SECTION B Tissue Infection 106

106 Toxoplasmosis
Luc Paris

KEY FEATURES be benign in immunocompetent persons but potentially severe in

immunocompromised patients and for the fetus. Today, we know
• Toxoplasma gondii is a common intracellular protozoan that the clinical spectrum and severity of disease depend on both
parasite with a worldwide distribution. the host and the pathogen’s genetic background, the immune
status of the host, and the host–parasite interaction. Toxoplasmosis
• Although T. gondii usually causes asymptomatic is a possible etiology for a severe infectious syndrome in travelers
infections, 10% to 20% of patients with acute infection living in or returning from tropical countries.
may develop cervical lymphadenopathy and/or a flu-like
illness. The clinical course is usually benign and
self-limited, with symptoms usually resolving within a EPIDEMIOLOGY
few weeks to months.
• Atypical strains of T. gondii are responsible for a severe
The Parasite and Its Life Cycle
infectious syndrome with pulmonary involvement seen Human infection is acquired by ingesting food or water contami-
in travelers living in or returning from South America, nated with oocysts shed in the feces of wild and domestic cats, or
particularly the Amazon area. tissue cysts in uncooked meat (Fig. 106.1). The oocyst is ovoid,
• Ocular Toxoplasma infection, an important cause of measures 9 × 13 µm, and can remain viable for more than a year
retinochoroiditis in America, can be the result of in moist soil. After sporulation (ranging from 2 days to 3 weeks,
congenital infection or infection after birth. In depending on the ambient temperature) takes place, the oocyst
congenital infection, patients are often asymptomatic is infectious. Millions of initially non-infectious (unsporulated)
until the second or third decade of life, when lesions oocysts are shed in the cat’s feces. Although oocysts are usually
develop in the eye. only shed for 1 to 2 weeks, large numbers may be shed.
Virtually all warm-blooded animals, especially birds and rodents,
• Congenital toxoplasmosis results from an acute primary can be intermediate hosts in nature and become infected after
infection acquired by the mother during pregnancy. The ingesting soil, water, or plant material contaminated with oocysts.
incidence and severity of congenital toxoplasmosis vary Oocysts transform into tachyzoites shortly after ingestion and
with the trimester during which infection was acquired. multiply rapidly during the acute infection. These rapidly dividing
• Immunodeficient patients often have central nervous (every 5–12 hours) tachyzoites localize in neural and muscle tissue
system (CNS) disease but may have retinochoroiditis, and are responsible for acute illness (Fig. 106.2). They destroy
pneumonitis, or other systemic disease. In patients with their host cells, enter adjacent cells, and give rise to focal necrosis
AIDS, toxoplasmic encephalitis is the most common with a vigorous local inflammatory reaction. Tachyzoites can cause
cause of intracerebral mass lesions. significant cell destruction before effective immunity is acquired.
• The diagnosis of T. gondii is based on serologic methods After 3 to 6 weeks, the infection persists with only slowly dividing
in immunocompetent individuals and parasitologic bradyzoites inside tissue cysts. Neither chemotherapy nor host
methods in immunocompromised individuals. immunity can affect the parasite once this transformation occurs.
The long-lived bradyzoites persist in a viable state inside cysts
• Treatment is not needed for a healthy person who is not
during the remainder of the host’s life without signs of host reaction;
pregnant. Treatment is usually recommended for
they are responsible for latency and reactivation.
pregnant women, persons who are
Cysts ranging in size from 5 to 50 µm in diameter appear
immunocompromised, or persons with ocular disease or
primarily in the brain, the retina, and in skeletal and cardiac muscles
severe illness.
(Fig. 106.3). Cysts are usually spherical in the brain but more
• The drug of choice for the treatment of symptomatic elongated in cardiac and skeletal muscles. Cats become infected
toxoplasmosis is pyrimethamine plus a sulfa drug, after consuming intermediate hosts harboring tissue cysts and
usually sulfadiazine. Trimethoprim–sulfamethoxazole may also become infected directly by ingestion of sporulated
may be used in many settings and may be preferred oocysts. Animals bred for human consumption and wild game
because of its wide availability. (e.g., venison) may also become infected with tissue cysts after
ingestion of sporulated oocysts in the environment. A very specific
phenomenon with T. gondii is the transmission of infection from
one intermediate host to another by carnivorism, without need
INTRODUCTION for passage through a definitive host.
Toxoplasmosis is caused by an intracellular protozoan parasite,
Toxoplasma gondii, which can infect humans and virtually all warm-
blooded animals worldwide. T. gondii was discovered in 1908
Transmission
simultaneously by Nicolle and Manceaux in Tunisia and Splendore Humans become infected by ingesting tissue cysts when eating
in Brazil, respectively, and toxoplasmosis became recognized as a raw or undercooked meat (lamb, beef, or pork) of animals harboring
human disease in 1939 to 1940.1 The complete life cycle of the tissue cysts and by ingestion of oocysts in soil-contaminated food
parasite was described at the end of the 1960s.2 Our understanding (raw vegetables) or drinking water—believed to be the major source
of this parasitic disease has evolved recently with the availability of infection in tropical areas. Transmission can also occur when
of new genomic data. Classically, Toxoplasma was considered to changing the litter box of a pet cat, by blood transfusion or organ
803
804 PART 5 Protozoal Infections

Northern developed countries Tropical areas

Soil, water and

raw vegetables

Mild clinical disease Risk of severe disease

Congenital transmission Graft to host transmission

Fig. 106.1 Life cycle of Toxoplasma gondii. Dashed arrow indicates transmission by tachyzoites; dark blue
arrows indicate transmission by cysts (bradyzoites); light blue arrows indicate transmission by oocysts.

Fig. 106.2 Numerous intracellular Toxoplasma gondii in bone marrow.

Stained with RAL555 ×1000. (From personal collection, Luc Paris,
Laboratoire de Parasitologie-Mycologie, Groupe Hospitalier Pitié-
Salpêtriére, Paris, France.) Fig. 106.3 Toxoplasma cysts in brain tissue.
 CHAPTER 106 Toxoplasmosis 805

Global status of Toxoplasma gondii prevalence

106

60%
40–60%
20–40%
10–20%
10%
No data

Fig. 106.4 Global status of Toxoplasma gondii seroprevalence. (Adapted from Pappas G, Roussos N,
Falagas, ME. Toxoplasmosis snapshots: global status of Toxoplasma gondii seroprevalence and implications
for pregnancy and congenital toxoplasmosis. Int J Parasitol 2009;39:1385–94.).

transplantation, and transplacentally from mother to fetus, leading Central Europe, the Middle East, parts of Southeast Asia, and
to congenital infections. Africa. A trend toward decreasing seroprevalence has been observed
A transplanted solid organ from a donor seropositive for toxo- in Africa: in Gabon, the prevalence in Franceville was 56% in
plasmosis can transmit T. gondii to a seronegative recipient. Heart 2007 compared with 71% 15 years earlier. Prevalence is generally
transplant recipients are particularly at risk for this mode of higher in South America (e.g., 53% in Southern Brazil) or in
acquisition, and additional cases have been described with other Africa (e.g., 46% in Tanzania and 40.8% in Lagos, Nigeria) than
organs (kidney, lung, liver). Although T. gondii has been isolated in India (20.3% in Bangalore) or in the Far East (<10% in Korea
from the peripheral blood of acutely symptomatic patients, or China).
transmission by transfusion is rare.
Transplacental infection occurs in approximately 30% of women
if they are first infected during pregnancy and thus have no pre-
Genetic Diversity of Toxoplasma gondii
existing immunity. The risk of transmission to the fetus is lowest Early studies of parasite genotypes revealed a clonal population
in the time just after conception (<1%) and increases to virtually structure comprising three lineages, named types I, II, and III.6
100% if the mother is infected just before delivery. Additionally, These archetypal lineages were isolated in Europe and North
transplacental transmission during chronic infection has been America from humans and domestic animals. Types I and III are
observed in immunosuppressed women. common worldwide; type II predominates in Western Europe
Although uncommon, occupational exposure and transmission and the United States but has not been described in South America
via needle stick can occur when working with live Toxoplasma- to date. Further studies performed on strains isolated in other
infected materials in the laboratory. geographic areas7 or from wild animals have revealed a greater
genetic diversity. There is a relationship between this genetic
diversity and the clinical expression of the infection, as shown in
Distribution and Prevalence South America where several cases of severe toxoplasmosis were
Toxoplasma is distributed worldwide, but the incidence in humans described in immunocompetent patients. Recombinant or atypical
varies widely (Fig. 106.4).3 Prevalence depends on local eating (unrelated to any of the archetypal lineages) strains were impli-
habits, environmental conditions, and the presence of definitive cated.8,9 These recombinant and atypical strains are not well adapted
hosts. Prevalence also increases with age. The overall prevalence to human hosts, potentially explaining the greater severity of human
in Western Europe is 30% to 50%. In France, the prevalence in infection. As more data become available from America and Africa,
pregnant women declined from more than 80% in the 1960s to a new classification is emerging with 11 haplogroups.10
54.3% in 1995, 43.8% in 2003, and to 37% in 2010.4 In the United
States, seroprevalence declined from 14.1% in the 1988 to 1994
National Health and Nutrition Examination Survey (NHANES),
Pathophysiology
to 9% in the 1999 to 2004 NHANES.5 This has been attributed The primary route of infection is via oral ingestion into the
to improved hygiene, new habits of food consumption (e.g., freezing gastrointestinal tract and progression through lymphatics to
of meat), and better awareness in the general population regarding widespread dissemination. Asexual multiplication of the parasite
the risks of consuming undercooked meat. occurs within the intestinal epithelial cells after ingestion of infective
In developing and tropical countries, prevalence depends on cysts. This early infection period is associated with peripheral
environmental conditions and climate. It is higher in urban than parasitemia with T. gondii tachyzoites circulating freely, or within
in rural areas, and in humid compared with dry climates. Foci of mononuclear phagocytic cells, until the development of an effective
high prevalence (>80%) exist in Latin America, parts of Eastern/ immune response. Differentiation of tachyzoites into bradyzoites
806 PART 5 Protozoal Infections

correlates with the onset of protective immunity and begins after immunosuppressive agents, and bone marrow transplant patients.
a few days. In the setting of T-cell immune deficiency, bradyzoites Such patients, if seronegative, are also at risk for newly acquired
can reactivate into tachyzoites. The genetic background of the infection. Initial diagnosis will often focus on a clinically local-
host may influence the risk of reactivation. In HIV-infected patients ized finding, whereas further evaluation will reveal disseminated
the risk of reactivated toxoplasmosis varies depending on the host’s infection. The most common clinical presentation is multifocal
human leukocyte antigen (HLA) haplotype.11 The absence of necrotizing encephalitis. Patients present with headache and a
effective T-cell immunity in the fetus explains the gravity of focal neurologic deficit; fever appears in 50% of cases.14 Other
congenital toxoplasmosis. common neurologic presentations include generalized seizures, with
or without encephalitis. Although meningeal signs are uncommon,
cerebrospinal fluid (CSF) mononuclear pleocytosis and mildly
CLINICAL MANIFESTATIONS elevated protein are common.
Although infection with T. gondii in developed countries is Computed tomography (CT) and magnetic resonance imaging
asymptomatic in 80% of newly infected patients, there are several (MRI) of the head typically show multiple, low-density lesions at
distinct clinical syndromes. the corticomedullary junction or in the basal ganglia that enhance
after administration of intravenous contrast (Fig. 106.5).
Another common clinical presentation is pneumonia (which
Acute Postnatal-Acquired Toxoplasmosis in can resemble pneumocystosis), but any organ can be involved
Immunocompetent Patients because T. gondii infects all nucleated cell types. Forty percent of
AIDS patients with ocular localization will also have a brain abscess.
In the 20% of patients with symptoms at presentation, the disease Disseminated toxoplasmosis usually presents with high and
is generally mild, similar to a mononucleosis or mild influenza-like prolonged fever with altered mental status, arthralgia, rash, and
illness. The incubation period is 1 to 2 weeks. The most frequent focal clinical (central nervous system [CNS] abscess, pneumonia)
symptoms are fever, asthenia, and a single, enlarged cervical lymph or laboratory (elevated liver enzymes, hemophagocytosis) findings.
node, but regional and generalized lymphadenopathy can occur. There is a higher rate of cerebral involvement in AIDS patients
The lymph nodes are non-tender and do not suppurate. Macular
or urticarial rash, arthralgia, myalgia, and hepatitis are less common
findings. Symptoms usually resolve spontaneously within a few
weeks or months. Ocular involvement is also possible—more
frequently reported in South America (particularly Brazil) —but
not specifically associated with recent primary infection or with
a wild toxoplasmosis cycle.
There have been fewer than 100 reported cases of severe primary
toxoplasmosis caused by an atypical or recombinant strain of
T. gondii in immunocompetent hosts. The majority of these patients
were infected in French Guiana, but cases have also been reported
from other areas. In some European cases, the source of infection
has been determined to be undercooked horse meat imported
from South America.12 Clinically, the patient presents with a marked,
non-specific infectious syndrome with visceral involvement. Fever
higher than 39°C for more than 10 days is prominent. In two-thirds
of cases there is weight loss of >5% body weight, generalized
lymphadenopathy, elevated liver enzyme levels, and pulmonary
involvement. Fifty percent of the patients have severe headache
and a third have diarrhea, hepatosplenomegaly, or chorioretinitis.
Other reported complications include Guillain–Barré syndrome,
pericarditis, myositis, and cutaneous rash. One third of the patients
have an acute respiratory distress syndrome, which without treat-
ment can be fatal. Lung involvement generally occurs 10 to 15
days after the onset of fever and may require hospitalization with
an associated poorer prognosis. Eleven cases of severe acute primary
toxoplasmosis in a village in Surinam were described; all the patients
were infected by the same atypical strain. There were five dis-
seminated acute toxoplasmosis cases, with one death; four less
severe cases (without hospitalization); and two lethal cases of
congenital toxoplasmosis. Different clinical outcomes may be
explained by different genetic backgrounds in hosts or by the size
or type of parasite inoculum.13 It is important to consider the
diagnosis of acute toxoplasmosis in patients who live in or have
recently traveled to South America—especially the Amazon
region—and who present with a severe infectious syndrome with
pulmonary involvement.

Toxoplasmosis in Immunocompromised Hosts

In immunocompromised patients, toxoplasmosis is a severe disease.
Most cases are reactivation of chronic infection resulting from
impaired T-cell immunity. High-risk groups include HIV-infected
patients with a CD4 cell counts <100/mm3, patients treated with Fig. 106.5 MRI of brain of patient with Toxoplasma encephalitis.
 CHAPTER 106 Toxoplasmosis 807

than in those whose immunosuppression is not HIV related where

pulmonary involvement is more frequent. In tropical areas, the
Ocular Toxoplasmosis 106
rate of Toxoplasma reactivation is dependent on the local prevalence Ocular toxoplasmosis is the main cause of posterior uveitis
of infection in the community. worldwide.21 The majority of ocular disease in immunocompetent
Although host factors are more important than parasite factors patients is postnatally acquired infection.22,23 Ocular involvement
in immunocompromised patients’ susceptibility to toxoplasmosis,15 is not specifically associated with recent primary infection, but it
the genetic makeup of the particular T. gondii strain involved may can be delayed several months (or even years) after primary infec-
be associated with atypical presentations. Ghosn et al.16 reported tion.24 In all cases, the main clinical presentation of Toxoplasma
one case of inguinal lymphadenopathy in a HIV patient with chorioretinitis is a focally necrotic retinal lesion with fuzzy outlines
undetectable viral load and CD4 cell count of >500/mm3. An (Fig. 106.6). It is accompanied by a whitish vitreous exudate that
atypical Toxoplasma strain was isolated from the lymph node, sometimes obscures the lesion.25 A new lesion can occasionally
suggesting that this patient was likely infected by T. gondii in arise from the edge of an old one. Chorioretinitis may be associated
the West Indies several years before. Severe generalized toxo- with edema of the retina and optic nerve, optic neuritis, iridocyclitis,
plasmosis with high fatality rates occurs when recipient-negative and, in rare instances, panuveitis. In congenital toxoplasmosis, the
persons receive donor-positive organs. Fortunately, prophylaxis ocular lesions are more likely bilateral compared with unilateral
with trimethoprim–sulfamethoxazole (TMP-SMX) is effective in lesions in postnatally acquired cases. Ocular toxoplasmosis is
preventing post-transplant toxoplasmosis.17 characterized by recurrent episodes of chorioretinitis that can be
associated with severe morbidity if the disease extends to structures
critical for vision or if there is a retinal detachment. The timing
Acute Toxoplasmosis During Pregnancy of recurrences is unpredictable, but the individual risk is estimated
Primary infection of the mother with consequent infection of the to be as high as 50%.
placenta is the mechanism for congenital transmission. The placenta A high prevalence of ocular toxoplasmosis has been reported
allows transmission to the fetus in 30% to 50% of infections in South America26 and Africa.27 In the UK, the risk of ocular
acquired in pregnancy. The rate of transplacental infection and toxoplasmosis is 100 times higher in black persons born in West
severity of disease in the fetus vary with the time of infection in Africa than in subjects born in Britain.27 In Brazil, the incidence
relation to gestation. When maternal infection occurs in the first of ocular toxoplasmosis is 17.7% compared with 0.6% in Alabama
trimester, the risk of fetal infection is only about 10% but disease is (United States). Similarly, in Brazil, the ocular sequelae of congenital
severe. When maternal infection occurs in the third trimester, the toxoplasmosis are more frequent, more recurrent, and more severe
risk of fetal infection rises to 65% and approaches 100% at term; than in Europe.28 As discussed previously, there is considerable
however, neonatal infection in these cases is usually asymptomatic. genetic diversity in tropical areas with many atypical strains of
Suspected or confirmed toxoplasmosis during pregnancy leads T. gondii circulating; in Brazil there is no archetypal strain II that
to complex and ongoing management challenges.18 With appropriate predominates in United States. Type II strain in France can be
monitoring and treatment of seroconversion, the great majority responsible for ocular toxoplasmosis in both immunocompetent
(70%–80%) of congenital infections are asymptomatic. In settings and immunocompromised patients.29 Cumulatively, these data
where such prenatal monitoring is unavailable, congenital infection suggest that some strains probably have a tropism for eye tissues
rates are much higher. but that there are also host factors involved in the occurrence of
One strategy is to place pregnant women suspected of having ocular toxoplasmosis.
toxoplasmosis on spiramycin 1 gm (usually about 3–4 million Units)
three times daily to reduce the risk for serious neurologic sequelae
while waiting for the results of serologic testing.19 If a recent
infection with toxoplasmosis is confirmed, an amniocentesis is
performed and Toxoplasma polymerase chain reaction (PCR) testing
of amniotic fluid is done. If the PCR is negative, infection did
not occur and spiramycin could be continued through delivery.
In resource-limited, lower-income countries, the sophisticated
reference laboratories for serologic testing and antenatal diagnostic
procedures are not available.

Congenital Toxoplasmosis
Severe congenital toxoplasmosis presents at birth with intracranial
calcifications, hydrocephalus, and chorioretinitis. The diagnosis
is more difficult in mild or asymptomatic forms. Sequelae may
develop just after delivery or later. Physicians must consider
congenital toxoplasmosis when a newborn exhibits ocular abnor-
malities (chorioretinitis, blindness, strabismus, cataracts, or nys-
tagmus), epilepsy, mental retardation, microcephaly, intracranial
calcifications, diarrhea, hypothermia, or anemia. The main
determinant of the severity of congenital toxoplasmosis remains
the stage of pregnancy at the time of infection. In non-archetypal
(i.e., not types I, II, or III) strains, primary infection of the mother
does not appear to have any unique consequences for the mother,
although the few reported cases have been associated with severe
congenital disease in the newborn.20 A reported case of re-infection
with congenital transmission in a mother who had been exposed
to toxoplasmosis before conception suggested that acquired
immunity against archetypal strains may not protect against
reinfection by atypical strains.12 Fig. 106.6 Active ocular toxoplasmosis.
808 PART 5 Protozoal Infections

DIAGNOSIS TABLE 106.1 Interpretation of Toxoplasma Antibody Tests

IgG IgM
Laboratory Diagnosis Result Result Report/Interpretation for Humans*

The differential diagnosis of the various syndromes of toxoplasmosis Negative Negative No serologic evidence of infection with
is broad, and laboratory confirmation is recommended in all Toxoplasma.
suspected cases, and is essential in the immunocompromised or Negative Equivocal Possible early acute infection or
in those with severe syndromes. The diagnosis of toxoplasmosis false-positive IgM reaction. Obtain a
is confirmed by direct detection of parasites in tissue specimens new specimen for IgG and IgM
or by serology. testing. If results for the second
specimen remain the same, the
patient is probably not infected with
Direct Detection and Identification of the Parasite Toxoplasma.
Negative Positive Possible acute infection or false-positive
Toxoplasma tachyzoites or cysts can be demonstrated on tissue
IgM result. Obtain a new specimen
imprints, biologic fluids (blood, bronchoalveolar lavage [BAL], for IgG and IgM testing. If results for
CSF, amniotic fluid), or biopsies (CNS, lymph node, bone marrow) the second specimen remain the
that are fixed and stained appropriately. The diagnosis of acute same, the IgM reaction is probably a
infection requires the visualization of tachyzoites. The tachyzoites false-positive.
of toxoplasmosis must be distinguished from other intracellular Equivocal Negative Indeterminate: obtain a new specimen
parasites such as Histoplasma, Leishmania, Sarcocystis, and Trypanosoma for testing or retest this specimen for
cruzi. Isolation of parasites from blood or other body fluids by IgG in a different assay.
intraperitoneal inoculation in mice is very useful in isolating the Equivocal Equivocal Indeterminate: obtain a new specimen
strain. The mice should be tested for the presence of Toxoplasma for both IgG and IgM testing.
organisms in the peritoneal fluid 6 to 10 days post-inoculation; Equivocal Positive Possible acute infection with
if no organisms are found, serology can be performed on the Toxoplasma. Obtain a new specimen
animals 4 to 6 weeks post-inoculation. There are no accepted cell for IgG and IgM testing. If results for
culture techniques for diagnosis because of a lack of sensitivity. the second specimen remain the
The detection of T. gondii DNA by real-time PCR is the more same or if the IgG becomes positive,
sensitive method for the diagnosis.30,31 Sensitivity using this both specimens should be sent to a
technique is 95% for antenatal diagnosis in amniotic fluid and reference laboratory with experience
for disseminated toxoplasmosis in blood. In localized toxoplasmosis, in diagnosis of toxoplasmosis for
further testing.
the sensitivity is similar if PCR is performed on an appropriate
sample (BAL, cerebral biopsy) but is less sensitive in blood. In Positive Negative Chronically infected with Toxoplasma
AIDS patients with cerebral abscesses, PCR on CSF is positive (not acute).
in only 30% to 60% of cases. Positive Equivocal Probably chronically infected with
Toxoplasma or false-positive IgM
reaction. Obtain a new specimen for
Serologic Testing IgM testing. If results with the second
specimen remain the same, both
Serologic diagnosis is the routine method of diagnosis for most specimens should be sent to a
patients and is based on the detection of T. gondii–specific immu- reference laboratory with experience
noglobulin (Ig)G and IgM antibodies. The interpretation of in the diagnosis of toxoplasmosis for
Toxoplasma antibody tests can be complex (Table 106.1). The first further testing.
serologic methods were developed by Sabin, Feldman (IgG), and Positive Positive Possible recent infection or false-positive
Remington (IgM).32,33 The great majority of laboratories use IgM reaction. Send the specimen to a
enzyme-linked immunosorbent assay (ELISA) or electro- reference laboratory with experience
chemiluminescence immunoassay (ECLIA). Agglutination and in the diagnosis of toxoplasmosis for
indirect hemagglutination tests are easy to perform. Results of further testing.
IgG studies are generally expressed as international units per *Except infants
milliliter (IU/mL), whereas IgM levels are reported as an index Adapted from CDC: https://www.cdc.gov/dpdx/toxoplasmosis/index.
or as serial dilutions. The modern gold standard for anti-Toxoplasma html.
IgG is Western blot; for IgM it is the immunosorbent agglutination
assay (ISAgA).
The determination of the avidity of anti-Toxoplasma IgG with swollen lymph nodes testing positive for toxoplasmosis
antibodies by their ability to stay bound to the antigen when developed the infection within the past 4 months.
exposed to chaotropic salt solutions can be useful to exclude an
early infection.34 Anti-Toxoplasma antibodies formed in the few Diagnosis of Acute Postnatal-Acquired
months after infection are less tightly bound (lower avidity) than
antibodies found much later in the infection (higher avidity). Avidity Toxoplasmosis in Immunocompetent Patients
assays may be useful in the differential diagnosis of lymphadenopathy Acute infection is assessed by seroconversion from a negative
and dating infection in pregnant women.30 Many manufacturers to a positive serology. It is the appearance of IgG that defines
provide automated methods for the avidity index calculation. If seroconversion; the presence of IgM alone can be non-specific
the avidity index is high, it excludes an acute toxoplasmosis during or related to cross-reactions. If no negative baseline sample exists,
the previous 3 to 5 months (depending on the reagent). A very a fourfold rise in IgG titers with dilution methods or a twofold
low avidity index can be suggestive for an acute toxoplasmosis,34,35 rise with ELISA or ECLIA methods, combined with a positive
but this index can commonly stay low in chronically infected IgM, drawn at 2- to 3-week intervals and run in parallel is highly
patients.34,36 The U.S. Food and Drug Administration (FDA)–cleared suggestive of an acute infection. Modern IgM immunosorbent
VIDAS TOXO IgG Avidity assay (bioMérieux Inc., Hazelwood, assays are very sensitive and specific, but the persistence of
MO) helps determine whether a pregnant woman or a person these IgM antibodies means that their presence is not, by itself,
 CHAPTER 106 Toxoplasmosis 809

sufficient to diagnose an acute infection. In such cases, a high

IgG avidity index may exclude an acute infection. The lack of
Diagnosis of Ocular Toxoplasmosis 106
standardization between assays may lead to discrepant results; no The current gold standard for diagnosis of ocular toxoplasmosis
conclusions can be drawn comparing two results obtained from two is a thorough ophthalmologic examination. In patients with atypical
different laboratories using different reagents. Routine serology lesions, laboratory methods may confirm the diagnosis.39 The most
tests are sufficient for diagnosis of “Guyanese toxoplasmosis” reliable method is aspiration of aqueous humor that can be tested
strains; serologic response to these strains is generally brisk, for specific antibody production or for T. gondii DNA by PCR.
with very high IgG titers and a long persistence of specific IgM The ratio of local specific intraocular antibody production compared
and IgA. with serum antibody (Goldmann–Witmer coefficient) is calculated
The differential diagnosis of acute toxoplasmosis is broad as: (anti-Toxoplasma IgG in aqueous humor/total IgG in aqueous
and includes infectious mononucleosis caused by Epstein–Barr humor) / (anti-Toxoplasma IgG in serum/total IgG in serum). A
and cytomegaloviruses, acute HIV infection, cat scratch disease, value of 2 is considered evidence of intraocular antibodyAb
tuberculosis, lymphoma, tularemia, Hodgkin’s disease, and synthesis. Immunoblotting for IgG and IgA can also be
sarcoidosis. utilized.40
The differential diagnosis of ocular toxoplasmosis includes
Diagnosis of Toxoplasmosis in uveitis caused by syphilis, tuberculosis, viruses, toxocariasis, leprosy,
and sarcoidosis.
Immunocompromised Hosts
Positive serology indicates only that the diagnosis is possible. A
negative serology excludes the diagnosis, except in case of primary
TREATMENT
infection; for these patients, the appearance of an IgM and IgG Most drugs used for the treatment of toxoplasmosis are active
response can be delayed. The diagnosis is confirmed by demonstra- only against the tachyzoite forms of the parasite, and treatment
tion of the parasite in biopsies or biologic fluids by PCR. In the does not eradicate the infection. Atovaquone has limited in vitro
case of cerebral lesions, a therapeutic trial is frequently initiated, activity against the cyst forms. See Table 106.2 for treatment details.
with biopsy performed only if there is no clinical improvement Specific treatment is not indicated for a healthy person with
after 1 week of treatment. Brain biopsy without a therapeutic trial mild symptoms who is not pregnant, as they usually resolve within
is indicated in immunocompromised patients with a negative a few weeks. Treatment is usually recommended for severe illness
specific IgG serologic test, non-enhancing single lesions, and those in the immunocompetent host, infection acquired during pregnancy,
on routine prophylaxis with TMP-SMX because these abnormalities clinical manifestations compatible with toxoplasmosis in immu-
are then unlikely to be caused by Toxoplasma. nosuppressed patients, congenital infection (whether the infant is
The most common clinical presentation of T. gondii infection symptomatic or not), or persons with active ocular disease or
among patients with AIDS is focal encephalitis with headache, severe illness. The treatment of toxoplasmosis in immuno-
confusion or motor weakness, and fever.37 Physical examination compromised patients is a medical emergency. Primary prophylaxis
might demonstrate focal neurologic abnormalities, and in the is used in severely immunosuppressed patients.
absence of treatment, disease progression results in seizures, stupor, Standard therapy for most indications is a combination of oral
and coma. pyrimethamine and a sulfonamide. A 200-mg loading dose of
Retinochoroiditis, pneumonia, and evidence of other multifocal pyrimethamine given in divided doses is followed by a daily dose
organ system involvement can be observed after dissemination of of 1 mg/kg in adults and every 1 to 3 days for children. In some
infection but are rare manifestations in this patient population. A cases, additional corticosteroid therapy against local inflammation
CT scan or MRI of the brain will typically show multiple contrast- is necessary, particularly in ocular involvement and in cerebral
enhancing lesions, often with associated edema (see Fig. 106.5).38 abscess.41,42
However, toxoplasmosis also can manifest as single lesions in the The new gold-standard therapy in tropical countries should
brain. be TMP-SMX. For immunocompromised individuals, maintenance
The differential diagnosis of CNS toxoplasmosis in immuno- therapy is given until effective immune reconstitution occurs.
compromised individuals mimics other causes of enhancing mass Additionally, primary prophylaxis is necessary for persons with
lesions such as lymphoma, metastatic carcinoma, tuberculoma, CD4 T-cell depletion of less than 200 cells/mm3. The regimen is
and brain abscess. the same for primary or secondary prophylaxis, with one tablet
(160 mg trimethoprim/800 mg sulfamethoxazole) daily.43–46
Treatment recommendations in pregnancy vary; in some
Diagnosis of Congenital Toxoplasmosis countries treatment by pyrimethamine–sulfonamide is systematically
The gold standard for the antenatal diagnosis of congenital given in cases of seroconversion after the first trimester of the
toxoplasmosis is PCR performed on amniotic fluid. If there are pregnancy. In other locations, spiramycin is given until the result
no abnormalities on fetal ultrasound, the mother is treated until of amniocentesis is known and pyrimethamine–sulfonamide used
delivery. If severe abnormalities are detected on ultrasound, medical only if the antenatal diagnosis is positive. There is also variability
interruption of the pregnancy might be considered based on the in the duration of the pyrimethamine–sulfonamide regimen used
parents’ choice and local laws. If an antenatal diagnosis is negative (only 1 month or until delivery). Changes in antibody titers are
or was not performed, neonatal diagnosis is done via child/mother not useful for monitoring responses to therapy.
comparison via the immunoblot method. A positive result of PCR Patients with Toxoplasma encephalitis should be monitored
or mouse inoculation for the placenta is not an argument for routinely for adverse events and clinical and radiologic improve-
diagnosis—it is possible to have placentitis without infection of ment. Common pyrimethamine toxicities include rash, nausea,
the fetus. After 1 week of life, the presence of anti-Toxoplasma and bone marrow suppression (neutropenia, anemia, and throm-
IgM, or after 3 weeks of life the presence of IgA in the child’s bocytopenia) that can often be reversed by increasing the dose of
serum, confirms the diagnosis. This presence must be confirmed folinic acid (leucovorin) to 50 to 100 mg/day administered in
by ISAgA. IgG passively transferred from mother to child should divided doses. Common sulfadiazine toxicities include rash, fever,
disappear by 10 to 12 months. leukopenia, hepatitis, nausea, vomiting, diarrhea, and crystalluria.
The differential diagnosis of congenital toxoplasmosis includes Common clindamycin toxicities include fever, rash, nausea, diarrhea
congenital infections with cytomegalovirus, herpes simplex, rubella, (including pseudomembranous colitis or diarrhea related to
Listeria, syphilis, T. cruzi, and erythroblastosis fetalis. Clostridium difficile toxin), and hepatotoxicity. Common TMP-SMX
810 PART 5 Protozoal Infections

TABLE 106.2 Current Treatment Recommendations for Toxoplasmosis

Recommended Drug Alternative Drug
Clinical Syndrome Regimen Comments Regimen Comments References
ACQUIRED POSTNATAL TOXOPLASMOSIS IN IMMUNOCOMPETENT INDIVIDUALS
Asymptomatic infection No treatment Exception is pregnant women Spiramycin 1 gram Spiramycin is not [42]
or mild illness (see text). (about 3-4 million an FDA-
Mild illness resolves Units) orally three approved drug.
spontaneously. times a day (adult)
Severe illness (visceral Adults: 200 mg of To avoid the hematologic If sulfa allergic or TMP-SMX
involvement or pyrimethamine given toxicity of pyrimethamine, intolerant then use 10 mg/kg/day
severe or persistent for 1 day as a loading folinic acid (leucovorin) is pyrimethamine plus (trimethoprim
symptoms) dose followed by administered in a dose of clindamycin at component) in
50–75 mg per day 5–10 mg daily for adults 600 mg orally or 2-3 doses
plus 1–1.5 g and 1 mg daily for intravenously four
sulfadiazine four times children. times daily.
per day. Treatment
may be indicated for
2–4 wk.
IMMUNOCOMPROMISED PATIENTS
Encephalitis in Adults: 200 loading mg Pyrimethamine penetrates the The preferred Add folinic acid if [43, 44]
HIV-infected of pyrimethamine brain even in the absence alternative regimen mental status is
patients with AIDS given for 1 day of inflammation. for patients who altered and until
followed by Adjunctive corticosteroids are unable to clinical
50–75 mg per day (e.g., dexamethasone) tolerate or who fail improvement is
plus sulfadiazine at should be administered to to respond to seen (generally
100–150 mg/kg (e.g., patients with TE when first-line therapy is 3–5 days).
4–6 g/day for an clinically indicated only for pyrimethamine plus If the patient is
adult in 1–1.5 g four treatment of a mass effect clindamycin plus comatose,
times per day plus associated with focal leucovorin treatment is
folinic acid lesions or associated TMP/SMX is initially given
[leucovorin] 5–10 mg edema. 10/50 mg/kg/day intravenously at
with each dose of Anticonvulsants should be given bid, or the same dose.
pyrimethamine) administered to patients 15/75 mg/kg/day. TMP-SMX was
Children: with TE who have a history Atovaquone at reported in a
pyrimethamine 1 mg/kg of seizures, but should not 1500 mg orally bid small (77
plus sulfadiazine be administered as plus patients)
100–150 mg/kg given prophylaxis to all patients. pyrimethamine. randomized trial
in four divided daily Anticonvulsants, if to be effective
doses. administered, should be and better
To avoid the continued at least through tolerated than
hematologic toxicity the period of acute pyrimethamine–
of this regimen, folinic therapy. sulfadiazine.
acid is administered Acute therapy for TE should Great inter-
in a dose of 25 mg be continued for at least individual
daily for adults and 6 wk,if there is clinical and variability in drug
7.5 mg for children radiologic improvement. atovaquone
daily for children. Longer courses might be absorption.
appropriate if clinical or
radiologic disease is
extensive or response is
incomplete at 6 wk.
Because of the potential
immunosuppressive effects
of corticosteroids, they
should be discontinued as
soon as clinically feasible.
Patients receiving
corticosteroids should be
monitored closely for the
development of other OIs,
including CMV retinitis and
TB disease.
 CHAPTER 106 Toxoplasmosis 811

TABLE 106.2 Current Treatment Recommendations for Toxoplasmosis—cont’d

106
Recommended Drug Alternative Drug
Clinical Syndrome Regimen Comments Regimen Comments References
Maintenance Pyrimethamine Suppressive treatment should Clindamycin
therapy in the 25–50 mg daily plus be continued for duration 300–450 mg three
immunocompromised sulfadiazine 2–4 g of immunosuppression. times daily.
daily plus leucovorin Regimen also protects TMP/SMX, give half
5 mg/kg daily against Pneumocystis the treatment dose,
jirovecii pneumonia. 5 mg/kg/day
All HIV-positive patients with trimethoprim
positive Toxoplasma component.
serology and CD4 T Dapsone at 50 mg
lymphocyte counts less daily plus
than 200/µL. pyrimethamine
If CD4 counts are above 50 mg/week and
200/µL and viral load is leucovorin 10 mg/
controlled, maintenance week
therapy can be stopped. 750 mg atovaquone
twice daily.
Pregnant women Spiramycin is Pyrimethamine is teratogenic
traditionally used and should not be used in
during the first and the first trimester.
second trimesters in
pregnant women who
seroconverted during
the first trimester of
pregnancy. The dose
is 3–4 g daily in
divided doses.
Pyrimethamine/
sulfadiazine and
leucovorin (for
late-second and third
trimesters) for women
with acute T. gondii
infection diagnosed at
a reference laboratory
during gestation.
Congenital Pyrimethamine plus a No uniform or consensus
toxoplasmosis in the sulfonamide, given to recommendations.
neonate the neonate for
3–12 mo depending
on the severity of the
disease and local
recommendations.
Sulfadiazine can be
replaced by
sulfadoxine with an
intake every 10 days.
Ocular toxoplasmosis Combination Maintenance therapy with Many other drug [45, 46]
pyrimethamine– TMP/SMX should be given combinations are
sulfonamide (same if a lesion is considered cited in the
regimen as used in vision-threatening or for literature, principally
immunocompromised) mono-ocular patients. pyrimethamine plus
and corticosteroids Long-term maintenance a macrolide, but
depending of the treatment reduces the rate there is no
intensity of local of recurrence. The best randomized study
inflammation (hyalitis). regimen is not determined, evaluating these
but should be one tablet regimens against
(80 mg/400 mg) per day if TMP/SMX.
adequately tolerated.
CMV, Cytomegalovirus; FDA, U.S. Food and Drug Administration; OI, opportunistic infection; TB, tuberculosis; TE, toxoplasmosis encephalitis.

toxicities include rash, fever, leukopenia, thrombocytopenia, and PREVENTION

hepatotoxicity. Drug interactions between anti-convulsants and
antiretroviral agents should be evaluated carefully and doses adjusted Several countries have a policy for the prevention of congenital
according to established guidelines. Several cases of neurologic toxoplasmosis, based on the serologic survey of the mother. In
disease have been attributed to immune reconstitution and the case of a negative result, in France, serologic testing is repeated
toxoplasmosis, but more data are needed to verify that such cases every month until delivery with a last sample 2 to 3 weeks post-
are immune reconstitution syndrome related to T. gondii.41 partum to verify the absence of peripartum infection. Hygienic
812 PART 5 Protozoal Infections

measures to prevent primary T. gondii infection are drawn directly characterization, experimental model of reinfection, and review. J Infect
from the knowledge about biologic characteristics of the infective Dis 2009;199:280–5.
stages of T. gondii: 13. Demar M, Ajzenberg D, Maubon D, et al. Fatal outbreak of human
toxoplasmosis along the Maroni River: epidemiological, clinical, and
• Cook meat until well done or stew. parasitological aspects. Clin Infect Dis 2007;45:e88–95.
• Avoid microwave cooking. 14. Luft BJ, Remington JS. Toxoplasmic encephalitis in AIDS. Clin Infect
• To eat raw meat safely, freeze it before hand to at least −20°C Dis 1992;15:211–22.
for at least 3 days. 15. Ajzenberg D, Year H, Marty P, et al. Genotype of 88 Toxoplasma
• Wash hands, knives, any containers, and the table thoroughly gondii isolates associated with toxoplasmosis in immunocompromised
patients and correlation with clinical findings. J Infect Dis 2009;199:
after meat manipulation or cutting of raw meat. 1155–67.
• Wash hands after gardening or other external activity with 16. Ghosn J, Paris L, Ajzenberg D, et al. Atypical toxoplasmic manifestation
contact with soil, and after having close contact with a cat. after discontinuation of maintenance therapy in a human immuno-
• Wash fruits and vegetables (especially those growing in contact deficiency virus type 1-infected patient with immune recovery. Clin
with soil) thoroughly before eating them raw. Infect Dis 2003;37:e112–14.
• If there is a cat: 17. Martina MN, Cervera C, Esforzado N, et al. Toxoplasma gondii primary
• The litter box should be changed every 2 days, preferably infection in renal transplant recipients. Two case reports and literature
by another person, or wear a mask and gloves when changing review. Transpl Int 2011;24:e6–12.
it. 18. Montoya JG, Remington JS. Management of Toxoplasma gondii infection
during pregnancy. Clin Infect Dis 2008;47:554–66.
• Keep it inside and feed it only canned or dried commercial 19. Cortina-Borja M, Tan HK, Wallon M, et al. Prenatal treatment
food. for serious neurological sequelae of congenital toxoplasmosis: an
The same recommendations must be given to immuno- observational prospective cohort study. PLoS Med 2010;7(10).
compromised patients seronegative for toxoplasmosis. 20. Ajzenberg D, Cogne N, Paris L, et al. Genotype of 86 Toxoplasma
gondii isolates associated with human congenital toxoplasmosis, and
correlation with clinical findings. J Infect Dis 2002;186:684–9.
CONCLUSION 21. Commodaro AG, Belfort RN, Rizzo LV, et al. Ocular toxoplasmosis:
an update and review of the literature. Mem Inst Oswaldo Cruz
Since its recognition as a human pathogen in 1939, understanding 2009;104:345–50.
of Toxoplasma has evolved dramatically. By the end of the 1990s, 22. Balasundaram MB, Andavar R, Palaniswamy M. Venkatapathy N.
description of T. gondii’s genetic composition has led to a better Outbreak of acquired ocular toxoplasmosis involving 248 patients.
understanding of its biologic diversity and pathologic variability. Arch Ophthalmol 2010;128:28–32.
We know today that the disease, once considered to be benign, 23. Montoya JG, Remington JS. Toxoplasmic chorioretinitis in the setting
is potentially severe in immunocompetent patients. Acute toxo- of acute acquired toxoplasmosis. Clin Infect Dis 1996;23:277–82.
24. Silveira C, Belfort R Jr, Muccioli C, et al. A follow-up study of
plasmosis must be considered in the differential diagnosis of a Toxoplasma gondii infection in southern Brazil. Am J Ophthalmol
patient living in or returning from tropical areas—particularly 2001;131:351–4.
the Amazon region of South America—who presents with a severe 25. Delair E, Latkany P, Noble AG, et al. Clinical manifestations of ocular
infectious syndrome with pulmonary involvement.47 toxoplasmosis. Ocul Immunol Inflamm 2011;19:91–102.
26. Glasner PD, Silveira C, Kruszon-Moran D, et al. An unusually high
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