely to have the most severe clinical
features of the disease.
Studies have found that most causes of toxoplasmosis in humans include eating
rare to medium cooked beef, working in an outside environment, and cat
exposure. In some cases, the actual source of transmission remains unclear
despite repeated investigation. Factors that predict congenital toxoplasmosis
have been found to include mother
’s birth outside the United States, multiparity, and the level of education of
the mother (the least and most educated appear to be at highest risk).
Presentation
The classical clinical triad of congenital toxoplasmosis includes retinitis,
hydrocephalus, and intracranial calcification, although this is present in only
a small number of cases (Fig. 3.3). Congenital toxoplasmosis is usually
asymptomatic at birth. As they grow older, a significant percentage of these
children have learning disabilities, visual impairment, or mental retardation.
Evaluation
Traditional TORCH titers are again of little value in the diagnosis of
congenital toxoplasmosis. Maternal IgG antibodies cross the placenta and are
positive in a good percentage of newborns. Commercially available IgM assays
are not recommended for routine use because they have very high false-positive
and false-negative rates. The reference laboratory at the Palo Alto Medical
Foundation, under the direction of Dr. Jack Remington, is the standard way of
making the laboratory diagnosis of congenital toxoplasmosis (Palo Alto Medical
Foundation; telephone number 650
–853–4828.) This laboratory performs a variety of specialized assays, including the
following:
Sabin Feldman dye test. This test measures primarily IgG antibodies. Any titer is considered positive.
Immunosorbent agglutination assay (IgM-ISAgA). This test is highly sensitive and recommended for infants in whom congenital
toxoplasmosis is suspected.
IgA enzyme-linked immunosorbent assay (ELISA). This test is actually more sensitive for detection of infection in newborns than
the IgM assay. Both tests are done if congenital toxoplasmosis is suspected.
Evaluation of infants with suspected congenital toxoplasmosis should also
include ophthalmologic examination and computed tomography or ultrasound of the
brain to determine whether hydrocephalus or calcifications are present.
Management of Confirmed Congenital Toxoplasmosis
Infants who are diagnosed with congenital toxoplasmosis require treatment. The
therapy for congenital toxoplasmosis is as follows:
Sulfadiazine, 100 mg/mL; half of child’s weight (in kilograms) equals number of mls, given twice a day
Pyrimethamine, 2 mg/mL; half of child’s weight (in kilograms) equals number of mls, given once a day
Folinic acid (leucovorin) 5-mg tablets, 2 tablets crushed in formula Monday,
Wednesday, and Friday
For all infants with both asymptomatic and symptomatic congenital infection,
therapy is recommended for 1 year.
Diagnosis of Acute Toxoplasmosis in Pregnant Women
Diagnosis of toxoplasmosis in pregnancy is difficult because most patients have
minimal symptoms; a mononucleosis-like illness or posterior cervical adenitis
is sometimes seen. In women at increased risk for primary toxoplasmosis,
screening for IgG antibodies can be performed. It is important to confirm all
screenings with follow-up testing at a reference laboratory. The panel of
testing available can often give an estimate of the timing of maternal
infection.
If the mother has had primary infection during pregnancy, fetal infection can be
evaluated using PCR of amniotic fluid. Serial ultrasound examinations looking
for hydrocephalus, organomegaly, and intracranial calcifications are used to
determine whether fetal infection is causing specific organ system disease.
Maternal antitoxoplasmosis treatment is frequently given in this situation
because it may reduce fetal damage.
Lymphocytic Choriomeningitis Virus
Epidemiology
Lymphocytic choriomeningitis virus (LCMV) is a single-stranded RNA virus that
causes chronic infection in house mice and pet hamsters, which then shed the
virus in the urine and feces. Humans may be infected by direct contact with
excreta or aerosolization of viral particles.
Presentation
It has become increasingly appreciated that LCMV may cause a congenital
infection characterized by periventricular calcification, hydrocephalus, and
chorioretinitis. This may give a symptom complex similar to other congenital
infections, particularly toxoplasmosis or CMV.
Diagnosis
The true incidence of LCMV congenital infection is not known because it is
likely that only the most extreme cases are diagnosed. The diagnosis should be
considered in the neonate with intracranial calcifications or hydrocephalous,
especially if the workup for toxoplasmosis and CMV are negative. Diagnosis is
by immunofluorescent antibody or ELISA.
Management
At the present time, there is no therapy for LCMV. Because of this newly
described syndrome, expectant mothers should be cautioned regarding contact
with mice and other rodents.
Human Immunodeficiency Virus
Epidemiology
A pregnant woman with untreated human immunodeficiency virus (HIV) has an
approximately 20% to 25% chance of giving birth to an infected infant. HIV can
be transmitted transplacentally at any stage of the pregnancy. Most infants are
infected at the time of delivery by exposure to maternal blood and body fluids.
HIV can also be transmitted during the postnatal period through breast-feeding.
HIV antibody crosses the placenta; thus, 100% of infants born to HIV-positive
women are HIV antibody positive. Maternal HIV antibody can persist in the child
for up to 18 months. The only certain statement regarding an HIV antibody–
positive infant is that the mother is infected.
Presentation
There are numerous presentations of the child with HIV infection. Some children
present in the first year of life with severe thrush, organomegaly, and failure
to thrive.
Pneumocystis jiroveci (formerly P. carinii), in a previously thriving infant is a classic presentation and should always
be considered in a child who suddenly develops severe interstitial pneumonia
and respiratory failure. A subset of children with HIV infection remain
relatively well for years, with the only signs being isolated developmental
delay or thrombocytopenia.
Diagnosis
Diagnosis of HIV infection in the infant is made by serum HIV PCR. This test is
obtained at 1 and 4 months of age. If these tests are negative, the child is
assumed uninfected. Positive test at this time indicates that true infection is
likely. Some clinicians follow infants for up to 18 months to document
seroreversion to HIV-negative antibody status.
Ongoing efforts continue to reduce mother-to-child transmission. In 1994, AIDS
Clinical Trial Group (ACTG) 076 was developed. In this protocol, zidovudine
(AZT) was given to the mother starting in the second trimester of pregnancy.
During delivery, intravenous AZT was given to the mother. After delivery, AZT
suspension (10 mg/mL) was given at a dose of 2 mg/kg every 6 hours for 6 weeks.
The transmission rate in this study dropped from 25% to 8%; the study was
stopped early because the statistically and clinically significant findings
could not ethically be kept from the control arm of the study.
During the past 10 years, the development of highly active antiretroviral
therapy (HAART) has led to further reduction in mother-to-child transmission.
Strong consideration for elective cesarean section is given, particularly if
maternal viral load exceeds 5,000 copies/mL. Intravenous AZT continues to be
given at time of delivery. After delivery, oral AZT is given to the child for 6
weeks. The 10 mg/mL suspension is given at a dose of 2 mg/kg orally every 6
hours. Currently, the incidence of transmission under these aggressive
protocols is less than 2%. It is likely that further refinements to reduce
maternal transmission (including additional drugs administered to the infant)
will be developed. Maternal transmission of HIV to infants should be considered
a highly preventable condition. All pregnant women should be counseled about
HIV testing. This ensures the diagnosis of women unaware of their infection and
protection of their unborn children.
Management
If effective protocols for prevention of maternal transmissions are used,
transmission of HIV from mother to child should be less than 2%. The diagnosis
of true HIV infection is made by PCR, showing viral copies of HIV at 1 and 4
months of age. If this indeed is documented, HIV infection is considered to
have occurred in the infant. Protocols for the management of infant HIV
infection are continually revised. Most specialist agree that HAART therapy
should be given once infant HIV infection has been documented. Although
monotherapy is used in the protocols preventing maternal transmission, for
actual treatment of confirmed disease, combination of at least three
antiretroviral drugs should be considered.
Selected Readings
Azimi PH, Janner D, Berne P, et al. Concentrations of procaine and aqueous
penicillin in the cerebrospinal fluid of infants treated for congenital
syphilis.
J Pediatr 1994;124(4):649–653.
Bale JF. Congenital infections. Neurol Clin 2002:20(4):1039–1060.
Bechtel RT, Haught KA, Mets MB. Lymphocytic choriomeningitis virus: a new
addition to the TORCH evaluation.
Arch Ophthalmol 1997;115(5):680–681.
Boyer KM. Diagnostic testing for congenital toxoplasmosis. Pediatr Infect Dis J 2001;20(1):59–60.
Litwin CM, Hill HR. Serologic and DNA-based testing for congenital and perinatal
infections.
Pediatr Infect Dis J 1997;16(12):1166–1175.
McAuley J, Boyer KM, Patel D, et al. Early and longitudinal evaluations of
treated infants and children and untreated historical patients with congenital
toxoplasmosis: the Chicago Collaborative Treatment Trial.
Clin Infect Dis 1994;18(1)38–72.
Michaels MG, Greenberg DP, Sabo DL, et al. Treatment of children with congenital
cytomegalovirus infection with ganciclovir.
Pediatr Infect Dis J 2003;22(6):504–509.
Michelow IC, Wendel GD, Norgard MV, et al. Central nervous system infection in
congenital syphilis.
N Engl J Med 2002;346(23):1792–1798.
Pictures
Book Source Details
- Book Title: Pediatric Infectious Disease
- Author(s): Donald Janner MD
- Year of Publication: 2004
- Copyright Details: Pediatric Infectious Disease, Copyright © 2004 Lippincott Williams & Wilkins.
More About Congenital syphilis
More Medical Textbooks Online about Congenital syphilis
Review other book chapters online related to Congenital syphilis:
Medical Books Excerpts
- Syphilis
- "Professional Guide to Diseases (Eighth Edition)" (2005)
- [ read ]
Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.
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More About This Book:
Title: Pediatric Infectious Disease
Authors: Donald Janner MD
Publisher: Lippincott Williams & Wilkins
Copyright: 2004
ISBN: 0-7817-5584-0
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