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 HIV/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 women, 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, and 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 [2-4]. 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 [5], whereas the seroprevalence is as high as 78 percent in some areas of Brazil [6].

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 9 percent between 1999 and 2004 [5].

Transmission — Felines are the only animals in which T. gondii can complete its reproductive cycle [7]. 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 [7]:

●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 mother to her 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 [8-11].

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 [12,13].

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 [14]. Most immunocompetent patients who develop symptoms have a benign, self-limited course that typically lasts from a few weeks to months [15-17].

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 non-pruritic maculopapular rash may also occur.

Lymphadenopathy — The most common clinical manifestation of acute toxoplasmosis is bilateral, symmetrical, nontender cervical adenopathy [18]. 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 [19], acute respiratory distress syndrome, myocarditis [20-22], pericarditis [23], polymyositis [24,25], hepatitis, posterior uveitis, or encephalitis.

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 (ELISA) is most commonly used due to overall performance and cost. In acute infection, IgM 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. DNA amplification of toxoplasma using PCR testing of blood can also confirm acute infection; however, the sensitivity varies and may be as low as 53 percent in patients with acute toxoplasmic lymphadenopathy, as parasites disappear from the peripheral circulation [26].

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

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 [18,27]. Granulomata and abscesses are not seen.

Tachyzoites have been identified on fine needle aspiration specimens from patients with toxoplasmic lymphadenitis [28]. 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 by polymerase chain reaction (PCR) [29,30]. (See "Diagnostic testing for toxoplasmosis infection", section on 'Polymerase chain reaction assays'.)

Differential diagnosis of acute systemic infection — Approximately 1 percent of acute Epstein-Barr virus (EBV)-seronegative mononucleosis syndromes are due to toxoplasmosis [31]. 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, Hodgkin disease, and lymphoma. (See "Hodgkin lymphoma: Epidemiology and risk factors" and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Overview of extrapulmonary manifestations of sarcoidosis".)

TREATMENT OF ACUTE INFECTION

Whom to treat — Acute toxoplasmosis is typically self-limited, and most immunocompetent, nonpregnant adults do not require treatment [32]. However, 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 women, as well as those with ocular disease, is discussed elsewhere. (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 [35]. The best evidence comes from a randomized trial of 46 patients with toxoplasmic lymphadenitis, where patients received trimethoprim-sulfamethoxazole (TMP-SMX; an alternative agent for the treatment of toxoplasmosis) or placebo for one month. At the end of treatment, patients treated with TMP-SMX 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) [36].

Choice of regimen — The antimicrobial regimens used to treat immunocompetent individuals are the same as those used in immunocompromised patients; however, the duration is shorter. (See "Toxoplasmosis in patients with HIV".)

One of the following oral regimens is typically administered for two to four weeks:

●Pyrimethamine (100 mg loading dose followed by 25 to 50 mg daily) plus sulfadiazine (2 to 4 grams daily in four divided doses) plus leucovorin calcium (10 to 25 mg daily)

●Pyrimethamine (100 mg loading dose followed by 25 to 50 mg daily) plus clindamycin (300 mg four times daily) plus leucovorin calcium (10 to 25 mg daily)

If pyrimethamine is not available, TMP-SMX (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 TMP-SMX as an alternative agent [36]. More detailed information on the use of TMP-SMX for the treatment of ocular disease is presented elsewhere. (See "Toxoplasmosis: Ocular disease".)

In patients with a sulfonamide allergy, atovaquone alone (750 mg four times daily) should be initiated, and sulfa desensitization should be attempted in those without a history of a severe reaction (eg, Stevens Johnson Syndrome) (see "Sulfonamide allergy in HIV-uninfected patients"). Such patients can subsequently be transitioned to TMP-SMX.

Other alternative regimens include a two- to four-week course of:

●Pyrimethamine (100 mg loading dose followed by 25 to 50 mg daily) plus atovaquone (750 mg four times daily) plus leucovorin calcium (10 to 25 mg daily)

●Pyrimethamine (100 mg loading dose followed by 25 to 50 mg daily) plus azithromycin (500 mg daily) plus leucovorin calcium (10 to 25 mg daily)

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

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 [37].

Common side effects of pyrimethamine include rash, nausea, and bone marrow suppression. Higher doses of leucovorin, up to 50 to 100 mg daily, can be administered to manage hematologic abnormalities [38]. 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

●Toxoplasmosis is caused by the intracellular protozoan parasite, Toxoplasma gondii, and has a worldwide distribution. (See 'Epidemiology' above.)

●There are three main T. gondii genotypes (types I, II, and III), which are prevalent in different geographic areas, and can impact the clinical presentation of T. gondii infection. (See 'Genotypes' above.)

●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.)

●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 mother to her fetus, and transmission through an organ transplantation from an infected donor. (See 'Transmission' above.)

●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.)

●Serologic testing is typically used to confirm the diagnosis. However, if a lymph node aspiration or biopsy is performed as part of the diagnostic evaluation, tachyzoites can be identified with immunoperoxidase or fluorescent antibody stains. (See 'Diagnosis' above.)

●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 'Choice of regimen' above.)

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