Toxoplasmosis: Acute systemic disease

INTRODUCTION — 

Toxoplasmosis, an infection with a worldwide distribution, is caused by the intracellular protozoan parasite, Toxoplasma gondii. Immunocompetent persons with primary infection are usually asymptomatic. However, in some immunocompetent individuals, T. gondii infection can present as an acute systemic infection or as ocular disease (eg, posterior uveitis).

After initial infection (even if asymptomatic), latent infection will persist for the life of the host. Immunocompromised individuals (eg, those with human immunodeficiency virus [HIV]/acquired immunodeficiency syndrome [AIDS], transplant recipients) can have reactivation of latent infection; such patients typically present with multiple central nervous system abscess-like, round processes with ring enhancement.

This topic will discuss the clinical manifestations, diagnosis, and treatment of acute systemic disease in immunocompetent persons. Discussions of ocular toxoplasmosis, and toxoplasmosis in individuals with HIV, pregnant individuals, and neonates are presented separately. (See "Toxoplasmosis: Ocular disease" and "Toxoplasmosis in patients with HIV" and "Toxoplasmosis and pregnancy" and "Congenital toxoplasmosis: Clinical features and diagnosis".)

EPIDEMIOLOGY

Genotypes — There are three main T. gondii genotypes (types I, II, and III), which are prevalent in different geographic areas [1]. There are also atypical genotypes, which exist in addition to genotypes I, II, and III [2-4].

Genotypes can impact the clinical presentation of T. gondii infection [1]. As an example, in Europe, where genotype II is present, 80 to 90 percent of individuals who become infected are asymptomatic. This is in contrast to South and Central America, where other genotypes are present, and infection is associated with a higher rate and increased severity of disease [5-7]. A mix of genotype I and II are the most prevalent in North America.

Prevalence — The seroprevalence of T. gondii infection ranges widely depending upon the geographic area. Seroepidemiologic surveys in the United States report that 11 percent of persons aged 6 to 49 are seropositive for T. gondii [8], whereas the seroprevalence is as high as 78 percent in some areas of Brazil [9].

In the United States, the prevalence is higher in non-Hispanic Black persons compared with non-Hispanic White persons, and in persons born outside the United States. For persons aged 12 to 49 born in the United States, the seroprevalence declined from 14 to 10.4 percent (95% CI 9.2-11.8) in 2014 [8].

Transmission — Felines are the only animals in which T. gondii can complete its reproductive cycle [10]. Following feline ingestion of any of the forms of T. gondii, the parasite infects the gut epithelial cells and reproduces. The feline then excretes infectious oocysts in feces.

When non-felines (mammals and birds), including humans, ingest T. gondii oocysts, the organisms invade intestinal epithelium and disseminate throughout the body. They then encyst in any type of nucleated cell and lie dormant within tissues for the life of the host.

There are four means of acquiring toxoplasmosis in humans [10]:

●Ingestion of infectious oocysts from the environment (usually from soil or fresh water sources contaminated with feline feces) or from contaminated fruits or vegetables

●Ingestion of tissue cysts in meat from an infected animal

●Vertical transmission from an infected parent to their fetus

●Transmission through an organ transplantation from an infected donor

In most resource-limited settings, infection is typically acquired through environmental exposures, such as water from lakes and reservoirs, since meats are usually not eaten undercooked. However, ingestion of undercooked meat is responsible for the majority of toxoplasmosis cases in Asia, Europe, and the United States [11,12].

In a case-control study that was conducted from 2002 to 2007 in the United States, a multivariate analysis found that T. gondii infection was associated with eating raw or undercooked foods (ground beef and lamb) and drinking unpasteurized goat's milk [11]. In addition, working with meat or owning three or more kittens was associated with an increased risk of infection. Eating undercooked venison is also a possible source in the United States [13,14].

CLINICAL MANIFESTATIONS — 

Immunocompetent persons with primary infection are usually asymptomatic. However, in some immunocompetent hosts, T. gondii infection can present as an acute systemic infection, which typically develops 5 to 23 days after exposure to the organism, especially if the infection is with so-called "atypical genotypes" that are more virulent [15]. Most immunocompetent patients who develop symptoms have a benign, self-limited course that typically lasts from a few weeks to months [16-18].

General symptoms — Patients with acute toxoplasmosis typically present with constitutional symptoms, such as fever, chills, and sweats; however, these symptoms are generally mild, and the febrile episodes usually last two to three days. Headaches, myalgias, pharyngitis, hepatosplenomegaly, and/or a diffuse nonpruritic maculopapular rash may also occur.

Lymphadenopathy — The most common clinical manifestation of acute toxoplasmosis is bilateral, symmetrical, nontender cervical adenopathy [19]. Approximately 20 to 30 percent develop generalized lymphadenopathy. The lymph nodes are usually smaller than 3 centimeters in size and are nonfluctuant. Unlike the fever, which lasts for a short duration, lymphadenopathy can persist for weeks. (See "Evaluation of peripheral lymphadenopathy in adults".)

Uncommon manifestations — On rare occasions, immunocompetent patients may present with severe disease such as pneumonitis [20], acute respiratory distress syndrome, myocarditis [21-23], pericarditis [24], polymyositis [25,26], hepatitis, posterior uveitis, or encephalitis. A more severe clinical course is expected in patients infected with atypical strains, especially those found in South America and probably Africa.

A detailed discussion of the ocular manifestations seen in the setting of acute toxoplasmosis is presented in a separate topic review. (See "Toxoplasmosis: Ocular disease", section on 'Posterior uveitis'.)

Laboratory findings — Laboratory findings are nonspecific in patients with toxoplasmosis. Patients may have a slight lymphocytosis with or without atypical cells. If atypical lymphocytes are present, they usually account for less than 10 percent of the total leukocyte count. Hepatic transaminases may also be slightly elevated, and there may be moderate increases in the C-reactive protein.

DIAGNOSIS — 

The diagnosis of toxoplasmosis should be considered in immunocompetent hosts who present with an acute onset of fever and lymphadenopathy. (See 'Clinical manifestations' above.)

Serologic testing — Serologic testing is typically used to determine if a patient has toxoplasmosis. An enzyme-linked immunosorbent assay is most commonly used due to overall performance and cost. In acute infection, immunoglobulin (Ig)M antibodies usually appear within one week of symptom onset and continue to rise. Toxoplasma-specific IgG antibodies subsequently follow within approximately two weeks of primary infection, peak within approximately eight weeks, and generally persist for life.

●For most patients, the diagnosis is eliminated if the patient has no evidence of either IgM or IgG antibodies. However, for those who present within one week of symptom onset, a repeat test should be performed.

●If the patient has IgM antibodies detected without the presence of IgG antibodies, the diagnosis of newly acquired toxoplasmosis is likely. However, a positive IgG antibody obtained approximately two weeks later is needed to confirm the diagnosis. The IgM-antibody reaction is usually considered a false-positive if IgM antibodies persist without the development of IgG antibodies after three weeks.

●If serial testing of two samples two weeks apart is not enough to establish whether the patient has had a recent infection, samples can be analyzed with an IgG-avidity assay. Deoxyribonucleic acid (DNA) amplification of toxoplasma using polymerase chain reaction (PCR) testing of blood can also confirm acute infection; however, the sensitivity varies. (See 'Polymerase chain reaction testing' below.)

A more detailed discussion of serologic testing is presented separately. (See "Diagnostic testing for toxoplasmosis infection", section on 'Serologic testing'.)

Polymerase chain reaction testing — Polymerase chain reaction (PCR) testing can detect parasite DNA in specimens such as blood, cerebrospinal fluid, aqueous humor, and bronchoalveolar lavage fluid. Parasites can also be detected with DNA amplification by PCR in lymph node specimens [27].

In some settings, when serologic testing is not enough to establish the diagnosis of acute infection, PCR testing of blood may be helpful to establish the diagnosis. However, the sensitivity of PCR testing varies [28]. In one study that evaluated 59 patients with acute toxoplasmosis based on clinical features and serologic testing, none had parasitic DNA detected by PCR in blood samples [29]. PCR testing is discussed in greater detail in a separate topic review. (See "Diagnostic testing for toxoplasmosis infection", section on 'Polymerase chain reaction assays'.)

Pathology — Histopathologic examination of lymph nodes typically reveals follicular hyperplasia, focal distension of sinuses with monocytoid cells, and irregular clusters of tissue macrophages with eosinophilic cytoplasm [19,30]. Granulomata and abscesses are not seen. Tachyzoites have been identified on fine needle aspiration specimens from patients with toxoplasmic lymphadenitis [31]. Although tachyzoites are difficult to demonstrate with standard stains, they may be observed with immunoperoxidase or fluorescent antibody stains. Parasites may also be detectable with DNA amplification.

Differential diagnosis of acute systemic infection — Approximately 1 percent of acute Epstein-Barr virus (EBV)-seronegative mononucleosis syndromes are due to toxoplasmosis [32]. Thus, acute toxoplasmosis should be considered in the differential diagnosis of patients who present with fever and adenopathy.

Alternative diagnoses include:

●Epstein-Barr virus infection – Acute toxoplasmosis and EBV infection can both present with adenopathy and atypical lymphocytosis. However, patients with EBV are more likely to present with pharyngitis and tonsillitis. The diagnosis for both infections is typically made through serologic testing. (See "Infectious mononucleosis" and "Clinical manifestations and treatment of Epstein-Barr virus infection" and "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults".)

●Cytomegalovirus infection – Both toxoplasmosis and cytomegalovirus (CMV) infection can cause a mononucleosis-like syndrome in immunocompetent adults. However, enlarged cervical nodes are not as common in patients with CMV disease. Serologic testing is typically used to diagnose CMV infection in this setting. (See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults".)

●Acute HIV infection – Many of the symptoms of acute toxoplasmosis overlap with the symptoms of acute HIV infection (eg, fever and generalized lymphadenopathy). Early HIV infection should be suspected in patients who have had a recent high-risk exposure (eg, unsafe sexual contacts or needle sharing); however, the absence of elicited risk factors cannot preclude the possibility of HIV infection since some patients may not disclose this information. Diagnostic testing for acute HIV infection generally includes the use of a combination antigen/antibody immunoassay as well as a measurement of the HIV viral load. (See "Acute and early HIV infection: Clinical manifestations and diagnosis".)

●Tularemia – Tularemia should be considered in patients with fever and adenopathy if they are at risk of exposure to Francisella tularensis (eg, farmers, veterinarians, hunters, landscapers, and meat handlers). However, unlike toxoplasmosis where the adenopathy is typically bilateral and nontender, patients with glandular tularemia generally have tender regional lymphadenopathy involving single or multiple nodes. The diagnosis of tularemia is based upon serologic testing. (See "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention".)

●Cat scratch disease – Cat scratch disease (CSD) due to Bartonella henselae should be considered in individuals (particularly children) with fever and adenopathy. However, unlike toxoplasmosis, the lymph nodes are almost always tender, have erythema of the overlying skin, and are occasionally suppurative. In addition, the location of the lymphadenopathy depends on the site of the inoculation; the most common locations are the axillary, epitrochlear, cervical, supraclavicular, and submandibular lymph nodes. Serology is typically used to diagnose CSD. (See "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease".)

●Tuberculosis – Tuberculosis should be considered in patients who present with cervical lymphadenopathy and fever. Patients with tuberculosis typically have a chronic presentation, and the physical examination reveals a firm, discrete mass or matted nodes fixed to surrounding structures; the overlying skin may be indurated. Diagnosis of tuberculous lymphadenitis is established by histopathology examination along with acid-fast bacilli smear and culture of lymph node material. (See "Tuberculous lymphadenitis".)

●Noninfectious causes – Other considerations in the differential diagnosis include noninfectious diseases such as sarcoidosis and various lymphomas. (See "Overview of extrapulmonary manifestations of sarcoidosis", section on 'Lymphatic system' and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Classic Hodgkin lymphoma: Presentation, evaluation, and diagnosis in adults".)

TREATMENT OF ACUTE INFECTION

Whom to treat — Acute toxoplasmosis is typically self-limited, and most immunocompetent, nonpregnant adults do not require treatment [33]. However, some patients may present with more severe disease, particularly in areas where there is a high risk of infection with more virulent, atypical genotypes. (See 'Genotypes' above and 'Clinical manifestations' above.)

We suggest treatment for those with severe or prolonged symptoms (eg, beyond a few weeks) and those with evidence of pneumonitis, myocarditis, meningoencephalitis, posterior uveitis, or polymyositis [33,34]. The management of immunocompromised hosts and pregnant patients, as well as those with ocular disease, is discussed separately. (See "Toxoplasmosis in patients with HIV" and "Toxoplasmosis and pregnancy" and "Toxoplasmosis: Ocular disease".)

There are limited data to support the benefit of treatment in immunocompetent patients with systemic infection [33]. The best evidence comes from a randomized trial of 46 patients with toxoplasmic lymphadenitis, where patients received trimethoprim-sulfamethoxazole (trimethoprim-sulfamethoxazole; an alternative agent for the treatment of toxoplasmosis) or placebo for one month. At the end of treatment, patients treated with trimethoprim-sulfamethoxazole were more likely to have a clinical and serologic response (ie, resolution of adenopathy and IgM <6 international units) compared with those who received placebo (65 versus 13 percent) [35].

Regimens for nonpregnant adults

Preferred — For nonpregnant adults who require treatment for acute toxoplasmosis, we suggest one of the following pyrimethamine-based regimens. If pyrimethamine is unavailable, trimethoprim-sulfamethoxazole can be used.

●Pyrimethamine plus sulfadiazine plus leucovorin OR pyrimethamine plus clindamycin plus leucovorin – These regimens are typically administered for two to four weeks. Optimal dosing for these preferred pyrimethamine-based regimens is uncertain, and clinical practice varies, including among UpToDate contributors. Dosing considerations for selected agents include:

•Oral pyrimethamine can be dosed as one of the following; varied approaches exist due to limited data:

-100 mg loading dose on day 1, followed by 25 to 50 mg daily. This dose is extrapolated from the dose endorsed by the United States Centers for Disease Control and Prevention (CDC) for the treatment of ocular toxoplasmosis [36]. That recommendation is based on several clinical studies that evaluated a loading dose followed by 25 mg daily, although the clinical outcomes of those studies were mainly visual function, which may not be impacted by antimicrobial therapy [37-39].

-50 to 75 mg daily. This is the manufacturer-recommended dose as approved by the US Food and Drug Administration (FDA); it is based on older experimental data [40].

•Oral sulfadiazine 2 to 4 grams daily in four divided doses. Oral clindamycin (300 mg four times daily) can be substituted for sulfadiazine.

•Oral leucovorin 10 to 25 mg daily. Leucovorin (folinic acid) reduces the side effects of treatment [41]. Folinic acid must not be confused with folic acid. Folic acid counteracts the effect of pyrimethamine and can result in prolonged disease activity due to incomplete control of parasite proliferation. In addition, if a patient is receiving folic acid therapy (eg, in conjunction with methotrexate therapy), it should be paused in patients receiving pyrimethamine therapy.

●Trimethoprim-sulfamethoxazole – If pyrimethamine is not available, trimethoprim-sulfamethoxazole (5 mg/kg trimethoprim and 25 mg/kg sulfamethoxazole given intravenously or orally twice daily; dosing is based upon the trimethoprim component) can be administered for two to four weeks.

Studies in patients with lymphadenitis and ocular disease support the use of trimethoprim-sulfamethoxazole as an alternative agent [35,42]. More detailed information on the use of trimethoprim-sulfamethoxazole for the treatment of ocular disease is presented elsewhere. (See "Toxoplasmosis: Ocular disease".)

Monitoring for adverse drug reactions is discussed below. (See 'Monitoring for adverse drug reactions' below.)

Alternative — Other options in patients intolerant of preferred regimens include a two- to four-week course of one of the following:

•Pyrimethamine (50 to 75 mg daily) plus atovaquone (750 mg four times daily) plus leucovorin calcium (10 to 25 mg daily)

•Pyrimethamine (50 to 75 mg daily) plus azithromycin (500 mg daily) plus leucovorin calcium (10 to 25 mg daily)

If pyrimethamine is unavailable and patients have a sulfonamide allergy, we initiate atovaquone alone (750 mg four times daily) and attempt desensitization for those without a history of a severe sulfonamide reaction (eg, Stevens-Johnson syndrome). If desensitization is successful, those patients can be transitioned to trimethoprim-sulfamethoxazole alone. (See 'Preferred' above.)

Monitoring for adverse drug reactions is discussed below. (See 'Monitoring for adverse drug reactions' below.)

Pregnant persons and children — Special considerations regarding antimicrobial therapy for pregnant persons and children are discussed separately. (See "Toxoplasmosis and pregnancy" and "Congenital toxoplasmosis: Treatment, outcome, and prevention".)

Monitoring for adverse drug reactions — For patients with acute infection who receive a short course of treatment (eg, two weeks), we do not perform laboratory testing to monitor for adverse reactions. However, for those who require more prolonged therapy, it is important to obtain a complete blood count and metabolic profile after two weeks [43].

Common side effects of pyrimethamine include rash, nausea, and bone marrow suppression (leucopenia). Higher doses of leucovorin, up to 50 to 100 mg daily, can be administered to manage hematologic abnormalities [44]. Sulfa-containing agents can lead to rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, crystalluria, and rarely, more severe reactions such as Stevens-Johnson syndrome. Clindamycin can lead to fever, rash, and nausea; clindamycin is also associated with diarrhea related to production of Clostridium difficile toxin. Additional information can be found in the individual drug information topics within UpToDate.

PREVENTION — 

The risk of human toxoplasmosis can be reduced by taking the following precautions:

●Cook meats to adequate temperatures (meat 145°F/63°C, ground meat 160°F/71°C, poultry 165°F/74°C).

●If the meat is not going to be adequately cooked (ie, served rare), it should be frozen at subzero temperatures for several days.

●Wash cutting boards and/or other kitchen utensils with hot water and soap after contact with raw meat or shellfish and greens from the garden.

●Avoid unpasteurized non-bovine milk.

●Wear gloves and/or wash hands with soap and water when there is contact with soil or sand that could be contaminated with cat feces.

●Wear gloves and/or wash hands with soap and water when there is contact with the cat litter of cats that forage outdoors or eat raw meat. Indoor house cats that are fed dry or canned processed cat food do not pose a risk.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Toxoplasmosis".)

SUMMARY AND RECOMMENDATIONS

●Microbiology – Toxoplasmosis is caused by the intracellular protozoan parasite, Toxoplasma gondii, and has a worldwide distribution. There are three main T. gondii genotypes (types I, II, and III), and additional atypical genotypes with increased virulence, which are prevalent in different geographic areas, and can impact the clinical presentation of T. gondii infection. (See 'Genotypes' above.)

●Seroprevalence – The seroprevalence ranges widely depending upon the geographic area. Seroepidemiologic surveys in the United States report that 11 percent of persons aged 6 to 49 are seropositive for T. gondii, whereas the seroprevalence is as high as 78 percent in some areas of Brazil. (See 'Prevalence' above.)

●Transmission – There are four means of acquiring toxoplasmosis in humans: ingestion of infectious oocysts from the environment, ingestion of tissue cysts in meat from an infected animals or from contaminated fruits or vegetables, vertical transmission from an infected pregnant individual to the fetus, and transmission through an organ transplantation from an infected donor. (See 'Transmission' above.)

●Clinical manifestations – Immunocompetent persons with primary infection are usually asymptomatic. However, in some immunocompetent hosts, T. gondii infection can present as an acute systemic infection, which typically develops 5 to 23 days after exposure to the organism. Such patients typically present with constitutional symptoms and bilateral, symmetrical, nontender cervical adenopathy. (See 'Clinical manifestations' above.)

Some patients may develop more severe disease such as pneumonitis, myocarditis, pericarditis, polymyositis, hepatitis, posterior uveitis, or encephalitis. Severe disease typically develops in those with atypical strains that are found in South America and probably Africa. (See 'Uncommon manifestations' above.)

●Diagnosis – The diagnosis of toxoplasmosis should be considered in immunocompetent hosts who present with an acute onset of fever and lymphadenopathy. Serologic testing is typically used to confirm the diagnosis.

●Treatment – Most immunocompetent, nonpregnant adults do not require treatment for acute infection since the disease is typically self-limited. However, we suggest treatment for those with severe or prolonged symptoms (eg, beyond a few weeks) (Grade 2C). (See 'Whom to treat' above.)

If treatment is indicated for acute systemic infection, a pyrimethamine-containing regimen (with either sulfadiazine or clindamycin) is typically preferred. However, if pyrimethamine is not available, trimethoprim-sulfamethoxazole can be administered. The duration of treatment is usually two to four weeks. (See 'Regimens for nonpregnant adults' above.)

●Prevention – The risk of human toxoplasmosis can be reduced by taking precautions to avoid exposure to T. gondii. (See 'Prevention' above.)