Toxoplasmosis

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Background

Toxoplasmosis is caused by infection with the protozoan Toxoplasma gondii, an obligate intracellular parasite. The infection produces a wide range of clinical syndromes in humans, land and sea mammals, and various bird species. T gondii has been recovered from locations throughout the world, except Antarctica (see the image below). (See Etiology and Pathophysiology.)


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Toxoplasmosis. Toxoplasma gondii tachyzoites (Giemsa stain).

Nicolle and Manceaux first described the organism in 1908, after they observed the parasites in the blood, spleen, and liver of a North African rodent, Ctenodactylus gondii. The parasite was named Toxoplasma (arclike form) gondii (after the rodent) in 1909. In 1923, Janku reported parasitic cysts in the retina of an infant who had hydrocephalus, seizures, and unilateral microphthalmia. Wolf, Cowan, and Paige (1937-1939) determined that these findings represented the syndrome of severe congenital T gondii infection.

There are 3 major genotypes (type I, type II, and type III) of T gondii. These genotypes differ in their pathogenicity and prevalence in people. In Europe and the United States, type II genotype is responsible for most cases of congenital toxoplasmosis.[1]

T gondii infects a large proportion of the world's population (perhaps one third) but uncommonly causes clinically significant disease.[2] However, certain individuals are at high risk for severe or life-threatening toxoplasmosis. Individuals at risk for toxoplasmosis include fetuses, newborns, and immunologically impaired patients. (See Etiology and Pathophysiology and Epidemiology.)

Congenital toxoplasmosis is usually a subclinical infection. Among immunodeficient individuals, toxoplasmosis most often occurs in those with defects of T-cell–mediated immunity, such as those with hematologic malignancies, bone marrow and solid organ transplants, or acquired immunodeficiency syndrome (AIDS).In most immunocompetent individuals, primary or chronic (latent) T gondii infection is asymptomatic. A small percentage of these patients eventually develop retinochoroiditis, lymphadenitis, or, rarely, myocarditis and polymyositis. (SeePresentation and Workup.)

Patient education

Primary prevention based on prenatal education could be an effective strategy to reduce congenital toxoplasmosis. Educate the public in toxoplasmosis-prevention methods, such as protecting children's play areas from cat litter. Mothers with toxoplasmosis must be completely informed of the disease’s potential consequences to the fetus.[3] [#Etiology]

Etiology and Pathophysiology

Life cycle of Toxoplasma gondii

T gondii has 2 distinct life cycles. The sexual cycle occurs only in cats, the definitive host. The asexual cycle occurs in other mammals (including humans) and various strains of birds. It consists of 2 forms: tachyzoites (the rapidly dividing form observed in the acute phase of infection) and bradyzoites (the slowly growing form observed in tissue cysts).

A cat becomes infected with T gondii by eating contaminated raw meat, wild birds, or mice. The organism’s sexual cycle then begins in the cat’s gastrointestinal (GI) tract. Macrogametocytes and microgametocytes develop from ingested bradyzoites and fuse to form zygotes. The zygotes then become encapsulated within a rigid wall and are shed as oocysts. The zygote sporulates and divides to form sporozoites within the oocyst. Sporozoites become infectious 24 hours or more after the cat sheds the oocyst via feces.

During a primary infection, the cat can excrete millions of oocysts daily for 1-3 weeks. The oocysts are very strong and may remain infectious for more than one year in warm humid environments.

T gondii oocysts, tachyzoites, and bradyzoites can cause infection in humans. Infection can occur by ingestion of oocysts following the handling of contaminated soil or cat litter or through the consumption of contaminated water or food sources (eg, unwashed garden vegetables). Transmission of tachyzoites to the fetus can occur via the placenta following primary maternal infection.

Rarely, infection by tachyzoites occurs from ingestion of unpasteurized milk or by direct entry into the bloodstream through a blood transfusion or laboratory accident. Transmission can also occur via ingestion of tissue cysts (bradyzoites) in undercooked or uncooked meat or through transplantation of an organ that contains tissue cysts. (Slaughterhouse workers and butchers may be at increased risk of infection.) In Europe and the United States, pork is the major source of T gondii infection in humans.

The seroprevalence of T gondii antibodies in the human population varies geographically, with prevalence rates approaching 90% in some European countries, while seropositivity rates in the United States have been estimated to fall between 10% and 15%.[4, 5] Infection with the human immunodeficiency virus (HIV) does not seem to effect T gondii seropositivity, and there does not appear to be any difference in the rate of toxoplasmosis infection among patients with AIDS with and without cats.[5]

Cellular invasion

As previously stated, T gondii oocysts are ingested in material contaminated by feces from infected cats. Oocysts may also be transported to food by flies and cockroaches. When T gondii is ingested, bradyzoites are released from cysts or sporozoites are released from oocysts, and the organisms enter gastrointestinal cells. Host cell receptors consisting of laminin, lectin, and SAG1 are involved in T gondii tachyzoite attachment and penetration. Tachyzoites multiply, rupture cells, and infect contiguous cells. They are transported via the lymphatics and are disseminated hematogenously throughout the tissues.

The ability of T gondii to actively penetrate host cells results in formation of a parasitophorous vacuole that is derived from the plasma membrane, which is entirely distinct from a normal phagocytic or endocytic compartment.[6] Following apical attachment, the parasite rapidly enters the host cell in a process that is significantly faster than phagocytosis. The vacuole is formed primarily by invagination of the host cell plasma membrane, which is pulled over the parasite through the concerted action of the actin-myosin cytoskeleton of the parasite. During invasion, the host cell is essentially passive and no change is detected in membrane ruffling, the actin cytoskeleton, or phosphorylation of host cell proteins. (See the images below.)


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Toxoplasmosis. Toxoplasma gondii tachyzoites in cell line.


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Toxoplasma gondii in infected monolayers of HeLa cells (Giemsa stain).

Tachyzoites proliferate, producing necrotic foci surrounded by a cellular reaction. Upon the development of a normal immune response, tachyzoites disappear from tissues. In immunodeficient individuals and in some apparently immunologically healthy patients, the acute infection progresses, resulting in potentially lethal consequences such as pneumonitis, myocarditis, and necrotizing encephalitis.

Tissue cysts form as early as 7 days after infection and remain for the lifespan of the host. The tissue cysts are up to 60μm in diameter, each containing up to 60,000 organisms. They produce little or no inflammatory response but cause recrudescent disease in immunocompromised patients or retinochoroiditis in congenitally infected older children.

Changes in T-lymphocyte levels

Alterations in subpopulations of T lymphocytes are profound and prolonged during acute acquired T gondii infection. These have been correlated with disease syndromes but not with disease outcome. Some patients with prolonged fever and malaise have lymphocytosis, increased suppressor T-cell counts, and a decreased helper-to-suppressor T-cell ratio. These patients may have fewer helper cells even when they are asymptomatic.

In some patients with lymphadenopathy, helper-cell counts are diminished for more than 6 months after infection onset. Ratios of T-cell subpopulations may also be abnormal in asymptomatic patients. Some patients with disseminated toxoplasmosis have a very marked reduction in T cells and a marked depression in the ratio of helper to suppressor T lymphocytes. Depletion of inducer T lymphocytes in patients with AIDS may contribute to the severe manifestations of toxoplasmosis observed in these patients.

Retinochoroiditis

Retinochoroiditis usually results from reactivation of congenital infection, although cases have been recorded that were part of acute infection.[7, 8]

There are 5 hypotheses related to the inflammatory process of ocular toxoplasmosis, as follows[9] :

When the organism reaches the eye through the bloodstream, depending on the host's immune status, a clinical or subclinical focus of infection begins in the retina. As the host's immune system responds and the tachyzoites convert themselves into bradyzoites, the cyst forms. The cyst is extremely resistant to the host's defenses, and a chronic, latent infection ensues. If a subclinical infection is present, no funduscopic changes are observed. The cyst remains in the normal-appearing retina. Whenever the host's immune function declines for any reason, the cyst wall may rupture, releasing organisms into the retina, and the inflammatory process restarts. If an active clinical lesion is present, healing occurs as a retinochoroidal scar. The cyst often remains inactive within or adjacent to the scar. (See the image below.)


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Inactive retinochoroidal scar secondary to toxoplasmosis

Toxoplasma parasites are rarely identified in aqueous humor samples from patients with active ocular toxoplasmosis.[10] This suggests that parasite proliferation occurs only during the early phase of infection and that the retinal damages are probably caused by subsequent inflammatory responses.

When human retinal pigment epithelium (RPE) cells are infected with Toxoplasma gondii, there is an increased production of several cytokines, including interleukin 1beta (IL-1ß), interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating factor, and intercellular adhesion molecule (ICAM).[11] Patients with acquired toxoplasmic retinochoroiditis exhibit higher levels of IL-1 than asymptomatic patients.[12]

It appears that IL-1 gene polymorphisms, in particular genotypes that are related with a high production of IL-1a, may be associated with recurrence of toxoplasmic retinochoroiditis.[13] IL-10 polymorphisms associated with a low production of IL-10 also appear to be associated with the occurrence of toxoplasmic retinochoroiditis.[14] In contrast, tumor necrosis factor (TNF)–alpha gene polymorphism has not been found to be associated with the occurrence or recurrence of toxoplasmic retinochoroiditis.[15]

Congenital toxoplasmosis

Approximately 10-20% of pregnant women infected with T gondii become symptomatic.[16] The most common signs of infection are lymphadenopathy and fever. If the mother was infected prior to pregnancy, there is virtually no risk of fetal infection, as long as she remains immunocompetent.[16]

When a mother is infected with T gondii during gestation, the parasite may be disseminated hematogenously to the placenta. When this occurs, infection may be transmitted to the fetus transplacentally or during vaginal delivery.[17, 18]

If the mother acquires the infection in the first trimester and it goes untreated, the risk of infection to the fetus is approximately 14-17%, and toxoplasmosis in the infant is usually severe. If the mother is infected in the third trimester and it goes untreated, the risk of fetal infection is approximately 59-65%, and involvement is mild or not apparent at birth. These different rates of transmission are most likely related to placental blood flow, the virulence and amount of T gondii acquired, and the immunologic ability of the mother to restrict parasitemia.

The most significant manifestation of toxoplasmosis in the fetus is encephalomyelitis, which may have severe results. Approximately 10% of prenatal T gondii infections result in abortion or neonatal death. In approximately 67-80% of prenatally infected infants, the infection is subclinical and can be diagnosed using only serological and other laboratory methods. Although these infants appear healthy at birth, they may develop clinical symptoms and deficiencies later in life.

Congenital toxoplasmosis caused by atypical genotypes is more severe than that caused by typical genotypes.[1]

Some infants with more severe congenital infection appear to have Toxoplasma antigen–specific lymphocytic anergy, which may be important in the pathogenesis of their disease. Monoclonal gammopathy of the immunoglobulin G (IgG) class has been described in congenitally infected infants, and IgM levels may be elevated in newborns with congenital toxoplasmosis. Glomerulonephritis with deposits of IgM, fibrinogen, and Toxoplasma antigen has been reported in congenitally infected individuals.

Circulating immune complexes have been detected in sera from an infant with congenital toxoplasmosis and in older individuals with systemic, febrile, and lymphadenopathic forms of toxoplasmosis. However, these complexes did not persist after signs and symptoms resolved. Total serum levels of IgA may be diminished in congenitally infected babies, but no predilection toward associated infections has been noted. The predilection toward predominant involvement of the central nervous system (CNS) and retina in this congenital infection has not been fully explained.

Infection in immunocompromised patients

Most cases of toxoplasmosis in immunocompromised patients are a consequence of latent infection and reactivation. In patients with AIDS, T gondii tissue cysts can reactivate with CD4 counts of less than 200 cells/μL; with counts of less than 100 cells/μL, clinical disease becomes more likely.[19] Without adequate prophylaxis or restoration of immune function, patients with CD4 counts of less than 100 cells/μL who are T gondii IgG-antibody positive have a 30% risk of eventually developing reactivation disease.[20]

Although toxoplasmosis in immunocompromised patients may manifest as retinochoroiditis, reactivation disease in these individuals is typically in the CNS, with brain involvement being common.

Toxoplasmic encephalitis and brain abscess present most commonly as headache, but focal neurologic deficits and seizures are as common. With significant disease, patients may also demonstrate the signs and symptoms of elevated intracranial pressure. Cerebral toxoplasmosis is generally identified on computed tomography (CT) scan as multiple ring-enhancing lesions; however, solitary lesions may be seen, and negative CT or magnetic resonance imaging (MRI) scans should not rule out the diagnosis of CNS toxoplasmosis.[21]

Aside from CNS toxoplasmosis, other conditions commonly identified in immunocompromised patients include toxoplasmic pneumonitis, myocarditis, and disseminated toxoplasmosis. Toxoplasmic pneumonitis typically presents with symptoms typical for an infectious pulmonary process, including fever, dyspnea, and cough. Chest radiography is often nonspecific, but findings may have an appearance similar to that of Pneumocystis (carinii) jiroveci pneumonia. Diagnosis is established via bronchoalveolar lavage. Most patients with extra-CNS manifestations of toxoplasmosis will also be noted to have CNS lesions when appropriate radiographic studies have been performed.[22]

Effects of toxoplasmosis on mental disorders

Recent investigations have suggested that chronic toxoplasmosis may play several roles in the etiology of different mental disorders.[23]

Numerous clinical studies have evaluated the prevalence of anti-Toxoplasma antibodies in patients with schizophrenia and other forms of severe psychiatric disorders. The most probable mechanism by which T gondii could cause schizophrenia is by affecting neurotransmitters in brain areas known to be involved in schizophrenia.[24, 25] According to these studies, bradyzoites of T gondii affect dopamine and other neurotransmitters in rodents and humans. A few studies have also investigated the association between T gondii infection and Parkinson and Alzheimer diseases.[26, 27]

Epidemiology

Occurrence in the United States

Approximately 225,000 cases of toxoplasmosis are reported each year, resulting in 5000 hospitalizations and 750 deaths, making T gondii the third most common cause of lethal foodborne disease in the United States.

Seropositivity rates in the United States have been reported to be between 10% and 15%, although sources vary, and higher infection rates have been estimated.[4, 5] In general, the incidence of the infection varies by population group and geographic locale. For example, the cultural habits of a population may affect the acquisition of T gondii infection from ingested tissue cysts in undercooked or uncooked meat.

The prevalence of T gondii antibodies in US military recruits decreased by one third from 1965-1989; the crude seropositivity rate among recruits from 49 states was 9.5% in 1989, compared with 14.4% in 1965. T gondii infection affects more than 3500 newborns in the United States each year. T gondii seropositivity rates among patients with HIV infection vary from 10-45%.

Toxoplasmosis are more common in southern states, in African Americans, and in populations with lower socioeconomic status.[28]

Intraocular toxoplasmosis manifested by necrotizing retinochoroiditis has been reported in 1-21% patients with acquired systemic infections. In a population study, 0.6% residents of Maryland were found to have scars consistent with ocular toxoplasmosis.[29]

Toxoplasmic encephalitis has been reported in 1-5% of patients with AIDS. Within the United States, significant differences are recognized in the incidence of toxoplasmic encephalitis by geographic region and by ethnic group. Toxoplasmosis in patients with AIDS is reported to occur 3 times more frequently in Florida than in other areas of the United States; in patients of Haitian origin with AIDS who live in Florida, 12-40% develop toxoplasmic encephalitis.

Toxoplasmic encephalitis has been reported to be the index AIDS diagnosis in 44-58% of patients with HIV infection who have toxoplasmic encephalitis.

International occurrence

In many populations, such as those in El Salvador and France, the seropositivity rate to T gondii is as high as 75% by the fourth decade of life. As many as 90% of adults in Paris are seropositive. Approximately 50% of the adult population in Germany is infected. Women of childbearing age in much of Western Europe, Africa, and South and Central America have seroprevalence rates of greater than 50%.[30]

Based on serologic studies, estimates suggest the incidence of primary maternal T gondii infection during pregnancy ranges from about 1-310 cases per 10,000 pregnancies in different populations in Europe, Asia, Australia, and the Americas. The incidence of prenatal T gondii infection within the same or similar populations has been estimated to range from about 1-120 cases per 10,000 births.[31, 32, 33, 34, 35]

The prevalence of immunocompromised patients is higher in some nations as a function of HIV/AIDS infection and also organ transplantation and immunomodulatory medication prescribing. In individuals with HIV infection, the seropositivity rate to T gondii is approximately 50-78% in certain areas of Western Europe and Africa.

Toxoplasmic encephalitis is the AIDS-defining diagnosis in 16% of patients with AIDS. In France, 37% of patients with AIDS have evidence of toxoplasmic encephalitis at autopsy.

Age-related demographics

With the exception of T gondii retinochoroiditis, older individuals are more likely to manifest clinically evident reactivation of Tgondii infection. Congenitally acquired Tgondii retinochoroiditis is more likely to recur in persons older than 40 years.[36]

Prognosis

Immunocompetent patients have an excellent prognosis, and lymphadenopathy and other symptoms generally resolve within weeks of infection.

Toxoplasmosis in immunodeficient patients often relapses if treatment is stopped. Suppressive therapy and immune reconstitution significantly reduce the risk of recurrent infection.

Multiple complications may occur in persons with congenital toxoplasmosis, including mental retardation, seizures, deafness, and blindness. Treatment may prevent the development of untoward sequelae in symptomatic and asymptomatic infants with congenital toxoplasmosis. Infants with congenitally acquired toxoplasmosis generally have a good prognosis and are on average developmentally identical to noninfected infants by the fourth year of life.

Toxoplasmic encephalitis and brain abscess can result in permanent neurologic sequelae, depending on the location of the lesion and the extent of local damage and inflammation. Basal ganglia seem to be preferentially involved. Seizure disorder or focal neurologic deficits may occur in persons with CNS toxoplasmosis.

Ophthalmic complications

Toxoplasmosis is the most common cause of intraocular inflammation and posterior uveitis in immunocompetent patients throughout the world. Toxoplasmosis is responsible for approximately 30-50% of all posterior uveitis cases in the United States.

Retinochoroiditis is a relatively common manifestation of T gondii infection. Ocular toxoplasmosis occurs when cysts deposited in or near the retina become active, producing tachyzoites. Focal necrotizing retinitis is the characteristic lesion, but retinal scars from prior reactivation are typically present. Presentation usually involves eye pain and decreased visual acuity. Adults who acquired disease in infancy usually present with bilateral eye involvement. Adults with acute infection generally present with unilateral ocular involvement.[37, 38, 36, 39]

Depending on the location and severity of toxoplasmic retinochoroiditis, infection can result in permanent retinal scarring and loss of visual acuity. Recurrent episodes are common, resulting in multiple areas of retinal scarring and functional loss. (See the images below.)


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Ophthalmic toxoplasmosis. Used with permission of Anton Drew, ophthalmic photographer, Adelaide, South Australia.


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Macular scar secondary to congenital toxoplasmosis. Visual acuity of the patient is 20/400


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Papillitis secondary to toxoplasmosis, necessitating immediate systemic therapy.


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Acute macular retinitis associated with primary acquired toxoplasmosis, requiring immediate systemic therapy


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Peripapillary scars secondary to toxoplasmosis


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Perimacular scars secondary to toxoplasmosis


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Inactive retinochoroidal scar secondary to toxoplasmosis

Vascular endothelial growth factor (VEGF) has been shown to be a key molecular player in the pathogenesis of choroidal neovascular membrane (CNV). In the current era of anti-VEGF therapy, the extraordinary results obtained in CNV secondary to age-related macular degeneration have been extrapolated to other causes of CNV with apparent good results.[40, 41] Currently available anti-VEGF agents include bevacizumab, ranibizumab, and pegaptanib sodium.

Secondary glaucoma may occur with anterior uveitis that is secondary to the obstruction of the outflow channels by the inflammatory cells. This condition may or may not be reversible.

Destruction of the trabecula by chronic inflammation and anterior synechiae may also create a chronic pharmacologically nonresponsive glaucoma.

Other ocular complications include:

Morbidity and mortality

Acute toxoplasmosis is asymptomatic in 80-90% of healthy hosts. In some apparently immunologically healthy patients, however, the acute infection progresses and may have lethal consequences.

Although a relatively small percentage of toxoplasmosis cases are congenital, they tend to account for most acute and fatal infections.

In immunosuppressed patients, T gondii infection, like other opportunistic infections, can lead to rapidly progressive, fatal disease. Indeed, toxoplasmosis is recognized as a major cause of neurologic morbidity and mortality among patients with advanced HIV disease.

However, the incidence of toxoplasmosis (including CNS disease) in patients with AIDS has declined dramatically, likely due to the evolution of highly active antiretroviral therapy (HAART) and the routine use of prophylaxis against P (carinii) jiroveci and T gondii. The incidence of CNS toxoplasmosis decreased from 5.4 cases per 1000 person-years between 1990 and 1992 to 2.2 cases per 1000 persons-years between 1996 and 1998.[42] The routine use of cotrimoxazole prophylaxis in the United States and internationally has also likely significantly decreased the incidence of CNS toxoplasmosis.

History

Only 10-20% of toxoplasmosis cases in adults and children are symptomatic. Toxoplasmosis is a serious and often life-threatening disease in immunodeficient patients. Congenital toxoplasmosis may manifest as a mild or severe neonatal disease, with onset during the first month of life or with sequelae or relapse of a previously undiagnosed infection at any time during infancy or later in life. Congenital toxoplasmosis has a wide variety of manifestations during the perinatal period.

Acute toxoplasmosis in immunocompetent persons

Acute toxoplasmosis in hosts who do not have AIDS but are immunodeficient

The disease in these patients may be newly acquired or a reactivation. It may be characterized as follows:

Symptoms associated with reactivation toxoplasmosis are dependent on the tissue or organ affected.

Clinical manifestations of toxoplasmosis in patients with AIDS

Brain involvement (ie, toxoplasmic encephalitis), with or without focal CNS lesions, is the most common manifestation of toxoplasmosis in individuals with AIDS.

Clinical findings include the following:

The characteristic presentation is usually a subacute onset, with focal neurologic abnormalities in 58-89% of cases. However, in 15-25% of cases, the clinical presentation is more abrupt, with seizures or cerebral hemorrhage. Most commonly, hemiparesis and/or speech abnormality is the major initial manifestation.

Brainstem involvement often produces cranial nerve lesions, and many patients exhibit cerebral dysfunction with disorientation, altered mental state, lethargy, and coma.

Less commonly, parkinsonism, focal dystonia, rubral tremor, hemichorea-hemiballismus, panhypopituitarism, diabetes insipidus, or syndrome of inappropriate antidiuretic hormone secretion may dominate the clinical picture.

In some patients, neuropsychiatric symptoms such as paranoid psychosis, dementia, anxiety, and agitation may be the major manifestations.

Diffuse toxoplasmic encephalitis may develop acutely and can be rapidly fatal; generalized cerebral dysfunction without focal signs is the most common manifestation, and CT scan findings are normal or reveal cerebral atrophy.

Spinal cord involvement manifests as motor or sensory disturbances of single or multiple limbs, bladder or bowel dysfunctions, or both and local pain. Patients may present with clinical findings similar to those of a spinal cord tumor. Cervical myelopathy, thoracic myelopathy, and conus medullaris syndrome have been reported.

Pulmonary toxoplasmosis (pneumonitis) due to toxoplasmosis is increasingly recognized in patients with AIDS who are not receiving appropriate anti-HIV drugs or primary prophylaxis for toxoplasmosis. The diagnosis may be confirmed by demonstrating T gondii in bronchoalveolar lavage fluid.

Pulmonary toxoplasmosis occurs mainly in patients with advanced AIDS (mean CD4+ count of 40 cells/µL ±75 standard deviation) and primarily manifests as a prolonged febrile illness with cough and dyspnea. Pulmonary toxoplasmosis may be clinically indistinguishable from P (carinii) jiroveci pneumonia, and the mortality rate, even when treated appropriately, may be as high as 35%.

Extrapulmonary toxoplasmosis develops in approximately 54% of persons with toxoplasmic pneumonitis.

Ocular toxoplasmosis, ie, toxoplasmic retinochoroiditis, is relatively uncommon in patients with AIDS; it commonly manifests as ocular pain and loss of visual acuity. Funduscopic examination usually demonstrates necrotizing lesions, which may be multifocal or bilateral. Overlying vitreal inflammation is often present and may be extensive. The optic nerve is involved in as many as 10% of cases.

Other, uncommon manifestations of toxoplasmosis in patients with AIDS include the following:

Congenital toxoplasmosis

This is most severe when maternal infection occurs early in pregnancy. Approximately 15-55% of congenitally infected children do not have detectable T gondii –specific IgM antibodies at birth or early infancy. Approximately 67% of patients have no signs or symptoms of infection.

Retinochoroiditis occurs in about 15% of patients, and intracranial calcifications develop in about 10%. Cerebrospinal fluid (CSF) pleocytosis and elevated protein values are present in 20% of patients.

Infected newborns have anemia, thrombocytopenia, and jaundice at birth. Microcephaly has been reported. Affected survivors may have mental retardation, seizures, visual defects, spasticity, hearing loss or other severe neurologic sequelae.

The prevalence of sensorineural hearing loss is as high as 28% in children who do not receive treatment.[43]

Ocular toxoplasmosis

Patients develop retinochoroiditis (focal necrotizing retinitis). They have a yellowish white, elevated cotton patch with indistinct margins. The lesions may occur in small clusters. Congenital disease is usually bilateral and acquired disease is usually unilateral.

Symptoms include the following:

Physical Examination

The acquired infection is usually subclinical and asymptomatic. In 10-20% of cases that become symptomatic, the patient develops a flulike illness characterized by fever, lymphadenopathy, malaise, myalgias, and a maculopapular skin rash that spares the palms and the soles.[44] In individuals who are immunocompetent, the disease is benign and self-limited. Hepatosplenomegaly can also occur. Infrequently, patients develop myocarditis, polymyositis, pneumonitis, hepatitis, or encephalitis

The most common form of symptomatic acute toxoplasmosis in immunocompetent individuals is lymphadenopathy. The typical presentation is painless, firm lymphadenopathy that is confined to 1 chain of nodes, most commonly cervical.

Ophthalmologic examination reveals multiple yellow-white cottonlike patches with indistinct margins located in small clusters in the posterior pole.

A flare-up of congenitally acquired retinochoroiditis is often associated with scarred lesions juxtaposed to the fresh lesion.

Ocular toxoplasmosis (retinochoroiditis)

Symptoms of retinochoroiditis include the following[45] :

Immunocompromised individuals (AIDS CD4 count < 100 cells/microL)

Host immune function plays an important role in the pathogenicity of toxoplasmosis. Symptoms depend largely on the organ system and tissue involved and may be gradual in onset over a few weeks. They include the following:

Multifocal, bilateral, and relentlessly progressive lesions characterize the ocular involvement. Because of their immunosuppression, these patients often have problems mounting an inflammatory reaction, which makes the formation of a retinochoroidal scar difficult. Often, the serologic diagnosis is also difficult.

Congenital toxoplasmosis

The classic clinical triad of retinochoroiditis, cerebral calcifications, and convulsions defines congenital toxoplasmosis. Other findings include the following:

Approach Considerations

Results from basic laboratory studies such as complete blood cell count (CBC), chemistries, and liver function tests (LFTs) are typically normal, although lymphocytosis may be present.

Direct detection

The diagnosis of toxoplasmosis is confirmed with the demonstration of T gondii organisms in blood, body fluids, or tissue. T gondii may be isolated from the blood via either inoculation of human cell lines or mouse inoculation. Mouse inoculation may require a longer time to yield results and also is likely to be more expensive. Isolation of T gondii from amniotic fluid is diagnostic of congenital infection by mouse inoculation.

Molecular diagnosis and polymerase chain reaction

Molecular diagnostic methods of diagnosing toxoplasmosis include techniques such as conventional polymerase chain reaction (PCR), nested PCR, and real-time PCR for detection of T gondii DNA in clinical samples. The original protocol for molecular detection of T gondii using con­ventional PCR targeted the B1 gene. Studies have also described detection of T gondii based on amplification of ITS-1 and 18S rDNA fragments, a method whose sensitiv­ity was similar to the B1 gene.

According to recent studies, the repetitive element of 529 bp in length has shown a sensitivity that is 10-times that of the sensitivity using the B1 gene. Real-time PCR detection of T gondii DNA based on the 529 bp repetitive element is the most frequently used molecular diagnostic approach for toxoplasmosis.

Polymerase chain reaction (PCR) assay testing on body fluids, including CSF, amniotic fluid, bronchoalveolar lavage fluid, and blood, may be useful in the diagnosis. However, PCR assay is capable of detecting T gondii deoxyribonucleic acid (DNA) in either an aqueous sample or a vitreous sample in only one third of patients with ocular toxoplasmosis.[46, 47]

Indirect detection

Indirect detection is performed in pregnant women and in immunocompromised patients. Detection of immunoglobulin G (IgG) is possible within 2 weeks of infection using the enzyme-linked immunosorbent assay (ELISA) test, the IgG avidity test, and the agglutination and differential agglutination tests. (Acute and convalescent sera have no role in the indirect detection of toxoplasmosis.)

Procedures

The following diagnostic procedures may be performed for toxoplasmosis:

Tachyzoites may be demonstrated in tissues or smears obtained from biopsy. They also can be seen in CSF. CSF also shows mononuclear pleocytosis and elevated protein level. Tachyzoites demonstrate acute infection, while tissue cysts and bradyzoites are seen in chronic/latent infection (although they may be present in acute infection/reactivation).

Testing in pregnancy

Although testing in pregnancy may not be indicated and treatment may not have established literature support, a low index of suspicion is needed to identify acute infection in pregnant patients.

Suspected congenital infection in a pregnant patient should be confirmed before administering treatment by having samples tested at a toxoplasmosis reference laboratory using tests that are as accurate as possible and correctly interpreted.[48]

Ophthalmic disease

Antibody titers do not correlate with ophthalmic disease. Antitoxoplasmic antibodies may be very low and should be tested in undiluted (1:1) samples if possible. The absence of antibodies rules out the disease; nevertheless, false-negative results do occur.

Invasive techniques are usually reserved for difficult cases, such as patients who are immunocompromised. Ocular fluids can demonstrate the presence of intraocular antibody production. Polymerase chain reaction assay can detect the causative organism.

Immunoglobulin Testing

Acute systemic toxoplasmosis has traditionally been diagnosed by seroconversion. Anti-Toxoplasma immunoglobulin G (IgG) titers present a 4-fold increase that peak 6-8 weeks following infection and then decline over the next 2 years, although they remain detectable for life. Anti-Toxoplasma IgM appears in the first week of the infection and then declines in the next few months. The presence of anti-Toxoplasma IgA has also been shown to be detectable in acute infection; however, since the titers can last for more than 1 year, its value in helping to diagnose an acute phase is limited.

Detection of IgG is possible within 2 weeks of infection using the ELISA test, the IgG avidity test, and the agglutination and differential agglutination tests. The presence of IgG indicates a likely past infection, while the presence of IgM usually indicates acute infection (particularly in the absence of IgG). However, IgM has, in some cases, been documented to persist for months or years.

Lack of IgG and IgM may exclude infection. IgM alone that then transitions to IgG without IgM or both IgG and IgM indicates likely acute infection. There is a significant rate of false IgM positivity. The sensitivities and specificities of the commercially available IgM and IgG tests vary substantially.

Sabin-Feldman dye test

The Sabin-Feldman dye test is a sensitive and specific neutralization test for toxoplasmosis. It is used to measure primarily IgG antibody and is the standard reference test for toxoplasmosis. However, it requires live T gondii organisms; therefore, it is not available in most laboratories. (It is used primarily as a confirmatory test in reference laboratories.) High titers suggest acute toxoplasmosis.[49]

Fluorescent antibody test

The indirect fluorescent antibody test is used to measure the same antibodies as the dye test. Titers parallel dye test titers. The IgM fluorescent antibody test is used to detect IgM antibodies within the first week of infection, but titers fall within a few months.

Hemagglutination test

The indirect hemagglutination test is easy to perform. However, it usually does not detect antibodies during the acute phase of toxoplasmosis. Titers tend to be higher and remain elevated longer.

ELISA test

The results from a double-sandwich IgM ELISA are more sensitive and specific than the results from other IgM tests.

Enzyme-linked immunofiltration assay (ELIFA) is based on the use of a microporous cellulose acetate membrane in a co-immunoelectrodiffusion procedure. The ELIFA method has a better diagnostic yield than specific IgM and/or IgA detection by immunocapture assay.[50]

IgG avidity test

The results of the IgG avidity test may help to differentiate patients with acute infection from those with chronic infection better than do 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.

IgG produced early in infection is less avid and binds to T gondii antigens more weakly than do antibodies produced later in the course of infection. High antibody avidity indicates an older, earlier infection. This test may be helpful in the setting of pregnancy, as the timing of infection has prognostic value. A long-term pattern occurring late in pregnancy does not exclude the possibility that the acute infection may have occurred during the first months of gestation.[51]

Imaging Studies

Head CT scanning in cerebral toxoplasmosis (general)

In most immunodeficient patients with toxoplasmic encephalitis, CT scans show multiple bilateral cerebral lesions. However, although multiple lesions are more common in persons with toxoplasmosis, they may be solitary. Therefore, a single lesion should not exclude toxoplasmic encephalitis as a diagnostic possibility.

Head CT scanning in cerebral toxoplasmosis (in patients with AIDS)

CT scans in patients with AIDS who have toxoplasmic encephalitis reveal multiple ring-enhancing lesions in 70-80% of cases. In patients with AIDS who have detectable Toxoplasma IgG and multiple ring-enhancing lesions on CT scans or MRIs, the predictive value for toxoplasmic encephalitis is approximately 80%.

Lesions tend to occur at the corticomedullary junction (frequently involving the basal ganglia) and are characteristically hypodense.

The number of lesions is frequently underestimated when assessed using CT scan images, although delayed imaging after a double dose of intravenous (IV) contrast material may improve the sensitivity of this modality. An enlarging, hypodense lesion that does not enhance is a poor prognostic sign.

Single-photon computed tomography

Single-photon computed tomography (SPECT) scanning is useful in distinguishing between CNS lymphoma and infection (ie, toxoplasmosis or any other infection).

PET scanning, radionuclide scanning, and MR techniques

Various positron emission tomography (PET) scanning, radionuclide scanning, and magnetic resonance techniques have been used to evaluate patients with AIDS who have focal CNS lesions and to specifically differentiate between toxoplasmosis and primary CNS lymphoma.

MRI

MRI has superior sensitivity (particularly if gadolinium is used for contrast) to CT scanning, and MRI scans often demonstrate a single or multiple lesion(s) or more extensive disease not apparent on CT scans. One study showed that MRI detected abnormalities in 40% of patients whose abnormalities were not detected on CT.[52]

Toxoplasmic encephalitis lesions on MRIs appear as high-signal abnormalities on T2-weighted studies and have a rim of enhancement surrounding the edema on T1-weighted, contrast-enhanced images.

Hence, MRI should be used as the initial procedure when feasible (and especially if a single lesion is demonstrated on CT scan images). Nevertheless, even characteristic lesions on CT scans or MRIs are not pathognomonic of toxoplasmic encephalitis.

The major differential diagnosis of focal CNS lesions in patients with AIDS is CNS lymphoma, which manifests as multiple enhancing lesions in 40% of cases.

The probability of toxoplasmic encephalitis falls and the probability of lymphoma rises in the presence of single lesions on MRI scans. Therefore, a brain biopsy may be required to obtain a definitive diagnosis in patients with a solitary lesion (especially if confirmed with MRI).

CT scanning abnormalities improve after 2-3 weeks of treatment in approximately 90% of patients with AIDS who have toxoplasmic encephalitis. Complete resolution takes 6 weeks to 6 months; peripheral lesions resolve more rapidly than do deeper ones.

Smaller lesions usually resolve completely within 3-5 weeks as shown on MRI, but lesions with a mass effect tend to resolve more slowly and leave a small residual lesion.

A radiologic response to therapy lags behind the clinical response, with better correlation by the end of acute therapy.

Ultrasonography

Ultrasonographic diagnosis of congenital toxoplasmosis in a fetus is available at 20-24 weeks' gestation. Fetal or neonatal ultrasonography can be useful in cases of known or suspected maternal acute infection and transplacental infection. Findings are generally nonspecific but include ventriculomegaly and CNS calcifications, particularly in the basal ganglia.

Histologic Findings

Histopathologic data for human toxoplasmosis has been obtained mostly from autopsy studies in infants and immunodeficient patients with serious infections. Such knowledge in immunocompetent patients is limited.

Pathologic findings are usually obtained from lymph node biopsy specimens in these patients. Multiple brain abscesses are commonly found, often involving the cerebral cortex and deep gray nuclei, less often the brainstem and cerebellum, and rarely the spinal cord. (See the images below.)


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Toxoplasmosis. Toxoplasma gondii tachyzoites (Giemsa stain).


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Toxoplasmosis. Toxoplasma gondii tachyzoites in cell line.


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Toxoplasma gondii in infected monolayers of HeLa cells (Giemsa stain).

In acute toxoplasmosis, lesions are composed of central necrotic foci with varying petechiae rounded by acute and chronic inflammation, vascular proliferation, and macrophage infiltration. Tachyzoites and bradyzoites in tissue cysts may be detected at the periphery of the necrotic foci. T gondii are commonly found on hematoxylin and eosin or Giemsa stains. However, parasites can be more easily described via immunohistochemical staining. The blood vessels in the area of necrotic lesions may demonstrate distinguished intimal proliferation or frank vasculitis with thrombosis and fibrinoid necrosis.

Chronic lesions are composed of small cystic fields containing a number of lipid- and hemosiderin-laden macrophages with surrounding gliosis. Parasites are difficult to find in older lesions.

Emergency Department Care

Care of the patient in the emergency department should be specific to the presenting manifestations of the disease. Adequate airway, breathing, and circulation must be assessed and treated accordingly. Adequate fluid resuscitation, pain control, and fever control must be ensured.

Neuroimaging should be considered for any immunocompromised patient with a new neurologic deficit, cranial nerve abnormality, severe headache, or altered mental status.

Because the symptoms associated with acute toxoplasmosis are nonspecific and dependent on the tissues involved, emergency providers must be vigilant and include other infectious and noninfectious etiologies in their differential diagnoses. As such, broad-spectrum antimicrobial therapy is often necessary early in the course of illness, prior to the performance of definitive testing and while the diagnosis may still be uncertain. Emergency consultation with relevant subspecialties may be required for assistance in empiric treatment and the diagnostic workup.

Approach Considerations

Treatment is usually unnecessary in asymptomatic hosts, except in children younger than 5 years. Symptomatic patients should be treated until immunity is ensured.

Outpatient care is sufficient for acquired toxoplasmosis in immunocompetent hosts and for persons with ocular toxoplasmosis. Inpatient care is appropriate initially for persons with CNS toxoplasmosis and for acute toxoplasmosis in immunocompromised hosts.

Patients with AIDS who have a CD4 count of less than 100 cells/μL should be commenced on suppressive therapy for T gondii until they undergo immune reconstitution.

Consultations

Subspecialty consultation is required for the seriously ill patient, according to organ-specific involvement. Moreover, in the setting of immunocompromise, involvement of one organ system (ie, retina) mandates analysis of further organ system involvement (ie, CNS). In addition to an infectious diseases specialist, the following are recommended consultations:

Follow-up

Follow-up visits should be scheduled every 2 weeks until the patient is stable, and then monthly during therapy. A CBC should be performed weekly for the first month, and then every 2 weeks. Renal and liver function tests should be performed monthly.

Infants with confirmed congenital toxoplasmosis should be followed for evidence of developmental delay and should receive ophthalmologic consultation and follow-up.

Activity

The level of activity in patients with toxoplasmosis depends on the severity of disease and the organ systems involved.

Deterrence and Prevention

Preventing toxoplasmosis is particularly important in seronegative immunocompromised patients and in pregnant women. Precautions against the disease include the following:

Moreover, travel to areas of high endemicity (Western Europe, South America) may increase the risk of exposure.

Avoiding transfusions of blood products from a donor who is seropositive to a patient who is seronegative and immunocompromised is prudent, when feasible. If possible, organ recipients who are seronegative should receive transplanted organs from donors who are seronegative.

Laboratory workers can become infected via ingestion of sporulated T gondii oocysts from feline fecal specimens or via skin or mucosal contact with either tachyzoites or bradyzoites in human or animal tissue or culture. Laboratories should have established protocols for handling specimens that contain viable T gondii and for responding to laboratory accidents.

Medication Summary

Currently recommended drugs in the treatment of toxoplasmosis act primarily against the tachyzoite form of T gondii; thus, they do not eradicate the encysted form (bradyzoite). Pyrimethamine is the most effective agent and is included in most drug regimens. Leucovorin (ie, folinic acid) should be administered concomitantly to prevent bone marrow suppression. Unless circumstances preclude using more than 1 drug, a second drug (eg, sulfadiazine, clindamycin) should be added.[53, 54, 55]

The efficacy of azithromycin, clarithromycin, atovaquone, dapsone, and cotrimoxazole is unclear; therefore, they should be used only as alternatives in combination with pyrimethamine. The most effective available therapeutic combination is pyrimethamine plus sulfadiazine or trisulfapyrimidines (eg, a combination of sulfamerazine, sulfamethazine, and sulfapyrazine). These agents are active against tachyzoites and are synergistic when used in combination.

Careful attention to dosing regimen is necessary because it differs depending on patient variables (eg, immune status, pregnancy). Pyrimethamine may be used with sulfonamides, quinine, and other antimalarials and with other antibiotics.

Nonpregnant patients

Immunocompetent, nonpregnant patients typically do not require treatment. Treatment of nonpregnant patients is described below.

The 6-week regimen is as follows:

Sulfadiazine or clindamycin can be substituted for azithromycin 500 mg daily or atovaquone 750 mg twice daily in immunocompetent patients or in patients with a history of allergy to the former drugs

Consider steroids in patients with radiologic midline shift, clinical deterioration after 48 hours, or elevated intracranial pressure.

Pregnant patients

The diagnosis of acute infection is often difficult to make during pregnancy, and the administration of empiric antimicrobial therapy is discouraged.

Substantial controversy exists regarding the efficacy of treatment during pregnancy in terms of reducing the risk of fetal exposure and the subsequent development of clinical disease such as retinochoroiditis or CNS abnormalities.

Controversy also exists regarding the optimal regimen for treating maternally acquired infection. Spiramycin and pyrimethamine-sulfonamide are used, but given the infrequency of fetal infection and the asymptomatic nature of most fetal infections, treatment effects are difficult to measure. Spiramycin appears to be somewhat more easily tolerated than pyrimethamine-sulfonamide.

A dosing regimen for pregnant patients is as follows:

Patients with AIDS

Patients with AIDS are treated with pyrimethamine 200 mg orally initially, followed by 50-75 mg/day orally plus folinic acid 10 mg/day orally plus sulfadiazine 4-8 g/day orally for as long as 6 weeks, followed by lifelong suppressive therapy or until immune reconstitution.

Suppressive therapy for patients with AIDS (CD4 count < 100 cells/μL) is pyrimethamine 50mg/day orally plus sulfadiazine 1-1.5 g/day orally plus folinic acid 10 mg/day orally for life or until immune reconstitution.

Patients with AIDS, CNS toxoplasmosis, and evidence of midline shift or increased intracranial pressure may also benefit from steroid therapy.

Diagnosing toxoplasmosis in the absence of definitive tissue or culture evidence may be perilous because serology may be misleading and a false-positive IgM result is somewhat common. Consequently, empiric therapy should be avoided.

Retinitis

The mere presence of a focus of retinitis is not always an indication for treatment. Small, peripheral lesions generally heal spontaneously and may be followed conservatively. On the other hand, lesions in the vascular arcade, lesions near the optic disc (Jensen papillitis), lesions in the papillomacular bundle, or large lesions (irrespective of location) are treated. Patients with severe, debilitating vitreitis are also treated aggressively. (See the image below.)


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Acute macular retinitis associated with primary acquired toxoplasmosis, requiring immediate systemic therapy

In a prospective trial, treatment with several regimens failed to shorten the duration of inflammatory activity or to prevent recurrences. However, treatment did reduce the size of the ultimate retinochoroidal scar.

In addition, experts differ on their preferred initial treatment. In a report, one third of respondents preferred triple therapy (ie, pyrimethamine, sulfadiazine, prednisone), and a little more than one quarter of respondents preferred quadruple therapy (ie, pyrimethamine, sulfadiazine, clindamycin, prednisone).

Sulfadiazine

Clinical Context:  Through competitive antagonism of PABA, sulfadiazine interferes with microbial growth. It is useful in the treatment of toxoplasmosis.

Trimethoprim and sulfamethoxazole (Bactrim DS, Septra DS)

Clinical Context:  Trimethoprim/sulfamethoxazole exerts bacteriostatic action through competitive antagonism with PABA. The double-strength tablet contains 800 mg of sulfamethoxazole and 160 mg of trimethoprim. The regular strength tablet contains 400 mg of sulfamethoxazole and 80 mg of trimethoprim.

Class Summary

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.

Sulfonamide antimicrobials exist as 3 forms in serum: free, conjugated (ie, acetylated and possibly others), and protein bound. The free form is considered therapeutically active.

Dapsone

Clinical Context:  Dapsone is bactericidal and bacteriostatic against mycobacteria. Its mechanism of action is similar to that of sulfonamides, ie, it is a competitive antagonist of PABA, preventing the formation of folic acid and inhibiting bacterial growth.

Class Summary

Antimicrobials with activity against mycobacteria may be used

Clindamycin (Cleocin)

Clinical Context:  Clindamycin is an alternative to sulfonamides. It may be beneficial when used with pyrimethamine in the acute treatment of CNS toxoplasmosis in patients with AIDS.

Class Summary

These agents are used to treat serious skin and soft-tissue staphylococcal infections. They are also effective against aerobic and anaerobic streptococci (except enterococci). They inhibit bacterial growth, possibly by blocking the dissociation of peptidyl transfer ribonucleic acid (t-RNA) from ribosomes, causing RNA-dependent protein synthesis to arrest.

Pyrimethamine (Daraprim)

Clinical Context:  This is a folic acid antagonist that selectively inhibits plasmodial dihydrofolate reductase. Pyrimethamine is highly selective against plasmodia and T gondii. A synergistic effect occurs when it is used conjointly with a sulfonamide to treat toxoplasmosis. Folinic acid should be given to all patients to prevent hematologic toxicity of pyrimethamine

Atovaquone (Mepron)

Clinical Context:  Atovaquone is a hydroxynaphthoquinone that inhibits the mitochondrial electron transport chain by competing with ubiquinone at the ubiquinone-cytochrome-c-reductase region (complex III). Inhibition of electron transport by atovaquone results in inhibition of nucleic acid and adenosine triphosphate (ATP) synthesis in parasites.

Class Summary

Protozoal infections occur throughout the world and are a major cause of morbidity and mortality in some regions. Immunocompromised patients are especially at risk. Primary immunodeficiency 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.

Azithromycin (Zithromax, Zmax)

Clinical Context:  Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms, thereby interfering with microbial protein synthesis. Nucleic acid synthesis is not affected.

Azithromycin concentrates in phagocytes and fibroblasts, as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration of the drug in phagocytes contributes to drug distribution to inflamed tissues. Azithromycin treats mild to moderate microbial infections.

Spiramycin

Clinical Context:  This is the drug of choice for maternal or fetal toxoplasmosis. It is an alternative therapy in other patient populations when pyrimethamine and sulfadiazine cannot be used.

Class Summary

Spiramycin is a macrolide antibiotic with an antibacterial spectrum similar to erythromycin and clindamycin. It is bacteriostatic at serum concentrations but may be bactericidal at achievable tissue concentrations. The mechanism of action is unclear, but it acts on the 50S subunit of bacterial ribosomes and interferes with translocation. Absorption from the GI tract is irregular (20-50% of the oral dose is absorbed). Following oral administration, peak plasma levels are achieved within 2-4 hours. Spiramycin has a longer half-life than erythromycin and sustains higher tissue levels.

Prednisone

Clinical Context:  Prednisone is used to limit inflammatory damage. The use of oral corticosteroids without antibiotic coverage may produce an immunodeficiency state that results in the rapid spread of tachyzoites and widespread retinitis. Antiparasitic agents should be stopped only after the steroids have been stopped. The steroids should never be used without antiparasitic coverage in the treatment of ocular toxoplasmosis.

Corticosteroids are probably not indicated in patients who are immunosuppressed. Some specialists wait 24-48 hours after the initiation of antibiotic therapy before starting prednisone, while others begin antibiotics and prednisone simultaneously.

Prednisolone acetate 1% (Pred Forte, Omnipred)

Clinical Context:  This agent decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability. The frequency of application depends on degree of ocular inflammation.

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli. In cases in which anterior uveitis is present, topical corticosteroids are used to treat the inflammation.

Leucovorin

Clinical Context:  This agent is also called folinic acid. Leucovorin is a derivative of folic acid that is used with folic acid antagonists, such as sulfonamides and pyrimethamine.

Class Summary

These agents are used to replenish folic acid when the patient is being treated with folic acid antagonists.

Cyclopentolate 0.5%, 1%, 2% (AK-Pentolate, Cyclogyl, Cylate)

Clinical Context:  This agent prevents the muscle of the ciliary body and the sphincter muscle of the iris from responding to cholinergic stimulation. It induces mydriasis in 30-60 minutes and cycloplegia in 25-75 minutes. Infants should not be given concentrations of more than 0.5%.

Class Summary

As in any eye with uveitis, posterior synechiae often form if a pupil is not mobilized. Anticholinergic agents, such as cyclopentolate, atropine, and homatropine, block the sphincter muscle of the iris and the muscle in the ciliary body that is responsible for accommodation to produce mydriasis and paralysis of accommodation.

Author

Murat Hökelek, MD, PhD, Professor, Department of Clinical Microbiology, Istanbul University Cerrahpasa Medical Faculty, Turkey

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center

Disclosure: Nothing to disclose.

Additional Contributors

Joseph U Becker, MD Fellow, Global Health and International Emergency Medicine, Stanford University School of Medicine

Joseph U Becker, MD is a member of the following medical societies: American College of Emergency Physicians, Emergency Medicine Residents Association, Phi Beta Kappa, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

John L Brusch, MD, FACP Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance

John L Brusch, MD, FACP is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Theodore J Gaeta, DO, MPH, FACEP Clinical Associate Professor, Department of Emergency Medicine, Weill Cornell Medical College; Vice Chairman and Program Director of Emergency Medicine Residency Program, Department of Emergency Medicine, New York Methodist Hospital; Academic Chair, Adjunct Professor, Department of Emergency Medicine, St George's University School of Medicine

Theodore J Gaeta, DO, MPH, FACEP is a member of the following medical societies: Alliance for Clinical Education, American College of Emergency Physicians, Clerkship Directors in Emergency Medicine, Council of Emergency Medicine Residency Directors, New York Academy of Medicine, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Rick Kulkarni, MD Attending Physician, Department of Emergency Medicine, Cambridge Health Alliance, Division of Emergency Medicine, Harvard Medical School

Rick Kulkarni, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine

Disclosure: WebMD Salary Employment

Mark L Plaster, MD, JD Executive Editor, Emergency Physicians Monthly

Mark L Plaster, MD, JD is a member of the following medical societies: American Academy of Emergency Medicine and American College of Emergency Physicians

Disclosure: M L Plaster Publishing Co LLC Ownership interest Management position

Amar Safdar, MD, FACP, FIDSA Associate Professor of Medicine, Consulting Staff, Department of Infectious Diseases, Infection Control and Employee Health, MD Anderson Cancer Center, University of Texas

Amar Safdar, MD, FACP, FIDSA is a member of the following medical societies: American College of Physicians, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, International Immunocompromised Host Society, New York Academy of Sciences, and South Carolina Medical Association

Disclosure: Nothing to disclose.

Joseph Sciammarella, MD, FACP, FACEP Major, Medical Corps, US Army Reserve; Attending Physician, Emergency Medicine, Weatherby Locums; President and Director of Education, Health Training/Consulting, Inc

Joseph Sciammarella, MD, FACP, FACEP is a member of the following medical societies: American College of Emergency Physicians, American College of Physicians, and American Medical Association

Disclosure: Nothing to disclose.

Richard H Sinert, DO Associate Professor of Emergency Medicine, Clinical Assistant Professor of Medicine, Research Director, State University of New York College of Medicine; Consulting Staff, Department of Emergency Medicine, Kings County Hospital Center

Richard H Sinert, DO is a member of the following medical societies: American College of Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Deepika Singh, MD Staff Physician, Department of Emergency Medicine, Lawrence and Memorial Hospital, New London, CT

Deepika Singh, MD is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, American Nurses Association, Emergency Medicine Residents Association, and Sigma Theta Tau International

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

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Toxoplasmosis. Toxoplasma gondii tachyzoites (Giemsa stain).

Toxoplasmosis. Toxoplasma gondii tachyzoites in cell line.

Toxoplasma gondii in infected monolayers of HeLa cells (Giemsa stain).

Inactive retinochoroidal scar secondary to toxoplasmosis

Ophthalmic toxoplasmosis. Used with permission of Anton Drew, ophthalmic photographer, Adelaide, South Australia.

Macular scar secondary to congenital toxoplasmosis. Visual acuity of the patient is 20/400

Papillitis secondary to toxoplasmosis, necessitating immediate systemic therapy.

Acute macular retinitis associated with primary acquired toxoplasmosis, requiring immediate systemic therapy

Peripapillary scars secondary to toxoplasmosis

Perimacular scars secondary to toxoplasmosis

Inactive retinochoroidal scar secondary to toxoplasmosis

Toxoplasmosis. Toxoplasma gondii tachyzoites (Giemsa stain).

Toxoplasmosis. Toxoplasma gondii tachyzoites in cell line.

Toxoplasma gondii in infected monolayers of HeLa cells (Giemsa stain).

Acute macular retinitis associated with primary acquired toxoplasmosis, requiring immediate systemic therapy

Toxoplasmosis. Toxoplasma gondii tachyzoites (Giemsa stain).

Toxoplasmosis. Toxoplasma gondii tachyzoites in cell line.

Toxoplasma gondii in infected monolayers of HeLa cells (Giemsa stain).

Ophthalmic toxoplasmosis. Used with permission of Anton Drew, ophthalmic photographer, Adelaide, South Australia.

Macular scar secondary to congenital toxoplasmosis. Visual acuity of the patient is 20/400

Papillitis secondary to toxoplasmosis, necessitating immediate systemic therapy.

Acute macular retinitis associated with primary acquired toxoplasmosis, requiring immediate systemic therapy

Peripapillary scars secondary to toxoplasmosis

Perimacular scars secondary to toxoplasmosis

Inactive retinochoroidal scar secondary to toxoplasmosis