Elsevier

The Lancet

Volume 363, Issue 9425, 12 June 2004, Pages 1965-1976
The Lancet

Seminar
Toxoplasmosis

https://doi.org/10.1016/S0140-6736(04)16412-XGet rights and content

Summary

Toxoplasma gondii is a protozoan parasite that infects up to a third of the world's population. Infection is mainly acquired by ingestion of food or water that is contaminated with oocysts shed by cats or by eating undercooked or raw meat containing tissue cysts. Primary infection is usually subclinical but in some patients cervical lymphadenopathy or ocular disease can be present. Infection acquired during pregnancy may cause severe damage to the fetus. In immunocompromised patients, reactivation of latent disease can cause life-threatening encephalitis. Diagnosis of toxoplasmosis can be established by direct detection of the parasite or by serological techniques. The most commonly used therapeutic regimen, and probably the most effective, is the combination of pyrimethamine with sulfadiazine and folinic acid. This Seminar provides an overview and update on management of patients with acute infection, pregnant women who acquire infection during gestation, fetuses or infants who are congenitally infected, those with ocular disease, and immunocompromised individuals. Controversy about the effectiveness of primary and secondary prevention in pregnant women is discussed. Important topics of current and future research are presented.

Introduction

Toxoplasma gondii is an obligate intracellular protozoan that belongs to the phylum Apicomplexa, subclass coccidia. It can take several different forms: the oocyst; the tachyzoite; and the cyst. The T gondii genome is haploid, except during sexual division in cats, and contains about 8×107 base pairs.1

Members of the cat family are definitive hosts of T gondii; replication of the parasite happens in the intestine of the cat, resulting in production of oocysts (figure 1).2 During acute infection, several million oocysts (10×12 μm) are shed in the faeces of cats for 7–21 days. After sporulation, which takes place between 1 and 21 days,3 oocysts containing sporozoites are infective when ingested by mammals (including man) and give rise to the tachyzoite stage.

Tachyzoites (2–4 (μm wide and 4–8 (μm long) are crescentic or oval and are the rapidly multiplying stages of the parasite (figure 1). They enter all nucleated cells by active penetration and form a cytoplasmic vacuole.4 After repeated replication, host cells are disrupted and tachyzoites are disseminated via the bloodstream and infect many tissues, including the CNS, eye, skeletal and heart muscle, and placenta. Replication leads to cell death and rapid invasion of neighbouring cells. The tachyzoite form causes a strong inflammatory response and tissue destruction and, therefore, causes clinical manifestations of disease. Tachyzoites are transformed into bradyzoites under the pressure of the immune response to form cysts.

Bradyzoites persist inside cysts for the life of the host (figure 1). They are morphologically identical to tachyzoites but multiply slowly, express stage-specific molecules, and are functionally different. Tissue cysts contain hundreds and thousands of bradyzoites and form within host cells in brain and skeletal and heart muscles. Bradyzoites can be released from cysts, transform back into tachyzoites, and cause recrudescence of infection in immunocompromised patients. Cysts are infective stages for intermediate and definitive hosts.

T gondii consists of three clonal lineages designated type I, II, and III, which differ in virulence and epidemiological pattern of occurrence.5, 6 Most strains isolated from patients with AIDS are type II. Type I and II strains have been recorded in patients with congenital disease, whereas strains isolated from animals are mostly genotype III.6, 7 Strain-specific peptides8 could allow typing of T gondii strains with serum from a patient.

Sexual recombination between two distinct and competing clonal lines of the parasite has driven natural evolution of virulence in Tgondii.9 Acquisition of direct oral transmission by the parasite seems to be a recent evolutionary change that has led to widespread expansion of Toxoplasma.10 Generation of specific gene-deficient strains of T gondii11, 12 and sequencing of the Toxoplasma genome (http://ToxoDB.org/) will provide further insight into virulence factors of the parasite and specific host immune responses.

Section snippets

Transmission

Human beings can be infected with T gondiiby ingestion or handling of undercooked or raw meat (mainly pork and lamb) containing tissue cysts or water or food containing oocysts excreted in the faeces of infected cats (figure 1). Most individuals are infected inadvertently, thus the specific route of transmission cannot usually be established. Variations in seroprevalence of T gondii seem to correlate with eating and hygiene habits of a population. This finding lends support to the contention

Pathogenesis

Inoculum size,43 virulence of the organism,44 genetic background,45 sex,46 and immunological status seem to affect the course of infection in human beings and animal models of toxoplasmosis. Once the parasite has been orally ingested, it actively invades intestinal epithelial cells or it gets phagocytosed by them.4, 47 Intracellularly, T gondii induces formation of a parasitophorous vacuole that contains secreted parasite proteins and excludes host proteins that would normally promote phagosome

Pathology

Histopathological changes in toxoplasmic lymphadenitis in immunocompetent individuals are frequently distinctive and sometimes diagnostic66 and consist of reactive follicular hyperplasia, irregular clusters of epithelioid histiocytes encroaching on and blurring the margins of the germinal centres, and focal distension of sinuses with monocytoid cells. Langhans giant cells, granulomas, microabscesses, foci of necrosis, and parasites (or their DNA)67 are not typically seen or detected. Eye

Clinical presentation

Clinically, infection with T gondii can go unnoticed or could cause signs and symptoms that vary depending on the immune status of the patient and the clinical setting—eg, immunocompetent, ocular disease, immunocompromised, or congenital toxoplasmosis.

Diagnosis

T gondii infection can be diagnosed indirectly with serological methods and directly by PCR, hybridisation, isolation, and histology. Whereas indirect serological methods are widely used in immunocompetent patients, definitive diagnosis in immunocompromised people is mostly undertaken by direct detection of the parasite (table 2). Direct demonstration of the organism (mouse inoculation, cell culture, or PCR for T gondii DNA) from cerebrospinal fluid, blood, and urine,84, 85 and ophthalmologic

Infection in the immunocompetent host

Immunocompetent adults and children with toxoplasmic lymphadenitis are usually not treated unless symptoms are severe or persistent. Characteristic histological criteria and findings of a panel of serological tests that accord with recently acquired infection are diagnostic for toxoplasmic lymphadenitis in older children and adults.99 If needed, treatment is usually administered for 2–4 weeks followed by reassessment of the patient's condition. The combination of pyrimethamine, sulfadiazine,

Prevention

Public-health measures to prevent T gondii infection are a possible approach to diminish burden of disease in human beings and animals. Wide differences exist in public-health policies to prevent congenital infection; however, data for the efficacy of such policies are scarce.134 Systematic serological screening of all pregnant women is undertaken only in France and Austria.42, 135 Uncertainty about incidence of congenital infection, cost-effectiveness, difficulties with sensitivity and

Outlook

Despite great progress in clinical and basic science research, many unresolved issues in toxoplasmosis remain to be addressed. These topics encompass important clinical issues such as epidemiology, diagnosis and treatment, and prevention (screening) strategies (panel).143

Search strategy and selection criteria

MEDLINE searches for recent new literature using a large number of keywords for both clinical and basic research topics were used as a primary source of references.

Reference lists in recent book chapters and review articles written by the authors were also used; inclusion or exclusion of individual manuscripts was based on scientific value and clinical importance.

Conflict of interest statement

None declared.

References (143)

  • GM Bhopale

    Development of a vaccine for toxoplasmosis: current status

    Microbes Infect

    (2003)
  • CG Luder et al.

    Toxoplasma gondii inhibits MHC class II expression in neural antigen-presenting cells by down-regulating the class II transactivator CIITA

    J Neuroimmunol

    (2003)
  • L Weiss et al.

    Infrequent detection of Toxoplasma gondii genome in toxoplasmic lymphadenitis: a polymerase chain reaction study

    Hum Pathol

    (1992)
  • BJ Luft et al.

    Outbreak of central-nervoussystem toxoplasmosis in western Europe and North America

    Lancet

    (1983)
  • GN Holland

    Reconsidering the pathogenesis of ocular toxoplasmosis

    Am J Ophthalmol

    (1999)
  • AJ Burnett et al.

    Multiple cases of acquired toxoplasmosis retinitis presenting in an outbreak

    Ophthalmology

    (1998)
  • Y Naot et al.

    IgM enzyme-linked immunosorbent assay test for the diagnosis of congenital Toxoplasma infection

    J Pediatr

    (1981)
  • AW Cornelissen et al.

    Determination of nuclear DNA of five eucoccidian parasites, Isospora (Toxoplasma) gondii, Sarcocystis cruzi, Eimeria tenella, E acervulina and Plasmodium berghei, with special reference to gamontogenesis and meiosis in I

    (T.) gondii. Parasitology

    (1984)
  • JK Frenkel

    Toxoplasmosis: parasite life cycle pathology and immunology

  • JP Dubey et al.

    The Toxoplasma gondii oocyst from cat feces

    J Exp Med

    (1970)
  • LD Sibley et al.

    Virulent strains of Toxoplasma gondii comprise a single clonal lineage

    Nature

    (1992)
  • DK Howe et al.

    Toxoplasma gondii comprises three clonal lineages: correlation of parasite genotype with human disease

    J Infect Dis

    (1995)
  • D Ajzenberg et al.

    Genotype of 86 Toxoplasma gondii isolates associated with human congenital toxoplasmosis, and correlation with clinical findings

    J Infect Dis

    (2002)
  • JT Kong et al.

    Serotyping of Toxoplasma gondii infections in humans using synthetic peptides

    J Infect Dis

    (2003)
  • ME Grigg et al.

    Success and virulence in Toxoplasma as the result of sexual recombination between two distinct ancestries

    Science

    (2001)
  • C Su et al.

    Recent expansion of Toxoplasma through enhanced oral transmission

    Science

    (2003)
  • BA Fox et al.

    De novo pyrimidine biosynthesis is required for virulence of

    Toxoplasma gondii. Nature

    (2002)
  • M Meissner et al.

    Role of Toxoplasma gondii myosin A in powering parasite gliding and host cell invasion

    Science

    (2002)
  • G Desmonts et al.

    Etude epidemiologique sur la toxoplasmose: ľinfluence de la cuisson des viandes de boucherie sur la frequence de ľinfectin humaine

    Rev Fr Etud Clin Biol

    (1965)
  • AJ Cook et al.

    Sources of toxoplasma infection in pregnant women: European multicentre case-control study

    BMJ

    (2000)
  • JS Remington et al.

    Toxoplasmosis

  • JP Dubey et al.

    High prevalence of viable Toxoplasma gondii infection in market weight pigs from a farm in Massachusetts

    J Parasitol

    (2002)
  • SM Teutsch et al.

    Epidemic toxoplasmosis associated with infected cats

    N Engl J Med

    (1979)
  • LM Bahia-Oliveira et al.

    Highly endemic, waterborne toxoplasmosis in north Rio de Janeiro state, Brazil

    Emerg Infect Dis

    (2003)
  • RG Brooks et al.

    Transplant-related infections

  • DM Israelski et al.

    Toxoplasmosis in the non-AIDS immunocompromised host

  • DE Kayhoe et al.

    Acquired toxoplasmosis: observations on two parasitologically proved cases treated with pyrimethamine and triple sulfonamides

    N Engl J Med

    (1957)
  • JS Remington et al.

    Acquired toxoplasmosis: infection versus disease

    Ann NY Acad Sci

    (1970)
  • N Guerina et al.

    Neonatal serologic screening and early treatment for congenital Toxoplasma gondii infection

    N Engl J Med

    (1994)
  • PA Jenum et al.

    Incidence of Toxoplasma gondii infection in 35,940 pregnant women in Norway and pregnancy outcome for infected women

    J Clin Microbiol

    (1998)
  • MF Gavinet et al.

    Congenital toxoplasmosis due to maternal reinfection during pregnancy

    J Clin Microbiol

    (1997)
  • N Vogel et al.

    Congenital toxoplasmosis transmitted from an immunologically competent mother infected before conception

    Clin Infect Dis

    (1996)
  • P Hohlfeld et al.

    Prenatal diagnosis of congenital toxoplasmosis with polymerase-chainreaction test on amniotic fluid

    N Engl J Med

    (1994)
  • F Daffos et al.

    Prenatal management of 746 pregnancies at risk for congenital toxoplasmosis

    Nengl J Med

    (1988)
  • CB Wilson et al.

    Development of adverse sequelae in children born with subclinical congenital Toxoplasma infection

    Pediatrics

    (1980)
  • M Wallon et al.

    Congenital toxoplasmosis: systematic review of evidence of efficacy of treatment in pregnancy

    BMJ

    (1999)
  • Low incidence of congenital toxoplasmosis in children born to women infected with human immunodeficiency virus

    Eur J Obstet Gynecol ReprodBiol

    (1996)
  • JL Jones et al.

    Toxoplasma gondii infection in the United States: seroprevalence and risk factors

    Am J Epidemiol

    (2001)
  • KL Smith et al.

    Prevalence of Toxoplasma gondii antibodies in US military recruits in 1989: comparison with data published in 1965

    Clin Infect Dis

    (1996)
  • H Aspock et al.

    Prevention of prenatal toxoplasmosis by serological screening of pregnant women in Austria

    Scand J Infect Dis Suppl

    (1992)
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