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Thursday, April 30, 2009


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Last Updated: March 30, 2006 Email to a Colleague

Synonyms and related keywords: toxoplasmosis, Toxoplasma gondii, congenital toxoplasmosis, congenital infection, bradyzoites, sporozoites, tachyzoites, chorioretinitis, Sabin-Feldman dye test

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Author: Hakan Leblebicioglu, MD, Chairman, Professor, Department of Infectious Diseases and Clinical Microbiology, Ondokuz Mayis University Medical School, Samsun, Turkey
Coauthor(s): Murat Hökelek, MD, PhD, Associate Professor, Technical Consultant of Parasitology Laboratory, Department of Clinical Microbiology, Ondokuz Mayýs University Medical School, Turkey; Itzhak Brook, MD, MSc, Professor, Department of Pediatrics, Georgetown University School of Medicine

Hakan Leblebicioglu, MD, is a member of the following medical societies: American Society for Microbiology

Editor(s): Robert W Tolan, Jr, MD, Chief of Allergy, Immunology and Infectious Diseases, The Children's Hospital at St Peter's University Hospital, Clinical Associate Professor of Pediatrics, Drexel University College of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Leslie L Barton, MD, Professor, Program Director, Department of Pediatrics, University of Arizona School of Medicine; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Russell W Steele, MD, Professor and Vice Chairman, Department of Pediatrics, Head, Division of Infectious Diseases, Louisiana State University Health Sciences Center


INTRODUCTION Section 2 of 11
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Background: Toxoplasma gondii is a widely distributed protozoan that usually causes an asymptomatic infection in the healthy host. Toxoplasmosis refers to a symptomatic infection by T gondii and can be acute or chronic. Apart from disease in immunocompromised individuals, congenital toxoplasmosis is the most serious manifestation of infection, resulting from vertical transmission of T gondii from a parasitemic mother to her offspring. The severity of disease depends on the gestational age at transmission. Ophthalmologic and neurologic disabilities are the most important consequences of infection and can be present even when the congenital infection is asymptomatic. Congenital toxoplasmosis is a preventable disease. Prepregnancy screening accompanied by serial titers and appropriate counseling in women with initial negative titers would minimize cases.

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

T gondii exists in 3 forms, as follows:

Bradyzoites are slowly multiplying organisms contained in tissue cysts, usually localized to muscle (skeletal and cardiac) and brain. They live in their host cells for months to years. Once ingested, gastric enzymes degrade the cyst wall, liberating viable bradyzoites.

Tachyzoites are rapidly dividing organisms found in tissues during the acute phase of infection. The tachyzoites are the forms responsible for tissue destruction. Multiplication continues until either cyst formation or host cell destruction occurs. After cell death, the free tachyzoites invade other cells and resume rapid multiplication.

Sporozoites (oocysts) result from the parasite's sexual cycle, which takes place in the epithelial cells of the cat intestine. When eliminated by the cat, these cysts must first undergo sporulation to become infectious, a process that takes 2-3 days in temperate climates and longer in cold climates. Therefore, the risk of infection is minimized if cat litter boxes are cleaned daily. Cats shed 1-100 million oocysts after the first infection, but, because of immunity, reinfection is rarely followed by reshedding of oocysts. Passive antibody transference to newborn kittens does not prevent shedding of oocysts.
Human horizontal infection occurs from ingesting food contaminated with oocysts or poorly cooked food containing tissue cysts (bradyzoites). Although experimental attempts to transmit tachyzoites by arthropods were negative, cockroaches and flies are believed to be able to transport oocysts to water and food. Because parasitemia can persist up to a year in healthy persons, blood transfusion is a potential source of infection. Once the individual is infected, the organism persists as tissue cysts for life. The degree of organ involvement varies considerably among patients but mostly depends on the immune status of the host. Fetuses and immunocompromised patients are most severely affected.

Vertical transmission is the cause of congenital toxoplasmosis. The infection can occur in utero or during a vaginal delivery. Transmission by breastfeeding has not been demonstrated. In general, only primary infection during pregnancy results in congenital toxoplasmosis. Thus, it is exceedingly rare for a woman to deliver a second child with congenital toxoplasmosis unless she is immunocompromised, usually from acquired immunodeficiency syndrome (AIDS). Infections that occur before but within 6 months of conception may result in transplacental transmission. Intrauterine exposure can result in an uninfected infant or infection that ranges from being asymptomatic to causing stillbirth. Approximately 30% of exposed fetuses acquire the infection, but most of the infants are asymptomatic. The severity of infection in the fetus depends on the gestational age at the time of transmission.

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


In the US: The frequency of congenital toxoplasmosis depends on the incidence of primary infection in women of childbearing age. The earlier a woman acquires a primary infection, the less likely she is to transmit the parasite to her offspring. Prevalence increases with age. In New York, antibody prevalence was 16% in women aged 15-19 years, 27% in women aged 20-24 years, 33% in women aged 25-29 years, 40% in women aged 30-34 years, and 50% in women older than 35 years. Rates in women of childbearing age in Palo Alto, California, dropped from 27% in 1964 to 10% in 1987. Other areas in the United States report positive antibody titers in women of childbearing age of 30% in Birmingham (1983), 12% in Chicago (1987), 14% in Massachusetts (1998), 3.3% in Denver (1986), 30% in Los Angeles (1993), 12% in Texas (1993), and 13% in New Hampshire (1998).

The prevalence of congenital infection can be indirectly estimated from the incidence rate of primary infection during pregnancy by multiplying the number of mothers who acquire infection during pregnancy by the transmission rate of the parasite to the fetus. On the basis of data from the National Health and Nutrition Examination Survey during 1989-1994, the incidence of primary infection for seronegative pregnant women was 0.27%. With 4 million births per year and an overall transmission rate of 33%, approximately 3500 infected children should be born in the United States every year. The rate likely varies by region.

Direct estimates of congenital infection may be derived by measuring anti-Toxoplasma IgM in newborn sera. However, this may underestimate the true incidence because infants with toxoplasmosis may not have demonstrable IgM in up to 20% of cases. In Alabama, the incidence was 0.1 per 1000 births. Health care workers in Massachusetts began screening sera of newborns in 1986. From 1986-1998, a total of 99 cases were detected (incidence of 1 in 10,000 births) in Massachusetts, but at least 6 cases were missed by the screening.

Internationally: Worldwide, the reported incidence of congenital toxoplasmosis is decreasing. The prevalence of positive antibody titers among pregnant women is often higher outside the United States. The rate of positive antibody titers is 81% in the Central African Republic, 48% in Tanzania, 23% in Zambia, 53-58% in Argentina, 36% in Austria, 46% in Belgium, 59% in Chile, 60% in Colombia, more than 75% in Ethiopia, 52% in France, and 46% in Guatemala. The estimated incidence of congenital toxoplasmosis is 6 per 1000 births in France, 2 per 1000 births in Poland, 7-10 per 1000 births in Colombia, and 3 per 1000 births in Slovenia.
Mortality/Morbidity: Fetuses and immunocompromised individuals are at particularly high risk for severe sequelae and even death. Infection acquired postnatally is usually much less severe.

Newborns with acute congenital toxoplasmosis often die in the first month of life.
Subacute congenital disease may not be observed until some time after birth, when symptoms start to appear.
Race: The incidence of disease depends on sanitary conditions and culinary habits. The ingestion of raw or poorly cooked meat increases the risk of toxoplasmosis. Individuals with poor sanitary conditions and those who eat raw or poorly cooked meat are at an increased risk of acquiring Toxoplasma infection, unrelated to race.

Sex: Incidence does not significantly vary between the sexes.

Age: Incidence of T gondii antibodies increases with increasing age. The seroconversion rate in women of childbearing age is 0.8% per year. The risk of transplacental transmission is greatest during the third trimester of pregnancy.

CLINICAL Section 3 of 11
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History: Pediatric toxoplasmosis can be acute or chronic, asymptomatic or symptomatic, and congenital or postnatally acquired.

Congenital toxoplasmosis is the consequence of transplacental hematogenous fetal infection by T gondii during primary infection in pregnant women. Primary infection in an otherwise healthy pregnant woman is asymptomatic in 60% of cases. Symptoms during pregnancy are frequently mild. The most common manifestations are fatigue, malaise, a low-grade fever, lymphadenopathy, and myalgias. Latent Toxoplasma infection with reactivation during pregnancy may lead to congenital infection only in immunocompromised women (most commonly, those with AIDS).
The classic triad of chorioretinitis, hydrocephalus, and intracranial calcifications cannot be used as a strict diagnostic criterion for congenital toxoplasmosis because a large number of cases would be missed. Congenital toxoplasmosis may occur in the following forms:
Neonatal disease
Disease occurring in the first months of life
Sequelae or relapse of previously undiagnosed infection
Subclinical infection
When clinically recognized in the neonate, congenital toxoplasmosis is very severe. Signs of generalized infection are usually present, such as intrauterine growth retardation, jaundice, hepatomegaly, splenomegaly, lymphadenopathy, and a rash. Neurologic signs are severe and always present. They include microcephaly or macrocephaly, bulging fontanelle, nystagmus, abnormal muscle tone, seizures, and delay of developmental milestone acquisition.
Most cases of chorioretinitis result from congenital infection, although patients are often asymptomatic until later in life. Symptoms include blurred vision, scotoma, pain, photophobia, and epiphora. Impairment of central vision occurs when the macula is involved, but vision may improve as inflammation resolves. Relapses of chorioretinitis are frequent but rarely accompanied by systemic signs or symptoms.
Latent toxoplasmosis may reactivate in women with human immunodeficiency virus (HIV) and result in congenital transmission. Congenital toxoplasmosis in the infant with HIV appears to run a more rapid course than in infants without HIV.

Lymphadenopathy is the most common form of symptomatic acute toxoplasmosis in immunocompetent individuals.
Patients typically present with painless firm lymphadenopathy that is confined to one chain of nodes, which are most commonly cervical. The suboccipital, supraclavicular, axillary, and inguinal groups may also be involved.
Other physical manifestations include a low-grade fever, occasional hepatosplenomegaly, and a rash.
Ophthalmologic examination reveals multiple yellow-white cottonlike patches with indistinct margins located in small clusters in the posterior pole.
Characteristically, a focal necrotizing retinitis develops that may atrophy and generate black pigment, or it may be associated with panuveitis. Papillitis is usually indicative of CNS disease. Flare-up of congenitally acquired chorioretinitis is often associated with scarred lesions in proximity to the fresh lesions.
Because of multifocal involvement of the CNS, clinical findings vary widely. They include alterations in mental status, seizures, motor weakness, cranial nerve disorders, sensory abnormalities, cerebellar signs, meningismus, movement disorders, and neuropsychiatric manifestations in patients with immunocompromise.

The etiologic agent is T gondii.
Congenital disease is passed transplacentally from the newly infected mother to the fetus during pregnancy.
Other syndromes may result from newly acquired infection or reactivation of latent infection.
Ingestion of meat or foods containing cysts or oocysts present in cat feces can cause infection.
Infection can be transmitted by blood transfusion or organ transplantation.
Hosts who are immunocompromised, especially those with defects in cellular immunity such as AIDS, are also at increased risk for severe disease.
DIFFERENTIALS Section 4 of 11
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Catscratch Disease
Cytomegalovirus Infection
Herpes Simplex Virus Infection
Listeria Infection
Lymph Node Disorders
Lymphocytic Choriomeningitis Virus
Mononucleosis and Epstein-Barr Virus Infection

Other Problems to be Considered:

Congenital toxoplasmosis - Encephalopathies, erythroblastosis fetalis, lymphocytic choriomeningitis virus infection
Toxoplasma encephalitis (TE) - Vasculitis, progressive multifocal leukoencephalopathy, malignancy, lymphocytic choriomeningitis virus infection

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Catscratch Disease

Cytomegalovirus Infection

Herpes Simplex Virus Infection



Listeria Infection

Lymph Node Disorders

Lymphocytic Choriomeningitis Virus

Mononucleosis and Epstein-Barr Virus Infection







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Brain Infection Overview

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Brain Infection Treatment

WORKUP Section 5 of 11
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Lab Studies:

Demonstration of T gondii in blood, body fluids, or tissues is evidence of infection.
Isolation by mouse inoculation of Toxoplasma from amniotic fluid or placental or fetal tissue is diagnostic of congenital infection.
Lymphocyte transformation in response to Toxoplasma antigens indicates previous infection in adults.
Detection of Toxoplasma antigens in blood or body fluids by means of enzyme-linked immunoassay (ELISA) indicates acute infection.
The Sabin-Feldman dye test is a sensitive and specific neutralization test. It measures IgG antibody and is the standard reference test for toxoplasmosis; however, it requires live T gondii and thus is not available in most laboratories. High titers suggest acute disease.
The indirect fluorescent antibody (IFA) test measures the same antibodies as the dye test. Titers parallel dye test titers. The IgM fluorescent antibody test can be used to detect IgM antibodies within the first week of infection, but titers fall within a few months.
The indirect hemagglutination test measures a different antibody than does the dye test. Titers tend to be higher and remain elevated longer.
The double-sandwich IgM ELISA is more sensitive and specific than other IgM detection tests.
The IgG avidity test may be able to discriminate acute from chronic infection better than alternative assays, such as assays that measure IgM antibodies. As is true for IgM antibody tests, the avidity test is most useful when performed early in gestation because a chronic pattern occurring late in pregnancy does not rule out the possibility that the acute infection may have occurred during the first months of gestation. A 2-fold rise in serum IgG obtained at 3-week intervals is diagnostic.
Performing polymerase chain reaction (PCR) on body fluids, including cerebrospinal fluid (CSF), amniotic fluid, bronchoalveolar lavage fluid, and blood, may be useful in establishing the diagnosis.
Imaging Studies:

Ultrasonography of the fetus to evaluate for evidence of congenital toxoplasmosis can be performed at 20-24 weeks' gestation.
Computed tomography (CT) of the brain is useful in cerebral toxoplasmosis.
In 70-80% of immunodeficient patients with TE, the CT scan depicts multiple bilateral ring-enhancing cerebral lesions.
Although multiple lesions are more common, finding a solitary lesion should not exclude TE.
The likelihood of TE is approximately 80% in AIDS patients with detectable Toxoplasma IgG and multiple ring-enhancing lesions.
Lesions are characteristically hypodense and tend to occur at the corticomedullary junction, frequently involving the basal ganglia.
CT frequently underestimates the number of lesions, although delayed imaging after a double dose of intravenous (IV) contrast material may improve the sensitivity of this imaging modality.
An enlarging hypodense lesion that does not enhance is a poor prognostic finding.
Improvement is seen in up to 90% of patients with AIDS and TE after 2-3 weeks of treatment. Complete resolution lasts from 6 weeks to 6 months; peripheral lesions resolve more rapidly than deeper ones. Radiographic response tends to lag behind clinical response.
Magnetic resonance imaging (MRI) is the preferred imaging modality to evaluate for lesions.
MRI has superior sensitivity, particularly if gadolinium is used for contrast. It can often depict lesions or more extensive disease not apparent on CT scan. Hence, MRI should be used as the initial imaging procedure when feasible and always follow CT demonstration of a single lesion.
MRI depicts TE lesions as high signal abnormalities on T2-weighted studies and reveals a rim of enhancement surrounding the edema on T1-weighted contrast-enhanced images.
Smaller lesions usually resolve completely on MRI studies within 3-5 weeks, but lesions with a mass effect tend to resolve more slowly and leave a small residual lesion.
Even characteristic lesions on CT or MRI are not pathognomonic of TE. The major differential diagnosis in patients with AIDS is CNS lymphoma, which appears with multiple enhancing lesions in 40% of cases.
To evaluate patients with AIDS and focal CNS lesions, a variety of positron emission tomography and radionuclide scans have been used, generally with minimal benefit over the above modalities.
Other Tests:

A skin test showing delayed hypersensitivity to Toxoplasma antigens may be a useful screening test.
Antibody levels in aqueous humor or CSF may reflect local antibody production and infection at these sites.
Perform an amniocentesis at 20-24 weeks' gestation in suspected cases of congenital disease.

When single lesions are depicted on MRI, the probability of TE falls and that of lymphoma rises. Brain biopsy is generally required to obtain a definitive diagnosis.
Histologic Findings: The histopathology of toxoplasmosis varies with the immune status of the host. In the healthy host with acquired toxoplasmosis, the characteristic histopathology of the lymph node is diagnostic, despite the relative paucity of organisms present. Typical findings include reactive follicular hyperplasia, irregular clusters of histiocytes encroaching on the margins of germinal centers, and focal distention of sinuses with monocytoid cells. Necrosis, granuloma formation, microabscesses, and vasculitis do not occur. At autopsy of normal hosts, tissue cysts are noted as incidental findings in skeletal muscle and myocardium, invoking little inflammatory response.
By contrast, in patients who are immunodeficient and in children with severe congenital toxoplasmosis, tachyzoite proliferation is accompanied by tissue necrosis and an intense, usually monocytic, inflammatory response. In patients with AIDS, toxoplasmosis typically produces brain abscesses that have a characteristic appearance. A central avascular area is surrounded by a region of necrosis and inflammatory cells that may also contain free and intracellular tachyzoites. Outside of the region of inflammation are cysts.

Demonstration of tachyzoites in a tissue specimen is required for definitive diagnosis of active infection. The presence of multiple cysts near an inflammatory lesion makes the diagnosis highly likely. Stains used to detect tachyzoites or cysts include hematoxylin and eosin, periodic acid-Schiff, and Gomori-methenamine silver. Immunoperoxidase and fluorescein-conjugated antibody stains can also be used. Wright-Giemsa staining of body fluid sediments of biopsy tissue touch preparations is a rapid and simple method for visualizing the organisms.

TREATMENT Section 6 of 11
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Medical Care:

Outpatient care is sufficient for acquired disease in patients with ocular toxoplasmosis and hosts who are immunocompetent.
Initial inpatient care is appropriate for patients with CNS toxoplasmosis and immunocompromised hosts with acute disease.
Usually, no treatment is necessary for asymptomatic hosts, except in those younger than 5 years.
Symptomatic patients should be treated until immunity is assured.
Immunocompetent patients who are not pregnant and have no vital organ damage can be observed without therapy. Suppressive therapy must continue for HIV-positive patients with active infection and a CD4+ count less than 200.

Infectious disease specialist
Diet: No special diet is required.

Activity: Limitation of activity depends on the severity of disease and the organ systems involved.

MEDICATION Section 7 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

The currently recommended drugs for T gondii infection act primarily against the tachyzoite form; thus, they do not eradicate the encysted form (bradyzoite). Pyrimethamine is the most effective agent and is included in most drug regimens. Leucovorin (folinic acid) should be administered concomitantly to avoid bone marrow suppression. Unless circumstances arise that preclude using more than one drug, a second drug, such as sulfadiazine or clindamycin, should be added. The efficacy of azithromycin, clarithromycin, atovaquone, dapsone, and cotrimoxazole (ie, trimethoprim-sulfamethoxazole) is unclear; therefore, they should only be used as alternatives in combination with pyrimethamine. The most effective available therapeutic combination is pyrimethamine plus sulfadiazine or trisulfapyrimidine (ie, combination of sulfamerazine, sulfamethazine, and sulfapyrazine). These agents are active against tachyzoites and are synergistic when used in combination.

Additional therapy with corticosteroids (prednisone, 1 mg/kg/d) should be considered with markedly elevated CSF protein (>1g/dL) and vision-threatening chorioretinitis.

Drug Category: Sulfonamide antimicrobials -- These agents exert bacteriostatic action through competitive antagonism with para-aminobenzoic acid (PABA). Microorganisms that require exogenous folic acid and do not synthesize folic acid (pteroylglutamic acid) are not susceptible to the action of sulfonamides. Resistant strains are capable of using folic acid precursors or preformed folic acid. These agents exist as 3 forms in serum—free, conjugated (ie, acetylated and possibly others), and protein bound. The free form is considered to be therapeutically active. Drug Name
Sulfadiazine (Microsulfon) -- Bacteriostatic agent that acts synergistically with pyrimethamine to treat T gondii.
Adult Dose Loading dose:
AIDS: 0.5-1.5 g PO q6h for 1-2 d (administer with pyrimethamine)
Non-AIDS: 0.25-1 g PO q6h for 1-2 d (administer with pyrimethamine)
Maintenance dose:
AIDS: 500 mg PO qid, administered with pyrimethamine 25 mg/d as lifelong therapy
Non-AIDS: 75 mg/kg PO once; not to exceed 4 g; followed by 1-1.5 g PO q6h for 2-4 wk
Pediatric Dose Acquired toxoplasmosis:
>1 year: 75 mg/kg/d PO once, followed by 50 mg/kg/d for 2-4 wk
Congenital toxoplasmosis:
100 mg/kg/d PO once, followed by 100 mg/kg/d divided q12h for 2-6 mo
Contraindications Documented hypersensitivity; breastfeeding women
Interactions Increases effect of oral anticoagulants and oral hypoglycemic agents; effects are decreased when administered concurrently with PABA or PABA metabolites of drugs (eg, proparacaine, tetracaine, sunscreens, procaine); sulfonamides may increase hypoglycemic effect of oral hypoglycemic agents; increases phenytoin levels as much as 80%
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Do not use during pregnancy at term because of risk of kernicterus in newborn; teratogenic potential of most sulfonamides has not been thoroughly investigated in either animals or humans; significant increased incidence of cleft palate and other bony abnormalities in offspring has been observed when certain sulfonamides of the short-, intermediate-, and long-acting types were administered to pregnant rats and mice in high oral doses (ie, 7-25 times the human dose); do not use in infants <2>1 month: 1 mg/kg/d PO; not to exceed 25 mg/d
Contraindications Documented hypersensitivity; G-6-PD deficiency
Interactions May inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists (eg, pyrimethamine), monitor for agranulocytosis during second and third months of therapy; probenecid increases dapsone toxicity; coadministration with trimethoprim may increase toxicity of both drugs; because of increased in renal clearance, levels may significantly decrease when administered concurrently with rifampin
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Perform weekly blood counts (first mo), then perform WBC counts monthly (6 mo), then semiannually; discontinue if significant reduction in platelets, leukocytes, or hematopoiesis is observed; caution in methemoglobin reductase deficiency, G-6-PD deficiency (patients receiving >200 mg/d), or hemoglobin M because of high risk for hemolysis and Heinz body formation; caution in patients exposed to other agents or conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; may cause peripheral neuropathy (rare) or phototoxicity when exposed to UV light
Drug Category: Lincosamide antimicrobials -- These agents inhibit bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Drug Name
Clindamycin (Cleocin) -- Alternative to sulfonamides. May be beneficial when used with pyrimethamine in short-term treatment of CNS toxoplasmosis in patients with AIDS.
Adult Dose Loading dose:
AIDS: 600 mg PO/IV q6h for 1-2 d (combined with pyrimethamine)
TE: 600 mg PO/IV q6h for 3-6 wk (combined with pyrimethamine)
Suppression: 300-450 mg PO q6-8h (combined with pyrimethamine)
Pediatric Dose 8-20 mg/kg/d PO as hydrochloride (cap) or 8-25 mg/kg/d PO as palmitate (susp) divided tid/qid; not to exceed 1.8 g/d
20-40 mg/kg/d IV/IM divided tid/qid; not to exceed 4.8 g/d
Contraindications Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis
Interactions Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects; antidiarrheals may delay absorption
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis by allowing overgrowth of Clostridium difficile
Drug Category: Antiprotozoal agents -- Protozoal infections occur throughout the world and are a major cause of morbidity and mortality in some regions. Patients who are immunocompromised are especially at risk. Primary immune deficiency is rare; whereas, secondary deficiency is more common. Immunosuppressive therapy, cancer and its treatment, HIV infection, and splenectomy may increase vulnerability to infection. Infectious risk is proportional to neutropenia duration and severity. Protozoal infections are typically more severe in immunocompromised patients than in immunocompetent patients. Drug Name
Pyrimethamine (Daraprim) -- Folic acid antagonist that selectively inhibits dihydrofolate reductase. Highly selective against plasmodia and T gondii. Synergistic effect when used conjointly with a sulfonamide to treat the latter.
Adult Dose Loading dose:
AIDS: 100-200 mg/d PO in combination with sulfadiazine 0.5-1.5 g PO q6h or clindamycin 600 mg PO q6h for 1-2 d
Non-AIDS: 50-200 mg/d PO in combination with sulfapyrimidine-type sulfonamide 0.25-1 g PO q6h for 2 doses
Maintenance dose:
Immunocompromise (ie, non-AIDS): 25-50 mg/d PO for at least 4-6 wk
AIDS: 50-75 mg/d PO for 3-6 wk initially; followed by maintenance therapy of 25 mg/d PO as lifelong therapy
Ocular: 25-50 mg/d PO for 4 wk
Congenital: 2 mg/kg/d PO for 2 d, then 1 mg/kg/d for 2-6 mo, then 1 mg/kg/d 3 times per wk for a minimum of 12 mo (in combination with sulfadiazine)
TE: 200 mg PO as a single dose initially, followed by 50-75 mg/d combined with sulfadiazine or clindamycin for at least 3 wk; as long as 6 wk or more may be required for severe disease
Immunocompetency: 25-50 mg/d PO for 2-4 wk
Prophylaxis/suppressive dose:
AIDS: 50 mg/wk PO combined with dapsone 50 mg/d to prevent first episode of TE in patients with AIDS; alternatively, suppress with 25-75 mg PO qd plus clindamycin 300-450 mg PO q6-8h
Pediatric Dose 2 mg/kg/d PO divided q12h for 2-4 d initially, then 1 mg/kg/d PO qd or divided q12h for 1 mo; not to exceed 25 mg/d
Contraindications Documented hypersensitivity; megaloblastic anemia due to folate deficiency
Interactions Coadministration with other antifolate drugs (eg, sulfonamides, trimethoprim, sulfamethoxazole) may increase risk of bone marrow suppression; discontinue if folate deficiency develops; folinic acid (leucovorin) should be administered until normal hematopoiesis restored; coadministration with lorazepam may cause mild hepatotoxicity
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Folic acid antagonist; most common adverse effect is dose-related bone marrow suppression, perform blood cell and platelet count twice weekly, decrease risk by concomitant administration of folinic acid (leucovorin), administer parenteral form of folinic acid 5-10 mg/d PO mixed with orange juice (<50>Spiramycin is a macrolide antibiotic with an antibacterial spectrum similar to that of erythromycin and clindamycin. It is bacteriostatic at serum concentrations but may be bactericidal at achievable tissue concentrations. Its mechanism of action is unclear, but it acts on the 50S subunit of bacterial ribosomes and interferes with translocation. Absorption from the gastrointestinal (GI) tract is irregular (20-50% of PO dose absorbed). Following PO administration, peak plasma levels are achieved within 2-4 h. Spiramycin has a longer half-life than erythromycin and sustains higher tissue levels. Drug Name
Azithromycin (Zithromax) -- Acts by binding to 50S ribosomal subunit of susceptible microorganisms and, thus, interfering with microbial protein synthesis. Nucleic acid synthesis is not affected.
Concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.
Treats mild-to-moderate microbial infections.
Adult Dose 500 mg PO day 1, followed by 250 mg/d for next 4 d
TE in AIDS patients: 1200-1500 mg PO qd for 3-6 wk
Pediatric Dose 10 mg/kg as single dose on day 1, not to exceed 500 mg/d; followed by 5 mg/kg on days 2-5, not to exceed 250 mg/d
Contraindications Documented hypersensitivity
Interactions May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Site reactions can occur with IV route; bacterial or fungal overgrowth may result from prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in impaired hepatic function, prolonged QT intervals, or pneumonia; caution in patients who are hospitalized, geriatric, or debilitated
Drug Name
Spiramycin (Rovamycine) -- DOC for maternal or fetal toxoplasmosis. Alternative therapy in other patient populations when unable to use pyrimethamine and sulfadiazine.
Adult Dose 3 g/d PO divided bid/qid for 3 wk, discontinue for 2 wk, then repeat at 5-wk cycles throughout pregnancy
Pediatric Dose 50-100 mg/kg/d PO divided bid/qid for 3-4 wk
Contraindications Documented hypersensitivity
Interactions Decreases bioavailability of carbidopa leading to decrease of levodopa levels
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Cross resistance between microorganism resistant to erythromycin and carbomycin; acute colitis experienced in 1% of patients; GI toxicity most common adverse effect; IV administration associated with peripheral paresthesias, irritation at injection site, dysesthesia, giddiness, pain, stiffness, burning sensation, and hot flashes; long-term use may result in superinfection; caution in cardiovascular disease, may prolong QT intervals; may elevate serum transaminases
Drug Category: Antidote -- Supplemental folinic acid is coadministered to prevent hematologic adverse effects caused by bone marrow suppression. Drug Name
Leucovorin (Wellcovorin) -- Also called folinic acid. Derivative of folic acid used with folic acid antagonists, such as sulfonamides and pyrimethamine.
Adult Dose 5-10 mg PO 3 times/wk
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; pernicious anemia or vitamin deficient megaloblastic anemias
Interactions Decreases effect of methotrexate, phenytoin, phenobarbital, sulfamethoxazole and trimethoprim combinations; increases toxicity of fluorouracil
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions May cause rash, pruritus, erythema, or urticaria
FOLLOW-UP Section 8 of 11
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Further Inpatient Care:

Standard precautions are recommended.
Further Outpatient Care:

Follow-up visits should occur every 2 weeks until the patient is stable, then monthly during therapy.
Obtain complete blood count weekly for the first month, then every 2 weeks.
Perform renal and liver function tests monthly.

Preventing the infection is particularly important for women who are pregnant and for patients who are seronegative and immunocompromised.
Avoid consuming raw or undercooked meat, unpasteurized milk, and uncooked eggs.
Wash hands after touching raw meat and after gardening or having other contact with soil.
Wash fruits and vegetables.
Avoid contact with cat feces.

To attempt to prevent congenital toxoplasmosis, routine serologic screening of pregnant women has been performed in order to identify fetuses at risk of becoming infected.
When feasible, avoid transfusions of blood products from a donor who is seropositive to a patient who is seronegative and immunocompromised.
If possible, recipients who are seronegative should receive transplanted organs from donors who are seronegative.

Seizure disorder or focal neurologic deficits may occur in CNS toxoplasmosis.
Partial or complete blindness may occur with ocular toxoplasmosis.
Multiple complications may occur with congenital toxoplasmosis, including mental retardation, seizures, deafness, and blindness.

Relapse often occurs in patients with immunocompromise if treatment is stopped.
Treatment may prevent the development of untoward sequelae in both symptomatic and asymptomatic infants with congenital toxoplasmosis.
Patient Education:

Mothers who are infected must be completely informed of potential consequences to their fetus.
Explain prevention methods, such as protecting children's play areas from cat litter.
For excellent patient education resources, visit eMedicine's Brain and Nervous System Center . Also, see eMedicine's patient education article Brain Infection.
MISCELLANEOUS Section 9 of 11
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Medical/Legal Pitfalls:

Misdiagnosis is possible.
PICTURES Section 10 of 11
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Caption: Picture 1. Toxoplasma gondii trophozoites in tissue culture.
View Full Size Image

Picture Type: Photo
BIBLIOGRAPHY Section 11 of 11
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Beaman MH: Toxoplasmosis. In: Rakel, ed. Conn's Current Therapy. 53rd ed. Philadelphia, Pa: WB Saunders 2001; 156-162[Full Text].
Bonfioli AA, Orefice F: Toxoplasmosis. Semin Ophthalmol 2005 Jul-Sep; 20(3): 129-41[Medline].
Boyer KM: Diagnostic testing for congenital toxoplasmosis. Pediatr Infect Dis J 2001; 20: 59-60[Medline].
Foulon W, Naessens A, Ho-Yen D: Prevention of congenital toxoplasmosis. J Perinat Med 2000; 28: 337-45[Medline].
Gardner WG: Toxoplasmosis. In: Dambro MR, ed. Griffith's 5-Minute Clinical Consult. Philadelphia, Pa: Lippincott Williams & Wilkins 1999; 1090-1091[Full Text].
Hill DE, Chirukandoth S, Dubey JP: Biology and epidemiology of Toxoplasma gondii in man and animals. Anim Health Res Rev 2005 Jun; 6(1): 41-61[Medline].
Jones JL, Lopez A, Wilson M, et al: Congenital toxoplasmosis: a review. Obstet Gynecol Surv 2001; 56: 296-305[Medline].
McLeod R, Boyer K, Roizen N, et al: The child with congenital toxoplasmosis. Curr Clin Top Infect Dis 2000; 20: 189-208[Medline].
Montoya JG, Rosso F: Diagnosis and management of toxoplasmosis. Clin Perinatol 2005 Sep; 32(3): 705-26[Medline].
Peyron F, Wallon M: Options for the pharmacotherapy of toxoplasmosis during pregnancy. Expert Opin Pharmacother 2001; 2: 1269-74[Medline].
Pinon JM, Dumon H, Chemla C, et al: Strategy for diagnosis of congenital toxoplasmosis: evaluation of methods comparing mothers and newborns and standard methods for postnatal detection of immunoglobulin G, M, and A antibodies. J Clin Microbiol 2001; 39: 2267-71[Medline].
Remington JS, Mc Leod R, Thulliez P: Toxoplasmosis. In: Remington JS and Klein JO,eds. Infectious Diseases of the Fetus and Newborn 2001; 205-346.
Robert-Gangneux F: Contribution of new techniques for the diagnosis of congenital toxoplasmosis. Clin Lab 2001; 47: 135-41[Medline].
Schwartzman JD: Toxoplasmosis. Curr Infect Dis Rep 2001; 3: 85-89[Medline].
Tenter AM, Heckeroth AR, Weiss LM, et al: Toxoplasma gondii: from animals to humans. Int J Parasitol 2000; 30: 1217-58[Medline].
Tierney LM Jr, McPhee SJ, Papadakis MA: Toxoplasmosis. In: Current Medical Diagnosis & Treatment. 40th ed. McGraw-Hill 2001; 1444-7.
Trikha I, Wig N: Management of toxoplasmosis in AIDS. Indian J Med Sci 2001; 55: 87-98[Medline].

Toxoplasmosis excerpt


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Last Updated: June 29, 2006 Email to a Colleague

Synonyms and related keywords: rubella, German measles, 3-day measles, roseola, röteln, roetheln, third disease, congenital rubella syndrome, CRS

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Author: Elias Ezike, MD, Fellow, Department of Pediatrics, Division of Pediatric Infectious Diseases, Children's Hospital of Michigan
Coauthor(s): Jocelyn Y Ang, MD, Assistant Professor, Department of Pediatrics, Division of Infectious Diseases, Children's Hospital of Michigan and Wayne State University; Basim Asmar, MD, Director, Department of Pediatrics, Division of Infectious Diseases, Children's Hospital of Michigan; Professor, Department of Pediatrics, Wayne State University School of Medicine

Elias Ezike, MD, is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, and Infectious Diseases Society of America

Editor(s): Leonard R Krilov, MD, Chief of Pediatric Infectious Diseases, Vice Chair, Department of Pediatrics, Professor of Pediatrics, Winthrop University Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Leslie L Barton, MD, Professor, Program Director, Department of Pediatrics, University of Arizona School of Medicine; Robert W Tolan, Jr, MD, Chief of Allergy, Immunology and Infectious Diseases, The Children's Hospital at St Peter's University Hospital, Clinical Associate Professor of Pediatrics, Drexel University College of Medicine; and Russell W Steele, MD, Professor and Vice Chairman, Department of Pediatrics, Head, Division of Infectious Diseases, Louisiana State University Health Sciences Center


INTRODUCTION Section 2 of 11
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Background: The name rubella is derived from a Latin term meaning "little red." Rubella is generally a benign communicable exanthematous disease. It is caused by rubella virus, which is a member of the Rubivirus genus of the family Togaviridae. Nearly one half of individuals infected with this virus are asymptomatic. Clinical manifestations and severity of illness vary with age. For instance, infection in younger children is characterized by mild constitutional symptoms, rash, and suboccipital adenopathy; conversely, in older children, adolescents, and adults, rubella may be complicated by arthralgia, arthritis, and thrombocytopenic purpura. Rare cases of rubella encephalitis have also been described in children.

The major complication of rubella is its teratogenic effects when pregnant women contract the disease, especially in the early weeks of gestation. The virus can be transmitted to the fetus through the placenta and is capable of causing serious congenital defects, abortions, and stillbirths. Fortunately, because of the successful immunization program initiated in the United States in 1969, rubella infection and congenital rubella syndrome rarely are seen today.

The few cases of rubella recorded in recent years involve susceptible individuals who have not been immunized with rubella vaccine and do not have a history of previous rubella infection.

An independent panel convened by the Centers for Disease Control and Prevention (CDC) in 2004 found that about 91% of the US population is immune to rubella. This explains the decreased number of outbreaks of rubella and congenital rubella syndrome reported in the recent years.


Postnatal rubella

The usual portal of entry of rubella virus is the respiratory epithelium of the nasopharynx. The virus is transmitted via the aerosolized particles from the respiratory tract secretions of infected individuals. The virus attaches to and invades the respiratory epithelium. It then spreads hematogenously (primary viremia) to regional and distant lymphatics and replicates in the reticuloendothelial system. This is followed by a secondary viremia that occurs 6-20 days after infection. During this viremic phase, rubella virus can be recovered from different body sites including lymph nodes, urine, cerebrospinal fluid, conjunctival sac, breast milk, synovial fluid, and lungs. Viremia peaks just before the onset of rash and disappears shortly thereafter. An infected person begins to shed the virus from the nasopharynx 3-8 days after exposure for 6-14 days after onset of the rash.

Congenital rubella syndrome

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


In the US: During the 1962-1965 worldwide epidemic, an estimated 12.5 million rubella cases occurred in the US, resulting in 20,000 cases of congenital rubella syndrome. Since the licensing of the live attenuated rubella vaccine in the United States in 1969, a substantial increase has been noted in the vaccination coverage among school-aged children and the population immunity. In 2004, the estimated vaccination coverage among school-aged children was about 95%, and the population immunity was about 91%.
As a result of the progress made in vaccination against rubella, a remarkable drop has occurred in the number of cases of rubella and congenital rubella syndrome. For instance, in 1969, a total of 57,686 cases of rubella and 31 cases of congenital rubella syndrome were recorded. Subsequently, from 1993-2000, the number of cases of rubella recorded annually decreased to a range of 128-364, and cases of congenital rubella syndrome also dropped to 4-9 cases per year. Since 2001, the annual number of rubella cases ranged from a record low of 7 in 2003 to 23 in 2001, and congenital rubella syndrome cases between 0-3 per year (see Table 1, Images 1 and 2).

An independent panel convened by the CDC in 2004 to assess progress towards elimination of rubella and congenital rubella syndrome in the United States concluded unanimously that rubella is no longer endemic in the United States. In fact, the pattern of virus genotypes isolated in recent years was consistent with virus originating in other parts of the world.

Following the near record-low levels in rubella incidence in the United States, the occurrence of isolated outbreaks among susceptible adults has also become rare. In fact no outbreak of rubella was reported from 2000-2005, in contrast to the preceding year interval, 1996-1999, when 16 outbreaks were reported. The median number of cases per outbreak was 21. The most recent cases occurred in New York during 1997-1998, Kansas in 1998, Nebraska in 1999, and Arkansas in 1999. Most of these outbreaks were reported in college campuses, military installations, prisons, and workplaces, including health care environments. In most instances, the individuals involved in these outbreaks have no history of rubella immunization. In addition, most of the outbreaks have been reported among persons who emigrated from countries where rubella is not included in the routine immunization schedule.

Internationally: Rubella occurs worldwide. The number of reported cases is high in countries where routine rubella immunization is either not available or was recently introduced. For instance, in Mexico in 1990, a total of 65,591 cases of rubella were reported. After the introduction of rubella vaccine into the childhood immunization schedule in 1998, the number of reported cases declined 68% to 21,173. In Europe, the incidence of rubella remains high. For instance, in 2003, a total of 304,320 cases were reported; 41% of these were from the Russian Federation, and 40% were from Romania.
Although the burden of congenital rubella syndrome is not well characterized in all countries, more than 100,000 cases are estimated to occur each year in developing countries alone. In Europe, a total of 47 cases of congenital rubella syndrome were reported from 2001-2003; 32% were from the Russian Federation, and 36% were from Romania.

Mortality/Morbidity: The morbidity and mortality rates of rubella disease dropped remarkably since the licensing of live attenuated rubella vaccine in 1969. In fact, in 1969, complicated rubella infection caused 29 fatalities in the United States, whereas from 1992-2001, only 0-2 deaths per year were recorded (see Table 1 and Image 3).

In contrast to postnatal rubella, which is not a debilitating disease, congenital rubella infection may result in growth delay, learning disability, mental retardation, hearing loss, congenital heart disease, and eye, endocrinologic, and neurologic abnormalities.

TABLE 1. Reported cases of Rubella, Deaths from Rubella, and number of cases of Congenital Rubella Syndrome (CRS) in the United States from 1969-2006*†

1969 57,686 29 31
1970 56,552 31 77
1971 45,086 20 68
1972 25,507 14 42
1973 27,804 16 35
1974 11,917 15 45
1975 16,652 21 30
1976 12,491 12 30
1977 20,395 17 23
1978 18,269 10 30
1979 11,795 1 62
1980 3,904 1 50
1981 2,077 5 19
1982 2,325 4 7
1983 970 3 22
1984 752 1 5
1985 630 1 0
1986 551 1 5
1987 306 0 5
1988 225 1 6
1989 396 4 3
1990 1,125 8 11
1991 1,401 1 47
1992 160 1 11
1993 192 0 5
1994 227 0 7
1995 128 1 6
1996 238 0 4
1997 181 0 5
1998 364 0 7
1999 267 0 9
2000 176 0 9
2001 23 2 3
2002 18 NA †† 1
2003 7 NA 1
2004* 7 NA 0
2005* 11 NA 1
2006* 1 NA 1

* = Data for reporting years 2004, 2005, and 2006 are provisional

†Data are from CDC: Summary of Notifiable Diseases, United States. MMWR Morb Mortal Wkly Rep 1997 Oct 31; 45(53): 1-87; CDC: Summary of Notifiable Diseases, United States. MMWR Morb Mortal Wkly Rep
1996 Oct 25; 44(53): 1-87; Summary of Notifiable Diseases, United States. MMWR Morb Mortal Wkly Rep
1994 Oct 21; 42(53): 1-73; Summary of Notifiable Diseases, United States. MMWR Morb Mortal Wkly Rep
2005 April 22; 52(54): 73-78; Deaths: National Center for Health Statistics Mortality Report for respective
years; and congenital rubella syndrome data from the National congenital Rubella Syndrome Registry.

†† NA indicates that data are not available

Race: No ethnic difference in incidence has been clearly demonstrated, although the characteristic rash is more difficult to diagnose in persons with dark skin.

Sex: No appreciable differences in infection rates by sex are apparent in children, but in adults, more cases are reported in women than in men. Rubella arthralgia and arthritis are more frequent in women than in men.

Age: Before licensing of the live attenuated vaccine in 1969, rubella in the United States was primarily a disease of school-aged children, with a peak incidence in children aged 5-9 years. Following widespread use of rubella vaccine in children, peak incidence has shifted to persons older than 20 years, who comprise 62% of cases of rubella reported in the United States.

CLINICAL Section 3 of 11
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Postnatal rubella
Exposure: Rubella virus is transmitted from person to person via the aerosolized particles from the respiratory tract. A history of exposure may not be present. Individuals may acquire the infection from a completely asymptomatic patient or from an individual shedding the virus during the incubation period.
Incubation period: The incubation is usually 14-21 days after exposure to a person with rubella.
Prodromal phase: Prodromal symptoms are unusual in young children but are common in adolescents and adults.
The following signs and symptoms usually appear 1-5 days before the onset of rash:

Eye pain on lateral and upward eye movement (a particularly troublesome complaint)


Sore throat


General body aches

Low-grade fever




Tender lymphadenopathy (particularly posterior auricular and suboccipital lymph nodes)

Forchheimer sign (an enanthem observed in 20% of patients with rubella during the prodromal period; can be present in some patients during the initial phase of the exanthem; consists of pinpoint or larger petechiae that usually occur on the soft palate)
Congenital rubella history focuses on the following:
The number of weeks of pregnancy when maternal exposure to rubella occurred (The risk of congenital rubella syndrome is higher if maternal exposure occurs during the first trimester.)
Maternal history of immunization or medical history of rubella
Evidence of intrauterine growth retardation during pregnancy
Manifestations suggestive of congenital rubella syndrome in a child

Postnatal rubella

The exanthem of rubella consists of a discrete rose-pink maculopapular rash ranging from 1-4 mm.

Rash in adults may be quite pruritic.

The synonym “3-day measles” derives from the typical course of rubella exanthem that starts initially on the face and neck and spreads centrifugally to the trunk and extremities within 24 hours. It then begins to fade on the face on the second day and disappears throughout the body by the end of the third day.

Temperature: Fever usually is not higher than 38.5°C (101.5°F).

Lymph nodes: Enlarged posterior auricular and suboccipital lymph nodes are usually found on physical examination.

Mouth: The Forchheimer sign may still be present on the soft palate.
Congenital rubella syndrome (see Table 2)
The classic triad presentation of congenital rubella syndrome consists of the following:

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

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

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

Intrauterine growth retardation, prematurity, stillbirth, and abortion

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




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

Bone lesions, such as radiographic lucencies

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

Hematologic disorders, such as anemia and thrombocytopenic purpura
Table 2. Clinicopathologic Abnormalities in Congenital Rubella

Abnormality Common/Uncommon Early/Delayed Comment

Intrauterine growth retardation Common Early

Prematurity Uncommon Early

Stillbirth Uncommon Early

Abortion Uncommon Early

Cardiovascular system

Patent ductus arteriosus Common Early May occur with pulmonary artery stenosis

Pulmonary artery stenosis Common Early Caused by intimal proliferation

Coarctation of the aorta Uncommon Early

Myocarditis Uncommon Early

Ventricular septal defect Uncommon Early

Atrial septal defect Uncommon Early


Cataract Common Early Unilateral or bilateral

Retinopathy Common Early Salt-and-pepper appearance; visual acuity unaffected; frequently unilateral

Cloudy cornea Uncommon Early Spontaneous resolution

Glaucoma Uncommon Early/Delayed May be bilateral

Microphthalmia Common Early Common in patients with unilateral cataract

Subretinal neovascularization Uncommon Delayed Retinopathy with macular scarring and loss of vision


Hearing loss Common Early/Delayed Usually bilateral; mostly sensorineural; may be central in origin; rare when maternal rubella occurs >4 months' gestation; sometimes progressive

Central nervous system

Meningoencephalitis Uncommon Early Transient

Microcephaly Uncommon Early May be associated with normal intelligence

Intracranial calcifications Uncommon Early

Encephalographic abnormalities Common Early Usually disappear by age 1 y

Mental retardation Common Delayed

Behavioral disorders Common Delayed Frequently related to deafness

Autism Uncommon Delayed

Chronic progressive panencephalitis Uncommon Delayed Manifest in second decade of life

Hypotonia Uncommon Early Transitory defect

Speech defects Common Delayed Uncommon in absence of hearing loss


Blueberry muffin spots Uncommon Early Represents dermal erythropoiesis

Chronic rubelliform rash Uncommon Early Usually generalized; lasts several weeks

Dermatoglyphic abnormalities Common Early


Interstitial pneumonia Uncommon Delayed Generalized; probably immunologically mediated


Hepatosplenomegaly Common Early Transient

Jaundice Uncommon Early Usually appears in the first day of life

Hepatitis Uncommon Early May not be associated with jaundice


Thrombocytopenia Common Early Transient; no response to steroid therapy

Anemia Uncommon Early Transient

Hemolytic anemia Uncommon Early Transient

Altered blood group expression Uncommon Early

Immune system

Hypogammaglobulinemia Uncommon Delayed Transient

Lymphadenopathy Uncommon Early Transient

Thymic hypoplasia Uncommon Early Fatal


Radiographic lucencies Common Early Transient; most common in distal femur and proximal tibia

Large anterior fontanel Uncommon Early

Micrognathia Uncommon Early

Endocrine glands

Diabetes mellitus Common Delayed Usually becomes apparent in second or third decade of life

Thyroid disease Uncommon Delayed Hypothyroidism, hyperthyroidism, and thyroiditis

Growth hormone deficiency Uncommon Delayed

Genitourinary system

Cryptorchidism Uncommon Early

Polycystic kidney Uncommon Early

Causes: Rubella and congenital rubella syndrome are caused by rubella virus. Only one antigenic type of rubella virus exists, and humans are the only natural hosts. The virus is spherical with a diameter of 50-70 nm, has a central core (ie, nucleocapsid), and is covered externally by a lipid-containing envelope. The nucleocapsid is composed of polypeptide (C protein) and a single-stranded ribonucleic acid (RNA).

Its outer envelope is made up of glycosylated lipoprotein, which contains 2 virus-specific polypeptides (E1, E2) and a host-cell–derived lipid. These 2 envelope proteins comprise the spiked 5- to 6-nm surface projections that are observed on the outer membrane of rubella virus and are important for the virulence of the virus.

Monoclonal antibodies directed against epitopes of E1 and E2 have neutralizing activity. Protein E1 is the viral hemagglutinin that binds both hemagglutination- and hemolysis-inhibiting antibodies.

Rubella virus is rapidly inactivated by 70% alcohol, ethylene oxide, formalin, ether, acetone, chloroform, free chlorine, deoxycholate, beta-propiolactone, ultraviolet light, extreme pH (<6.8 or >8.1), heat (>56°C), and cold (from -10 to -20°C). It is resistant to thimerosal and is stable at temperatures of -60°C or less. DIFFERENTIALS Section 4 of 11
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WORKUP Section 5 of 11
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Lab Studies:

Postnatal rubella
A clinical diagnosis of rubella may be difficult to make because many exanthematic diseases may mimic rubella infection. In addition, as many as 50% of rubella infections may be subclinical; therefore, laboratory studies are important to confirm the diagnosis of acute rubella infection.
The laboratory diagnosis of rubella can be made either though serologic testing or by viral culture. The serologic diagnosis consists of demonstrating the presence of rubella-specific immunoglobulin M (IgM) antibody in a single serum sample or observation of a significant (>4-fold) rise in rubella-specific immunoglobulin G (IgG) antibody titer between the acute and convalescent serum specimens drawn 2-3 weeks apart.
False-positive rubella IgM test results have been reported in persons with other viral infections (eg, acute Epstein-Barr virus [EBV], infectious mononucleosis, cytomegalovirus [CMV] infection, parvovirus B19 infection) and in the presence of rheumatoid factor (RF).
To demonstrate a 4-fold rise in rubella-specific IgG antibody, a serum sample should be obtained as soon as possible during the acute phase of infection and tested for rubella-specific IgG antibody. An aliquot of this serum should be frozen and stored for repeat testing later. Then, a second serum specimen is collected at 2-3 weeks and tested in the same laboratory at the same time with the first serum sample. The levels of rubella-specific IgG are compared between the first and the second sample to show a significant rise in antibody titers.
Several techniques are available for serologic testing, including the following:

Enzyme-linked immunosorbent assay (ELISA)

Immunofluorescent assay (IFA)

Latex agglutination (LA) test

Hemagglutination inhibition (HI) test

Complement fixation (CF) test

Passive hemagglutination antibody (PHA) test

Hemolysis-in-gel test
Among all the serologic tests available, ELISA is the most widely used because it is relatively inexpensive, technically easy to perform, rapid, and very sensitive.
Rubella viral cultures are time consuming, expensive, not readily available, and used mainly for tracking the epidemiology of rubella virus during an outbreak.

The most commonly used method for isolation of rubella virus from clinical specimens, taken from an infected person, is the interference technique using African green monkey kidney (AGMK) cells and an enterovirus.

The specimen (urine or nasopharyngeal swab) is inoculated onto primary AGMK monolayers. After 9-12 days, the cultures are challenged with an enterovirus. If rubella is present, it interferes with the challenge virus and no cytopathic effect (CPE) is observed on the AGMK cells. HI, CF, and immunofluorescence techniques have also been used to detect rubella-specific antigens in tissue culture.
Congenital rubella
Congenital rubella in infants and children is diagnosed by viral isolation or by serologic testing. In contrast to postnatal infection, viral isolation is the preferred technique in congenital rubella syndrome because rubella serology may be difficult to interpret in view of transplacental passage of rubella-specific maternal IgG antibody. In addition, rubella-specific IgM antibody may not be detectable at the time of evaluation. Congenital rubella syndrome has also been diagnosed using placental biopsy, rubella antigen detection by monoclonal antibody, and PCR.
Specimens used for viral isolation in congenital rubella include nasopharyngeal swab, urine, cerebrospinal fluid, and buffy coat of the blood.
In some infants with congenital rubella syndrome, rubella virus can persist and can be isolated from the nasopharyngeal and urine cultures throughout the first year of life or later.
The same serologic testing methods (ELISA, IFA, LA, HI, CF) discussed for postnatal rubella can be used to detect specific antibodies in congenital infection.
Rubella-specific IgM antibody is actively produced by the fetus or neonate and may be detected in the cord blood or neonatal serum.
Congenital rubella syndrome should be strongly suspected in infants older than 3 months if rubella-specific IgG antibody levels are observed and do not decline at the rate expected from passive transfer of maternal antibody (ie, equivalent of a 2-fold decline in HI titer per mo) in a compatible clinical situation.
Patients with concomitant immunodeficiency, such as agammaglobulinemia or dysgammaglobulinemia, may have a false-negative serology result for rubella. Therefore, viral isolation is required to confirm the diagnosis in this group of patients.
Imaging Studies:

Postnatal rubella: Imaging studies usually are not performed in postnatal rubella.
Congenital rubella syndrome
Chest radiography is indicated for infants who develop respiratory distress or other respiratory symptoms to exclude rubella-related interstitial pneumonitis or pulmonary edema that may result from congestive heart failure in children with severe or complicated congenital heart anomalies.
Radiography of the long bones may reveal radiolucencies in the metaphyses of long bones.
Echocardiography is important for patients with congenital heart defects to help diagnose the type of heart anomaly and evaluate the severity of the heart defect so that appropriate surgical plans can be made.
Computed tomography (CT) scan of the head may reveal intracranial calcifications and enlargement of the ventricles.
Magnetic resonance imaging (MRI) of the head may reveal cortical atrophy and white matter changes in patients with late-onset progressive panencephalitis.
Other Tests:

CBC count may reveal leukopenia and thrombocytopenia. It is used to monitor the course of thrombocytopenia.
Liver function tests, such as total and direct bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase levels may reveal hepatic injury due to disseminated rubella infection, especially in neonates.

Lumbar puncture is indicated to evaluate for possible causes in children who develop signs and symptoms of meningoencephalitis, such as full anterior fontanelle, irritability, hypotonia, seizures, lethargy, head retraction, and arching of the back.
In patients with rubella-related meningoencephalitis, cerebrospinal fluid examination usually reveals normal glucose levels, normal or slightly elevated protein levels, and mild pleocytosis (20-100 WBC/mm3) with lymphocyte predominance.
Histologic Findings:
Postnatal rubella: Histologically cutaneous lesions are nonspecific and demonstrate only a mild, superficial, perivascular, lymphocytic infiltrate.

Congential rubella: The gross neuropathologic features that present during autopsy of babies who are stillborn include microcephaly and various other malformations (ie, polymicrogyria, nonhemorrhagic subependymal germinal matrix cysts). Histologically, chronic inflammatory cells are found in the meninges and surrounding the intraparenchymal blood vessels. The vessel walls also show foci of subintimal fibrosis and mineralization.
TREATMENT Section 6 of 11
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Medical Care:

Postnatal rubella
Treatment is supportive. No specific antiviral agent for rubella is currently available.

Starch baths and antihistamines may be useful for adult patients with uncomplicated rubella and troublesome itching.

For complicated cases, treatment is as follows:

For severe arthritis affecting weight-bearing joints, encourage rest. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be helpful, but corticosteroids are not indicated.

For patients with encephalitis, provide supportive care with adequate fluid and electrolyte maintenance.

Thrombocytopenia usually is self-limited but, if severe, consider intravenous immunoglobulin (IVIG). Corticosteroids have not demonstrated any specific benefit. Splenectomy is not indicated.
Congenital rubella syndrome
Treatment is supportive.
Provide vision screening and hearing screening for asymptomatic newborns.

Treatment of symptomatic newborns is as follows:

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

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

Hepatosplenomegaly is monitored clinically. No intervention is required.

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

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

Infants who have a rubella-related heart abnormality should be carefully observed for signs of congestive heart failure. Echocardiography may be essential for diagnosis of heart defects.
Contact isolation is required for patients with congenital rubella during hospitalizations because babies are infected at birth and usually are contagious until older than 1 year unless viral cultures have produced negative results.
Surgical Care:

Postnatal rubella: Surgical care is not indicated.
Congenital rubella syndrome
Surgical treatment may be required for congenital heart anomalies, including PDA, coarctation of aorta, ventricular septal defect (VSD), atrial septal defect (ASD), and pulmonary artery stenosis.
Surgical treatment may be required for eye defects such as glaucoma, cataract, and retinal neovascularization.

Infectious disease specialist: Consult an infectious disease specialist for complicated postnatal rubella and congenital rubella syndrome.
Otolaryngologist: Audiometric testing and other hearing screening tests are necessary to promptly diagnose hearing loss in children who may benefit from proper educational programs.
Cardiologist and cardiothoracic surgeon: Children with congenital heart diseases require cardiology referral and echocardiography for adequate management. Lifesaving cardiac repair may be necessary.
Ophthalmologist: An ophthalmologic evaluation and follow-up care are necessary in children with ocular abnormalities. Glaucoma, cataract, and retinal neovascularization may require surgical intervention.
Neurologist: A neurologic evaluation and follow-up care are needed for children who have CNS anomalies, including motor weakness and delay, poor balance, mental retardation, behavioral abnormalities, and learning deficits.
Rehabilitation specialist: Adequate rehabilitation programs comprising physical and occupational therapy may be beneficial for patients with motor weakness and motor delay.
Diet: Diet is as tolerated.

Activity: Activity in rubella can be maintained as tolerated; however, rest is advised for patients who develop arthralgia or arthritis.

MEDICATION Section 7 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

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

FOLLOW-UP Section 8 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Further Inpatient Care:

Infants with complicated congenital rubella syndrome who develop respiratory distress need to be admitted to a neonatal intensive care unit (NICU) for management of hypoxia and, if necessary, ventilatory support.
Some babies may develop severe feeding problems necessitating nasogastric or gastrostomy tube feeding.
Significant hyperbilirubinemia may require inpatient treatment with phototherapy or exchange transfusion.
Further Outpatient Care:

Outpatient follow-up care is not necessary for patients with postnatal rubella.
Careful follow-up care after discharge from the hospital for patients with congenital rubella syndrome is composed of the following:
Hearing evaluation
Vision screening
Developmental screening
Monitor blood sugar levels and perform thyroid function tests when clinically indicated.
Education and rehabilitation follow-up care are important for children with congenital rubella.

Prevention of outbreaks from persons infected with rubella: All persons who have contact with patients infected with rubella or children with congenital rubella syndrome (eg, caregivers, household contacts, medical personnel, laboratory workers) should be immune to rubella to prevent rubella outbreaks from persons infected with rubella virus.
Isolation of hospitalized patients: Droplet precautions and standard precautions are recommended for 7 days after the onset of rash in patients with postnatally acquired rubella infections. Contact isolation is indicated for children with proven or suspected congenital rubella infection until they are aged at least 1 year unless nasopharyngeal swab and urine cultures after age 3 months are repeatedly negative for rubella virus. Some authorities suggest that an infant should be considered infectious until 2 cultures of clinical specimens obtained 1 month apart are negative for rubella virus.

School and child care centers: Children diagnosed with postnatal rubella should be excluded from school or child care centers for 7 days after onset of the rash.

Rubella vaccine

Rubella infection may be acquired from an infected asymptomatic person or from a patient during the incubation period for which infected persons may begin to shed the virus and, therefore, are contagious before the onset of symptoms. As a result, the most effective preventive strategy for rubella infection is the administration of rubella vaccine.

In the United States, the only licensed rubella vaccine since 1979 is the 27/3 strain, which is grown in human diploid cell cultures. It is available in 3 forms: as a combined vaccine with measles, mumps, and rubella (MMR), which is most widely used; a combined vaccine with measles, mumps, rubella, and varicella (MMRV), licensed by the US Food and Drug Administration on September 6, 2005; and in monovalent rubella vaccine, which is less frequently used. All 3 forms of vaccine are administered by subcutaneous injection at a standard dose of 0.5 mL.

After administration of a single dose of rubella vaccine, protective serum antibody develops in at least 95% of recipients older than 1 year. Studies have shown that a single dose confers long-term immunity, probably lifelong immunity, against clinical and asymptomatic infection in more than 90% of immunized persons.
MMR vaccine recommendation
Routine childhood immunization: Children receive 2 doses of MMR vaccine.

The first dose of MMR is received at age 12-15 months.

The second dose of MMR is received at age 4-6 years. Children who have not received the second dose by the time they enter school should receive it as soon as possible but no later than age 11-12 years.

Persons at risk: Persons who have not received at least 1 dose of the vaccine or who have no serologic evidence of immunity to rubella are susceptible to rubella and should be immunized with MMR vaccine.

MMR vaccine is especially recommended for all adults at risk of rubella infection (eg, college students, military recruits, health care personnel).

Although birth before 1957 generally is considered presumptive evidence of rubella immunity, serologic surveys of hospital workers indicate that approximately 6% of those born before 1957 do not have detectable rubella antibody. Therefore, health care facilities should consider recommending a dose of MMR vaccine to unvaccinated personnel (whether born before or after 1957) who do not have serologic evidence of rubella immunity.

All postpubertal females without documentation of immunity should be vaccinated unless they are known to be pregnant. Birth before 1957 or clinical diagnosis of rubella is not acceptable evidence of infection for women who could become pregnant because it is only presumptive evidence, not proof, of immunity. Women receiving the vaccine should be counseled not to become pregnant within 28 days of vaccine administration.

Routine serologic testing: Such testing is not recommended before administering the vaccine.
Precautions and contraindications of MMR vaccine
Recent administration of IG: Because IG preparations may interfere with the serologic response of rubella and the other components of MMR, the vaccine should be deferred to a later date depending on the dose and the type of IG given. For instance, patients receiving high doses of IG (1600-2000 mg/kg body weight), such as those given for treatment of Kawasaki disease and idiopathic thrombocytopenic purpura (ITP), should wait as long as 11 months before receiving MMR. Conversely, patients receiving low doses (eg, 10 mg/kg used in hepatitis B prophylaxis) should wait only 3 months before receiving MMR vaccine (refer to table 3.33 on page 423 of 2003 Red Book: Report of the Committee on Infectious Diseases for all suggested intervals).

Altered immunity: Enhanced replication of vaccine viruses may occur in persons who have immune deficiency diseases and in other persons with immunosuppression. Severe immunosuppression may be caused by many disease conditions, such as congenital immunodeficiency, HIV infection, and hematologic or generalized malignancy, and by therapy with immunosuppressive agents (eg, large doses of corticosteroids). For some of these conditions, all affected persons are severely immunocompromised. For other conditions, such as HIV infection, the degree to which the immune system is compromised depends on the severity of the condition, which, in turn, depends on the disease or treatment stage. Ultimately, the patient's physician must assume the responsibility for determining whether the patient is severely immunocompromised on the basis of clinical or laboratory assessment.

Persons infected with HIV

MMR should be administered to all asymptomatic persons infected with HIV who do not have evidence of severe immunosuppression (CD4 >15%). It also should be considered for all symptomatic persons infected with HIV who do not have evidence of severe immunosuppression (see Table 3) because persons infected with HIV are at increased risk of severe complications if infected with the natural strain of rubella virus.

The benefit of immunizing nonseverely immunosuppressed patients infected with HIV with MMR vaccine outweighs any vaccine adverse effects. Studies have shown that the immunologic response to live- and killed-antigen vaccines may decrease as HIV progresses and that vaccination early in the course of HIV infection may be more likely to induce an immune response. Therefore, it is important to immunize infants infected with HIV without severe immunosuppression with MMR vaccine as soon as possible after age 1 year. Consideration should be given to administration of the second dose of MMR vaccine as soon as 28 days after the first dose rather than waiting until the child is ready to enter kindergarten or first grade.
Table 3. Age-Specific CD4+ T-lymphocyte Count and Percentage of Total Lymphocytes as a Criteria for Severe Immunosuppression in Persons with HIV

Age Range
<12 mo 1-5 y 6-12 y ³13 y
Total CD4+ T-lymphocytes <750/mcL <500/mcL <200/mcL <200/mcL
CD4+ T-lymphocytes
(as % of total lymphocytes) <15% <15% <15% <14%


Systemically absorbed steroids can suppress the immune system in an otherwise healthy person. However, neither the dose nor the duration of therapy sufficient to cause immune suppression is well defined. Many experts agree that live virus vaccines, such as MMR and its components, may still be given when (1) steroid therapy is short term (ie, <14 d) with low-to-moderate doses, (2) low-to-moderate doses are administered daily or on alternate days, (3) long-term alternate-day treatment involves short-acting preparations, (4) steroids are used as physiologic maintenance for replacement therapy, and (5) steroids are administered topically (eg, eyes, skin), by aerosol, or by intraarticular, bursal, or tendon injection.

Most clinicians agree that persons who have received systemic steroid doses of more than or equivalent to a prednisone dose of 2 mg/kg of body weight or a total dose of 20 mg administered daily or on alternate days for an interval of more than 14 days should avoid vaccination with MMR for at least 1 month following the cessation of steroid therapy.

Persons who receive steroid doses of more than or equivalent to prednisone doses of 2 mg/kg or 20 mg total dose daily or on alternate days for an interval of less than 14 days generally can receive MMR, although some experts prefer waiting until 2 weeks after completion of therapy.

Persons who have received prolonged or extensive topical, aerosol, or other local corticosteroid therapy that causes clinical or laboratory evidence of systemic immunosuppression should also avoid vaccination with MMR for at least 1 month.
Leukemia: Persons with leukemia in remission who were not immune to measles, rubella, or mumps when leukemia was diagnosed may receive MMR or its component vaccines. For individuals who have received chemotherapy, MMR vaccine can be given 3 months after termination of chemotherapy and the patient's immune status recovery.

Pregnancy: MMR should not be given to pregnant women because of the theoretical risk of rubella infection to the fetus. Data collected by the CDC reveal the estimated risk to be 1.6%. However, no cases of congenital defects have been reported in the offspring of women who inadvertently received the vaccine in their first trimester of pregnancy. Healthcare providers should routinely conduct a rubella IgG test for all pregnant women at the earliest prenatal visit. A positive rubella IgG antibody test indicates rubella immunity. Pregnant women who are found to be susceptible should be monitored for signs of rubella during pregnancy and should be advised to avoid contact with persons with rash illness. Rubella vaccine should be administered to nonimmune persons upon completion of pregnancy, preferably prior to discharge from the hospital.

Severe illness: Generally, vaccination of persons with moderate or severe febrile illness should be deferred until they have recovered from the acute phase of their illness to avoid superimposing adverse effects of vaccination on the underlying illness or mistakenly attributing a manifestation of the underlying illness to the vaccine.


Rubella virus strain contained in MMR is grown in human diploid cell cultures, while the other 2 components, measles and mumps virus strains, are produced in chick embryo fibroblasts but do not contain significant amounts of egg white (ovalbumin) cross-reacting proteins. MMR also contains hydrolyzed gelatin as a stabilizer and trace amounts of neomycin. Anaphylactic reaction to MMR is rare. Recent data indicate that allergic reactions are mostly caused by other components of the vaccine, such as gelatin and neomycin.

Among persons who are allergic to eggs, the risk of serious allergic reactions, such as anaphylaxis, following administration of MMR is extremely low. For this reason, skin testing with vaccine is not predictive of allergic reactions to the vaccination and, therefore, is not required before administering MMR to persons who are allergic to eggs. Similarly, the administration of gradually increasing doses of vaccine is not required.

Nonanaphylactic reactions to MMR, such as urticaria and contact dermatitis, are not contraindications to immunization.

Children who developed a significant hypersensitivity reaction following the first dose of MMR vaccine should have serologic testing to determine immunity to the component of the vaccines. If shown to be immune, they should not receive a second dose of the vaccine. If the second dose is necessary, these children should have adequate evaluation for possible serious reaction to the vaccine, and skin testing should be considered before administration of the vaccine.

MMR immunization is contraindicated in children who have had immediate anaphylactic reaction following previous administration of the vaccine. However, these patients require serologic testing to determine whether they are immune to the components of the vaccine.

In case of history of anaphylactic reaction to topically or systematically administered neomycin, consultation with an allergist or immunologist is warranted. In addition, MMR should be administered only in settings where such reactions could be properly managed.
Adverse reactions to MMR

Fever of 39.4°C (103°F) or higher may develop in 5-15% of vaccine recipients from 5-12 days after immunization.

Rash develops in 5% of patients 7-10 days after vaccination.

Mild lymphadenopathy is common.

Joint pain is observed in 0.5% of young children.

Arthralgia is experienced in 25% of females who are past puberty.

Transient arthritis occurs in 10% of females who are past puberty.

Joint complaints occur approximately 7-21 days following MMR vaccination.

Rare cases of transient peripheral neuritic symptoms, such as paresthesia and pain in the arms and legs, have been reported.

Transient and benign thrombocytopenia within 2 months of immunization has been reported in 1 per 25,000-40,000 immunized children.

CNS manifestations have also been reported, but no causal relationship with rubella vaccine has been demonstrated.

Joint involvement: Arthralgia and arthritis are the most common complications of rubella in adolescents and adults. Females are affected 4-5 times more frequently than males. The joints are involved in up to one third of adult women; the fingers, wrists, knees, and ankles are the most frequently involved. Massive effusions often accompany rubella arthritis, and symptoms may persist for 10-14 days. Arthralgia usually begins with the onset of the rash and clears without sequelae within 2-30 days.
Thrombocytopenia: This is a rare complication, occurring in 1 per 3000 cases. Children are affected more frequently than adults, and girls are affected more often than boys. It is self-limited and lasts from a few days to several months.
Neurologic manifestations: Encephalitis is a rare complication and occurs with greater frequency in children. It occurs in 1 per 5000 cases and usually is observed 2-4 days after the onset of rash. In some patients, encephalitis may accompany the rash or be delayed as much as 1 week after onset of the exanthem. Cerebrospinal fluid examination usually shows mild pleocytosis (20-100 WBC/mm3) with predominance of lymphocytes. Glucose level is usually normal, while protein levels may be normal or slightly elevated. Rubella encephalitis usually resolves with little or no significant neurologic sequelae.
Mild hepatitis has been a rarely reported complication of acquired rubella.

The prognosis of postnatal rubella is good with full recovery, while congenital rubella syndrome may have a poor outcome with severe multiple-organ damage.
Patient Education:

All pregnant women should avoid any contact with persons infected with rubella.
All susceptible individuals should be immunized.
No special precaution is necessary in the household setting of a child with congenital rubella syndrome, although parents should be counseled regarding potential serious risk to pregnant women exposed to the child.
For excellent patient education resources, visit eMedicine's Children's Health Center and Bacterial and Viral Infections Center. Also, see eMedicine's patient education articles Measles; Skin Rashes in Children; and Immunization Schedule, Children.
MISCELLANEOUS Section 9 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Medical/Legal Pitfalls:

Failure to diagnose rubella in an infected person may result in a potential outbreak among susceptible persons.
Failure to diagnose rubella in women early in pregnancy and offer the option of therapeutic abortion may result in development of congenital rubella syndrome in their infants.
Failure to provide adequate vaccination to susceptible persons increases their risk of acquiring the infection.
Special Concerns:

Care of women who are pregnant and exposed to rubella virus
If a pregnant woman is exposed to rubella virus in the first trimester of gestation, serologic investigation should be performed promptly.

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

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

The options for a woman exposed to rubella in early pregnancy include pregnancy termination for confirmed infection or administration of IG if termination is not acceptable under any circumstances.
Postexposure prophylaxis during pregnancy
IG administered to a pregnant woman following exposure to rubella is controversial and may not prevent infection of the fetus. The IG may modify the clinical manifestations in the mother without diminishing the viral replication and, therefore, leave the fetus unprotected.

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

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

Whether a higher dose of IG given intravenously is useful to prevent congenital rubella syndrome is unknown.
Consequence of RA 27/3 rubella vaccine administered inadvertently during the first trimester of pregnancy
Concern exists that RA 27/3 rubella vaccine, licensed in the United States in 1979, might have a greater teratogenic and fetotropic potential than earlier vaccines. However, no evidence indicates that the vaccine caused congenital rubella syndrome or any fetal abnormalities in the offspring of the 272 susceptible women who inadvertently received RA 27/3 vaccine within 3 months of their pregnancy from 1979-1988. Similarly, data collected before 1979 have shown no cases of congenital rubella syndrome in the offspring of women who were unknowingly immunized with other types of rubella vaccines during the first trimester of gestation.

Notwithstanding this evidence, recommended guidelines continue to state that pregnancy is a contraindication to the administration of rubella vaccines because vaccine viruses can cross the placenta barrier and infect the fetus.

Inadvertent vaccination of pregnant women during early pregnancy should not be a reason to consider interruption of pregnancy because no teratogenic effects attributable to rubella vaccines have been reported.
Rubella reinfection
Reinfection is a rubella infection occurring in an individual known to be immune to rubella either through naturally acquired disease or as a result of immunization against rubella infection. Rubella reinfection is estimated to occur in 5-10% of persons previously immune to rubella. It is usually subclinical but occasionally may be clinically apparent.

Maternal reinfection is uncommon but can occur, and, as noted above, congenital rubella syndrome occurring after maternal reinfection has been rarely been reported in the literature, especially after a clinically apparent rubella reinfection. Thus, all pregnant women should avoid rubella exposure.
Provided that appropriate sera are taken, a primary rubella infection can usually be distinguished from a reinfection on the basis of serologic response at the time of reinfection. In both primary infection and reinfection, a significant rise occurs in rubella-specific IgG antibody, but in a primary infection, a strong IgM antibody response also occurs and persists for approximately 4-12 weeks. In reinfection, IgM antibody either is not produced or found only in low concentrations. Thus, reinfection can be diagnosed if the initial sample taken at the moment of rubella exposure is IgG positive, implying rubella immunity, and a significant rise in rubella-specific IgG with a negative or low rubella-specific IgM antibody titer is demonstrated in a subsequent serum sample collected about 2 weeks later.
PICTURES Section 10 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Caption: Picture 1. Number of rubella cases per year.
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Picture Type: Graph
Caption: Picture 2. Number of congenital rubella syndrome cases per year.
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Picture Type: Graph
Caption: Picture 3. Deaths from rubella per year.
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Picture Type: Graph
BIBLIOGRAPHY Section 11 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

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Rubella excerpt



Firman Abdullah Bung

drFirman Abdullah SpOG / ObGyn

drFirman Abdullah SpOG / ObGyn


Dr Firman Abdullah SpOG/ OBGYN, Bukittinggi, Sumatera Barat ,Indonesia

Dr Firman Abdullah SpOG/ OBGYN,                              Bukittinggi, Sumatera Barat ,Indonesia

Bukittinggi , Sumatera Barat , Indonesia

Bukittinggi , Sumatera Barat  , Indonesia
Balaikota Bukittinggi

dr Firman Abdullah SpOG / OBGYN

dr Firman Abdullah SpOG / OBGYN

Ngarai Sianok ,Bukittinggi, Sumatera Barat.Indonesia

Ngarai Sianok ,Bukittinggi, Sumatera Barat.Indonesia

Brevet in Specialist Obstetric's & Gynecologist 1998

Brevet in Specialist Obstetric's & Gynecologist 1998
dr Firman Abdullah SpOG/ObGyn

Dokter Spesialis Kebidanan dan Penyakit Kandungan . ( Obstetric's and Gynaecologist ) . Jl.Bahder Johan no.227,Depan pasar pagi ,Tembok .Bukittinggi 26124 ,HP:0812 660 1614. West Sumatra,Indonesia

Sikuai Beach ,West Sumatra ,Indonesia

Sikuai Beach ,West Sumatra ,Indonesia

Fort de Kock, Bukittinggi