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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. To define a clinical diagnosis (form of disease, type, severity, course of disease).

7. To prescribe the treatment taking into account age, severity of illness.

8. To write out a prescription.

9. 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 end-organ 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 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 1-4% 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 child-care 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 10-20% 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 6-12% 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 full-term 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 ................
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