Toxoplasma gondii (Toxoplasmosis)

Toxoplasma gondii , a parasite with worldwide distribution, is responsible for a significant disease burden in humans. Primary infection can be asymptomatic, mildly symptomatic with a mononucleosis like illness and/or lymphadenopathy, or it can cause severe ocular disease, even in immunocompetent people. ^, It also can result in substantial neurologic and ocular sequelae in congenitally infected children. Atypical and more virulent T. gondii strains can be associated with community-acquired pneumonia, disseminated disease, and even death among otherwise healthy individuals in certain tropical areas. High attack rates and an unusual presentation, with a tickborne-disease-like illness with leukopenia, lymhopenia, thrombocytopenia, and transaminitis, has been reported after exposure to infected game-meat. Reactivation of chronic infection can occur in severely immunosuppressed individuals and cause life-threatening disease. Patients with profound T-lymphocyte-mediated immune compromise are at high risk of reactivation, if not receiving anti- Toxoplasma prophylaxis. At-risk groups include those with the acquired immunodeficiency syndrome (AIDS), ^, hematopoietic stem cell transplants recipients, and patients receiving high doses of corticosteroids and other biologic agents such as monoclonal antibodies (e.g., alemtuzumab, adalimumab, infliximab, rituximab, natalizumab). Studies addressing the possible link of latent Toxoplasma infection with psychiatric disorders and cancer have been inconclusive.

Pathogen and Life Cycle

T. gondii is an obligate intracellular parasite with the capacity to infect almost any warm-blooded animal. The parasite has three infectious stages: tachyzoites, which are responsible for rapid spread of the parasite between cells and tissues and the clinical manifestations of toxoplasmosis; bradyzoites, which are contained within tissue cysts, maintain chronic infection, and stay dormant for the life of the host unless the immune system is severely compromised (with the exception of local reactivations in the eye that can occur in immunocompetent patients); and sporozoites, which are contained within oocysts, are shed by members of the felid family, and widely disseminate the agent in the environment. A sexual cycle only takes place in the small intestine of felids, allowing for the exchange of genetic material between strains and potentially generating variant strains in geographic areas where wild and large cats can travel long distances. ^,

Genotyping studies have identified several clonal lineages of T. gondii in Europe, North America, and South America. ^, Toxoplasma genetic studies have grouped the parasite worldwide into sixteen haplogroups. Haplogroup 2 is predominantly seen in Europe, whereas in North America haplogroups 1, 2, 3, and atypical strains are more common. Haplogroup 12 has also been seen in North America and has been associated with more aggressive clinical presentations. In South America, haplogroup 2 is rarely seen, and predominance of 1, 3, and atypical have been reported. ^,

Investigators have suggested that differences in T. gondii strains may partially explain the observed differences in the clinical spectrum of infection in different parts of the world, particularly between Europe, North America, and South America. Atypical T. gondii strains have been reported from several areas of the world, including North America and Mexico, ^, Central and South America, Australia and Africa. ^, ^, This finding should be taken into consideration when clinical syndromes consistent with severe toxoplasmosis are encountered in individuals returning from these areas or in toxoplasmosis cases associated with game meat. ^, Significant differences in the prevalence and severity of major manifestations (e.g., chorioretinitis, brain calcifications, and hydrocephalus in children with congenital toxoplasmosis) have been observed in the US, South America, Middle East, France and other Western European countries. ^, ^, For example, the ocular manifestations of congenital toxoplasmosis in children in Brazil are more severe than in children in Europe. Primary acute infections have resulted in pneumonia, acute hepatitis, fever of unknown origin, and death, even in HIV-negative and immunocompetent individuals in South America, particularly when atypical more virulent T. gondii strains and/or infections with high parasite load were implicated.

Cats, both domestic and wild, are the definitive hosts and are responsible for widespread existence of the parasite throughout the world. Although occasionally cats become ill, most are asymptomatic. Cats shed oocysts following the ingestion of any of the infectious stages of the parasite, tissue cysts, and oocysts. As many as 10 million oocysts can be shed in a single day in the feces of an infected cat, for periods varying from 7–20 days. Oocysts can remain viable in moist soil for as long as 18 months; it is from this environmental source that other felids and intermediate hosts, including other animals and humans, can acquire infection. Cats can be infected by eating meat of infected rodents, birds, or other animals.

Epidemiology

Population seroprevalence of T. gondii infection varies by geographic location, thus reflecting the likelihood of having been exposed to oocysts in soil, untreated water, vegetables, raw shellfish and other food or to tissue cysts in uncooked or raw meat. ^, The age-adjusted seroprevalence of T. gondii infection in the US based on the most recent national survey (2011–2014) was 10.4% for people ≥6 years of age and 7.5% for women of childbearing age (15–44 years); the infection rate is lower among children (0.9% for 6–11 year old and 3% for 12–19 year old-children). However, even in the US, seroprevalence can be as high as 20%–25% in certain socioeconomic, racial, and ethnic groups, and particularly in certain foreign-born individuals. Seroprevalence in several other parts of the world are much higher (e.g., 60%–80% in areas in Central and South America and Africa). Seroprevalence increases with age and usually is associated inversely with socioeconomic status.

Humans and other vertebrates are incidental hosts and become infected primarily by the oral route through ingestion of environmental oocysts or infected meat containing tissue cysts ( Fig. 273.1 ). Acquisition of infection through the oral route can occur by any one of the following : (1) accidental ingestion of oocysts through soil contaminated foods (e.g., fruits, vegetables, raw shellfish, drinking water) during gardening or during cleaning cat litter; (2) ingestion of viable tissue cysts through eating raw, undercooked, microwaved, cured, dried, or smoked meat or by ingesting cross-contaminated food; or (3) drinking infected unpasteurized raw milk. ^, Vertical transmission occurs during gestation. Humans also can acquire infection through receipt of an organ transplant from an infected donor and, more rarely, during a laboratory accident. Main risk factors for acute T. gondii infection in the US identified in a 2009 study were eating raw ground beef, rare lamb, or locally produced cured, dried, or smoked meat; working with meat; drinking unpasteurized goat milk; or having ≥3 kittens. An additional risk factor identified in this study was eating raw oysters, clams, or mussels. Untreated water has been reported to be the source of major community outbreaks of acute toxoplasmosis in Canada and Brazil. T. gondii has also been detected (by PCR) in drinking water in endemic regions (e.g., in South Mexico). Clusters of acute toxoplasma infections in families have also been documented in the US. ^, Up to 50% of individuals with confirmed acute T. gondii infection have no known risk factors identified. ^,

FIGURE 273.1, Life cycle of Toxoplasma gondii

Congenital infection usually is the result of a woman acquiring primary infection during gestation or within 3 months before conception. ^, ^, Pregnant women with chronic infection before gestation rarely have transmitted infection to their fetus unless significantly immunocompromised and not on prophylaxis/suppressive therapy with spiramycin throughout gestation. Congenital toxoplasmosis from chronically infected pregnant women, resulting from reinfection during gestation with a different T. gondii strain, has been reported in two case reports. ^,

The incidence of acute primary Toxoplasma infections during gestation in the US in the early 1960s was estimated to be 1.1/1000 pregnant women. There are no recent surveillance data for acute Toxoplasma infections during pregnancy in the US, but given the overall decrease in seroprevalence, the current incidence is likely lower. The estimated global incidence of acute Toxoplasma infections during pregnancy is 1.1% (95% CI: 0.9%–1.2%) with a wide range across countries; the incidence, when more stringent criteria for acute Toxoplasma infections are used, is 0.6% (95% CI: 0.4%–0.7%).

The overall rate of transmission to the fetus in women who seroconvert during gestation was 50% and 60% before the introduction of spiramycin and 25%–30% thereafter. The rate of vertical transmission increases and the severity of disease decreases with advancing gestational age at the time of maternal infection ( Fig. 273.2 ). In treated women, vertical transmission rates are about 6% at 13 weeks of gestation, 40% at 26 weeks, and 72% at 36 weeks ( Fig. 273.2 ). More recently reported rates of mother-to-child-transmission rates from France were similar (11%, 47%, and 64%, respectively), and the risk for clinical signs in the infected fetus has been estimated at 56% for maternal infections at 12 weeks of gestation, 17% at 24 weeks, and 9% at 36 weeks, respectively.

FIGURE 273.2, (A) Risk for congenital infection by gestational age at maternal seroconversion. (B) Risk for developing clinical signs before the age of 3 years, according to gestational age at maternal seroconversion. CI, confidence interval.

The global burden of congenital toxoplasmosis is estimated to be 190,000 cases per year with an overall global incidence of 15 cases per 10,000 live births. The incidence of congenital toxoplasmosis in certain world regions is higher (e.g., 18–34 cases per 10,000 live births in parts of South America). The severity of disease also is higher in those regions.

The incidence of congenital toxoplasmosis in the US according to early reports from the New England Newborn Screening Program (1986–1992) was estimated to be 0.82 cases/10,000 live births. Since then, the incidence has been decreasing; in 2006–2014, it was estimated to be 0.23 cases/10,000 live births in Massachusetts and, in 2015–2018, 0.14 cases/10,000 live births in Massachusetts. However, the true incidence of congenital toxoplasmosis in the US might be higher because the sensitivity of the newborn screening test (filter paper blot spot Toxoplasma- IgM) used in the New England Newborn Screening Program is only 50%–75%, and fetal losses were not counted. ^,

The incidence of congenital toxoplasmosis at birth in France in 2007 was 2.9 cases per 10,000 live births, whereas the prevalence was 3.3 cases per 10,000 live births and the incidence of symptomatic congenital toxoplasmosis was 0.34 cases per 10,000 live births.

Pathogenesis and Immune Response

Following oral ingestion of tissue cysts (e.g., in infected meat) or oocysts (e.g., in contaminated soil, water, or food), gastric juices disrupt cyst walls and release bradyzoites (from tissue cysts) and sporozoites (from oocysts), which are converted to tachyzoites. Because of their capacity to move by gliding, flexing, undulating, and rotating, tachyzoites easily infect contiguous cells. Tachyzoites also can infect distant tissues by hematogenous or lymphatic spread. Tachyzoites likely infect Peyer patches and the spleen first, followed by the lungs and liver. Parasitemia can be detected for several days during the early stages of acute infection and probably lasts for approximately 14 days. Tachyzoites ultimately arrive at sites such as the brain, eye, heart, and skeletal muscle where, under the pressure of the immune system and other factors, they are converted into bradyzoites.

In immunocompetent hosts, an effective immune response controls the proliferation of the rapidly replicating tachyzoite and induces conversion to the metabolically slower bradyzoite, thereby facilitating the formation of tissue cysts (chronic infection). A master regulator for tachyzoite to bradyzoite conversion has been identified. Tissue cysts likely persist for the life of the host, most commonly in the brain, retina, and cardiac and skeletal muscles. Innate, humoral, and cellular immune responses are induced to prevent the uncontrolled proliferation of tachyzoites. With the exception of chorioretinitis, latent T. gondii infection typically remains quiescent for life, unless severe immunosuppression occurs.

In immunocompromised patients previously latently infected with T. gondii, significant depletion of T-lymphocyte-mediated immune responses can facilitate reactivation of infection.

Clinical Manifestations

Signs and symptoms of toxoplasmosis can result from primary infection or reactivation. In both forms, the rapid proliferation of the tachyzoite and its corresponding inflammatory immune response are responsible for the clinical manifestations. Primary infection can be asymptomatic in many children, and recognized risk factors may not be present. Thus, when clinical symptomatology can be consistent with acute toxoplasmosis, testing for toxoplasmosis only those with conventional epidemiologic risk factors may miss about half of toxoplasmosis cases. ^,

Severity of toxoplasmosis during primary infection or reactivation can be influenced by the virulence of the infecting strain, inoculum size, infectious form (e.g., oocyst vs. tissue cyst), immune competence and genetics of the host (e.g., presence of HLA-DQ3), and, for congenital toxoplasmosis, by the absence of prenatal and/or postnatal treatment. ^, ^, ^, ^, Reports from several large observational studies provide supportive evidence for the efficacy of prenatal screening and treatment programs in reducing mother-to-child-transmission risk and ameliorating the severity of congenital toxoplasmosis. ^,

Acute Primary Infection in Immunocompetent Patients

Although most children and adults are asymptomatic during an acute primary T. gondii infection, in ∼10% of patients, the following symptoms or syndromes, alone or in various combinations, have been reported: mononucleosis-like illness, fever (up to 104°F or 40°C), malaise, fatigue, myalgia, arthralgia, lymphadenopathy, headache, sore throat, nausea, abdominal pain, eye symptoms including decrease in visual acuity, floaters and eye pain, and occasionally skin rash. In community-outbreak settings (and/or in certain tropical areas), as many as 82% of infected people were symptomatic, and up to 19% had eye disease.

Lymphadenopathy

Lymphadenopathy can be localized or generalized. A solitary, occipital, and painlessly enlarged lymph node can be the sole manifestation of toxoplasmosis in a child, pregnant woman, or adult. However, more generalized lymphadenopathy, cervical, occipital, axillary, inguinal, mediastinal, and abdominal lymphadenopathy can also occur. Lymph nodes usually are 1–3 cm in size, nonsuppurative, and nontender, and the lymphadenopathy usually regresses within 3 months. Relapse of lymphadenopathy can occur between 3 and 6 months; persistence of lymphadenopathy beyond 6 months is rare and should suggest an alternate diagnosis.

Ocular Toxoplasmosis

Ocular toxoplasmosis can be the result of congenital toxoplasmosis, reactivation of a chronic latent ocular infection from congenital toxoplasmosis, postnatally acquired acute primary infection, or reactivation of chronic latent ocular infection from a postnatally acquired infection. In the US, >10% of cases of ocular toxoplasmosis result from a primary, postnatally acquired acute infection. ^, T. gondii retinal lesions, resulting from reactivation of chronic latent ocular infection, often appear as whitish infiltrates attached to a darkly pigmented border of an old scar ( Fig 273.3 ). Retinal lesions tend to be less typical in immunocompromised patients.

FIGURE 273.3, Toxoplasmic chorioretinitis in a congenitally infected child. The sharply demarcated quiescent scar is pigmented ( double arrows ). Contiguous to this older lesion is a fluffy, active new lesion (satellite lesion) ( single arrow ).

Signs of ocular toxoplasmosis include vitritis, presence of inflammatory cells in the anterior chamber, panuveitis, chorioretinitis, choroidal neovascular membrane formation, retinal vasculitis, retinal hemorrhage, retinal detachment, retinal necrosis, chorioretinal scar, satellite lesions associated with preexisting chorioretinal scar, and transient mydriasis ( Box 273.1 ). ^, Three forms of toxoplasmic retinal disease have been described: large destructive lesions, punctate inner lesions, and punctate deep lesions. Small partial thickness lesions involving the inner or outer layers of the retina have been described early in the course in patients with AIDS. Neuroretinitis can occur with associated papillitis and optic disc edema. Cataracts, macular edema, and glaucoma have been reported. Macular lesions are commonly present in those with congenital toxoplasmosis. Extensive toxoplasmic retinitis can be confused with necrotizing herpetic retinopathies. A variety of complications have been described, including epiretinal membranes, macular edema, subretinal neovascularization, retinal detachment, retinal vessel occlusion, and frosted branch angiitis.

BOX 273.1

Clinical Manifestations of Congenital Toxoplasmosis (Listed Alphabetically)

Ophthalmologic Findings	Neurologic Findings	Hematologic Findings
Signs Cataract Chorioretinal edema Chorioretinal scars ^∗ (macular, peripheral, juxtapapillary) Chorioretinitis ^∗ (bilateral or unilateral, posterior pole macular lesions ^∗ or peripheral lesions; yellowish-white cotton-like patches in the fundus; solitary or small clusters; lesions of various ages; sharp borders in older lesions) Choroidal neovascular (CNV) membranes (vision threatening) ^, ^, ^, Detachment of posterior hyaloid membrane Iritis (if associated with posterior pole lesions) Leukocoria ^, Macular edema ^∗ Microphthalmia-Microcornea Necrotizing retinitis ^∗ Optic nerve atrophy Papilledema ^∗ Papillitis ^∗ Retinal detachment ^, Vitritis ∗ (with or without anterior chamber inflammation ) Symptoms Amblyopia Nystagmus ∗ Strabismus ∗ (convergent or divergent) Visual impairment/vision loss ∗	CSF: pleocytosis, lymphocytosis (mild/moderate); eosinophilia, elevated protein (up to 1000 mg/dL); ∗ ^, ^a hypoglycorrhachia Signs Brain lesions ring enhancing, mimicking brain abscess (rare) Brain masses Corpus callosum dysgenesis Encephalomalacia multifocal ^, Encephalomyelitis (eosinophilic) ^, Hydrocephalus ∗ (obstructive or non-obstructive) ^b ^, ^, Hypotonia ∗ (or abnormal muscle tone/spasticity) Intracranial calcifications ∗ (multiple 1–3 mm echogenic nodular foci; scattered in white matter, in periventricular areas, curvilinear streaks in basal ganglia, nodular calcifications, linear calcifications) Macrocephaly ∗ Microcephaly Periventricular cysts Periventricular diffuse echogenicity Spinal cord lesions (including spinal cord hemorrhage) ^, ^, Symptoms A wide spectrum of neurologic manifestations have been reported ranging from subtle neurologic signs to massive severe acute encephalopathy Cerebral palsy Coordination problems ^∗ Delay in developmental milestones ∗ (psychomotor retardation, IQ <70 ) Nerve palsies (cranial) Seizures Sensorineural hearing loss Spasticity ∗	Anemia Cholestasis Disseminated intravascular coagulation (DIC) Hepatitis Hyperbilirubinemia Thrombocytopenia ∗ Other Findings Diabetes insipidus (central) (rare) Hepatic calcifications ∗ Hepatomegaly or Hepatosplenomegaly ∗ Jaundice Lymphadenopathy Myocarditis Pneumonia Prematurity ∗ ^,226 Rash (petechial; blueberry muffin rash; purpura, maculopapular) Sepsis like illness (disseminated disease with multiple organ failure, acute respiratory distress syndrome, DIC) (rare) Splenomegaly ∗ Temperature instability (particularly with CNS lesions around the third ventricle) (rare)

Ophthalmologic Findings

Neurologic Findings

Hematologic Findings

Signs

Cataract
Chorioretinal edema
Chorioretinal scars ^∗ (macular, peripheral, juxtapapillary)
Chorioretinitis ^∗ (bilateral or unilateral, posterior pole macular lesions ^∗ or peripheral lesions; yellowish-white cotton-like patches in the fundus; solitary or small clusters; lesions of various ages; sharp borders in older lesions)
Choroidal neovascular (CNV) membranes (vision threatening) ^, ^, ^,
Detachment of posterior hyaloid membrane
Iritis (if associated with posterior pole lesions)
Leukocoria ^,
Macular edema ^∗
Microphthalmia-Microcornea
Necrotizing retinitis ^∗
Optic nerve atrophy
Papilledema ^∗
Papillitis ^∗
Retinal detachment ^,
Vitritis ∗ (with or without anterior chamber inflammation )

Symptoms

Amblyopia
Nystagmus ∗
Strabismus ∗ (convergent or divergent)
Visual impairment/vision loss ∗

CSF: pleocytosis, lymphocytosis (mild/moderate); eosinophilia, elevated protein (up to 1000 mg/dL); ∗ ^, ^a hypoglycorrhachia

Signs

Brain lesions ring enhancing, mimicking brain abscess (rare)
Brain masses
Corpus callosum dysgenesis
Encephalomalacia multifocal ^,
Encephalomyelitis (eosinophilic) ^,
Hydrocephalus ∗ (obstructive or non-obstructive) ^b ^, ^,
Hypotonia ∗ (or abnormal muscle tone/spasticity)
Intracranial calcifications ∗ (multiple 1–3 mm echogenic nodular foci; scattered in white matter, in periventricular areas, curvilinear streaks in basal ganglia, nodular calcifications, linear calcifications)
Macrocephaly ∗
Microcephaly
Periventricular cysts
Periventricular diffuse echogenicity
Spinal cord lesions (including spinal cord hemorrhage) ^, ^,

Symptoms

A wide spectrum of neurologic manifestations have been reported ranging from subtle neurologic signs to massive severe acute encephalopathy
Cerebral palsy
Coordination problems ^∗
Delay in developmental milestones ∗ (psychomotor retardation, IQ <70 )
Nerve palsies (cranial)
Seizures
Sensorineural hearing loss
Spasticity ∗

Anemia
Cholestasis
Disseminated intravascular coagulation (DIC)
Hepatitis
Hyperbilirubinemia
Thrombocytopenia ∗

Other Findings

Diabetes insipidus (central) (rare)
Hepatic calcifications ∗
Hepatomegaly or Hepatosplenomegaly ∗
Jaundice
Lymphadenopathy
Myocarditis
Pneumonia
Prematurity ∗ ^,226
Rash (petechial; blueberry muffin rash; purpura, maculopapular)
Sepsis like illness (disseminated disease with multiple organ failure, acute respiratory distress syndrome, DIC) (rare)
Splenomegaly ∗
Temperature instability (particularly with CNS lesions around the third ventricle) (rare)

∗ Represents the most common findings according to the Remington lab experience.

a Elevated CSF protein from brain tissue necrosis that autolyzes and gradually sloughs into the ventricles

b Hydrocephalus primarily develops from periaqueductal and periventricular vasculitis and necrosis; obstruction of aqueduct of Sylvius from severe ependymitis. In some cases, intense periventricular necrosis (rather than obstruction of ventricular passages) causes the development of hydrocephalus. ^, ^, ^, ^,

Clusters of small, partial thickness retinal lesions can occur, but there is usually only one focus of active disease at any given time. Active retinal inflammation resolves even without treatment, leaving hyperpigmented scars; recurrence develop as satellite lesions. The duration of active retinal infection (active tachyzoite proliferation) and the intensity of the inflammatory response appear to determine the characteristics of ocular toxoplasmosis. Optic coherence tomography (OCT), OCT angiography (OCTA), and fundus fluorescein angiography (FFA) (for the detection of retinal vasculitis, and fluorescein extravasation) should be considered in the evaluation of patients with suspected toxoplasmic chorioretinitis.

Other Manifestations in Immunocompetent Patients

Rarely, other syndromes such as hepatitis, pneumonia, myocarditis, myositis, and disseminated disease have been described in immunocompetent individuals. ^, Use of high dose steroids for acute illnesses in previously healthy children can reactivate a chronic latent infection with detrimental outcomes. A tick-borne-disease-like clinical presentation, with leukopenia, lymphopenia, thrombocytopenia, and transaminitis, has been reported in association with ingestion of T. gondii infected venison.

Congenital Toxoplasmosis

In countries (e.g., in France) where serologic screening and prenatal treatment for toxoplasmosis is systematically offered to pregnant women, most fetuses and newborns infected with T. gondii either do not exhibit any clinical signs of disease on initial evaluation or have only mild disease. However, clinical manifestations of toxoplasmosis can still be discovered years later. For example, in cohorts of prenatally treated infants in France, the initial eye lesions in congenitally infected children with toxoplasmic chorioretinitis were detected after 7 months of age in 75% of those and after 3 years of age in 50% of those ( Fig. 273.3 ). In 34% of those, recurrences of eye disease or new eye lesions (or both) can occur up to 12 years after the first eye lesion. In Europe, the quality of life and visual performance of patients with treated congentially toxoplasmosis (whose mothers were also prenatally treated) does not appear to be significantly affected. However, in South America, where most infants with congenital toxoplasmosis have not been diagnosed and treated prenatally, the long-term impact of ocular toxoplasmosis remains concerning. ^, ^,

In the US, where there is no universal prenatal screening for toxoplasmosis, most congenitally infected infants evaluated at toxoplasmosis reference centers, born to mothers who did not receive treatment during pregnancy, were symptomatic. Based on data from 153 congenitally infected children (prenatally untreated) followed at a referral center at the University of Chicago, 77% had severe disease at birth, 11% had mild disease, and 12% had no clinical signs. ^, ^, In contrast, the respective numbers in France were 3%, 10%, and 85% respectively. Among infants in the US who were not treated during their first year of life, more than 70% developed at least one new chorioretinal lesions by 10 years of age.

Congenital infection can result in fetal death or a wide variety of central nervous system and other organ abnormalities ( Box 273.1 ). Findings on fetal ultrasound include hydrocephalus, intracranial calcifications, intrahepatic calcifications, echogenic bowel, ascites, pericardial or pleural effusions, and intrauterine growth restriction ^, ^, ( Box 273.2 ).

BOX 273.2

Fetal Ultrasound Findings of Congenital Toxoplasmosis (Listed Alphabetically)

Fetal Ultrasound Findings

Ascites ∗

∗ Represents the most common findings according to the Remington lab experience.
Echogenic bowel ∗
Fetal death
Hydrocephalus ∗
Hydrops fetalis
Hepato-splenomegaly
Intracranial densities/calcifications ∗
Intrahepatic densities/calcifications ∗
Intrauterine growth restriction (IUGR) ∗
Pericardial/pleural effusions ∗
Placenta hyperdensities
Placenta increased thickness

The classic triad of chorioretinitis, hydrocephalus, and brain calcifications is highly suggestive of congenital toxoplasmosis. ^, ^, ^, The clinical manifestation reported in infants/children with congenital toxoplasmosis are shown in Box 273.1 . Newborns can be asymptomatic at birth or have any of the following clinical manifestations, alone or in combination: ^, ^, ^, ^, strabismus, nystagmus, deceased visual acuity, blindness, chorioretinitis, vitritis, cataract, choroidal neovascular membranes (CNV), ^, ventriculomegaly, hydrocephalus, multiple echogenic nodular foci consistent with intracranial calcifications, diffuse periventricular echogenicity, periventricular cysts, ^, dysgenesis of corpus callosum, macrocephaly or microcephaly, seizures, encephalitis, psychomotor or mental retardation, hearing loss, pneumonia, hepatosplenomegaly, jaundice, or skin rash. Rare cases of disseminated neonatal congenital toxoplasmosis have been reported, ^, including presentation as hemophagocytic syndrome in preterm infants.

More severe ocular disease is seen in children with congenital toxoplasmosis from certain parts of the world. For example, in comparison to children from Europe, those with congenital toxoplasmosis in Brazil, more often develop severe chorioretinitis, with multiple and larger eye lesions, and lesions located in the posterior pole causing visual impairment. ^, These differences might be attributed to more virulent strains implicated in South America and/or lack of universal prenatal screening and treatment of pregnant women in these regions. Fetal infection early in gestation, at the time of fetal retinal development, could explain the predominance of macular lesions in congenital toxoplasmosis.

Chronic Infection in Immunocompetent Children

During the chronic stage of infection, T. gondii does not cause overt symptoms in most immunocompetent people. However, acute toxoplasmic chorioretinitis can develop in chronically infected, immunocompetent individuals, from local ocular reactivation of the parasite and subsequent host immune response. Ocular reactivation can occur in congenitally or postnatally infected individuals. In a French study, among 327 infants with congenital toxoplasmosis—the majority of whose mothers were prenatally treated—24% had at least 1 chorioretinal lesion after a median follow-up of 6 years and 29% of those had at least 1 new event (reactivation, new lesion or both) up to 10 years after the detection of the first lesion. These lesions often occur in the macula region and at the borders of preexisting scars. In contrast, ocular disease from reactivation of a postnatally acquired chronic latent infection typically occurs in individuals >50 years of age and cause peripheral and unilateral retinal lesions.

Reactivation of Chronic Infection in the Immunocompromised Patient

Reactivation of chronic infection in immunocompromised individuals can manifest as multiple brain abscesses, diffuse encephalitis, meningoencephalitis, seizures, chorioretinitis, fever of unknown origin, pneumonia, myocarditis, hepatitis, hepatosplenomegaly, lymphadenopathy, and skin rash. ^, Some immunocompromised patients develop disseminated toxoplasmosis with shock-like picture and multiorgan failure or hemophagocytic syndrome. ^, Toxoplasmosis disease in immunocompromised patients can be rapidly fatal. ^,

Immunocompromised patients at risk for severe infection include patients with AIDS, hematopoietic stem cell and solid organ transplant recipients, ^, ^, ^, and patients receiving immunosuppressive medications or monoclonal antibodies.

Diagnosis

Laboratory methods for the diagnosis of T. gondii infection and toxoplasmosis include serology, polymerase chain reaction (PCR), metagenomics cell free DNA, histopathologic examination of tissue, and body fluids. Regardless of the presence of symptoms, serologic tests can establish whether a patient is infected or not, and if infected, whether acutely infected or chronically infected.

Clinically available serological tests include T. gondii -specific IgG, IgM, IgA, IgE, and IgG-avidity, and differential agglutination (AC/HS). A novel multiplex plasmonic GOLD platform (pGOLD) has been validated for the detection of T. gondii antibodies in whole blood, serum, and saliva, and is currently available at some reference laboratories as an additional diagnostic tool. Toxoplasmosis point of care tests that detect IgG and IgM antibodies based on lateral flow chromatography assay method have been studied and have the potential to be used in prenatal screening programs, once FDA approved.

Acute and Chronic Infection

With the use of commercial kits for the detection of IgG and IgM, most laboratories can reliably diagnose the absence of T. gondii infection (negative IgG/negative IgM) and chronic infection (positive IgG/negative IgM). In contrast, confirmation of an acute infection should be done at a reference laboratory. It should not be based solely on a positive IgM at a commercial lab because IgM antibodies can remain positive for months (even years) after an acute infection, and can also be falsely positive. Among patients with positive IgM results at commercial laboratories, only 22% were confirmed to have an acute Toxoplasma infection when their serum was tested at the National Reference Laboratory for the diagnosis of toxoplasmosis in the US with an additional comprehensive panel of tests. Of the remaining patients, 74% had evidence of past infection, 2% were not infected, and 2% had indeterminate IgM results. At the National Reference Laboratory for Toxoplasmosis in the US, a panel of confirmatory tests (IgG avidity, differential agglutination AC/HS , IgA, IgE, plasmonic GOLD IgG and IgM ) are available in addition to the gold-standard dye test for IgG and the double sandwich capture enzyme-linked immunosorbent assay for IgM (IgM ISAGA, that is recommended for infants <6 months). Some commercial laboratories in the U.S. also offer the FDA approved Toxoplasma IgG-avidity test and Toxoplasma IgA ELISA tests.

Definitive Diagnosis

The serologic diagnosis of acute primary T. gondii infection (in immunocompetent patients) can be based on a characteristic serologic profile; positive IgG (high titer), positive IgM (high titer) and/or positive IgA and /or IgE, low IgG avidity, and acute pattern in the AC/HS differential agglutination test.

In immunocompromised patients, the diagnosis of acute toxoplasmosis (acute primary T. gondii infection or reactivation of chronic infection) also can be made by (1) detection of parasite DNA by real-time PCR (or metagenomics) in body fluids (blood, cerebrospinal fluid, bronchoalveolar lavage, urine, pleural fluid, pericardial fluid, vitreous fluid) or tissue biopsies; (2) identification of tachyzoites in body fluids (rare); (3) identification of tachyzoites in histopathologic examinations with special stains (e.g., hematoxylin-eosin and Wright–Giemsa stains or T. gondii specific immunoperoxidase stains) (rare); and (4) visualization of tissue cysts surrounded by a pathologic inflammatory response in tissue biopsies, with or without visible tachyzoites.

A positive T. gondii PCR (1) in amniotic fluid is diagnostic of fetal infection, (2) in cerebrospinal fluid of toxoplasmic encephalitis (or congenital toxoplasmosis with CNS disease), (3) in bronchoalveolar fluid of toxoplasmic pneumonia, (4) in aqueous or vitreous fluid, of toxoplasmic chorioretinitis, and (5) in peripheral blood and urine, of disseminated toxoplasmosis or provides further confirmation of congenital toxoplasmosis. PCR from body fluids or tissues can be falsely negative in patients receiving anti- Toxoplasma treatment. The rate of T. gondii PCR detection in blood, CSF, and urine of children with congenital toxoplasmosis is low (29%, 46%, and 50%, respectively); however, there is large uncertainty in these estimates due to small study sample sizes. ^, In toxoplasmic lymphadenitis, the T. gondii PCR from the lymph node biopsy may be negative because lymphadenopathy is primarily triggered by an immunologic response to the parasite. In those cases, the diagnosis can be made presumptively by positive Toxoplasma IgG along with pathognomonic histologic findings showing reactive follicular hyperplasia, irregular clusters of epithelioid histiocytes encroaching on and blurring the margins of the germinal centers, and focal distention of sinuses with monocytoid cells.

T.gondii PCR and metagenomic cell free DNA can be helpful in the diagnosis of Toxoplasmosis, particularly in severely immunocompromised patients with disseminated disease, when the time to diagnosis is of critical importance.

In cases of eye disease reactivation, the diagnosis of ocular toxoplasmosis can be made if the patient has classic eye findings and positive Toxoplasma IgG (IgM antibodies are often negative in such cases). Children with ocular toxoplasmosis (either from a congenitally acquired infection or from a postnatally acquired infection) invariably have a positive Toxoplasma IgG.

Diagnosis in Pregnancy

The diagnosis of toxoplasmosis during pregnancy is primarily accomplished by the use of maternal serologic tests (for the diagnosis of maternal infection) and by amniotic fluid PCR and fetal ultrasound (for the diagnosis of fetal infection). For appropriate interpretation of results, clinical information on the mother is required, including (1) the gestational age at testing, (2) the presence of clinical signs and symptoms of toxoplasmosis during gestation or shortly before conception (including signs and symptoms from possible reactivation of eye disease during gestation), (3) the presence of immunosuppression including HIV infection, ^, and (4) the presence of underlying autoimmune diseases, primary immunodeficiencies, and/or use of immunosuppressive medications or biologic agents (such as monoclonal antibodies).

In countries where routine prenatal screening has been implemented, Toxoplasma seronegative women are identified on their first prenatal visit and are screened monthly (e.g., France) or every 3 months (e.g., Austria, Germany, Italy) until delivery. Seroconversion is defined as a change from undetectable to detectable IgG anti- Toxoplasma antibodies. In patients who seroconvert, the IgM test becomes positive first, usually at high titers. Seroconversion during gestation is diagnostic of acute Toxoplasma infection acquired during pregnancy. In contrast, in countries where no routine prenatal screening is used, prenatal diagnosis of T. gondii infection is often based on a single serum sample tested during gestation.

Maternal Serologic Test Results

In general, results at a commercial laboratory that show IgG negative/IgM negative or IgG positive/IgM negative are reliable and do not need to be further confirmed at a reference laboratory. The five possible serologic scenarios that can be encountered in pregnant women (and their interpretation thereof) are the following:

1.
IgG negative and IgM negative: The pregnant woman (if able to produce immunoglobulins) has no evidence of previous T. gondii infection.
2.
IgG positive but at a low titer and IgM negative: The pregnant woman was most likely infected at least 6 months before the date of testing.
3.
IgG positive and IgM positive: A positive IgM test result at a commercial lab cannot be used alone to establish the diagnosis of acute T. gondii infection. Additional confirmatory testing at a reference lab (with an additional panel of tests [e.g., IgA, IgE, IgG-avidity and/or differential agglutination AC/HS test]) is required.
4.
IgG positive at high titers and IgM positive or negative: The pregnant woman’s serology should be evaluated at a reference laboratories with an additional panel of tests and/or follow up testing to confirm or exclude recently acquired acute infection.
5.
IgG negative but positive IgM: The pregnant woman (a) could have been infected very recently or (b) the positive IgM result could represent a false-positive result. Sera should be submitted to a reference laboratory for confirmatory testing. Follow-up testing 2–4 weeks later is needed to evaluate for the development of IgG seropositivity. In such cases, subsequent IgG seropositivity/seroconversion, would be diagnostic of a recently acquired infection. In contrast, persistence of IgG negativity in subsequent testing (even if the IgM remains positive) could be suggestive of false positive IgM.

Results of serologic tests performed late in gestation (in the second half of gestation) can be difficult to interpret and it is usually not possible to safely exclude the possibility of an acute primary infection acquired early in gestation, unless (1) a serum sample during the first 16 weeks of gestation can be located and tested, (2) the woman is seronegative late in gestation, or (3) the serologic test results are clearly suggestive of an infection acquired in the distant past (e.g., >12 months before testing [chronic pattern in the AC/HS]). However, a positive IgG, IgM, and/or IgA late in gestation at high titers are suggestive of an acute T. gondii infection acquired late in gestation.

Polymerase Chain Reaction Testing on Amniotic Fluid

If a diagnosis of acute Toxoplasma infection during pregnancy is serologically confirmed or highly suspected, the fetus must be evaluated for infection. Amniotic fluid (AF) PCR is the laboratory method of choice to determine the status of fetal infection and guide maternal and neonatal treatment. In the presence of antenatal maternal treatment, the diagnosis of congenital infection cannot be reliably excluded on the basis of neonatal serologic testing alone, because postnatal IgM and IgA antibodies can be falsely negative if the mother was prenatally treated. The results of the AF PCR can also be affected by maternal treatment if the mother received anti- Toxoplasma therapy for several days before the amniocentesis. Thus it is critical to obtain the AF PCR as soon as possible after the diagnosis of acute Toxoplasma infection in the mother.

The diagnostic accuracy of AF-PCR depends on the trimester of pregnancy when maternal infection occurred. A negative AF PCR result is very reliable in excluding fetal infection for early gestation maternal infections. However, the negative predictive value of AF PCR is lower for maternal infections acquired late in gestation. Conversely, a positive AF PCR at any time during gestation is diagnostic of congenital toxoplasmosis and can be used to guide maternal treatment during the remainder of the pregnancy and neonatal treatment.

Regardless of negative AF PCR results, all pregnant women diagnosed with acute Toxoplasma infection during gestation should be started on anti- Toxoplasma suppressive therapy and undergo monthly fetal ultrasounds and their infants should undergo comprehensive postnatal evaluation, to exclude congenital toxoplasmosis.

Fetal Ultrasound

Fetal ultrasonography can help determine whether the fetus has been affected. Ultrasound can reveal fetal death, or hydrocephalus, brain calcifications, periventricular cysts, hepatic calcifications, splenomegaly, ascites, echogenic bowel, pericardial or pleural effusions, or intrauterine growth retardation ( Box 273.2 ).

Diagnosis in the Neonate

The approach to the evaluation of infants for congenital toxoplasmosis is shown in Box 273.3 and Box 273.4 . In the newborn, congenital toxoplasmosis can be diagnosed by positive T.gondii AF PCR during gestation, and/or positive neonatal Toxoplasma IgG and IgA or IgM, and/or positive T. gondii PCR in blood/urine or CSF and/or parasite isolation from any body fluid/tissue (rare).

BOX 273.3

Evaluation of Newborns/Infants With Suspected Congenital Toxoplasmosis (CT)

CSF, cerebrospinal fluid; EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; ELFA, enzyme-linked fluorescent immunoassay; Ig, immunoglobulin; ISAGA, immunosorbent agglutination assay; MRI, magnetic resonance imaging; PCR, polymerase chain reaction.

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