Background

Toxoplasmosis is a zoonotic infection in humans caused by the protozoal intracellular parasite Toxoplasma gondii. Cats are the primary hosts, while humans and other mammals serve as intermediate hosts. Infection with T gondii is common among humans, and it is estimated that one third of the world's population has been exposed.[1] However, most infections are subclinical, and disease typically only becomes apparent in congenitally acquired infection and in patients with significant immunodeficiency such as in acquired immunodeficiency syndrome (AIDS). Toxoplasma infection is generally acquired via eating undercooked or raw meat infected with tissue cysts, via ingestion of food or water contaminated with infected cat feces, or congenitally from mother to fetus. Rare case reports of individuals becoming infected through blood transfusions or organ transplantation have also been reported. 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 are between 10% and 15%.[2, 3] HIV infection does not seem to effect T gondii seropositivity, and there does not appear to be any difference in the rate of toxoplasmosis infection among AIDS patients with and without cats.[3]

Pathophysiology
Life cycle of Toxoplasma gondii
The life cycle of T gondii involves several forms. The oocyte is produced in the feline intestine and produces sporozoites. Sporozoites mature outside of the cat to become tachyzoites, which infect a wide variety of tissues, producing an inflammatory response and a wide array of symptoms. Tachyzoites eventually form tissue cysts in which bradyzoites develop and replicate. In most immunocompetent hosts, bradyzoites are confined to the tissue cysts in which they are slowly replicating; however, in the setting of immune compromise bradyzoites can become tachyzoites, and thus spread infection again to different tissues. Humans enter the life cycle of T gondii by ingesting meat infected with tissue cysts, or ingesting materials contaminated with infectious oocysts. T gondii may also be acquired transplacentally or via transplantation of infected organs or blood transfusions.[4]

Infection in the immunocompetent host

Eighty to ninety percent of T gondii infections in immunocompetent hosts are asymptomatic.[3] Generally, when acute infection is symptomatic, symptoms include symmetric lymphadenopathy, fever, and a nonspecific rash.[4, 5] The vast majority of cases are benign and resolve within weeks. However, severe manifestations of infection, including chorioretinitis, can occur in immunocompetent hosts.

Chorioretinitis or ocular toxoplasmosis 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.[5,
6, 7]

Congenital infection
Approximately 10-20% of pregnant women infected with T gondii become symptomatic.[8] 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; however, if the infection is acquired during the pregnancy, there is risk of infection to the fetus. The rate of transplacental infection has been estimated to be 50% for untreated mothers and 25% for treated mothers.[8] The rate of fetal infection varies with trimester with 10-25% of infections occurring in the first trimester, 30% in the second trimester, and 50% in the third trimester. Infection during the first or second trimesters appears to be most severe. The clinical features of congenitally acquired T gondii infection include chorioretinitis, blindness, seizures, microcephaly, anemia, and encephalitis.[7] Infections acquired during the third trimester are usually subclinical; however, clinical disease may still occur later in life. Seventy-five percent of infants congenitally infected with T gondii manifest no symptoms, 14% had evidence of chorioretinitis and 9% demonstrate signs of CNS involvement.[9]

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 less than 200 cells/ L, and, with counts less than 100 cells/ L, clinical disease becomes more likely.[10] Patients with CD4 counts less than 100 cell/ L and who are T gondii IgG antibody positive have a 30% risk of eventually developing reactivation disease without adequate prophylaxis or restoration of immune function.[11] Although toxoplasmosis in immunocompromised patients may manifest as chorioretinitis, reactivation disease in these individuals is typically in the central nervous system with brain involvement being common. Toxoplasmic encephalitis and brain abscess presents 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 CT scan as multiple ring-enhancing lesions; however, solitary lesions may be seen, and negative CT or MRI scans should not rule out the diagnosis of CNS toxoplasmosis.[4]

Aside from CNS toxoplasmosis, toxoplasmic pneumonitis, myocarditis, as well as disseminated toxoplasmosis are also commonly identified in immunocompromised patients. 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 jiroveci pneumonia. Diagnosis is established via bronchoalveolar lavage (BAL). Most patients with extra-CNS manifestations of toxoplasmosis will also be noted to have CNS lesions when appropriate radiographic studies have been performed.[12]

Epidemiology
Frequency
United States The overall seroprevalence of T gondii in the United States is approximately 15%, and rates of T gondii exposure in HIV patients are similar to those of the general public.[2] In patients with AIDS who have positive Tgondii antibodies, the risk of developing toxoplasmosis is roughly 30% unless prophylactic or antiretroviral medications are commenced. Among immunocompetent patients, clinically evident toxoplasmosis is more likely to occur after the fifth decade of life. Congenital toxoplasmosis is thought to depend on the trimester during which the maternal infection is acquired, with 10-25% of infections occurring in the first trimester, 30% in the second trimester, and 50% in the third trimester.[13] International The seroprevalence of T gondii antibodies varies geographically with some countries such as France and some developing nations reporting antibody positivity rates to T gondii infection as high as 80%.[14] The development of toxoplasmosis among immunocompetent patients does not seem to vary from region to region; however, the prevalence of immunocompromised patients is higher in some nations as a function of both HIV/AIDS infection and also organ transplantation and immunomodulatory medication prescribing.

Mortality/Morbidity
The incidence of toxoplasmosis (including CNS disease) in patients with AIDS has declined dramatically in the recent past likely due to the evolution of highly active antiretroviral therapy (HAART) and the routine use of prophylaxis against Pneumocystis jiroveci and T gondii. The incidence of CNS toxoplasmosis decreased from 5.4 per 1000 person-years between 1990 and 1992 to 2.2 per 1000 in 1996 to 1998.[15] The routine use of cotrimoxazole prophylaxis both in the United States and internationally has also likely significantly decreased the incidence of CNS toxoplasmosis. Depending on the location and severity of toxoplasmic chorioretinitis, 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. 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.

Race
While there do exist differences in the seroprevalence of infection among different ethnic groups, these differences likely reflect the regionality of infection rather than a particular susceptibility to infection.

Sex
Although toxoplasmosis is well studied in women of childbearing age because of its detrimental effects on the fetus, no difference in prevalence between the sexes is reported.

Age
No difference in seroprevalence based on age has been noted; however, with the exception of T gondii chorioretinitis, older individuals are more likely to manifest clinically evident reactivation of Tgondii infection. Congenitally acquired Tgondii chorioretinitis is more likely to recur in those older than 40 years.[7]

History

Immunocompetent individuals o Usually asymptomatic, self-limited illness lasting, at most, weeks o Nonspecific, flulike illness, with prominent, symmetric, and nontender lymphadenopathy Ocular toxoplasmosis (chorioretinitis) o Usually painful o Impaired vision, either sudden or gradual, depending on the site of infection o May see floaters Immunocompromised individuals o May have flulike symptoms, lymphadenopathy o CNS toxoplasmosis - Seizure, dysequilibrium, cranial nerve deficits, altered mental status, focal neurologic deficits, headache o Toxoplasmic pneumonitis - Typical symptoms of a pulmonary infection, mirroring in particular Pneumocystis jiroveci, including nonproductive cough, dyspnea, chest discomfort, and fever o Symptoms associated with reactivation toxoplasmosis are dependent on the tissue or organ affected. Congenital toxoplasmosis o May have variable symptoms, including petechial rash, jaundice, developmental delay, and seizure o Ventriculomegaly and cerebral calcification may be evident in CNS imaging o Visual defects, blindness

Physical

Immunocompetent individuals o Usually asymptomatic o Isolated cervical or occipital adenopathy, symmetric, nontender, lasting 4-6 weeks o Infrequently, may cause myocarditis, polymyositis, pneumonitis, hepatitis, encephalitis Ocular toxoplasmosis (chorioretinitis), shown in the image below

Ophthalmic toxoplasmosis. Used with permission of Anton Drew, ophthalmic photographer, Adelaide, South Australia. o Decreased visual acuity; other deficits depend on the location of the lesion o White focal lesions with inflammation of vitreous humor (the classic "headlight in the fog" appearance) seen on ophthalmoscopic examination o Recurrent lesions at the border of the chorioretinal scars Congenital toxoplasmosis o Usually normal prenatal sonogram findings but may show intracranial calcifications, dilated ventricles, enlarged liver, ascites, and thickened placenta o Neonatal hydrocephalus, microcephaly, intracranial calcifications, chorioretinitis, strabismus, blindness, epilepsy, psychomotor or mental retardation, thrombocytopenia (petechia), anemia o Rare classic triad - Chorioretinitis, hydrocephalus, and cerebral calcifications Immunocompromised individuals (AIDS CD4 < 100) o Symptoms may be gradual in onset over a few weeks o Symptoms depend largely on the organ system and tissue involved o CNS toxoplasmosis - Seizure, mental status change, focal motor deficits, cranial nerve disturbances, sensory disturbances, cerebellar abnormalities, movement disorders, neuropsychiatric findings o Chorioretinitis (similar to that seen in immunocompetent individuals) o Pneumonitis (more common in patients who have undergone bone marrow transplantation and in patients with AIDS) - Nonproductive cough, blood-tinged sputum, hypoxia (symptoms indistinguishable from P jiroveci) o Septic shocklike presentation

Causes

Immunocompetent individuals - Oral-fecal acquisition of parasite from food or water contaminated with cat feces (oocytes) or eating undercooked meat (especially pork and lamb) with tissue cysts

Ocular toxoplasmosis (chorioretinitis) o Usually reactivation of congenital infection o Few cases recorded as part of acute infection Immunocompromised individuals - Almost always reactivation of latent infection Congenital toxoplasmosis o Parasite crosses the placenta from maternal circulation and then enters the fetus. o Infection is less frequent but more serious if the mother becomes infected from up to 3 months before pregnancy until end of the second trimester.[14] o Infection of the fetus is more frequent but less severe if maternal infection occurs in the third trimester.[14]

Differential Diagnoses

Acute HIV infection Brain Abscess CMV retinitis CNS lymphoma CNS tuberculosis Cytomegalovirus encephalitis Cytomegalovirus ventriculitis Disseminated tuberculosis Epstein-Barr virus (mononucleosis) Leukemia Lymphoma Pneumocystis jiroveci pneumonia Progressive multifocal leukoencephalopathy Sarcoidosis Syphilis Tularemia

Laboratory Studies

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. Indirect detection o Indirect detection is performed in pregnant women and immunocompromised patients. o Detection of immunoglobulin G (IgG) is possible within 2 weeks of infection using enzyme-linked immunoassay (ELISA), IgG avidity test, and agglutination and differential agglutination test. 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 IgM false positivity. o The sensitivities and specificities of the commercially available IgM and IgG tests vary substantially. o Acute and convalescent sera have no role. o Sabin-Feldman dye test: Live organisms are used to demonstrate the presence of anti-T gondii antibodies. This test is primarily used as a confirmatory test at reference laboratories. o IgG avidity test: IgG produced early in infection is less avid and binds to T gondii antigens more weakly than 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. Direct detection o Polymerase chain reaction (PCR) amplification of T gondii genes is possible (samples may be taken of the CSF, blood, lymph node, or tissue biopsies or aqueous humor). o 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 but may be present in acute infection/reactivation. o Culture: 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.

Imaging Studies

MRI is more sensitive than CT (and CT with contrast is more sensitive than without) for detecting brain lesions due to toxoplasmosis. One study showed that MRI detected abnormalities in 40% of patients whose abnormalities were not detected on CT.[16] Typical CNS findings include multiple ring-enhancing lesions with associated brain edema, although single lesions are also seen (also see Toxoplasmosis, CNS). Single-photon computed tomography (SPECT) is useful in distinguishing between CNS lymphoma and infection (ie, toxoplasmosis or any other infection). 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.

Procedures

Lumbar puncture (after imaging to identify evidence of increased intracranial pressure [ICP]) Brain biopsy Lymph node biopsy

Amniocentesis Bronchoalveolar lavage

Emergency Department Care

Care of the patient in the ED 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 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. See Medication for medication regimens. Emergency consultation with relevant subspecialties may be required for assistance in empiric treatment and the diagnostic workup.

Consultations
Subspecialty consultation is required for the seriously ill patient, according to organ-specific involvement. In the setting of immunocompromise, involvement of one organ system (ie, retina) mandates analysis of further organ system involvement (ie, CNS). Consultations may include ophthalmology, neurology/neurosurgery, and infectious diseases/HIV.

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

Six-week regimen o Pyrimethamine (100 mg loading dose PO followed by 25-50 mg/d) plus sulfadiazine (2-4 g/d divided qid) OR o Pyrimethamine (100 mg loading dose PO followed by 25-50 mg/d) plus clindamycin (300 mg PO qid) o Folinic acid (leucovorin) (10-25 mg/d) should be given to all patients to prevent hematologic toxicity of pyrimethamine. o TMP (10 mg/kg daily) SMX (50 mg/kg/daily) for 4 weeks May substitute sulfadiazine or clindamycin for azithromycin 500 mg daily or atovaquone 750 mg bid in immunocompetent patients or in patients with 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 chorioretinitis or CNS abnormalities. Controversy also exists regarding the optimal regimen for treating maternally acquired infection. Spiramycin and pyrimethamine-sulfonamide are both 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. o Spiramycin 1 g PO q8h o If amniotic fluid test result for T gondii is positive: 3 weeks of pyrimethamine (50 mg/d PO) and sulfadiazine (3 g/d PO in 2-3 divided doses) alternating with 3week course of spiramycin 1 g tid for maternal treatment OR o Pyrimethamine (25 mg/d PO) and sulfadiazine (4 g/d PO) divided bid/qid until delivery (this agent may be associated with marrow suppression and pancytopenia) AND o Leucovorin 10-25 mg/d PO to prevent bone marrow suppression

Patients with AIDS

Patients with AIDS are treated with pyrimethamine 200 mg PO initially, followed by 5075 mg/d PO plus folinic acid 10 mg/d PO plus sulfadiazine 4-8 g/d PO for as long as 6 weeks, followed by lifelong suppressive therapy or until immune reconstitution. Suppressive therapy for patients with AIDS (CD4 < 100) is pyrimethamine 50 mg/d PO plus sulfadiazine 1-1.5 g/d PO plus folinic acid 10 mg/d PO 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 (see above). 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, as such, empiric therapy should be avoided.

Anti-infectives
Class Summary
Empiric anti-infective therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

View full drug information

Spiramycin (Rovamycine)

DOC for maternal or fetal toxoplasmosis. Alternative therapy in other patient populations when unable to use pyrimethamine and sulfadiazine. View full drug information

Pyrimethamine (Daraprim)

Folic acid antagonist that selectively inhibits plasmodial dihydrofolate reductase. Highly selective against plasmodia and T gondii. Folinic acid should be given to all patients to prevent hematologic toxicity of pyrimethamine View full drug information

Sulfadiazine (Microsulfon)

Through competitive antagonism of PABA, interferes with microbial growth. Useful in treatment of toxoplasmosis. View full drug information

Clindamycin (Cleocin)

As alternative to sulfonamides, may be beneficial when used in combination with pyrimethamine in acute treatment of CNS toxoplasmosis in patients with AIDS. View full drug information

Azithromycin (Zithromax)

Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. 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. May substitute sulfadiazine or clindamycin for azithromycin in immunocompetent patients or in patients with history of allergy to the former drugs. View full drug information

Atovaquone (Mepron)

A hydroxynaphthoquinone that inhibits mitochondrial electron transport chain by competing with ubiquinone at ubiquinone-cytochrome-c-reductase region (complex III). Inhibition of electron transport by atovaquone will result in inhibition of nucleic acid and ATP synthesis in parasites. Atovaquone has shown activity against bradyzoites in animal models of toxoplasmosis. May substitute sulfadiazine or clindamycin for atovaquone.

Antidote, Folic Acid Antagonist

Class Summary
These agents are used to replenish folic acid when the patient is being treated with folic acid antagonists. View full drug information

Leucovorin (Wellcovorin)

Also called folinic acid. Derivative of folic acid used with folic acid antagonists, such as sulfonamides and pyrimethamine.

Further Outpatient Care

AIDS patients with CD4 counts less than 100 cells/ L should be commenced on suppressive therapy for T gondii until they undergo immune reconstitution. Infants with confirmed congenital toxoplasmosis should be followed for evidence of developmental delay and should receive ophthalmologic consultation and follow-up.

Deterrence/Prevention
Prevention of T gondii infection includes the following:

All meat should be thoroughly cooked. Careful handwashing should be done after handling raw meat. Fruits and vegetables should be washed before eating them. Pregnant women should wear gloves while gardening, thoroughly wash their hands afterwards, and avoid contact with cat feces. Pregnant women and HIV patients with cats are at no increased risk of toxoplasmosis compared with those without cats. Travel to areas of high endemicity (Western Europe, South America) may increase the risk of exposure. Primary and secondary prevention should be completed for AIDS patients. As discussed in Treatment, controversy exists regarding whether or not treatment of maternal infection prevents either fetal infection or the adverse outcomes rarely associated with congenitally acquired infection. Currently, no systematic screening program exists for T gondii in the United States for either AIDS patients or pregnant women. France, with a much higher seroprevalence of T gondii exposure, does mandate monthly screening during pregnancy, although the results of this effort are difficult to measure given the infrequency of fetal infection and the generally good long-term prognosis of disease.

Development of vaccines for use in nonimmune women of childbearing age and household cats is being investigated.

Complications

Seizures CNS deficits dependent on the territory effected. Basal ganglia seem to be preferentially involved. Septic shock Partial or complete blindness Congenital complications o Mental retardation o Seizures o Deafness o Blindness

Prognosis
Relapse is frequent with patients who are immunocompromised. Suppressive therapy and immune reconstitution significantly reduce the risk of recurrent infection.

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