Toxoplasmosis (Toxoplasma gondii)

Toxoplasma gondii, an obligate, intracellular, apicomplexan protozoan, is acquired perorally, transplacentally, or rarely parenterally in laboratory accidents, transfusions, or from a transplanted organ. In immunologically normal children, acute acquired infection most often is asymptomatic or unrecognized, but may cause lymphadenopathy or affect almost any organ. Once acquired, latent encysted organisms persist in the host throughout life. In immunocompromised persons, initial acquisition or recrudescence of latent organisms can cause signs or symptoms related to the central nervous system (CNS) or result in systemic disease, as in bone marrow transplant recipients. If untreated, congenital infection usually causes disease that manifests either perinatally or later in life, most frequently chorioretinitis and CNS lesions. Other manifestations, such as intrauterine growth restriction, prematurity, cognitive and motor deficits, fever, lymphadenopathy, rash, hearing loss, pneumonitis, hepatitis, thrombocytopenia, and cerebrospinal fluid (CSF) inflammatory changes may also occur. Unrecognized congenital toxoplasmosis in infants with HIV infection may be fulminant.

Etiology

Toxoplasma gondii is a coccidian protozoan that multiplies only in living cells. It is descended from an ancient, free-living, single-celled extracellular parasite called Colpodella that shares some ultrastructural features with T. gondii . Tachyzoites, the pathogenic form of the parasite in active infections, are oval or crescent-like, measuring 2-4 × 4-7 µm. Tissue cysts, which are 10-100 µm in diameter, may contain 1000s of latent parasites called bradyzoites and will remain in tissues, especially the CNS and skeletal and heart muscle, for the life of the host. Toxoplasma can multiply in all tissues of mammals and birds.

Oocysts , another form of the parasite, are formed in the cat intestine. Newly infected, nonimmune cats and other Felidae species are the definitive hosts of T. gondii, in which genetic exchange occurs during a sexual cycle. Toxoplasma organisms are transmitted to cats when the cat ingests infected meat containing encysted bradyzoites or ingests oocysts containing sporozoites excreted by other recently infected cats. The parasites then multiply through schizogonic and gametogonic cycles in the distal ileal epithelium of the cat intestine. Oocysts containing 2 sporocysts are excreted, and, under proper conditions of temperature and moisture, each sporocyst matures into 4 sporozoites. For approximately 2 wk the cat excretes 10 ⁵ -10 ⁷ oocysts daily, which may retain their viability for >1 yr in a suitable environment. Oocysts sporulate 1-5 days after excretion and are then infectious. Oocysts are killed by drying or boiling but not exposure to bleach. Oocysts have been isolated from soil and sand frequented by cats, and outbreaks associated with contaminated food and water have been reported. Oocysts and tissue cysts are sources of animal and human infections ( Fig. 316.1 A and B ). There are genetically distinct genetic types of T. gondii that have different virulence for mice (and likely for humans) and form different numbers of cysts in the brain of outbred mice. In the United States, there are 4 predominant clonal lineages called types I , II , III , and IV (haplogroup XII) in addition to atypical, recombinant types ( Fig. 316.1 C ). There is 1 predominant clonal type (type II) in France, Austria, and Poland, and nonarchetypal parasites are prevalent in Brazil, Guyana, French Guiana, and Central America ( Fig. 316.1 D ). Secreted molecules are primary virulence factors that differ between genetic lineages called strains ( Fig. 316.1 E ).

Fig. 316.1, The parasite: Toxoplasma life cycle, ancient ancestor, ultrastructure, life cycle stages affecting humans, genetic variation, and global seroprevalence.

Epidemiology

Toxoplasma infection is ubiquitous in animals and is one of the most common latent infections of humans throughout the world, infecting, and remaining in, approximately 2 billion people. Prevalence varies considerably among people and animals in different geographic areas. In different areas of the world, approximately 3–35% of pork, 7–60% of lamb, and 0–9% of beef contain T. gondii organisms. Significant antibody titers are detected in 50–80% of residents of some localities, such as France, Brazil, and Central America, and in <5% in other areas. The current prevalence estimate in the United States is 10%, but prevalence varies in differing demographies. For example, in the study of Lancaster County pregnant women in an Amish community, prevalence was 50%.There appears to be a higher prevalence of infection in some warmer, more humid climates. Non type II parasites are more common in mothers of congenitally infected infants in warm, moist southern climates, in rural areas, in those with lower socioeconomic status, and with Hispanic ethnicity in the United States. Non–type II parasites are more often associated with prematurity and severe congenital infection in the United States.

Human infection in older children and adults is usually acquired orally by eating undercooked or raw meat that contains cysts or food (e.g., salad greens) or other material contaminated with oocysts from acutely infected cats. Freezing meat to −20°C (−4°F) or heating meat to 66°C (150.8°F) renders the tissue cysts noninfectious. Outbreaks of acute acquired infection have occurred in families, at social gatherings, and in restaurants where people have consumed the same infected food or water. Toxoplasma organisms are not known to be transmitted from person to person except for transplacental infection from mother to fetus and, rarely, by organ transplantation or transfusion. T. gondii has been noted in the prostate gland and sperm of nonhuman animals, but no sexual transmission between humans has been proved.

Seronegative transplant recipients who receive an organ or bone marrow from seropositive donors have experienced life-threatening illness requiring therapy. Seropositive recipients who receive an infected donor organ may have increased serologic titers without recognized, associated disease. Laboratory accidents have resulted in infections, including fatalities.

Congenital Toxoplasmosis

Transmission to the fetus usually follows acquisition of primary infection by an immunologically normal pregnant woman during gestation. Congenital transmission from mothers infected before pregnancy is extremely rare except for immunocompromised women who are chronically infected. The estimated incidence of congenital infection in the United States ranges from 1 in 1,000 to 1 in 8,000 live births. An estimated 15 million people are living with congenital toxoplasmosis worldwide. The incidence of infection among pregnant women depends on the general risk for infection in the specific locale and the proportion of the population that has not been infected previously.

Pathogenesis

T. gondii is acquired by children and adults from ingesting food that contains cysts or that is contaminated with oocysts from acutely infected cats. Oocysts also may be transported to food by flies and cockroaches. They may be carried to people on the fur of dogs. When the organism is ingested, bradyzoites are released from cysts or sporozoites from oocysts. The organisms enter gastrointestinal (GI) cells, where they multiply, rupture cells, infect contiguous cells, enter the lymphatics and blood, and disseminate lymphohematogenously throughout the body. Tachyzoites proliferate, producing necrotic foci surrounded by a cellular reaction. With development of a normal immune response that is both humoral and cell mediated, tachyzoites disappear from tissues. In immunocompromised persons and also some apparently immunocompetent persons, acute infection progresses and may cause potentially lethal disease, including pneumonitis, myocarditis, or encephalitis.

Alterations of T-lymphocyte populations during acute T. gondii infection are common and include lymphocytosis, increased CD8 ⁺ T-cell count, and decreased CD4 ⁺ /CD8 ⁺ ratio. Characteristic histopathologic changes in lymph nodes during acute infection include reactive follicular hyperplasia with irregular clusters of epithelioid histiocytes that encroach on and blur margins of germinal centers, and focal distention of sinuses with monocytoid cells. Depletion of CD4 ⁺ T cells in patients with AIDS predisposes to severe manifestations of toxoplasmosis.

Cysts form as early as 7 days after infection and remain for the life of the host. During latent infection they produce little or no inflammatory response but can cause recrudescent disease in immunocompromised persons. Recrudescent chorioretinitis can occur in children and adults with postnatally acquired infection and in older children and adults with congenitally acquired infection. Host and parasite genetics influence outcomes.

Congenital Toxoplasmosis

When a mother acquires infection during gestation, organisms may disseminate hematogenously to the placenta. Infection may be transmitted to the fetus transplacentally or during vaginal delivery. Of untreated maternal infections acquired in the first trimester, approximately 17% of fetuses are infected, usually with severe disease. Of untreated maternal infection acquired in the third trimester, approximately 65% of fetuses are infected, usually with disease that is milder or inapparent at birth. These different rates of transmission and outcomes are most likely related to placental blood flow, virulence, inoculum of T. gondii, and immunologic capacity of the mother and fetus to limit parasitemia.

Examination of the placenta of infected newborns may reveal chronic inflammation and cysts. Tachyzoites can be seen with Wright or Giemsa stains but are best demonstrated with immunoperoxidase technique. Tissue cysts stain well with periodic acid–Schiff and silver stains as well as with the immunoperoxidase technique. Gross or microscopic areas of necrosis may be present in many tissues, especially the CNS, choroid and retina, heart, lungs, skeletal muscle, liver, and spleen. Areas of calcification occur in the brain.

Almost all congenitally infected individuals who are not treated manifest signs or symptoms of infection, such as chorioretinitis, by adolescence. Some severely involved infants with congenital infection appear to have Toxoplasma antigen–specific cell-mediated hyporesponsiveness, which may be important in the pathogenesis of disease.

Clinical Manifestations

Manifestations of primary infection with T. gondii are highly variable and are influenced primarily by host immunocompetence. There may be no signs or symptoms or severe disease. Reactivation of previously asymptomatic congenital toxoplasmosis usually manifests as ocular toxoplasmosis.

Acquired Toxoplasmosis

Immunocompetent children who acquire infection postnatally generally do not have clinically recognizable symptoms. When clinical manifestations are apparent, they may include almost any combination of fever, stiff neck, myalgia, arthralgia, maculopapular rash that spares the palms and soles, localized or generalized lymphadenopathy, hepatomegaly, hepatitis, reactive lymphocytosis, meningitis, brain abscess, encephalitis, confusion, malaise, pneumonia, polymyositis, pericarditis, pericardial effusion, and myocarditis. Chorioretinitis occurs in approximately 1% of U.S. cases and in 20% of cases in epidemics in Brazil at 2 years after infection. Approximately 10% of mothers of congenitally infected infants have eye lesions on dilated indirect ophthalmoscopic examinations. Postnatally acquired chorioretinal lesions cannot be distinguished from congenitally acquired lesions based on appearance. In some areas of Brazil, 80% of the population is infected, 20% of whom have retinal involvement, with 50% of those >50 yr old. Symptoms and signs of active ocular infection may be present for a few weeks only or may persist for many months.

The most common manifestation of acute acquired toxoplasmosis is enlargement of 1 or a few cervical lymph nodes. Cases of Toxoplasma lymphadenopathy can resemble infectious mononucleosis, lymphoma, or other lymphadenopathies (see Chapter 517 ). Pectoral, mediastinal, mesenteric, and retroperitoneal lymph nodes may be involved. Involvement of intraabdominal lymph nodes may be associated with fever, mimicking appendicitis. Nodes may be tender but do not suppurate. Lymphadenopathy may wax and wane for as long as 1-2 yr. However, almost all patients with lymphadenopathy recover spontaneously without antimicrobial therapy. Significant organ involvement in immunologically normal persons is uncommon, although some individuals have significant morbidity, including rare cases of encephalitis, brain abscesses, hepatitis, myocarditis, pericarditis, and polymyositis. In persons acquiring T . gondii in Guyana near the Maroni River, and along Amazon tributaries, a severe form of life-threatening, multivisceral involvement with fever has occurred.

Ocular Toxoplasmosis

In the United States and Western Europe, T. gondii is estimated to cause 35% of cases of chorioretinitis ( Fig. 316.2 ). In Brazil, T. gondii retinal lesions are common. Clinical manifestations include blurred vision, visual floaters, photophobia, epiphora, and, with macular involvement, loss of central vision. Ocular findings of congenital toxoplasmosis also include strabismus, microphthalmia, microcornea, cataracts, anisometropia, nystagmus, glaucoma, optic neuritis, and optic atrophy. Episodic recurrences are common, but precipitating factors have not been defined. Recurrent, active disease usually occurs at school-entry age and during adolescence. Anecdotally, stress or trauma seems to precipitate symptoms. Recurrences are most common closest to the time of acquisition of infection, and treatment leads to resolution of activity.

Fig. 316.2, Toxoplasmic chorioretinitis.

Immunocompromised Persons

Disseminated T. gondii infection among older children who are immunocompromised by AIDS, malignancy, cytotoxic therapy, corticosteroids, or immunosuppressive drugs given for organ transplantation involves the CNS in 50% of cases and may also involve the heart, lungs, and GI tract. Stem cell transplant recipients present a special problem, because active infection is difficult to diagnose serologically. After transplantation, T. gondii –specific antibody levels may remain the same, increase, or decrease, and can even become undetectable. Toxoplasmosis in transplantation patients almost always results from transplantation from a seropositive donor to a seronegative recipient. Thus, knowledge of the serologic status of the donor and recipient is essential. Active infection is often fulminant and rapidly fatal without treatment. Following blood PCR can establish diagnosis and monitor efficacy of treatment.

Congenital T. gondii infection in infants with HIV infection is rare in the United States but can be a severe and fulminant disease with substantial CNS involvement. Alternatively, it may be more indolent in presentation, with focal neurologic deficits or systemic manifestations such as pneumonitis occurring with progressive CD4 depletion in the highly active antiretroviral therapy (HAART)–untreated infant.

From 25–50% of persons with T. gondii antibodies and HIV infection without antiretroviral treatment eventually experience toxoplasmic encephalitis , which is fatal if not treated. HAART and trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis to prevent Pneumocystis have diminished the incidence of toxoplasmosis in patients with HIV infection, but toxoplasmic encephalitis remains a presenting manifestation in some adult patients with AIDS. Typical findings include fever, headache, altered mental status, psychosis, cognitive impairment, seizures, and focal neurologic defects, including hemiparesis, aphasia, ataxia, visual field loss, cranial nerve palsies, and dysmetria or movement disorders. In adult patients with AIDS, toxoplasmic retinal lesions are often large with diffuse necrosis and contain many organisms but little inflammatory cellular infiltrate. Diagnosis of presumptive toxoplasmic encephalitis based on neuroradiologic studies in patients with AIDS necessitates a prompt therapeutic trial of medications effective against T. gondii. Clear clinical improvement within 7-14 days and improvement of neuroradiologic findings within 3 wk make the presumptive diagnosis almost certain.

Congenital Toxoplasmosis

Congenital toxoplasmosis usually occurs when a woman acquires primary infection while pregnant. Most often, maternal infection is asymptomatic or without specific symptoms or signs. As with other adults with acute toxoplasmosis, lymphadenopathy is the most commonly identified physical finding.

In monozygotic twins the clinical pattern of involvement is most often similar, whereas in dizygotic twins the manifestations often differ, including cases of congenital infection in only 1 twin. The major histocompatibility complex class II gene DQ3 appears to be more common than DQ1 among HIV-infected persons seropositive for T. gondii who develop toxoplasmic encephalitis, as well as in children with congenital toxoplasmosis who develop hydrocephalus. These findings suggest that the presence of HLA-DQ3 is a risk factor for severity of toxoplasmosis. Other allelic variants of genes, including COL2A , ABC4R , P2X7R , NALP1 , ALOX12, TLR9 , and ERAAP , are also associated with increased susceptibility.

Congenital infection may present as a mild or severe neonatal disease. It may also present with sequelae or relapse of a previously undiagnosed and untreated infection later in infancy or even later in life. There is a wide variety of manifestations of congenital infection, ranging from hydrops fetalis and perinatal death to small size for gestational age, prematurity, peripheral retinal scars, persistent jaundice, mild thrombocytopenia, CSF pleocytosis, and the characteristic triad of chorioretinitis, hydrocephalus, and cerebral calcifications. More than 50% of congenitally infected infants are considered normal in the perinatal period, but almost all such children will develop ocular involvement later in life if they are not treated during infancy. Neurologic signs such as convulsions, setting-sun sign with downward gaze, and hydrocephalus with increased head circumference may be associated with substantial cerebral damage or with relatively mild inflammation obstructing the aqueduct of Sylvius. If affected infants are treated and shunted promptly, signs and symptoms may resolve, and development may be normal.

The spectrum and frequency of neonatal manifestations of 210 newborns with congenital Toxoplasma infection identified by a serologic screening program of pregnant women in France were described in 1984. In this study, 10% had severe congenital toxoplasmosis with CNS involvement, eye lesions, and general systemic manifestations; 34% had mild involvement with normal clinical examination results other than retinal scars on dilated indirect exams or isolated intracranial calcifications in brain CT scans; and 55% had no detectable manifestations. These numbers represent an underestimation of the incidence of severe congenital infection for several reasons: the most severe cases, including most who died, were not referred; therapeutic abortion sometimes was performed when acute acquired infection of the mother was diagnosed early during pregnancy; in utero spiramycin therapy prevented or diminished the severity of infection; only 13 of the 210 congenitally infected newborns had brain CT, and only 77% of these 210 infants had a CSF examination. Routine newborn examinations often yield normal findings for congenitally infected infants, but more careful evaluations may reveal significant abnormalities. A 2012 analysis of the National Collaborative Chicago-Based Congenital Toxoplasmosis Study (NCCCTS, 1981–2009) data found that 72% of children at or near birth had chorioretinal scars, 70% had CNS calcifications, 12% microcephaly, 37% hydrocephalus, 41% thrombocytopenia, 39% hepatomegaly, 32% splenomegaly, and 41% were born prematurely ( Fig. 316.3 ). In one study of 28 infants in New England, identified by a universal state-mandated serologic screening program for T. gondii –specific IgM, 26 (93%) had normal findings on routine newborn examination, but 14 (50%) had significant abnormalities detected with more careful evaluation. The abnormalities included retinal scars (7 infants), active chorioretinitis (3 infants), and CNS abnormalities (8 infants). In Fiocruz, Belo Horizonte, Brazil, infection is common, affecting 1 in 600 live births. Half these infected infants have active chorioretinitis at birth. When the infection is acquired in utero and the fetus is treated by drug therapy of the pregnant woman with pyrimethamine , sulfadiazine , and leucovorin , signs and symptoms in the infant may be prevented. The newborn infant may appear normal with no CSF abnormalities and no brain or eye disease. In utero therapy initiated rapidly results in a reduction of ocular and neurologic sequelae.

Fig. 316.3, Congenital toxoplasmosis: manifestations at presentation.

There is also a wide spectrum of symptoms of untreated congenital toxoplasmosis that presents later in the 1st yr of life ( Table 316.1 ). These children may have IQ scores of <70, and have convulsions and severely impaired vision.

Table 316.1

Signs and Symptoms Occurring Before Diagnosis or During the Course of Untreated Acute Congenital Toxoplasmosis in 152 Infants (A) and in 101 of These Same Children After They Had Been Followed ≥4 Yr (B)

Adapted from Eichenwald H: A study of congenital toxoplasmosis. In Slim JC, editor: Human toxoplasmosis , Copenhagen, 1960, Munksgaard, pp. 41–49. Study performed in 1947. The most severely involved institutionalized patients were not included in the later study of 101 children.

SIGNS AND SYMPTOMS	FREQUENCY OF OCCURRENCE IN PATIENTS WITH
SIGNS AND SYMPTOMS	“Neurologic” Disease *	“Generalized” Disease ^†
A. INFANTS	108 PATIENTS (%)	44 PATIENTS (%)
Chorioretinitis	102 (94)	29 (66)
Abnormal cerebrospinal fluid	59 (55)	37 (84)
Anemia	55 (51)	34 (77)
Convulsions	54 (50)	8 (18)
Intracranial calcification	54 (50)	2 (4)
Jaundice	31 (29)	35 (80)
Hydrocephalus	30 (28)	0 (0)
Fever	27 (25)	34 (77)
Splenomegaly	23 (21)	40 (90)
Lymphadenopathy	18 (17)	30 (68)
Hepatomegaly	18 (17)	34 (77)
Vomiting	17 (16)	21 (48)
Microcephaly	14 (13)	0 (0)
Diarrhea	7 (6)	11 (25)
Cataracts	5 (5)	0 (0)
Eosinophilia	6 (4)	8 (18)
Abnormal bleeding	3 (3)	8 (18)
Hypothermia	2 (2)	9 (20)
Glaucoma	2 (2)	0 (0)
Optic atrophy	2 (2)	0 (0)
Microphthalmia	2 (2)	0 (0)
Rash	1 (1)	11 (25)
Pneumonitis	0 (0)	18 (41)
B. CHILDREN ≥4 YR OLD	70 PATIENTS (%)	31 PATIENTS (%)
Intellectual impairment	62 (89)	25 (81)
Convulsions	58 (83)	24 (77)
Spasticity and palsies	53 (76)	18 (58)
Severely impaired vision	48 (69)	13 (42)
Hydrocephalus or microcephaly	31 (44)	2 (6)
Deafness	12 (17)	3 (10)
Normal	6 (9)	5 (16)

* Patients with otherwise undiagnosed central nervous system disease in the 1st yr of life.

† Patients with otherwise undiagnosed nonneurologic diseases during the 1st 2 mo of life.

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