Toxoplasma gondii

280  José G. Montoya, John C. Boothroyd, and Joseph A. Kovacs

SHORT VIEW SUMMARY

Definition
• Toxoplasma gondii is a ubiquitous coccidian
protozoan that usually causes asymptomatic
infection in humans but can cause significant
disease in congenitally infected infants and
immunodeficient patients and occasionally in
immunocompetent individuals.
Epidemiology
• Toxoplasmosis is a worldwide zoonosis that
can infect a wide range of animals and birds.
• Transmission to humans is mainly by ingestion
of viable tissue cysts in meat or of food or
water contaminated with oocysts. Less
commonly, there is congenital transmission or
transplantation of an infected organ.
• Positive immunoglobulin G (IgG) representing
prior infection increases with age;
seroprevalence is ≈11% in the United States
and up to ≈78% in other parts of the world.
• Congenital transmission occurs almost
exclusively when a seronegative mother
becomes infected during pregnancy.
Retinochoroiditis can occur after congenital
infection or recently acquired infection.
Infection in human immunodeficiency virus
(HIV)/acquired immunodeficiency syndrome
patients almost always results from
reactivation of latent infection. Among organ
transplant patients, disease can result from
either newly acquired infection from the
transplanted organ or from reactivation of
latent infection.
Microbiology
• Toxoplasma organisms are exclusively
intracellular. The sexual phase occurs in felines.
Excreted oocysts require 1 to 5 days to
become infectious. Tachyzoites actively
replicate in essentially all cell types. Tissue
cysts with intracystic bradyzoites maintain
organism viability during latent infection.
• Tachyzoites replicate well in tissue culture and
are responsible for clinical manifestations
during primary infection or reactivation of
latent infection.
• Multiple strains are identified by genotyping.
Strains differ in virulence, with the most
virulent strains so far reported being found in
South America.
Diagnosis
• Direct detection of the organism is by
polymerase chain reaction (PCR) assay,
histopathology with immunoperoxidase
staining, or, less commonly, by tissue culture or
mouse inoculation.
• Serologic assays can help distinguish acute
from chronic infection and can identify
patients at risk for reactivation.
Immunoglobulin M (IgM)-positive test results
should be confirmed at a reference laboratory
(e.g., the Palo Alto Medical Foundation–
Toxoplasma Serology Laboratory [PAMF-TSL];
www.pamf.org/serology/).
• Maternal infection is often asymptomatic;
serology shows acute infection, and IgM-
positive test results must be confirmed at a
reference laboratory. Congenital infection may
be asymptomatic or appear with neurologic or
ocular manifestations; this form is diagnosed
in utero by PCR of amniotic fluid or after birth
by serology or PCR.
• Chorioretinitis may be asymptomatic or show
visual loss; ophthalmologic examination and
PCR of vitreous or aqueous fluid are
performed. The Goldmann-Witmer coefficient
(anti-Toxoplasma IgG/total IgG in aqueous
fluid divided by anti-Toxoplasma IgG/total IgG
in serum) can be helpful.
• HIV-infected patients usually present with focal
neurologic symptoms. Patients are usually IgG
positive and IgM negative, computed
tomography or magnetic resonance imaging
may show one or more contrast-enhancing
lesions, cerebrospinal fluid PCR is specific but
not sensitive, brain biopsy sensitivity is
improved by immunoperoxidase staining, and
diagnosis is often presumptive and extends to a
response to empirical therapy.
• Immunodeficient patients present with
encephalopathy, seizures, pneumonia, and fever.
Diagnosis is based on positive PCR or
histopathology. Hematopoietic stem cell
transplantation (HSCT) requires pretransplant
serology; solid-organ transplantation requires
pretransplant serology in the donor and recipient.
Therapy
• Immunocompetent patients: These patients
usually require no therapy if asymptomatic;
they may benefit from treatment if symptoms
are severe or persist.
• Immunocompromised patients: The therapy
dosage is pyrimethamine (200-mg load, then
50 to 75 mg/day) plus sulfadiazine (1000 to
1500 mg every 6 hours) plus leucovorin (10 to
20 mg/day). The dosage is then decreased to
maintenance dosing of pyrimethamine (25 to
50 mg/day) plus sulfadiazine (500 to 1000 mg
every 6 hours) plus leucovorin (10 to 20 mg/
day) after 3 to 6 weeks if a clinical response
occurs. Alternatives include pyrimethamine, as
above, plus leucovorin plus either clindamycin
(intravenous [IV] or oral [PO]; 600 mg every 6
hours) or atovaquone (1500 mg every 12
hours). Another alternative is
trimethoprim-sulfamethoxazole (TMP-SMX) (IV
or PO; 5 mg/kg of TMP every 12 hours).
Corticosteroids are given only for clinically
significant edema or mass effect, and
anticonvulsants are given only after a seizure.
• HIV patients: Start antiretroviral therapy (ART)
after 2 to 3 weeks; stop anti-Toxoplasma
medications if the CD4 count is greater than
200 cells/mm3 for more than 6 months. High
relapse rate occurs without ART and
maintenance therapy.
• Acute infection in pregnant women less than
or equal to 18 weeks of gestation: Give
spiramycin (1 g every 8 hours; available at no
cost through the PAMF-TSL and the U.S. Food
and Drug Administration) until delivery. If
infection in the fetus is documented or
suspected, or if at greater than 18 weeks of
gestation, give pyrimethamine (50 mg every
12 hours for 2 days, then 50 mg/day) plus
sulfadiazine (initial dose 75 mg/kg, followed
by 50 mg/kg every 12 hours; maximum, 4 g/
day), plus folinic acid (10 to 20 mg/day).
Before 14 to 18 weeks of gestation, give no
pyrimethamine or leucovorin.
• Congenitally infected infant: Give
pyrimethamine (1 mg/kg every 12 hours for 2
days, then 1 mg/kg/day for 2 or 6 months); then
this dose is given every Monday, Wednesday,
and Friday; plus sulfadiazine (50 mg/kg every
12 hours) plus folinic acid (10 mg three times
weekly) for at least 12 months.
• Chorioretinitis patients: If therapy is clinically
indicated, give pyrimethamine (100-mg
loading dose over 24 hours, then 25 to 50 mg/
day) plus sulfadiazine (1 g every 6 hours) plus
leucovorin (10 to 20 mg/day) for 4 to 6 weeks.
TMP-SMX, one double-strength tablet every 3
days, can prevent relapse.
Prevention and Prophylaxis
• Avoid undercooked meat and potentially
contaminated food or water; clean cat litter
daily.
• Immunocompromised patients: Give TMP-SMX,
one double-strength or single-strength tablet
daily. An alternative is dapsone (50 mg/day)
plus pyrimethamine (50 mg/wk) plus
leucovorin (25 mg/wk). If the patient has HIV,
start if the CD4 count is less than 100 to 200
cells/mm3; discontinue if the patient is on ART
and the CD4 count is greater than 200 cells/
mm3 for at least 3 months (primary
prophylaxis) or 6 months (secondary
prophylaxis). For HSCT recipients, start
TMP-SMX after engraftment. If the patient is a
solid-organ transplant recipient, start at
transplantation if classified as D+ or R+.

3122
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 3122.e1
KEYWORDS
acquired immunodeficiency syndrome; antiretroviral therapy;
bradyzoite; cats; chorioretinitis; dapsone; encephalitis; lamb; oocyst;

Chapter 280  Toxoplasma gondii

pork; pregnancy; pyrimethamine; spiramycin; tachyzoite; tissue cyst;
Toxoplasma gondii; toxoplasmosis; trimethoprim-sulfamethoxazole;
zoonosis

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Although Toxoplasma gondii infects a large proportion of the world’s
human population, it is an uncommon cause of disease. Certain indi-
viduals, however, are at high risk for severe or life-threatening disease
because of this parasite. These include congenitally infected fetuses and
newborns and immunologically impaired individuals. Congenital
toxoplasmosis is the result of maternal infection acquired during gesta-
tion, an infection that is most often clinically inapparent. In immuno-
deficient patients, toxoplasmosis most often occurs in persons with
defects in T-cell–mediated immunity, such as those receiving cortico-
steroids, anti–tumor necrosis factor (TNF) therapies, certain monoclo-
nal antibodies, or cytotoxic drugs, and in those with hematologic
malignancies, organ transplants, or acquired immunodeficiency syn-
drome (AIDS). In the vast majority of otherwise immunocompetent
individuals, primary or chronic (latent) infection with T. gondii is
asymptomatic; after the acute infection, a small percentage suffer cho-
rioretinitis; lymphadenitis; or, even more rarely, hepatitis, myocarditis,
and polymyositis.1
T. gondii was first observed in the North African rodent (Ctenodac-
tylus gundi) by Nicolle and Manceaux in 19082 and was recognized as
a cause of human disease in an 11-month-old congenitally infected
child by Janku in 1923.3 It was reported as a cause of encephalitis by
Wolf, Cowen, and Paige, who in 1939 observed it in a newborn who
presented with seizures, intracranial calcifications, hydrocephalus, and
chorioretinitis.4
Although relatively few cases of severe toxoplasmosis in adults were
reported during the ensuing years, the remarkable report in 1968 by
Vietzke and his colleagues,5 from the National Cancer Institute of the
National Institutes of Health, highlighted T. gondii as a cause of life-
threatening infection in patients with malignancy, predominantly in
those with hematologic malignancies. Brain involvement with focal
areas of encephalitis was the primary finding at autopsy in these
patients. Since that time, several hundred cases in non-AIDS immuno-
deficient patients have been recorded in the literature.6 In 1983, the first
report of toxoplasmosis in AIDS patients appeared.7 Toxoplasmic
encephalitis (TE) subsequently was recognized as the major cause of
space-occupying lesions in the brains of these patients, almost all of
whom had serologic evidence of prior exposure to the parasite.7 Despite
the significant advances that have been achieved in the recent past,
major challenges remain in the areas of prevention and management
of the acute infection in pregnancy, the fetus, and the newborn,8 and
in the understanding and treatment of toxoplasmic chorioretinitis9 and
infection in immunocompromised individuals.1,6,10
ETIOLOGY
T. gondii is a coccidian parasite of felids with humans and other warm-
blooded animals serving as intermediate hosts. It belongs to the sub-
phylum Apicomplexa, class Sporozoa, and exists in nature in many
forms: macrogametes and microgametes, the oocyst (which releases
sporozoites), the tissue cyst (which contains and may release bradyzo-
ites), and the tachyzoite (Fig. 280-1).11
Population genetic analysis has demonstrated that, at least within
Europe and North America, most organisms isolated from both
domesticated animals and humans can be grouped into one of three
clonal genotypes—types I to III—that may identify clinically relevant
biologic differences.12 Clear differences have been observed in the fre-
quency of parasite genotypes when T. gondii isolates from animals were
compared with those of humans. Type III strains are common in
animals but observed significantly less often in cases of human toxo-
plasmosis; most cases in humans in Europe and North America are
caused by type II strains. Type II strains are significantly more often
associated with reactivation of chronic infections and accounted for
65% of strains isolated from AIDS patients.13 Both type I and type II
strains have been associated with human congenital toxoplasmosis.13-15
To date, types II and III have not been detected in immunocompetent
individuals with severe ocular disease.16 Atypical and recombinant
strains have been identified with increasing frequency in regions other
than the United States and Europe and from animals other than
humans and domestic animals; some of these strains appear to be
associated with more severe disease, suggesting greater virulence, even
in immunocompetent individuals.17,18 The most exhaustive studies
have now identified six major population clades,19 although detailed
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3123
sequence analysis indicates there is a varied amount of genetic exchange
within and between these clades.20 Hence, although the “three-
dominant-strain” paradigm is holding for humans in Europe and
North America, the situation appears much more complex in other
Chapter 280  Toxoplasma gondii
regions and in other animal hosts.
ORGANISM STAGES
Oocyst
Cats eventually shed oocysts after they ingest any of the three forms of
the parasite, at which time an enteroepithelial cycle begins. This sexual
form of reproduction begins when the parasites penetrate the epithelial
cells of the small intestine and initiate development of asexual and
sexual (gametogony) forms of the parasite. Oocyst wall formation
begins around the fertilized gamete, and when still immature, oocysts
are discharged into the intestinal lumen by rupture of intestinal epi-
thelial cells.11 Unsporulated oocysts are subspherical to spherical and
measure 10 × 12 µm in diameter (see Fig. 280-1A). Oocysts are formed
in the small intestine only in felids and are excreted in the feces for
periods varying from 7 to 20 days. More than 100 million oocysts may
be shed in the feces in a single day.11 Sporulation, required for oocysts
to become infectious, occurs outside the cat within 1 to 5 days, depend-
ing on temperature and the availability of oxygen. Sporulated oocysts
contain two sporocysts (see Fig. 280-1A), each of which contains four
sporozoites. Maturation is more rapid at warm temperatures (2 to 3
days at 24° C compared with 14 to 21 days at 11° C).11 Oocysts may
remain viable for as long as 18 months in moist soil; this results in an
environmental reservoir from which incidental hosts may be infected.
Recent clues to some of the features that make oocysts so robust have
come from proteomic and transcriptomic analyses.21,22 Among other
findings, these studies have revealed an abundance of small tyrosine-
rich proteins in the oocyst wall. Cross-linking of the tyrosines in these
proteins could confer a natural “sun-screen” for the sporozoites within
because they are strong absorbers of ultraviolet light.
Tachyzoite
The tachyzoite form (see Fig. 280-1B) is oval to crescentic and mea-
sures 2 to 3 µm wide and 5 to 7 µm long; it requires an intracellular
habitat to multiply despite having all of the usual eukaryotic machinery
necessary for reproduction. Tachyzoites are seen in both primary and
reactivated infection; their presence is the hallmark of active infection.
They reside and multiply within vacuoles in their host’s cells, can infect
virtually all phagocytic and nonphagocytic cell types,11 and multiply
approximately every 6 to 8 hours to form rosettes.23 Continuous mul-
tiplication leads to cell disruption and release of organisms that go on
to invade nearby cells or are transported to other areas of the body by
blood and lymph.24 Tachyzoites appear to actively and rapidly migrate
across epithelial cells and may traffic to distant sites while extracellu-
lar.25 Recent evidence suggests they might also use the infected host
cell as a “Trojan horse” to traffic and gain access to tissues that might
not otherwise be easily accessed.26
At the anterior end of the tachyzoite, there is a cone-shaped struc-
ture termed the conoid. It is protruded during the parasite’s entry into
host cells. Rhoptries, numbering 4 to 12, are club-shaped organelles
that terminate within the conoid. The rhoptries, together with sur-
rounding small, rod-shaped organelles (micronemes), have important
secretory functions for parasitic invasion. Dense granules are organelles
distributed throughout the cytoplasm. Their contents are released into
a vacuole, termed the parasitophorous vacuole, that is formed around
the parasite during entry into the cell and also into the external envi-
ronment as excreted-secreted antigens.11
The rhoptries and micronemes produce a collection of proteins
that are crucial for the invasion process.27 These appear to mediate
the attachment to the host cell, including the moving junction, a
ringlike point of contact between the parasite and host cell surface
that migrates down the length of the parasite during invasion. The
rhoptries also inject proteins into the host cell that are critical in
manipulating the host cell, presumably to the advantage of the para-
site.28 These rhoptry proteins are very different (polymorphic) between
different strains of T. gondii and appear responsible for many of the
differences in virulence seen for types I, II and III in mice, as described
earlier.
Part III  Infectious Diseases and Their Etiologic Agents 3124

A B

C D
FIGURE 280-1  The three forms of Toxoplasma gondii observed in nature. A, Oocysts. Unsporulated oocyst (top left). Sporulated oocyst with
two sporocysts (top right). Four sporozoites (arrows) are visible in one of the sporocysts. Transmission electron micrograph of a sporulated oocyst (bottom).
Note the thin oocyst wall (large arrow), two sporocysts (arrowheads), and sporozoites, one of which is cut longitudinally. B, Giemsa stain demonstrating
two rosettes of intracellular tachyzoites in a mouse bone marrow macrophage. C, Giemsa-stained smear of mouse peritoneal fluid demonstrating
the tachyzoite form. D, Hematoxylin and eosin stain of the cyst form in brain. (A courtesy Dr. J.P. Dubey, U.S. Department of Agriculture. Beltsville, MD.
B to D courtesy Dr. Jack S. Remington, Stanford University and Palo Alto Medical Foundation.)

Tachyzoites cannot survive desiccation, freezing and thawing, or
extended exposure to gastric digestive juices.24 They are propagated
in the laboratory in the peritoneum of mice and in cultured cells.
Tachyzoites can be visualized in sections stained with hematoxylin and
eosin but are better visualized with Wright-Giemsa and immunoper-
oxidase stains.29
A fourth organelle that is restricted to Toxoplasma and its Apicom-
plexa cousins is the apicoplast.30 This is akin to chloroplasts of plants,
with a similar evolutionary origin involving endosymbiotic algae, but
photosynthetic functions have been completely lost. It has its own
DNA, RNA, and protein translation, the latter of which is prokaryotic
in nature, making for a very attractive target for drug therapies. Indeed,
one of the currently used drugs for treatment of human infection,
clindamycin, targets the ribosomes of the apicoplast.31 A major role of
this organelle is fatty acid biosynthesis.30 Recent work with Plasmo-
dium, which also has this organelle, has demonstrated that the apico-
plast is crucial to the synthesis of isoprenoids,32 making further work
on attacking this Achilles heel an attractive prospect.
Tissue Cyst
Once the tachyzoite has invaded the target cell, it can undergo stage
conversion into the bradyzoite form.11 Tachyzoites and bradyzoites are
structurally and phenotypically different. Tachyzoites multiply rapidly
and synchronously, forming rosettes and lysing the cell, whereas the
more slowly replicating bradyzoites form tissue cysts. Molecules are
expressed in a stage-specific manner and are responsible for certain of
the phenotypic differences between tachyzoites and bradyzoites.
Interferon-γ (IFN-γ), nitric oxide (NO), heat shock proteins, and pH
and temperature manipulations can trigger conversion of tachyzoites
to bradyzoites in vitro and perhaps in vivo as well.11
Tissue cysts grow and remain within the host cell cytoplasm as the
intracystic form wherein the bradyzoites continue to divide. Tissue
cysts vary in size from younger ones that contain only a few brady­zoites
to older tissue cysts that may contain several thousand brady­zoites and
may reach more than 100 µm in size (see Fig. 280-1D). They appear
spherical in the brain and conform to the shape of muscle fibers in heart
and skeletal muscles. The central nervous system (CNS); eye; and skel-
etal, smooth, and heart muscles appear to be the most common sites of
latent infection.33 Because of their persistence in tissues, demonstration
of tissue cysts in histologic sections does not necessarily mean that the
infection was recently acquired or that it is clinically relevant. Tissue
cysts stain well with periodic acid–Schiff, Wright-Giemsa, Gomori
methenamine silver, and immunoperoxidase stains. Tissue cysts in
meat are rendered nonviable by γ-irradiation (0.4 kGy),34 heating meat
throughout to 67° C, or freezing to −20° C for 24 hours and then
thawing,35,36 but not by gentle heating in a microwave.37

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Although the tachyzoite form appears to be indiscriminate in the
type of host cell parasitized, it has been suggested that, in brain tissue,
there is a predilection for tissue cyst formation to occur predominantly
within neurons.38,39 However, it has been shown that tissue cysts can
form within astrocytes cultured in vitro.40 In an electron microscopic
study of the pathologic changes in brains of infected mice, tissue cysts
were observed to remain intracellular throughout the period of study
(22 months).38 There is compelling evidence to suggest that bradyzoites
can exit from intact tissue cysts and invade contiguous cells, where they
convert to the tachyzoite form.41 This is the likely explanation for the
appearance of “daughter” cysts or clumps of cysts in the brain. Recent
evidence suggests that neurons are capable of destroying the invaded
parasite and/or that rhoptry proteins are injected into cells they do not
infect.42 These results have implications for how the parasite comman-
deers host functions.
TRANSMISSION AND
EPIDEMIOLOGY
T. gondii infection is a worldwide zoonosis. The organism infects her-
bivorous, omnivorous, and carnivorous animals, including birds.43
Infection in humans most commonly occurs through the ingestion of
raw or undercooked meat that contains tissue cysts, through the inges-
tion of water or food contaminated with oocysts, or congenitally
through transplacental transmission from a mother who acquired her
infection during gestation (Fig. 280-2). Less common are transmission
by transplantation of an infected organ or transfusion of contaminated
blood cells. Transmission has also occurred by accidental sticks with
contaminated needles44 or through exposing open lesions or mucosal
surfaces to the parasite.45 Because the sexual cycle of the parasite takes
Raw milk
Meat, other
tissue
Vertical
transmission
Tissue cysts
Grazing
Carnivorism
FIGURE 280-2  Transmission and life cycle of Toxoplasma gondii.
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3125
place in the small bowel of members of the cat family, cats play a sig-
nificant role as powerful amplifiers of the infection in nature (see
“Oocyst”).11 Epidemiologic surveys have revealed that in most areas of
the world, the presence of cats is of primary importance for the trans-
Chapter 280  Toxoplasma gondii
mission of the parasite. Excretion of oocysts has been reported to occur
in approximately 1% of cats in diverse areas of the world.45 Wild felines,
and especially bobcats in the United States, may be among the most
important sources of oocysts.46
Although ingestion of raw or undercooked meat that contains
viable T. gondii tissue cysts will result in infection, the relative fre-
quency with which this occurs in relation to the frequency of infection
caused by ingestion of oocysts is unclear. For instance, in countries
such as France, where eating undercooked meat is common and the
prevalence of the infection is high, meat may be an important cause of
the infection. (It was in Paris that the meat-to-human hypothesis of
spread of T. gondii was proved.47) In contrast are countries such as
those in Central and South America, where the prevalence of the infec-
tion in humans is high but the ingestion of undercooked meat is
uncommon. In these areas, oocysts may be the more important source
of human infection.48 Until a newly described method for distinguish-
ing bradyzoite- versus oocyst-initiated infection is validated in these
regions,49 their respective contributions to human infection will largely
remain a matter of speculation.
Ingestion of tissue cysts in infected meat (primarily pork and lamb)
is a major source of the infection in humans in the United States.50,51
T. gondii infection is common in many animals used for food, espe-
cially sheep and pigs, with a lower prevalence in cattle, horses, and
water buffaloes. Infection resulting in transmission to humans has also
been documented in wild game animals.52 Organisms may survive in
Untreated Fruits and
water vegetables
Soil Raw shellfish
Oocyst
Cat feces
Oocyst
Oocyst Tissue cysts
 3126
tissue cysts in these animals for years and can be found in nearly all
edible portions of an animal.53 A seminal study on the prevalence of
T. gondii in samples of meat used for human consumption (obtained
from grocery stores) was performed in the United States in the 1960s.54
Part III  Infectious Diseases and Their Etiologic Agents
The parasite was isolated from 32% of pork chops and 4% of lamb
chops; there were no isolations from beef, and indeed, cattle appear
to be generally not an important intermediate host for this parasite.55
A recent polymerase chain reaction (PCR)-based study in England
found 33% (19/57) of pork and 67% (6/9) of lamb samples positive for
T. gondii DNA.56
Serologic surveys conducted in the past 20 years in the United
States indicate that the prevalence of T. gondii in pigs is declining, with
an overall prevalence of 2.6% in a recent National Animal Health
Monitoring Survey.57 This reduction in T. gondii prevalence has been
attributed to changing management practices and consolidation of pig
production into large-scale operations. However, there are still many
isolated small swine farms, including those that raise organic pigs, and
the prevalence of T. gondii in these animals can be greater than 90%.58
Of note, meat for human consumption is not routinely inspected for
T. gondii infection in the United States or elsewhere in the world.59
Seroprevalence of T. gondii infection in a study of lambs in the mid-
Atlantic region was recently reported to be 27%.60 Although T. gondii
infection of sheep is widely prevalent, the public health importance of
this is unclear because, in the United States, meat from adult sheep is
not usually used for human consumption.45 Reports of suspect trans-
mission by unpasteurized goat’s milk have appeared.61,62 In addition to
differences in how meat is cooked, the tendency for beef to harbor few,
if any, cysts compared with lamb and pork may partly explain the dif-
ferences in seroprevalence in the United States versus Europe; beef
accounts for a much greater fraction of meat consumed in the United
States compared with Europe, where lamb and pork are more popular.
T. gondii infection is prevalent in game animals, especially black
bears (80% infected) and white-tailed deer, as well as in raccoons (60%
infected).53 Infection in raccoons and bears is a good indicator of the
prevalence of T. gondii in the environment because these animals are
scavengers. Thus, wild animal meat can serve as a source of the infec-
tion for hunters and their families, especially when care is not taken
while eviscerating and handling the game or when meat and other
organs from these animals is served undercooked or uncooked.53
Although T. gondii tissue cysts may be found in edible tissues of
chickens,63 poultry products are probably not important in the trans-
mission of T. gondii to humans because they are usually frozen for
storage and thoroughly cooked to avoid diseases that could be caused
by contamination by other organisms.45 The parasite has been isolated
from chicken eggs.64
The ingestion of vegetables and other food products contaminated
with oocysts probably accounts for infection in seropositive vegetari-
ans. Although isolation of tachyzoites from secretions of people with
the acute infection has been claimed, human-to-human transmission
of infection by this route has not been established. Outbreaks within
families and other groups are common,65-67 but there is no evidence
of natural human-to-human transmission other than from mother
to fetus.
Several epidemiologic studies have identified water as a potential
source for T. gondii infection both in humans and animals.65,68-71 In
vitro studies have demonstrated that oocysts can sporulate in seawater
within 1 to 3 days, can survive in seawater for up to 6 months, and can
survive in water treated with sodium hypochlorite or ozone, but not
ultraviolet radiation.72-74 Population mapping studies of acutely infected
individuals as well as case-control studies linked drinking unfiltered
water (presumably contaminated with oocysts) to an outbreak of toxo-
plasmosis in a municipality in the Western Canadian province of
British Columbia65 and to high endemic rates of toxoplasmosis in Rio
de Janeiro State, Brazil.69 In another Brazilian outbreak, T. gondii
organisms were detected in water by a variety of methods from an
implicated reservoir.75 Coastal freshwater runoff was observed to be a
risk factor for T. gondii infection among southern sea otters along the
California coast.76
In humans, the incidence of T. gondii antibodies increases with
increasing age; the incidence does not vary significantly between sexes.
The incidence tends to be less in cold regions, in hot and arid areas,
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and at high elevations. Slaughterhouse workers may have an increased
risk for infection. The prevalence of antibody titers to T. gondii varies
considerably among different geographic areas and also among indi-
viduals within a given population. These differences depend on a
variety of factors, including culinary habits and cleanliness of sur-
roundings. A decrease in antibody prevalence over the past few decades
has been observed in many countries. In the United States, the sero­
prevalence in U.S. military recruits decreased by one third between
1965 and 1989; the crude seropositivity rate among recruits from 49
states was 9.5% in 1989 compared with 14.4% in 1965.77 As another
example, in the 1970s, 24% of women in the childbearing age group in
Palo Alto, California were seropositive, whereas the rate in 2008 was
10%. Seroprevalence rates in the United States among such women
range from 3% to greater than 35%, whereas rates greater than 50% are
present in women of childbearing age in much of Western Europe,
Africa, and South and Central America.78 The recent (1999 to 2004)
overall age-adjusted seroprevalence of T. gondii infection in the United
States, based on a study of 15,960 persons aged 6 to 49, was reported
to be 10.8%, with a seroprevalence among women aged 15 to 44 years
of 11%.79 This study found an approximately 25% to 40% decline in
seroprevalence compared with a similar survey a decade earlier.
Although the prevalence of the infection appears to be declining in
certain areas of the world, such as Europe and the United States, this
has not been the case or it has been documented to have increased in
other geographic locales.78
T. gondii may survive in citrated blood at 4° C for as long as 50 days,
and infection has been transmitted through transfusion of whole blood
or white blood cells. Leukocyte transfusions may pose a special risk.80
The transmission of infection by organ transplantation has been docu-
mented and may result from the transplantation of an organ (e.g., heart)
from a seropositive donor to a seronegative recipient.81 In bone marrow
transplant recipients, toxoplasmosis almost always is a result of recru-
descence of a latent infection rather than from the transplant.82,83
The incidence of TE among HIV-infected individuals directly cor-
relates with the prevalence of T. gondii antibodies among the general
HIV-infected population, the degree of immunosuppression (best
measured by the CD4 cell count),84 the use of effective prophylactic
treatment regimens against development of TE, and the immunologic
response to antiretroviral therapy (ART).85 AIDS-associated TE and
toxoplasmosis involving other organs are almost always due to reacti-
vation of a chronic (latent) infection that results from the progressive
immune dysfunction that develops in these patients.86 It is estimated
that 20% to 47% of AIDS patients who are infected with T. gondii but
are not taking anti-Toxoplasma prophylaxis or antiretroviral drugs will
ultimately develop TE.84,86 This makes TE a major concern in areas
where the use of antiretrovirals is still a treatment relatively few HIV-
positive individuals receive.
In recent years a substantial decline in the incidence of TE87 and
toxoplasmosis-associated deaths88 has been seen in HIV-infected
patients who adhere to effective anti-Toxoplasma prophylactic regi-
mens and to ART.
In the United States, T. gondii seropositivity among HIV-infected
patients varies from 10% to 45%86 and directly correlates with the
seropositivity in the general non–HIV-infected population. In con-
trast, the seroprevalence is approximately 50% to 78% in certain areas
of Western Europe and Africa.89,90 In a study in France, 1215 (72.2%)
of 1683 HIV-infected patients had serologic evidence of exposure to T.
gondii.91 During the study period (1988 to 1995), the overall incidence
of toxoplasmosis in this population was estimated to be 1.53 per 100
patient-years, with an increase from 0.68 per 100 patient-years in 1988
to 2.1 per 100 patient-years in 1992, and a subsequent decline to 0.19
per 100 patient-years in 1995 that was likely related to the widespread
use of anti-Toxoplasma prophylaxis. Toxoplasmosis is rare in the HIV-
infected pediatric population: 0.06 cases per 100 patient-years were
reported among more than 3000 patients participating in clinical trials
in the pre-ART era but during a time when Pneumocystis carinii pneu-
monia (PCP) prophylaxis was recommended.92
Of interest is the low reported incidence of TE in Africa, despite T.
gondii seroprevalence rates of 32% to 78%. Lack of autopsy data and a
lack of neuroimaging studies likely contribute to the low reported
incidence. It has also been suggested that because of poor access to

medical care, many HIV-infected patients in Africa succumb to infec-
tion with organisms such as Mycobacterium tuberculosis before they
develop the opportunistic infections associated with the advanced
stage of HIV infection, including toxoplasmosis. However, in one
autopsy series, from the Ivory Coast, of 175 patients with AIDS-
defining abnormalities, the prevalence of TE was 21%.93
T. gondii infection may be acquired after the acquisition of HIV
infection. Seroconversion rates between 2% and 5.5% have been
reported in patients followed for periods up to 28 months.94
Even before the emergence of AIDS, TE had been recognized as a
cause of incapacitating disease and death among HIV-negative immu-
nosuppressed patients,6,95 especially in those whose underlying disease
or therapy caused a deficiency in cell-mediated immunity. Patients
with hematologic malignancies, especially those with Hodgkin’s
disease, are at a particularly higher risk to develop recrudescence of
the infection. Among organ transplantation patients, those with heart,
lung, kidney, and bone marrow transplants develop toxoplasmosis at a
higher rate.
PATHOGENESIS AND IMMUNITY
T. gondii multiplies intracellularly at the site of invasion (the gastroin-
testinal tract is the major route for and the initial site of infection in
nature); bradyzoites released from tissue cysts or sporozoites released
from oocysts penetrate, differentiate to tachyzoites, and then rapidly
multiply within intestinal epithelial cells. Organisms may spread first
to the mesenteric lymph nodes and then to distant organs by invasion
of lymphatics and blood. T. gondii tachyzoites infect virtually all cell
types, and cell invasion occurs as an active process. Survival of tachyzo-
ites is due to the formation of a parasitophorous vacuole that lacks host
proteins necessary for fusion with lysosomes,96 and consequently acidi-
fication does not occur. Active invasion of macrophages by tachyzoites
does not trigger oxidative killing mechanisms. With the appearance of
humoral and cellular immunity, only those parasites protected by an
intracellular habitat or within tissue cysts survive. An effective immune
response significantly reduces the number of tachyzoites in all tissues,
and after the initial acute stages, tachyzoites are rarely demonstrable
histologically in tissues of infected immunocompetent humans.
Tachyzoites are killed by reactive oxygen intermediates,97 acidification,98
osmotic fluctuations, reactive nitrogen intermediates,99 intracellular
tryptophan depletion,100 and specific antibody combined with comple-
ment.101 In rodents, two classes of immune-stimulated guanosine tri-
phosphate (GTP)ases play a crucial role in destruction of tachyzoites
within the parasitophorous vacuole: the p47 immunity-related GTPases
(IRGs)102 and the larger GTP-binding proteins (GBPs).103
Tissue cyst formation takes place in multiple organs and tissues
during the first week of infection. Despite the ability to isolate T. gondii
from normal brains of chronically infected humans, the tissue cyst
form is rarely observed in histologic preparations; it has been isolated
from both brain and skeletal muscle in 10% of 52 T. gondii–seropositive
patients who, at autopsy, had no clinical or pathologic evidence of the
infection.33 The tissue cyst form is responsible for residual (chronic or
latent) infection and persists primarily in the brain, skeletal and heart
muscle, and the eye.33,104
In immunocompetent individuals, the initial infection and the
resultant seeding of different organs leads to a chronic or latent infec-
tion with little, if any, clinical significance. This chronic stage of the
infection corresponds to the asymptomatic persistence of the tissue
cyst form in multiple tissues. It is believed that periodically, bradyzoites
are released from tissue cysts or that cysts “rupture”; cyst disruption in
this setting appears to be a clinically silent process effectively contained
by the immune system and in the CNS likely results in small inflam-
matory nodules, with a limited degree of neuronal cell death and
architectural damage.41 However, several investigators have suggested
that chronic infection may not be completely asymptomatic and may
result in important behavioral changes and neuropsychiatric disor-
ders,105 although definitive studies to support such associations have
not yet been reported.
Toxoplasmosis in severely immunodeficient individuals may be
caused by primary infection or be the result of recrudescence of a latent
infection. It is widely held that reactivation is the result of disruption
of the tissue cyst form, followed by differentiation to and uncontrolled
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3127
proliferation of tachyzoites and tissue destruction. In individuals with
deficient cell-mediated immunity, rapid, uncontrolled proliferation of
T. gondii results in progressively enlarging necrotic lesions. It has been
postulated that damage to any organ in these patients, including the
Chapter 280  Toxoplasma gondii
brain, eye, heart, lung, skeletal muscle, gastrointestinal tract, and pan-
creas, can result directly from tissue cyst disruption in the parenchyma
of the organ itself or from tissue cyst disruption elsewhere in the body,
followed by subsequent spread to that organ.106 Hematogenous spread
is supported by the observation of the development of simultaneous
lesions in the brain and the presence of parasitemia in 14% to 38% of
AIDS patients with TE.107,108
Infection with T. gondii induces both humoral and cell-mediated
immune responses. A well-orchestrated and effective systemic immune
response, combining both innate and adaptive mechanisms, is respon-
sible for the early disappearance of T. gondii from peripheral blood
during the acute infection and limits the parasite burden in other
organs. Immunity in the immunocompetent host is lifelong. Exoge-
nous reinfection, which has been demonstrated in laboratory animals,
likely also occurs in humans but does not appear to result in clinically
apparent disease, although, in one case report, a chronically infected
pregnant woman was infected with a highly virulent strain that resulted
in infection of the fetus.109
Because T. gondii is a natural parasite of rodents, inbred mice have
been used extensively as an animal model for studies of both immunity
and immunopathology in this protozoan infection and have yielded a
remarkably detailed picture of its host interaction.110-112 When tachyzo-
ites invade, they inject the contents of their rhoptries into the host cell
cytosol. This delivers not only some of the machinery needed for inva-
sion (contained within the rhoptry necks and known as RON proteins)
but also a collection of “effectors” that intercept or co-opt host immune
pathways, presumably to the parasite’s advantage. These effectors
include the rhoptry protein, ROP16, which functions as a mimic of
host Janus kinases (JAKs), phosphorylating critical tyrosines on host
STATs (signal transducers and activators of transcription). Depending
on the particular flavor of ROP16 that a given strain carries, the host
immune response can be driven in differing directions, either more or
less inflammatory, and this can have a profound effect on the host’s
response and ultimate outcome of the infection. In the case of another
pair of injected ROPs, ROP5 and ROP18, the target is murine IRGs, a
key part of a mouse cell’s defense machinery.113 Normally, IRGs attack
the membrane of the vacuole in which a pathogen resides, disrupting
it and leading to death of the organisms within. ROP5 and ROP18,
however, collaborate to phosphorylate and thereby inactivate IRGs
although, again, the effectiveness of this depends on the specific alleles
of ROP5 and ROP18 that a given strain of Toxoplasma carries. Lastly,
dense granules can also introduce polymorphic effectors into the host
cell; one such effector, GRA15, has been shown to be crucial to the
activation of one of the most central transcription factors in mam-
malian immune response, nuclear factor kappa B.114
It is important to recognize that these findings do not necessarily
represent the mechanisms underlying the immune response to T.
gondii in humans. For example, although the effect of ROP16 on STATs
may well have a parallel in human cells, IRGs are not part of the human
immune response, and so ROP5 and ROP18, if they are impacting the
outcome of human infection, must be doing so by acting on other
targets, such as activating transcription factor-6β.115 Similarly, Toll-like
receptors TLR11 and TLR12 play a major role in the induction of
interleukin-12 (IL-12) and host resistance in the mouse, but neither
receptor exists in humans, indicating that innate recognition of the
parasite in humans must involve distinct mechanisms. This might
involve another branch of the innate immune system, NLRs (nucleo-
tide oligomerization domain [NOD]-like receptors), that detect molec-
ular signatures or patterns specific to various pathogens. Recent work
has suggested that susceptibility to Toxoplasma infection in humans is
associated with a polymorphism in a human NLR known as NALP1
(NACHT-LRR-PYD domains–containing protein 1).116 The overall
question of how Toxoplasma is sensed by the innate arm of the human
immune system and how different strains of the parasite do this with
differing degrees of success is just beginning to be explored.
T cells, macrophages, and type 1 cytokines (IFN-γ, IL-12) are
crucial for control of T. gondii infection. Adoptive transfer and
 3128
depletion experiments in murine models not only proved that T cells
are essential for control of T. gondii infection but also demonstrated an
interplay between CD4+ and CD8+ T cells in both the induction of
resistance and the maintenance of latency. Expansion of both natural
Part III  Infectious Diseases and Their Etiologic Agents
killer (NK) and γδ T cells early in infection provides innate resistance
while the adaptive response mediated through αβ CD4 and CD8 T
cells develops. These different subsets of T cells and NK cells are likely
to protect the host by secreting cytokines, such as IFN-γ, IL-2, and
TNF-α, and apparently not by lysing T. gondii–infected cells.117-120 Den-
dritic cells and inflammatory monocytes also play an important role
in control of acute infection and the early production of IL-12.120,121
NK-cell–derived IFN-γ appears critical to the differentiation of IL-12–
producing dendritic cells.120 Early studies suggested that neutrophils
were an important component of the early response, but more recent
studies suggest that they are not and may, in fact, contribute to the
pathology.121
The co-stimulatory molecules CD28 and CD40 ligand are pivotal
for the regulation of IL-12 and IFN-γ production in response to the
parasite.122 T. gondii infection of antigen-presenting cells, such as den-
dritic cells and macrophages, causes upregulation of the counter-
receptors for CD28 and CD40L, CD80/CD86, and CD40.122 Binding of
CD80/CD86 to CD28 enhances production of IFN-γ by CD4+ T cells.
In addition, binding of CD40L to CD40 triggers IL-12 secretion, which
in turn enhances production of IFN-γ. The relevance of CD40L in the
immune response to T. gondii is supported by reports of TE and dis-
seminated toxoplasmosis in children with congenital defects in CD40L
signaling (hyper-IgM syndrome).123 Moreover, recent studies have
demonstrated that expression of CD40L is defective on CD4+ T cells
from HIV-infected patients.124 This deficiency may play a role in defec-
tive IL-12/IFN-γ production associated with HIV infection.
Cytokines play a critical role in defense against the infection and
are important in the pathogenesis of toxoplasmosis and TE.125 IL-12
enhances survival of T-cell–deficient mice during T. gondii infection,
by stimulating the production of IFN-γ by NK cells,126 and is thought
to also regulate the expression of the latter cytokine by T cells in
immunocompetent mice.127 IFN-γ has been shown to play a significant
role in the prevention or development of TE in mice.128 The administra-
tion to chronically infected mice of a monoclonal antibody against
IFN-γ resulted in a dramatic worsening in the degree of encephalitis.129
In mice with active TE, treatment with IFN-γ significantly reduced the
inflammatory response and numbers of tachyzoites.130
Differences in IL-12 levels elicited during infection by different
strains of the parasite may be responsible for some of the strain-specific
differences in virulence in mice.131 These differences appear to be
related to the activation (phosphorylation) of the transcription factor
STAT3, which in turn is dependent on the particular allele of ROP16
injected by a given strain, as detailed earlier.132
TNF-α is another cytokine pivotal for control of T. gondii infection.
TNF-α is required for triggering of IFN-γ–mediated activation of mac-
rophages for T. gondii killing activity133 and for nitric oxide (NO, an
inhibitor of T. gondii replication) production by macrophages.134 The
administration of TNF-α neutralizing antibody to infected mice
caused the death of the mice and an increase in the number of T. gondii
tissue cysts in the brains of survivors.135
IL-10 has been shown to deactivate macrophages and result in
reduced in vitro killing of T. gondii. IL-4 and IL-6, which are usually
considered downregulatory cytokines, have been shown to be impor-
tant in resistance against TE in the murine model.136,137 IL-7 has also
been shown to have a protective role against T. gondii in mice.138
During the early stages of the infection, IL-12, IL-1, and TNF act in
concert with IL-15 to stimulate NK cells to produce IFN-γ.139
IL-17140 and IL-23141,142 have also been implicated in the generation
of a potent immune response but are not thought be essential for host
resistance.
Several hypotheses have been proposed to explain the role of IFN-γ
in host resistance to T. gondii. Involvement of reactive nitrogen inter-
mediates (including NO) is suggested by the observation that l-NG-
monomethyl-l-arginine acetate (l-NMMA), a competitive analogue of
l-arginine, simultaneously inhibits NO synthesis and intracellular
tachyzoite killing by cytokine-activated peritoneal macrophages and
microglial cells.99,143,144 In addition, mice in which NO synthesis is
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impaired as a result of genetic disruptions of the IFN-γ or IFN-1 genes
succumb to the acute infection.145,146 Similar enhanced susceptibility
was observed in mice treated with the reactive nitrogen intermediate
inhibitor aminoguanidine147 and in nitric oxide synthase–deficient
mice.148 The protective role of NO appears to be tissue-specific rather
than systemic.148 Because control of the acute infection in vivo was
unaffected by nitric oxide synthase deficiency, the major role of reac-
tive nitrogen intermediates appears to be to maintain control of estab-
lished infections in this mouse model.148
The IFN-γ–inducible p47 GTPases IRGM3 (IGTP) and IRGM1
(LRG47) have been shown to be required for host control of T. gondii
infection in the mouse,149 and recent studies have linked IRGM3 with
the autophagic destruction of Toxoplasma-containing vacuoles in
IFN-γ–activated macrophages.150,151
Immunoglobulin G (IgG), IgM, IgA, and IgE antibodies are pro-
duced in response to the infection. Extracellular tachyzoites are lysed
by specific antibody when combined with complement. In mice,
humoral immunity results in limited protection against less virulent
strains of T. gondii but not against virulent strains.152
Both astrocytes and microglia likely play important roles in the
immune response against T. gondii within the CNS. In the early stages
of TE in both humans and mice, there is a remarkable and widespread
astrocytosis restricted to areas in which the parasite is detected.125
Whereas T. gondii can invade, survive, and multiply within astrocytes,
they are killed by activated microglia.153
GENETIC SUSCEPTIBILITY
The observations in mice that genetic factors in the host contribute to
the development and severity of TE154-156 and the fact that not all HIV-
infected patients with positive T. gondii serologic findings develop TE
suggested the possibility that genetic factors may also play a role in the
predisposition of AIDS patients for this disease.157 The major histo-
compatibility complex (MHC) class II gene DQ3 (HLA-DQ3) has been
significantly associated with the development of TE in North American
white AIDS patients, whereas HLA-DQ1 was marginally protective.157
HLA-DQ3 was also significantly associated with the development of
hydrocephalus in children with congenital toxoplasmosis.158 In the
latter study, a mouse model transgenic for human MHC class II found
higher organism burden with the HLA-DQ3 than HLA-DQ1 genotype.
In a South American white population, a study using a higher resolu-
tion typing method identified HLA-DQB*0402 and HLA-DRB1*08
genes, which were in linkage disequilibrium, as risk factors for TE,
whereas alleles of HLA-DQB3 were not.159 Thus, further studies are
needed to better define the contribution of various HLA alleles to
susceptibility to TE. In single studies, polymorphisms in other genes,
including those for IL-10, TLR9, NLR family, pyrin domain–containing
protein 1 (NALP1, also known as NLRP1), and purinergic receptor
P2X(7) (P2RX7) have been associated with congenital toxoplasmosis
or retinochoroiditis.116,160-162
PATHOLOGY
Our knowledge of the pathology of infection in humans has come
largely from autopsy studies in severely infected infants and immuno-
deficient patients. Data from immunocompetent adults are limited
almost entirely to results obtained from lymph node biopsy speci-
mens163 and occasionally from myocardial or skeletal muscle tissue
specimens.164 In addition to the direct demonstration of parasites in
tissue and associated pathology, recent studies have revealed that the
impact of the parasite may extend to many more cells than are actively
infected, that is, mouse studies have shown evidence of injected rhoptry
proteins in upward of 50-fold more neurons in a chronically infected
brain than actually harbor parasites at that time.42 The impact of these
“injected-uninfected” cells on pathogenesis and other interactions with
the host has yet to be determined.
Lymph Node
The histopathologic changes in toxoplasmic lymphadenitis (TL) in
immunocompetent individuals are frequently distinctive and often
diagnostic (Fig. 280-3A).163 There is a typical triad of findings: a reac-
tive follicular hyperplasia, irregular clusters of epithelioid histiocytes
encroaching on and blurring the margins of the germinal centers, and
 3129

Chapter 280  Toxoplasma gondii

A B

C D
FIGURE 280-3  Histologic features of Toxoplasma gondii in humans. A, Hematoxylin and eosin (H&E) stain of a lymph node biopsy specimen
from an immunocompetent patient with toxoplasmic lymphadenitis. B, Positive immunoperoxidase stain of a brain biopsy specimen in a patient with
acquired immunodeficiency syndrome and toxoplasmic encephalitis. C, H&E stain of a right ventricle endomyocardial biopsy specimen from a patient
with toxoplasmic myocarditis. Organisms are seen within myocytes (see text under “Clinical Manifestations”). D, H&E stain of a right quadriceps muscle
biopsy specimen depicting tissue cyst from the same patient as shown in C. She also developed toxoplasmic polymyositis. (A courtesy Dr. Henry Masur,
Critical Care Medicine Department, National Institutes of Health, Bethesda, MD. B to D courtesy Dr. Jack S. Remington, Stanford University and Palo Alto
Medical Foundation.)

focal distention of sinuses with monocytoid cells (see Fig. 280-3A).165
Langerhans giant cells, granulomas, microabscesses, and foci of necro-
sis are not typically seen. Rarely, tachyzoites or tissue cysts are demon-
strable. T. gondii DNA has infrequently been amplified from lymph
node tissue.166
Central Nervous System
Damage to the CNS by T. gondii is characterized by multiple foci of
enlarging necrosis and microglial nodules.167 Necrosis is the most
prominent feature of the disease because of vascular involvement by
the lesions. In cases of congenital toxoplasmosis, necrosis of the brain
is most intense in the cortex and basal ganglia and at times in the
periventricular areas.8,168 The necrotic areas may calcify and lead to
striking radiographic findings suggestive but not pathognomonic of
toxoplasmosis. Hydrocephalus may result from obstruction of the
aqueduct of Sylvius or foramen of Monro. Tachyzoites and tissue cysts
may be seen in and adjacent to necrotic foci, near or in glial nodules,
in perivascular regions, and in cerebral tissue uninvolved by inflam-
matory change.169 The necrotic brain tissue autolyzes and is gradually
shed into the ventricles. The protein content of such ventricular fluid
may be in the range of grams per deciliter and has been shown to
contain significant amounts of T. gondii antigens.
The presence of multiple brain abscesses is the most characteristic
feature of TE in severely immunodeficient patients and is particularly
characteristic in patients with AIDS.6,170 Brain abscesses in AIDS
patients are characterized by three histologic zones. The central area is
avascular. Surrounding this is an intermediate hyperemic area with a
prominent inflammatory infiltrate and perivascular cuffing by lympho-
cytes, plasma cells, and macrophages. Many tachyzoites and, at times,
tissue cysts as well, appear at the margins of necrotic areas. An outer
peripheral zone contains T. gondii tissue cysts.171 In the areas around
the abscesses, edema, vasculitis, hemorrhage, and cerebral infarction
secondary to vascular involvement may also be present.172 Important
associated features in TE are the presence of arteritis, perivascular
cuffing, and astrocytosis. Because these findings may also be present
in patients with viral encephalitis, immunoperoxidase staining is
important for differentiating these pathologic processes. Widespread,
poorly demarcated, and confluent areas of necrosis with minimal
inflammatory response are seen in some patients.172 Identification of
tachyzoites is pathognomonic of active infection, but their visualiza-
tion may be difficult in hematoxylin and eosin–stained sections. The
use of immunoperoxidase staining markedly improves the identifica-
tion of both tissue cyst and tachyzoite forms and highlights the pres-
ence of T. gondii antigens (see Fig. 280-3B).29 T. gondii DNA can be
amplified from cerebrospinal fluid (CSF) or brain biopsy specimens of
patients with TE.173 Of note, PCR-positive results in brain biopsy speci-
mens need to be interpreted with caution. These results may be positive
in patients chronically infected with the parasite whose CNS pathology
can be explained by a diagnosis other than TE.
At autopsy in AIDS patients with TE, there is almost universal
involvement of the cerebral hemispheres and a remarkable predilec-
tion for the basal ganglia.86 In a consecutive autopsy study of 204
patients who died of AIDS, 46 (23%) had morphologic evidence of
cerebral toxoplasmosis.172 In 38 (83%) of the 46 cases, histologic evi-
dence of toxoplasmosis was restricted to the CNS. The cerebral hemi-
spheres were affected in 91% of cases and the rostral basal ganglia
in 78%.
A “diffuse form” of TE has been described with histopathologic
findings of widespread microglial nodules without abscess formation
in the gray matter of the cerebrum, cerebellum, and brainstem.174 In

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 3130
these patients, involvement by T. gondii was confirmed by immuno-
peroxidase stains that demonstrated tissue cysts and tachyzoites. In
diffuse TE, the clinical course progresses rapidly to death. It has been
postulated that in such cases, the lack of characteristic findings on
Part III  Infectious Diseases and Their Etiologic Agents
computed tomography (CT) or magnetic resonance imaging (MRI)
studies is due to insufficient time for abscesses to form before death
occurs.
Leptomeningitis is infrequent and, when present, occurs over adja-
cent areas of encephalitis. Spinal cord necrotizing lesions are seen at
autopsy in approximately 6% of patients with TE. The differential diag-
nosis of TE lesions includes CNS lymphoma, progressive multifocal
leukoencephalopathy, and infection caused by organisms such as cyto-
megalovirus (CMV), Cryptococcus neoformans, Aspergillus spp., and
M. tuberculosis. More than one agent may be present.
Lung
Pulmonary toxoplasmosis in the immunodeficient patient may appear
in the form of interstitial pneumonitis, necrotizing pneumonitis, con-
solidation, pleural effusion, empyema, or all of these.175 The pneumo-
nitis is associated with the development of fibrinous or fibrinopurulent
exudate. Tachyzoites may be found in alveolocytes, alveolar macro-
phages, pleural fluid, or extracellularly within alveolar exudate. T.
gondii DNA may be demonstrated in bronchoalveolar lavage (BAL)
fluid by the PCR.176
Eye
Chorioretinitis in AIDS patients is characterized by segmental panoph-
thalmitis and areas of coagulative necrosis associated with tissue cysts
and tachyzoites.177 Numerous organisms in the absence of remarkable
inflammation may be seen around thrombosed retinal vessels adjacent
to necrotic areas. Multiple and bilateral lesions may occur.177 Amplifi-
cation of parasite DNA in both aqueous humor and vitreous fluid has
confirmed or supported the diagnosis of toxoplasmic chorioretinitis in
patients with atypical retinal findings for ocular toxoplasmosis or who
are immunocompromised.178,179
Eye infection in immunocompetent patients produces acute cho-
rioretinitis characterized by severe inflammation and necrosis.177
Granulomatous inflammation of the choroid is secondary to the
necrotizing retinitis. There may be exudation into the vitreous or
invasion of the vitreous by a budding mass of capillaries. Although
rare, tachyzoites and tissue cysts may be demonstrated in the retina.
The pathogenesis of recurrent chorioretinitis is controversial. One
school proposes that rupture of tissue cysts releases viable organisms
that induce necrosis and inflammation, whereas another school
contends that chorioretinitis results from a hypersensitivity reaction
triggered by unknown causes.177 A study demonstrating efficacy of
trimethoprim-sulfamethoxazole (TMP-SMX) in preventing recur-
rences of chorioretinitis is consistent with the hypothesis that active
organism replication is necessary for recurrence.180
Recent studies have revealed a much higher incidence of ocular
disease, which is often severe, among infected immunocompetent
persons in South America than in North America or Europe.181-184 This
difference seems most likely to be due to differences in the strains of
Toxoplasma that predominate in these different regions.17 This is con-
sistent with observations within the United States, where specific
strains appeared to be associated with severe disease, although these
studies involved relatively few patients and cannot be considered
definitive.185
Skeletal and Heart Muscle
Myositis caused by T. gondii has been reported in as high as 4% of
HIV-infected patients who present with neuromuscular symptoms,
and the same percentage has been observed in autopsy series of AIDS
patients in whom a systematic histologic evaluation of the skeletal
muscle was performed.186 Successful isolation from skeletal muscle
biopsies has been reported.187 Microscopy has revealed necrotic muscle
fibers with a variable inflammatory reaction. Skeletal muscle involve-
ment has also been reported in the non-AIDS immunodeficient
patient.6,164
Toxoplasmic myocarditis is frequently noted at autopsy in AIDS
patients but is usually clinically inapparent,188 with CNS manifestations
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predominating.189 Focal necrosis with edema and an inflammatory
infiltrate is typical,188 although abscesses may also be noted.188,189
Similar histologic findings are seen in the non-AIDS immunodeficient
population,6 and in both groups cardiac myocytes may be packed with
tachyzoites (to produce pseudocysts) in the absence of an inflamma-
tory response.
Biopsy-proven toxoplasmic myocarditis and polymyositis in the
setting of acute toxoplasmosis have been reported in otherwise
immunocompetent individuals and in patients on corticosteroids
(see Fig. 280-3C and D).164
Other Organ Systems
Extensive involvement of the gastrointestinal tract in AIDS patients
may occur with tremendous variation in the inflammatory
response.190,191 Hemorrhagic gastritis and colitis have been described.192
Other organs reported to be involved during toxoplasmosis include
the liver,193 pancreas,194 seminiferous tubules,195 prostate,195 adrenals,196
kidneys,197 and bone marrow.198
CLINICAL MANIFESTATIONS
Toxoplasmosis describes the clinical or pathologic disease caused by T.
gondii and is distinct from T. gondii infection, which is asymptomatic
in the vast majority of immunocompetent patients.
Toxoplasmosis is conveniently classified into five categories: (1)
acquired in the immunocompetent patient, (2) acquired or reactivated
in the immunodeficient patient, (3) ocular, (4) in pregnancy, and (5)
congenital. In any category, the clinical presentations are not specific
for toxoplasmosis, and a wide differential diagnosis must be considered
for each clinical syndrome. Furthermore, methods of diagnosis and
interpretation of test results may differ for each clinical category. Sero-
logic test results consistent with an infection acquired in the distant
past for a nonimmunocompromised pregnant woman in her first half
of pregnancy are interpreted as no risk for congenital toxoplasmosis,
whereas the same results for a patient about to undergo an allogeneic
hematopoietic stem cell or bone marrow transplant are interpreted as
high risk for life-threatening toxoplasmosis in the post-transplant
period, particularly if the patient develops graft-versus-host disease
(GVHD).
Toxoplasmosis in the
Immunocompetent Patient
In the United States and Europe, only 10% to 20% of cases of T. gondii
infection in immunocompetent adults and children are symptom-
atic.199 Recent reports suggest that this proportion may be higher in
other areas of the world, such as Brazil and other countries in South
America.181,184 In addition, it appears that disease severity can also be
greater in countries outside Europe and the United States. For instance,
community outbreaks of acute toxoplasmosis with an unusually severe
clinical presentation have been recently reported from Suriname and
French Guiana.200,201 In two reports, immunocompetent patients pre-
sented with severe disseminated disease, including pneumonia and
hepatitis, that resulted in four deaths, including one newborn and one
fetus, among 22 patients. Based on genotype analysis with microsatel-
lite markers, “atypical” strains (i.e., not one of the three major strains
seen in Europe and North America) were responsible for these out-
breaks. The remarkable differences in clinical presentation of toxoplas-
mosis among patients from various regions of the world have significant
implications when generating a differential diagnosis in travelers from
the United States and Europe who become ill.
When clinical manifestations are present, toxoplasmosis most often
manifests as painless cervical lymphadenopathy, but any or all lymph
node groups may be enlarged. On palpation, the nodes are usually
discrete and nontender, rarely more than 3 cm in diameter, may vary
in firmness, and do not suppurate.202 However, the nodes may be occa-
sionally tender or matted. Fever, malaise, night sweats, myalgias, sore
throat, arthralgias, maculopapular rash, hepatosplenomegaly, or small
numbers of atypical lymphocytes (less than 10%) may be present.
The clinical picture may resemble infectious mononucleosis or CMV
infection, but toxoplasmosis probably causes no more than 1% of
“mononucleosis” syndromes.203 Retroperitoneal or mesenteric lymph-
adenopathy may produce abdominal pain accompanied by diarrhea.

Neurocognitive abnormalities appear to be common during the acute
infection among immunocompetent patients, according to a recent
report.204
Toxoplasmic chorioretinitis as a manifestation of acute acquired
infection is more common than previously recognized.205-207 Chorio-
retinitis in the setting of acute acquired toxoplasmosis can occur either
sporadically or in the context of an epidemic of acute toxoplasmo-
sis.206,208 For further discussion of this clinical entity, see “Ocular Toxo-
plasmosis in Immunocompetent Patients.”
In most cases, the clinical course of toxoplasmosis in the immuno-
competent patient is benign and self-limited. Symptoms, if present,
usually resolve within a few months and rarely persist beyond 12
months. Lymphadenopathy may wax and wane for months and, in
unusual cases, for 1 year or longer. Rarely, an apparently healthy person
develops clinically overt disease, for instance, fever of unknown origin
or potentially fatal disseminated disease, with myocarditis, pneumoni-
tis, hepatitis, or encephalitis. In children, nephrotic syndrome has been
reported in association with acute toxoplasmosis.209 These more aggres-
sive forms of the disease have been more commonly reported from
South America.200,201 None of the clinical presentations of acquired
toxoplasmosis is distinctive; the differential diagnosis of TL includes
lymphoma, infectious mononucleosis, CMV or human herpesvirus 6
(HHV-6) “mononucleosis,” cat-scratch disease, sarcoidosis, tuberculo-
sis, tularemia, metastatic carcinoma, and leukemia. Acute acquired
toxoplasmosis associated with multiorgan involvement has been
reported to mimic other causes of pneumonitis, hepatitis, myocarditis,
polymyositis, or fever of unknown origin in apparently immunocom-
petent patients.199
T. gondii has been estimated to cause 3% to 7% of clinically signifi-
cant lymphadenopathy.202 The major diagnostic confusion with toxo-
plasmic lymphadenopathy occurs with Hodgkin’s disease and the
lymphomas. The diagnosis of recently acquired toxoplasmic lymph-
adenopathy is easily made serologically, but unfortunately, physicians
often do not consider this diagnosis in patients with lymphadenopathy.
Serologic test titers diagnostic of acute T. gondii infection are often
obtained after histologic examination of a biopsied node has suggested
the possibility of toxoplasmosis.210
Myocarditis as a manifestation of acute toxoplasmosis has been
reported in relatively few patients.164,211,212 It may occur clinically as an
isolated disease process or as part of a variety of manifestations of dis-
seminated infection. Manifestations include arrhythmias, pericarditis,
and heart failure.164
Myositis resembling polymyositis as a manifestation of acute toxo-
plasmosis has also been reported infrequently.164,213,214 Dermatomyosi-
tis has been associated with toxoplasmosis, although a cause-and-effect
relationship has not been proved.215,216
The clinical features of toxoplasmic myocarditis and polymyositis
are illustrated by a case in which both were present in the same indi-
vidual.164 A 43-year-old woman presented with cardiogenic pulmonary
edema, followed by progressive sinus bradycardia and subsequent
complete heart block; viral myocarditis was considered the most likely
diagnosis. During the ensuing months, she developed proximal muscle
weakness while being treated with corticosteroids; an endomyocardial
biopsy (see Fig. 280-3C) and a quadriceps muscle biopsy (see Fig. 280-
3D) revealed T. gondii.164 Her symptoms improved on pyrimethamine-
sulfadiazine. One year after her initial presentation with myocarditis,
retinal lesions characteristic of toxoplasmic chorioretinitis were
observed in her right eye. Serologic test results and follow-up were
consistent with recently acquired toxoplasmosis.164
Several epidemiologic studies have suggested an association
between infection with T. gondii and schizophrenia and other mental
illnesses but a definitive etiologic role of the parasite in such disorders
has not been established.217-219 Population based studies that include
large cohorts of patients followed since gestation will be necessary to
clarify this potential association.
Toxoplasmosis in the  
Immunodeficient Patient
In immunocompromised patients toxoplasmosis can present with a
wide spectrum of clinical manifestations. Disseminated disease has a
100% case-fatality rate if untreated. Early diagnosis requires a high
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3131
index of suspicion because routine laboratory tests to detect bacterial,
viral, or fungal infections will not alert clinical laboratory personnel
or the clinician to the presence of T. gondii as the etiologic agent.
T-cell–mediated immunity defects appear to confer the highest risk for
Chapter 280  Toxoplasma gondii
toxoplasmosis as observed in patients with hematologic malignancies
(especially Hodgkin’s disease and other lymphomas), organ transplant
recipients, or AIDS and those receiving immunosuppressive therapy
with high doses of corticosteroids or immunomodulators, such as anti–
TNF-α agents, for instance, natalizumab or alemtuzumab.220 In immu-
nodeficient patients, encephalitis, pneumonitis, and myocarditis reflect
active infection in the most commonly involved organs.6 Pneumonitis
is a common and underrecognized manifestation of toxoplasmosis in
these patients. Fever of unknown origin may be the sole manifestation
of toxoplasmosis in the early stages of the disease. Disseminated infec-
tion with multiorgan involvement is not unusual; clinical manifesta-
tions may not necessarily reflect the extent and severity of the
disseminated infection. Mortality approaches 100% if the infection is
not treated or is treated only late in its course. Whereas serious toxo-
plasmosis in these patients often reflects recrudescence of a latent
infection acquired in the distant past (as observed in the setting of
AIDS or bone marrow transplantation), it may also result from recently
acquired acute infection (as observed in solid-organ transplants
through the transplanted organ) or, more rarely, through the oral route.
Although clinical manifestations are similar in patients with different
causes for their immunosuppression, additional considerations are
provided here for the organ transplant recipient and patient with AIDS.
Toxoplasmosis in the Solid-Organ
Transplant Patient
Patients with solid-organ transplants will develop toxoplasmosis most
commonly as a result of acquiring T. gondii infection through the
transplanted organ, when the allograft of a seropositive donor (D+) is
given to a seronegative recipient (R−), resulting in a D+/R− mismatch
(Table 280-1). Toxoplasmosis can also be the result of reactivation of
a previously acquired infection in the recipient, regardless of the sero-
logic status of the donor (D−/R+ or D+/R+, see Table 280-1). Fever is
often the first manifestation in transplant recipients, followed by signs
referable to the brain and lungs.
Knowledge of the overall prevalence of Toxoplasma antibodies in a
population does not accurately predict the percentage of D+/R− T.
gondii mismatches. Rather, this will depend on the prevalence of T.
gondii antibodies in the age groups of the donor and recipient popula-
tions. For example, in a given geographic area, the prevalence of anti-
bodies in young heart donors may be 3% to 10%, whereas in the older
population of individuals who would more likely be recipients, it may
be 15% to 30%. Testing for Toxoplasma IgG antibodies should be per-
formed in every organ transplant candidate before transplantation and
on serum from every organ donor. This will allow identification of
those recipients at greatest risk of developing toxoplasmosis either
because they were seronegative before transplantation and received an
organ from a seropositive individual or because they were seropositive
TABLE 280-1  Source of Toxoplasmosis in the
Organ Transplant Patient
Transplant of an Infected Organ to a Seronegative Recipient
(D+R−)
Heart
Heart-lung
Kidney
Liver and liver/pancreas
Bone marrow (rare)
Reactivation of Latent Infection in a Seropositive Recipient
(D−R+ and D+R+)
Bone marrow
Hematopoietic stem cell
Liver
Kidney (rare)
D, donor; R, recipient.
 3132
before transplantation and thus are at risk for reactivation of their
latent (chronic) Toxoplasma infection. Unfortunately, Toxoplasma
serologies obtained in the early months post-transplantation frequently
are not helpful, even in the presence of serious toxoplasmosis in these
Part III  Infectious Diseases and Their Etiologic Agents
patients. T. gondii antibodies demonstrable before transplantation
might become negative, rise, or show no change post-transplantation
despite life-threatening toxoplasmosis.221 Transfusion may further
compound the difficulties encountered in serodiagnosis.
The incidence of toxoplasmosis among various organ transplant
recipients managed at 11 tertiary care hospitals in Spain between 2000
and 2009 was 0.14% (22/15,800).222 The incidence was significantly
greater in heart compared with kidney and liver recipients. The only
independent risk factor identified in multivariate analysis was negative
serostatus before transplant. Overall mortality was 14%, although two
of the three deaths occurred in untreated patients who were diagnosed
at autopsy.
At autopsy, histopathologic evidence of multiorgan involvement
has been observed, most commonly of the brain, heart, and lungs but
also including the eyes, liver, pancreas, adrenal, and kidney.
Heart Transplantation
In a review of infections in cardiac transplant recipients at Stanford
Medical Center from 1980 to 1996, results of serologic testing for
Toxoplasma were available for 582 donors (35 [6%] had T. gondii–
specific IgG antibodies) and 607 recipients (98 [16%] were positive).223
Results of serologic testing for Toxoplasma were available for 575 D/R
pairs; of these, 454 (79%) were D−/R−, 84 (14.6%) D−/R+, 32 (5.6%) D+/
R−, and 5 (0.8%) D+/R+. Of the 32 D+/R− patients, 16 were receiving
TMP-SMX and/or pyrimethamine prophylaxis, and none developed
toxoplasmosis; however, 4 (25%) of the 16 D+/R− patients who were not
taking either TMP-SMX or pyrimethamine developed toxoplasmosis,
and all died of the infection. None of the 98 patients who were sero-
positive for T. gondii preoperatively developed clinical evidence of
reactivation of the infection. The importance of prophylaxis is further
evidenced from an earlier study at Papworth Hospital in England. Fatal
or severe toxoplasmosis developed in 57% (4/7) of D+R− mismatched
heart transplant patients not receiving prophylaxis. Use of pyrimeth-
amine, 25 mg/day for 6 weeks reduced the transmission rate to 14%
(5/37). In those patients who received pyrimethamine and were
infected by the donor heart, only 1 (20%) developed symptoms of the
infection in contrast to 4 of 4 (100%) who did not receive pyrimeth-
amine prophylaxis. Subsequently, prophylaxis with TMP-SMX (480 mg
twice daily orally for 1 year post-transplantation and when on oral
prednisolone) was used in heart and lung transplant patients. Of those
who were alive at 3 months post-transplantation, 28 (8.75%) were T.
gondii mismatches; none had evidence of having acquired Toxoplasma
infection. These investigators observed that use of prophylaxis might
prolong the period before observation of seroconversion of donor-
acquired infection in heart transplant patients for as long as 14 months
post-transplantation.224,225
Toxoplasmosis in heart transplant recipients may simulate organ
rejection. In such cases, toxoplasmosis has frequently been diagnosed
by endomyocardial biopsy.
It is important to recognize that many heart transplant recipients
with T. gondii antibodies before transplantation may show increases
in T. gondii–specific antibodies (IgG and IgM). These patients have
not necessarily developed a clinical illness that can be attributed to
toxoplasmosis.
Kidney Transplantation
In a review of 31 cases of toxoplasmosis in renal transplant patients,
the majority occurred within the first 3 months after transplantation;
3 cases occurred more than 1 year after transplantation, and 9 occurred
during or immediately after a rejection episode.226 The greatest risk was
in D+/R− mismatches. Fever, CNS signs, and pneumonia were the main
clinical features. Chest radiographs showed bilateral pneumonia in
most cases. The most common organs involved in the 15 cases diag-
nosed at autopsy were brain, heart, and lungs. T. gondii was not demon-
strable in the kidneys. Whereas the overall mortality rate was 64%, 10
of 11 treated patients survived, emphasizing the importance of early
diagnosis and treatment. Acute toxoplasmosis in two recipients of
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renal allografts from the same donor has occurred. Chorioretinitis has
been reported as the presenting manifestation of toxoplasmosis in a
kidney transplant patient.227
Liver Transplantation
After orthotopic liver transplantation, toxoplasmosis most often results
from activation of a latent infection in the transplanted allograft,228 but
it occurs as well from activation of a quiescent pretransplantation infec-
tion in the recipient. In most published cases, clinical manifestations of
toxoplasmosis appeared within the first 3 months post-transplantation.
Fever was usually the first manifestation, and pneumonia, meningitis/
encephalitis, and multiorgan failure were frequently observed. Retino-
choroiditis requiring enucleation was observed in one patient.229
Although it is a rare event, toxoplasmosis in this population is most
often fatal.230
Toxoplasmosis in the Bone Marrow
Transplant and Hematopoietic Stem
Cell Transplant Recipient
Donor bone marrow from the patient (autologous) or a matched
related or unrelated donor (allogeneic) used to be the only source of
cells for bone marrow transplant (BMT) recipients. Stem cell trans-
plantation is now also done using stem cells harvested from the periph-
eral blood (hematopoietic stem cell transplant [HSCT]) of the patient
(autologous), matched related or unrelated donor (allogeneic), matched
parent (haploid), or less commonly, umbilical cord blood. To keep this
literature separate, HSCT and BMT are presented separately in this
section. A review of 41 cases of toxoplasmosis in patients who had
undergone HSCT in 15 European transplantation centers, from 1994
through 1998, found no cases among 6787 autologous HSCT, whereas
it occurred in 0.97% of 4231 allogeneic transplants.231 The relatively
low number of cases in their large survey is likely due to the use of
TMP-SMX prophylaxis after engraftment in all allogeneic BMTs in
91% of the institutions. Of the patients with available serologies before
transplantation, 94% were seropositive for T. gondii. GVHD had devel-
oped before toxoplasmosis in 73%. Thirty patients (73%) had not
received prophylaxis for toxoplasmosis, and only 3 were receiving it at
the time of disease onset. Median time of onset was day 64 (range, 4
to 516 days). Fever with neurologic or pulmonary symptoms was seen
most commonly; myocarditis was frequently seen at autopsy. Six
patients had fever without evidence of organ involvement. Twenty-two
(63%) died of toxoplasmosis. It is noteworthy that of the 23 patients
who received specific therapy for toxoplasmosis for greater than or
equal to 6 days, 11 (48%) had a complete response, and 3 (13%) others
improved. In 106 T. gondii–seropositive adult recipients of HSCTs, the
incidence of reactivation of toxoplasmosis in the first 6 months after
transplantation was prospectively studied.232 Toxoplasma serologies
had been obtained pretransplantation. The incidence of reactivation
within 6 months after transplantation, as established by a positive PCR
test result in peripheral blood, was observed in 16 of the 106 patients
(16%). Of the 16 patients with positive PCR test results, 6 (38%) devel-
oped disease (toxoplasmosis). Thus, PCR may be useful in monitoring
at-risk patients (i.e., seropositive patients identified in the pretrans-
plantation period) (see “Diagnosis”).
Survival in this setting is highest in patients with ocular and/or
isolated cerebral toxoplasmosis, primarily when treatment is begun as
soon as the diagnosis is suspected.82,231 Survival in the presence of dis-
seminated toxoplasmosis is rare in these HSCT patients.82,231 Although
reactivation of latent Toxoplasma infection in allogeneic HSCT recipi-
ents most often occurs in the first 6 months post-transplantation (the
majority occur in the first 30 to 90 days), late reactivation has been
observed and must be considered in patients in whom late-onset
(beyond 6 months post-transplantation) GVHD occurs.232,233
The incidence of toxoplasmosis in BMT has been reported to range
from 0.3% to 5% and is influenced by the prevalence of pretransplanta-
tion antibodies and whether toxoplasmosis prophylaxis was used.
Major risk factors for toxoplasmosis included the presence of pretrans-
plantion T. gondii antibodies in recipients and the occurrence of
GVHD. In a review of 110 published cases of toxoplasmosis after
BMT,82 96% occurred after allogeneic BMT. Onset post-transplantation
occurred on days 1 to 30 in 13%, on days 31 to 100 in 64%, and on

days greater than 100 in 23%. The infection occurred primarily in
recipients who were seropositive pretransplantation (88%), meaning
infection was more often reactivation in the recipient—not trans-
planted from the donor. The diagnosis was made antemortem in only
3133
may be the first sign; if pulmonary infiltrates are observed, especially
in the setting of rapid deterioration, immediate attempts at diagnosis
must be made and empirical treatment begun. Undoubtedly, the high
mortality in many instances has been due to lack of early diagnosis and

Chapter 280  Toxoplasma gondii

47% of the cases. Overall mortality was 80% (median, 87 days post-
transplantation), and in 66%, it was attributed to toxoplasmosis
(median, 74 days post-transplantation). Patients with isolated cerebral
involvement had a better outcome (58% survival) than patients with
disseminated toxoplasmosis (20% survival); underlying disease was the
only factor associated with clinical presentation, with acute leukemia
being more common in patients with disseminated disease.
TMP-SMX prophylaxis, primarily used by transplantation teams to
prevent Pneumocystis pneumonia, has been successful in prevention of
toxoplasmosis. In HSCT patients, this is usually begun after engraft-
ment because of the potential of the drug combination for bone marrow
suppression. The delay in instituting prophylaxis likely results in many
more cases of toxoplasmosis than would be expected to occur if ade-
quate prophylaxis was begun early after transplantation. This problem
highlights the importance of PCR monitoring of at-risk patients and
identifying additional drugs for prophylaxis in these patients.234
Toxoplasmosis in BMT patients frequently involves the lung
(usually in the setting of multiorgan disease), with a high associated
mortality (>90%) (Fig. 280-4). Most patients die within 7 days of onset
of pulmonary symptoms and often suffer acute respiratory distress
syndrome. In a review of 25 cases of pulmonary toxoplasmosis in BMT,
onset of symptoms referable to the lungs occurred from 7 days to
1 year post-BMT; the majority occurred in the first 6 weeks.235 Fever
treatment. The organism can be observed on microscopic examination
of BAL material. PCR on material obtained at BAL may be the diag-
nostic procedure of choice.235 PCR also can be performed on blood,
serum, CSF, and bone marrow aspirates.
Ocular toxoplasmosis has been reported after allogeneic and autol-
ogous BMT and HSCT. In some cases, the ocular disease was due to
reactivation of a previously observed toxoplasmic chorioretinitis,
whereas in most, it has been associated with disseminated infection.
Definitive diagnosis has been by direct observation of the parasite in
histopathology sections, culture of tissue samples, or by PCR on vitre-
ous fluid.
Toxoplasmosis in the AIDS Patient
Clinical manifestations of toxoplasmosis in AIDS patients commonly
reflect encephalitis (i.e., TE), or infection of the lung (pneumonitis),
and the eye (chorioretinitis).236 Toxoplasmosis with multiorgan
involvement manifesting with acute respiratory failure and hemody-
namic abnormalities similar to septic shock has been reported,
although septic shock has not been definitely proved to be due to
T. gondii.237 TE is the most common presentation of toxoplasmosis in
AIDS patients and is a frequent cause of focal CNS lesions in these
patients.86 A wide range of clinical findings, including altered mental
state, seizures, weakness, cranial nerve disturbances, sensory abnor-

A 4/23/2012 4/24/2012 5/8/2012

B 4/24/2012 5/3/2012

FIGURE 280-4  Pulmonary toxoplasmosis. Serial chest radiographs (A) and computed tomography scans of the chest (B) of a patient who had
received a haplo-cord transplant as treatment for myelodysplastic syndrome complicating aplastic anemia and subsequently presented with pulmonary
symptoms. Pulmonary toxoplasmosis was diagnosed by polymerase chain reaction (PCR) of a bronchoalveolar lavage sample obtained on April 24, 2012.
The patient also had a positive PCR for toxoplasmosis in blood and cerebrospinal fluid. The patient responded to treatment with intravenous trimethoprim-
sulfamethoxazole and subsequently oral pyrimethamine-sulfadiazine-leucovorin, with resolution of pneumonia and conversion of PCR to negative.
(Courtesy Dr. Richard Childs, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.)

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 3134
malities, cerebellar signs, meningismus, movement disorders, and
neuropsychiatric manifestations are seen in TE. The characteristic pre-
sentation usually has a subacute onset with focal neurologic abnor-
malities in 58% to 89% of patients. However, in 15% to 25% of cases,
Part III  Infectious Diseases and Their Etiologic Agents

the clinical presentation may be more abrupt, with seizures or cerebral

hemorrhage. Most commonly, hemiparesis or abnormalities of speech,
or both, are the major initial manifestations. Brainstem involvement
often produces cranial nerve lesions, and many patients exhibit cere-
bral dysfunction with disorientation, altered mental state, lethargy, and
coma. Less commonly, parkinsonism, focal dystonia, rubral tremor,
hemichorea-hemiballismus, panhypopituitarism, diabetes insipidus, or
the syndrome of inappropriate antidiuretic hormone secretion may
dominate the clinical picture. In some patients, neuropsychiatric
symptoms, such as paranoid psychosis, dementia, anxiety, and agita-
tion, may be the major manifestations.
Diffuse TE174 has been reported in relatively few AIDS patients; its
actual incidence is unknown. This form of TE may manifest acutely A
and can be rapidly fatal; generalized cerebral dysfunction without focal
signs is the most common manifestation, and CT scans may be within
normal limits or reveal cerebral atrophy.
Spinal cord involvement by T. gondii in AIDS patients manifests as
motor or sensory disturbances of single or multiple limbs, bladder or
bowel dysfunctions (or both), and local pain. Patients may present with
a clinical syndrome resembling a spinal cord tumor. Reports of cervical
myelopathy,238 thoracic myelopathy,239 and conus medullaris syn-
drome240 have been published.
Pulmonary disease caused by toxoplasmosis has been reported in
patients with AIDS, and the diagnosis may be made by demonstration
of the parasite in BAL fluid.241 In France, before ART and routine
use of prophylaxis, the prevalence of pulmonary toxoplasmosis in
patients dually infected with HIV and T. gondii was estimated to be
approximately 5%.242 Pulmonary toxoplasmosis occurs mainly in
patients with advanced AIDS (mean CD4 count, 40 cells/mm3 ± 75 SD)
and primarily presents as a prolonged febrile illness with cough and B
dyspnea,241 which may be clinically indistinguishable from Pneumo­
cystis pneumonia. Mortality, even when treated appropriately, may
be as high as 35%. Extrapulmonary disease may be present in about
50% of cases with toxoplasmic pneumonitis.237 Often, pulmonary toxo-
plasmosis is not associated with TE; however, TE may develop after
successful treatment of pulmonary toxoplasmosis when therapy is dis-
continued. The differential diagnosis of toxoplasmic pneumonitis
includes Pneumocystis pneumonia, viral pneumonia (e.g., caused by
CMV or community-acquired respiratory viruses), pneumonia caused
by atypical pathogens (e.g., Chlamydia spp., Mycoplasma pneumoniae),
and infection with M. tuberculosis, Cryptococcus neoformans, Coccidi-
oides spp., and Histoplasma capsulatum.
Toxoplasmic chorioretinitis is seen relatively infrequently in AIDS
patients243; it commonly manifests with ocular pain and loss of visual
acuity (Fig. 280-5). Funduscopic examination usually demonstrates
necrotizing lesions that may be multifocal or bilateral.243 Overlying
vitreal inflammation is often present and may be extensive. The optic
nerve may be involved in as many as 10% of cases. Toxoplasmic cho- C
rioretinitis in AIDS patients has been associated with concurrent TE
FIGURE 280-5  Toxoplasmic chorioretinitis. A, Active chorioretinitis
in up to 63% of patients. The differential diagnosis of toxoplasmic with two lesions and vitreous haze, in a human immunodeficiency virus–
chorioretinitis in AIDS patients includes CMV retinitis, syphilis, infected patient. B, A large inactive macular lesion typical of congenital
herpes simplex, varicella zoster, and candidiasis. The diagnosis relies disease. C, Active chorioretinitis in an immunocompetent patient from an
primarily on clinical findings and the response to anti–T. gondii endemic region in Brazil. There is an inactive lesion on the right. Note the
therapy, although definitive diagnosis may be made by demonstration macular star, which is due to an exudate around the macula. (Courtesy Dr.
of the organism in retinal biopsies,243 isolation of the parasite from Robert Nussenblatt, National Eye Institute, National Institutes of Health,
vitreous aspirates,244 or amplification of the parasite DNA by PCR.178 Bethesda, MD; Dr. Claudio Silveira, Erechim, Brazil; and Dr. Rubens Belfort,
Gastrointestinal involvement may result in abdominal pain, ascites São Paulo Brazil.)
(resulting from involvement of the stomach, peritoneum, or pancreas),
or diarrhea. Acute hepatic failure caused by T. gondii has been accounting for 26% of such cases in one recent study, with a 1-year
reported,193 as has musculoskeletal involvement.186 estimated survival of 77%.246 In contrast to mycobacterial and crypto-
Although the incidence of toxoplasmosis in HIV-infected patients coccal infections, immune reconstitution inflammatory syndrome
began to decrease after the broad use of TMP-SMX for PCP prophy- after the initiation of ART has been only rarely reported in association
laxis, the incidence decreased dramatically as a result of the immune with toxoplasmosis.247-250 In patients with CD4 counts that are sus-
reconstitution associated with ART regimens. Approximately fourfold tained to levels greater than 200 cells/µL for 3 to 6 months while
decreases in both incidence and death have been reported after the receiving ART, prophylaxis regimens can be safely discontinued,
wide availability of ART regimens.87,88,245 Yet despite this, TE remains although rare cases of disease can occur even in patients with well-
one of the most common HIV-related neurologic disorders, controlled HIV infection.251-254

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There are no data on whether the strain of T. gondii affects the
clinical outcome of infection in AIDS patients, and there are conflict-
ing reports on whether a particular strain is more likely to cause infec-
tion in such patients.13,255
Ocular Toxoplasmosis in
Immunocompetent Patients
T. gondii is one of the most frequently identified etiologies of uveitis
and the most commonly identified pathogen to infect the retina of
otherwise immunocompetent individuals.256 It accounted for 8.4% of
cases of uveitis seen in a clinic in San Francisco over a 24-year period.257
Toxoplasmosis is responsible for more than 85% of posterior uveitis
cases in southern Brazil, where, in one study, 9.5% of 21 seroconverters
and 8.3% of 131 seropositive patients without ocular involvement
developed typical lesions during 7 years of follow-up.258-260 Chorioreti-
nal lesions may result from congenital or postnatally acquired infec-
tion. In both these situations, lesions may occur during the acute or
latent (chronic) stage of the infection.206,261 Recurrences are frequent,
occurring in 79% of patients followed for more than 5 years in one
study, with a median time to recurrence of 2 years; they tend to occur
in clusters, that is, immediately after an episode rather than randomly,
are more common in patients older than 40 years, are more common
in the eye originally involved, and may be more common after cataract
extraction.262-264
It is frequently difficult to determine whether the original infection
was congenital or acquired in patients who suffer recurrences of cho-
rioretinitis.207 Although previously it was thought that less than 1% of
cases were acute infections, the remainder being reactivations, recent
evidence indicate that 11.7% of U.S. ocular infections are acute.264a
Patients who present with chorioretinitis as a late sequela of the infec-
tion acquired in utero tend to have more severe disease and are more
frequently in the second and third decades of life (it is rare after the
age of 40 years); bilateral disease, old retinal scars, and involvement of
the macula are hallmarks of the retinal disease in these cases, as are
recurrences (see Fig. 280-5).8 By contrast, patients who present with
toxoplasmic chorioretinitis in the setting of acute toxoplasmosis are
more often between the fourth and sixth decades of life, most often
have unilateral involvement, and have eye lesions that usually spare the
macula and do not present with associated old scars.206,207
Whereas acquired T. gondii infection in otherwise healthy adults is
most often subclinical, toxoplasmic chorioretinitis in these individuals
may result in complete or partial loss of vision or in glaucoma, and
it may necessitate enucleation.8,265 Acute chorioretinitis may produce
symptoms of blurred vision, scotoma, pain, photophobia, and epiph-
ora. Impairment or a loss of central vision occurs when the macula is
involved. As inflammation resolves, vision improves, frequently
without complete recovery of visual acuity, caused in large part by
macular scar formation.257 In most cases, toxoplasmic chorioretinitis
is diagnosed by ophthalmologic examination, and empirical therapy
directed against the organism is often instituted based on clinical find-
ings and serologic test results. Typical features of toxoplasmic chorio-
retinitis include intensely white focal lesions with an overlying, intense,
vitreous inflammatory reaction (see Fig. 280-5). Focal necrotizing
retinitis initially appears in the fundus as a yellowish-white, elevated
cotton patch with indistinct margins, usually on the posterior pole. The
lesions are often in small clusters, and individual lesions in the cluster
may be of varied ages. With healing, the lesions pale, atrophy, and
develop black pigment (see Fig. 280-5). There can also be an associated,
secondary iridocyclitis and increased intraocular pressure.265 The
classic “headlight in the fog” appearance is due to the presence of active
retinal lesions with severe vitreous inflammatory reaction. The choroid
is secondarily inflamed. Recurrent lesions tend to occur at the borders
of chorioretinal scars, and scars are often found in clusters. Panuveitis
may accompany chorioretinitis, but isolated anterior uveitis has never
been proved to occur.
Although the morphology of the lesions of acute toxoplasmic cho-
rioretinitis in the setting of postnatally acquired disease may be indis-
tinguishable from those observed in patients who suffer acute eye
disease in later life caused by a congenitally acquired infection, it is
important to attempt to establish which type of the infection (postna-
tally acquired or congenital) is occurring in a given patient.206 It appears
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3135
that the congenitally acquired disease has a more guarded prognosis.
From the public health perspective, it is important epidemiologically
to establish whether the patient has acute acquired infection, to initiate
efforts to identify the possible source of T. gondii infection and to
Chapter 280  Toxoplasma gondii
determine whether other individuals who may be at high risk for
developing severe, life-threatening disease (i.e., fetuses of serologically
negative pregnant women or immunodeficient individuals) shared the
same exposure as the individual with acute acquired toxoplasmic cho-
rioretinitis. Serologic tests have been useful in establishing whether
such patients have been infected recently.205,206 In patients with cho­
rioretinitis and IgG antibodies, additional serologic tests should be
performed to determine whether the patient’s infection is recently
acquired.206
T. gondii chorioretinitis may resemble the posterior uveitis of
tuberculosis, syphilis, leprosy, or presumed ocular histoplasmosis
syndrome.
Atypical clinical and serologic manifestations of toxoplasmic cho-
rioretinitis have been reported most commonly in elderly and in
immunodeficient individuals.178,266 Patients are considered to have
atypical-appearing lesions when one or more of the following features
are present: multiple foci of active retinitis, acute retinal necrosis
syndrome (vitritis, peripheral retinitis, retinal vasculitis), significant
intraretinal hemorrhage, an absence of ophthalmoscopically visible
chorioretinal scarring. In patients with atypical lesions or an inade-
quate clinical response to anti-Toxoplasma therapy or in whom other
diagnostic procedures have not proved helpful, obtaining vitreous or
aqueous fluid (in some cases indicated for therapeutic reasons as well)
for PCR should be considered early in the workup (see “Diagnosis”).179
In the future, it may be possible to routinely determine which strain
of the parasite is responsible for the infection and make a more accu-
rate prognosis. Preliminary indications are that strain type may play
an important part in determining the course of the infection,184,185 and
methods to distinguish strain type by looking for strain-specific anti-
bodies using polymorphic peptides have shown promise.75,267
Toxoplasmosis during Pregnancy
As in other immunocompetent individuals, acute Toxoplasma infec-
tion is asymptomatic in the majority of pregnant women. Based on
newly developed serologic assays that can detect antibodies to sporo-
zoites,49 the majority of women in one U.S. study appeared to have been
initially infected with oocysts, and a high proportion were unable to
identify the potential source of such infection.268 Given these factors,
women should be universally screened by serology to maximize
diagnosis of toxoplasmosis during pregnancy. The most commonly
recognized clinical manifestation of recent infection is regional lymph-
adenopathy. The primary concern is transmission of infection to the
fetus. The risk to the fetus does not correlate with whether the infection
in the mother was symptomatic or asymptomatic during gestation.
Transmission to the fetus has been limited almost solely to those
women who acquire the infection during gestation. Otherwise healthy
women with prior Toxoplasma infection are protected from transmit-
ting the infection to their fetuses. Rare exceptions to this dictum have
been observed. In immunocompetent women infected with T. gondii
shortly before conception, transmission to the fetus has occurred; in
these very rare instances, the acute infection was acquired within 3
months of conception.269-271 Transmission to the fetus has been rarely
recognized as a consequence of reactivation of latent T. gondii infection
in immunocompromised women infected with T. gondii before con-
ception (chronic infection) (e.g., pregnant women coinfected with HIV
and T. gondii,272 patients with systemic lupus erythematosus who are
being treated with corticosteroids). In addition, reinfection with a
second, more aggressive strain of T. gondii of otherwise healthy preg-
nant women who are already chronically infected with the parasite has
been proposed and documented as a possible mechanism of transmis-
sion to the fetus.109,269
Congenital Toxoplasmosis
Congenital infection may present in one of five forms: (1) ultrasound
abnormalities consistent with toxoplasmosis or positive amniotic fluid
PCR test results in the fetus; (2) neonatal disease; (3) disease (mild or
severe) occurring in the first months of life; (4) sequelae or relapse of
 3136
a previously undiagnosed infection during infancy, childhood, or ado-
lescence; and (5) subclinical infection.
Data accumulated from prospective studies indicate that the inci-
dence and severity of congenital toxoplasmosis vary with the trimester
Part III  Infectious Diseases and Their Etiologic Agents
during which the infection was acquired by the mother.8 Moreover,
there is an inverse relationship between the frequency of transmission
and the severity of disease. Infants born of mothers who acquire their
infection in the first and second trimester more frequently show severe
congenital toxoplasmosis.273 In contrast, the majority of children born
of women who acquire their infection during the third trimester are
born with the subclinical form of the infection. However, if left
untreated, as many as 85% of these latter children develop signs and
symptoms of the disease, in most cases chorioretinitis or delays in
development.274,275 Although the majority of neonates born to mothers
infected later in gestation have subclinical infection, recent reports
suggest that when infected with a more virulent or atypical strain,
severe congenital disease may occur despite having acquired their
infection late in gestation.276
Infection acquired in the first trimester by women who were not
treated with anti–T. gondii drugs resulted in congenital infection in 25%
of cases in one report.273 For second- and third-trimester infections, the
incidences of fetal infection were 54% and 65%, respectively.273 The
overall rate of vertical transmission in this study of untreated women
was 50%.273 Early treatment of the mother with spiramycin appears to
reduce the incidence of congenital infection by about 60%.273,277,278-280
Maternal infection acquired around the time of conception and within
the first 2 weeks of gestation and treated with spiramycin usually does
not result in transmission.279 Because of the high transmission rates
observed in the late second trimester and during the third trimester, it
is recommended that pyrimethamine-sulfadiazine be used in patients
in whom acute infection is highly suspected or confirmed as having
occurred at 18 weeks of gestation or later.
Frequency of transmission to the fetus and severity of disease in the
offspring appear to be significantly affected by drug treatment with
spiramycin and pyrimethamine-sulfadiazine as well. In cohorts where
most of the mothers have been treated during gestation, transmission
rates were low in the first trimester. (i.e., 6% [95% confidence interval
{CI}, 3% to 9%)] at 13 weeks) and increased as expected with advanc-
ing gestational age (i.e., 40% [95% CI, 33% to 47%] at 26 weeks and
72% [95% CI, 60% to 81%] at 36 weeks)281 The overall rate of vertical
transmission in this study of treated women was 29% (95% CI, 25%
to 33%).281 Clinical signs in the infected infant were more likely
observed in offspring of women whose infection was acquired early in
gestation. Depending on when during gestation the mother acquired
her infection, the risk for severity of clinical manifestations in an
infected fetus was 61% (95% CI, 34% to 85%) at 13 weeks, 25% (95%
CI, 18% to 33%) at 26 weeks, and 9% (95% CI, 4% to 17%) at 36
weeks.281 A recent study reported the lowest rates of overall trans­
mission (4.8%) and clinical manifestations in the newborn (1.6%)
published to date.282 In this cohort, pregnant women with T. gondii
infection acquired during gestation received spiramycin until the 16th
week of gestation, followed by at least 4 weeks of a pyrimethamine-
sulfadiazine–folinic acid combination independent of the infection
status of the fetus. If fetal infection was suspected (e.g., ultrasound
abnormalities suggestive of congenital infection are observed) or con-
firmed (e.g., positive amniotic fluid PCR test), combination treatment
was continued until delivery. In their cohort, their rates of transmission
for the first, second, and third trimester were 1.3%, 10.6%, and 21.7%,
respectively. Another study reported that prenatal treatment with spi-
ramycin and/or pyrimethamine-sulfadiazine resulted in a significantly
reduced risk of severe neurologic sequelae or death in the infected
offspring.283 Of note, recently severe congenital toxoplasmosis has only
been reported from countries such as the United States and Brazil,
where universal screening and treatment during gestation have not
been implemented.284,285
In addition to gestational age and treatment, transmission rates and
severity of congenital disease are also likely to be affected by the strain
of the parasite, infecting form of the parasite (cyst vs. oocyst), parasite
load,286 and immune status and genetics of the host.
Clinical manifestations of congenital toxoplasmosis vary. Most
signs and clinical presentations are nonspecific and may mimic disease
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caused by organisms such as herpes simplex virus, CMV, and rubella
virus. Signs include chorioretinitis, strabismus, blindness, epilepsy,
psychomotor or mental retardation, anemia, jaundice, rash, petechiae
resulting from thrombocytopenia, encephalitis, pneumonitis, micro-
cephaly, intracranial calcification, hydrocephalus, diarrhea, hypother-
mia, and nonspecific illness.8 There may be no sequelae, or sequelae
may develop or be evident at various times after birth.
A detailed examination by an experienced clinician may be neces-
sary to detect signs of the infection.8 In one prospective study,287 210
congenitally infected infants were identified: 2 patients (0.9%) died, 21
(10.9%) had severe disease, 71 (33.8%) were mildly afflicted, and 116
(54.4%) were without signs of the infection. More intensive examina-
tion of the latter 116 infants revealed abnormalities in 39; abnormal
CSF was detected in 22 infants, chorioretinitis was seen in 17, and
intracranial calcifications were found in 10. Premature infants often
suffer CNS disease and ocular disease in the first 3 months of life. Full-
term infants frequently develop a milder disease manifested by hepa-
tosplenomegaly and lymphadenopathy that usually appear in the first
2 months of life. In these infants, disease reflecting damage to the CNS
may occur later, and eye disease may occur months to years after birth.
Most untreated infants with subclinical infection at birth subse-
quently develop signs or symptoms of congenital toxoplasmosis,
including chorioretinitis, which may lead to blindness, neurologic
manifestations such as seizures, and sensorineural hearing loss.275,288
Prospective observational studies suggest that early initiation of spe-
cific therapy (prenatally and postnatally) in infants with congenital
infection but without clinical signs will markedly reduce untoward
sequelae.289,290 In one cohort, among children who were diagnosed with
toxoplasmic chorioretinitis only after their first year of life (thus, who
were not treated during their first year of life), new chorioretinal
lesions were detected in more than 70%,291 whereas among 108 con-
genitally infected children treated during their first year of life, only
31% developed at least one new chorioretinal lesion. Thirteen percent
had occurrences when they were 10 years or older, indicating that
long-term follow-up is important.289,292 It appears that, when treated,
initially asymptomatic congenital toxoplasmosis has an overall good
prognosis.289
Uncommonly, latent T. gondii infection may reactivate in HIV-
infected women and result in congenital transmission of the parasite.
Congenital toxoplasmosis appears to occur more frequently in the
offspring of women infected with both HIV and T. gondii than in those
of women who are infected with T. gondii but not with HIV.293 Infants
with congenital toxoplasmosis born to HIV-infected mothers are also
infected with HIV, suggesting that factors predisposing to the vertical
transmission of HIV also favor the transmission of T. gondii, or vice
versa. Congenital toxoplasmosis in the HIV-infected infant appears to
run a more rapid course than that in the non–HIV-infected infant, with
the development of failure to thrive, fever, hepatosplenomegaly, cho-
rioretinitis, and seizures. Most children have multiorgan involvement,
including CNS, cardiac, and pulmonary disease.
It has been recently reported that T. gondii causes more severe
ocular disease in congenitally infected children in Brazil when com-
pared with those in Europe.182 As stated earlier, this may be explained
by the fact that pregnant women in Brazil are not routinely screened
and treated for toxoplasmosis during gestation and possibly that more
virulent genotypes of the parasite predominate in Brazil but are rarely
found in Europe.
Congenital toxoplasmosis must be differentiated from rubella virus,
CMV, herpes simplex virus, HHV-6, parvovirus B19, and lymphocytic
choriomeningitis virus infections; syphilis, listeriosis, and other bacte-
rial infections; other infectious encephalopathies; erythroblastosis
fetalis; and sepsis. Herpes simplex virus, CMV, rubella virus, and syph-
ilis may cause chorioretinitis; both CMV and rubella have been associ-
ated with hydrocephalus, microcephaly, and cerebral calcification. A
markedly elevated CSF protein concentration is a hallmark of congeni-
tal toxoplasmosis.
T. gondii infection acquired during pregnancy has been implicated
in spontaneous abortion, stillbirth, and premature births. On rare
occasions, T. gondii has been isolated from the abortuses of women
with chronic infection, but the frequency of T. gondii infection as a
cause of abortion is unknown and controversial.

As with ocular disease, the strain of T. gondii may have an impact
on the outcome of congenital infection. Studies in Europe have revealed
conflicting data on whether type I strains, in particular, might be more
likely to be responsible for congenital infection and/or serious
disease.14,15,294 Non–type II strains were associated with prematurity
and severity of disease at birth in a study from the United States that
used serologic tests as a method to determine the strain type.295 As
more accurate and sensitive tests for determining the genotype of an
infecting strain are developed, this picture could change significantly.
DIAGNOSIS
When considering toxoplasmosis in the differential diagnosis of a
patient’s illness, emphasis should not be placed on whether the patient
has been exposed to cats. Transmission of oocysts virtually always
occurs without the knowledge of the patient and may be unrelated to
direct exposure to a cat (e.g., transmission by contaminated vegetables,
other foods, or water). Patients with an indoor cat that is only fed
cooked food are not at risk of acquiring the infection from that cat.
Serologic investigation of a cat to establish whether it is a potential
source of the infection should be discouraged; the prevalence of T.
gondii antibodies among cats in a given locale is usually similar to their
prevalence in humans. Seropositivity does not predict shedding of
oocysts. Acute toxoplasmosis has been documented in patients without
known epidemiologic risk factors for acute infection.
Because the clinical manifestations of T. gondii infection may be
protean and nonspecific, toxoplasmosis must be carefully considered
in the differential diagnosis of a large variety of clinical presentations.
The correct diagnostic tests must be performed and appropriately
interpreted in light of the patient’s clinical presentation. The usefulness
of a given diagnostic method may differ considerably with the clinical
entity, which can be toxoplasmosis in the immunocompetent or immu-
nodeficient patient, ocular toxoplasmosis, toxoplasmosis in pregnancy,
or congenital toxoplasmosis.296
Acute infection is diagnosed by characteristic serologic test results;
demonstration of tachyzoites in histologic sections of tissue or in cyto-
logic preparations of body fluids; amplification of T. gondii DNA or
isolation of the parasite in blood or body fluids; the demonstration of
a characteristic lymph node histologic appearance; or demonstration
of T. gondii tissue cysts in the placenta, fetus, or neonate.8 Rarely,
asymptomatic patients with latent infection have recurrent parasit-
emia.297 Isolation of T. gondii from the tissues of older children or
adults may only reflect the presence of tissue cysts. Finding numerous
tissue cysts in tissue sections, especially associated with inflammation,
suggests but does not prove the presence of active infection.
Serologic Tests for Demonstration   who have a primary immunodeficiency (e.g., congenital agammaglob-
of Antibody
The use of serologic tests for the demonstration of specific antibody to
T. gondii tachyzoites is the primary method of diagnosis. A large
number of tests have been described, some of which are available only
in highly specialized laboratories. Different serologic tests often
measure different antibodies that possess unique patterns of rise and
fall with the time after infection.296 However, initial serologic testing
can be accomplished by simultaneously requesting IgG and IgM anti-
body tests. This task can be easily achieved by hospital-based, com-
mercial, or nonreference laboratories. Only positive results in IgM
antibody tests need to be sent for confirmatory testing to reference
laboratories (see later).
There is no single serologic test that can be used to support the
diagnosis of acute or chronic infection by T. gondii. In most cases, a
battery of tests is required to enable the distinction between acute and
chronic infection. Which particular combination of tests is used
depends on the specific clinical category of the patient (i.e., pregnant
vs. immunodeficient patient; see “Clinical Manifestations”), the inter-
val between acquisition of infection and sampling of sera,210 and the
question posed by the practitioner. The clinician must be familiar with
these problems and consult reference laboratories if the need arises. A
panel of tests consisting of the Sabin-Feldman dye test (DT; detecting
IgG), the IgM-, IgA-, and IgE–enzyme-linked immunosorbent assays
(ELISAs), differential agglutination test (measures IgG antibody and
is also known as the AC/HS test), and the IgG avidity test is used
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3137
successfully by the Palo Alto Medical Foundation–Toxoplasma Serol-
ogy Laboratory (PAMF-TSL, 650-853-4828, www.pamf.org/serology/)
to determine whether serologic test results are more likely consistent
with infection acquired in the recent or more distant past.164,206,210,298-300
Chapter 280  Toxoplasma gondii
It is also important to note that a new test has been developed that
shows great promise for discriminating between an infection derived
from ingestion of oocysts versus tissue cysts.49 Assuming this test can
be thoroughly validated in humans, a logistically challenging task given
the general lack of individuals with a definitively known source of
infection, this new test could be extremely beneficial. It relies on detec-
tion of antibodies to a protein that is abundantly expressed in sporo-
zoites but not in tachyzoites or bradyzoites, and it has the potential to
address both the epidemiologic origins of infection in different cohorts/
regions and could also allow a determination of whether disease initi-
ated by one or other means leads to different clinical outcomes. What
follows below concerns only the generic detection of a Toxoplasma
“infection,” that is, tachyzoites, without regard to the original source
of that infection, but such refinement is something anxiously antici-
pated for the near future.
Immunoglobulin G Antibodies
The most widely used tests for the measurement of IgG antibody are
the Sabin-Feldman DT,301 ELISA,302,303 the indirect fluorescent antibody
(IFA) test,304 and the modified direct agglutination test.305 In these tests,
IgG antibodies usually appear within 1 to 2 weeks of acquisition of the
infection, peak within 1 to 2 months, fall at variable rates, and usually
persist for life at relatively low titers.
Recent reports have shown that detecting antibodies to strain-
specific peptides can reveal the genotype of the infecting strain;
although this approach has been helpful in epidemiologic studies, it
has not yet been developed into a reliable, clinically useful diagnostic
method.267,295
Sabin-Feldman Dye Test
The Sabin-Feldman DT is the reference serologic test against which
other methods have been evaluated.301 It is a sensitive and specific
neutralization test. It measures primarily IgG antibodies that usually
appear 1 to 2 weeks after the initiation of infection, reach peak titers
in 6 to 8 weeks, and then gradually decline over 6 to 12 months.8 Titers,
usually at low levels, probably persist for life. This test is available in
only a few reference laboratories, primarily because live organisms are
required. A negative Sabin-Feldman DT practically rules out prior
exposure to T. gondii, except in patients who have been infected very
recently (e.g., within 1 to 2 weeks of exposure), are significantly immu-
nocompromised (e.g., allogeneic bone marrow transplant patients), or
ulinemia). Early in infection (e.g., within 4 weeks of infection), patients
may be negative in IgG-ELISA, agglutination, or IFA kits but positive
in the DT. However, although rare, cases of documented TE and cho-
rioretinitis have been reported in DT-negative patients.
Indirect Fluorescent Antibody Test
The IFA test appears to measure the same antibodies as the DT, and its
titers tend to parallel DT titers.8 False-positive results may occur with
sera that contain antinuclear antibodies,306 and false-negative results
may occur in sera with low IgG antibody titers. Use of the Toxoplasma
IFA test should be discouraged because of the relative high frequency
of false-negative and false-positive results.
Agglutination and AC/HS Tests
The agglutination test using formalin-preserved whole tachyzoites is
available commercially (bioMérieux, Marcy-l’Etoile, France) and
detects IgG antibody. The test is very sensitive to IgM antibody, and
“natural” IgM antibody causes nonspecific agglutination in sera that
yield negative results when tested in the DT and the IFA test. This
problem is avoided by including 2-mercaptoethanol in the test. The
method is accurate, simple to perform, inexpensive, and excellent for
screening purposes.307 This method, that is, with mercaptoethanol,
should not be used for the measurement of IgM antibodies.
When two different compounds (i.e., acetone and formalin) are
used to fix parasites for use in the agglutination test, a “differential”
 3138
agglutination test (AC/HS test) results because the different antigenic
preparations vary in their ability to recognize sera obtained during the
acute and chronic stages of the infection.308 This test has proved useful
in helping differentiate acute from chronic infections and is best used
Part III  Infectious Diseases and Their Etiologic Agents
in combination with a battery of other tests. When the AC/HS yields
a “nonacute” pattern, the infection has been present for at least 12
months from the time of serum sampling.309
Immunoglobulin G Enzyme-Linked
Immunosorbent Assay
The IgG-ELISA method is now the most widely used for the demon-
stration of IgG antibodies to T. gondii. Most commercial IgG antibody
test kits are accurate for demonstration of IgG antibodies; however, it
is important to recognize that one cannot use a single IgG titer, no
matter what its level, to predict whether the infection was recently
acquired or acquired in the distant past.
Immunoglobulin G Avidity Test
A number of tests for avidity of Toxoplasma IgG antibodies have been
introduced to help differentiate between recently acquired and distant
infection.310 This method is based on the observation that during acute
T. gondii infection, IgG antibodies bind antigen weakly (i.e., have low
avidity), whereas chronically infected patients have more strongly
binding (high avidity) antibodies.310 Protein-denaturing reagents,
including urea, are used to dissociate the antibody-antigen complex.
Low or equivocal avidity test results can persist for months to years
after the primary infection,310 and for this reason, a low or equivocal
avidity test result must not be used to determine whether the infection
was acquired recently. The time of conversion from low or equivocal
to high avidity is highly variable among different individuals, including
pregnant women.298,311,312 However, it has been demonstrated that once
the avidity test result is high, the patient was infected at least 3 to 5
months earlier.312 This timing depends on the method used. High-
avidity test results by the IgG-VIDAS avidity test (VIDAS Toxoplasma
IgG Avidity, bioMérieux), for example, have been essentially found
only in pregnant women who have been infected for at least 4
months.300,313,314
The avidity test should only be used as an additional confirmatory
diagnostic method in patients with positive and/or equivocal IgM test
results or when the results of a battery of tests are equivocal or inter-
preted as consistent with the possibility of a recently acquired infec-
tion. Health care providers involved in the care of pregnant women
should be aware that avidity testing is only a confirmatory test. It
should not be used alone as a definitive test for decision making.
Immunoglobulin M Antibodies
IgM antibodies may appear earlier and decline more rapidly than IgG
antibodies. IgM antibody tests have been widely used for the diagnosis
of acute infection and to determine whether a pregnant woman has
been infected during gestation or before conception. There has been a
heightened awareness of the fact that titers in tests for IgM antibodies
may persist for years after the acute infection and that the reliability of
commercially available assays varies considerably.315-317 Both the labo-
ratory performing the test and the physician requesting the test should
be aware of this problem. In 1997, the U.S. Food and Drug Administra-
tion (FDA) issued a health advisory warning about the use of T. gondii
IgM commercial test kits as the sole determinant of recent infection in
pregnant women.318 At present, the decision to treat or undertake other
medical interventions, including the termination of pregnancy, should
be based on clinical evaluation and additional testing performed in
reference or research laboratories with experience in the diagnosis of
toxoplasmosis. For further discussion, see “Toxoplasma gondii Infec-
tion in Pregnancy.”319 The persistence of IgM antibodies for several
years appears not to have clinical significance.8
Immunoglobulin M Indirect Fluorescent
Antibody Test
IgM-IFA antibody appears within the first week of infection; titers
rise rapidly and then fall to low titers and usually disappear within a
few months. Low titers may persist 1 year or longer.320 Antinuclear
antibodies and rheumatoid factor may cause false-positive results.321
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IgG-blocking antibodies can cause false-negative results in this test
when IgG is not removed.322
Immunoglobulin M Enzyme-Linked
Immunosorbent Assay
The double-sandwich IgM-ELISA for detection of IgM-specific anti-
bodies to T. gondii323-325 is currently the most widely used method for
demonstration of IgM antibodies to T. gondii in adults, the fetus, and
newborns.8 In contrast to the conventional method, in which the wells
of microtiter plates are coated with antigen, the wells are coated with
specific antibody to IgM. The double-sandwich IgM-ELISA is more
sensitive than the IgM-IFA test for diagnosis of recently acquired infec-
tion, and serum samples that are negative in the DT but that contain
either antinuclear antibodies or rheumatoid factor and thus cause
false-positive results in the IgM-IFA test are negative in the double-
sandwich IgM-ELISA. This latter observation is attributed to the fact
that serum IgM fractions are separated from IgG fractions during the
initial step in the double-sandwich IgM-ELISA procedure.8
Despite the wide distribution of commercial test kits to measure
IgM antibodies, these kits often have low specificity, and the reported
results are frequently misinterpreted. False-positive results and the
problems associated with the persistence of positive titers, even years
after the initial infection, remain major obstacles to correct interpreta-
tion of the results obtained in these tests.316
Immunoglobulin M Immunosorbent
Agglutination Assay
The IgM immunosorbent agglutination assay (IgM-ISAGA) (bioMéri-
eux), which binds the patient’s IgM to a solid surface and uses intact,
killed tachyzoites to detect IgM antibodies, is highly sensitive.326 The
test is simple to perform, does not require the use of enzyme conjugate,
and is read in the same manner as the agglutination test. Overall, it is
more sensitive and specific than the IgM-IFA test. The presence of
rheumatoid factor or antinuclear antibodies does not cause false-
positive results in the IgM-ISAGA. In adults, it is more sensitive but
much less specific than the double-sandwich IgM-ELISA method. In
infants the IgM-ISAGA is the most sensitive method and is used effec-
tively for diagnosis of congenital infection in infants 6 months of age
or younger.327 A positive IgM-ISAGA test result in the first 10 days of
life should be repeated after 10 days to rule out the possibility of mater-
nal contamination of IgM antibodies. The ISAGA method has also
been used to detect IgA and IgE antibodies.
Immunoglobulin A Antibodies
IgA antibodies may be detected in sera of acutely infected adults and
congenitally infected infants using ELISA or ISAGA.328-330 As is true
for IgM antibodies to the parasite, IgA antibodies may persist for many
months or more than 1 year. However, IgA antibodies tend to disap-
pear earlier than the IgM, and their presence at high titers is usually
associated with early infections (e.g., within 3 months of the date of
serum sampling). The increased sensitivity of IgA assays over IgM
assays for the diagnosis of congenital toxoplasmosis represents a major
advance in the serologic diagnosis of the infection in the fetus and
newborn.330 IgA antibodies are rarely detectable by ELISA in sera of
AIDS patients with TE.330 If IgA antibodies are detected in the newborn
during the first 10 days of life, the test should be repeated 10 days after
birth to make certain that what is being measured is not contaminating
maternal IgA antibodies. The possibility that such contamination
might occur is the reason that under most circumstances, peripheral
blood rather than cord serum be used to measure IgM, IgA, or IgE
antibodies in the newborn.
Immunoglobulin E Antibodies
IgE antibodies are detectable by ELISA in sera of acutely infected
adults,331,332 congenitally infected infants,331,332 and children with con-
genital toxoplasmic chorioretinitis.333 The duration of IgE seropositiv-
ity is briefer than that with IgM or IgA antibodies and hence appears
useful for identifying recently acquired infections.210,332 T. gondii–
specific IgE antibody has been detected in patients with TE and may
be useful as a marker for TE in this population of patients.332 IgE anti-
bodies have been reported to be present in 85.7% of asymptomatic

seroconverters and in 100% of seroconverters with overt toxoplasmo-
sis.334 For neonatal diagnosis of congenital toxoplasmosis, IgE was less
sensitive than IgM and IgA, but simultaneous measurement of the
three immunoglobulins at birth improved the diagnostic yield to
81%.334 Emergence of specific IgE during postnatal treatment for con-
genital toxoplasmosis may indicate poor adherence or inadequate
dosing.
Polymerase Chain Reaction
PCR amplification for the detection of T. gondii DNA in body fluids
and tissues has successfully diagnosed congenital,279,335 ocular,178,179
pulmonary,176 cerebral, and disseminated toxoplasmosis.336,337 PCR of
amniotic fluid has revolutionized the diagnosis of intrauterine T. gondii
infection by enabling an early diagnosis to be made, thereby avoiding
the use of invasive procedures on the fetus.8,335 PCR has also been suc-
cessfully used on samples of CSF, blood, urine, and placental and fetal
tissues for diagnosis of congenital infection.8,338-341 The sensitivity of
PCR in CSF varies between 11% and 77%, whereas the specificity is
close to 100%.336 PCR may also detect the parasite in buffy coat speci-
mens of AIDS patients with TE.337 The sensitivity of PCR on whole
blood or buffy coat ranges from 15% to 85%. PCR on blood appears
to be a valuable tool primarily in patients with disseminated disease;
it is less sensitive in the detection of TE because a relatively low per-
centage of AIDS patients with TE have parasitemia.342,343 Therapy for
toxoplasmosis appears to influence the sensitivity of the method; sen-
sitivity is higher in CSF or blood samples collected before or within
the first week of therapy.337 In a recent case report, quantitative real-
time PCR proved useful for the diagnosis and monitoring of Toxo-
plasma infection in a heart transplant recipient who developed
toxoplasmosis after TMP-SMX for PCP prophylaxis had been stopped.
Decreasing parasitic burdens in sequential samples of cerebrospinal
fluid, blood, and BAL fluid correlated with a favorable outcome and
allowed modulation of the immunosuppressive drug regimen in this
patient.344 Peripheral blood PCR has also been found to be positive in
immunocompetent patients in Brazil who present with symptomatic
ocular toxoplasmosis as a result of reactivation of an infection acquired
in the distant past.345 It is unclear whether these findings only apply to
patients in this area of the world, where atypical and more virulent
strains are common in contrast to Europe and the United States.
Because there is no standardized PCR assay, performance charac-
teristics will vary widely depending on the laboratory, gene target,
primers, and sample preparation.346 Primers targeting multicopy B1 or
AF146527 (also known as the 529-bp repeat element) genes appear to
be the most sensitive and are the most broadly used.346-348 A number
of investigators have reported a higher sensitivity of the 529-bp target
for the prenatal diagnosis of congenital toxoplasmosis when compared
with the B1 gene.349 For maximal reliability, clinical samples should
be sent to reference laboratories experienced in performing this
assay.340,350
A retrospective analysis of French laboratories performing routine
surveillance on blood from HSCT patients using PCR for the AF146527
gene found that 23 of 1220 blood samples (1.9%) were positive, a lower
figure than other series.350a Fifteen patients were not receiving TMP-
SMX prophylaxis and were treated for toxoplasmosis. The other
eight were simply continued on TMP-SMX prophylaxis. No clinical
signs of toxoplasmosis resulted. This and other studies suggest that
a PCR-based pre-emptive strategy is useful in the earlier diagnosis
and treatment of Toxoplasma infection, before patients develop organ
involvement.232,350b
Histologic Diagnosis
Demonstration of tachyzoites in tissue sections or smears of body fluid
(e.g., CSF, amniotic fluid, or BAL) establishes the diagnosis of acute
infection or reactivation of a latent infection.8 It is often difficult to
demonstrate tachyzoites in stained tissue sections. Multiple tissue cysts
near an inflammatory necrotic lesion can be considered as diagnostic
of acute infection or reactivation of a latent infection.351 Fluorescent
antibody staining may be useful, but this method often yields nonspe-
cific results.352 The immunoperoxidase technique, which uses antisera
to T. gondii, has proved both sensitive and specific; it has been used
successfully in clinical settings to demonstrate the organisms in the
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3139
29
CNS of patients with TE. Both the fluorescent antibody and immu-
noperoxidase methods are applicable to unfixed or formalin-fixed
paraffin-embedded tissue sections.29 Fluorescein-labeled monoclonal
antibodies to T. gondii for staining touch preparations of specimens353
Chapter 280  Toxoplasma gondii
and rapid electron microscopy354 have been used successfully to diag-
nose TE.
A rapid, technically simple, but underused method is the detection
of T. gondii in air-dried, Wright-Giemsa–stained slides of centrifuged
(e.g., cytocentrifuged) sediment of CSF or of brain aspirate or in
impression smears of biopsy tissue.
Endomyocardial biopsy has been used successfully to diagnose
toxoplasmosis in heart transplant recipients.355 Characteristic histo-
logic criteria alone are probably sufficient to establish the diagnosis
of TL in older children and adults (see “Lymph Node” under
“Pathology”).163
Isolation of Toxoplasma gondii
Although largely replaced by use of PCR, isolation of T. gondii from
blood or body fluids can also be used to establish that the infection is
acute. In neonates, isolation of the organism from the placenta is highly
suggestive of fetal involvement, and isolation from fetal tissues is diag-
nostic of congenital infection.8 Attempts at isolation of the parasite can
be performed by mouse inoculation or inoculation of tissue cell cul-
tures.8 In tissue cell cultures, parasite-laden cells can be demonstrated
with appropriate staining, and plaques are formed in which tachyzoites
are easily recognized. Tissue cell culture has the advantage of wide-
spread availability (e.g., virology laboratories) and yields results more
rapidly (within 3 to 6 days) than does mouse inoculation.
Radiologic Methods
Radiologic studies are of particular help in patients with toxoplasmosis
of the CNS. The presence of calcifications in the brain of a newborn,
detected by radiography, ultrasonography, or CT, should heighten the
suspicion of T. gondii as the cause of the disease (Fig. 280-6A). In
severely affected infants with congenital toxoplasmosis, unilateral or,
more often, bilateral and symmetrical dilatation of the ventricles is a
common finding.8
In the majority of immunodeficient patients with TE, CT scans
show multiple bilateral cerebral lesions.356 Although multiple lesions
are more common in toxoplasmosis, they also may be solitary; a single
lesion should not exclude TE as a diagnostic possibility. Clinicians
should be aware that toxoplasmosis may manifest as an encephalitis
that at autopsy is “diffuse,” in which case, the neuroimaging study
results may appear normal or reveal findings suggestive of HIV
encephalopathy.174
CT scans in AIDS patients with TE reveal multiple ring-enhancing
lesions in 70% to 80% of the cases.236 In AIDS patients who are not
receiving appropriate ART or anti-Toxoplasma prophylaxis but have
detectable Toxoplasma IgG and multiple ring-enhancing lesions seen
on CT or MRI, the predictive value for TE is approximately 80%.357
Lesions tend to occur at the corticomedullary junction (frequently
involving the basal ganglia) and are characteristically hypodense.358,359
The number of lesions is frequently underestimated by CT, although
delayed imaging after a double dose of intravenous (IV) contrast mate-
rial may improve the sensitivity of this modality.358-360 An enlarging
hypodense lesion that does not enhance is a poor prognostic sign.361
TE lesions on MRI studies appear as high-signal abnormalities on
T2-weighted studies and reveal a rim of enhancement surrounding the
edema on T1-weighted contrast-enhanced images (see Fig. 280-6B and
C). MRI has superior sensitivity compared with CT, particularly if
gadolinium is used for contrast, and often demonstrates a lesion or
lesions or more extensive disease not seen by CT.360,362 Hence, MRI
should be used as the initial procedure when feasible (or if a single
lesion is demonstrated by CT). Nevertheless, even characteristic lesions
on CT or MRI studies are not pathognomonic of TE. The major dif-
ferential diagnosis of focal CNS lesions in AIDS patients is CNS lym-
phoma, which may manifest with multiple enhancing lesions in 40%
of cases. The probability of TE falls and the probability of lymphoma
rises in the presence of single lesions on MRI.356 A brain biopsy may
therefore be required in the patient with a solitary lesion, especially if
confirmed by MRI, to obtain a definitive diagnosis.363 In non-AIDS
Part III  Infectious Diseases and Their Etiologic Agents 3140

C
FIGURE 280-6  Imaging studies of central nervous system toxoplasmosis. A, Computed tomography (CT) scan of an infant born with congenital
toxoplasmosis, illustrating the calcifications and hydrocephalus that are typically seen in the brain. B, CT scan with contrast enhancement (left) and
T2-weighted magnetic resonance imaging (MRI) scan (right) of an acquired immumodeficiency syndrome (AIDS) patient with toxoplasmic encephalitis,
demonstrating multiple lesions, which are more easily identified in the MRI scan. C, T1-weighted MRI scan without (left) and with (right) contrast enhance-
ment, of an AIDS patient with toxoplasmic encephalitis. Note the ring-enhancing lesion on the right.

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immunocompromised patients, TE can also present as single or mul-
tiple ring-enhancing lesions. However, additional etiologies, including
invasive fungal, nocardial, and mycobacterial infections, are more
common in these patients with this radiologic presentation than in
AIDS patients. Early brain biopsy and empirical treatment with a wider
antimicrobial spectrum is usually required in non-AIDS immunocom-
promised patients with multiple space-occupying brain lesions.
In AIDS patients with TE, CT-scan improvement is seen in up to
90% of patients after 2 to 3 weeks of treatment.356,358 Complete resolu-
tion takes from 6 weeks to 12 months; peripheral lesions resolve more
rapidly than deeper ones. Smaller lesions usually resolve completely on
MRI studies within 3 to 5 weeks, but lesions with a mass effect tend to
resolve more slowly and leave a small residual lesion.364 A radiologic
response to therapy lags behind the clinical response, with better cor-
relation between them observed by the end of acute therapy.365
CT and MRI in toxoplasmic myelopathy usually demonstrates
localized enlargement of the spinal cord,239,366 which may result in
obstruction to dye flow on myelography.239 Gadolinium enhancement
of MRI studies usually highlights as an intramedullary lesion at the site
of spinal cord enlargement.366
A variety of positron-emission tomography (PET) scanning,367
radionuclide scanning,368 and MRI techniques369 have been used
to evaluate AIDS patients with focal CNS lesions, specifically to differ-
entiate between toxoplasmosis and primary CNS lymphoma.369
18
F-fluorodeoxyglucose PET scanning is now widely used in the evalu-
ation of patients with tumors. There is a significantly higher uptake of
18
F-fluorodeoxyglucose in patients with cerebral lymphoma than in
patients with TE.370 Radionuclide scanning has also been used to dif-
ferentiate between CNS toxoplasmosis and lymphoma. Neoplasms
usually demonstrate increased uptake of thallium-201 on both early and
late scanning.369 Although published studies suggest a high sensitivity
and specificity of these studies, in practice they often are not helpful, in
part because of variability in uptake and in part because they are often
used after an empirical trial of anti-Toxoplasma therapy. Thallium scans
may have decreased diagnostic utility in the setting of ART.371
Proton magnetic resonance spectroscopy to evaluate brain lesions
has been used in a few patients. Magnetic resonance spectroscopy in
patients with TE reveals an elevation in the lactate and lipid contents369
and a decrease in the levels of choline. In contrast, MR spectroscopy
in patients with CNS lymphoma reveals mildly elevated levels of
choline.369
Cerebrospinal Fluid Abnormalities
CSF abnormalities in patients with TE are nonspecific; mild mono-
nuclear pleocytosis and mild to moderate elevations in CSF protein are
often observed, and hypoglycorrhachia is uncommon.198,372 Almost
unique to infants with neonatal toxoplasmosis, however, is the very
high protein content of the ventricular fluid and eosinophilia. Although,
in some infants, the protein level is just slightly above normal, in others
it can be measured in grams per deciliter rather than in milligrams per
deciliter.8 Demonstration of intrathecal production of T. gondii–specific
IgG or IgM in the absence of CSF contamination with blood is diag-
nostic of TE.373,374
Diagnosis of Specific Clinical Entities
The initial step in pursuing the diagnosis of T. gondii infection or
toxoplasmosis is to determine whether the patient has been exposed
to the parasite. In virtually all cases, tests for IgG antibodies reliably
establish the presence or absence of the infection; a negative IgG test
essentially rules out prior or recent exposure to the parasite. However,
clinicians should be aware that IgG antibodies may be absent in immu-
nocompetent patients who have been tested within the first 2 weeks of
the acute infection, in patients with severe immunodeficiencies involv-
ing defective production of IgG antibodies, and in BMT patients
despite having had detectable IgG antibodies in the pretransplantation
period. Because of the higher sensitivity of the IgG DT, on occasion,
IgG antibodies are initially negative in commercially available kits but
positive in the IgG DT (see “Serologic Tests for Demonstration of
Antibody”). In addition, cases of documented toxoplasmic chorioreti-
nitis and TE in adult patients have been observed in which IgG anti-
bodies were not demonstrable; such cases are very uncommon.
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3141
In the presence of clinical illness, it is important to establish whether
the patient’s symptoms are due to a recently acquired infection or to
recrudescence of latent infection (chronic infection) or are unrelated
to the infection. A true negative IgM test in an otherwise immunologi-
Chapter 280  Toxoplasma gondii
cally normal individual essentially rules out that the infection has been
acquired in recent months. A positive IgM test is more difficult to
interpret correctly. One must not assume that a positive IgM test result
is diagnostic of recently acquired infection. The presence of T. gondii–
specific IgM antibodies can be interpreted as a true-positive result
consistent with recently acquired infection, a true-positive result con-
sistent with a chronic infection (IgM antibodies have been shown to
persist in some individuals for as long as several years after the acute
infection), or a false-positive result. To establish which of these is most
likely in a given case, confirmatory testing in a reference laboratory
should be performed whenever feasible.316,318
The use of a combination or battery of tests has been useful for
determining whether the patient has been recently infected or infected
in the more distant past.210,299 If the patient has received a blood
transfusion, serologic tests may measure exogenously administered
rather than endogenous antibody. The use of serologic tests to evalu-
ate the response to therapy should be discouraged. The PAMF-TSL
currently serves as a reference laboratory. Physicians in the PAMF-
TSL also offer interpretation of test results and consultation on treat-
ment and patient management to clinicians in the United States and
worldwide.
Toxoplasmosis in the
Immunocompetent Patient
Tests for IgG and IgM antibodies should be used for initial evaluation
of immunocompetent patients. Testing of serial specimens obtained 3
weeks apart (in parallel) provides the best discriminatory power if the
results in the initial specimen are equivocal. Negative results in both
of these tests virtually rules out the diagnosis of toxoplasmosis. Early
in infection, IgG antibodies may not be detectable, whereas IgM anti-
bodies are present, hence the need for both tests to be performed.
Acute infection is supported by documented seroconversion of IgG or
IgM antibodies or a greater than two-tube rise in antibody titer in sera
run in parallel. A single high titer of any immunoglobulin antibodies
is insufficient to make the diagnosis; IgG antibodies may persist at high
titers for many years,8 and IgM antibodies may be detectable for more
than 12 months. When only a single serum sample is available, a
battery or combination of tests is usually required in determining the
likelihood that the infection is acute.
Toxoplasmosis should be considered in the differential diagnosis of
lymphadenopathy, whether or not symptoms are present and especially
in those without symptoms. Confirmatory serologic tests should be
obtained in such patients. The interval between the clinical onset of
lymphadenopathy and the date that the specimen is drawn is critical
for interpretation of the test results.210 In patients whose serum is
available during the first 3 months after the clinical onset, at least
the IgG test and the IgM-ELISA are positive. In those patients in
whom sera are obtained more than 3 months after the clinical onset,
the IgM-ELISA is most likely to be negative, but the IgG test and at
least one of the following tests are positive: IgA-ELISA, IgE-ELISA,
IgE-ISAGA, or AC/HS test.210 A high IgG avidity test result in an
individual who has recent onset of lymphadenopathy (e.g., within 2 to
3 months of sera sampling) suggests a cause other than toxoplasmo-
sis,309 and further workup is warranted. A nonacute AC/HS pattern
in an individual at less than 12 months after clinical onset of lymph-
adenopathy should suggest an etiology other than TL. In such cases,
investigation for alternative causes, including malignancy, should be
undertaken.309
Histologic diagnosis can be useful in some cases of suspected toxo-
plasmosis in the immunocompetent patient. The histologic criteria for
the diagnosis of TL has been well established (see Fig. 280-3A) (see
“Histologic Diagnosis”).163 In this setting, there is no need to visualize
the parasite. Endomyocardial biopsy and biopsy of skeletal muscle have
been successfully used to establish T. gondii as the etiologic agent of
myocarditis and polymyositis in rare cases in immunocompetent
patients.164 Isolation studies and PCR have rarely proved useful in
immunocompetent patients.
 3142
Toxoplasmosis in the   tissue cyst may only reflect chronic infection unless it is associated with
Immunodeficient Patient
Because reactivation of chronic infection is the most common cause
of toxoplasmosis in patients with AIDS, malignancies, or organ trans-
Part III  Infectious Diseases and Their Etiologic Agents
plants, initial assessment of these patients should routinely include an
assay for T. gondii IgG antibodies. IgG antibody testing should be
ideally performed as soon as it is established that the patient is immu-
nocompromised or is about to be immunosuppressed. Those with a
positive result are at risk of reactivation of the infection; those with a
negative result should be instructed on how they can prevent becoming
infected (see “Prevention”). Those at highest risk (e.g., HIV-infected
patients not receiving appropriate ART or anti-Toxoplasma prophy-
laxis) who are initially seronegative should be retested on an annual
basis to determine whether they have seroconverted. Sero­negative
organ transplant recipients should be identified before transplantation
because they will be at risk for infection if a seropositive donor who
can potentially transmit the parasite via the allograft is selected. In this
setting, administration of anti-Toxoplasma prophylaxis in the post-
transplantation period can avoid unnecessary morbidity and
mortality.81
In patients with AIDS and toxoplasmosis, the IgG titer may be
relatively low, and tests for IgM, IgA, and IgE antibodies are usually
negative.236
In the early postoperative period in heart transplant recipients with
pretransplantation Toxoplasma antibodies who present with a clinical
illness, serologic test results may be misleading.221,355 In these patients,
results indicating apparent reactivation (a rising IgG and IgM titer)
may be present in the absence of clinically apparent infection. In addi-
tion, serologic test results consistent with chronic infection may be
seen in the presence of toxoplasmosis.221,355 In heart transplant recipi-
ents in whom toxoplasmosis is suspected as a cause of altered myocar-
dial function, endomyocardial biopsy has proved useful.355 The parasite
has been demonstrated in the myocardium of patients in whom the
biopsy was performed because of a suspicion of rejection.355 PCR
testing of peripheral blood, BAL, CSF, vitreous fluid, and other body
fluids or tissues may prove to be useful in patients with solid-organ
transplants who are suspected to have toxoplasmosis.
Diagnosis in the bone marrow transplant recipient often requires
special consideration. It is critical in all BMT patients that a serum IgG
titer be performed before the transplantation. Toxoplasmosis in these
patients is almost always due to recrudescence of a latent infection.
After BMT, the preexisting IgG antibody titer may rise, remain stable,
decrease, or become negative. Thus, post-transplantation serology fre-
quently is not helpful in this group of patients and emphasizes the
need for knowing the patients’ pretransplantation serologic status.
Clinical evidence of encephalitis, pneumonia, fever, brain lesions, or
any other unexplained syndrome in BMT patients with preexisting T.
gondii IgG antibodies must include toxoplasmosis in the differential
diagnosis. The ultimate diagnosis of toxoplasmosis in these patients
requires the use of histologic, PCR, or isolation methods to detect the
presence of the parasite. In patients with allogeneic HSCT who are IgG
antibody test positive for T. gondii before transplantation, routine PCR
testing of peripheral blood specimens in the post-transplantation
period has been proposed as an appropriate tool for guiding preemp-
tive therapy. In one report of 106 patients, toxoplasmosis developed
in 38% of those who were PCR positive versus 0% in those who were
PCR negative.232 In later studies, however, a first positive PCR was seen
only at the time of presentation with clinical symptoms or subsequent
to that.350b,375
Serologic tests in patients with hypoglobulinemia or agammaglob-
ulinemia may not be useful to diagnose toxoplasmosis; active infection
can occur in these patients in the setting of negative IgG titers.
A definitive diagnosis of toxoplasmosis in the immunodeficient
patient relies on histologic demonstration of the parasite (usually in
association with an inflammatory process), on detection of T. gondii
DNA by PCR, or on isolation of the parasite. PCR or attempts to isolate
the parasite can be performed in essentially any body fluid or tissue
that is clinically affected; peripheral blood testing by PCR (and in some
instances for isolation) should be considered in immunocompromised
patients suspected to have toxoplasmosis. The presence of tachyzoites
is diagnostic of active infection. The presence of a solitary T. gondii
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an area of inflammation (e.g., as seen in myocardial biopsy); however,
visualization of several tissue cysts virtually always means that active
infection is present.
When clinical signs suggest involvement of the CNS or spinal cord,
the workup should include CT or MRI (see “Radiologic Methods”) of
the brain. These studies should be performed even if the neurologic
examination does not reveal focal deficits.
A lumbar puncture should be performed if it can be done safely,
ideally before or soon after initiation of therapy; PCR can then
be performed on the CSF specimen. A positive Toxoplasma PCR essen-
tially confirms the diagnosis of TE. CSF can also be sent for isolation
studies if available. PCR examination of the CSF also can be used for
the detection of Epstein-Barr virus, JC virus, or CMV DNA in patients
in whom primary CNS lymphoma, progressive multifocal leukoen-
cephalopathy, or CMV ventriculitis, respectively, have been entertained
in the differential diagnosis. Especially in HIV-infected patients, a posi-
tive Epstein-Barr virus PCR in the setting of a focal contrast-enhancing
CNS lesion is strongly suggestive of CNS lymphoma.377 Demonstration
of the intrathecal production of T. gondii–specific antibody within the
CSF may help confirm the diagnosis of TE.374 Unless sufficient CSF is
available, we suggest that the highest priority be for PCR and an attempt
at isolation of the parasite. Detection of T. gondii–specific IgM has a
very low yield and is not recommended.
Empirical anti–T. gondii therapy for patients with multiple ring-
enhancing brain lesions (usually established by MRI), positive IgG
antibody titers against T. gondii, and AIDS (e.g., patients with a CD4
count of <200 cells/mm3) is accepted practice; a clinical and radiologic
response to specific anti–T. gondii therapy essentially confirms the
diagnosis of TE (Fig. 280-7). Use of adjunctive corticosteroids to
decrease cerebral edema can cause temporary clinical improvement
that is incorrectly attributed to the pyrimethamine and sulfa. This
empirical approach is not recommended for non-AIDS immunocom-
promised patients with this presentation because the differential diag-
nosis is wider and often includes other etiologic agents, such as invasive
molds, nocardia, bacterial brain abscess, and mycobacteria. In these
patients, an early brain biopsy is recommended. Brain biopsy should
be considered in AIDS patients with presumed TE if there is a single
lesion on MRI, a negative IgG antibody test, an inadequate clinical
response (within a 2- to 3-week period) or progression during optimal
therapy, or in patients whom the physician considers to have adhered
to an effective prophylactic regimen against T. gondii (e.g., TMP-SMX).
An impression smear of the brain biopsy specimen can be made and
immediately examined for the presence of tachyzoites by using the
conventional Wright-Giemsa stain used for blood smears in most labo-
ratories. The brain specimen should then be submitted to the pathol-
ogy and microbiology departments for appropriate workup. In addition
to hematoxylin and eosin staining, T. gondii–specific immunoperoxi-
dase staining should be performed. Because the amount of brain tissue
obtained at aspiration or biopsy is usually small, sufficient tissue for
mouse inoculation may not be available; however, this should be per-
formed whenever feasible. A positive result may often be obtained with
far less than 1 g of brain tissue. PCR has been used successfully in brain
tissue to diagnose TE,378 but a positive result should be interpreted with
caution because it may not distinguish between the patient with TE
from one with latent infection (asymptomatic carrier of brain tissue
cysts) who has CNS pathology resulting from a process other than
toxoplasmosis.
In the appropriate clinical setting, it is important to include toxo-
plasmosis in the differential diagnosis of pulmonary symptoms, par-
ticularly in those individuals with interstitial infiltrates or ground-glass
opacities. Wright-Giemsa staining and PCR of BAL specimens are
useful for the diagnosis of pulmonary toxoplasmosis.176,379
In patients with visual symptoms in whom toxoplasmic chorioreti-
nitis is a possibility, PCR examination of vitreous or aqueous fluid can
be considered and is particularly helpful in patients with atypical clini-
cal features of toxoplasmic chorioretinitis and in immunocompro-
mised patients.179,266,380 Of note, PCR examination of the vitreous fluid
can also be helpful when other etiologic agents, such as herpes simplex
virus, varicella-zoster virus, or CMV, are considered in the differential
diagnosis.
 3143
CNS signs/symptoms in HIV-positive patients

Chapter 280  Toxoplasma gondii

Unknown Toxoplasma lgG antibody Negative Diagnosis of TE
unlikely

Positive
Request serology and proceed
with algorithm that favors
empirical treatment until
results are known
CT/MRI with
contrast (MRI
preferable)

No lesions
Single lesion (if CT is negative,
MRI is advised) Workup for causes
other than TE.
MRI if CT was Multiple lesions Repeat MRI in 42-78
If MRI not
initially performed on CT/MRI hours if all
available
investigations negative.

Single lesion Multiple lesions

Long list of possibilities if other Presumptive diagnosis

symptoms, signs, or laboratory Improved of TE. Continue
investigations are unrevealing Brain biopsy Treat empirically clinically treatment for 3-6
not available for TE by 7 days weeks, followed by
maintenance therapy.

Consider lumbar puncture (if the risk No improvement

for herniation is judged to be low) clinically by 10-14 days
PCR for: or clinical deterioration by day 3
T. gondii
Epstein-Barr virus
JC virus
Cytology
Consider brain biopsy
Isolation, PCR
Histopathology Definitive diagnosis
Immunoperoxidase
AFB, Giemsa, Gram stains

FIGURE 280-7  Diagnostic approach and management algorithm for human immunodeficiency virus (HIV)-infected patients with central
nervous system (CNS) symptoms or signs that might potentially be toxoplasmic encephalitis (TE). AFB, acid-fast bacilli; CT, computed tomog-
raphy; IgG, immunoglobulin G; MRI, magnetic resonance imaging; PCR, polymerase chain reaction.

The intraocular production of T. gondii–specific IgG antibodies has
also been reported to be diagnostically useful.381 Local antibody pro-
duction in aqueous humor can be quantified by calculating the
Goldmann-Witmer (GW) coefficient. The GW coefficient expresses
the level of Toxoplasma-specific IgG relative to the level of total IgG in
the aqueous humor as a fraction of the level of Toxoplasma-specific
IgG relative to the level of the total IgG in the serum.382 The GW coef-
ficient = Toxoplasma IgG/total IgG in aqueous humor ÷ Toxoplasma
IgG/total IgG in serum. A coefficient greater than 2 is considered posi-
tive and diagnostic of ocular toxoplasmosis. It has been well established
that, in contrast to ocular viral infections, the GW coefficient is a more
sensitive method than PCR for the diagnosis of ocular toxoplasmosis.
However, PCR in vitreous fluid appears to be superior to the GW coef-
ficient in immunocompromised patients, the elderly, and those with
atypical lesions and extensive retinochoroiditis.
PCR and isolation studies in peripheral blood can help establish T.
gondii as the etiologic agent of a febrile syndrome or systemic symp-
toms of unclear cause.337,383 These studies tend to have a higher yield
early in the disease and before or shortly after specific anti–T. gondii
therapy is initiated.337
In pursuing the diagnosis, histologic examination with the appro-
priate stains and mouse inoculation can be attempted in virtually any
tissue suspected of being involved by T. gondii. Body fluids that should
be considered for examination by PCR include CSF, blood, vitreous,
aqueous, and BAL specimens. Reference laboratories should be con-
tacted before diagnostic procedures to optimize the handling of the
specimens and their yield.
Ocular Toxoplasmosis
In patients with active chorioretinitis caused by reactivation of con-
genital T. gondii infection, low titers of IgG antibody are usual and IgM
antibodies are not usually detected. In contrast, in patients with cho-
rioretinitis as a result of an acute infection, IgG and IgM antibodies
will be detected. Positive IgM test results should always be confirmed
at a reference laboratory.382
In most cases, toxoplasmic chorioretinitis is diagnosed by oph-
thalmologic examination, and empirical therapy directed against the
organism is often instituted based on clinical findings and serologic
test results. In a number of patients, the morphology of the retinal
lesion or lesions may be nondiagnostic, or the response to treatment

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 3144
may be suboptimal, or both. In such cases (unclear clinical diagnosis
or inadequate clinical response, or both), the detection of an abnor-
mal T. gondii–antibody response in ocular fluids (Goldman-Witmer
coefficient),380,384 or demonstration of the parasite by isolation, histo-
Part III  Infectious Diseases and Their Etiologic Agents
pathologic examination, or PCR have been used successfully to estab-
lish the diagnosis.382,385 PCR has been used in both vitreous and
aqueous fluids in an attempt to support or confirm the diagnosis of T.
gondii as the cause of the retinal lesions.178,179,266,380 In patients in
whom toxoplas­mosis is considered in the differential diagnosis but in
whom the presentation is atypical, PCR is a useful diagnostic aid.
Vitreous biopsy is a potentially hazardous procedure, and its use
should be considered only when other diagnostic measures have not
revealed a cause.
Toxoplasma gondii Infection in Pregnancy
Acute acquired T. gondii infection is diagnosed serologically by the
same methods used for immunocompetent adults discussed earlier
(Fig. 280-8).319 Special care is taken to determine whether the infection
was acquired before or after conception. This determination is fre-
quently difficult because routine serologic screening is not conducted
in pregnant women in the United States.
The diagnosis of acute T. gondii infection or toxoplasmosis ideally
requires demonstration of a rise in titers in serial serum samples (either
conversion from a negative to a positive titer or a fourfold rise from a
low to a higher titer).8 These specimens should be obtained at least 3
weeks apart and be tested in parallel. Because the diagnosis is fre-
quently considered relatively late in the course of the patient’s preg-
nancy, serologic test titers may already have reached their peak at the
time the first serum is obtained for testing. Therefore, it is often difficult
to discriminate between infections acquired recently (possibly during
pregnancy) and those acquired in the more distant past, when the only
available serum sample has been obtained in the third trimester of the
pregnancy. Thus, the initial serum should be obtained as early as pos-
sible during gestation.
Initial screening of maternal serum involves testing for IgG and
IgM antibodies; a lack of both immunoglobulin antibodies essentially
excludes active infection but identifies the patient as being at risk for
acquisition of the infection and hence in need of instruction about
primary prevention. The presence of IgG antibodies in the absence of
IgM antibodies in the first two trimesters almost always indicates
chronic maternal infection with essentially no risk to the fetus (the
exceptions are severely immunodeficient patients). In the third trimes-
ter, a negative IgM test titer is most likely consistent with a chronic
maternal infection but does not exclude the possibility of an acute
infection acquired early in pregnancy; this is especially true in those
patients who exhibit a rapid decline in their IgM titers during the acute
infection. In these cases, the use of other serologic tests (e.g., IgA, IgE,
AC/HS, avidity) may be of particular help.
A positive IgM test result requires further assessment with confir-
matory testing at a reference laboratory (see also “Diagnosis of Specific
Clinical Entities”).299,316,318,319 The use of confirmatory testing with a
combination of serologic tests in a reference laboratory has proved
helpful in discriminating between recently and more distantly acquired
infections, and having an expert interpret the results to the patient’s
physician has been shown to reduce unnecessary induced abortions
among pregnant women reported to have IgM antibodies.299 Women
who are informed that they have a positive IgM test titer and that it
signifies that their offspring will or might be infected often choose
abortion. Unfortunately, a positive IgM test may not necessarily indi-
cate infection acquired during gestation (a false-positive result or per-
sistence of a IgM-positive result in the chronic stage of the infection),
and thus, the abortion may not be indicated. It is for this reason that
confirmatory testing in a reference laboratory has been recommended
by many experts and by the FDA.318
A number of tests for avidity of Toxoplasma IgG antibodies
have been introduced to help differentiate between recently acquired
and distant infection.310,311,386 Studies of the kinetics of the avidity of
IgG in pregnant women who have seroconverted during gestation
have shown that women with high-avidity test results have been
infected with T. gondii for at least 3 to 5 months. Recently, it has been
demonstrated that, when used as a confirmatory test, along with a
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battery of other tests, in women in their first 16 weeks of gestation,
detection of high-avidity IgG antibodies by the IgG-VIDAS avidity
test, for example, can be a useful addition to the discriminatory
power of a combination of tests in distinguishing recently acquired
from chronic infection.296,300,314 It is critical to recognize that the value
of the avidity test is in the first 3 to 5 months of gestation (i.e., the
fetus of a woman in the 14th week of gestation with a positive IgM
test and a high-avidity result is not at risk for congenital toxoplasmo-
sis).300 Because low or equivocal avidity test results may persist for
many months, their presence does not necessarily indicate recently
acquired infection.
Confirmatory testing, using a battery of tests and the VIDAS avidity
method in pregnant women during their first 24 weeks of gestation,
has the potential to decrease the need for follow-up sera and thereby
reduce costs, to make the need for PCR on amniotic fluid and for treat-
ment of the mother with spiramycin unnecessary, to remove the preg-
nant woman’s anxiety associated with further testing, and to decrease
unnecessary abortions.298-300 Although the avidity test represents an
additional confirmatory method (most useful if high-avidity antibod-
ies are detected within the first 16 weeks of gestation), it should not be
used as the only confirmatory test for pregnant women with positive
IgG and/or IgM antibodies because of the potential to misinterpret
low- or borderline-avidity antibody results.
Once the diagnosis of acute acquired infection during pregnancy
has been presumptively established, diagnostic efforts should focus on
determining whether the fetus has been infected.
Congenital Infection in the Fetus  
and Newborn
Prenatal diagnosis of fetal infection is advised when a diagnosis of
acute infection is established or highly suspected in a pregnant woman.
Methods to obtain fetal blood, such as periumbilical fetal blood sam-
pling, have been largely abandoned because of the rate of false-negative
prenatal diagnoses, the risk involved for the fetus, and the delay in
obtaining definitive results with conventional parasitologic tests.279
Prenatal diagnosis of congenital toxoplasmosis is presently based
on ultrasonography and amniocentesis. PCR on amniotic fluid for the
detection of T. gondii–specific DNA performed at 18 weeks of gesta-
tion or later is more sensitive, more rapid, and safer than conventional
diagnostic procedures involving fetal blood sampling.279,387 Amniotic
fluid should be tested by PCR in all cases, with serologic test results
diagnostic of or highly suggestive of acute acquired infection during
pregnancy, and also if there is evidence of fetal damage by ultrasound
examination (e.g., hydrocephalus and/or calcifications). In a prospec-
tive cohort study conducted in France, amniotic fluid PCR was per-
formed in 261 women who had been identified as having an acute
infection during gestation through routine prenatal screening for
toxoplasmosis.387 Overall sensitivity and negative predictive value of
the amniotic fluid PCR for the diagnosis of congenital infection were
92.2% (95% CI, 81% to 98%) and 98.1% (95% CI, 95% to 99.5%),
respectively. Specificity and the positive predictive value were 100%.387
Overall sensitivity has been reported by several groups as varying
from 65% to 92.2%; specificity and the positive predictive value have
been reported to be 100% by most groups.346,388 Recently, one group
proposed a novel and more realistic interpretation of amniotic fluid
PCR test results according to the pretest probability of infection and
gestational age at the time of maternal infection388; their analysis
revealed that negative test results are more significant than previously
thought, given that transmission only occurs in a percentage of women
at various stages of gestation and that a negative amniotic fluid PCR
further reduces this percentage. Of note, the vast majority of their
pregnant women, as is the case for all studies reported from Western
Europe, received the benefit of prenatal treatment. Thus, caution
should be exercised when attempting to apply risks of congenital
infection to infants born to women who were not treated during gesta-
tion. The preferable time for amniocentesis is at 18 weeks of gestation
or later if acute infection was acquired after 18 weeks. The sensitivity
of the amniotic fluid PCR test appears to be lower when the amnio-
centesis is performed before 18 weeks of gestation279 and should be
avoided before 18 weeks for the purpose of diagnosing congenital
toxoplasmosis.
 3145

• Routine serologic screening is recommended during pregnancy, regardless of

epidemiologic history or presence of illness during gestation1
• In addition, serologic testing should be performed during pregnancy in the presence of:

Chapter 280  Toxoplasma gondii

o Flulike or unexplained illness
o Lymphadenopathy
o Fetal ultrasound suggestive of congenital infection

Toxoplasma IgG and IgM

Can be performed at nonreference, hospital-based, or
commercial laboratory

IgG neg IgG pos IgM pos or equivocal. Send serum

IgM neg IgM neg to a reference laboratory for
confirmatory testing.4

No serologic evidence • If <18 weeks’ gestation If seroconversion documented or

of Toxoplasma Infection acquired in the reference laboratory confirms acute
infection. Risk of C.T. distant past and before infection acquired during pregnancy:
only if woman gestation. Risk for C.T. 1. Treatment 5 should be promptly
acquires infection essentially zero unless instituted: (a) spiramycin6 if infection
during pregnancy. patient is acquired before 18 weeks’
Counseling should be immunocompromised. gestation or (b) pyrimethamine7 plus
provided on how to • If >18 weeks’ gestation sulfadiazine plus folinic acid 8 if
avoid primary T. It is difficult to establish acquired at or after 18 weeks
gondii infection (see whether infection occurred 2. If safe and feasible, amniotic fluid
Table 280-4). during or before pregnancy obtained at 18 weeks or onward
should be tested for Toxoplasma PCR
3. Fetal ultrasound should be
obtained for the detection of
abnormalities suggestive of C.T.
Follow-up testing 4. Switch spiramycin to
during gestation to • If <18 weeks’ gestation pyrimethamine plus sulfadiazine plus
detect seroconversion2 No further action required folinic acid if amniotic fluid PCR is
• If >18 weeks’ gestation positive or ultrasound is abnormal
Attempt to obtain earlier 5. Consider testing close household
serum for testing or results contacts for the diagnosis of acute
of previous Toxoplasma Toxoplasma infection or
serologic tests obtained toxoplasmosis in individuals at high
before current pregnancy3 risk
If seroconversion and consult reference
detected (i.e., IgG pos, laboratory.
IgM pos), follow IgM-
pos algorithm

FIGURE 280-8  Diagnostic approach and management algorithm of toxoplasmosis during pregnancy. Most of the initial serologic screening
can be accomplished by nonreference or commercial laboratories. Only positive immunoglobulin M results should be considered for additional testing
and consultation with medical experts at a reference laboratory. C.T., congenital toxoplasmosis; IgG, immunoglobulin G; IgM, immunoglobulin M; neg,
negative test result; pos, positive test result.
1
Up to 50% of women who acquire Toxoplasma infection during gestation do not have a known risk factor for acute infection or an illness suggestive
of toxoplasmosis. Thus, to identify all women at risk, serologic screening should be performed in all pregnant women, along with other routine screening
tests.
2
In a recent study from Lyon, France, monthly screening of seronegative pregnant women was reported to significantly decrease the risk of vertical
transmission and of clinical signs at 3 years of age.476
3
Consider consultation with a physician expert in management of toxoplasmosis during pregnancy (e.g., in the United States, Palo Alto Medical
Foundation–Toxoplasma Serology Laboratory [PAMF-TSL], www.pamf.org/serology/; 650-853-4828; e-mail, toxolab@pamf.org or U.S. [Chicago] National
Collaborative Treatment Trial Study [NCCTS]; 773-834-4152).
4
Consider sending serum sample to a reference laboratory (e.g., PAMF-TSL).
5
Treatment regimens vary by country. The pyrimethamine-sulfadiazine–folinic acid regimen should not be offered to any pregnant women before 12
weeks of gestation because of potential teratogenicity. In some centers in Europe, this regimen is offered at 14 weeks of gestation or later; in the United
States, it is recommended at 18 weeks or later.
6
Spiramycin is not commercially available in the United States. It can be obtained at no cost and after consultation (with PAMF-TSL or the NCCTS through
the U.S. Food and Drug Administration.
7
When using pyrimethamine, folic acid should be discontinued from the prenatal multivitamins. Folic acid can potentially counteract the antiparasitic
effect of the drug.
8
Folic acid should not be erroneously used instead of folinic acid.

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 3146
Maternal IgG antibodies present in the newborn may reflect either
past or recent infection in the mother. For this reason, tests for the
detection of IgA and IgM antibodies are commonly used for the diag-
nosis of infection in the newborn (Fig. 280-9). It is essential that
Part III  Infectious Diseases and Their Etiologic Agents
maternal contamination of blood obtained at birth be excluded; serum
samples obtained from peripheral blood and not from the umbilical
cords are preferred. In a retrospective study of 164 untreated infants
aged 0 to 180 days, in the United States, T. gondii–specific IgM, IgA,
and IgE antibodies were demonstrable in 86.6%, 77.4%, and 40.2% of
the infants, respectively.284 Testing for IgM and IgA antibodies increased
the sensitivity of making the diagnosis of congenital toxoplasmosis to
93%, compared with testing for IgM or IgA alone. The sensitivity of
the IgM and IgA has been reported to be somewhat lower in cohorts
of treated (prenatal treatment) infants: 64% to 70% for IgM, 53% to
65% for IgA, and 66% to 81% for both.388
If IgG antibodies are detected but serologic tests for IgM and IgA
antibodies are negative and T. gondii is not isolated, follow-up sero-
logic testing in suspect cases is indicated to attempt to establish the
diagnosis. Maternally transferred antibodies usually decline and disap-
pear within 6 to 12 months.
Studies using the Western blot technique have shown that maternal
and infant sera may recognize different T. gondii antigens when the
infant is congenitally infected.389,390 Combining Western blot with
conventional serologic analysis (i.e., IgG, IgM, and IgA tests) has
been reported to be more sensitive for the diagnosis of congenital
toxoplasmosis at birth and within the first 3 months of life than either
test alone.390-392 Recently, three IgM-bands at 75, 90, and 100 kDa (also
known as the “IgM triplet”) have been reported to increase the sensitiv-
ity of the diagnosis of congenital toxoplasmosis to 95.8% when com-
bined with prenatal and serologic neonatal tests.393
Additional diagnostic methods that have been used successfully to
diagnose the infection in infants are direct demonstration of the organ-
ism by isolation in mice or cell culture (e.g., placental tissue, body
fluid) and PCR in body fluids (e.g., CSF, blood, and urine).341,394-397
Evaluation of infants with suspected congenital toxoplasmosis should
always include ophthalmologic examination, radiologic studies (par-
ticularly to detect the presence of cerebral calcifications; if feasible, CT
is preferred over ultrasound), and examination of CSF. A more detailed
discussion of diagnostic procedures in congenitally infected infants is
available in a chapter by Remington and colleagues.8
In the absence of a systematic screening program for pregnant
women, a secondary prevention program that consists of serologic
testing of all newborns for IgM antibodies against T. gondii has been
implemented in Massachusetts.398,399 Using routine screening of all
newborns, congenital infection was confirmed in approximately 1 in
12,000 infants. More than 90% of these were identified only through
neonatal screening and not through initial clinical examination.
In infants with congenital toxoplasmosis or congenital infection, a
rebound in IgG and IgM antibody titers is frequently observed after
discontinuation of therapy. In our experience, such a serologic rebound
has not been shown to be clinically significant.8
THERAPY
Currently recommended drugs against T. gondii act primarily against
the tachyzoite form and thus do not eradicate the encysted form (brady-
zoite). Pyrimethamine is considered to be the most effective anti-
Toxoplasma agent and, if feasible, should always be included in drug
regimens used against the parasite. Pyrimethamine is a folic acid antag-
onist. The most common side effect is dose-related suppression of the
bone marrow, which may be decreased by concomitant administration
of folinic acid (calcium leucovorin). It is not well established how often
a blood count should be obtained; a reasonable strategy would be to
check a peripheral blood cell and platelet count twice weekly until
hematologic parameters have stabilized in a nontoxic range, and then
every 2 to 4 weeks. Folinic acid should be administered concomitantly
to avoid bone marrow suppression. The parenteral form of folinic acid
is well absorbed orally, and 10 to 20 mg of folinic acid (up to 50 mg/
day is used in AIDS patients) may be given orally (e.g., with orange
juice at the same time as the pyrimethamine). Whereas folinic acid does
not inhibit the action of pyrimethamine on tachyzoites, folic acid does
and should not be used in patients being treated with pyrimethamine.
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Less serious side effects of pyrimethamine include gastrointestinal dis-
tress, rash, headaches, and a bad taste in the mouth.
Unless there are circumstances that preclude the use of more
than one drug, there is no role for monotherapy in the treatment of
toxoplasmosis. A second drug, such as sulfadiazine or clindamycin,
should be added. Sulfadiazine acts synergistically with pyrimethamine;
most other sulfonamides have inferior activity. The patient must
maintain a good urine output to prevent crystalluria and oliguria.
The most common side effects associated with sulfadiazine are skin
rashes, which may be life-threatening,400 and crystal-induced nephro-
toxicity.401 Worsening encephalopathy, hallucinations, or a new onset
of psychiatric symptoms in patients with AIDS may be sulfadiazine
induced and must be considered in the patient who is nonrespon-
sive to otherwise appropriate anti-Toxoplasma treatment.402 A drug
rash with sulfonamide therapy does not necessarily preclude its use
because successful desensitization protocols have been reported.403,404
Clindamycin appears to act by targeting translation in the apico-
plast of T. gondii.31 Adverse reactions to clindamycin include rash,
nausea, vomiting, and diarrhea, which may be associated with Clos-
tridium difficile infection. Myopathy with electromyographic abnor-
malities and elevated serum creatine phosphokinase levels have been
described.405
Although clinical experience with TMP-SMX is more limited, this
drug combination, which targets folate metabolism in a manner similar
to pyrimethamine plus sulfadiazine, has documented activity and can
be used in patients requiring parenteral therapy.406 Atovaquone com-
bined with pyrimethamine or sulfadiazine, or in unusual circum-
stances as a single agent, is another less-well-studied alternative for
patients who can be treated with oral therapy. The role of other drugs,
including azithromycin, clarithromycin, atovaquone, and dapsone is
less clear; they should only be used as alternatives to the regimens
described above and should be used in combination with pyrimeth-
amine whenever possible.
Spiramycin has been used in pregnant women to attempt to
reduce transmission to the fetus; it has not been shown to be effective
for acute therapy, maintenance therapy, or primary prophylaxis of
TE in AIDS patients. There is no evidence that spiramycin is
teratogenic.
Although drugs used to treat toxoplasmosis in the setting of differ-
ent clinical entities are basically the same, careful attention should be
given to the dosing and dosing regimen. Recommended doses in
immunocompromised patients are usually higher than those in immu-
nocompetent patients. For instance, the recommended dose of pyri-
methamine for patients with TE is 50 to 75 mg/day after a loading dose
of 200 mg, whereas the dose to treat fetal infection during pregnancy
is 25 to 50 mg/day after a loading dose of 100 mg/day for 2 days in the
mother.
Therapy Regimens in Specific  
Clinical Entities
Toxoplasmosis in the Immunocompetent
Patient
Treatment of immunocompetent adults with the lymphadenopathic
form is rarely indicated; this form is usually self-limited. One small
randomized trial demonstrated efficacy of a 1-month course of
TMP-SMX in reducing lymphadenopathy (65% response vs. 22% for
placebo).407 If visceral disease is clinically overt or symptoms are severe
or persistent, treatment may be indicated for 2 to 4 weeks, followed by
reassessment of the patient’s condition (Table 280-2). Infections
acquired by laboratory accident or transfusion of blood products are
potentially more severe, and patients who have been infected in these
ways probably should be treated (see Table 280-2).
Toxoplasmosis in the Immunodeficient Patient
Because experience with treatment of toxoplasmosis in immunodefi-
cient patients has been most extensively studied in patients with AIDS,
this section focuses primarily on this group of patients. However,
information on treatment in AIDS patients likely can, in large part and
in the absence of data, be extrapolated directly to other immunodefi-
cient patients (see Table 280-2).
 3147

• Screen all newborns born to mothers suspected or confirmed to have acquired T. gondii
infection during gestation
• Consider neonatal serologic screening in newborns born to mothers who were not screened

Chapter 280  Toxoplasma gondii

during gestation1
• In addition, laboratory testing should be performed at birth in the presence of:
o Visual abnormalities (e.g., strabismus, blindness, chorioretinitis)
o Encephalitis, seizures, hydrocephaly, or microcephaly
o Brain or hepatic calcifications
o Unexplained sepsis
o Hepatosplenomegaly
o Pneumonitis
o Anemia, jaundice, petechiae, thrombocytopenia
o Skin rash, diarrhea, hypothermia

• Toxoplasma IgG, IgM, IgA

o Can be performed at nonreference, hospital-based,
or commercial laboratories.
o However, recommend IgG, IgM-ISAGA, and IgA
at reference laboratory2
• If clinical suspicion is high:
o Toxoplasma PCR in peripheral blood, urine, and
CSF3
o Ophthalmologic evaluation by pediatric retinal
specialist
o Hearing evaluation
o Ultrasound or CT (preferred) scan of the brain
o Lumbar puncture for CSF3 examination4

Initial treatment indicated54 Initial treatment not indicated; Treatment and serologic follow-
• Positive results for lgG plus serologic follow-up indicated up not indicated
positive results for: • Positive results for IgG in the
o IgM in serum sample obtained absence of major clinical signs • Newborn:
after 5 days of life and/or plus negative results for: o Negative IgG and
o IgA in serum sample obtained o IgM and o Negative IgM and
after 10 days of life and/or o IgA and, if performed: o Negative IgA
o PCR in peripheral blood, urine, o PCR in peripheral blood, urine,
or CSF and CSF and
• Positive results for IgG plus • Follow-up of serum IgG every 4
o Major clinical signs65 present to 8 weeks, IgG of maternal • Mother
plus origin typically falls by half every o Negative IgG and
6
o Newborn was born to a mother month7 o Negative IgM
who was infected during • Serologic test results in the
gestation mother can aid in the
interpretation of newborn’s
serologies

FIGURE 280-9  Diagnostic approach and management algorithm of the newborn whose mother has been suspected or confirmed to have
acquired toxoplasmosis during gestation. CSF, cerebrospinal fluid; CT, computed tomography; IgG, IgM, and IgA, immunoglobulins G, M, and A,
respectively; ISAGA, immunosorbent agglutination assay; PCR, polymerase chain reaction.
1
Consider consultation with a physician expert in management of toxoplasmosis during pregnancy (e.g., in the United States, Palo Alto Medical
Foundation–Toxoplasma Serology Laboratory [PAMF-TSL], www.pamf.org/serology/; 650-853-4828; e-mail, toxolab@pamf.org or U.S. [Chicago] National
Collaborative Treatment Trial Study, 773-834-4152).
2
Consider sending serum sample to a reference laboratory (e.g., PAMF-TSL).
3
If lumbar puncture is clinically indicated, deemed safe, and feasible.
4
In an attempt to confirm the diagnosis of congenital toxoplasmosis, CSF should be sent for cell count and differential (congenital toxoplasmosis is one
of the few causes of eosinophilic meningitis), protein (congenital toxoplasmosis is one of the few causes of extreme elevation of CSF protein), glucose,
and T. gondii PCR.
5
The recommended regimen is pyrimethamine plus sulfadiazine plus folinic acid (see text).
6
Major clinical signs are referred here: chorioretinitis, brain calcifications, and hydrocephalus.
7
Maternally transferred IgG antibodies usually decline and disappear within 6 to 12 months of life.

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 3148

TABLE 280-2  Treatment Regimens for Toxoplasmosis in Immunocompetent and Immunocompromised

Patients*
IMMUNOCOMPROMISED PATIENTS, INCLUDING
Part III  Infectious Diseases and Their Etiologic Agents

THOSE WITH AIDS, TRANSPLANTS, CANCER, OR

†
IMMUNOCOMPETENT PATIENTS TAKING IMMUNOSUPPRESSOR DRUGS‡
Preferred Regimen
Pyrimethamine (PO) 50 mg q12h for 2 days, followed by 25-50 mg daily 200-mg loading dose, followed by 50 (<60 kg)-75 mg/day (≥60 kg)
plus
Folinic acid§ (PO) 10-20 mg daily (during and 1 wk after therapy with 10 to 20 mg daily (up to 50 mg/day) (during and 1 wk after
pyrimethamine) therapy with pyrimethamine)
plus
Sulfadiazine (PO) 1 g q6h 1000 (<60 kg)-1500 mg (≥60 kg) q6h
Preferred Alternative Regimens
Pyrimethamine–folinic acid Same doses as above Same doses as above
plus
Clindamycin (PO or IV) 300 mg q6h 600 mg q6h (up to 1200 mg q6h)
or
Atovaquone (PO) 1500 mg PO twice daily 1500 mg PO twice daily
Trimethoprim-sulfamethoxazole (PO or IV) 10 mg/kg/day (trimethoprim component) divided in 10 mg/kg/day (trimethoprim component) divided in two to three
two to three doses doses (doses as high as 15-20 mg/kg/day have been used)
Alternative Regimens with Limited Supportive Data‖
Pyrimethamine–folinic acid Same doses as above Same doses as above
plus
Clarithromycin (PO) 500 mg q12h 500 mg q12h
or
Dapsone (PO) 100 mg/day 100 mg/day
or
Azithromycin (PO) 900-1200 mg/day 900-1200 mg/day
Sulfadiazine (PO) Same doses as above Same doses as above
plus
Atovaquone (PO) Same doses as above Same doses as above
*Assistance is available for the diagnosis and management of toxoplasmosis at the Palo Alto Medical Foundation–Toxoplasma Serology Laboratory; Palo Alto, CA;
www.pamf.org/serology/; 650-853-4828; toxolab@pamf.org.
†
Indicated in patients with (1) ocular disease associated with primary infection or reactivation of latent infection; (2) severe disease including myocarditis, myositis,
hepatitis, pneumonia, brain, or skin lesions and lymphadenopathy; (3) persisting symptoms; and (4) laboratory accidents.
‡
After the successful use of a combination regimen during the acute/primary therapy phase, same agents at half doses are usually used for maintenance or secondary
prophylaxis; for pyrimethamine, use 25 mg (<60 kg) to 50 mg/day (>60 kg); for clindamycin, use 600 mg PO every 8 hours.
§
Folinic acid (leucovorin); should always be given with pyrimethamine to minimize toxicity; folic acid must not be used as a substitute for folinic acid.
‖
These agents have been used in clinical studies with small numbers of patients and have response rates lower than the standard regimens (see text for references). They
should be used only in patients who are intolerant of the standard regimens.
AIDS, acquired immunodeficiency syndrome; IV, intravenous; PO, orally.

If left untreated, toxoplasmosis in immunodeficient patients is often
lethal. Treatment is recommended for 4 to 6 weeks after the resolution
of all signs and symptoms (often for 6 months or longer). At one
medical center, 80% of non-AIDS immunodeficient patients with toxo-
plasmosis improved with specific therapy.408 This rate of improvement
is similar to that observed in appropriately treated AIDS patients with
TE.365,409 Chronic (latent) asymptomatic infection in immunodeficient
patients is not treated.
The exact dosing schedule for the treatment of toxoplasmosis in
non-AIDS immunocompromised patients has not been defined.
However, useful information in this regard has resulted from studies
performed in AIDS patients with toxoplasmosis.
Therapy for toxoplasmosis in AIDS patients includes acute
(primary or induction) treatment, maintenance treatment (secondary
prophylaxis), and primary prophylaxis. There are no convincing data
from prospective, carefully designed trials to allow the recommenda-
tion of monotherapy for induction, maintenance, or primary prophy-
laxis. Because relapse occurs in up to 80% of cases400 after the
discontinuation of primary therapy, maintenance therapy is recom-
mended for all patients until the CD4 count rises above 200 cells/mm3
for at least 6 months in response to ART (plasma HIV viral load will
often be below detection limits during this period).
Acute therapy should be for at least 3 weeks,86 and up to 6 weeks
or more may be required for more severely ill patients who have not
achieved a complete response. Pyrimethamine combined with sulfa-
diazine and folinic acid is the therapy of choice for AIDS patients with
toxoplasmosis and is the standard to which experimental regimens
should be compared. This regimen is associated with clinical response
in 68% to 95% of patients with TE.409,410 Unfortunately, up to 40% of
patients develop side effects from one or more of the drugs, often
requiring discontinuation of one or both agents.198,356 Pyrimethamine-
clindamycin and folinic acid appear comparable in efficacy to
pyrimethamine-sulfadiazine,409,411 but this combination also has sub-
stantial toxicity. TMP-SMX412-414 (at 10 mg/kg/day of the TMP compo-
nent, divided in two doses) has shown efficacy similar to the
pyrimethamine-sulfadiazine regimen (with a more rapid radiologic
response in the TMP-SMX group) in a randomized pilot trial in 77
patients with AIDS406; this provides an alternative regimen for situa-
tions in which parenteral therapy is required or when pyrimethamine
is unavailable. An international, noncomparative study of atova-
quone415,416 (administered orally as a suspension) combined with either
pyrimethamine or sulfadiazine as treatment for acute disease demon-
strated 6-week response rates of 75% (21 of 28 patients) for atovaquone-
pyrimethamine and 82% (9 of 11) for atovaquone-sulfadiazine.417
Serum levels of atovaquone may predict response but are not com-
mercially available.416 Doses of atovaquone lower than currently rec-
ommended for treatment (750 mg bid vs. 1500 mg bid) can often
achieve therapeutic levels if not co-administered with efavirenz, which
can reduce atovaquone levels by approximately 45%.417a TMP-SMX and
atovaquone both are active against Pneumocystis, and thus anti-
Pneumocystis prophylaxis does not need to be administered when
these drugs are used. Because clindamycin-pyrimethamine has no

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demonstrated anti-Pneumocystis activity, additional prophylaxis (e.g.,
aerosolized pentamidine) needs to be co-administered if patients are
at risk for developing Pneumocystis pneumonia.
In a 13-patient pilot study of TE using the combination of pyri-
methamine, 75 mg/day, and clarithromycin, 1 g every 12 hours, 62%
of patients had a complete and 23% a partial clinical response; 15% of
patients died by week 3 of therapy,418 and adverse events resulted in
discontinuation of therapy in 27%. No long-term follow-up data are
available, and no additional studies with this drug combination have
been published. Doses of clarithromycin higher than 500 mg twice
daily have been associated with increased mortality in HIV-infected
patients receiving therapy for Mycobacterium avium infection and
should not be used.419,420
Dapsone in combination with pyrimethamine has been reported
anecdotally to be effective for the treatment of TE when used in an
oral dose of 100 mg/day with 25 mg/day of oral pyrimethamine.421
Doxycycline has had success in the treatment of TE in a few patients
when used at 300 mg/day IV in three divided doses.422 A dosage
of 100 mg twice a day was given to six patients intolerant to
pyrimethamine-sulfadiazine, but five had associated neurologic and
radiologic recurrences while receiving the drug.423 Further studies are
needed to compare the relative efficacy and toxicity of these alternative
regimens. Although azithromycin plus pyrimethamine is effective for
the treatment of some cases of TE in AIDS patients, its use should be
limited, based on results of a recent study demonstrating an inferior
response rate, especially during maintenance therapy.424,425 Alternative
regimens used for acute therapy and their dosage schedules are listed
in Table 280-2.
Corticosteroids are often given to patients with TE for the reduction
of cerebral edema and raised intracranial pressure. The clinical response
and survival in patients with TE who received corticosteroids in addi-
tion to antimicrobial therapy has been reported to be no different from
that of those who received antimicrobial agents alone.365 The use of
these agents may complicate the interpretation of empirical therapy of
TE because partial clinical and radiologic improvement may be seen
solely resulting from a reduction in cerebral edema and inflammation
or a response of CNS lymphoma; moreover, they may further compro-
mise the immune systems of these already very immunodeficient
patients. Their use thus should be limited to situations where clinically
significant edema or a mass effect is present.
Seizures occur in up to 35% of patients with TE.356 One retrospec-
tive study demonstrated a poorer outcome in those patients who
received anticonvulsant therapy, compared with those who did not.400
Whether this result represents a true drug effect or a selection bias,
given that those receiving anticonvulsant therapy are likely to be more
severely ill, is unclear. Anticonvulsant agents may be responsible for
numerous side effects and drug interactions; for instance, potentially
serious interactions can occur between agents such as carbamazepine,
phenobarbital, or phenytoin and other drugs used to treat HIV infec-
tion, such as protease inhibitors. Anticonvulsant therapy is probably
best administered only when seizures have occurred.400
The time to clinical response in AIDS patients with TE who were
receiving appropriate anti-Toxoplasma therapy has been evaluated in a
study that included an objective, graded neurologic examination.365 Of
those with a response, 91% improved with respect to at least half of
their baseline abnormalities by day 14.365 AIDS patients with presumed
TE had some degree of improvement within 7 to 10 days of the initia-
tion of appropriate anti-Toxoplasma therapy. By contrast, a significant
number of patients with an alternative diagnosis, including lymphoma,
exhibited signs of clinical deterioration as early as 3 to 5 days after the
initiation of the empirical regimen for presumed TE.365 Headaches and
seizures were insensitive indicators for a response to therapy. In some
cases, toxoplasmosis has progressed to death despite the use of appro-
priate drug regimens.409,411
After successful primary therapy, drug dosages are generally
decreased for maintenance therapy. No single maintenance regimen
that is efficacious with an acceptable adverse reaction profile has yet
been identified. Relapse of TE occurs in approximately 20% to 30% of
patients who are receiving maintenance therapy, in part because of
nonadherence to and patient intolerance of the prescribed regimen.198
Pyrimethamine, 25 mg/day, plus sulfadiazine, 500 mg four times daily,
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3149
409
has been associated with the lowest relapse rate and is recommended
unless there are contraindications to its use. When daily therapy with
pyrimethamine-sulfadiazine was compared with a twice-weekly regi-
men for the prevention of recurrence of TE, the latter was found to be
Chapter 280  Toxoplasma gondii
less effective.426,427 Although a subsequent trial by the same group
found that three-times weekly therapy was equivalent to daily therapy,
the relapse rates for both groups (≈14.5/100 patient-years) was higher
than was seen with daily therapy (4.4/100 patient-years) in the earlier
study.427,428 Patients receiving the pyrimethamine-sulfadiazine combi-
nation do not require another regimen for PCP prophylaxis. Whereas
25% of patients receiving pyrimethamine-clindamycin subsequently
developed PCP,429 no patient receiving pyrimethamine-sulfadiazine
developed PCP.427,429 One 17-patient study demonstrated that TMP-
SMX could be safely substituted for pyrimethamine-sulfadiazine after
a median of 24-months maintenance therapy in patients also receiving
ART; the major benefit was in decreasing pill burden.430
Because of drug toxicity, many patients are unable to continue
taking the pyrimethamine-sulfadiazine combination for maintenance
therapy. A higher relapse rate has been reported with the use
of pyrimethamine-clindamycin compared with pyrimethamine-
sulfadiazine for secondary prophylaxis of TE; hence, it is recommended
that the clindamycin dose be 1800 mg/day if tolerated.409,431,432 Encour-
aging results have been reported with other drug combinations. These
include Fansidar (pyrimethamine-sulfadoxine), which has been used
in a dose of one tablet twice weekly,433 and pyrimethamine-dapsone
administered on an intermittent schedule (two to three times a
week).434-436 The long half-life of these agents allowed the longer dosing
interval, but Fansidar may have an increased risk of severe cutaneous
reactions, and the longer half-life results in slower drug clearance after
discontinuation of therapy.437 When pyrimethamine was used alone as
maintenance therapy at 50 mg/day438,439 and 100 mg/day,438 the relapse
rates were 10% to 28% and 5%, respectively. Atovaquone alone or in
combination regimens also appears to have activity based on uncon-
trolled trials; combination therapy (with sulfadiazine or pyrimeth-
amine) should be used whenever possible.415-417,440
The optimal time to initiate ART in HIV-infected patients with TE
has not been well defined. In one randomized trial of 282 patients with
opportunistic infections other than tuberculosis (only 5% with TE),
which compared early (median, 12 days after initiation of opportunis-
tic infection therapy) to deferred (median, 45 days) initiation of ART,
the secondary end point of AIDS progression or death occurred sig-
nificantly less frequently in the early initiation group.441 Thus, in the
absence of contraindications, ART can reasonably be started 2 to 3
weeks after diagnosis of TE.
Primary prophylaxis against T. gondii in patients with AIDS has
been shown to be effective in preventing acute TE.442-445 In addition,
the use of new highly active ART in HIV-infected patients has had a
profound effect in decreasing the incidence of TE in these patients.87,88
Primary prophylaxis is recommended for patients who have detectable
Toxoplasma IgG antibodies and whose lowest CD4+ count has been less
than 100/mm3 (many experts use less than 200/mm3 as the cutoff
rather than 100/mm3), regardless of the HIV RNA viral load.432
TMP-SMX (1 double-strength or single-strength tablet/day), dapsone
(50 mg/day) plus pyrimethamine (50 mg/week), and Fansidar (twice
weekly) have been reported to be effective in preventing the first
episode of TE.432,442,445,446
Studies have demonstrated that it is safe to discontinue primary or
secondary anti-Toxoplasma prophylaxis when the recovery of a CD4+
count greater than 200 cells/mm3 is achieved and sustained in patients
on ART.251-253,447,448 Current recommendations are to discontinue pro-
phylaxis when the CD4 count has risen above 200 cells/mm3 for at least
3 months (primary prophylaxis) or 6 months (secondary prophy-
laxis).432 It is important to recognize that in most of these studies, the
median CD4 count was greater than 300 cells/mm3 at enrollment, and
viral loads were below detection limits or reasonably controlled in
most patients.
At present, TMP-SMX is used by most transplant teams as prophy-
laxis against Pneumocystis pneumonia. Its use has also been shown to
protect against toxoplasmosis. However, TMP-SMX is not protective
in every case, and some patients are not able to tolerate the drug com-
bination. In addition, in some patients sulfonamides may be
 3150
contraindicated. Thus, use of TMP-SMX alone may be sufficient for
prevention of toxoplasmosis in patients who are seronegative for T.
gondii anti­bodies and who receive heart transplants from seropositive
donors (i.e., D+/R− patients).449 The optimal schedule for administra-
Part III  Infectious Diseases and Their Etiologic Agents
tion of TMP-SMX in heart transplant patients has not been defined.
Physicians must decide whether a schedule of daily administration or
administration three times each week is to be used. We routinely rec-
ommend daily use of TMP-SMX whenever feasible.10
Roxithromycin, administered at 900 mg once a week (may be
given in three divided doses),450 has been reported in a small random-
ized trial to be effective for primary prophylaxis; roxithromycin is
unavailable in the United States. Based on a number of clinical trials,
pyrimethamine alone cannot be recommended for primary prophy-
laxis.84,451,452 Clarithromycin453 and spiramycin454 have been ineffective
for primary prophylaxis when they were used alone. In a randomized,
placebo-controlled, primary prophylaxis trial, clindamycin (600 mg/
day) was associated with an unacceptably high rate of associated gas-
trointestinal disease, in particular diarrhea.455
Data on the outcome of treatment of AIDS patients with toxoplas-
mosis outside the CNS are limited; available information on the
therapy of ocular243,456,457 and pulmonary involvement237,458 indicates
that these forms of toxoplasmosis are also responsive to treatment.
Therapy was successful in 50% to 77% of patients with pulmonary
toxoplasmosis.237,458
The hematologic toxicity associated with zidovudine and the high
doses of pyrimethamine used for the treatment of TE are additive.
Other drugs used in treating HIV-infected patients that cause myelo-
suppression include ganciclovir, flucytosine, TMP, pentamidine, che-
motherapy agents, and IFN-α.
Ocular Toxoplasmosis
The decision to treat active toxoplasmic chorioretinitis should be made
based on a complete ophthalmologic evaluation. A recent report from
the American Academy of Ophthalmology highlighted the limited
data that are available from randomized controlled trials with well-
defined end points demonstrating the benefits of therapy.459 Treatment
is most likely indicated in the following settings: any decrease in visual
acuity, macular or peripapillary lesions, lesions greater than one optic
disk diameter, lesions associated with a moderate-to-severe vitreous
inflammatory reaction, the presence of multiple active lesions, the
persistence of active disease for more than 1 month, and any ocular
lesions associated with recently acquired infection. Because the disease
can be self-limited in immunocompetent patients, many clinicians may
not treat small, peripheral retinal lesions that are not immediately
vision threatening.9,265,460-462
The reported benefits of medical therapy are related primarily to
the clinical presentation.265,460 Because there is so much variation in the
clinical manifestations of the retinal disease, and because the disease
may be self-limited even without treatment, the response to therapy is
difficult to interpret. The combination of pyrimethamine (100-mg
loading dose given over 24 hours for 2 days, followed by 25 to 50 mg
daily) and sulfadiazine (1 g given four times daily for 4 to 6 weeks),
depending on the clinical response, which is considered “classic”
therapy for ocular toxoplasmosis, is the most common drug combina-
tion used (see Table 280-2).460 TMP-SMX showed responses similar to
pyrimethamine-sulfadiazine in a recent randomized, single-blind trial,
although the latter regimen was used at lower-than-standard doses.463
Two recent, open, randomized trials found no differences in response
rates to intravitreal clindamycin plus dexamethasone compared with
an oral regimen combining pyrimethamine, sulfadiazine, leucovorin,
and prednisone/prednisolone.464,465
Clindamycin (300 mg orally every 6 hours for a minimum of 3
weeks) has also been used with favorable clinical results.460 Other drugs
that may have activity but have been inadequately studied include
atovaquone and pyrimethamine plus azithromycin.466,467
Systemic corticosteroids are indicated when lesions involve the
macula, optic nerve head, or papillomacular bundle. Photocoagulation
has been used both for the treatment of active lesions and for prophy-
laxis against the spread of lesions because new lesions appear contigu-
ous to old lesions.460 In some patients, vitrectomy and lentectomy may
be necessary.
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Given the high relapse rate seen in some patients with ocular
toxoplasmosis, prevention of recurrences would be highly desirable.
A randomized, open-label trial of 124 patients in Brazil found that
TMP-SMX (1 double-strength tablet every 3 days) was effective in
decreasing the frequency of recurrences from 24% to 7% in a popu-
lation at high risk for recurrences.180 If confirmed in other popula-
tions, such a regimen could be beneficial in patients with frequent
or severe recurrences. A follow-up report noted that once TMP-SMX
was stopped, recurrence rates in both groups were similar over a
10-year period, suggesting that benefit was seen only while continu-
ing therapy.467a
For the approach to ocular toxoplasmosis during pregnancy see
“Acute Acquired Toxoplasma Infection in Pregnant Women.”
Acute Acquired Toxoplasma Infection
in Pregnant Women
Treatment of the acutely infected pregnant woman does not eliminate
but does appear to decrease the incidence and severity of fetal infec-
tion. Because there is usually a delay between the acquisition of acute
maternal infection, infection of the placenta, and subsequent infection
of the fetus, identification of acute maternal infection necessitates
immediate institution of treatment of the mother. Most experience of
maternal treatment to prevent transmission to the fetus has been with
spiramycin (3 g/day, obtainable in the United States from the FDA,
301-796-1400; after hours, 301-796-8210) (Table 280-3). Spiramycin
has been accepted by most investigators as being effective in reducing
the frequency of maternal transmission of T. gondii to the fetus by
approximately 60%.277,319 Spiramycin is indicated for patients con-
firmed or suspected to have been infected before 18 weeks of gestation.
It appears that its maximal efficacy is best achieved when given within
8 weeks of seroconversion.280 Spiramcyin should be continued until
delivery, even if results of the amniotic fluid PCR are negative and
ultrasound examinations are normal. A retrospective study suggested
that the combination of spiramycin and TMP-SMX (after the 14th
week) is effective in reducing transmission during the second trimester,
compared with historical control subjects.468 If spiramycin cannot be
used or is not available, it may be replaced by sulfadiazine (with appro-
priate precautions at term) or clindamycin alone. However, there are
no data on the efficacy of sulfonamides, including sulfadiazine, or
clindamycin when these drugs are used for this purpose.
Because spiramycin does not reliably cross the placenta,469 if fetal
infection is documented or highly suspected or maternal infection is
confirmed or highly suspected of having been acquired at 18 weeks of
gestation or later, the recommended therapeutic regimen is the com-
bination of sulfadiazine (initial dose 75 mg/kg, followed by 50 mg/kg
every 12 hours; maximum, 4 g/day), pyrimethamine (50 mg every 12
hours for 2 days, followed by 50 mg daily), and folinic acid (10 to
20 mg daily, during and 1 week after completion of pyrimethamine
therapy) (see Table 280-3). Such treatment might be an alternative to
the termination of pregnancy when abortion is not allowed by law or
for women who desire to continue their pregnancy. Pyrimethamine
should not be used in the first 18 weeks of pregnancy because of a
concern for teratogenicity, although some centers in Europe will use
it as early as 12 to 14 weeks. In this circumstance, if indicated, sulfa­
diazine plus clindamycin can be considered, although there are no
data on its efficacy in this situation.8 In addition, pyrimethamine-
sulfadiazine is also recommended for pregnant women in whom a
recently acquired acute infection is highly suspected or confirmed
during the late second or third trimesters; this is due to the high rates
of vertical transmission observed in those stages of gestation and
should be recommended even though fetal infection may not yet have
been confirmed.
A group of European investigators reported between 1999 and 2007
that, in their studies, a significant effect of prenatal treatment on the
risk of vertical transmission and clinical signs of congenital toxoplas-
mosis was not detected.470-473 These results are not surprising because
the studies included very few untreated women in their analysis, most
untreated women were infected during the third trimester, and severe
cases were excluded.474,475 More recently, several studies from Europe
have consistently reported evidence for an association between early
treatment and reduced risk in the incidence and severity of congenital
 3151

TABLE 280-3  Treatment Regimens for TABLE 280-4  Measures to Prevent Primary
Toxoplasmosis during Pregnancy and for Toxoplasma gondii Infection
Congenital Disease* • Avoid contact with materials potentially contaminated with cat feces,

Chapter 280  Toxoplasma gondii

INDICATION DRUG REGIMEN especially handling of cat litter and gardening. Gloves are advised when these
activities are necessary. Because oocysts require 1 to 2 days to mature,
Pregnant Women dispose of all cat feces daily.
Pregnant women suspected Spiramycin (oral)†: 1 g (3 million units) q8h • Disinfect cat litter box with near boiling water for 5 minutes before handling.
or confirmed of having (for a total of 3 g or 9 million units/day) • Avoid mucous membrane contact when handling raw meat.
acquired infection before Spiramycin should be continued until delivery, • Wash hands thoroughly after contact with raw meat.
18 weeks of gestation. even if fetal infection is not detected (e.g., • Kitchen surfaces and utensils that have come in contact with raw meat
Not recommended during negative amniotic fluid PCR test and should be washed.
pregnancy if the fetus has negative follow-up ultrasound) • Freeze meat to –20° C for at least 48 hours.
documented or suspected • Cook meat to 67° C (153° F) or “well done” (meat should not be “pink” in
infection (see below) the center).
• Avoid ingestion of dried, smoked, or cured meat because they may be
Pregnant women at ≥18 Pyrimethamine: 50 mg q12h for 2 days,
infectious.
weeks of gestation and   followed by 50 mg daily
• Wash fruits and vegetables before consumption.
(1) in whom it is suspected plus
• Refrain from skinning animals.
or confirmed that acute Sulfadiazine: 75 mg/kg (first dose), followed
• Avoid drinking untreated water potentially contaminated with oocysts.
infection was acquired at by 50 mg/kg q12h (max., 4 g/day)
• Avoid drinking unpasteurized goat’s milk.
or after 18 weeks of plus
• Avoid eating raw oysters, clams, and mussels.
gestation or (2) who have Folinic acid†: 10-20 mg daily during and for
a positive amniotic fluid 1 wk after pyrimethamine therapy
PCR test or an abnormal Pyrimethamine is teratogenic and should not
ultrasound suggestive of be used during pregnancy before week 18
congenital toxoplasmosis (in some centers in Europe, it is used as early
as week 14). Sulfadiazine should not be used
alone; consider clindamycin plus sulfadiazine.
Congenital Infection
Detailed information on and recommendations for the postnatal treat-
Infants
ment of congenital toxoplasmosis are reviewed elsewhere,8 but we
Congenital infection; Pyrimethamine: 1 mg/kg q12h for 2 days,
treatment regimen is followed by 1 mg/kg/day for 2 or 6 mo,
favor continuous sulfadiazine (50 mg/kg every 12 hours), pyrimeth-
usually recommended   followed by 1 mg/kg/day every Monday, amine (loading dose, 1 mg/kg every 12 hours for 2 days; then begin-
for 1 yr Wednesday, and Friday ning on day 3, 1 mg/kg per day for 2 or 6 months; then this dose every
plus Monday, Wednesday, and Friday), and folinic acid (10 mg three times
Sulfadiazine: 50 mg/kg q12h
plus
weekly during and for 1 week after pyrimethamine therapy) for a
Folinic acid‡: 10 mg three times weekly minimum of 12 months (see Table 280-3).475,478 Other groups have used
Prednisone (if CSF protein ≥1 g/dL or pyrimethamine-sulfadiazine-folinic acid alternated with spiramycin
severe chorioretinitis): 0.5 mg/kg q12h (100 mg/kg/day).8 Serial follow-up to gauge the response of the infant
(until CSF protein <1 g/dL or resolution of
severe chorioretinitis)
to therapy should include neuroradiology, ophthalmologic examina-
tions, and CSF analysis if indicated.8
Older Children
For guidance on therapy in congenital cases, we recommend that
Active disease; treatment is Pyrimethamine: 1 mg/kg q12h (max., 50 mg) physicians contact Dr. Rima McLeod (773-834-4152) at the University
usually continued for for 2 days, followed by 1 mg/kg/day (max.,
1-2 wk beyond resolution 25 mg) of Chicago, where a major study, the National Collaborative Treat-
of clinical manifestations plus ment Trial, on the appropriate management of these cases is being
Sulfadiazine: 75 mg/kg (first dose), followed performed.478 This study has shown that outcomes are substantially
by 50 mg/kg q12h (max., 4 g/day) better for most, but not all, infants treated from the neonatal period
plus
Folinic acid3: 10-20 mg three times weekly for 12 months with pyrimethamine-sulfadiazine and leucovorin, com-
Prednisone (severe chorioretinitis): pared with historical control subjects receiving no or short-course
1 mg/kg/day in two divided doses; max., therapy.478-481 Improvement in intellectual function, regression of reti-
40 mg/day, rapid taper nal lesions, reduction in anticonvulsant drug requirements, and pre-
*Assistance is available for the diagnosis and management of toxoplasmosis at the vention of auditory sequelae appear to be the major benefits of such
Palo Alto Medical Foundation–Toxoplasma Serology Laboratory; Palo Alto, CA; treatment, which was combined with CSF shunting if required.478
www.pamf.org/serology/; 650-853-4828; toxolab@pamf.org; or U.S. (Chicago)
National Collaborative Treatment Trial Study; 773-834-4152. Signs of active infection resolved within weeks of initiation of treat-
†
Spiramycin is not teratogenic, and it is available in the United States through ment. In a significant number of treated children, cerebral calcifica-
the investigational new drug process at the U.S. Food and Drug Administration tions diminished in size or resolved.481 More recently, they also
(301-796-1600). Prior consultation with medical consultants is required. reported that new central chorioretinal lesions were uncommon (14%)
‡
Folinic acid (leucovorin) should always be given with pyrimethamine to minimize
toxicity; folic acid must not be used as a substitute for folinic acid. in children with congenital toxoplasmosis who have been treated
CSF, cerebrospinal fluid; max., maximum; PCR, polymerase chain reaction. during their first year of life, compared with historical reports of much
higher rates (≥82%) for untreated children or those treated for only
1 month near birth.292

toxoplasmosis.280,282,283,476 Given that recent studies have consistently PREVENTION

suggested a clinically significant benefit,474 and that a significant benefit
was never ruled out in previous studies, most authorities continue to
recommend spiramycin or pyrimethamine-sulfadiazine for women
with suspected or confirmed acute T. gondii infection acquired during
gestation.
Pregnant women with toxoplasmic chorioretinitis as a result of
reactivation of chronic disease do not have a higher risk to transmit
the parasite to their offspring than do pregnant women who have been
infected before pregnancy and do not have ocular disease.477 Their eye
disease should be treated according to the indications discussed in the
section “Ocular Toxoplasmosis.” Pregnant women with toxoplasmic
chorioretinitis thought to be a manifestation of recently acquired infec-
tion should be treated because of both the eye disease and the risk of
transmission of the infection to their fetus.
General Methods
Prevention is most important in seronegative pregnant women and
immunodeficient patients. It is most readily accomplished through
education of these patients by their personal physicians (Table 280-
4). The goal is to avoid the ingestion of and contact with tissue cysts
or sporulated oocysts. Tissue cysts in meat are made noninfectious
by heating the meat to 66° C (meat should be cooked to “well done”
with no pink meat visible in the center), or by freezing it to −20° C
(which is not attainable in most home freezers) for at least 48 hours.
Meat that is smoked, cured in brine, or dried may still be infectious.
Oysters, clams, or mussels should not be eaten raw. Hands should
be washed thoroughly after handling raw meat or vegetables, eggs
should not be eaten raw, and unpasteurized milk (particularly milk
from goats) should be avoided. Vectors such as flies and cockroaches

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 3152

TABLE 280-5  Rates of Congenital Transmission in 270 Women and the Sensitivity and Negative Predictive
Value of Amniotic Fluid PCR for Prenatal Diagnosis of Congenital Toxoplasmosis, According to Gestational
Age at Which Maternal Infection Was Acquired
Part III  Infectious Diseases and Their Etiologic Agents

GESTATIONAL AGE AT MATERNAL AMNIOTIC FLUID PCR

INFECTION* (wk) NO. OF INFECTED FETUSES†/TOTAL (%) Sensitivity (CI) (%) NPV (CI) (%)
≤6 0/14 (0) N/A 100 (78-100)
7-11 7/50 (14) 29 (8-65) 90 (81-98)
12-16 7/61 (11.5) 57 (21-94) 95 (86-98)
17-21 14/66 (21.2) 93 (68-99) 98 (90-99.7)
22-26 16/36 (44.4) 63 (39-86) 77 (61-93)
27-31 19/30 (63.3) 68 (48-89) 65 (42-87)
≥32 12/13 (92.3) 50 (22-78) 14 (3-52)
TOTAL 75/270 (28) N/A N/A
*Maternal infection was diagnosed by seroconversion in the 270 women; 261 (97%) were given treatment with spiramycin.
†
Congenital infection was diagnosed by the persistence of Toxoplasma immunoglobulin antibodies after 1 year of life.
CI, confidence interval; N/A, not applicable; NPV, negative predictive value; PCR, polymerase chain reaction.
Note: The positive predictive value was 100%, regardless of gestational age.
Modified from Montoya JG, Remington JS. Management of Toxoplasma gondii infection during pregnancy. Clin Infect Dis. 2008;47:554-566.

should be controlled. Areas contaminated with cat feces should be
avoided altogether. Disposable gloves should be worn while dispos-
ing of cat litter material, working in the garden, or cleaning a child’s
sandbox. Oocysts are killed if the cat litter pan is soaked in nearly
boiling water for 5 minutes. If the litter pan is cleaned every day,
oocysts will not have a chance to sporulate. Serologic testing of cats
is unwarranted because testing does not demonstrate whether the
infected cat is excreting oocysts. Untreated water has been shown
to be an effective vehicle for the transmission of the parasite, and
drinking water sources potentially contaminated with oocyts should
be avoided.
Serologic Screening and Prophylaxis
Acute Toxoplasma gondii Infection and
Toxoplasmosis in the Immunodeficient
Patient
Transmission of T. gondii and death caused by the infection have
resulted from the transfusion of leukocyte-rich blood products and by
organ transplantation in immunodeficient patients. Transmission of
infection by these routes may occur frequently enough to warrant
screening for antibody to T. gondii in leukocyte-rich blood product
donors and possibly to exclude seropositive people as organ donors to
seronegative potential recipients whenever feasible.
Primary prophylaxis can prevent toxoplasmosis in patients dually
infected with HIV and T. gondii (see “Toxoplasmosis in the Immuno-
deficient Patient” under “Therapy”). Prophylactic treatment (pyri-
methamine, 25 mg orally every day for 6 weeks after transplantation)
has been used with apparent success in seronegative recipients of
hearts transplanted from seropositive donors.482 However, TMP-SMX
used for PCP prophylaxis in solid-organ transplant patients is also
effective as primary prophylaxis against T. gondii and can be used
without addition of pyrimethamine. Primary prophylaxis in BMT
and HSCT patients is particularly challenging because TMP-SMX
cannot safely be used early (i.e., before engraftment), whereas in
patients with all other transplant organs, it can be used immediately
after transplantation.
Congenital Toxoplasma gondii Infection
and Toxoplasmosis
Congenital toxoplasmosis is a preventable disease. It is therefore the
responsibility of physicians who care for pregnant women to educate
them on how they can prevent themselves from becoming infected (and
thereby not place their fetus at risk). A lack of adoption of a systematic
serologic screening program in the United States leaves education as the
principal means of preventing this tragic disease. If physicians choose
to screen their patients serologically, the appropriate tests must be used,
the laboratory performing the tests must be competent, and the test
results must be interpreted correctly. Nonreference laboratories can
effectively accomplish the initial screening testing by simultaneously
performing IgG and IgM antibody tests. Women with positive results
in the initial IgG antibody test should have a test for IgM antibody
performed on the same serum. Only IgM-positive test results need to
be sent to a reference laboratory for confirmatory testing (e.g., PAMF-
TSL).316,318 Clinical decisions should not be made based on positive
IgM test results alone. In patients with IgG antibodies at any titer, a
negative IgM antibody test result in the first trimester, and no clinical
signs of acute toxoplasmosis, no further testing would be necessary
because the probability of acute acquired infection in these women is
extremely low. Given the same circumstances in the second trimester of
pregnancy, a negative IgM test result rules out, for practical purposes,
recent acquisition of acute infection. A negative IgM test in the third
trimester may occur in a patient who acquired the infection earlier
in gestation.
In some countries (e.g., France, Austria, Italy, Slovenia, Lithuania,
and Uruguay), initially seronegative pregnant women are retested at
various intervals during gestation to detect seroconversion and insti-
tute treatment. Monthly screening of seronegative pregnant women
was recently reported to significantly decrease the risk of vertical
transmission and of clinical signs at 3 years of age.476 The appropri-
ate use of prenatal diagnosis, followed by the optimal use of spira-
mycin and/or pyrimethamine-sulfadiazine-folinic acid can markedly
reduce the incidence of clinically significant congenital toxoplasmo-
sis.* Its absence is often associated with poor outcomes.284 Results of
a study in France279 on the incidence of T. gondii infection in fetuses
of women whose date of acquiring the infection during the gesta-
tion was known and who were treated with spiramycin are shown in
Table 280-5.
In pregnant women infected with both HIV and T. gondii, we rec-
ommend that primary prophylaxis against T. gondii be introduced
when their CD4 T-cell count falls below 200/mm3. If the patient is
receiving TMP-SMX, additional prophylaxis is probably not necessary.
Otherwise, spiramycin can be used at a dose of 3 g/day.
ACKNOWLEDGMENTS
We gratefully acknowledge and thank Dr. Jack S. Remington, whose
lifelong study of toxoplasmosis and authorship of previous editions of
this chapter provided the foundation upon which the current chapter
is based. We would also like to thank Dr. Alan Sher for his review of
the manuscript and helpful suggestions.
*References 279, 282, 283, 476, 483, 484.

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 3153
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