Download “Toxoplasmosis, Cytomegalovirus infection, Herpes simplex I, II types”.

Vinnytsia National Pirogov Memorial Medical University
Department of Children Infectious Diseases
“Approved”
at sub-faculty meeting
“__”_____2012, protocol №_____
Head of Department
prof. _______I.I. Nezgoda
STUDY GUIDE FOR INDEPENDENT WORK OF STUDENTS
Topic: “Toxoplasmosis, Cytomegalovirus infection, Herpes simplex I, II
types”.
Course V
English-speaking Students’
Medical Faculty
Composed by assistant O.V. Bodnariuk
Vinnitsa
2012
I. The theme urgency
Toxoplasma infection is ubiquitous in animals and is one of the most common latent infections of humans
throughout the world. The incidence varies considerably among people and animals in different
geographic areas.
Human cytomegalovirus (CMV) is a member of the Herpesviridae family with wide distribution. Most
CMV infections are inapparent, but the virus can cause a variety of clinical illnesses that range in severity
from mild to fatal. CMV is the most common congenital infection, which occasionally causes the
syndrome of cytomegalic inclusion disease (hepatosplenomegaly, jaundice, petechia, purpura, and
microcephaly).
Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) are two species of the herpes virus family,
Herpesviridae, which cause infections in humans.[1] Eight members of herpes virus infect
humans to cause a variety of illnesses including cold sores, chickenpox or varicella, shingles or
herpes zoster (VZV), cytomegalovirus (CMV), and various cancers, and can cause brain
inflammation (encephalitis). All viruses in the herpes family produce life-long infections.
II. Startup aims of the study.
To teach students major methods of Toxoplasmosis, Cytomegalovirus infection, Herpes
simplex I, II types and their treatment.
Student should have knowledge:
1. Etiology and properties of the cause and causing factors of Toxoplasmosis,
Cytomegalovirus infection, Herpes simplex I, II types.
2. Epidemiology (source of infection, ways of transmission, age-old receptivity and
morbidity) theirs.
3. Pathogenesis of disease, pathomorphologic changes in the skin and staggered organs.
4. Classification of clinical forms of herpetic infection.
5. Clinic of typical form of Toxoplasmosis, Cytomegalovirus infection, Herpes simplex I,
II types
6. Complications of Toxoplasmosis, Cytomegalovirus infection, Herpes simplex I, II types.
7. Methods of laboratory research of these infection.
8. Principles of therapy of Toxoplasmosis, Cytomegalovirus infection, Herpes simplex I, II
types.
9. Measures of prophylaxis of Toxoplasmosis, Cytomegalovirus infection, Herpes simplex
I, II types.
A student should be able:
1. To follow the basic rules of work with a patient sick with Toxoplasmosis,
Cytomegalovirus infection, Herpes simplex I, II types
2. To take anamnesis with the estimation of epidemiology information (taking into account
seasonality, origin of febricities, polymorphism of clinical signs of illness).
3. To examine a patient and reveal the basic clinical signs of illness.
4. To represent information of anamnesis and objective inspection in a hospital chart and
formulate the preliminary diagnosis.
5. To write a plan of examination.
6.
7.
8.
9.
To define a clinical diagnosis (form of disease, type, severity, course of disease).
To prescribe the treatment taking into account age, severity of illness.
To write out a prescription.
To organize disease measures in the hearth of infection (to find out the source of
infection, fill an urgent report in SES, to set a quarantine, to define the circle of contact
persons).
10. To write epicrisis with the estimation of development of illness, results of inspection,
efficiency of treatment, prognosis, by recommendations for a subsequent supervision or
treatment depending on the form of Toxoplasmosis, Cytomegalovirus infection, Herpes
simplex I, II types.
11. Perform diagnostic options in patient with Toxoplasmosis, Cytomegalovirus infection,
Herpes simplex I, II types.
12. Make differential diagnosis.
13. Interpret data of laboratory studies.
14. Causes of complications of Toxoplasmosis, Cytomegalovirus infection, Herpes simplex I,
II types in children .
15. Indications for hospitalization of children with Toxoplasmosis, Cytomegalovirus
infection, Herpes simplex I, II types..
16. Principles of treatment of children with Toxoplasmosis, Cytomegalovirus infection,
Herpes simplex I, II types.
17. Discharge from hospital and attendance the children’s institutions by children with
Toxoplasmosis, Cytomegalovirus infection, Herpes simplex I, II types.
III. Educational aims of the study
- forming the deontological presentations, skills of conduct with the patients;
- to develop deontological presentations, be able to carry out deontology approach to the
patient;
- to develop the presentations of influence of ecological and socio-economic factors on the
state of health;
- to develop sense of responsibility for a time illness and loyalty of professional actions;
- to acquire the skills of psychological contact establishment and creation of trusting
relations between the doctor and the patient and his parents;
- the development of responsibility sense for time illness and completeness of patient’s
investigation.
IV.
The questions for self-check:
1. Indexes of morbidity from Toxoplasmosis, Cytomegalovirus infection, Herpes simplex I,
II types in Ukraine.
2. Sources of Toxoplasmosis, Cytomegalovirus infection, Herpes simplex I, II types.
3. The ways of transmission of Toxoplasmosis, Cytomegalovirus infection, Herpes simplex
I, II types in children.
4. Prophylactic measures in the hearth of infection.
5. Conditions necessary for development of Toxoplasmosis, Cytomegalovirus infection,
Herpes simplex I, II types in children.
6.
Duration of incubation period of the Toxoplasmosis, Cytomegalovirus infection, Herpes
simplex I, II types in children.
7. Clinical forms of Toxoplasmosis, Cytomegalovirus infection, Herpes simplex I, II types
in children.
8. Clinical diagnostics of Toxoplasmosis, Cytomegalovirus infection, Herpes simplex I, II
types
9. What clinical forms of Toxoplasmosis, Cytomegalovirus infection, Herpes simplex I, II
types occur in children of early age?
10. Laboratory methods of inspection of the patients with Toxoplasmosis, Cytomegalovirus
infection, Herpes simplex I, II types.
11. What complications occur in children more frequently?
12. Causes of complications of Toxoplasmosis, Cytomegalovirus infection, Herpes simplex
I, II types in children.
13. Indications for hospitalization of children with Toxoplasmosis, Cytomegalovirus
infection, Herpes simplex I, II types.
14. Principles of treatment of children with Toxoplasmosis, Cytomegalovirus infection,
Herpes simplex I, II types.
15. Discharge from hospital and attendance the children’s institutions by children with
Toxoplasmosis, Cytomegalovirus infection, Herpes simplex I, II types.
V. The contents of a theme
Toxoplasma gondii, an obligate intracellular protozoan, is acquired perorally, transplacentally,
or, rarely, parenterally in laboratory accidents; by transfusion; or from a transplanted organ. In the
immunologically normal child, the acute acquired infection may be asymptomatic, cause
lymphadenopathy, or damage almost any organ. Once acquired, the latent encysted organism persists for
the lifetime of the host. In the immunocompromised infant or child, either initial acquisition or
recrudescence of latent organisms often causes signs or symptoms related to the central nervous system
(CNS). Infection acquired congenitally, if untreated, almost always causes signs or symptoms in the
perinatal period or later in life. The most frequent of these signs are due to chorioretinitis and CNS
lesions. However, other manifestations, such as intrauterine growth retardation, fever, lymphadenopathy,
rash, hearing loss, pneumonitis, hepatitis, and thrombocytopenia, also occur. Congenital toxoplasmosis in
infants with human immunodeficiency virus (HIV) infection may be fulminant.
ETIOLOGY.
T. gondii is a coccidian protozoan. Its tachyzoites are oval or crescent-like, multiply only in living
cells, and measure 2-4 × 4-7 mum. Tissue cysts, which are 10-100 mum in diameter, may contain
thousands of parasites and remain in tissues, especially the CNS and skeletal and heart muscle, for the life
of the host. Toxoplasma can multiply in all tissues of mammals and birds, and its disease spectrum is
expressed with remarkable similarity in different host species.
Newly infected cats and other Felidae excrete infectious Toxoplasma oocysts in their feces.
Toxoplasma are acquired by susceptible cats by ingestion of infected meat containing encysted
brandyzoites or by ingestion of oocysts excreted by other recently infected cats. The parasites then
multiply through schizogonic and gametogonic cycles in the distal ileal epithelium of the cat intestine.
Oocysts containing two sporocysts are excreted, and under proper conditions of temperature and
moisture, each sporocyst matures into four sporozoites. For about 2 wk the cat excretes 105 -107
oocysts/day, which, in a suitable environment, may retain their viability for a year or more. Oocysts
sporulate 1-5 days after excretion and are then infectious. Oocysts are killed by drying, boiling, and
exposure to some strong chemicals, but not to bleach. Oocysts have been isolated from soil and sand
frequented by cats, and outbreaks associated with contaminated water have been reported. Oocysts and
tissue cysts are the sources of animal and human infections (Fig. 280-1) .
EPIDEMIOLOGY.
Toxoplasma infection is ubiquitous in animals and is one of the most common latent infections of
humans throughout the world. The incidence varies considerably among people and animals in different
geographic areas. In many areas of the world, approximately 5.35% of pork, 9-60% of lamb, and 0-9% of
beef contain T. gondii organisms. Significant antibody titers have been detected in 50-80% of residents of
some localities and in < 5% in others. A higher prevalence of infection usually occurs in warmer, more
humid climates.
Human infection is usually acquired by the oral route via undercooked or raw meat that contains
cysts or by ingestion of oocysts. Freezing meat to -20°C or heating it to 66°C renders the cysts
noninfectious. Outbreaks of acute acquired infection have occurred in families who have consumed the
same infected food. Except for transplacental infection from mother to fetus and, rarely, by organ
transplantation or transfusion, Toxoplasma are not transmitted from person to person.
Seronegative transplant recipients who receive an organ (e.g., heart or kidney) from seropositive
donors have experienced life-threatening illness requiring therapy. Seropositive recipients may have
increased serologic titers without associated disease.
Congenital Toxoplasmosis.
Transmission to the fetus usually occurs when the infection is acquired by an immunologically
normal mother during gestation. Congenital transmission from immunologically normal women infected
prior to pregnancy is extremely rare. Immunocompromised women who are chronically infected have
transmitted the infection to their fetuses. The incidence of congenital infection in the United States ranges
from 1/1,000 to 1/8,000 live births. The incidence of newly acquired infection in a population of pregnant
women depends on the risk of becoming infected in that specific geographic area and the proportion of
the population that has not been previously infected.
PATHOGENESIS.
T. gondii is usually acquired by children and adults from ingesting food that contains cysts or that
is contaminated with oocysts usually from acutely infected cats. Oocysts also may be transported to food
by flies and cockroaches. When the organism is ingested, bradyzoites are released from cysts or
sporozoites from oocysts, and the organisms then enter gastrointestinal cells. They multiply, rupture cells,
and infect contiguous cells. They are transported via the lymphatics and disseminated hematogenously
throughout the body. Tachyzoites proliferate, producing necrotic focuses surrounded by a cellular
reaction. With the development of a normal immune response (humoral and cell-mediated), tachyzoites
disappear from tissues. In immunodeficient individuals and some apparently immunologically normal
patients, the acute infection progresses and may cause potentially lethal involvement such as pneumonitis,
myocarditis, or necrotizing encephalitis.
In acute acquired lymphadenopathic toxoplasmosis, characteristic lymph node changes include
reactive follicular hyperplasia with irregular clusters of epithelioid histiocytes that encroach on and blur
the margins of germinal centers. Focal distention of sinuses with monocytoid cells also occurs.
Cysts form as early as 7 days after infection and remain for the life span of the host. During latent
infection they produce little or no inflammatory response but cause recrudescent disease in
immunocompromised patients or chorioretinitis in older children who acquired the infection congenitally.
Congenital Toxoplasmosis.
When a mother acquires the infection during gestation, the organism may disseminate
hematogenously to the placenta. When this occurs, infection may be transmitted to the fetus
transplacentally or during vaginal delivery. Of untreated maternal infections acquired in the first
trimester, approximately 17% of fetuses are infected, usually with severe disease. Of untreated maternal
infection acquired in the third trimester, approximately 65% of fetuses are infected, usually with disease
that is mild or inapparent at birth. These different rates of transmission and outcomes are most likely
related to placental blood flow, the virulence and amount of T. gondii acquired, and the immunologic
ability of the mother to restrict parasitemia.
Examination of the placenta of infected newborns may reveal chronic inflammation and cysts.
Tachyzoites can be seen with Wright or Giemsa stains but are best demonstrated with the
immunoperoxidase technique. The tissue cyst stains well with periodic acid-Schiff (PAS) and silver stains
as well as with the immunoperoxidase technique. Gross or microscopic areas of necrosis may be present
in many tissues, especially the central nervous system, choroid and retina, heart, lungs, skeletal muscle,
liver, and spleen. Areas of calcification occur in the brain.
Almost all congenitally infected individuals manifest signs or symptoms of infection, such as
chorioretinitis, by adolescence if they are not treated in the newborn period. Some severely involved
infants with congenital infection appear to have Toxoplasma antigen-specific anergy of their
lymphocytes, which may be important in the pathogenesis of their disease. The predilection to
predominant involvement of the CNS and eye in congenital infection has not been fully explained.
Immunity.
There are profound and prolonged alterations of T-lymphocyte populations during acute acquired
T. gondii infections, but they have not correlated with outcome. Lymphocytosis, increased CD8+ count,
and decreased CD4+ :CD8+ ratio are commonly present. Depletion of CD4+ cells in patients with
acquired immunodeficiency syndrome (AIDS) may contribute to the severe manifestations of
toxoplasmosis seen in these patients.
CLINICAL MANIFESTATIONS.
The manifestations of primary infection with T. gondii are highly variable and influenced
primarily by host immunocompetence. Reactivation of previously asymptomatic congenital
toxoplasmosis is usually manifest as ocular toxoplasmosis.
Acquired Toxoplasmosis.
Immunologically normal children who acquire the infection postnatally may have no clinically
recognizable disease. When clinical manifestations are apparent, they may include almost any
combination of fever, stiff neck, myalgia, arthralgia, maculopapular rash that spares the palms and soles,
localized or generalized lymphadenopathy, hepatomegaly, hepatitis, reactive lymphocytosis, meningitis,
brain abscess, encephalitis, confusion, malaise, pneumonia, polymyositis, pericarditis, pericardial
effusion, and myocarditis. Chorioretinitis, usually unilateral, occurs in approximately 1% of cases.
Symptoms may be present for a few days only or may persist many months. The most common
manifestation is enlargement of one or a few lymph nodes in the cervical region. Cases of Toxoplasma
lymphadenopathy rarely resemble infectious mononucleosis (due to Epstein-Barr virus or
cytomegalovirus), Hodgkin disease, or other lymphadenopathies (Chapter 496) . In the pectoral area in
older girls and women, the nodes may be confused with breast neoplasms. Mediastinal, mesenteric, and
retroperitoneal lymph nodes may be involved.
Involvement of intra-abdominal lymph nodes may be associated with fever and mimic
appendicitis. Nodes may be tender but do not suppurate. Lymphadenopathy may appear and disappear for
as long as 1 to 2 yr.
Most patients with malaise and lymphadenopathy recover spontaneously without antimicrobial
therapy. Significant organ involvement in immunologically normal individuals is uncommon, but some
individuals have suffered significant morbidity.
Ocular Toxoplasmosis.
In the United States and Western Europe, T. gondii has been estimated to cause 35% of cases of
chorioretinitis (Fig. 280-2) . In Brazil, retinal lesions with the appearance of toxoplasmic chorioretinitis
have occurred in multiple members of the same family. Retinal lesions are present in 30% of those who
are seropositive for T. gondii infection in Brazil. Manifestations include blurred vision, photophobia,
epiphora, and, with macular involvement, loss of central vision. Findings due to congenital ocular
toxoplasmosis also include strabismus, microophthalmia, microcornea, cataract, anisometropia, and
nystagmus. Episodic recurrences are common, but precipitating factors have not been defined.
Immunocompromised Persons.
Congenital T. gondii infection in infants with AIDS is usually a fulminant, rapidly fatal disorder,
involving brain and other organs such as the lung and heart. Disseminated T. gondii infections also occur
in older children who are immunocompromised by AIDS, by malignancies and cytotoxic therapy or
corticosteroids, or by immunosuppressive drugs given for organ transplantation. Immunocompromised
individuals experience the clinical forms of Toxoplasma infection that occur in immunologically normal
individuals. Signs and symptoms that are referable to the CNS are the most frequent manifestations of
severe disease (occurring in 50% of patients), although other organs also may be involved, including the
heart, gastrointestinal tract, and testes.
Bone marrow transplant recipients present a special problem because active infection in these
patients is difficult to diagnose. Specific antibody level may not increase in serum or may be absent. In
most instances, active infection occurs in a child with prior evidence of latent infection.
Individuals who have antibodies to T. gondii and HIV infection are at significant risk of
development of toxoplasmic encephalitis, which may be the presenting manifestation of AIDS. In patients
with AIDS, toxoplasmic encephalitis is fatal if not treated. Typical findings of CNS toxoplasmosis in
patients with AIDS include fever, headache, altered mental status, psychosis, cognitive impairment,
seizures and focal neurologic defects, including hemiparesis, aphasia, ataxia, visual field loss, cranial
nerve palsies, and dysmetric or movement disorders. Uncommon findings of CNS involvement include
meningismus, panhypopituitarism, and the syndrome of inappropriate antidiuretic hormone. In adult
patients with AIDS, toxoplasmic retinal lesions are often large with diffuse necrosis and contain many
organisms but little inflammatory cellular infiltrate.
Toxoplasmic encephalitis and congenital toxoplasmosis are a particular problem in
immunocompromised individuals from areas where the incidence of latent infection is high.
Approximately 25-50% of patients with AIDS and Toxoplasma antibodies ultimately experience
toxoplasmic encephalitis in the absence of prophylaxis with trimethoprim-sulfamethoxazole and
treatment of HIV infection with protease inhibitors. The reason only a subpopulation of latently infected
individuals experiences toxoplasmic encephalitis is unknown. A diagnosis of presumptive toxoplasmic
encephalitis in patients with AIDS should prompt a therapeutic trial of medications effective against T.
gondii. Clear clinical improvement within 7-14 days and improvement in findings of neuroradiological
studies within 3 wk after therapy is initiated make the presumptive diagnosis almost certain.
Congenital Toxoplasmosis.
The signs and symptoms associated with acute acquired T. gondii infection in the pregnant
woman are the same as those seen in the immunologically normal child, most commonly
lymphadenopathy. Congenital infection also may be transmitted by an asymptomatic immunosuppressed
woman (e.g., those treated with corticosteroids and those with HIV infection).
GENETICS.
In monozygotic twins the clinical pattern of involvement is most often similar, whereas in
dizygotic twins manifestations often differ. In dizygotic twins severe manifestations in one twin have led
to a diagnosis of subclinical disease in the other twin. Also, congenital infection has occurred in only one
twin of a pair of dizygotic twins. The major histocompatibility complex (MHC) class II gene DQ3
appears to be more frequent in patients seropositive for T. gondii infection with AIDS and toxoplasmic
encephalitis than in patients seropositive for T. gondii infection with AIDS who do not have toxoplasmic
encephalitis, and in children with congenital toxoplasmosis and hydrocephalus as compared with those
without hydrocephalus.
SPECTRUM AND FREQUENCY OF SIGNS AND SYMPTOMS.
Congenital infection may present as a mild or severe neonatal disease, with onset during the 1st
month of life, or with sequelae or relapse of a previously undiagnosed infection at any time during
infancy or later in life. A wide variety of manifestations of congenital infection occur in the perinatal
period. These range from relatively mild signs, such as small size for gestational age, prematurity,
peripheral retinal scars, persistent jaundice, mild thrombocytopenia, and cerebrospinal fluid pleocytosis,
to the classic triad of signs consisting of chorioretinitis, hydrocephalus, and cerebral calcifications.
Infection may result in erythroblastosis, hydrops fetalis, and perinatal death. More than half of
congenitally infected infants are considered normal in the perinatal period, but almost all such children
will have ocular involvement later in life. Neurologic signs in neonates, which include convulsions,
setting-sun sign, and an increase in head circumference due to hydrocephalus, may be associated with
substantial cerebral damage. However, such signs also may occur in association with encephalitis without
extensive destruction or with relatively mild inflammation adjacent to and obstructing the aqueduct of
Sylvius. If such infants are treated promptly, signs and symptoms may resolve, and they may develop
normally.
The spectrum and frequency of manifestations that develop in the perinatal period in infants with
congenital Toxoplasma infection are presented in Table 280-1 . Infection in most of these 210 infants was
initially suspected because their mothers were identified by a serologic screening program that detected
pregnant women with acute acquired T. gondii infection. Twenty-one infants (10%) had severe congenital
toxoplasmosis with CNS involvement, eye lesions, and general systemic manifestations. Seventy-one
(34%) had mild involvement with normal clinical examination results other than retinal scars or isolated
intracranial calcifications. One hundred and sixteen (55%) had no detectable manifestations; this may
reflect the difficulties associated with funduscopic examination of the peripheral retina in infants and
young children. These figures represent an underestimation of the relative frequency of severe congenital
infection for the following reasons: The most severe cases, including most of those individuals who died,
were not referred; therapeutic abortion was often performed when acute acquired infection of the mother
was diagnosed early during pregnancy; in utero spiramycin therapy may have diminished the severity of
infection; and only 13 infants had CT brain scans and 23% did not have a cerebrospinal fluid
examination. Routine newborn examinations often yield normal findings for congenitally infected infants,
but more careful evaluations may reveal significant abnormalities: Specifically, of 28 infants who were
detected by a universal state mandated serologic screening program for T. gondii-specific
immunoglobulin M (IgM), 26 had normal findings of routine newborn examinations and 14 had
significant abnormalities detected with more careful evaluation. These abnormalities included retinal
scars (7 infants), active chorioretinitis (3 infants), and CNS abnormalities (8 infants).
The clinical spectrum and natural history of untreated congenital toxoplasmosis, which is
clinically apparent in the first year of life, are presented in Table 280-2 . More than 80% of these children
had IQ of less than 70, and many had convulsions and severely impaired vision.
SKIN.
Cutaneous manifestations in infants with congenital toxoplasmosis include rashes, petechiae,
ecchymoses, or large hemorrhages secondary to thrombocytopenia. Rashes may be fine punctate, diffuse
maculopapular, lenticular, deep blue-red, sharply defined macular, and diffuse blue papules. Macular
rashes involving the entire body, including the palms and soles; exfoliative dermatitis; and cutaneous
calcifications have been described. Jaundice due to hepatic involvement with T. gondii and/or hemolysis,
cyanosis due to interstitial pneumonitis from congenital infection, and edema secondary to myocarditis or
nephrotic syndrome may be present. Jaundice and conjugated hyperbilirubinemia may persist for months.
SYSTEMIC SIGNS.
From 25% to more than 50% of infants with clinically apparent disease at birth are born
prematurely. Low Apgar scores also are common. Intrauterine growth retardation and instability of
temperature regulation may occur. Other systemic manifestations include lymphadenopathy,
hepatosplenomegaly, myocarditis, pneumonitis, nephrotic syndrome, vomiting, diarrhea, and feeding
problems. Bands of metaphyseal lucency and irregularity of the line of provisional calcification at the
epiphyseal plate may occur without periosteal reaction in the ribs, femurs, and vertebrae. Congenital
toxoplasmosis may be confused with isosensitization causing erythroblastosis fetalis; the Coombs test
result is usually negative with congenital T. gondii infection.
ENDOCRINE ABNORMALITIES.
Endocrine abnormalities may occur secondary to hypothalamic or pituitary involvement or endorgan involvement. The following have been reported: myxedema, persistent hypernatremia with
vasopressin-sensitive diabetes insipidus without polyuria or polydipsia, sexual precocity, and partial
anterior hypopituitarism.
CENTRAL NERVOUS SYSTEM.
Neurologic manifestations of congenital toxoplasmosis vary from massive acute encephalopathy
to subtle neurologic syndromes. Toxoplasmosis should be considered as a cause of any undiagnosed
neurologic disease in children < 1 yr of age, especially if retinal lesions are present.
Hydrocephalus may be the sole clinical neurologic manifestation of congenital toxoplasmosis and
may either be compensated or require shunt placement. Hydrocephalus may present in the perinatal
period, progress after the perinatal period, or, less commonly, present later in life. Patterns of seizures are
protean and have included focal motor seizures, petit and grand mal seizures, muscular twitching,
opisthotonus, and hypsarrhythmia (which may resolve with corticotropin [ACTH] therapy). Spinal or
bulbar involvement may be manifested by paralysis of the extremities, difficulty in swallowing, and
respiratory distress. Microcephaly usually reflects severe brain damage, but some children with
microcephaly due to congenital toxoplasmosis who have been treated appear to function normally in the
early years of life. Untreated congenital toxoplasmosis that is symptomatic in the first year of life can
cause substantial diminution in cognitive function and developmental delays. Intellectual impairment also
occurs in some children with subclinical infection despite treatment with pyrimethamine and
sulfonamides for 1 mo. Seizures and focal motor defects may become apparent after the newborn period,
even when infection is subclinical at birth.
Cerebrospinal fluid (CSF) abnormalities occur in at least one third of infants with congenital
toxoplasmosis. Local production of T. gondii-specific antibodies may be demonstrated in CSF fluid of
congenitally infected individuals (see later under Diagnosis). CT scan of the brain with contrast
enhancement is useful to detect calcifications, determine ventricular size, image active inflammatory
lesions and demonstrate porencephalic cystic structures (Fig. 280-3) . Calcifications occur throughout the
brain, but there appears to be a special propensity for development of such lesions in the caudate nucleus
(i.e., especially basal ganglia area), choroid plexus, and subependyma. Ultrasonography may be useful for
following ventricular size in congenitally infected babies. Magnetic resonance imaging (MRI), CT with
contrast enhancement, and radionucleotide brain scans may be useful for detecting active inflammatory
lesions.
EYES.
Almost all untreated congenitally infected individuals will develop chorioretinal lesions by
adulthood, and about 50% will have severe visual impairment. T. gondii causes a focal necrotizing
retinitis in congenitally infected individuals (see Fig. 280-2) . Retinal detachment may occur. Any part of
the retina may be involved, either unilaterally or bilaterally, including the maculae. The optic nerve may
be involved, and toxoplasmic lesions that involve projections of the visual pathways in the brain or the
visual cortex also may lead to visual impairment. In association with retinal lesions and vitritis, the
anterior uvea may be intensely inflamed, leading to erythema of the external eye. Other ocular findings
include cells and protein in the anterior chamber, large keratic precipitates, posterior synechiae, nodules
on the iris, and neovascular formation on the surface of the iris, sometimes with an associated increase in
intraocular pressure and development of glaucoma. The extraocular musculature may also be involved
directly. Other manifestations include strabismus, nystagmus, visual impairment, and micro-ophthalmia.
The differential diagnosis of lesions resembling those of ocular toxoplasmosis includes congenital
colobomatous defect and other inflammatory lesions due to cytomegalovirus, Treponema pallidum,
Mycobacterium tuberculosis, or vasculitis. Ocular toxoplasmosis is a recurrent and progressive disease
that requires multiple courses of therapy. Couvreur et al. report limited data that suggest that occurrence
of lesions in the early years of life may be prevented by instituting antimicrobial treatment (with
pyrimethamine and sulfonamides in alternate months with spiramycin) during the first year of life. Brzin
et al. have noted that treatment of the infected fetus in utero followed by treatment in the first year of life
with pyrimethamine, sulfadiazine and leukovorin reduces the incidence and the severity of the retinal
disease.
EARS.
Sensorineural hearing loss, both mild and severe, may occur. It is not known whether this is a
static or progressive disorder. Treatment in the first year of life is associated with diminished occurrence
of this sequela.
CONCOMITANT INFECTIONS.
Congenital toxoplasmosis in infants with HIV infection usually presents as a severe and fulminant
illness with substantial CNS involvement but also may be more indolent in its presentation with focal
neurologic deficits or systemic manifestations such as pneumonitis.
DIAGNOSIS.
Diagnosis of acute Toxoplasma infection can be established by isolation of T. gondii from blood
or body fluids and also by demonstration of tachyzoites in sections or preparations of tissues and body
fluids, cysts in the placenta or tissues of a fetus or newborn, and characteristic lymph node histologic
features. Serologic tests also are very useful for diagnosis.
Culture.
Organisms are isolated by inoculation of body fluids, leukocytes, or tissue specimens into mice or
tissue cultures. Body fluids should be processed and inoculated immediately, but T. gondii has been
isolated from tissues and blood that have been stored at 4°C overnight. Freezing or treatment of
specimens with formalin kills T. gondii. Six to 10 days after inoculation into mice, or earlier if mice die,
peritoneal fluids should be examined for tachyzoites. If they survive for 6 wk and there is antibody in sera
of the inoculated mouse, definitive diagnosis is made by visualization of Toxoplasma cysts in mouse
brain. If cysts are not seen, subinoculations of mouse tissue into other mice are performed.
Microscopic examination of tissue culture inoculated with T. gondii shows necrotic, heavily
infected cells with numerous extracellular tachyzoites. Isolation of T. gondii from blood or body fluids
reflects acute infection. Except in the fetus or neonate it is usually not possible to distinguish acute from
past infection by isolation of T. gondii from tissues such as skeletal muscle, lung, brain, or eye obtained
by biopsy or at autopsy.
Diagnosis of acute infection can be made by demonstration of tachyzoites in biopsy tissue
sections, bone marrow aspirate, or body fluids such as CSF or amniotic fluid. Immunofluorescent
antibody and immunoperoxidase staining techniques may be necessary because it is often difficult to see
the tachyzoite with ordinary stains. Tissue cysts are diagnostic of infection but do not differentiate
between acute and chronic infection; the presence of many cysts suggests recent acute infection. Cysts in
the placenta or tissues of the newborn infant establish the diagnosis of congenital infection. Characteristic
histologic features strongly suggest the diagnosis of toxoplasmic lymphadenitis.
Serologic Testing.
Multiple serologic tests may be necessary to confirm the diagnosis of congenital or acutely
acquired Toxoplasma infection. Each laboratory that reports serologic test results must have established
values for their tests that diagnose infection in specific clinical settings, provide interpretation of their
results, and assure appropriate quality control before therapy is based on serologic test results. Serologic
test results used as the basis for therapy should be confirmed in a reference laboratory.
The Sabin-Feldman dye test is sensitive and specific. It measures primarily IgG antibodies.
Results should be expressed in international units (IU/mL), based on international standard reference sera
available from the World Health Organization.
The IgG indirect fluorescent-antibody (IgG-IFA) test measures the same antibodies as the dye
test, and the titers tend to be parallel. These antibodies usually appear 1-2 wk after infection, reach high
titers (
1:1,000) after 6-8 wk, and then decline over months to years. Low titers (1:4 to 1:64) usually
persist for life. Antibody titer does not correlate with severity of illness. Approximately half of the
commercially available IFA kits for T. gondii have been found to be improperly standardized and may
yield significant numbers of false-positive and false-negative results.
An agglutination test (Bio-Merieux, Lyon, France) that is available commercially in Europe uses
formalin-preserved whole parasites to detect IgM antibodies. This test is accurate, simple to perform, and
inexpensive.
The IgM indirect fluorescent antibody (IgM-IFA) test is useful for the diagnosis of acute infection
with T. gondii in the older child because IgM antibodies appear earlier (often by 5 days after infection)
and disappear sooner than IgG antibodies. In most instances, antibodies detected by the test rise rapidly
(to levels of 1:50 to <1:1,000) and fall to low titers (1:10 or 1:20) or disappear after weeks or months.
However, some patients continue to have positive results at low titers for as long as several years. The
IgM-IFA test detects Toxoplasma-specific IgM in only approximately 25% of congenitally infected
infants at birth. IgM antibodies also are often not present in sera of immunodeficient patients with acute
toxoplasmosis or in most patients with active toxoplasmosis present only in the eye. The IgM-IFA test
may yield false-positive results as a result of rheumatoid factor.
The double-sandwich enzyme-linked immunosorbent assay (ELISA) is more sensitive and
specific than the IgM-IFA test for detection of Toxoplasma IgM antibodies. In the older child, a level of
IgM antibodies against Toxoplasma in serum of 2.0 or greater (value of one reference laboratory; each
laboratory must establish its own values) indicates that Toxoplasma infection has most likely been
acquired recently. IgM-ELISA detects approximately 75% of infants with congenital infection. IgMELISA avoids both the false-positive results due to rheumatoid factor and false-negative results due to
high levels of passively transferred maternal IgG antibody in fetal serum, as occurs in the IgM-IFA test.
Results obtained with commercial kits must be interpreted with caution since false-positive reactions are
not infrequent. Care must also be taken to determine whether the kits have been standardized for
diagnosis of infection in specific clinical settings (e.g., in the newborn infant). The IgA ELISA is a more
sensitive test than the IgM ELISA for detection of congenital infection in the fetus and newborn as well
as for detection of acute infection in some pregnant women.
The immunosorbent agglutination assay (ISAGA) combines trapping of a patient's IgM to a solid
surface and use of formalin-fixed organisms or antigen-coated latex particles. It is read as an
agglutination test. There are no false-positive results due to rheumatoid factor or antinuclear antibodies.
IgM antibodies to Toxoplasma are detected by the IgM-IFA test for a shorter time than they are by the
IgM-ELISA. The IgM ISAGA is more sensitive than the IgM ELISA and may detect specific IgM
antibodies before and for longer periods than the IgM ELISA. At present, IgM ISAGA is the best test for
diagnosis of congenital infection in the newborn. The IgE ELISA and IgE ISAGA are also useful in
establishing the diagnosis of congenital toxoplasmosis or acute acquired T. gondii infection.
The differential agglutination test (HS/SC) compares antibody titers obtained with formalin-fixed
tachyzoites (HS antigen) with titers obtained using acetone- or methanol-fixed tachyzoites (AC antigen)
to differentiate recent and remote infections in adults and older children. This method may be particularly
useful in differentiating remote infection in pregnant women, since levels of IgM and IgA antibodies
detectable by ELISA or ISAGA may remain elevated for prolonged periods (e.g., months to years in
adults and older children).
The indirect hemagglutination (IHA) test measures different T. gondii antibodies from those
measured in the IFA and dye tests. They may persist for years. However, the IHA test should not be used
in infants with suspected congenital infection or in screening for infection acquired during pregnancy
because it may be negative for too long a period early during infection.
A relatively higher level of Toxoplasma antibody in the aqueous humor or in cerebrospinal fluid
demonstrates local production of antibody during active ocular or CNS toxoplasmosis. This comparison is
calculated as follows:Significant correlation coefficients [C] are 8 or more (eye), 4 or more (CNS for
congenital infection), and over 1 (CNS for patients with AIDS). If the serum dye test titer is 300 IU/mL or
more, most often it is not possible to demonstrate significant local antibody production using this formula
with either the dye test or the IgM-IFA test titer. IgM antibody may be present in CSF.
Toxoplasma antigen has been detected during acute Toxoplasma infection but not in sera of
uninfected or chronically infected individuals. Antigen was present in the serum, amniotic fluid, and
cerebrospinal fluid in the few infants tested with congenital infections.
Comparative Western immunoblot tests of sera from a mother and baby may detect congenital
infection. Infection is suspected when the mother's serum and her baby's serum contain antibodies that
react with different Toxoplasma antigens.
Enzyme-linked immunofiltration assay (ELIFA), using micropore membranes, permits
simultaneous study of antibody specificity by immunoprecipitation and characterization of antibody
isotypes by immunofiltration with enzyme-labeled antibodies. This method may be capable of detecting
85% of cases of congenital infection in the first few days of life. It is still being evaluated.
Polymerase chain reaction (PCR) is used to amplify the DNA of T. gondii, which then can be
detected by using a DNA probe. Detection of a repetitive T. gondii gene, the B1 gene, in amniotic fluid is
the procedure of choice for establishing the diagnosis of congenital Toxoplasma infection in the fetus.
The sensitivity and specificity of this test using amniotic fluid obtained at
18 weeks gestation are approximately 95%. PCR of vitreous fluid has been used to diagnose
ocular toxoplasmosis.
Lymphocyte blastogenesis to Toxoplasma antigens has been used to diagnose congenital
toxoplasmosis if a question persists concerning the diagnosis and other test results are negative. However,
a negative result does not exclude the diagnosis, as many infected infants do not respond to T. gondii
antigens in the newborn period.
Acquired Toxoplasmosis.
Recent infection is diagnosed by seroconversion from a negative to a positive IgG antibody titer
(in the absence of transfer of antibody by transfusion); a serial two-tube rise in Toxoplasma-specific IgG
titer when sera are obtained 3 wk apart and tested in parallel; or the presence of Toxoplasma-specific IgM
antibody.
Ocular Toxoplasmosis.
IgG antibody titers of 1:4 to 1:64 are usual in older children with active toxoplasmic
chorioretinitis. When the retinal lesions are characteristic and serologic tests findings are positive, the
diagnosis is likely. PCR of vitreous fluid has been used to diagnose ocular toxoplasmosis but is
infrequently performed because of the risks associated with obtaining vitreous fluid.
Immunocompromised Persons.
IgG antibody titers may be low, and Toxoplasma-specific IgM is often absent in
immunocompromised individuals with toxoplasmosis. Demonstration of Toxoplasma antigens or DNA in
serum, blood, and CSF may identify disseminated Toxoplasma infection in immunocompromised
persons.
Resolution of CNS lesions during a therapeutic trial of pyrimethamine and sulfadiazine has been
useful in patients with AIDS. Brain biopsy has been used to establish the diagnosis of toxoplasmic
encephalitis when there is no response to this therapeutic trial or to exclude other likely diagnoses.
Congenital Toxoplasmosis.
Fetal ultrasound examination, performed every 2 wk during gestation, and PCR analysis of
amniotic fluid are used for prenatal diagnosis. T. gondii may also be isolated from the placenta.
Serologic tests are the most useful in establishing a diagnosis of congenital toxoplasmosis. Either
persistent or rising titers in the dye or IFA test or a positive IgM ELISA or ISAGA result is diagnostic of
congenital toxoplasmosis. The half-life of IgM is 3-5 days, so if there is a placental leak, the level of IgM
antibodies in the infant's serum falls significantly within 1-2 wk. Passively transferred maternal IgG
antibodies may require many months to a year to disappear from the infant's serum, depending on the
magnitude of the original titer. Synthesis of Toxoplasma antibody is usually demonstrable by the third
month of life if the infant is untreated. If the infant is treated, synthesis may be delayed until the ninth
month of life, and, infrequently, it may not occur at all. When an infant begins to synthesize antibody,
infection may be documented serologically even without demonstration of IgM antibodies by a rise in the
ratio of specific serum antibody titer to the total IgG, whereas the ratio will fall if the specific antibody
has been passively transferred from the mother.
At birth, when a diagnosis of congenital toxoplasmosis is suspected, the following diagnostic
studies should be performed: general, ophthalmologic, and neurologic examinations; head CT scan;
attempt to isolate T. gondii from the placenta and the infant's white blood cells from umbilical cord blood
and buffy coat; measurement of serum Toxoplasma-specific IgG, IgM, IgA, and IgE antibodies and the
total amount of IgM and IgG in serum; lumbar puncture including analysis of CSF for cells, glucose,
protein, Toxoplasma-specific IgG and IgM antibodies, and total amount of IgG; and evaluations of CSF
for T. gondii by PCR and inoculation into mice. The presence of Toxoplasma-specific IgM in CSF that is
not contaminated with blood, or local antibody production of Toxoplasma-specific IgG antibody
demonstrated in CSF establishes the diagnosis of congenital Toxoplasma infection.
Many manifestations of congenital toxoplasmosis occur in other perinatal diseases, especially
disease caused by cytomegalovirus. Neither cerebral calcification nor chorioretinitis is pathognomonic.
Fewer than 50% of children < 5 yr of age with chorioretinitis satisfy the serologic criteria for congenital
toxoplasmosis; the causes of most of the other cases are unknown. The clinical picture in the newborn
infant may also be compatible with sepsis, aseptic meningitis, syphilis, or hemolytic disease.
TREATMENT.
Pyrimethamine plus sulfadiazine or trisulfapyrimidines act synergistically against Toxoplasma.
Combined therapy is indicated to treat many of the forms of toxoplasmosis. However, use of
pyrimethamine is contraindicated during the first trimester of pregnancy. Spiramycin should be used to
prevent transmission of infection to the fetus of acutely infected pregnant women and to treat congenital
toxoplasmosis. Pyrimethamine inhibits the enzyme dihydrofolate reductase (DHFR), and thus the
synthesis of folic acid, and therefore produces a dose-related, reversible, and usually gradual depression
of the bone marrow, resulting in thrombocytopenia, leukopenia, and anemia. Neutropenia is the most
common side effect in treated infants. All patients treated with pyrimethamine should have platelet and
white blood cell counts twice weekly. Seizures may occur with overdosage of pyrimethamine. Folinic
acid (calcium leukovorin) should always be administered concomitantly with pyrimethamine to prevent
suppression of the bone marrow. Potential toxic effects of sulfonamides (e.g., crystalluria, hematuria, and
rash) should be monitored. Hypersensitivity reactions occur, especially in patients with AIDS.
Acquired Toxoplasmosis.
Patients with lymphadenopathy do not need specific treatment unless they have severe and
persistent symptoms or evidence of damage to vital organs. If such signs and symptoms occur, treatment
with pyrimethamine, sulfadiazine, and leukovorin should be initiated. Patients who appear to be
immunologically normal but have severe and persistent symptoms or damage to vital organs (e.g.,
chorioretinitis, myocarditis) need specific therapy until these specific symptoms resolve, followed by
therapy for an additional 2 wk. This therapy usually lasts for at least 4-6 wk; the optimal duration of
therapy is unknown. A loading dose of pyrimethamine for older children is 2 mg/kg/24 hr (maximum 50
mg), given for the first 2 days of treatment. The maintenance dose is 1 mg/kg/24 hr(maximum: 25 mg/24
hr). Folinic acid is administered orally at a dosage of 5-20 mg three times/wk (or even daily depending on
the white blood cell count). Sulfadiazine or trisulfapyrimidine is administered to children >1 yr of age
with a loading dose of 75 mg/kg/24 hr followed by 50 mg/kg/24 hr.
Ocular Toxoplasmosis.
Patients with ocular toxoplasmosis are usually treated with pyrimethamine, sulfadiazine, and
leukovorin for approximately 1 wk after the lesion develops a quiescent appearance (i.e., sharp borders
and associated inflammatory cells in the vitreous resolve), which usually occurs in 2-4 wk. Within 7-10
days the borders of the retinal lesions sharpen, and visual acuity usually returns to that noted before
development of the acute lesion. Systemic corticosteroids have been administered concomitantly with
antimicrobial treatment when lesions involve the macula, optic nerve head, or papillomacular bundle.
Photocoagulation has been used to treat active lesions and prevent spread (i.e., most new lesions appear
contiguous to old ones). Occasionally vitrectomy and removal of the lens are needed to restore visual
acuity.
Immunocompromised Persons.
Serologic evidence of acute infection in an immunocompromised patient, regardless of whether
signs and symptoms of infection are present or tachyzoites are present in tissue, are indications for
therapy similar to that described for immunocompetent children with symptoms of organ injury. It is
important to establish the diagnosis as rapidly as possible and institute treatment early. In
immunocompromised patients other than those with AIDS, therapy should be continued for at least 4-6
wk beyond complete resolution of all signs and symptoms of active disease. Careful follow-up
observation of these patients is imperative because relapse may occur, requiring prompt reinstitution of
therapy. Relapse is frequent in patients with AIDS, and suppressive therapy with pyrimethamine and
sulfonamides should be continued for life. Therapy usually induces a beneficial response clinically, but it
does not eradicate cysts from the CNS and perhaps not from other tissues either. Prophylactic treatment
with trimethroprim-sulfamethoxazole for Pneumocystis carinii pneumonia appears to reduce the
incidence of toxoplasmosis in patients with AIDS.
Treatment of Congenital Toxoplasmosis.
All infected newborns should be treated, whether or not they have clinical manifestations of the
infection. In infants with congenital infection, treatment may be effective in interrupting acute disease
that damages vital organs. Infants should be treated for 1 yr with oral pyrimethamine (1-2 mg/kg/24 hr for
2 days, then 1 mg/kg/24 hr for 2 mo or 6 mo, then 1 mg/kg/24 hr Monday, Wednesday, and Friday),
sulfadiazine or triple sulfonamides (100 mg/kg/24 hr loading dose, then 100 mg/kg/24 hr divided in 2
doses) and calcium leukovorin (5-10 mg/kg/24 hr Monday, Wednesday, and Friday). In the U.S. National
Collaborative Study, the relative efficacy in reducing sequelae of infection and the safety of treatment,
with 2 versus 6 months of the higher dosage of pyrimethamine are being compared. Pyrimethamine,
available only in tablet form, may be crushed and administered in a suspension with juice or food. The
effectiveness of these regimens has not been proved, but they are considered reasonable empirical
recommendations. Information concerning the U.S. National Colloborative Study evaluating these
regimens can be obtained from Dr. Rima McLeod by calling (773)-834-4152. Prednisone (1 mg/kg/24 hr
orally in divided doses) has been utilized in addition when active chorioretinitis involves the macula or
the CSF protein is
1,000 mg/dL at birth, but its efficacy also is not established.
Treatment of Pregnant Women with T. gondii Infection.
The immunologically normal pregnant woman who acquired T. gondii before conception does not
need treatment to prevent congenital infection of her fetus. Although data are not available to allow for a
definitive time interval, if infection occurs in the 6 mo prior to conception, it is reasonable to evaluate the
fetus and treat to prevent congenital infection in the fetus in the same manner as described for the acutely
infected pregnant patient. Treatment of a pregnant woman who acquires infection at any time during
pregnancy reduces the chance of congenital infection in her infant by approximately 60%. The
medications used are spiramycin and pyrimethamine in combination with sulfadiazine or triple
sulfonamides. Spiramycin is available in the United States through the FDA (telephone 302-443-7580).
Because pyrimethamine is potentially teratogenic, spiramycin is administered in the 1st trimester. The
dose of spiramycin is 1 g each 8 hr given without food; lower doses are less effective. Toxicity is
infrequent. Adverse reactions include paresthesias, rash, nausea, vomiting, and diarrhea. Treatment during
the remainder of pregnancy with pyrimethamine and a sulfonamide should be continued at dosages
similar to those recommended for therapy of the symptomatic immunocompetent patient with acquired
toxoplasmosis. Treatment of the mother of an infected fetus with pyrimethamine and a sulfonamide
reduces infection in the placenta and the severity of disease in the newborn.
The approach in France to congenital toxoplasmosis includes systematic serologic screening of all
women of childbearing age and again intrapartum. Mothers with acute infection are treated with
spiramycin, which decreases the transmission from 60% to 23%. Ultrasound and amniocentesis for PCR
after 18 wk gestation are used for fetal diagnosis; they have 97% sensitivity and 100% specificity. Fetal
infection is treated with pyrimethamine and sulfadiazine, or by termination of pregnancy. This strategy
has excellent outcome with normal development of children. Only 19% have subtle findings of congenital
infection, including intracranial calcifications (13%) and chorioretinal scars (6%), although 39% have
chorioretinal scars detected at follow-up observation during later childhood.
Chronically infected pregnant women who have been immunocompromised by cytotoxic drugs or
corticosteroid therapy have transmitted T. gondii to their fetuses. Such women should be treated with
spiramycin throughout gestation. The best approach to prevention of congenital toxoplasmosis in the fetus
of a pregnant woman with HIV infection and inactive T. gondii infection is unknown. If the pregnancy is
not terminated, the mother should be treated with spiramycin during the first 17 wk of gestation and then
with pyrimethamine and sulfadiazine until term. In a study of adult patients with AIDS, a dose of 75 mg
pyrimethamine/24 hr and high dosages of intravenously administered clindamycin (1,200 mg every 6 hr
intravenously) appeared equal in efficacy to sulfonamides and pyrimethamine. Other currently
experimental agents include the macrolides roxithromycin and azithromycin.
PROGNOSIS.
Early institution of specific treatment for congenitally infected infants usually cures the
manifestations of toxoplasmosis such as active chorioretinitis, meningitis, encephalitis, hepatitis,
splenomegaly, and thrombocytopenia. Hydrocephalus due to aqueductal obstruction may develop or
become worse during therapy. Such treatment also may reduce the incidence of some sequelae, such as
diminished cognitive or abnormal motor function. Without therapy, chorioretinitis often recurs. Children
with extensive involvement at birth may function normally later in life or have mild to severe impairment
of vision, hearing, cognitive function, and other neurologic functions. Delays in diagnosis and therapy,
perinatal hypoglycemia, hypoxia, hypotension, repeated shunt infections, and severe visual impairment
are associated with a poorer prognosis. The prognosis is guarded but is not necessarily poor for infected
babies. Treatment with pyrimethamine and sulfadiazine does not eradicate the encysted parasite. No
protective vaccine is available.
PREVENTION.
Methods of prevention are outlined in Figure 280-1 . Counseling women about these methods of
preventing transmission of T. gondii during pregnancy can substantially reduce acquisition of infection
during gestation. Women who do not have specific antibody to T. gondii prior to pregnancy should only
eat well cooked meat during pregnancy and avoid contact with oocysts excreted by cats. Cats that are kept
in-doors, maintained on prepared diets, and not fed fresh, uncooked meat should not contact encysted T.
gondii or shed oocysts. Serologic screening, ultrasound monitoring, and treatment of pregnant women
during gestation can also reduce the incidence and manifestations of congenital toxoplasmosis.
Human cytomegalovirus (CMV) is a member of the Herpesviridae family with wide distribution.
Most CMV infections are inapparent, but the virus can cause a variety of clinical illnesses that range in
severity from mild to fatal. CMV is the most common congenital infection, which occasionally causes the
syndrome of cytomegalic inclusion disease (hepatosplenomegaly, jaundice, petechia, purpura, and
microcephaly). In immunocompetent adults, the infection is occasionally characterized by a
mononucleosis-like syndrome. In immunosuppressed individuals, including recipients of transplants and
patients with AIDS, CMV pneumonitis, retinitis, and gastrointestinal disease are common and can be
fatal.
Primary infection occurs in a seronegative, susceptible host. Recurrent infection represents
reactivation of latent infection or reinfection in a seropositive immune host. Disease may result from
primary or recurrent CMV infection, but the former is a more common cause of severe disease.
ETIOLOGY.
CMV is the largest of the herpesviruses, with a genome of 240 kb and a virus diameter of 200 nm.
It contains double-stranded DNA in a 64-nm core enclosed by an icosahedral capsid composed of 162
capsomers. The core is assembled in the nucleus of the host cells. The capsid is surrounded by a poorly
defined amorphous tegument, which is itself surrounded by a loosely applied, lipid-containing envelope.
The envelope is acquired during the budding process through the nuclear membrane into a cytoplasmic
vacuole, which contains the protein components of the envelope. Mature viruses exit the cells by reverse
pinocytosis. Serologic tests do not define specific serotypes. In contrast, restriction endonuclease analysis
of CMV DNA shows that, although all known human strains are genetically homologous, none are
identical unless they were obtained from epidemiologically related cases.
EPIDEMIOLOGY.
Seroepidemiologic surveys demonstrate CMV infection in every population examined worldwide.
The prevalence of infection, which increases with age, is higher in developing countries and among lower
socioeconomic strata of the more developed nations. Transmission sources of CMV include saliva, breast
milk, cervical and vaginal secretions, urine, semen, stools, and blood. The spread of CMV requires very
close or intimate contact because it is very labile. Transmission occurs by direct person-to-person contact,
but indirect transmission is possible via contaminated fomites.
The incidence of congenital infection ranges from 0.2-2.4% of all live births, with the higher rates
in populations with a lower standard of living. The fetus may become infected as a consequence of
primary and recurrent maternal infection. The risk for fetal infection is greatest with maternal primary
CMV infection (40%) and much less likely with recurrent infection (< 1%). In the United States, from 14% of pregnant women acquire primary CMV infection, with as many as 8,000 newborns with
neurodevelopmental sequelae associated with congenital CMV infection.
Perinatal transmission is common, reaching 10-60% by 6 mo of age. The most important sources
of virus are genital tract secretions at delivery and breast milk. Infected infants excrete virus for years in
saliva and urine.
After the 1st year of life, the prevalence of infection is dependent on group activities, with childcare centers contributing to the rapid spread of CMV in childhood. Infection rates of 50-80% during
childhood are common. For children who are not exposed to other toddlers, the rate of infection increases
very slowly throughout the first decade of life. A second peak occurs in adolescence as a result of sexual
transmission. Seronegative child-care workers and parents of young children shedding CMV have a 1020% annual risk of acquiring CMV, which contrasts with 1-3% per year for the general population.
Health care providers are not at increased risk for acquiring CMV infection from patients.
Nosocomial infection is a hazard of transfusion of blood and blood products. In a population with a 50%
prevalence of CMV infection, the risk has been estimated at 2.7% per unit of whole blood. Leukocyte
transfusions pose a much greater risk. Infection is usually asymptomatic, but even in well children and
adults there is a risk of disease if the recipient is seronegative and receives multiple units.
Immunocompromised patients and seronegative premature infants have a much higher (10-30%)
risk of disease. CMV infection is transmitted in transplanted organs (e.g., kidney, heart, and bone
marrow). After transplantation, many patients excrete CMV as a result of infection acquired from the
donor organ or from reactivation of latent infection caused by immunosuppression. Seronegative
recipients of organs from seropositive donors are at greatest risk for severe disease.
PATHOGENESIS.
Cytomegalic cells are strikingly enlarged epithelial or mesenchymal cells with large intranuclear
inclusions and smaller intracytoplasmic inclusions, and are pathognomonic for CMV infection. The virus
induces focal mononuclear cell infiltrates, which may be present with or without cytomegalic cells. The
virus may induce focal necrosis in the brain and liver, which may be extensive and accompanied by
granulomatous change with calcifications. The lung, liver, kidney, gastrointestinal tract, and salivary and
other exocrine glands are the most commonly affected organs, although the virus has been found in most
cell types. The extent of abnormal organ function and the quantity of virus that can be recovered from
infected organs are not related to the number of cytomegalic inclusion-bearing cells, which may be few or
absent in each organ section examined.
CLINICAL MANIFESTATIONS.
The signs and symptoms of CMV infection vary with age, route of transmission, and
immunocompetence of the patient. The infection is subclinical in most patients. In young children,
primary CMV infection occasionally causes pneumonitis, hepatomegaly, hepatitis, and petechial rashes.
In older children, adolescents, and adults, CMV may cause mononucleosis-like syndrome characterized
by fatigue, malaise, myalgia, headache, fever, hepatosplenomegaly, abnormal liver function test results,
and atypical lymphocytosis. The course of CMV mononucleosis is generally mild, lasting 2-3 wk. An
occasional patient may present with persistent fever, overt hepatitis, or morbilliform rash, or a
combination. Recurrent infections are asymptomatic in the immunocompetent host.
Immunocompromised Hosts.
In immunocompromised individuals, the risk of CMV disease is increased with both primary and
recurrent infections (Chapter 179) . Illness with a primary infection includes pneumonitis (most
common), hepatitis, chorioretinitis, gastrointestinal disease, or fever with leukopenia as isolated entities
or as manifestations of generalized disease, which is often fatal. The risk is greatest in bone marrow
transplant recipients and in patients with AIDS. Pneumonia, retinitis, and involvement of the central
nervous system and gastrointestinal tract are usually severe and progressive. Submucosal ulcerations can
occur anywhere in the gastrointestinal tract. Hemorrhage and perforation are known complications, as are
pancreatitis and cholecystitis.
Congenital Infection.
The condition of symptomatic congenital CMV infection was originally called cytomegalic
inclusion disease. Only 5% of all congenitally infected infants have severe cytomegalic inclusion disease,
another 5% have mild involvement, and 90% are born with subclinical but chronic CMV infection. The
most characteristic signs and symptoms include intrauterine growth retardation, prematurity,
hepatosplenomegaly and jaundice, thrombocytopenia and purpura, and microcephaly and intracranial
calcifications. Other neurologic problems include chorioretinitis, sensorineural hearing loss, and mild
increases in cerebrospinal fluid protein. Symptomatic newborns are usually easy to identify. Most
symptomatic congenital infections and those resulting in sequelae are caused by primary rather than
recurrent infections in pregnant women. Asymptomatic congenital CMV infection is likely a leading
cause of sensorineural hearing loss in young children, occurring in approximately 7% of infected infants.
Perinatal Infection.
Infections resulting from exposure to CMV in the maternal genital tract at delivery or in breast
milk occur despite the presence of maternally derived, passively acquired antibody. Approximately 612% of seropositive mothers transmit CMV to their infants by contaminated cervical-vaginal secretions
and 50% by breast milk. The majority of infants remain asymptomatic and do not exhibit sequelae.
Occasionally, perinatally acquired CMV infection is associated with pneumonitis. Premature and ill fullterm infants may have neurologic sequelae and psychomotor retardation. However, the risk of hearing
loss, chorioretinitis, and microcephaly does not appear to be increased.
Seronegative premature infants with birth weights of <1,500 g with transfusion-acquired CMV
infection have a 40% risk of experiencing hepatosplenomegaly, pneumonitis, gray pallor, jaundice,
petechiae, thrombocytopenia, atypical lymphocytosis, and hemolytic anemia.
DIAGNOSIS.
Active CMV infection is best demonstrated by virus isolation from urine, saliva, bronchoalveolar
washings, breast milk, cervical secretions, buffy coat, and tissues obtained by biopsy. Rapid (24 hr)
identification is now routine with the centrifugation-enhanced rapid culture system based on the detection
of CMV early antigens using monoclonal antibodies. Several methods are used for rapid detection of
CMV antigens, and polymerase chain reaction (PCR) and DNA hybridization techniques are also
available for rapid diagnosis. The presence of viral shedding and active infection does not distinguish
between primary and recurrent infections. A primary infection is confirmed by seroconversion or the
simultaneous detection of immunoglobulin (Ig) M as well as IgG antibodies. Rising IgG antibody titers
may be caused by primary and recurrent infection and must be interpreted carefully.
Sensitive and specific serologic tests to measure IgG antibodies are available in diagnostic
laboratories. Complement fixation, neutralization, anticomplement immunofluorescence, and indirect
immunofluorescence assays are preferable to define increases in antibody titers because they are
quantitative. In contrast, radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) are
less reliable for demonstrating significant changes in titers because most laboratories establish binding
ratio (RIA) and absorbance units (ELISA) at a fixed serum dilution to compare the quantities of
antibodies present in two sera. A simple increase in antibody titers in initially seropositive patients must
be interpreted with caution because these are occasionally seen years after primary infection. IgG
antibodies persist for life. IgM antibodies can be demonstrated transiently (4-16 wk) during the acute
phase of symptomatic as well as asymptomatic primary infection in adults. RIA, ELISA, and an IgM
capture RIA have acceptable specificity and sensitivity to detect primary infections. IgM antibodies are
rarely found with these assays (0.2-1%) in patients with recurrent infection.
A recurrent infection is defined by the reappearance of viral excretion in a patient known to have
been seropositive in the past. The distinction between reactivation of endogenous virus and reinfection
with a different strain of CMV requires restriction enzyme analysis of viral DNA to demonstrate
polymorphisms between viral isolates.
In immunocompromised patients, excretion of CMV, increases in IgG titers, and even the
presence of IgM antibodies are common, making the distinction between primary and recurrent infections
more difficult. Demonstrating viremia by buffy coat culture or detection of CMV DNA implies active
disease and worse prognosis regardless of whether the type of infection is primary, recurrent, or
uncertain.
Congenital Infection.
The definitive method for diagnosis of congenital CMV infection is virus isolation or
demonstration of specific DNA sequences by PCR. This must be performed at or shortly after birth. Urine
and saliva are the best specimens for culture. Infants with congenital CMV infection may excrete CMV in
high titers in the urine for several months. An IgG antibody test is of little diagnostic value because a
positive result also reflects maternal antibodies, although a negative result excludes the diagnosis of
congenital CMV infection. Demonstration of stable or rising titers in serial specimens during the first year
of life does not help because acquired infection in the first few months of life is common. In general, IgM
tests lack sensitivity and specificity and are unreliable for diagnosis of congenital CMV infection.
Congenital toxoplasmosis and syphilis must also be considered.
CMV infection can be diagnosed in utero by isolation of the virus from the amniotic fluid. A
negative culture does not exclude fetal infection because the interval between maternal infection and fetal
infection is unknown. Although isolation of CMV by this means documents fetal infection, it does not
indicate whether the newborn will have a symptomatic or an asymptomatic infection.
TREATMENT.
Ganciclovir combined with immune globulin, either standard intravenous immunoglobulin
(IVIG) or hyperimmune CMV IVIG, has been used to treat life-threatening CMV infections in
immunocompromised hosts (e.g., bone marrow, heart, and kidney transplant recipients and patients with
AIDS). Two published regimens are ganciclovir (7.5 mg/kg/24 hr intravenously divided every 8 hr for 14
days) with CMV IVIG (400 mg/kg on days 1, 2, and 7, and 200 mg/kg on day 14); and ganciclovir (7.5
mg/kg/24 hr intravenously divided every 8 hr for 20 days with IVIG 500 mg/kg every other day for 10
doses).
CMV retinitis and gastrointestinal disease appear to be clinically responsive to therapy but, like
viral excretion, often recur on cessation. Toxicity with ganciclovir is frequent and often severe, including
neutropenia, thrombocytopenia, liver dysfunction, reduction in spermatogenesis, and gastrointestinal and
renal abnormalities. Foscarnet is an alternative antiviral agent, although there is limited information of its
use in children.
Congenital Infection.
A phase II study with ganciclovir (12 mg/kg 24 hr for a total of 6 wk) showed hearing
improvement or stabilization in 5 of 30 infants, suggesting efficacy. A randomized study of symptomatic
congenital CMV infection is in progress.
PROGNOSIS.
Patients with CMV mononucleosis usually recover fully, although some have a protracted
symptomatic illness. Most immunocompromised patients also recover uneventfully, but many experience
severe pneumonitis, with a high fatality rate if hypoxemia develops. CMV infection and disease may be
terminal events in individuals with increased susceptibility to infections such as patients with AIDS.
Congenital Disease.
The prognosis for normal development with symptomatic cytomegalic inclusion disease is poor;
more than 90% of these children demonstrate central nervous system and hearing defects in later years. In
infants with subclinical infection, the outlook is much better. The primary concern is the subsequent
development of sensorineural hearing loss (5-10%), chorioretinitis (3-5%), and other less frequent
manifestations such as developmental abnormalities, microcephaly, and neurologic deficits.
PREVENTION.
The use of CMV-free blood products, especially for premature newborns, and, whenever
possible, the use of organs from CMV-free donors for transplantation represent important measures to
prevent CMV infection and disease in patients at high risk.
Pregnant women who are CMV seropositive are at low risk of delivering a symptomatic newborn.
If possible, pregnant women should have a CMV serologic test, especially if they care for young children
who are potential CMV excreters. Those who are CMV seronegative should be counseled regarding good
handwashing and other hygienic measures and avoidance of contact with oral secretions of others.
Passive Immunoprophylaxis.
The use of IVIG or CMV IVIG for prophylaxis of infection in solid organ and bone marrow
transplant recipients reduces the risk of symptomatic disease but does not prevent infection. The efficacy
of prophylaxis is more striking when the hazard of primary CMV infection is greatest, such as in bone
marrow transplantation. There is no consensus for a uniform prophylaxis regimen for CMV infection.
Recommended regimens include either IVIG (1,000 mg/kg) or CMV IVIG (500 mg/kg) given as a single
intravenous dose beginning within 72 hr of transplantation and once weekly thereafter until day 90-120
after transplantation.
Active Immunization.
The beneficial role of immunity is substantial, as illustrated by the fact that most severe disease
follows primary infection, especially in congenital infection, transfusion-acquired infection, and infection
in transplant recipients. Candidates for a CMV vaccine include seronegative women of childbearing age
and seronegative transplant recipients. Live, attenuated vaccines such as the Towne strain prototype are
immunogenic, but immunity wanes quickly. Vaccine virus does not seem to be transmissible. The vaccine
does not protect renal transplant recipients from CMV infection, but appears to reduce the virulence of
primary infection. In a study of vaccine efficacy in normal adult women, the Towne strain vaccine did not
provide protection against naturally acquired infection. Other types of vaccines, such as subunit and
recombinant vaccines, are being evaluated in early clinical trials.
Herpes simplex virus 1 and 2 (HSV-1 and HSV-2)
They are also called Human Herpes Virus 1 and 2 (HHV-1 and HHV-2) and are
neurotropic and neuroinvasive viruses; they enter and hide in the human nervous system,
accounting for their durability in the human body. HSV-1 is commonly associated with herpes
outbreaks of the face known as cold sores or fever blisters, whereas HSV-2 is more often
associated with genital herpes.
An infection by a herpes simplex virus is marked by watery blisters in the skin or mucous
membranes of the mouth, lips or genitals. Lesions heal with a scab characteristic of herpetic
disease. However, the infection is persistent and symptoms may recur periodically as outbreaks
of sores near the site of original infection. After the initial, or primary, infection, HSV becomes
latent in the cell bodies of nerves in the area. Some infected people experience sporadic episodes
of viral reactivation, followed by transportation of the virus via the nerve's axon to the skin,
where virus replication and shedding occurs.
Herpes is contagious if the carrier is producing and shedding the virus. This is especially
likely during an outbreak but possible at other times. There is no cure yet, but there are
treatments which reduce the likelihood of viral shedding.
Transmission
HSV is transmitted during close contact with an infected person who is shedding virus
from the skin, in saliva or in secretions from the genitals. This horizontal transmission of the
virus is more likely to occur when sores are present, although viral shedding, and therefore
transmission, does occur in the absence of visible sores. In addition, vertical transmission of
HSV may occur between mother and child during childbirth, which can be fatal to the infant.
The immature immune system of the child is unable to defend against the virus and even if
treated, the infection can result in inflammation of the brain (encephalitis) that may cause brain
damage. Transmission occurs when the infant passes through the birth canal, but the risk of
infection is reduced if there are no symptoms or exposed blisters during delivery. The first
outbreak after exposure to HSV is commonly more severe than future outbreaks, as the body has
not had a chance to produce antibodies; this first outbreak carries a low (~1%) risk of developing
aseptic meningitis.
Disorders
HSV infection causes several distinct medical disorders. Common infection of the skin or
mucosa may affect the face and mouth (orofacial herpes), genitalia (genital herpes), or hands
(herpes whitlow). More serious disorders occur when the virus infects and damages the eye
(herpes keratitis), or invades the central nervous system, damaging the brain (herpes
encephalitis). Patients with immature or suppressed immune systems, such as newborns,
transplant recipients, or AIDS patients are prone to severe complications from HSV infections.
HSV infection has also been associated with bipolar disorder, schizophrenia and Alzheimer's
disease, although this is often dependent on the genetics of the infected person .
In all cases HSV is never removed from the body by the immune system. Following a
primary infection, the virus enters the nerves at the site of primary infection, migrates to the cell
body of the neuron, and becomes latent in the ganglion. As a result of primary infection, the
body produces antibodies to the particular type of HSV involved, preventing a subsequent
infection of that type at a different site. In HSV-1 infected individuals, seroconversion after an
oral infection will prevent additional HSV-1 infections such as whitlow, genital herpes, and
keratitis. Prior HSV-1 seroconversion seems to ameliorate the symptoms of a later HSV-2
infection, however HSV-2 can still be contracted. Most indications are that an HSV-2 infection
contracted prior to HSV-1 seroconversion will immunize that person against HSV-1 infection.
This is not necessarily good, as prior HSV-1 infection has the tendency to ameliorate the effects
of symptomatic HSV-2 reoccurrences.
Orofacial infection
Herpes affects the face and mouth. Infection occurs when the virus comes into contact
with oral mucosa or abraded skin. Infection by the type 1 strain of herpes simplex virus (HSV-1)
is the most common cause of orofacial herpes, though cases of oral infection by the type 2 strain
are increasing.
Herpes infections are largely asymptomatic; when symptoms appear they will
typically resolve within two weeks. The main symptom of oral infection is acute herpetic
gingivostomatitis (inflammation of the mucosa of the cheek and gums), which occurs within 5–
10 days of infection. Other symptoms may also develop, including painful ulcers—sometimes
confused with canker sores—fever, and sore throat. Primary HSV infection in adolescents
frequently manifests as severe pharyngitis with lesions developing on the cheek and gums. Some
individuals develop difficulty in swallowing (dysphagia) and swollen lymph nodes
(lymphadenopathy). Primary HSV infections in adults often results in pharyngitis similar to that
observed in glandular fever (infectious mononucleosis), but gingivostomatitis is less likely.
Recurrent oral infection is more common with HSV-1 infections than with HSV-2.
Prodromal symptoms often precede a recurrence. Symptoms typically begin with tingling
(itching) and reddening of the skin around the infected site. Eventually, fluid-filled blisters form
on the lip (labial) tissue and the area between the lip and skin (vermilion border). The recurrent
infection is thus often called herpes simplex labialis. Rare reinfections occur inside the mouth
(intraoral HSV stomatitis) affecting the gums, alveolar ridge, hard palate, and the back of the
tongue, possibly accompanied by herpes labialis.
Genital infection
Following the classification HSV into two distinct categories of HSV-1 and HSV-2 in the
60s, it was established that "HSV-2 was below the waist, HSV-1 was above the waist". Although
genital herpes is largely believed to be caused by HSV-2, genital HSV-1 infections are
increasing and now exceed 50% in certain populations, and that rule of thumb no longer applies.
HSV is believed to be asymptomatic in the majority of cases, thus aiding contagion and
hindering containment. When symptomatic, the typical manifestation of a primary HSV-1 or
HSV-2 genital infection is clusters of inflamed papules and vesicles on the outer surface of the
genitals resembling cold sores. These usually appear 4–7 days after sexual exposure to HSV for
the first time.Genital HSV-1 infection recurs at rate of about one sixth of that of genital HSV-2.
Neonatal HSV infection is a rare but serious condition, usually caused by vertical
transmission of HSV from mother to newborn. The majority of cases (85%) occur during birth
when the baby comes in contact with infected genital secretions in the birth canal, an estimated
5% are infected in utero, and approximately 10% of cases are acquired postnatally. Detection
and prevention is difficult because transmission is asymptomatic in 60% - 98% of cases.
Neonatal HSV rates in the U.S. are estimated to be between 1 in 3,000 and 1 in 20,000 live
births. Approximately 22% of pregnant women have had previous exposure to HSV-2, and an
additional 2% acquire the virus during pregnancy, mirroring the HSV-2 infection rate in the
general population.The risk of transmission to the newborn is 30-57% in cases where the mother
acquired a primary infection in the third trimester of pregnancy. Risk of transmission by a
mother with existing antibodies for both HSV-1 and HSV-2 has a much lower (1-3%)
transmission rate. This in part is due to the transfer of significant titer of protective maternal
antibodies to the fetus from about the seventh month of pregnancy. However, shedding of HSV1 from both primary genital infection and reactivations is associated with higher transmission
from mother to infant.
Neonatal herpes manifests itself in three forms: skin, eyes, and mouth herpes (SEM)
sometimes referred to as "localized", disseminated herpes (DIS), and central nervous system
herpes(CNS). SEM herpes is characterized by external lesions but no internal organ
involvement. Lesions are likely to appear on trauma sites such as the attachment site of fetal
scalp electrodes, forceps or vacuum extractors that are used during delivery, in the margin of the
eyes, the nasopharynx, and in areas associated with trauma or surgery (including circumcision).
DIS herpes affects internal organs, particularly the liver. CNS herpes is an infection of the
nervous system and the brain that can lead to encephalitis. Infants with CNS herpes present with
seizures, tremors, lethargy, and irritability, they feed poorly, have unstable temperatures, and
their fontanelle (soft spot of the skull) may bulge. CNS herpes is associated with highest
morbidity, and DIS herpes has a higher mortality rate. These categories are not mutually
exclusive and there is often overlap of two or more types. SEM herpes has the best prognosis of
the three, however, if left untreated it may progress to disseminated or CNS herpes with its
attendant increases in mortality and morbidity. Death from neonatal HSV disease in the U.S. is
currently decreasing; The current death rate is about 25%, down from as high as 85% in
untreated cases just a few decades ago. Other complications from neonatal herpes include
prematurity with approximately 50% of cases having a gestation of 38 weeks or less, and a
concurrent sepsis in approximately one quarter of cases that further clouds speedy diagnosis.
Reductions in morbidity and mortality are due to the use of antiviral treatments such as
vidarabine and acyclovir. However, morbidity and mortality still remain high due to diagnosis of
DIS and CNS herpes coming too late for effective antiviral administration; early diagnosis is
difficult in the 20-40% of infected neonates that have no visible lesions. Harrison's Principles of
Internal Medicine, recommends that pregnant women with active genital herpes lesions at the
time of labor be delivered by caesarean section. Women whose herpes is not active can be
managed with acyclovir. The current practice is to deliver women with primary or first episode
non primary infection via caesarean section, and those with recurrrent infection vaginally, even
in the presence of lesions because of the low risk (1-3%) of vertical transmission associated with
recurrent herpes.
Viral meningitis
HSV-2 is the most common cause of Mollaret's meningitis, a type of recurrent viral
meningitis. This condition was first described in 1944 by French neurologist Pierre Mollaret.
Recurrences usually last a few days or a few weeks, and resolve without treatment. They may
recur weekly or monthly for approximately 5 years following primary infection.
Diagnosis
Primary orofacial herpes is readily identified by clinical examination of persons with no
previous history of lesions and contact with an individual with known HSV-1 infection. The
appearance and distribution of sores in these individuals typically presents as multiple, round,
superficial oral ulcers, accompanied by acute gingivitis. Adults with non-typical presentation are
more difficult to diagnose. Prodromal symptoms that occur before the appearance of herpetic
lesions help differentiate HSV symptoms from the similar symptoms of other disorders, such as
allergic stomatitis. When lesions do not appear inside the mouth primary orofacial herpes is
sometimes mistaken for impetigo, a bacterial infection. Common mouth ulcers (aphthous ulcer)
also resemble intraoral herpes, but do not present a vesicular stage.
Genital herpes can be more difficult to diagnose than oral herpes since most HSV-2infected persons have no classical symptoms.Further confusing diagnosis, several other
conditions resemble genital herpes, including lichen planus, atopic dermatitis, and
urethritis.Laboratory testing is often used to confirm a diagnosis of genital herpes. Laboratory
tests include: culture of the virus, direct fluorescent antibody (DFA) studies to detect virus, skin
biopsy, and polymerase chain reaction (PCR) to test for presence of viral DNA. Although these
procedures produce highly sensitive and specific diagnoses, their high costs and time constraints
discourage their regular use in clinical practice.
Serological tests for antibodies to HSV are rarely useful to diagnosis and not routinely
used in clinical practice, but are important in epidemiological studies. Serologic assays cannot
differentiate between antibodies generated in response to a genital versus an oral HSV infection,
and as such cannot confirm the site of infection. Absence of antibody to HSV-2 does not exclude
genital infection because of the increasing incidence of genital infections caused by HSV-1.
Antiviral medication
Antiviral medications used against herpes viruses work by interfering with viral
replication, effectively slowing the replication rate of the virus and providing a greater
opportunity for the immune response to intervene. All drugs in this class depend on the activity
of the viral enzyme thymidine kinase to convert the drug sequentially from its prodrug form to
monophosphate (with one phosphate group), diphosphate (with two phosphate groups), and
finally to the triphosphate (with three phosphate groups) form which interferes with viral DNA
replication.
The antiviral medication acyclovir
There are several prescription antiviral medications for controlling herpes simplex
outbreaks, including aciclovir (Zovirax), valaciclovir (Valtrex), famciclovir (Famvir), and
penciclovir. Aciclovir was the original, and prototypical, member of this drug class; it is now
available in generic brands at a greatly reduced cost. Valaciclovir and famciclovir—prodrugs of
aciclovir and penciclovir, respectively—have improved solubility in water and better
bioavailability when taken orally. Aciclovir is the recommended antiviral for suppressive therapy
for use during the last months of pregnancy to prevent transmission of herpes simplex to the
neonate in cases of maternal recurrent herpes.. The use of valaciclovir and famciclovir, while
potentially improving treatment compliance and efficacy, are still undergoing safety evaluation
in this context.
Several studies with mice provide evidence that treatment with famciclovir soon after
initial infection can help lower the incidence of future outbreaks, by reducing the amount of
latent virus in the neural ganglia. A review of human subjects treated with famciclovir during
their first herpes episode supports these findings, with only 4.2 percent of famciclovir-treated
patients experiencing a recurrence within one to six months after the first outbreak, compared to
19 percent of acyclovir-treated patients. Despite these promising results, early famciclovir
treatment for herpes has yet to find mainstream adoption. However, the potential effect on
latency drops to zero a few months post-infection.
Antiviral medications are also available as topical creams for treating recurrent outbreaks
on the lips, although their effectiveness is disputed. Penciclovir cream has a 7-17 hour longer
cellular half-life than aciclovir cream, increasing its effectiveness relative to aciclovir when
topically applied.
]Tromantadine is available as a gel that inhibits the entry and spread of the virus by
altering the surface composition of skin cells and inhibiting release of viral genetic material.
Zilactin is a topical analgesic barrier treatment, which forms a "shield" at the area of application
to prevent a sore from increasing in size, and decrease viral spreading during the healing process.
Other drugs
Cimetidine, a common component of heartburn medication, has been shown to lessen the
severity of herpes zoster outbreaks in several different instances. This is an off-label use of the
drug. It and probenecid have been shown to reduce the renal clearance of acyclovir. These
compounds also reduce the rate, but not the extent, at which valaciclovir is converted into
aciclovir.
Another treatment is the use of petroleum jelly. Healing of cold sores is sped by barring
water or saliva from reaching the sore.
Vaccines
Zostavax is a live vaccine developed by Merck & Co. (September, 2008) which has been
shown to reduce the incidence of herpes zoster
VI. Control materials for the preliminary and final stages of the lesson
Tests and tasks
1. A 9-year-old boy has been ill for 2 days. Now he has fever up to 37,5°С, maculae, papules,
vesicles on his skin, skin of the head. Vesicles are round, situated on an unindurated base,
surrounded by erythematous corona.
What is your diagnosis?
A. Smallpox
B. Scarlet fever
C. Herpetic infection
D. Streptodermia
E. Varicella
2. A 7-year-old girl was in contact with a patient with herpes zoster. Fever up to 39,3°С,
polymorphic rash (maculae, papules, crusts, vesicles) on her skin and mucous membranes of oral
cavity have occurred at the 7th day of illness.
What is your diagnosis?
A. Smallpox
B. Herpes simplex
C. Herpes zoster
D. Varicella
E. Streptoderma
3. A 4-year-old girl has severe form of varicella.
What medication should not be administered(choose one answer)?
A. Acyclovir
B. Specific immunoglobulin
C. Recombinant interferon
D. Inductor of endogenous interferon
E. Steroid hormones
4. An 8-year-old boy is not ill with varicella. He had been in touch with the child, who had
varicellas.
He can fall ill within:
A. 28 days
B. 17 days
C. 21 days
D. 14 days
E. 11-21 days
5. A 9 -year-old boy has fever, polymorphic rash - maculae, papules, vesicles and crusts on his
face, skin of the head, trunk, limb and extremities. Severe headache, vomiting, ataxia, slow down
and discoordination of motion have occured on the 10th day of illness.
What the complication occurred?
A. Encephalitis
B. Serous meningitis
C. Neyrotoxycosis
D. Encephalitis reaction
E. Meningo- encephalitis
Correct answers for tests
N
Answers
1
E
2
D
3
A
4
E
5
A
VII. Literature
№
Author(s)
1.
Mikhailova
A.M., Minkov
I.P., Savchuk
A.I.
Publishing
house
Year of
edition,
vol.,
issue
Number
of
pages
Odessa
2003
236
Name of source
City,
(textbook, manual, monograph,
etc.)
Infection diseases in children.
2.
Jonathan Cohan
Infectious disease.
Harcourt
Publisher
s limited
2004
2nd
edition
2136
3.
David C Dale
Infectious diseases The clinician
guide to Diagnosis, Treatment and
Prevention.
WebMD
Corporati
on
2004
edition
310
4.
Duker Krugman's
Infectious Diseases of Children.
Mosby
11th
edition
1574
5.
Fleisher
Textbook of Pediatric Emergency
Medicine.
4th
edition